Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3.

PubMed

Zhou, Ning; Ye, Yong; Wang, Xingxu; Ma, Ben; Wu, Jian; Li, Lei; Wang, Lin; Wang, Dao Wen; Zou, Yunzeng

2017-04-01

Fibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation. HSF1 activity is decreased in fibrotic hearts. HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction. Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC. HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3. Active Smad3 blocks the anti-fibrotic effect of HSF1.

Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling

PubMed Central

Chen, Zhidan; Li, Yang; Wang, Ying; Qian, Juying; Ma, Hong; Wang, Xiang; Jiang, Guoliang; Liu, Ming; An, Yanpeng; Ma, Leilei; Kang, Le; Jia, Jianguo; Yang, Chunjie; Zhang, Guoping; Chen, Ying; Gao, Wei; Fu, Mingqiang; Huang, Zheyong; Tang, Huiru; Zhu, Yichun; Ge, Junbo; Gong, Hui; Zou, Yunzeng

2018-01-01

Low density lipoprotein receptor-related protein 6 (LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood. Methods: We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice. Results: Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group. Tamoxifen-inducible cardiac-specific LRP6 knockout mice developed acute heart failure and mitochondrial dysfunction with reduced survival. Proteomic analysis suggests the fatty acid metabolism disorder involving peroxisome proliferator-activated receptors (PPARs) signaling in the LRP6 deficient heart. Accumulation of mitochondrial targeting to autophagosomes and lipid droplet were observed in LRP6 deletion hearts. Further analysis revealed cardiac LRP6 deletion suppressed autophagic degradation and fatty acid utilization, coinciding with activation of dynamin-related protein 1 (Drp1) and downregulation of nuclear TFEB (Transcription factor EB). Injection of Mdivi-1, a Drp1 inhibitor, not only promoted nuclear translocation of TFEB, but also partially rescued autophagic degradation, improved PPARs signaling, and attenuated cardiac dysfunction induced by cardiac specific LRP6 deletion. Conclusions: Cardiac LRP6 deficiency greatly suppressed autophagic degradation and fatty acid utilization, and subsequently leads to lethal dilated cardiomyopathy and cardiac dysfunction through activation of Drp1 signaling. It suggests that heart failure progression may be attenuated by therapeutic modulation of LRP6 expression. PMID:29344294

Valsartan attenuates cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling.

PubMed

Zhang, M-J; Gu, Y; Wang, H; Zhu, P-F; Liu, X-Y; Wu, J

2016-01-01

Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. Up-regulated galectin-3 signaling might also be involved in the pathogenesis in this CRS model. The beneficial effects of valsartan in terms of attenuating cardiac and renal hypertrophy and reducing 24 hours albumin in this model might partly be mediated through down-regulating galectin-3 signal pathway.

Cardiac and autonomic nerve function after reduced-intensity stem cell transplantation for hematologic malignancy in patients with pre-transplant cardiac dysfunction.

PubMed

Nakane, Takahiko; Nakamae, Hirohisa; Muro, Takashi; Yamagishi, Hiroyuki; Kobayashi, Yoshiki; Aimoto, Mizuki; Sakamoto, Erina; Terada, Yoshiki; Nakamae, Mika; Koh, Ki-Ryang; Yamane, Takahisa; Yoshiyama, Minoru; Hino, Masayuki

2009-09-01

Recent reports have shown that cardiomyopathy caused by hemochromatosis in severe aplastic anemia is reversible after reduced-intensity allogeneic stem-cell transplantation (RIST). We comprehensively evaluated cardiac and autonomic nerve function to determine whether cardiac dysfunction due to causes other than hemochromatosis is attenuated after RIST. In five patients with cardiac dysfunction before transplant, we analyzed the changes in cardiac and autonomic nerve function after transplant, using electrocardiography (ECG), echocardiography, radionuclide angiography (RNA), serum markers, and heart rate variability (HRV), before and up to 100 days after transplant. There was no significant improvement in cardiac function in any patient and no significant alteration in ECG, echocardiogram, RNA, or serum markers. However, on time-domain analysis of HRV, the SD of normal-to-normal RR intervals (SDNN) and the coefficient of variation of the RR interval (CVRR) decreased significantly 30 and 60 days after transplant (P = 0.04 and 0.01, respectively). Similarly, on frequency-domain analysis of HRV, low and high frequency power (LF and HF) significantly and temporarily decreased (P = 0.003 and 0.03, respectively). Notably, in one patient who had acute heart failure after transplantation, the values of SDNN, CVRR, r-MSSD, LF, and HF at 30 and 60 days after transplantation were the lowest of all the patients. In conclusion, this study suggests that (a) RIST is well-tolerated in patients with cardiac dysfunction, but we cannot expect improvement in cardiac dysfunction due to causes other than hemochromatosis; and (b) monitoring HRV may be useful in predicting cardiac events after RIST.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

PubMed Central

Afzal, Muhammad R.; Samanta, Anweshan; Xuan, Yu-Ting; Girgis, Magdy; Elias, Harold K; Zhu, Yanqing; Davani, Arash; Yang, Yanjuan; Chen, Xing; Ye, Sheng; Wang, Ou-Li; Chen, Lei; Hauptman, Jeryl; Vincent, Robert J.; Dawn, Buddhadeb

2016-01-01

Rationale The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. Objective To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy, and to elucidate the underlying molecular pathways. Methods and Results Wild-type (WT) and IL-6 knockout (IL-6−/−) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6−/− mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6−/− hearts after TAC. Transcriptional and protein assays of myocardial tissue identified CaMKII and STAT3 activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from WT and IL-6−/− mice exposed to pro-hypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. Conclusions Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension. PMID:27126808

Bilirubin attenuates bufadienolide-induced ventricular arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated intracellular Na(+) levels.

PubMed

Ma, Hongyue; Zhang, Junfeng; Jiang, Jiejun; Zhou, Jing; Xu, Huiqin; Zhan, Zhen; Wu, Qinan; Duan, Jinao

2012-03-01

Bufadienolides, known ligands of the sodium pump, have been shown to inhibit the proliferation of several cancer cell types. However, their development to date as anticancer agents has been impaired by a narrow therapeutic margin resulting from their potential to induce cardiotoxicity. In the present study, we examined the effects of bilirubin, an endogenous antioxidant, on the cardiotoxicity of bufadienolides (derived from toad venom) in guinea-pigs. The results showed that bufadienolides (8 mg/kg) caused ventricular arrhythmias, conduction block, cardiac dysfunction and death in guinea-pigs. Pretreatment with bilirubin (75 and 150 mg/kg) significantly prevented bufadienolide-induced premature ventricular complexes, ventricular tachycardia, ventricular fibrillation and death. Bilirubin also markedly improved the inhibition of cardiac contraction in bufadienolide-treated guinea-pigs as evidenced by increases in left ventricular systolic pressure and decreases in left ventricular diastolic pressure in vivo. Furthermore, bilirubin significantly reduced the intracellular sodium content ([Na(+)]( i )) in ex vivo bufadienolide-stimulated guinea-pig ventricular myocytes loaded with the sodium indicator Sodium Green. An antitumor study showed that bilirubin did not compromise the ability of bufadienolides to inhibit gastric cancer cell MGC-803 proliferation. These results suggested that bilirubin can attenuate bufadienolide-induced arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated [Na(+)]( i ) and may improve bufadienolide therapeutic index in cancer treatment.

Early Effects of Prolonged Cardiac Arrest and Ischemic Postconditioning during Cardiopulmonary Resuscitation on Cardiac and Brain Mitochondrial Function in Pigs.

PubMed

Matsuura, Timothy R; Bartos, Jason A; Tsangaris, Adamantios; Shekar, Kadambari Chandra; Olson, Matthew D; Riess, Matthias L; Bienengraeber, Martin; Aufderheide, Tom P; Neumar, Robert W; Rees, Jennifer N; McKnite, Scott H; Dikalova, Anna E; Dikalov, Sergey I; Douglas, Hunter F; Yannopoulos, Demetris

2017-07-01

Out-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR). A total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue. Compared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain. Fifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs. Copyright © 2017 Elsevier B.V. All rights reserved.

Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury

PubMed Central

Liu, Yunen; Tan, Dehong; Shi, Lin; Liu, Xinwei; Zhang, Yubiao; Tong, Changci; Song, Dequn; Hou, Mingxiao

2015-01-01

We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE. PMID:26133371

Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy.

PubMed

von Lueder, Thomas G; Wang, Bing H; Kompa, Andrew R; Huang, Li; Webb, Randy; Jordaan, Pierre; Atar, Dan; Krum, Henry

2015-01-01

Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells. One week after MI, adult male Sprague-Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (-9.8±0.5 versus -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MI-ARNi versus MI-vehicle had lower cardiac weights (P<0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II-mediated effects. LCZ696 attenuated cardiac remodeling and dysfunction after MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker. © 2014 American Heart Association, Inc.

Magnolia Bioactive Constituent 4-O-Methylhonokiol Prevents the Impairment of Cardiac Insulin Signaling and the Cardiac Pathogenesis in High-Fat Diet-Induced Obese Mice

PubMed Central

Zhang, Zhiguo; Chen, Jing; Zhou, Shanshan; Wang, Shudong; Cai, Xiaohong; Conklin, Daniel J.; Kim, Ki-Soo; Kim, Ki Ho; Tan, Yi; Zheng, Yang; Kim, Young Heui; Cai, Lu

2015-01-01

In obesity, cardiac insulin resistance is a putative cause of cardiac hypertrophy and dysfunction. In our previous study, we observed that Magnolia extract BL153 attenuated high-fat-diet (HFD)-induced cardiac pathogenic changes. In this study, we further investigated the protective effects of the BL153 bioactive constituent, 4-O-methylhonokiol (MH), against HFD-induced cardiac pathogenesis and its possible mechanisms. C57BL/6J mice were fed a normal diet or a HFD with gavage administration of vehicle, BL153, or MH (low or high dose) daily for 24 weeks. Treatment with MH attenuated HFD-induced obesity, as evidenced by body weight gain, and cardiac pathogenesis, as assessed by the heart weight and echocardiography. Mechanistically, MH treatment significantly reduced HFD-induced impairment of cardiac insulin signaling by preferentially augmenting Akt2 signaling. MH also inhibited cardiac expression of the inflammatory factors tumor necrosis factor-α and plasminogen activator inhibitor-1 and increased the phosphorylation of nuclear factor erythroid-derived 2-like 2 (Nrf2) as well as the expression of a Nrf2 downstream target gene heme oxygenase-1. The increased Nrf2 signaling was associated with decreased oxidative stress and damage, as reflected by lowered malondialdehyde and 3-nitrotyrosine levels. Furthermore, MH reduced HFD-induced cardiac lipid accumulation along with lowering expression of cardiac fatty acid translocase/CD36 protein. These results suggest that MH, a bioactive constituent of Magnolia, prevents HFD-induced cardiac pathogenesis by attenuating the impairment of cardiac insulin signaling, perhaps via activation of Nrf2 and Akt2 signaling to attenuate CD36-mediated lipid accumulation and lipotoxicity. PMID:26157343

Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction by inhibiting PP2A activity.

PubMed

Okuhara, Yoshitaka; Yokoe, Shunichi; Iwasaku, Toshihiro; Eguchi, Akiyo; Nishimura, Koichi; Li, Wen; Oboshi, Makiko; Naito, Yoshiro; Mano, Toshiaki; Asahi, Michio; Okamura, Haruki; Masuyama, Tohru; Hirotani, Shinichi

2017-09-15

Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes. IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.

PubMed

Zhang, Rong-Huai; Gao, Jian-Yuan; Guo, Hai-Tao; Scott, Glenda I; Eason, Anna R; Wang, Xiao-Ming; Ren, Jun

2013-01-01

Alcohol intake is associated with myocardial contractile dysfunction and apoptosis although the precise mechanism is unclear. This study was designed to examine the effect of the cytochrome P450 enzyme CYP2E1 inhibition on ethanol-induced cardiac dysfunction. Adult male mice were fed a 4% ethanol liquid or pair-fed control diet for 6weeks. Following 2weeks of diet feeding, a cohort of mice started to receive the CYP2E1 inhibitor diallyl sulfide (100mg/kg/d, i.p.) for the remaining feeding duration. Cardiac function was assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate CYP2E1, heme oxygenase-1 (HO-1), iNOS, the intracellular Ca(2+) regulatory proteins sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)Ca(2+) exchanger and phospholamban, pro-apoptotic protein cleaved caspase-3, Bax, c-Jun-NH(2)-terminal kinase (JNK) and apoptosis signal-regulating kinase (ASK-1). Ethanol led to elevated levels of CYP2E1, iNOS and phospholamban, decreased levels of HO-1 and Na(+)Ca(2+) exchanger, cardiac contractile and intracellular Ca(2+) defects, cardiac fibrosis, overt O(2)(-) production, and apoptosis accompanied with increased phosphorylation of JNK and ASK-1, the effects were significantly attenuated or ablated by diallyl sulfide. Inhibitors of JNK and ASK-1 but not HO-1 inducer or iNOS inhibitor obliterated ethanol-induced cardiomyocyte contractile dysfunction, substantiating a role for JNK and ASK-1 signaling in ethanol-induced myocardial injury. Taken together, these findings suggest that ethanol metabolism through CYP2E1 may contribute to the pathogenesis of alcoholic cardiomyopathy including myocardial contractile dysfunction, oxidative stress and apoptosis, possibly through activation of JNK and ASK-1 signaling. Copyright © 2012 Elsevier B.V. All rights reserved.

Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

PubMed Central

Elnakish, Mohammad T.; Ahmed, Amany A. E.; Mohler, Peter J.; Janssen, Paul M. L.

2015-01-01

Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models. PMID:26146529

Down-regulation of fibroblast growth factor 2 and its co-receptors heparan sulfate proteoglycans by resveratrol underlies the improvement of cardiac dysfunction in experimental diabetes.

PubMed

Strunz, Célia Maria Cássaro; Roggerio, Alessandra; Cruz, Paula Lázara; Pacanaro, Ana Paula; Salemi, Vera Maria Cury; Benvenuti, Luiz Alberto; Mansur, Antonio de Pádua; Irigoyen, Maria Cláudia

2017-02-01

Cardiac remodeling in diabetes involves cardiac hypertrophy and fibrosis, and fibroblast growth factor 2 (FGF2) is an important mediator of this process. Resveratrol, a polyphenolic antioxidant, reportedly promotes the improvement of cardiac dysfunction in diabetic rats. However, little information exists linking the amelioration of the cardiac function promoted by resveratrol and the expression of FGF2 and its co-receptors, heparan sulfate proteoglycans (HSPGs: Glypican-1 and Syndecan-4), in cardiac muscle of Type 2 diabetic rats. Diabetes was induced experimentally by the injection of streptozotocin and nicotinamide, and the rats were treated with resveratrol for 6 weeks. According to our results, there is an up-regulation of the expression of genes and/or proteins of Glypican-1, Syndecan-4, FGF2, peroxisome proliferator-activated receptor gamma and AMP-activated protein kinase in diabetic rats. On the other hand, resveratrol treatment promoted the attenuation of left ventricular diastolic dysfunction and the down-regulation of the expression of all proteins under study. The trigger for the changes in gene expression and protein synthesis promoted by resveratrol was the presence of diabetes. The negative modulation conducted by resveratrol on FGF2 and HSPGs expression, which are involved in cardiac remodeling, underlies the amelioration of cardiac function. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy.

PubMed

Cappetta, Donato; Esposito, Grazia; Piegari, Elena; Russo, Rosa; Ciuffreda, Loreta Pia; Rivellino, Alessia; Berrino, Liberato; Rossi, Francesco; De Angelis, Antonella; Urbanek, Konrad

2016-02-15

Doxorubicin (DOXO) is an effective anti-neoplastic drug but its clinical benefits are hampered by cardiotoxicity. Oxidative stress, apoptosis and myocardial fibrosis mediate the anthracycline cardiomyopathy. ROS trigger TGF-β pathway that activates cardiac fibroblasts promoting fibrosis. Myocardial stiffness contributes to diastolic dysfunction, less studied aspect of anthracycline cardiomyopathy. Considering the role of SIRT1 in the inhibition of the TGF-β/SMAD3 pathway, resveratrol (RES), a SIRT1 activator, might improve cardiac function by interfering with the development of cardiac fibrosis in a model of DOXO-induced cardiomyopathy. F344 rats received a cumulative dose of 15 mg/kg of DOXO in 2 weeks or DOXO+RES (DOXO and RES, 2.5mg/kg/day, concomitantly for 2 weeks and then RES alone for 1 more week). The effects of RES on cardiac fibroblasts were also tested in vitro. Along with systolic dysfunction, DOXO was also responsible of diastolic abnormalities. Myocardial stiffness correlated with fibroblast activation and collagen deposition. DOXO+RES co-treatment significantly improved ± dP/dt and, more interestingly, ameliorated end-diastolic pressure/volume relationship. Treatment with RES resulted in reduced fibrosis and fibroblast activation and, most importantly, the mortality rate was significantly reduced in DOXO+RES group. Fibroblasts isolated from DOXO+RES-treated rats, in which SIRT1 was upregulated, showed decreased levels of TGF-β and pSMAD3/SMAD3 when compared to cells isolated from DOXO-exposed hearts. Our findings reveal a key role of SIRT1 in supporting animal survival and functional parameters of the heart. SIRT1 activation by interfering with fibrogenesis can improve relaxation properties of myocardium and attenuate myocardial remodeling related to chemotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

AMP-Activated Protein Kinase Deficiency Rescues Paraquat-Induced Cardiac Contractile Dysfunction Through an Autophagy-Dependent Mechanism

PubMed Central

Wang, Qiurong; Yang, Lifang; Hua, Yinan; Nair, Sreejayan; Xu, Xihui; Ren, Jun

2014-01-01

Aim: Paraquat, a quaternary nitrogen herbicide, is a highly toxic prooxidant resulting in multi-organ failure including the heart although the underlying mechanism still remains elusive. This study was designed to examine the role of the cellular fuel sensor AMP-activated protein kinase (AMPK) in paraquat-induced cardiac contractile and mitochondrial injury. Results: Wild-type and transgenic mice with overexpression of a mutant AMPK α2 subunit (kinase dead, KD), with reduced activity in both α1 and α2 subunits, were administered with paraquat (45 mg/kg) for 48 h. Paraquat elicited cardiac mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic diameter and reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca2+ handling, reduced cell survival, and overt mitochondrial damage (loss in mitochondrial membrane potential). In addition, paraquat treatment promoted phosphorylation of AMPK and autophagy. Interestingly, deficiency in AMPK attenuated paraquat-induced cardiac contractile and intracellular Ca2+ derangement. The beneficial effect of AMPK inhibition was associated with inhibition of the AMPK-TSC-mTOR-ULK1 signaling cascade. In vitro study revealed that inhibitors for AMPK and autophagy attenuated paraquat-induced cardiomyocyte contractile dysfunction. Conclusion: Taken together, our findings revealed that AMPK may mediate paraquat-induced myocardial anomalies possibly by regulating the AMPK/mTOR-dependent autophagy. PMID:25092649

Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge

PubMed Central

Song, Erfei; Jahng, James WS; Chong, Lisa P; Sung, Hye K; Han, Meng; Luo, Cuiting; Wu, Donghai; Boo, Stellar; Hinz, Boris; Cooper, Matthew A; Robertson, Avril AB; Berger, Thorsten; Mak, Tak W; George, Isaac; Schulze, P Christian; Wang, Yu; Xu, Aimin; Sweeney, Gary

2017-01-01

Lipocalin-2 (also known as NGAL) levels are elevated in obesity and diabetes yet relatively little is known regarding effects on the heart. We induced pressure overload (PO) in mice and found that lipocalin-2 knockout (LKO) mice exhibited less PO-induced autophagy and NLRP3 inflammasome activation than Wt. PO-induced mitochondrial damage was reduced and autophagic flux greater in LKO mice, which correlated with less cardiac dysfunction. All of these observations were negated upon adenoviral-mediated restoration of normal lipocalin-2 levels in LKO. Studies in primary cardiac fibroblasts indicated that lipocalin-2 enhanced priming and activation of NLRP3-inflammasome, detected by increased IL-1β, IL-18 and Caspase-1 activation. This was attenuated in cells isolated from NLRP3-deficient mice or upon pharmacological inhibition of NLRP3. Furthermore, lipocalin-2 induced release of HMGB1 from cells and NLRP3-inflammasome activation was attenuated by TLR4 inhibition. We also found evidence of increased inflammasome activation and reduced autophagy in cardiac biopsy samples from heart failure patients. Overall, this study provides new mechanistic insight on the detrimental role of lipocalin-2 in the development of cardiac dysfunction. PMID:28670364

Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge.

PubMed

Song, Erfei; Jahng, James Ws; Chong, Lisa P; Sung, Hye K; Han, Meng; Luo, Cuiting; Wu, Donghai; Boo, Stellar; Hinz, Boris; Cooper, Matthew A; Robertson, Avril Ab; Berger, Thorsten; Mak, Tak W; George, Isaac; Schulze, P Christian; Wang, Yu; Xu, Aimin; Sweeney, Gary

2017-01-01

Lipocalin-2 (also known as NGAL) levels are elevated in obesity and diabetes yet relatively little is known regarding effects on the heart. We induced pressure overload (PO) in mice and found that lipocalin-2 knockout (LKO) mice exhibited less PO-induced autophagy and NLRP3 inflammasome activation than Wt. PO-induced mitochondrial damage was reduced and autophagic flux greater in LKO mice, which correlated with less cardiac dysfunction. All of these observations were negated upon adenoviral-mediated restoration of normal lipocalin-2 levels in LKO. Studies in primary cardiac fibroblasts indicated that lipocalin-2 enhanced priming and activation of NLRP3-inflammasome, detected by increased IL-1β, IL-18 and Caspase-1 activation. This was attenuated in cells isolated from NLRP3-deficient mice or upon pharmacological inhibition of NLRP3. Furthermore, lipocalin-2 induced release of HMGB1 from cells and NLRP3-inflammasome activation was attenuated by TLR4 inhibition. We also found evidence of increased inflammasome activation and reduced autophagy in cardiac biopsy samples from heart failure patients. Overall, this study provides new mechanistic insight on the detrimental role of lipocalin-2 in the development of cardiac dysfunction.

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

PubMed

Li, Xintao; Cao, Tingting; Ma, Shuo; Jing, Zehao; Bi, Yue; Zhou, Jicheng; Chen, Chong; Yu, Deqin; Zhu, Liang; Li, Shuzhuang

2017-11-05

Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca 2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-α production by monocytes and reduced the circulating TNF-α levels. With curcumin pretreatment, ROS production and Ca 2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca 2+ overload in cardiomyocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction.

PubMed

Fu, Hai Ying; Sanada, Shoji; Matsuzaki, Takashi; Liao, Yulin; Okuda, Keiji; Yamato, Masaki; Tsuchida, Shota; Araki, Ryo; Asano, Yoshihiro; Asanuma, Hiroshi; Asakura, Masanori; French, Brent A; Sakata, Yasushi; Kitakaze, Masafumi; Minamino, Tetsuo

2016-03-04

Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment. © 2016 American Heart Association, Inc.

Vidarabine, an Anti-Herpes Virus Agent, Protects Against the Development of Heart Failure With Relatively Mild Side-Effects on Cardiac Function in a Canine Model of Pacing-Induced Dilated Cardiomyopathy.

PubMed

Nakamura, Takashi; Fujita, Takayuki; Kishimura, Megumi; Suita, Kenji; Hidaka, Yuko; Cai, Wenqian; Umemura, Masanari; Yokoyama, Utako; Uechi, Masami; Ishikawa, Yoshihiro

2016-11-25

In heart failure patients, chronic hyperactivation of sympathetic signaling is known to exacerbate cardiac dysfunction. In this study, the cardioprotective effect of vidarabine, an anti-herpes virus agent, which we identified as a cardiac adenylyl cyclase inhibitor, in dogs with pacing-induced dilated cardiomyopathy (DCM) was evaluated. In addition, the adverse effects of vidarabine on basal cardiac function was compared to those of the β-blocker, carvedilol.Methods and Results:Vidarabine and carvedilol attenuated the development of pacing-induced systolic dysfunction significantly and with equal effectiveness. Both agents also inhibited the development of cardiac apoptosis and fibrosis and reduced the Na + -Ca 2+ exchanger-1 protein level in the heart. Importantly, carvedilol significantly enlarged the left ventricle and atrium; vidarabine, in contrast, did not. Vidarabine-treated dogs maintained cardiac response to β-AR stimulation better than carvedilol-treated dogs did. Vidarabine may protect against pacing-induced DCM with less suppression of basal cardiac function than carvedilol in a dog model. (Circ J 2016; 80: 2496-2505).

Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction

PubMed Central

Zhang, Yingmei; Li, Linlin; Hua, Yinan; Nunn, Jennifer M.; Dong, Feng; Yanagisawa, Masashi; Ren, Jun

2012-01-01

Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4°C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1α were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1α as well as upregulated UCP2 and activation of GSK3β, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3β inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function. PMID:22442497

Attenuating the defibrillation dosage decreases postresuscitation myocardial dysfunction in a swine model of pediatric ventricular fibrillation

PubMed Central

Berg, Marc D.; Banville, Isabelle L.; Chapman, Fred W.; Walker, Robert G.; Gaballa, Mohammed A.; Hilwig, Ronald W.; Samson, Ricardo A.; Kern, Karl B.; Berg, Robert A.

2009-01-01

Objective The optimal biphasic defibrillation dose for children is unknown. Postresuscitation myocardial dysfunction is common and may be worsened by higher defibrillation doses. Adult-dose automated external defibrillators are commonly available; pediatric doses can be delivered by attenuating the adult defibrillation dose through a pediatric pads/cable system. The objective was to investigate whether unattenuated (adult) dose biphasic defibrillation results in greater postresuscitation myocardial dysfunction and damage than attenuated (pediatric) defibrillation. Design Laboratory animal experiment. Setting University animal laboratory. Subjects Domestic swine weighing 19 ± 3.6 kg. Interventions Fifty-two piglets were randomized to receive biphasic defibrillation using either adult-dose shocks of 200, 300, and 360 J or pediatric-dose shocks of ~50, 75, and 85 J after 7 mins of untreated ventricular fibrillation. Contrast left ventriculograms were obtained at baseline and then at 1, 2, 3, and 4 hrs postresuscitation. Postresuscitation left ventricular ejection fraction and cardiac troponins were evaluated. Measurements and Main Results By design, piglets in the adult-dose group received shocks with more energy (261 ± 65 J vs. 72 ± 12 J, p < .001) and higher peak current (37 ± 8 A vs. 13 ± 2 A, p < .001) at the largest defibrillation dose needed. In both groups, left ventricular ejection fraction was reduced significantly at 1, 2, and 4 hrs from baseline and improved during the 4 hrs postresuscitation. The decrease in left ventricular ejection fraction from baseline was greater after adult-dose defibrillation. Plasma cardiac troponin levels were elevated 4 hrs postresuscitation in 11 of 19 adult-dose piglets vs. four of 20 pediatric-dose piglets (p = .02). Conclusions Unattenuated adult-dose defibrillation results in a greater frequency of myocardial damage and worse postresuscitation myocardial function than pediatric doses in a swine model of prolonged out-of-hospital pediatric ventricular fibrillation cardiac arrest. These data support the use of pediatric attenuating electrodes with adult biphasic automated external defibrillators to defibrillate children. PMID:18496405

Aerobic exercise training promotes additional cardiac benefits better than resistance exercise training in postmenopausal rats with diabetes.

PubMed

Quinteiro, Hugo; Buzin, Morgana; Conti, Filipe Fernandes; Dias, Danielle da Silva; Figueroa, Diego; Llesuy, Susana; Irigoyen, Maria-Cláudia; Sanches, Iris Callado; De Angelis, Kátia

2015-05-01

The aim of this study was to evaluate the effects of aerobic exercise training or resistance exercise training on cardiac morphometric, functional, and oxidative stress parameters in rats with ovarian hormone deprivation and diabetes. Female Wistar rats (200-220 g) were divided into a sham-operated group (euglycemic sham-operated sedentary [ES]; n = 8) and three ovariectomized (bilateral removal of ovaries) and diabetic (streptozotocin 50 mg/kg IV) groups as follows: diabetic ovariectomized sedentary (DOS; n = 8), diabetic ovariectomized undergoing aerobic exercise training (DOTA; n = 8), and diabetic ovariectomized undergoing resistance exercise training (DOTR; n = 8). After 8 weeks of resistance (ladder) or aerobic (treadmill) exercise training, left ventricle function and morphometry were evaluated by echocardiography, whereas oxidative stress was evaluated at the left ventricle. The DOS group presented with increased left ventricle cavity in diastole and relative wall thickness (RWT), and these changes were attenuated in both DOTA and DOTR groups. Systolic and diastolic function was impaired in the DOS group compared with the ES group, and only the DOTA group was able to reverse this dysfunction. Lipoperoxidation and glutathione redox balance were improved in both trained groups compared with the DOS group. Glutathione peroxidase and superoxide dismutase were higher in the DOTA group than in the other studied groups. Correlations were observed between lipoperoxidation and left ventricle cavity in diastole (r = 0.55), between redox balance and RWT (r = 0.62), and between lipoperoxidation and RWT (r = -0.60). Aerobic exercise training and resistance exercise training promote attenuation of cardiac morphometric dysfunction associated with a reduction in oxidative stress in an experimental model of diabetes and menopause. However, only dynamic aerobic exercise training is able to attenuate systolic and diastolic dysfunction under this condition.

Docosahexaenoic acid supplementation alters key properties of cardiac mitochondria and modestly attenuates development of left ventricular dysfunction in pressure overload-induced heart failure.

PubMed

Dabkowski, Erinne R; O'Connell, Kelly A; Xu, Wenhong; Ribeiro, Rogerio F; Hecker, Peter A; Shekar, Kadambari Chandra; Daneault, Caroline; Des Rosiers, Christine; Stanley, William C

2013-12-01

Supplementation with the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is beneficial in heart failure patients, however the mechanisms are unclear. DHA is incorporated into membrane phospholipids, which may prevent mitochondrial dysfunction. Thus we assessed the effects of DHA supplementation on cardiac mitochondria and the development of heart failure caused by aortic pressure overload. Pathological cardiac hypertrophy was generated in rats by thoracic aortic constriction. Animals were fed either a standard diet or were supplemented with DHA (2.3 % of energy intake). After 14 weeks, heart failure was evident by left ventricular hypertrophy and chamber enlargement compared to shams. Left ventricle fractional shortening was unaffected by DHA treatment in sham animals (44.1 ± 1.6 % vs. 43.5 ± 2.2 % for standard diet and DHA, respectively), and decreased with heart failure in both treatment groups, but to a lesser extent in DHA treated animals (34.9 ± 1.7 %) than with the standard diet (29.7 ± 1.5 %, P < 0.03). DHA supplementation increased DHA content in mitochondrial phospholipids and decreased membrane viscosity. Myocardial mitochondrial oxidative capacity was decreased by heart failure and unaffected by DHA. DHA treatment enhanced Ca(2+) uptake by subsarcolemmal mitochondria in both sham and heart failure groups. Further, DHA lessened Ca(2+)-induced mitochondria swelling, an index of permeability transition, in heart failure animals. Heart failure increased hydrogen peroxide-induced mitochondrial permeability transition compared to sham, which was partially attenuated in interfibrillar mitochondria by treatment with DHA. DHA decreased mitochondrial membrane viscosity and accelerated Ca(2+) uptake, and attenuated susceptibility to mitochondrial permeability transition and development of left ventricular dysfunction.

Enhancing fatty acid utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing optic atrophy 1 processing in the failing heart.

PubMed

Guo, Yongzheng; Wang, Zhen; Qin, Xinghua; Xu, Jie; Hou, Zuoxu; Yang, Hongyan; Mao, Xuechao; Xing, Wenjuan; Li, Xiaoliang; Zhang, Xing; Gao, Feng

2018-06-01

Heart failure (HF) is characterized by reduced fatty acid (FA) utilization associated with mitochondrial dysfunction. Recent evidence has shown that enhancing FA utilization may provide cardioprotection against HF. Our aim was to investigate the effects and the underlying mechanisms of cardiac FA utilization on cardiac function in response to pressure overload. Transverse aortic constriction (TAC) was used in C57 mice to establish pressure overload-induced HF. TAC mice fed on a high fat diet (HFD) exhibited increased cardiac FA utilization and improved cardiac function and survival compared with those on control diet. Such cardioprotection could also be provided by cardiac-specific overexpression of CD36. Notably, both HFD and CD36 overexpression attenuated mitochondrial fragmentation and improved mitochondrial function in the failing heart. Pressure overload decreased ATP-dependent metalloprotease (YME1L) expression and induced the proteolytic cleavage of the dynamin-like guanosine triphosphatase OPA1 as a result of suppressed FA utilization. Enhancing FA utilization upregulated YME1L expression and subsequently rebalanced OPA1 processing, resulting in restoration of mitochondrial morphology in the failing heart. In addition, cardiac-specific overexpression of YME1L exerted similar cardioprotective effects against HF to those provided by HFD or CD36 overexpression. These findings demonstrate that enhancing FA utilization ameliorates mitochondrial fragmentation and cardiac dysfunction via rebalancing OPA1 processing in pressure overload-induced HF, suggesting a unique metabolic intervention approach to improving cardiac functions in HF.

Local sympathetic denervation attenuates myocardial inflammation and improves cardiac function after myocardial infarction in mice

PubMed Central

Ziegler, Karin A; Ahles, Andrea; Wille, Timo; Kerler, Julia; Ramanujam, Deepak; Engelhardt, Stefan

2018-01-01

Abstract Aims Cardiac inflammation has been suggested to be regulated by the sympathetic nervous system (SNS). However, due to the lack of methodology to surgically eliminate the myocardial SNS in mice, neuronal control of cardiac inflammation remains ill-defined. Here, we report a procedure for local cardiac sympathetic denervation in mice and tested its effect in a mouse model of heart failure post-myocardial infarction. Methods and results Upon preparation of the carotid bifurcation, the right and the left superior cervical ganglia were localized and their pre- and postganglionic branches dissected before removal of the ganglion. Ganglionectomy led to an almost entire loss of myocardial sympathetic innervation in the left ventricular anterior wall. When applied at the time of myocardial infarction (MI), cardiac sympathetic denervation did not affect acute myocardial damage and infarct size. In contrast, cardiac sympathetic denervation significantly attenuated chronic consequences of MI, including myocardial inflammation, myocyte hypertrophy, and overall cardiac dysfunction. Conclusion These data suggest a critical role for local sympathetic control of cardiac inflammation. Our model of myocardial sympathetic denervation in mice should prove useful to further dissect the molecular mechanisms underlying cardiac neural control. PMID:29186414

FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy.

PubMed

Zhang, Yuan; Edgley, Amanda J; Cox, Alison J; Powell, Andrew K; Wang, Bing; Kompa, Andrew R; Stapleton, David I; Zammit, Steven C; Williams, Spencer J; Krum, Henry; Gilbert, Richard E; Kelly, Darren J

2012-05-01

Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm(2); P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05). A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.

Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism

PubMed Central

Salomé Campos, Dijon Henrique; Grippa Sant’Ana, Paula; Okoshi, Katashi; Padovani, Carlos Roberto; Masahiro Murata, Gilson; Nguyen, Son; Kolwicz, Stephen C.; Cicogna, Antonio Carlos

2018-01-01

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue. PMID:29494668

Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII.

PubMed

Sag, Can M; Wolff, Hendrik A; Neumann, Kay; Opiela, Marie-Kristin; Zhang, Juqian; Steuer, Felicia; Sowa, Thomas; Gupta, Shamindra; Schirmer, Markus; Hünlich, Mark; Rave-Fränk, Margret; Hess, Clemens F; Anderson, Mark E; Shah, Ajay M; Christiansen, Hans; Maier, Lars S

2013-11-01

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.

HSP27 Alleviates Cardiac Aging in Mice via a Mechanism Involving Antioxidation and Mitophagy Activation.

PubMed

Lin, Shenglan; Wang, Yana; Zhang, Xiaojin; Kong, Qiuyue; Li, Chuanfu; Li, Yuehua; Ding, Zhengnian; Liu, Li

2016-01-01

Aging-induced cardiac dysfunction is a prominent feature of cardiac aging. Heat shock protein 27 (HSP27) protects cardiac function against ischemia or chemical challenge. We hypothesized that HSP27 attenuates cardiac aging. Transgenic (Tg) mice with cardiac-specific expression of the HSP27 gene and wild-type (WT) littermates were employed in the experiments. Echocardiography revealed a significant decline in the cardiac function of old WT mice compared with young WT mice. In striking contrast, the aging-induced impairment of cardiac function was attenuated in old Tg mice compared with old WT mice. Levels of cardiac aging markers were lower in old Tg mouse hearts than in old WT mouse hearts. Less interstitial fibrosis and lower contents of reactive oxygen species and ubiquitin-conjugated proteins were detected in old Tg hearts than in old WT hearts. Furthermore, old Tg hearts demonstrated lower accumulation of LC3-II and p62 than old WT hearts. Levels of Atg13, Vps34, and Rab7 were also higher in old Tg hearts than in old WT hearts. Additionally, old Tg hearts had higher levels of PINK1 and Parkin than old WT hearts, suggesting that mitophagy was activated in old Tg hearts. Taken together, HSP27 alleviated cardiac aging and this action involved antioxidation and mitophagy activation.

Deficiency of insulin-like growth factor 1 reduces vulnerability to chronic alcohol intake-induced cardiomyocyte mechanical dysfunction: role of AMPK.

PubMed

Ge, Wei; Li, Qun; Turdi, Subat; Wang, Xiao-Ming; Ren, Jun

2011-08-01

Circulating insulin-like growth factor I (IGF-1) levels are closely associated with cardiac performance although the role of IGF-1 in alcoholic cardiac dysfunction is unknown. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on chronic alcohol-induced cardiomyocyte contractile and intracellular Ca(2+) dysfunction. Adult male C57 and LID mice were placed on a 4% alcohol diet for 15 weeks. Cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-relengthening (TR(90) ), change in fura-fluorescence intensity (ΔFFI) and intracellular Ca(2+) decay. Levels of apoptotic regulators caspase-3, Bcl-2 and c-Jun NH2-terminal kinase (JNK), the ethanol metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2), as well as the cellular fuel gauge AMP-activated protein kinase (AMPK) were evaluated. Chronic alcohol intake enlarged myocyte cross-sectional area, reduced PS, ± dL/dt and ΔFFI as well as prolonged TR(90) and intracellular Ca(2+) decay, the effect of which was greatly attenuated by IGF-1 deficiency. The beneficial effect of LID against alcoholic cardiac mechanical defect was ablated by IGF-1 replenishment. Alcohol intake increased caspase-3 activity/expression although it down-regulated Bcl-2, ALDH2 and pAMPK without affecting JNK and AMPK. IGF-1 deficiency attenuated alcoholism-induced responses in all these proteins with the exception of Bcl-2. In addition, the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside abrogated short-term ethanol incubation-elicited cardiac mechanical dysfunction. Taken together, these data suggested that IGF-1 deficiency may reduce the sensitivity to ethanol-induced myocardial mechanical dysfunction. Our data further depicted a likely role of Caspase-3, ALDH2 and AMPK activation in IGF-1 deficiency induced 'desensitization' of alcoholic cardiomyopathy. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy

PubMed Central

Rajesh, Mohanraj; Mukhopadhyay, Partha; Bátkai, Sándor; Patel, Vivek; Saito, Keita; Matsumoto, Shingo; Kashiwaya, Yoshihiro; Horváth, Béla; Mukhopadhyay, Bani; Becker, Lauren; Haskó, György; Liaudet, Lucas; Wink, David A; Veves, Aristidis; Mechoulam, Raphael; Pacher, Pál

2010-01-01

Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrosative stress, cell death and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background CBD, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts antiinflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by pressure-volume system. Oxidative stress, cell death and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrosative stress, NF-κB and MAPK (JNK and p-38, p38α) activation, enhanced expression of adhesion molecules (ICAM-1, VCAM-1), TNF-α, markers of fibrosis (TGF-β, CTGF, fibronectin, collagen-1, MMP-2 and MMP-9), enhanced cell death (caspase 3/7 and PARP activity, chromatin fragmentation and TUNEL) and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, NF-κB activation and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of cannabidiol in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrosative stress, inflammation, cell death and fibrosis. PMID:21144973

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy.

PubMed

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-10-01

Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. Wild-type (WT) and TLR4 knockout (TLR⁻/⁻) mice were challenged with lethal toxin (2 µg·g⁻¹, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP-LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca²⁺ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy

PubMed Central

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-01-01

BACKGROUND AND PURPOSE Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. EXPERIMENTAL APPROACH Wild-type (WT) and TLR4 knockout (TLR−/−) mice were challenged with lethal toxin (2 µg·g−1, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP–LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). KEY RESULTS In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca2+ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. CONCLUSION AND IMPLICATIONS Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. PMID:22612289

Pyridostigmine prevents peripheral vascular endothelial dysfunction in rats with myocardial infarction.

PubMed

Qin, Fangfang; Lu, Yi; He, Xi; Zhao, Ming; Bi, Xueyuan; Yu, Xiaojiang; Liu, Jinjun; Zang, Weijin

2014-03-01

1. Myocardial infarction (MI) is characterized by the withdrawal of vagal activity and increased sympathetic activity. We have shown previously that pyridostigmine (PYR), an acetylcholinesterase inhibitor, was able to improve vagal activity and ameliorate cardiac dysfunction following MI. However, the effect of PYR on endothelial dysfunction in peripheral arteries after MI remains unclear. 2. In the present study, MI was induced by coronary artery ligation in adult Sprague-Dawley rats. Rats were treated intragastrically with saline or PYR (approximately 31 mg/kg per day) for 2 weeks, at which time haemodynamic and parasympathetic parameters and the vascular reactivity of isolated mesenteric arteries were measured and the ultrastructure of the endothelium evaluated. 3. Compared with the MI group, PYR not only improved cardiac function, vagal nerve activity and endothelial impairment, but also reduced intravascular superoxide anion and malondialdehyde. In addition, in the PYR-treated MI group, nitric oxide (NO) bioavailability was increased and attenuated endothelium-dependent relaxations were improved, whereas restored vasodilator responses were inhibited by N(G)-nitro-L-arginine methyl ester. 4. Based on our results, PYR is able to attenuate the impairment of peripheral endothelial function and maintain endothelial ultrastructural integrity in MI rats by inhibiting reactive oxygen species production, enhancing NO bioavailability and improving vagal activity. © 2014 Wiley Publishing Asia Pty Ltd.

Cardio-Metabolic Effects of HIV Protease Inhibitors (Lopinavir/Ritonavir)

PubMed Central

Reyskens, Kathleen M. S. E.; Fisher, Tarryn-Lee; Schisler, Jonathan C.; O'Connor, Wendi G.; Rogers, Arlin B.; Willis, Monte S.; Planesse, Cynthia; Boyer, Florence; Rondeau, Philippe; Bourdon, Emmanuel; Essop, M. Faadiel

2013-01-01

Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction. PMID:24098634

Vildagliptin reduces cardiac ischemic-reperfusion injury in obese orchiectomized rats.

PubMed

Pongkan, Wanpitak; Pintana, Hiranya; Jaiwongkam, Thidarat; Kredphoo, Sasiwan; Sivasinprasasn, Sivaporn; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2016-10-01

Obesity and testosterone deprivation are associated with coronary artery disease. Testosterone and vildagliptin (dipeptidyl peptidase-4 inhibitors) exert cardioprotection during ischemic-reperfusion (I/R) injury. However, the effect of these drugs on I/R heart in a testosterone-deprived, obese, insulin-resistant model is unclear. This study investigated the effects of testosterone and vildagliptin on cardiac function, arrhythmias and the infarct size in I/R heart of testosterone-deprived rats with obese insulin resistance. Orchiectomized (O) or sham operated (S) male Wistar rats were divided into 2 groups to receive normal diet (ND) or high-fat diet (HFD) for 12 weeks. Orchiectomized rats in each diet were divided to receive testosterone (2 mg/kg), vildagliptin (3 mg/kg) or the vehicle daily for 4 weeks. Then, I/R was performed by a 30-min left anterior descending coronary artery ligation, followed by a 120-min reperfusion. LV function, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. HFD groups developed insulin resistance at week 12. At week 16, cardiac function was impaired in NDO, HFO and HFS rats, but was restored in all testosterone- and vildagliptin-treated rats. During I/R injury, arrhythmia scores, infarct size and cardiac mitochondrial dysfunction were prominently increased in NDO, HFO and HFS rats, compared with those in NDS rats. Treatment with either testosterone or vildagliptin similarly attenuated these impairments during I/R injury. These finding suggest that both testosterone replacement and vildagliptin share similar efficacy for cardioprotection during I/R injury by decreasing the infarct size and attenuating cardiac mitochondrial dysfunction caused by I/R injury in testosterone-deprived rats with obese insulin resistance. © 2016 Society for Endocrinology.

Cannabidiol limits Tcell-mediated chronic autoimmune myocarditis: implications to autoimmune disorders and organ transplantation.

PubMed

Lee, Wen-Shin; Erdelyi, Katalin; Matyas, Csaba; Mukhopadhyay, Partha; Varga, Zoltan V; Liaudet, Lucas; Haskó, György; Čiháková, Daniela; Mechoulam, Raphael; Pacher, Pal

2016-01-08

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a non-psychoactive constituent of Marijuana which exerts antiinflammatory effects independent from classical cannabinoid receptors. Recently 80 clinical trials have been reported investigating the effects of CBD in various diseases from inflammatory bowel disease to graft-versus-host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received FDA approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T cell-infiltration, profound inflammatory response, fibrosis (measured by qRT-PCR, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.

Cannabidiol Limits T Cell–Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

PubMed Central

Lee, Wen-Shin; Erdelyi, Katalin; Matyas, Csaba; Mukhopadhyay, Partha; Varga, Zoltan V; Liaudet, Lucas; Hask’, György; ’iháková, Daniela; Mechoulam, Raphael; Pacher, Pal

2016-01-01

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell–mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell–mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation. PMID:26772776

Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload.

PubMed

Beetz, Nadine; Rommel, Carolin; Schnick, Tilman; Neumann, Elena; Lother, Achim; Monroy-Ordonez, Elsa Beatriz; Zeeb, Martin; Preissl, Sebastian; Gilsbach, Ralf; Melchior-Becker, Ariane; Rylski, Bartosz; Stoll, Monika; Schaefer, Liliana; Beyersdorf, Friedhelm; Stiller, Brigitte; Hein, Lutz

2016-12-01

Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sirtuin-3 (SIRT3) protein attenuates doxorubicin-induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes

USDA-ARS?s Scientific Manuscript database

Doxorubicin (DOX) is a chemotherapeutic agent effective in the treatment of many cancers. However, cardiac dysfunction caused by DOX limits its clinical use. DOX is believed to be harmful to cardiomyocytes by interfering with the mitochondrial phospholipid cardiolipin and causing inefficient electro...

Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure.

PubMed

Shirakabe, Akihiro; Zhai, Peiyong; Ikeda, Yoshiyuki; Saito, Toshiro; Maejima, Yasuhiro; Hsu, Chiao-Po; Nomura, Masatoshi; Egashira, Kensuke; Levine, Beth; Sadoshima, Junichi

2016-03-29

Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload. © 2016 American Heart Association, Inc.

Endoplasmic reticulum Chaperon Tauroursodeoxycholic Acid Alleviates Obesity-Induced Myocardial Contractile Dysfunction

PubMed Central

Ceylan-Isik, Asli F.; Sreejayan, Nair; Ren, Jun

2010-01-01

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated TUDCA (50 mg/kg/d, p.o.) or vehicle for 5 wks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca2+ properties were assessed. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity and protein expression of intracellular Ca2+ regulatory proteins were measured using 45Ca2+ uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lower systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca2+ properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decreased in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity. PMID:21035453

Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

PubMed Central

Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

2014-01-01

Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

Soluble epoxide hydrolase inhibition does not prevent cardiac remodeling and dysfunction after aortic constriction in rats and mice.

PubMed

Morgan, Lisa A; Olzinski, Alan R; Upson, John J; Zhao, Shufang; Wang, Tao; Eisennagel, Stephen H; Hoang, Bao; Tunstead, James R; Marino, Joseph P; Willette, Robert N; Jucker, Beat M; Behm, David J

2013-04-01

Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.

Effects of Calorie Restriction on Cardioprotection and Cardiovascular Health

PubMed Central

Ahmet, Ismayil; Tae, Hyun-Jin; de Cabo, Rafael; Lakatta, Edward G.; Talan, Mark I.

2011-01-01

Multiple health benefits of calorie restriction (CR) and alternate day fasting (ADF) regimens are widely recognized. Experimental data concerning the effects of calorie restriction on cardiac health are more controversial, ranging from evidence that ADF protects heart from ischemic damage but results in developing of diastolic dysfunction, to reports that CR ameliorates the age-associated diastolic dysfunction. Here we investigated the effects of chronic CR on morphology and function of the cardiovascular system of aged rats and cardioprotective effect of CR against ischemic damage in the experimental rat model of MI. Cardiovascular fitness of 24-mo old Fisher 344 rats maintained through life on ad libitum (AL) or CR diets was extensively evaluated via echocardiography, dobutamine stress test, pressure-volume loop analyses, pulse wave velocity measurements, and histology. Groups of 2-mo old AL and 29-mo old CR rats were studied for comparison. Myocardial infarction (MI) was induced by a permanent ligation of the anterior descending coronary artery in 5-mo old rats maintained for 3 months on CR or AL. MI size was evaluated histologically 24 hrs following coronary ligation. Cardiac remodeling was followed-up via echocardiography. Age-associated changes in 24-mo old rats consisted of 33% increase of fibrosis in the myocardium and more than 2 fold increase of the collagen in the tunica media of the aorta. There was a significant decrease in the density and total number of cardiomyocytes, while their size was increased. These morphological changes were manifested in a decline of systolic and diastolic cardiac function, increase of left ventricular and aortic stiffness, and arterio-ventricular uncoupling. Tachycardic response to dobutamine challenge was absent in the old rats. Compared to AL rats, 24-mo old CR rats had reduced levels of cardiac and aortic fibrosis, increased density of cardiomyocytes that were smaller in size, attenuated diastolic dysfunction, normal systolic function and arterio-ventricular coupling. Tachycardic response to dobutamine was also intact in CR 24-mo old rats and aortic stiffness was reduced. Adjustment for body weight differences through ratiometric or allometric scaling did not affect the overall pattern of differences between AL and CR rats. Attenuation of morphological and functional age-associated changes in 24-mo old CR rats either was not observed at all or was smaller in 29-mo old CR rats. Size of MI induced by a permanent coronary ligation as well as post-MI cardiac remodeling and function were similar in CR and AL rats. CR does not increase tolerance of myocardium to ischemic damage, but attenuates the age-associated changes in the heart and major vessels. The attenuation of age-associated changes by CR cannot be explained by the effect of lower body weight but are attributable to more intimate cellular mechanisms of CR itself. Attenuation of age-associated changes by CR waned with advancing age, and is consistent with the idea that CR postponed senescence. PMID:21586294

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.

PubMed

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E; Seidman, J G; Pu, William T; Wang, Da-Zhi

2015-11-02

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

PubMed Central

Huang, Zhan-Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong-Liang; Seidman, Christine E.; Seidman, J.G.; Pu, William T.; Wang, Da-Zhi

2015-01-01

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression. PMID:26436652

Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins.

PubMed

Fernandes, Rafael Oliveira; De Castro, Alexandre Luz; Bonetto, Jéssica Hellen Poletto; Ortiz, Vanessa Duarte; Müller, Dalvana Daneliza; Campos-Carraro, Cristina; Barbosa, Silvia; Neves, Laura Tartari; Xavier, Léder Leal; Schenkel, Paulo Cavalheiro; Singal, Pawan; Khaper, Neelam; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane

2016-08-01

This study investigated whether sulforaphane (SFN), a compound found in cruciferous vegetables, could attenuate the progression of post-myocardial infarction (MI) cardiac remodeling. Male Wistar rats (350 g) were allocated to four groups: SHAM (n=8), SHAM+SFN (n=7), MI (n=8) and MI+SFN (n=5). On the third day after surgery, cardiac function was assessed and SFN treatment (5 mg/kg/day) was started. At the end of 25 days of treatment, cardiac function was assessed and heart was collected to measure collagen content, oxidative stress and protein kinase. MI and MI+SFN groups presented cardiac dysfunction, without signs of congestion. Sulforaphane reduced fibrosis (2.1-fold) in infarcted rats, which was associated with a slight attenuation in the cardiac remodeling process. Both infarcted groups presented increases in the oxidative markers xanthine oxidase and 4-hydroxinonenal, as well as a parallel increase in the antioxidant enzymes glutathione peroxidase and superoxide dismutase. Moreover, sulforaphane stimulated the cytoprotective heme oxygenase-1 (HO-1) (38%). Oxidative markers correlated with ERK 1/2 activation. In the MI+SFN group, up-regulation of ERK 1/2 (34%) and Akt (35%), as well as down-regulation of p38 (52%), was observed. This change in the prosurvival kinase balance in the MI+SFN group was related to a down-regulation of apoptosis pathways (Bax/Bcl-2/caspase-3). Sulforaphane was unable to modulate autophagy. Taken together, sulforaphane increased HO-1, which may generate a redox environment in the cardiac tissue favorable to activation of prosurvival and deactivation of prodeath pathways. In conclusion, this natural compound contributes to attenuation of the fibrotic process, which may contribute to mitigation against the progression of cardiac remodeling postinfarction. Copyright © 2016 Elsevier Inc. All rights reserved.

Highly purified eicosapentaenoic acid ameliorates cardiac injury and adipose tissue inflammation in a rat model of metabolic syndrome

PubMed Central

Ito, S.; Sano, Y.; Nagasawa, K.; Matsuura, N.; Yamada, Y.; Uchinaka, A.; Murohara, T.

2016-01-01

Summary Introduction n‐3 Polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), which are abundant in fish oil, have been shown to delay the onset of cardiovascular events. We previously established DahlS.Z‐Lepr fa/Lepr fa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats, as a model of metabolic syndrome. This study has now explored the influence of highly purified EPA on cardiac and adipose tissue pathophysiology in this animal model. Materials and methods DS/obese rats were administered EPA (300 or 1,000 mg kg−1 d−1, per os) or vehicle from age 9 to 13 weeks. Homozygous lean (DahlS.Z‐Lepr +/Lepr +, or DS/lean) littermates were studied as controls. Results Whereas EPA had no effect on body weight, food intake or systolic blood pressure in DS/obese rats, it attenuated cardiac fibrosis, diastolic dysfunction, oxidative stress and inflammation in these animals. In addition, EPA did not affect insulin resistance but reduced adipocyte hypertrophy and inflammation in visceral fat of DS/obese rats. Moreover, EPA increased circulating levels of adiponectin as well as attenuated both the down‐regulation of AMP‐activated protein kinase phosphorylation and the up‐regulation of phosphorylation of the p65 subunit of nuclear factor‐kB in the heart of DS/obese rats. Conclusions Treatment of DS/obese rats with EPA did not affect hypertension but reduced cardiac fibrosis and diastolic dysfunction, with the latter effects being accompanied by AMP‐activated protein kinase activation and inactivation of nuclear factor‐kB signalling in the heart, possibly as a result of an increase in adiponectin secretion. EPA may be suitable for the treatment of cardiac injury associated with metabolic syndrome. PMID:27708849

Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation.

PubMed

Xu, Xihui; Pang, Jiaojiao; Chen, Yuguo; Bucala, Richard; Zhang, Yingmei; Ren, Jun

2016-03-04

Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca(2+) properties were examined in young (3-4 mo) or old (24 mo) wild type and MIF knockout (MIF(-/-)) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF(-/-) mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart.

Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis

PubMed Central

2016-01-01

Doxorubicin (DOX) remains the most effective anticancer agent which is widely used in several adult and pediatric cancers, but its application is limited for its cardiotoxicity and hepatotoxicity. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for many diseases. In this study, we found that intraperitoneal injection of hydrogen-rich saline (H2 saline) ameliorated the mortality, cardiac dysfunction, and histopathological changes caused by DOX in rats. Meanwhile, serum brain natriuretic peptide (BNP), aspartate transaminase (AST), alanine transaminase (ALT), albumin (ALB), tissue reactive oxygen species (ROS), and malondialdehyde (MDA) levels were also attenuated after H2 saline treatment. What is more, we further demonstrated that H2 saline treatment could inhibit cardiac and hepatic inflammation and apoptosis relative proteins expressions by western blotting test. In conclusion, our results revealed a protective effect of H2 saline on DOX-induced cardiotoxicity and hepatotoxicity in rats by inhibiting inflammation and apoptosis. PMID:28104928

Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation

PubMed Central

Guo, Rui; Ren, Jun

2012-01-01

Aims Binge drinking often triggers compromised myocardial contractile function while activating AMP-activated protein kinase (AMPK). Given the role of AMPK in the initiation of autophagy through the mammalian target of rapamycin complex 1 (mTORC1) and Unc51-like kinase (ULK1), this study was designed to examine the impact of AMPK deficiency on cardiac function and the mechanism involved with a focus on autophagy following an acute ethanol challenge. Methods and results Wild-type (WT) and transgenic mice overexpressing a kinase-dead (KD) α2 isoform (K45R mutation) of AMPK were challenged with ethanol. Glucose tolerance, echocardiography, Langendorff heart and cardiomyocyte contractile function, autophagy, and autophagic signalling including AMPK, acetyl-CoA carboxylase (ACC), mTOR, the mTORC1-associated protein Raptor, and ULK1 were examined. Ethanol exposure triggered glucose intolerance and compromised cardiac contraction accompanied by increased phosphorylation of AMPK and ACC as well as autophagosome accumulation (increased LC3II and p62), the effects of which were attenuated or mitigated by AMPK deficiency or inhibition. Ethanol dampened and stimulated, respectively, the phosphorylation of mTOR and Raptor, the effects of which were abolished by AMPK deficiency. ULK1 phosphorylation at Ser757 and Ser777 was down-regulated and up-regulated, respectively, by ethanol, the effect of which was nullified by AMPK deficiency or inhibition. Moreover, the ethanol challenge enhanced LC3 puncta in H9c2 cells and promoted cardiac contractile dysfunction, and these effects were ablated by the inhibition of autophagy or AMPK. Lysosomal inhibition failed to accentuate ethanol-induced increases in LC3II and p62. Conclusion In summary, these data suggest that ethanol exposure may trigger myocardial dysfunction through a mechanism associated with AMPK-mTORC1-ULK1-mediated autophagy. PMID:22451512

mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

PubMed Central

Taneike, Manabu; Nishida, Kazuhiko; Omiya, Shigemiki; Zarrinpashneh, Elham; Misaka, Tomofumi; Kitazume-Taneike, Rika; Austin, Ruth; Takaoka, Minoru; Yamaguchi, Osamu; Gambello, Michael J.; Shah, Ajay M.; Otsu, Kinya

2016-01-01

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts. PMID:27023784

N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress

PubMed Central

Chen, Fangping; Hadfield, Jessalyn M.; Berzingi, Chalak; Hollander, John M.; Miller, Diane B.; Nichols, Cody E.

2013-01-01

Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77–82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca2+ concentration responses to extracellular Ca2+ (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10−3 M) normalized calcium handling in response to ISO and extracellular Ca2+ concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca2+ (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy. PMID:23722706

MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance▿

PubMed Central

Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

2008-01-01

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias. PMID:18332105

MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance.

PubMed

Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

2008-05-01

We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.

PubMed

De Blasio, Miles J; Huynh, Karina; Qin, Chengxue; Rosli, Sarah; Kiriazis, Helen; Ayer, Anita; Cemerlang, Nelly; Stocker, Roland; Du, Xiao-Jun; McMullen, Julie R; Ritchie, Rebecca H

2015-10-01

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and β-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

Angiotensin II-Induced End-Organ Damage in Mice Is Attenuated by Human Exosomes and by an Exosomal Y RNA Fragment.

PubMed

Cambier, Linda; Giani, Jorge F; Liu, Weixin; Ijichi, Takeshi; Echavez, Antonio K; Valle, Jackelyn; Marbán, Eduardo

2018-06-04

Hypertension often leads to cardiovascular disease and kidney dysfunction. Exosomes secreted from cardiosphere-derived cells (CDC-exo) and their most abundant small RNA constituent, the Y RNA fragment EV-YF1, exert therapeutic benefits after myocardial infarction. Here, we investigated the effects of CDC-exo and EV-YF1, each administered individually, in a model of cardiac hypertrophy and kidney injury induced by chronic infusion of Ang (angiotensin) II. After 2 weeks of Ang II, multiple doses of CDC-exo or EV-YF1 were administered retro-orbitally. Ang II infusion induced an elevation in systolic blood pressure that was not affected by CDC-exo or EV-YF1. Echocardiography confirmed that Ang II infusion led to cardiac hypertrophy. CDC-exo and EV-YF1 both attenuated cardiac hypertrophy and reduced cardiac inflammation and fibrosis. In addition, both CDC-exo and EV-YF1 improved kidney function and diminished renal inflammation and fibrosis. The beneficial effects of CDC-exo and EV-YF1 were associated with changes in the expression of the anti-inflammatory cytokine IL (interleukin)-10 in plasma, heart, spleen, and kidney. In summary, infusions of CDC-exo or EV-YF1 attenuated cardiac hypertrophy and renal injury induced by Ang II infusion, without affecting blood pressure, in association with altered IL-10 expression. Exosomes and their defined noncoding RNA contents may represent potential new therapeutic approaches for hypertension-associated cardiovascular and renal damage. © 2018 American Heart Association, Inc.

Kinin B1 receptor blockade and ACE inhibition attenuate cardiac postinfarction remodeling and heart failure in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Xinchun

Introduction: The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results: Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, andmore » improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion: The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor. - Highlights: • We examined the role of kinin B1 receptors in the development of heart failure. • Kinin B1 receptor blockade attenuates post-infarction cardiac remodeling. • Kinin B1 receptor blockade improves dysfunction, and prevented heart failure. • B1 receptor blockade does not affect the cardio-protection of an ACE inhibitor.« less

Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-β1 signaling.

PubMed

Zhang, Cheng-Lin; Zhao, Qian; Liang, Hui; Qiao, Xue; Wang, Jin-Yu; Wu, Dan; Wu, Li-Ling; Li, Li

2018-03-01

Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium and results in decreased ventricular compliance and diastolic dysfunction. Cartilage intermediate layer protein-1 (CILP-1), a novel identified cardiac matricellular protein, is upregulated in most conditions associated with cardiac remodeling, however, whether CILP-1 is involved in pressure overload-induced fibrotic response is unknown. Here, we investigated whether CILP-1 was critically involved in the fibrotic remodeling induced by pressure overload. Western blot analysis and immunofluorescence staining showed that CILP-1 was predominantly detected in cardiac myocytes and to a less extent in the interstitium. In isolated adult mouse ventricular myocytes and nonmyocytes, CILP-1 was found to be mainly synthesized by myocytes. CILP-1 expression in left ventricles was upregulated in C57BL/6 mice undergoing transverse aortic constriction (TAC). Myocardial CILP-1 knockdown aggravated whereas CILP-1 overexpression attenuated TAC-induced ventricular remodeling and dysfunction, as measured by echocardiography test, morphological examination, and gene expressions of fibrotic molecules. Incubation of cardiac fibroblasts with the conditioned medium containing full-length, N-terminal, or C-terminal CILP-1 inhibited transforming growth factor (TGF)-β1-induced Smad3 phosphorylation and the subsequent profibrotic events. We first demonstrated that C-terminal CILP-1 increased Akt phosphorylation, promoted the interaction between Akt and Smad3, and suppressed Smad3 phosphorylation. Blockade of PI3K-Akt pathway attenuated the inhibitory effect of C-CILP-1 on TGF-β1-induced Smad3 activation. We conclude that CILP-1 is a novel ECM protein possessing anti-fibrotic ability in pressure overload-induced fibrotic remodeling. This anti-fibrotic effect of CILP-1 attributes to interfering TGF-β1 signaling through its N- and C- terminal fragments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Novel therapeutic effects of sesamin on diabetes-induced cardiac dysfunction.

PubMed

Thuy, Tran Duong; Phan, Nam Nhut; Wang, Chih-Yang; Yu, Han-Gang; Wang, Shu-Yin; Huang, Pung-Ling; Do, Yi-Yin; Lin, Yen-Chang

2017-05-01

Diabetes is a risk factor that increases the occurrence and severity of cardiovascular events. Cardiovascular complications are the leading cause of mortality of 75% of patients with diabetes >40 years old. Sesamin, the bioactive compound extracted from Sesamum indicum, is a natural compound that has diverse beneficial effects on hypoglycemia and reducing cholesterol. The aim of this study is to investigate sesamin effects to diabetes-inducing cardiac hypertrophy. In the present study bioinformatics analysis demonstrated cardiac hypertrophy signaling may be the most important pathway for upregulating genes in sesamin-treated groups. To verify the bioinformatics prediction, sesamin was used as the main bioactive compound to attenuate the impact of diabetes induced by streptozotocin (STZ) on cardiac function in a rat model. The results revealed that oral administration of sesamin for 4 weeks (100 and 200 mg/kg body weight) marginally improved blood glucose levels, body weight and significantly ameliorated the effects on heart rate and blood pressure in rats with type 1 diabetes relative to control rats. The QT interval of sesamin was also reduced relative to the control group. The findings indicated that sesamin has potential cardioprotective effects in the STZ-induced diabetes model. This suggested that this can be used as a novel treatment for patients with diabetes with cardiac dysfunction complication.

Novel therapeutic effects of sesamin on diabetes-induced cardiac dysfunction

PubMed Central

Thuy, Tran Duong; Phan, Nam Nhut; Wang, Chih-Yang; Yu, Han-Gang; Wang, Shu-Yin; Huang, Pung-Ling; Do, Yi-Yin; Lin, Yen-Chang

2017-01-01

Diabetes is a risk factor that increases the occurrence and severity of cardiovascular events. Cardiovascular complications are the leading cause of mortality of 75% of patients with diabetes >40 years old. Sesamin, the bioactive compound extracted from Sesamum indicum, is a natural compound that has diverse beneficial effects on hypoglycemia and reducing cholesterol. The aim of this study is to investigate sesamin effects to diabetes-inducing cardiac hypertrophy. In the present study bioinformatics analysis demonstrated cardiac hypertrophy signaling may be the most important pathway for upregulating genes in sesamin-treated groups. To verify the bioinformatics prediction, sesamin was used as the main bioactive compound to attenuate the impact of diabetes induced by streptozotocin (STZ) on cardiac function in a rat model. The results revealed that oral administration of sesamin for 4 weeks (100 and 200 mg/kg body weight) marginally improved blood glucose levels, body weight and significantly ameliorated the effects on heart rate and blood pressure in rats with type 1 diabetes relative to control rats. The QT interval of sesamin was also reduced relative to the control group. The findings indicated that sesamin has potential cardioprotective effects in the STZ-induced diabetes model. This suggested that this can be used as a novel treatment for patients with diabetes with cardiac dysfunction complication. PMID:28358428

The amelioration of cardiac dysfunction after myocardial infarction by the injection of keratin biomaterials derived from human hair.

PubMed

Shen, Deliang; Wang, Xiaofang; Zhang, Li; Zhao, Xiaoyan; Li, Jingyi; Cheng, Ke; Zhang, Jinying

2011-12-01

Cardiac dysfunction following acute myocardial infarction is a major cause of advanced cardiomyopathy. Conventional pharmacological therapies rely on prompt reperfusion and prevention of repetitive maladaptive pathways. Keratin biomaterials can be manufactured in an autologous fashion and are effective in various models of tissue regeneration. However, its potential application in cardiac regeneration has not been tested. Keratin biomaterials were derived from human hair and its structure morphology, carryover of beneficial factors, biocompatibility with cardiomyocytes, and in vivo degradation profile were characterized. After delivery into infarcted rat hearts, the keratin scaffolds were efficiently infiltrated by cardiomyocytes and endothelial cells. Injection of keratin biomaterials promotes angiogenesis but does not exacerbate inflammation in the post-MI hearts. Compared to control-injected animals, keratin biomaterials-injected animals exhibited preservation of cardiac function and attenuation of adverse ventricular remodeling over the 8 week following time course. Tissue western blot analysis revealed up-regulation of beneficial factors (BMP4, NGF, TGF-beta) in the keratin-injected hearts. The salient functional benefits, the simplicity of manufacturing and the potentially autologous nature of this biomaterial provide impetus for further translation to the clinic. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prevention of liver cancer cachexia-induced cardiac wasting and heart failure.

PubMed

Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J S; Beadle, John; Argiles, Josep M; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D

2014-04-01

Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion.

PubMed

Mackins, Christina J; Kano, Seiichiro; Seyedi, Nahid; Schäfer, Ulrich; Reid, Alicia C; Machida, Takuji; Silver, Randi B; Levi, Roberto

2006-04-01

Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I-forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell-derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell-deficient mice than in control hearts. Thus, mast cell-derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell-derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.

Calcineurin Regulates Myocardial Function during Acute Endotoxemia

PubMed Central

Joshi, Mandar S.; Julian, Mark W.; Huff, Jennifer E.; Bauer, John A.; Xia, Yong; Crouser, Elliott D.

2006-01-01

Rationale: Cyclosporin A (CsA) is known to preserve cardiac contractile function during endotoxemia, but the mechanism is unclear. Increased nitric oxide (NO) production and altered mitochondrial function are implicated as mechanisms contributing to sepsis-induced cardiac dysfunction, and CsA has the capacity to reduce NO production and inhibit mitochondrial dysfunction relating to the mitochondrial permeability transition (MPT). Objectives: We hypothesized that CsA would protect against endotoxin-mediated cardiac contractile dysfunction by attenuating NO production and preserving mitochondrial function. Methods: Left ventricular function was measured continuously over 4 h in cats assigned as follows: control animals (n = 7); LPS alone (3 mg/kg, n = 8); and CsA (6 mg/kg, n = 7), a calcineurin inhibitor that blocks the MPT, or tacrolimus (FK506, 0.1 mg/kg, n = 7), a calcineurin inhibitor lacking MPT activity, followed in 30 min by LPS. Myocardial tissue was then analyzed for NO synthase-2 expression, tissue nitration, protein carbonylation, and mitochondrial morphology and function. Measurements and Main Results: LPS treatment resulted in impaired left ventricular contractility, altered mitochondrial morphology and function, and increased protein nitration. As hypothesized, CsA pretreatment normalized cardiac performance and mitochondrial respiration and reduced myocardial protein nitration. Unexpectedly, FK506 pretreatment had similar effects, normalizing both cardiac and mitochondrial parameters. However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia. Conclusions: Our data indicate that calcineurin is a critical regulator of mitochondrial respiration, tissue nitration, protein carbonylation, and contractile function in the heart during acute endotoxemia. PMID:16424445

Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.

PubMed

Eirin, Alfonso; Zhu, Xiang-Yang; Ferguson, Christopher M; Riester, Scott M; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

2015-01-19

Percutaneous transluminal renal angioplasty (PTRA) fails to fully improve cardiac injury and dysfunction in patients with renovascular hypertension (RVH). Mesenchymal stem cells (MSCs) restore renal function, but their potential for attenuating cardiac injury after reversal of RVH has not been explored. We hypothesized that replenishment of MSCs during PTRA would improve cardiac function and oxygenation, and decrease myocardial injury in porcine RVH. Pigs were studied after 16 weeks of RVH, RVH treated 4 weeks earlier with PTRA with or without adjunct intra-renal delivery of MSC (10^6 cells), and controls. Cardiac structure, function (fast-computed tomography (CT)), and myocardial oxygenation (Blood-Oxygen-Level-Dependent- magnetic resonance imaging) were assessed in-vivo. Myocardial microvascular density (micro-CT) and myocardial injury were evaluated ex-vivo. Kidney venous and systemic blood levels of inflammatory markers were measured and their renal release calculated. PTRA normalized blood pressure, yet stenotic-kidney glomerular filtration rate, similarly blunted in RVH and RVH + PTRA, normalized only in PTRA + MSC-treated pigs. PTRA attenuated left ventricular remodeling, whereas myocardial oxygenation, subendocardial microvascular density, and diastolic function remained decreased in RVH + PTRA, but normalized in RVH + PTRA-MSC. Circulating isoprostane levels and renal release of inflammatory cytokines increased in RVH and RVH + PTRA, but normalized in RVH + PTRA-MSC, as did myocardial oxidative stress, inflammation, collagen deposition, and fibrosis. Intra-renal MSC delivery during PTRA preserved stenotic-kidney function, reduced systemic oxidative stress and inflammation, and thereby improved cardiac function, oxygenation, and myocardial injury four weeks after revascularization, suggesting a therapeutic potential for adjunctive MSC delivery to preserve cardiac function and structure after reversal of experimental RVH.

TVP1022 attenuates cardiac remodeling and kidney dysfunction in experimental volume overload-induced congestive heart failure.

PubMed

Abassi, Zaid A; Barac, Yaron D; Kostin, Sawa; Roguin, Ariel; Ovcharenko, Elena; Awad, Hoda; Blank, Ayelet; Bar-Am, Orit; Amit, Tamar; Schaper, Jutta; Youdim, Moussa; Binah, Ofer

2011-07-01

Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats. In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome c and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na(+) excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction. TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state.

Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure.

PubMed

Lataro, Renata M; Silva, Carlos A A; Fazan, Rubens; Rossi, Marcos A; Prado, Cibele M; Godinho, Rosely O; Salgado, Helio C

2013-10-15

Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

CXCR6 deficiency attenuates pressure overload-induced monocytes migration and cardiac fibrosis through downregulating TNF-α-dependent MMP9 pathway

PubMed Central

Wang, Jia-Hong; Su, Feng; Wang, Shijun; Lu, Xian-Cheng; Zhang, Shao-Heng; Chen, De; Chen, Nan-Nan; Zhong, Jing-Quan

2014-01-01

An immerging role of TNF-α in collagen synthesis and cardiac fibrosis implies the significance of TNF-α production in the development of myocardial remodeling. Our previous study showed a reduction of TNF-α and attenuated cardiac remodeling in CXCR6 knockout (KO) mice after ischemia/reperfusion injury. However, the potential mechanism of TNF-α-mediated cardiac fibrosis with pressure overload has not been well elucidated. In the present study, we aim to investigate the role of CXCR6 in TNF-α release and myocardial remodeling in response to pressure overload. Pressure overload was performed by constriction of transverse aorta (TAC) surgery on CXCR6 KO mice and C57 wild-type (WT) counterparts. At 6 weeks after TAC, cardiac remodeling was assessed by echocardiography, cardiac TNF-α release and its type I receptor (TNFRI), were detected by ELISA and western blot, collagen genes Col1a1 (type I) and Col3a1 (type III) were examined by real-time PCR. Compared with CXCR6 WT mice, CXCR6 KO mice exhibited less cardiac dysfunction, reduced expression of TNFRI, Col1a1 and Col3a. In vitro, we confirmed that CXCR6 deficiency led to reduced homing and infiltration of CD11b+ monocytes, which contributed to attenuated TNF-α release in myocardium. Furthermore, TNFRI antagonist pretreatment blocked AT1 receptor signaling and NOX4 expression, reduced collagen synthesis, and blunted the activity of MMP9 in CXCR6 WT mice after TAC, but these were not observed in CXCR6 KO mice. In the present work, we propose a mechanism that CXCR6 is essential for pressure overload-mediated myocardial recruitment of monocytes, which contributes to cardiac fibrosis through TNF-α-dependent MMP9 activation and collagen synthesis. PMID:25400729

CXCR6 deficiency attenuates pressure overload-induced monocytes migration and cardiac fibrosis through downregulating TNF-α-dependent MMP9 pathway.

PubMed

Wang, Jia-Hong; Su, Feng; Wang, Shijun; Lu, Xian-Cheng; Zhang, Shao-Heng; Chen, De; Chen, Nan-Nan; Zhong, Jing-Quan

2014-01-01

An immerging role of TNF-α in collagen synthesis and cardiac fibrosis implies the significance of TNF-α production in the development of myocardial remodeling. Our previous study showed a reduction of TNF-α and attenuated cardiac remodeling in CXCR6 knockout (KO) mice after ischemia/reperfusion injury. However, the potential mechanism of TNF-α-mediated cardiac fibrosis with pressure overload has not been well elucidated. In the present study, we aim to investigate the role of CXCR6 in TNF-α release and myocardial remodeling in response to pressure overload. Pressure overload was performed by constriction of transverse aorta (TAC) surgery on CXCR6 KO mice and C57 wild-type (WT) counterparts. At 6 weeks after TAC, cardiac remodeling was assessed by echocardiography, cardiac TNF-α release and its type I receptor (TNFRI), were detected by ELISA and western blot, collagen genes Col1a1 (type I) and Col3a1 (type III) were examined by real-time PCR. Compared with CXCR6 WT mice, CXCR6 KO mice exhibited less cardiac dysfunction, reduced expression of TNFRI, Col1a1 and Col3a. In vitro, we confirmed that CXCR6 deficiency led to reduced homing and infiltration of CD11b(+) monocytes, which contributed to attenuated TNF-α release in myocardium. Furthermore, TNFRI antagonist pretreatment blocked AT1 receptor signaling and NOX4 expression, reduced collagen synthesis, and blunted the activity of MMP9 in CXCR6 WT mice after TAC, but these were not observed in CXCR6 KO mice. In the present work, we propose a mechanism that CXCR6 is essential for pressure overload-mediated myocardial recruitment of monocytes, which contributes to cardiac fibrosis through TNF-α-dependent MMP9 activation and collagen synthesis.

Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction.

PubMed

Bender, Shawn B; DeMarco, Vincent G; Padilla, Jaume; Jenkins, Nathan T; Habibi, Javad; Garro, Mona; Pulakat, Lakshmi; Aroor, Annayya R; Jaffe, Iris Z; Sowers, James R

2015-05-01

Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance. © 2015 American Heart Association, Inc.

RECCAS - REmoval of Cytokines during CArdiac Surgery: study protocol for a randomised controlled trial.

PubMed

Baumann, Andreas; Buchwald, Dirk; Annecke, Thorsten; Hellmich, Martin; Zahn, Peter K; Hohn, Andreas

2016-03-12

On-pump cardiac surgery triggers a significant postoperative systemic inflammatory response, sometimes resulting in multiple-organ dysfunction associated with poor clinical outcome. Extracorporeal cytokine elimination with a novel haemoadsorption (HA) device (CytoSorb®) promises to attenuate inflammatory response. This study primarily assesses the efficacy of intraoperative HA during cardiopulmonary bypass (CPB) to reduce the proinflammatory cytokine burden during and after on-pump cardiac surgery, and secondarily, we aim to evaluate effects on postoperative organ dysfunction and outcomes in patients at high risk. This will be a single-centre randomised, two-arm, patient-blinded trial of intraoperative HA in patients undergoing on-pump cardiac surgery. Subjects will be allocated to receive either CPB with intraoperative HA or standard CPB without HA. The primary outcome is the difference in mean interleukin 6 (IL-6) serum levels between the two study groups on admission to the intensive care unit. A total number of 40 subjects was calculated as necessary to detect a clinically relevant 30 % reduction in postoperative IL-6 levels. Secondary objectives evaluate effects of HA on markers of inflammation up to 48 hours postoperatively, damage to the endothelial glycocalyx and effects on clinical scores and parameters of postoperative organ dysfunction and outcomes. In this pilot trial we try to assess whether intraoperative HA with CytoSorb® can relevantly reduce postoperative IL-6 levels in patients undergoing on-pump cardiac surgery. Differences in secondary outcome variables between the study groups may give rise to further studies and may lead to a better understanding of the mechanisms of haemoadsorption. German Clinical Trials Register number DRKS00007928 (Date of registration 3 Aug 2015).

Aerobic Exercise Training Prevents Heart Failure-Induced Skeletal Muscle Atrophy by Anti-Catabolic, but Not Anabolic Actions

PubMed Central

Souza, Rodrigo W. A.; Piedade, Warlen P.; Soares, Luana C.; Souza, Paula A. T.; Aguiar, Andreo F.; Vechetti-Júnior, Ivan J.; Campos, Dijon H. S.; Fernandes, Ana A. H.; Okoshi, Katashi; Carvalho, Robson F.; Cicogna, Antonio C.; Dal-Pai-Silva, Maeli

2014-01-01

Background Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. Methods and Results We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-α serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-α, NFκB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters were decreased. Interestingly, changes in anabolic factor expression (IGF-I, AKT, and mTOR) were not observed. Nevertheless, in the plantaris muscle, ET maintained high PGC1α levels. Conclusions Thus, the ET capability to attenuate cardiac function during the transition from cardiac dysfunction to HF was accompanied by a prevention of skeletal muscle atrophy that did not occur via an increase in anabolic factors, but through anti-catabolic activity, presumably caused by PGC1α action. These findings indicate the therapeutic potential of aerobic ET to block HF-induced muscle atrophy by counteracting the increased catabolic state. PMID:25330387

Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

PubMed Central

Springer, Jochen; Tschirner, Anika; Haghikia, Arash; von Haehling, Stephan; Lal, Hind; Grzesiak, Aleksandra; Kaschina, Elena; Palus, Sandra; Pötsch, Mareike; von Websky, Karoline; Hocher, Berthold; Latouche, Celine; Jaisser, Frederic; Morawietz, Lars; Coats, Andrew J.S.; Beadle, John; Argiles, Josep M.; Thum, Thomas; Földes, Gabor; Doehner, Wolfram; Hilfiker-Kleiner, Denise; Force, Thomas; Anker, Stefan D.

2014-01-01

Aims Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). Methods and results Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. Conclusion Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer. PMID:23990596

Increasing regulatory T cells with interleukin-2 and interleukin-2 antibody complexes attenuates lung inflammation and heart failure progression

PubMed Central

Wang, Huan; Hou, Lei; Kwak, Dongmin; Fassett, John; Xu, Xin; Chen, Angela; Chen, Wei; Blazar, Bruce R.; Xu, Yawei; Hall, Jennifer L.; Ge, Jun-bo; Bache, Robert J.; Chen, Yingjie

2016-01-01

Congestive heart failure (CHF) is associated with an increase of leukocyte infiltration, pro-inflammatory cytokines and fibrosis in the heart and lung. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) suppress inflammatory responses in various clinical conditions. We postulated that expansion of Tregs attenuates CHF progression by reducing cardiac and lung inflammation. We investigated the effects of Interleukin-2 (IL-2) plus IL-2 monoclonal antibody clone JES6-1 complexes (IL2/JES6-1) on induction of Tregs, transverse aortic constriction (TAC)-induced cardiac and lung inflammation and CHF progression in mice. We demonstrated that end-stage CHF caused a massive increase of lung macrophages and T cells, as well as relatively mild LV leukocyte infiltration. Administration of IL2/JES6-1 caused a ~6-fold increase of Tregs within CD4+ T cells in the spleen, lung and heart of mice. IL2/JES6-1 treatment of mice with existing TAC-induced left ventricular (LV) failure markedly reduced lung and right ventricular (RV) weight, and improved LV ejection fraction and LV end-diastolic pressure. Mechanistically, IL2/JES6-1 treatment significantly increased Tregs, suppressed CD4+ T-cell accumulation, dramatically attenuated leukocyte infiltration including decreasing CD45+ cells, macrophages, CD8+ T cells and effector memory CD8+, and reduced pro-inflammatory cytokine expressions and fibrosis in the lung of mice. Furthermore, IL2/JES6-1 administered before TAC attenuated the development of LV hypertrophy and dysfunction in mice. Our data indicate that increasing Tregs through administration of IL2/JES6-1 effectively attenuates pulmonary inflammation, RV hypertrophy and further LV dysfunction in mice with existing LV failure, suggesting strategies to properly expand Tregs may be useful in reducing CHF progression. PMID:27160197

Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway.

PubMed

Deng, Ke-Qiong; Li, Jing; She, Zhi-Gang; Gong, Jun; Cheng, Wen-Lin; Gong, Fu-Han; Zhu, Xue-Yong; Zhang, Yan; Wang, Zhihua; Li, Hongliang

2017-10-01

Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8 -knockout or Mfge8 -overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy. © 2017 American Heart Association, Inc.

Myocardial Dysfunction and Shock after Cardiac Arrest

PubMed Central

Jentzer, Jacob C.; Chonde, Meshe D.; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies. PMID:26421284

Myocardial Dysfunction and Shock after Cardiac Arrest.

PubMed

Jentzer, Jacob C; Chonde, Meshe D; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies.

Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity.

PubMed

Marín-Royo, Gema; Gallardo, Isabel; Martínez-Martínez, Ernesto; Gutiérrez, Beatriz; Jurado-López, Raquel; López-Andrés, Natalia; Gutiérrez-Tenorio, Josué; Rial, Eduardo; Bartolomé, Marı A Visitación; Nieto, María Luisa; Cachofeiro, Victoria

2018-02-05

Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18 F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction . © 2018. Published by The Company of Biologists Ltd.

Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity

PubMed Central

Marín-Royo, Gema; Gallardo, Isabel; Martínez-Martínez, Ernesto; Gutiérrez, Beatriz; Jurado-López, Raquel; López-Andrés, Natalia; Gutiérrez-Tenorio, Josué; Rial, Eduardo; Bartolomé, María Visitación; Nieto, María Luisa

2018-01-01

ABSTRACT Obesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction. PMID:29361517

Thymol, a dietary monoterpene phenol abrogates mitochondrial dysfunction in β-adrenergic agonist induced myocardial infarcted rats by inhibiting oxidative stress.

PubMed

Nagoor Meeran, M F; Jagadeesh, G S; Selvaraj, P

2016-01-25

Mitochondrial dysfunction has been suggested to be one of the important pathological events in isoproterenol (ISO), a synthetic catecholamine and β-adrenergic agonist induced myocardial infarction (MI). In this context, we have evaluated the impact of thymol against ISO induced oxidative stress and calcium uniporter malfunction involved in the pathology of mitochondrial dysfunction in rats. Male albino Wistar rats were pre and co-treated with thymol (7.5 mg/kg body weight) daily for 7 days. Isoproterenol (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce MI. To explore the extent of cardiac mitochondrial damage, the activities/levels of cardiac marker enzymes, mitochondrial lipid peroxidation products, antioxidants, lipids, calcium, adenosine triphosphate and multi marker enzymes were evaluated. Isoproterenol induced myocardial infarcted rats showed a significant increase in the activities of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, lipids, calcium, and a significant decrease in the activities/levels of heart mitochondrial superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, isocitrate, malate, α-ketoglutarate and NADH-dehydrogenases, cytochrome-C-oxidase, and adenosine triphosphate. Thymol pre and co-treatment showed near normalized effects on all the biochemical parameters studied. Transmission electron microscopic findings and mitochondrial swelling studies confirmed our biochemical findings. The in vitro study also revealed the potent free-radical scavenging activity of thymol. Thus, thymol attenuates the involvement of ISO against oxidative stress and calcium uniporter malfunction associated with mitochondrial dysfunction in rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Roselle is cardioprotective in diet-induced obesity rat model with myocardial infarction.

PubMed

Si, Lislivia Yiang-Nee; Ali, Siti Aishah Mohd; Latip, Jalifah; Fauzi, Norsyahida Mohd; Budin, Siti Balkis; Zainalabidin, Satirah

2017-12-15

Obesity increase the risks of hypertension and myocardial infarction (MI) mediated by oxidative stress. This study was undertaken to investigate the actions of roselle aqueous extract (R) on cardiotoxicity in obese (OB) rats and thereon OB rats subjected to MI. Male Sprague-Dawley rats were fed with either normal diet or high-fat diet for 8weeks. Firstly, OB rats were divided into (1) OB and (2) OB+R (100mg/kg, p.o, 28days). Then, OB rats were subjected to MI (ISO, 85mg/kg, s.c, 2days) and divided into three groups: (1) OB+MI, (2) OB+MI+R and (3) OB+MI+enalapril for another 4weeks. Roselle ameliorated OB and OB+MI's cardiac systolic dysfunction and reduced cardiac hypertrophy and fibrosis. The increased oxidative markers and decreased antioxidant enzymes in OB and OB+MI groups were all attenuated by roselle. These observations indicate the protective effect of roselle on cardiac dysfunction in OB and OB+MI rats, which suggest its potential to be developed as a nutraceutical product for obese and obese patients with MI in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.

PubMed

Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao; Zhang, Peng; Deng, Ke-Qiong; Gong, Jun; Ren, Shuxun; Wang, Xinghua; Chen, Iris; Wang, He; Gao, Chen; Yokota, Tomohiro; Ang, Yen Sin; Li, Shen; Cass, Ashley; Vondriska, Thomas M; Li, Guangping; Deb, Arjun; Srivastava, Deepak; Yang, Huang-Tian; Xiao, Xinshu; Li, Hongliang; Wang, Yibin

2016-10-01

Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.

The long noncoding RNA Wisper controls cardiac fibrosis and remodeling

PubMed Central

Micheletti, Rudi; Plaisance, Isabelle; Abraham, Brian J.; Sarre, Alexandre; Ting, Ching-Chia; Alexanian, Michael; Maric, Daniel; Maison, Damien; Nemir, Mohamed; Young, Richard A.; Schroen, Blanche; González, Arantxa; Ounzain, Samir; Pedrazzini, Thierry

2017-01-01

Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer–associated RNA) as a cardiac fibroblast–enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO-mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix. Together, our findings identify Wisper as a cardiac fibroblast–enriched super-enhancer–associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart. PMID:28637928

Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.

PubMed

Mishra, Shikha; Guan, Jian; Plovie, Eva; Seldin, David C; Connors, Lawreen H; Merlini, Giampaolo; Falk, Rodney H; MacRae, Calum A; Liao, Ronglih

2013-07-01

Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.

Targeted P2X7 R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction.

PubMed

Gao, Hongmei; Yin, Jie; Shi, Yugen; Hu, Hesheng; Li, Xiaolu; Xue, Mei; Cheng, Wenjuan; Wang, Ye; Li, Xinran; Li, Yongkang; Wang, Yu; Yan, Suhua

2017-04-01

Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although P2X 7 R is a key immune mediator, its role has yet to be explored. We investigated whether P2X 7 R regulates NF-κB and affects cardiac sympathetic reinnervation in rats undergoing MI. An adenoviral vector with a short hairpin RNA (shRNA) sequence inserted was adopted for the inhibition of P2X 7 R in vivo. Myocardial infarction was induced by left coronary artery ligation, and immediately after that, recombinant P2X 7 R-shRNA adenovirus, negative adenovirus (control), or normal saline solution (vehicle) was injected intramyocardially around the MI region and border areas. A high level of P2X 7 R was activated in the infarcted tissue at an early stage. The administration of P2X 7 R RNAi resulted in the inhibition of Akt and Erk1/2 phosphorylation and decreased the activation of NF-κB and macrophage infiltration, as well as attenuated the expression of nerve growth factor (NGF). Eventually, the NGF-induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP 43). At 7 days post-MI, the arrhythmia score of programmed electrical stimulation in the vehicle-treated infarcted rats was higher than the MI-shRNA group. Further amelioration of cardiac dysfunction was also detected. The administration of P2X 7 R RNAi during the acute inflammatory response phase prevented the process of sympathetic hyperinnervation after MI, which was associated in part with inhibiting the Akt and ERK1/2 pathways and NF-κB activation. © 2016 John Wiley & Sons Ltd.

[Pyr1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction

PubMed Central

Serpooshan, Vahid; Sivanesan, Senthilkumar; Huang, Xiaoran; Mahmoudi, Morteza; Malkovskiy, Andrey V.; Zhao, Mingming; Inayathullah, Mohammed; Wagh, Dhananjay; Zhang, Xuexiang J.; Metzler, Scott; Bernstein, Daniel; Wu, Joseph C.; Ruiz-Lozano, Pilar; Rajadas, Jayakumar

2017-01-01

Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient in vivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both in vitro and in vivo. Moreover, intraperitoneal injection of [Pyr1]-apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics. PMID:25443792

Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload.

PubMed

El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K; Gardner, Jason D

2018-05-18

The cardiac extracellular matrix is a complex architectural network that serves many functions including providing structural and biochemical support to surrounding cells, and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of the pro-inflammatory and pro-fibrotic responses induce a vicious cycle which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Further, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In this study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study are that LOX inhibition: (a) prevented VO-induced increases in LV wall stress, (b) partially attenuated VO-induced ventricular hypertrophy, (c) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors (TIMPs), and (d) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however our studies suggest a potential link between the two since LOX inhibition completely attenuated the VO-induced increases in MMPs. Overall, our studies demonstrate key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO.

Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

PubMed

Puukila, Stephanie; Fernandes, Rafael Oliveira; Türck, Patrick; Carraro, Cristina Campos; Bonetto, Jéssica Hellen Poletto; de Lima-Seolin, Bruna Gazzi; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane; Boreham, Douglas; Khaper, Neelam

2017-08-01

Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

Augmented endothelial l-arginine transport ameliorates pressure-overload-induced cardiac hypertrophy.

PubMed

Rajapakse, Niwanthi W; Johnston, Tamara; Kiriazis, Helen; Chin-Dusting, Jaye P; Du, Xiao-Jun; Kaye, David M

2015-07-01

What is the central question of this study? What is the potential role of endothelial NO production via overexpression of the l-arginine transporter, CAT1, as a mitigator of cardiac hypertrophy? What is the main finding and its importance? Augmentation of endothelium-specific l-arginine transport via CAT1 can attenuate pressure-overload-dependent cardiac hypertrophy and fibrosis. Our findings support the conclusion that interventions that improve endothelial l-arginine transport may provide therapeutic utility in the setting of myocardial hypertrophy. Such modifications may be introduced by exercise training or locally delivered gene therapy, but further experimental and clinical studies are required. Endothelial dysfunction has been postulated to play a central role in the development of cardiac hypertrophy, probably as a result of reduced NO bioavailability. We tested the hypothesis that increased endothelial NO production, mediated by increased l-arginine transport, could attenuate pressure-overload-induced cardiac hypertrophy. Echocardiography and blood pressure measurements were performed 15 weeks after transverse aortic constriction (TAC) in wild-type (WT) mice (n = 12) and in mice with endothelium-specific overexpression of the l-arginine transporter, CAT1 (CAT+; n = 12). Transverse aortic constriction induced greater increases in heart weight to body weight ratio in WT (by 47%) than CAT+ mice (by 25%) compared with the respective controls (P ≤ 0.05). Likewise, the increase in left ventricular wall thickness induced by TAC was significantly attenuated in CAT+ mice (P = 0.05). Cardiac collagen type I mRNA expression was greater in WT mice with TAC (by 22%; P = 0.03), but not in CAT+ mice with TAC, compared with the respective controls. Transverse aortic constriction also induced lesser increases in β-myosin heavy chain mRNA expression in CAT+ mice compared with WT (P ≤ 0.05). Left ventricular systolic pressure after TAC was 36 and 39% greater in WT and CAT+ mice, respectively, compared with the respective controls (P ≤ 0.001). Transverse aortic constriction had little effect on left ventricular end-diastolic pressure in both genotypes. Taken together, these data indicate that augmenting endothelial function by overexpression of l-arginine transport can attenuate pressure-overload-induced cardiac hypertrophy. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

IGF-1 Prevents Diastolic and Systolic Dysfunction Associated with Cardiomyopathy and Preserves Adrenergic Sensitivity

PubMed Central

Roof, Steve R.; Boslett, James; Russell, Duncan; del Rio, Carlos; Alecusan, Joe; Zweier, Jay L.; Ziolo, Mark T.; Hamlin, Robert; Mohler, Peter J.; Curran, Jerry

2015-01-01

Aims Insulin-like growth factor 1 (IGF-1)-dependent signaling promotes exercise-induced physiological cardiac hypertrophy. However, the in vivo therapeutic potential of IGF-1 for heart disease is not well established. Here we test the potential therapeutic benefits of IGF-1 on cardiac function using an in vivo model of chronic catecholamine-induced cardiomyopathy. Methods Rats were perfused with isoproterenol via osmotic pump (1 mg/kg/day) and treated with 2 mg/kg IGF-1 (2 mg/kg/day, 6 days a week) for 2 or 4 weeks. Echocardiography, ECG, and blood pressure were assessed. In vivo pressure-volume loop studies were conducted at 4 weeks. Heart sections were analyzed for fibrosis and apoptosis, and relevant biochemical signaling cascades were assessed. Results After 4 weeks, diastolic function (EDPVR, EDP, tau, E/A ratio), systolic function (PRSW, ESPVR, dP/dtmax), and structural remodeling (LV chamber diameter, wall thickness) were all adversely affected in isoproterenol-treated rats. All these detrimental effects were attenuated in rats treated with Iso+IGF-1. Isoproterenol-dependent effects on BP were attenuated by IGF-1 treatment. Adrenergic sensitivity was blunted in isoproterenol-treated rats but was preserved by IGF-1 treatment. Immunoblots indicate that cardioprotective p110α signaling and activated Akt are selectively upregulated in Iso+IGF-1 treated hearts. Expression of iNOS was significantly increased in both the Iso and Iso+IGF-1 groups, however tetrahydrobiopterin (BH4) levels were decreased in the Iso group and maintained by IGF-1 treatment. Conclusion IGF-1 treatment attenuates diastolic and systolic dysfunction associated with chronic catecholamine-induced cardiomyopathy while preserving adrenergic sensitivity and promoting BH4 production. These data support the potential use of IGF-1 therapy for clinical applications for cardiomyopathies. PMID:26399932

Differential involvement of various sources of reactive oxygen species in thyroxin-induced hemodynamic changes and contractile dysfunction of the heart and diaphragm muscles

PubMed Central

Elnakish, Mohammad T.; Schultz, Eric J.; Gearinger, Rachel L.; Saad, Nancy S.; Rastogi, Neha; Ahmed, Amany A.E.; Mohler, Peter J.; Janssen, Paul M.L.

2015-01-01

Thyroid hormones are key regulators of basal metabolic state and oxidative metabolism. Hyperthyroidism has been reported to cause significant alterations in hemodynamics, and in cardiac and diaphragm muscle function, all of which have been linked to increased oxidative stress. However, the definite source of increased reactive oxygen species (ROS) in each of these phenotypes is still unknown. The goal of the current study was to test the hypothesis that thyroxin (T4) may produce distinct hemodynamic, cardiac, and diaphragm muscle abnormalities by differentially affecting various sources of ROS. Wild-type and T4 mice with and without 2-week treatments with allopurinol (xanthine oxidase inhibitor), apocynin (NADPH oxidase inhibitor), L-NIO (nitric oxide synthase inhibitor), or MitoTEMPO (mitochondria-targeted antioxidant) were studied. Blood pressure and echocardiography were noninvasively evaluated, followed by ex vivo assessments of isolated heart and diaphragm muscle functions. Treatment with L-NIO attenuated the T4-induced hypertension in mice. However, apocynin improved the left-ventricular (LV) dysfunction without preventing the cardiac hypertrophy in these mice. Both allopurinol and MitoTEMPO reduced the T4-induced fatigability of the diaphragm muscles. In conclusion, we show here for the first time that T4 exerts differential effects on various sources of ROS to induce distinct cardiovascular and skeletal muscle phenotypes. Additionally, we find that T4-induced LV dysfunction is independent of cardiac hypertrophy and NADPH oxidase is a key player in this process. Furthermore, we prove the significance of both xanthine oxidase and mitochondrial ROS pathways in T4-induced fatigability of diaphragm muscles. Finally, we confirm the importance of the nitric oxide pathway in T4-induced hypertension. PMID:25795514

Naringin protects against lipopolysaccharide-induced cardiac injury in mice.

PubMed

Xianchu, Liu; Lan, Professor Zheng; Qiufang, Li; Yi, Liu; Xiangcheng, Ruan; Wenqi, Hou; Yang, Ding

2016-12-01

Previous research has demonstrated that lipopolysaccharide (LPS) can induce sepsis and lead to myocardial dysfunction. Naringin has various biological activities in LPS-induced sepsis. In this study, our aim was to investigate the effects of Naringin on LPS-induced cardiac injury and clarify its potential mechanism. We found that in vivo treatment with Naringin significantly ameliorated body weight loss, and attenuated cardiac histopathological changes after LPS challenge. Furthermore, Naringin inhibited LPS-induced increase of TNF-α, IL-1β and IL-6 activities to alleviate inflammatory response in heart. Moreover, Naringin supplement dramatically increased SOD levels, and prevented MDA levels to ameliorate oxidative stress compared with the LPS group in heart. Lastly, treatment with Naringin also significantly decreased the ratio of BAX to BCL-2 to resist apoptosis in heart. It is concluded that Naringin may be a promising therapeutic agent on LPS-induced cardiac injury by anti-inflammatory, anti-oxidant and anti-apoptotic effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid.

PubMed

Li, Chun-jun; Lv, Lin; Li, Hui; Yu, De-min

2012-06-19

Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model. Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot. DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation. These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.

Sixty-Four-Section Cardiac Computed Tomography in Mechanical Prosthetic Heart Valve Dysfunction: Thrombus or Pannus.

PubMed

Gündüz, Sabahattin; Özkan, Mehmet; Kalçik, Macit; Gürsoy, Ozan Mustafa; Astarcioğlu, Mehmet Ali; Karakoyun, Süleyman; Aykan, Ahmet Çağri; Biteker, Murat; Gökdeniz, Tayyar; Kaya, Hasan; Yesin, Mahmut; Duran, Nilüfer Ekşi; Sevinç, Deniz; Güneysu, Tahsin

2015-12-01

Distinguishing pannus and thrombus in patients with prosthetic valve dysfunction is essential for the selection of proper treatment. We have investigated the utility of 64-slice multidetector computed tomography (MDCT) in distinguishing between pannus and thrombus, the latter amenable to thrombolysis. Sixty-two (23 men, mean age 44±14 years) patients with suspected mechanical prosthetic valve dysfunction assessed by transesophageal echocardiography were included in this prospective observational trial. Subsequently, MDCT was performed before any treatment was started. Periprosthetic masses were detected by MDCT in 46 patients, and their attenuation values were measured as Hounsfield Units (HU). Patients underwent thrombolysis unless contraindicated, and those with a contraindication or failed thrombolysis underwent surgery. A mass which was completely lysed or surgically detected as a clot was classified as thrombus, whereas a mass which was surgically detected as tissue overgrowth was classified as pannus. A definitive diagnosis could be achieved in 37 patients with 39 MDCT masses (22 thrombus and 17 pannus). The mean attenuation value of 22 thrombotic masses was significantly lower than that in 17 pannus (87±59 versus 322±122; P<0.001). Area under the receiver operating characteristic curve was 0.96 (95% confidence interval: 0.91-0.99; P<0.001), and a cutoff point of HU≥145 provided high sensitivity (87.5%) and specificity (95.5%) in discriminating pannus from thrombus. Complete lysis was more common for masses with HU<90 compared with those with HU 90 to 145 (100% versus 42.1%; P=0.007). Sixty-four slice MDCT is helpful in identifying masses amenable to thrombolysis in patients with prosthetic valve dysfunction. A high (HU≥145) attenuation suggests pannus overgrowth, whereas a lower value is associated with thrombus formation. A higher attenuation (HU>90) is associated with reduced lysis rates. © 2015 American Heart Association, Inc.

l-Arginine Attenuates Cardiac Dysfunction, But Further Down-Regulates α-Myosin Heavy Chain Expression in Isoproterenol-Induced Cardiomyopathy.

PubMed

Kralova, Eva; Doka, Gabriel; Pivackova, Lenka; Srankova, Jasna; Kuracinova, Kristina; Janega, Pavol; Babal, Pavel; Klimas, Jan; Krenek, Peter

2015-10-01

In view of previously reported increased capacity for nitric oxide production, we suggested that l-arginine (ARG), the nitric oxide synthase (NOS) substrate, supplementation would improve cardiac function in isoproterenol (ISO)-induced heart failure. Male Wistar rats were treated with ISO for 8 days (5 mg/kg/day, i.p.) or vehicle. ARG was given to control (ARG) and ISO-treated (ISO+ARG) rats in water (0.4 g/kg/day). ISO administration was associated with 40% mortality, ventricular hypertrophy, decreased heart rate, left ventricular dysfunction, fibrosis and ECG signs of ischaemia. RT-PCR showed increased mRNA levels of cardiac hypertrophy marker atrial natriuretic peptide, but not BNP, decreased expression of myosin heavy chain isoform MYH6 and unaltered expression of pathological MYH7. ISO increased the protein levels of endothelial nitric oxide synthase, but at the same time it markedly up-regulated mRNA and protein levels of gp91phox, a catalytical subunit of superoxide-producing NADPH oxidase. Fibrosis was markedly increased by ISO. ARG treatment moderately ameliorated left ventricular dysfunction, but was without effect on cardiac hypertrophy and fibrosis. Combination of ISO and ARG led to a decrease in cav-1 expression, a further increase in MYH7 expression and a down-regulation of MYH6 that inversely correlated with gp91phox mRNA levels. Although ARG, at least partially, improved ISO-impaired basal left ventricular systolic function, it failed to reduce cardiac hypertrophy, fibrosis, oxidative stress and mortality. The protection of contractile performance might be related to increased capacity for nitric oxide production and the up-regulation of MYH7 which may compensate for the marked down-regulation of the major MYH6 isoform. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Pharmacologic inhibition of the enzymatic effects of tissue transglutaminase reduces cardiac fibrosis and attenuates cardiomyocyte hypertrophy following pressure overload.

PubMed

Shinde, Arti V; Su, Ya; Palanski, Brad A; Fujikura, Kana; Garcia, Mario J; Frangogiannis, Nikolaos G

2018-04-01

Tissue transglutaminase (tTG) is a multifunctional protein with a wide range of enzymatic and non-enzymatic functions. We have recently demonstrated that tTG expression is upregulated in the pressure-overloaded myocardium and exerts fibrogenic actions promoting diastolic dysfunction, while preventing chamber dilation. Our current investigation dissects the in vivo and in vitro roles of the enzymatic effects of tTG on fibrotic remodeling in pressure-overloaded myocardium. Using a mouse model of transverse aortic constriction, we demonstrated perivascular and interstitial tTG activation in the remodeling pressure-overloaded heart. tTG inhibition through administration of the selective small molecule tTG inhibitor ERW1041E attenuated left ventricular diastolic dysfunction and reduced cardiomyocyte hypertrophy and interstitial fibrosis in the pressure-overloaded heart, without affecting chamber dimensions and ejection fraction. In vivo, tTG inhibition markedly reduced myocardial collagen mRNA and protein levels and attenuated transcription of fibrosis-associated genes. In contrast, addition of exogenous recombinant tTG to fibroblast-populated collagen pads had no significant effects on collagen transcription, and instead increased synthesis of matrix metalloproteinase (MMP)3 and tissue inhibitor of metalloproteinases (TIMP)1 through transamidase-independent actions. However, enzymatic effects of matrix-bound tTG increased the thickness of pericellular collagen in fibroblast-populated pads. tTG exerts distinct enzymatic and non-enzymatic functions in the remodeling pressure-overloaded heart. The enzymatic effects of tTG are fibrogenic and promote diastolic dysfunction, but do not directly modulate the pro-fibrotic transcriptional program of fibroblasts. Targeting transamidase-dependent actions of tTG may be a promising therapeutic strategy in patients with heart failure and fibrosis-associated diastolic dysfunction. Copyright © 2018 Elsevier Ltd. All rights reserved.

Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: Protection by substance P receptor blockade.

PubMed

Mak, I Tong; Chmielinska, Joanna J; Kramer, Jay H; Spurney, Christopher F; Weglicki, William B

2011-01-01

Hypomagnesemia (Hypo-Mg) in rodents leads to neurogenic inflammation associated with substance P (SP) elevations; neutral endopeptidase (NEP) is a principle cell surface proteolytic enzyme, which degrades SP. The effects of chronic Hypo-Mg on neutrophil NEP activity, cell activation and the associated cardiac dysfunction were examined. Male Sprague-Dawley rats (180 g) were fed Mg-sufficient or Mg-deficient (Hypo-Mg) diets for five weeks. Enriched blood neutrophils were isolated at the end of one, three and five weeks by step gradient centrifugation. NEP enzymatic activity decreased by 20% (P value was nonsignificant), 50% (P<0.025) and 57% (P<0.01), respectively, for week 1, 3 and 5 Hypo-Mg rats. In association, neutrophil basal superoxide (•O(2) (-))-generating activities were elevated: 30% at week 1 (P value was nonsignificant), and fourfold to sevenfold for weeks 3 to 5 (P<0.01). Maximal phorbol myristate acetate-stimulated •O(2) (-) production by Hypo-Mg neutrophils increased twofold at week 5. Also, plasma 8-isoprostane levels were elevated twofold to threefold, and red blood cell glutathione decreased by 50% (P<0.01) after three to five weeks of chronic Hypo-Mg. When Hypo-Mg rats were treated with the SP receptor blocker (L-703,606), neutrophil NEP activities were retained at 75% (week 3) and 77% (week 5) (P<0.05); activation of neutrophil •O(2) (-) and other oxidative indexes were also significantly (P<0.05) attenuated. After five weeks, histochemical (hematoxylin and eosin) staining of Hypo-Mg-treated rat ventricles revealed significant white blood cell infiltration, which was substantially reduced by L-703,606. Echocardiography after three weeks of Hypo-Mg only showed modest diastolic impairment, but five weeks resulted in significant (P<0.05) depression in both left ventricular systolic and diastolic functions; changes in these functional parameters were attenuated by L-703,606. NEP activity regulates neutrophil •O(2) (-) formation by controlling SP bioavailability. When oxidative inactivation of NEP is prevented by SP receptor blockade, partial protection is afforded against cardiac contractile dysfunction.

Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: Protection by substance P receptor blockade

PubMed Central

Mak, I Tong; Chmielinska, Joanna J; Kramer, Jay H; Spurney, Christopher F; Weglicki, William B

2011-01-01

BACKGROUND/OBJECTIVE: Hypomagnesemia (Hypo-Mg) in rodents leads to neurogenic inflammation associated with substance P (SP) elevations; neutral endopeptidase (NEP) is a principle cell surface proteolytic enzyme, which degrades SP. The effects of chronic Hypo-Mg on neutrophil NEP activity, cell activation and the associated cardiac dysfunction were examined. METHODS/RESULTS: Male Sprague-Dawley rats (180 g) were fed Mg-sufficient or Mg-deficient (Hypo-Mg) diets for five weeks. Enriched blood neutrophils were isolated at the end of one, three and five weeks by step gradient centrifugation. NEP enzymatic activity decreased by 20% (P value was nonsignificant), 50% (P<0.025) and 57% (P<0.01), respectively, for week 1, 3 and 5 Hypo-Mg rats. In association, neutrophil basal superoxide (•O2−)-generating activities were elevated: 30% at week 1 (P value was nonsignificant), and fourfold to sevenfold for weeks 3 to 5 (P<0.01). Maximal phorbol myristate acetate-stimulated •O2− production by Hypo-Mg neutrophils increased twofold at week 5. Also, plasma 8-isoprostane levels were elevated twofold to threefold, and red blood cell glutathione decreased by 50% (P<0.01) after three to five weeks of chronic Hypo-Mg. When Hypo-Mg rats were treated with the SP receptor blocker (L-703,606), neutrophil NEP activities were retained at 75% (week 3) and 77% (week 5) (P<0.05); activation of neutrophil •O2− and other oxidative indexes were also significantly (P<0.05) attenuated. After five weeks, histochemical (hematoxylin and eosin) staining of Hypo-Mg-treated rat ventricles revealed significant white blood cell infiltration, which was substantially reduced by L-703,606. Echocardiography after three weeks of Hypo-Mg only showed modest diastolic impairment, but five weeks resulted in significant (P<0.05) depression in both left ventricular systolic and diastolic functions; changes in these functional parameters were attenuated by L-703,606. CONCLUSION: NEP activity regulates neutrophil •O2− formation by controlling SP bioavailability. When oxidative inactivation of NEP is prevented by SP receptor blockade, partial protection is afforded against cardiac contractile dysfunction. PMID:22131854

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

PubMed Central

Jeong, Mark Y.; Lin, Ying H.; Wennersten, Sara A.; Demos-Davies, Kimberly M.; Cavasin, Maria A.; Mahaffey, Jennifer H.; Monzani, Valmen; Saripalli, Chandrasekhar; Mascagni, Paolo; Reece, T. Brett; Ambardekar, Amrut V.; Granzier, Henk L.; Dinarello, Charles A.; McKinsey, Timothy A.

2018-01-01

There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor–mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans. PMID:29437146

Renal denervation improves cardiac function in rats with chronic heart failure: Effects on expression of β-adrenoceptors

PubMed Central

Zheng, Hong; Liu, Xuefei; Sharma, Neeru M.

2016-01-01

Chronic activation of the sympathetic drive contributes to cardiac remodeling and dysfunction during chronic heart failure (HF). The present study was undertaken to assess whether renal denervation (RDN) would abrogate the sympathoexcitation in HF and ameliorate the adrenergic dysfunction and cardiac damage. Ligation of the left coronary artery was used to induce HF in Sprague-Dawley rats. Four weeks after surgery, RDN was performed, 1 wk before the final measurements. At the end of the protocol, cardiac function was assessed by measuring ventricular hemodynamics. Rats with HF had an average infarct area >30% of the left ventricle and left ventricular end-diastolic pressure (LVEDP) >20 mmHg. β1- and β2-adrenoceptor proteins in the left ventricle were reduced by 37 and 49%, respectively, in the rats with HF. RDN lowered elevated levels of urinary excretion of norepinephrine and brain natriuretic peptide levels in the hearts of rats with HF. RDN also decreased LVEDP to 10 mmHg and improved basal dP/dt to within the normal range in rats with HF. RDN blunted loss of β1-adrenoceptor (by 47%) and β2-adrenoceptor (by 100%) protein expression and improved isoproterenol (0.5 μg/kg)-induced increase in +dP/dt (by 71%) and −dP/dt (by 62%) in rats with HF. RDN also attenuated the increase in collagen 1 expression in the left ventricles of rats with HF. These findings demonstrate that RDN initiated in chronic HF condition improves cardiac function mediated by adrenergic agonist and blunts β-adrenoceptor expression loss, providing mechanistic insights for RDN-induced improvements in cardiac function in the HF condition. PMID:27288440

Effects of long-term treatment with eicosapentaenoic acid on the heart subjected to ischemia/reperfusion and hypoxia/reoxygenation in rats.

PubMed

Takeo, S; Nasa, Y; Tanonaka, K; Yabe, K; Nojiri, M; Hayashi, M; Sasaki, H; Ida, K; Yanai, K

1998-11-01

The effects of eicosapentaenoic acid (EPA) and long-term treatment with EPA-ethylester (EPA-E) were examined in perfused rat hearts subjected to ischemia/reperfusion and adult rat cardiomyocytes subjected to hypoxia/reoxygenation. EPA (0.1 microM) improved postischemic contractile dysfunction of the ischemic/reperfused heart. EPA (10 microM) attenuated hypoxia/reoxygenation-induced morphological deterioration of cardiomyocytes. The results suggest the presence of direct cardioprotective effects of EPA. Rats were orally treated for 4 weeks with 1 g/kg/day of EPA-E to elucidate ex vivo effects of EPA, and the fatty acid composition of cardiac phospholipids was determined. The percent ratio of EPA in total fatty acids of cardiac phospholipids increased whereas that of arachidonic acid decreased. The percent ratio of n-3/n-6 fatty acid did not increase. Treatment with EPA-E did not improve the post-ischemic contractile function, but attenuated the ischemia/reperfusion-induced release of prostaglandins during reperfusion. Treatment with EPA-E preserved a better morphological appearance of the cardiomyocytes subjected to hypoxia/reoxygenation. The results suggest that the mechanisms responsible for cytoprotective effects of hypoxic/reoxygenated cardiomyocytes or inhibition of metabolic alterations of the ischemic/reperfused heart by long-term EPA-E treatment did not contribute substantially to recovery of post-ischemic contractile dysfunction. The direct in vitro effects of EPA may play a role in the protection of the heart from ischemia/reperfusion or hypoxia/reoxygenation injury.

Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction

PubMed Central

Wang, Ning-Ping; Wang, Zhang-Feng; Tootle, Stephanie; Philip, Tiji; Zhao, Zhi-Qing

2012-01-01

BACKGROUND AND PURPOSE Curcumin, the natural yellow pigment extracted from the rhizomes of the plant curcuma longa, has been demonstrated to exhibit a variety of potent beneficial effects, acting as an antioxidant, anti-inflammatory and anti-fibrotic. In this study we tested the hypothesis that curcumin attenuates maladaptive cardiac repair and improves cardiac function after ischaemia and reperfusion by reducing degradation of extracellular matrix (ECM) and inhibiting synthesis of collagens via TGFβ/Smad-mediated signalling pathway. EXPERIMENTAL APPROACH Sprague-Dawley rats were subjected to 45 min of ischaemia followed by 7, 21 and 42 days of reperfusion respectively. Curcumin was fed orally at a dose of 150 mg·kg−1·day−1 only during reperfusion. KEY RESULTS Curcumin reduced the level of malondialdehyde, inhibited activity of MMPs, preserved ECM from degradation and attenuated collagen deposition, as it reduced the extent of collagen-rich scar and increased mass of viable myocardium. In addition to reducing collagen synthesis and fibrosis in the ischaemic/reperfused myocardium, curcumin significantly down-regulated the expression of TGFβ1 and phospho-Smad2/3, and up-regulated Smad7 and also increased the population of α-smooth muscle actin expressing myofibroblasts within the infarcted myocardium relative to the control. Echocardiography showed it significantly improved left ventricular end-diastolic volume, stroke volume and ejection fraction. The wall thickness of the infarcted middle anterior septum in the curcumin group was also greater than that in the control group. CONCLUSION AND IMPLICATIONS Dietary curcumin is effective at inhibiting maladaptive cardiac repair and preserving cardiac function after ischaemia and reperfusion. Curcumin has potential as a treatment for patients who have had a heart attack. PMID:22823335

G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress.

PubMed

Wang, Hao; Sun, Xuming; Lin, Marina S; Ferrario, Carlos M; Van Remmen, Holly; Groban, Leanne

2018-04-25

Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress-related genes. GPER KO mice also displayed increased heart weight, cardiac collagen deposition, and Doppler-derived filling pressure, and decreased percent fractional shortening and early mitral annular velocity compared with WT controls. Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5-dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1-decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin-endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss. Copyright © 2018 Elsevier Inc. All rights reserved.

Detecting Regional Myocardial Abnormalities in Patients With Wolff-Parkinson-White Syndrome With the Use of ECG-Gated Cardiac MDCT.

PubMed

Lee, Hye-Jeong; Uhm, Jae-Sun; Joung, Boyoung; Hong, Yoo Jin; Hur, Jin; Choi, Byoung Wook; Kim, Young Jin

2016-04-01

Myocardial dyskinesia caused by the accessory pathway and related reversible heart failure have been well documented in echocardiographic studies of pediatric patients with Wolff-Parkinson-White (WPW) syndrome. However, the long-term effects of dyskinesia on the myocardium of adult patients have not been studied in depth. The goal of the present study was to evaluate regional myocardial abnormalities on cardiac CT examinations of adult patients with WPW syndrome. Of 74 patients with WPW syndrome who underwent cardiac CT from January 2006 through December 2013, 58 patients (mean [± SD] age, 52.2 ± 12.7 years), 36 (62.1%) of whom were men, were included in the study after the presence of combined cardiac disease was excluded. Two observers blindly evaluated myocardial thickness and attenuation on cardiac CT scans. On the basis of CT findings, patients were classified as having either normal or abnormal findings. We compared the two groups for other clinical findings, including observations from ECG, echocardiography, and electrophysiologic study. Of the 58 patients studied, 16 patients (27.6%) were found to have myocardial abnormalities (i.e., abnormal wall thinning with or without low attenuation). All abnormal findings corresponded with the location of the accessory pathway. Patients with abnormal findings had statistically significantly decreased left ventricular function, compared with patients with normal findings (p < 0.001). The frequency of regional wall motion abnormality was statistically significantly higher in patients with abnormal findings (p = 0.043). However, echocardiography documented structurally normal hearts in all patients. A relatively high frequency (27.6%) of regional myocardial abnormalities was observed on the cardiac CT examinations of adult patients with WPW syndrome. These abnormal findings might reflect the long-term effects of dyskinesia, suggesting irreversible myocardial injury that ultimately causes left ventricular dysfunction.

Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress

PubMed Central

Rani, Shilpa; Sreenivasaiah, Pradeep Kumar; Kim, Jin Ock; Lee, Mi Young; Kang, Wan Seok; Kim, Yong Sook; Ahn, Youngkeun; Park, Woo Jin; Cho, Chunghee

2017-01-01

Pressure overload in the heart induces pathological hypertrophy and is associated with cardiac dysfunction. Apoptosis and fibrosis signaling initiated by the endoplasmic reticulum stress (ERS) is known to contribute to these maladaptive effects. The aim of this study was to investigate whether reduction of ERS by a known chemical chaperone, tauroursodeoxycholic acid (TUDCA) can attenuate pressure overload-induced cardiac remodeling in a mouse model of transverse aortic constriction (TAC). Oral administration of TUDCA at a dose of 300 mg/kg body weight (BW) in the TUDCA-TAC group reduced ERS markers (GRP78, p-PERK, and p-eIf2α), compared to the Vehicle (Veh)-TAC group. TUDCA administration, for 4 weeks after TAC significantly reduced cardiac hypertrophy as shown by the reduced heart weight (HW) to BW ratio, and expression of hypertrophic marker genes (ANF, BNP, and α-SKA). Masson's trichrome staining showed that myocardial fibrosis and collagen deposition were also significantly reduced in the TUDCA-TAC group. We also found that TUDCA significantly decreased expression of TGF-β signaling proteins and collagen isoforms. TUDCA administration also reduced cardiac apoptosis and the related proteins in the TUDCA-TAC group. Microarray analysis followed by gene ontology (GO) and pathway analysis demonstrated that extracellular matrix genes responsible for hypertrophy and fibrosis, and mitochondrial genes responsible for apoptosis and fatty acid metabolism were significantly altered in the Veh-TAC group, but the alterations were normalized in the TUDCA-TAC group, suggesting potential of TUDCA in treatment of heart diseases related to pressure-overload. PMID:28426781

Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure.

PubMed

Jin, Li; Piao, Zhe Hao; Sun, Simei; Liu, Bin; Ryu, Yuhee; Choi, Sin Young; Kim, Gwi Ran; Kim, Hyung-Seok; Kee, Hae Jin; Jeong, Myung Ho

2017-12-01

Gallic acid, a trihydroxybenzoic acid found in tea and other plants, attenuates cardiac hypertrophy, fibrosis, and hypertension in animal models. However, the role of gallic acid in heart failure remains unknown. In this study, we show that gallic acid administration prevents heart failure-induced pulmonary fibrosis. Heart failure induced in mice, 8weeks after transverse aortic constriction (TAC) surgery, was confirmed by echocardiography. Treatment for 2weeks with gallic acid but not furosemide prevented cardiac dysfunction in mice. Gallic acid significantly inhibited TAC-induced pathological changes in the lungs, such as increased lung mass, pulmonary fibrosis, and damaged alveolar morphology. It also decreased the expression of fibrosis-related genes, including collagen types I and III, fibronectin, connective tissue growth factor (CTGF), and phosphorylated Smad3. Further, it inhibited the expression of epithelial-mesenchymal transition (EMT)-related genes, such as N-cadherin, vimentin, E-cadherin, SNAI1, and TWIST1. We suggest that gallic acid has therapeutic potential for the treatment of heart failure-induced pulmonary fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

PubMed Central

Zhang, Wei-Wei; Bai, Feng; Wang, Jin; Zheng, Rong-Hua; Yang, Li-Wang; James, Erskine A; Zhao, Zhi-Qing

2017-01-01

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p<0.05) and ejection fraction (82%±3% vs 60%±5%, p<0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure. PMID:29081650

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor.

PubMed

Zhang, Wei-Wei; Bai, Feng; Wang, Jin; Zheng, Rong-Hua; Yang, Li-Wang; James, Erskine A; Zhao, Zhi-Qing

2017-01-01

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p <0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p <0.05) and ejection fraction (82%±3% vs 60%±5%, p <0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure.

Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway.

PubMed

Zhang, Zhiguo; Wang, Shudong; Zhou, Shanshan; Yan, Xiaoqing; Wang, Yonggang; Chen, Jing; Mellen, Nicholas; Kong, Maiying; Gu, Junlian; Tan, Yi; Zheng, Yang; Cai, Lu

2014-12-01

Type 2 diabetes mellitus (T2DM)-induced cardiomyopathy is associated with cardiac oxidative stress, inflammation, and remodeling. Sulforaphane (SFN), an isothiocyanate naturally presenting in widely consumed vegetables, particularly broccoli, plays an important role in cardiac protection from diabetes. We investigated the effect of SFN on T2DM-induced cardiac lipid accumulation and subsequent cardiomyopathy. Male C57BL/6J mice were fed a high-fat diet for 3months to induce insulin resistance, followed by a treatment with 100mg/kg body-weight streptozotocin to induce hyperglycemia; we referred to it as the T2DM mouse model. Other age-matched mice were fed a normal diet as control. T2DM and control mice were treated with or without 4-month SFN at 0.5mg/kg daily five days a week. At the study's end, cardiac function was assessed. SFN treatment significantly attenuated cardiac remodeling and dysfunction induced by T2DM. SFN treatment also significantly inhibited cardiac lipid accumulation, measured by Oil Red O staining, and improved cardiac inflammation oxidative stress and fibrosis, shown by down-regulating diabetes-induced PAI-1, TNF-α, CTGF, TGF-β, 3-NT, and 4-HNE expression. Elevated 4-HNE resulted in the increase of 4-HNE-LKB1 adducts that should inhibit LKB1 and subsequent AMPK activity. SFN upregulated the expression of Nrf2 and its downstream genes, NQO1 and HO-1, decreased 4-HNE-LKB1 adducts and then reversed diabetes-induced inhibition of LKB1/AMPK and its downstream targets, including sirtuin 1, PGC-1α, phosphorylated acetyl-CoA carboxylase, carnitine palmitoyl transferase-1, ULK1, and light chain-3 II. These results suggest that SFN treatment to T2DM mice may attenuate the cardiac oxidative stress-induced inhibition of LKB1/AMPK signaling pathway, thereby preventing T2DM-induced lipotoxicity and cardiomyopathy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cardiac macrophages promote diastolic dysfunction.

PubMed

Hulsmans, Maarten; Sager, Hendrik B; Roh, Jason D; Valero-Muñoz, María; Houstis, Nicholas E; Iwamoto, Yoshiko; Sun, Yuan; Wilson, Richard M; Wojtkiewicz, Gregory; Tricot, Benoit; Osborne, Michael T; Hung, Judy; Vinegoni, Claudio; Naxerova, Kamila; Sosnovik, David E; Zile, Michael R; Bradshaw, Amy D; Liao, Ronglih; Tawakol, Ahmed; Weissleder, Ralph; Rosenzweig, Anthony; Swirski, Filip K; Sam, Flora; Nahrendorf, Matthias

2018-02-05

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18 F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction. © 2018 Hulsmans et al.

The extracellular matrix in myocardial injury, repair, and remodeling

PubMed Central

2017-01-01

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration. PMID:28459429

Cardioprotection by 6-gingerol in diabetic rats.

PubMed

El-Bassossy, Hany M; Elberry, Ahmed A; Ghareib, Salah A; Azhar, Ahmad; Banjar, Zainy Mohammed; Watson, Malcolm L

2016-09-02

The current study was conducted to evaluate the effect of 6-gingerol (6G) on cardiac complications in streptozotocin (STZ)-induced diabetic (DM) rats. STZ-induced DM rats (single 50 mg/kg i.p. injection, 15 days prior to drug treatment) or time-matched controls were treated with 6G (75 mg/day route orally). After a further 8 weeks, blood was collected for biochemical analysis and 8-isoprostenol was measured in urine. Cardiac hemodynamics and ECG was assessed. 6G significantly attenuated the increased level of blood glucose in diabetic rats and improved cardiac hemodynamics in including RR interval, max dP/dt, min dP/dt and Tau. In addition, 6G alleviated the elevated ST segment, T amplitude and R amplitude with no significant effect on disturbed levels of adiponectin, TGF-β or 8-isoprostenol induced by diabetes. The results showed that treatment with 6G has an ameliorative effect on cardiac dysfunction induced by diabetes. Which may be not related to its potential antioxidant effect. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes

PubMed Central

Qian, Li; Huang, Yu; Spencer, C. Ian; Foley, Amy; Vedantham, Vasanth; Liu, Lei; Conway, Simon J.; Fu, Ji-dong; Srivastava, Deepak

2012-01-01

SUMMARY The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported that cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here, we use genetic lineage-tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became bi-nucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast activating peptide, Thymosin β4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes. PMID:22522929

Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats.

PubMed

Hwang, Hyun Seok; Bleske, Barry E; Ghannam, Michael M J; Converso, Kimber; Russell, Mark W; Hunter, James C; Boluyt, Marvin O

2008-02-01

Hawthorn (Crataegus) is a natural product used to treat patients with heart failure. The effects of hawthorn on cardiac remodeling, however, are not known. The purpose was to determine the effects of hawthorn treatment on remodeling and function of the left ventricle (LV) after 1 month of pressure overload-induced cardiac hypertrophy. Sprague-Dawley rats (male, 300 g) were subjected to sham operation (SH) or aortic constriction (AC) for 4 weeks and treated with Hawthorn (Crataegus-Extract- WS1442;1.3, 13, 130 mg kg(-1) day(-1); AC-L, AC-M, AC-H) or vehicle (SH-V, AC-V) for 3 weeks after surgery. Systolic and diastolic function were measured using echocardiographic assessment at baseline and 4 weeks after AC. AC increased the LV/body weight ratio by 34% in vehicle and hawthorn treated rats. Hawthorn markedly reduced LV chamber volumes (VOL) after AC [systolic VOL, mean +/- SEM, mm(3): SH-V, 87 +/- 13; AC-V, 93 +/- 12; AC-L, 62 +/- 9; AC-M, 68 +/- 12; AC-H; 50 +/- 11 and diastolic VOL: SH-V, 433 +/- 45; AC-V, 412 +/- 57; AC-L, 313 +/- 25; AC-M, 319 +/- 37; AC-H, 264 +/- 25 (p < 0.05)] and augmented relative wall thickness, mm: SH-V, 0.45 +/- 0.02; AC-V, 0.65 +/- 0.05; AC-L, 0.71 +/- 0.03; AC-M, 0.74 +/- 0.06; AC-H, 0.80 +/- 0.09 (p < 0.05). AC reduced velocity of circumferential shortening (Vcf(c)) by 28% compared with SH-V. Hawthorn attenuated the AC-induced decrease in Vcf(c) (p < 0.05). Hawthorn treatment modifies left ventricular remodeling and counteracts myocardial dysfunction in early pressure overload-induced cardiac hypertrophy.

Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure.

PubMed

Liu, Ting; Takimoto, Eiki; Dimaano, Veronica L; DeMazumder, Deeptankar; Kettlewell, Sarah; Smith, Godfrey; Sidor, Agnieszka; Abraham, Theodore P; O'Rourke, Brian

2014-06-20

In cardiomyocytes from failing hearts, insufficient mitochondrial Ca(2+) accumulation secondary to cytoplasmic Na(+) overload decreases NAD(P)H/NAD(P)(+) redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca(2+) with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger. Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily β-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group <4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham-operated animals. The findings demonstrate the critical role played by altered mitochondrial Ca(2+) dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF. © 2014 American Heart Association, Inc.

Inhibiting Mitochondrial Na+/Ca2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure

PubMed Central

Liu, Ting; Takimoto, Eiki; Dimaano, Veronica L.; DeMazumder, Deeptankar; Kettlewell, Sarah; Smith, Godfrey; Sidor, Agnieszka; Abraham, Theodore P.; O’Rourke, Brian

2014-01-01

Rationale In cardiomyocytes from failing hearts, insufficient mitochondrial Ca2+ ([Ca2+]m) accumulation secondary to cytoplasmic Na+ overload decreases NAD(P)H/NAD(P)+ redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing [Ca2+]m with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na+/Ca2+ exchanger. Objective To determine if chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). Methods and Results Here, we describe a novel guinea-pig HF/SCD model employing aortic constriction combined with daily β-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi+CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure-overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared to sham-operated controls; in contrast, cardiac function was completely preserved in the ACi+CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group within 4 weeks of aortic constriction, while the death rate in the ACi+CGP group was not different from sham-operated animals. Conclusions The findings demonstrate the critical role played by altered mitochondrial Ca2+ dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF. PMID:24780171

Never in mitosis gene A related kinase-6 attenuates pressure overload-induced activation of the protein kinase B pathway and cardiac hypertrophy.

PubMed

Bian, Zhouyan; Liao, Haihan; Zhang, Yan; Wu, Qingqing; Zhou, Heng; Yang, Zheng; Fu, Jinrong; Wang, Teng; Yan, Ling; Shen, Difei; Li, Hongliang; Tang, Qizhu

2014-01-01

Cardiac hypertrophy appears to be a specialized form of cellular growth that involves the proliferation control and cell cycle regulation. NIMA (never in mitosis, gene A)-related kinase-6 (Nek6) is a cell cycle regulatory gene that could induce centriole duplication, and control cell proliferation and survival. However, the exact effect of Nek6 on cardiac hypertrophy has not yet been reported. In the present study, the loss- and gain-of-function experiments were performed in Nek6 gene-deficient (Nek6-/-) mice and Nek6 overexpressing H9c2 cells to clarify whether Nek6 which promotes the cell cycle also mediates cardiac hypertrophy. Cardiac hypertrophy was induced by transthoracic aorta constriction (TAC) and then evaluated by echocardiography, pathological and molecular analyses in vivo. We got novel findings that the absence of Nek6 promoted cardiac hypertrophy, fibrosis and cardiac dysfunction, which were accompanied by a significant activation of the protein kinase B (Akt) signaling in an experimental model of TAC. Consistent with this, the overexpression of Nek6 prevented hypertrophy in H9c2 cells induced by angiotonin II and inhibited Akt signaling in vitro. In conclusion, our results demonstrate that the cell cycle regulatory gene Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway.

Loss or Inhibition of uPA or MMP-9 Attenuates LV Remodeling and Dysfunction after Acute Pressure Overload in Mice

PubMed Central

Heymans, Stephane; Lupu, Florea; Terclavers, Sven; Vanwetswinkel, Bjorn; Herbert, Jean-Marc; Baker, Andrew; Collen, Desire; Carmeliet, Peter; Moons, Lieve

2005-01-01

Left ventricular (LV) hypertrophy is a natural response of the heart to increased pressure loading, but accompanying fibrosis and dilatation may result in irreversible life-threatening heart failure. Matrix metalloproteinases (MMPs) have been invoked in various cardiac diseases, however, direct genetic evidence for a role of the plasminogen activator (PA) and MMP systems in pressure overload-induced LV hypertrophy and in heart failure is lacking. Therefore, the consequences of transverse aortic banding (TAB) were analyzed in mice lacking tissue-type PA (t-PA−/−), urokinase-type PA (u-PA−/−), or gelatinase-B (MMP-9−/−), and in wild-type (WT) mice after adenoviral gene transfer of the PA-inhibitor PAI-1 or the MMP-inhibitor TIMP-1. TAB elevated LV pressure comparably in all genotypes. In WT and t-PA−/− mice, cardiomyocyte hypertrophy was associated with myocardial fibrosis, LV dilatation and dysfunction, and pump failure after 7 weeks. In contrast, in u-PA−/− mice or in WT mice after PAI-1- and TIMP-1-gene transfer, cardiomyocyte hypertrophy was moderate and only minimally associated with cardiac fibrosis and LV dilatation, resulting in better preservation of pump function. Deficiency of MMP-9 had an intermediate effect. These findings suggest that the use of u-PA- or MMP-inhibitors might preserve cardiac pump function in LV pressure overloading. PMID:15631996

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

PubMed

Sabharwal, Rasna; Chapleau, Mark W

2014-04-01

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.

Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5'-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells.

PubMed

Chang, Wenguang; Zhang, Ming; Meng, Zhaojie; Yu, Yang; Yao, Fan; Hatch, Grant M; Chen, Li

2015-12-15

Diabetic cardiomyopathy is the major cause of death in type 2 diabetic patients. Berberine is an isoquinoline alkaloid extract from traditional chinese herbs and its hypoglycemic and hypolipidemic effects make it a promising drug for treatment of type 2 diabetes. We examined if berberine improved cardiac function and attenuated cardiac hypertrophy and fibrosis in high fat diet and streptozotocin induced-type 2 diabetic rats in vivo and reduced expression of hypertrophy markers in palmitate-induced hypertrophic H9c2 cells in vitro. Treatment of diabetic animals with berberine partially improved cardiac function and restored fasting blood insulin, fasting blood glucose, total cholesterol, and triglyceride levels to that of control. In addition, berberine treatment of diabetic animals increased cardiac 5'-adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (AKT) activation and reduced glycogen synthase kinase 3 beta (GSK3β) activation compared to control. Palmitate incubation of H9c2 cells resulted in cellular hypertrophy and decreased expression of alpha-myosin heavy chain (α-MHC) and increased expression of beta-myosin heavy chain (β-MHC) compared to controls. Berberine treatment of palmitate-incubated H9c2 cells reduced hypertrophy, increased α-MHC expression and decreased β-MHC expression. In addition, berberine treatment of palmitate-incubated H9c2 cells increased AMPK and AKT activation and reduced GSK3β activation. The presence of the AMPK inhibitor Compound C attenuated the effects of berberine. The results strongly indicate that berberine treatment may be protective against the development of diabetic cardiomyopathy. Copyright © 2015 Elsevier B.V. All rights reserved.

A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

PubMed

Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

2017-03-15

Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2 UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction-induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Hypoxia-Induced Mitogenic Factor Promotes Cardiac Hypertrophy via Calcium-Dependent and Hypoxia-Inducible Factor-1α Mechanisms.

PubMed

Kumar, Santosh; Wang, Gang; Liu, Wenjuan; Ding, Wenwen; Dong, Ming; Zheng, Na; Ye, Hongyu; Liu, Jie

2018-06-11

HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like α) is a secretory and cytokine-like protein and serves as a critical stimulator of hypoxia-induced pulmonary hypertension. With a role for HIMF in heart disease unknown, we explored the possible roles for HIMF in cardiac hypertrophy by overexpressing and knocking down HIMF in cardiomyocytes and characterizing HIMF gene ( himf ) knockout mice. We found that HIMF mRNA and protein levels were upregulated in phenylephrine-stimulated cardiomyocyte hypertrophy and our mouse model of transverse aortic constriction-induced cardiac hypertrophy, as well as in human hearts with dilated cardiomyopathy. Furthermore, HIMF overexpression could induce cardiomyocyte hypertrophy, as characterized by elevated protein expression of hypertrophic biomarkers (ANP [atrial natriuretic peptide] and β-MHC [myosin heavy chain-β]) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and himf ablation in knockout mice significantly attenuated transverse aortic constriction-induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca 2+ concentration and activated the CaN-NFAT (calcineurin-nuclear factor of activated T cell) and MAPK (mitogen-activated protein kinase) pathways; this effect could be prevented by reducing cytosolic Ca 2+ concentration with L-type Ca 2+ channel blocker nifedipine or inhibiting the CaSR (Ca 2+ sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1α (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1α upregulation in transverse aortic constriction mice. Knockdown of HIF-1α attenuated HIMF-induced cardiomyocyte hypertrophy. In conclusion, HIMF has a critical role in the development of cardiac hypertrophy, and targeting HIMF may represent a potential therapeutic strategy. © 2018 American Heart Association, Inc.

Ablation of toll-like receptor 4 attenuates aging-induced myocardial remodeling and contractile dysfunction through NCoRI-HDAC1-mediated regulation of autophagy.

PubMed

Wang, Shuyi; Ge, Wei; Harns, Carrie; Meng, Xianzhong; Zhang, Yingmei; Ren, Jun

2018-04-13

Aging is usually accompanied with overt structural and functional changes as well as suppressed autophagy in the heart although the precise regulatory mechanisms are somewhat unknown. Here we evaluated the role of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in cardiac aging and the underlying mechanism with a focus on autophagy. Cardiac geometry and function were monitored in young or old wild-type (WT) and TLR4 knockout (TLR4 -/- ) mice using echocardiography, IonOptix® edge-detection and fura-2 techniques. Levels of autophagy and mitophagy, nuclear receptor corepressor 1 (NCoR1) and histone deacetylase I (HDAC1) were examined using western blot. Transmission electronic microscopy (TEM) was employed to monitor myocardial ultrastructure. Our results revealed that TLR4 ablation alleviated advanced aging (24 months)-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte cross-sectional area), contractile function and intracellular Ca 2+ handling as well as autophagy and mitophagy [Beclin-1, Atg5, LC3B, PTEN-induced putative kinase 1 (PINK1), Parkin and p62]. Aging downregulated levels of NCoR1 and HDAC1 as well as their interaction, the effects were significantly attenuated or negated by TLR4 ablation. Advanced aging disturbed myocardial ultrastructure as evidenced by loss of myofilament alignment and swollen mitochondria, which was obliterated by TLR4 ablation. Moreover, aging suppressed autophagy (GFP-LC3B puncta) in neonatal mouse cardiomyocytes, the effect of which was negated by the TLR4 inhibitor CLI-095. Inhibition of HDCA1 using apicidin cancelled off CLI095-induced beneficial response of GFP-LC3B puncta against aging. Our data collectively indicate a role for TLR4-mediated autophagy in cardiac remodeling and contractile dysfunction in aging through a HDAC1-NCoR1-dependent mechanism. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hot shot induction and reperfusion with a specific blocker of the es-ENT1 nucleoside transporter before and after hypothermic cardioplegia abolishes myocardial stunning in acutely ischemic hearts despite metabolic derangement: Hot shot drug delivery before hypothermic cardioplegia

PubMed Central

Abd-Elfattah, Anwar Saad; Tuchy, Gert E.; Jessen, Michael E.; Salter, David R.; Goldstein, Jacques P.; Brunsting, Louis A.; Wechsler, Andrew S.

2013-01-01

Objective Simultaneous inhibition of the cardiac equilibrative-p-nitrobenzylthioinosine (NBMPR)–sensitive (es) type of the equilibrative nucleoside transport 1 (ENT1) nucleoside transporter, with NBMPR, and adenosine deaminase, with erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA), prevents release of myocardial purines and attenuates myocardial stunning and fibrillation in canine models of warm ischemia and reperfusion. It is not known whether prolonged administration of hypothermic cardioplegia influences purine release and EHNA/NBMPR-mediated cardioprotection in acutely ischemic hearts. Methods Anesthetized dogs (n = 46), which underwent normothermic aortic crossclamping for 20 minutes on-pump, were divided to determine (1) purine release with induction of intermittent antegrade or continuous retrograde hypothermic cardioplegia and reperfusion, (2) the effects of postischemic treatment with 100 µM EHNA and 25 µM NBMPR on purine release and global functional recovery, and (3) whether a hot shot and reperfusion with EHNA/NBMPR inhibits purine release and attenuates ventricular dysfunction of ischemic hearts. Myocardial biopsies and coronary sinus effluents were obtained and analyzed using high-performance liquid chromatography. Results Warm ischemia depleted myocardial adenosine triphosphate and elevated purines (ie, inosine > adenosine) as markers of ischemia. Induction of intermittent antegrade or continuous retrograde hypothermic (4°C) cardioplegia releases purines until the heart becomes cold (<20°C). During reperfusion, the levels of hypoxanthine and xanthine (free radical substrates) were >90% of purines in coronary sinus effluent. Reperfusion with EHNA/NBMPR abolished ventricular dysfunction in acutely ischemic hearts with and without a hot shot and hypothermic cardioplegic arrest. Conclusions Induction of hypothermic cardioplegia releases purines from ischemic hearts until they become cold, whereas reperfusion induces massive purine release and myocardial stunning. Inhibition of cardiac es-ENT1 nucleoside transporter abolishes postischemic reperfusion injury in warm and cold cardiac surgery. PMID:23422047

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction.

PubMed

Zhao, Shu-Li; Zhang, Yao-Jun; Li, Ming-Hui; Zhang, Xin-Lei; Chen, Shao-Liang

2014-03-17

Elevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI. A pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks. Overexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-β1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks. Therapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI.

Effects of Kefir on the Cardiac Autonomic Tones and Baroreflex Sensitivity in Spontaneously Hypertensive Rats

PubMed Central

Klippel, Brunella F.; Duemke, Licia B.; Leal, Marcos A.; Friques, Andreia G. F.; Dantas, Eduardo M.; Dalvi, Rodolfo F.; Gava, Agata L.; Pereira, Thiago M. C.; Andrade, Tadeu U.; Meyrelles, Silvana S.; Campagnaro, Bianca P.; Vasquez, Elisardo C.

2016-01-01

Aims: It has been previously shown that the probiotic kefir (a symbiotic matrix containing acid bacteria and yeasts) attenuated the hypertension and the endothelial dysfunction in spontaneously hypertensive rats (SHR). In the present study, the effect of chronic administration of kefir on the cardiac autonomic control of heart rate (HR) and baroreflex sensitivity (BRS) in SHR was evaluated. Methods: SHR were treated with kefir (0.3 mL/100 g body weight) for 60 days and compared with non-treated SHR and with normotensive Wistar-Kyoto rats. Cardiac autonomic vagal (VT) and sympathetic (ST) tones were estimated through the blockade of the cardiac muscarinic receptors (methylatropine) and the blockade of β1−adrenoceptor (atenolol). The BRS was evaluated by the tachycardia and bradycardia responses to vasoactive drug-induced decreases and increases in arterial blood pressure (BP), respectively. Additionally, spontaneous BRS was estimated by autoregressive spectral analysis. Results: Kefir-treated SHR exhibited significant attenuation of basal BP, HR, and cardiac hypertrophy compared to non-treated SHR (12, 13, and 21%, respectively). Cardiac VT and ST were significantly altered in the SHR (~40 and ~90 bpm) compared with Wistar rats (~120 and ~30 bpm) and were partially recovered in SHR-kefir (~90 and ~25 bpm). SHR exhibited an impaired bradycardic BRS (~50%) compared with Wistar rats, which was reduced to ~40% in the kefir-treated SHR and abolished by methylatropine in all groups. SHR also exhibited a significant impairment of the tachycardic BRS (~23%) compared with Wistar rats and this difference was reduced to 8% in the SHR-kefir. Under the action of atenolol the residual reflex tachycardia was smaller in SHR than in Wistar rats and kefir attenuated this abnormality. Spectral analysis revealed increased low frequency components of BP (~3.5-fold) and pulse interval (~2-fold) compared with Wistar rats and these differences were reduced by kefir-treatment to ~1.6- and ~1.5-fold, respectively. Spectral analysis also showed an impairment of spontaneous BRS in SHR, but kefir-treatment caused only a tendency to reverse this result. Conclusions: The novelty of this study is that daily chronic consumption of a low dose of kefir reduced the impairment of the cardiac autonomic control of HR and of the impaired BRS in SHR. PMID:27375490

Effects of Kefir on the Cardiac Autonomic Tones and Baroreflex Sensitivity in Spontaneously Hypertensive Rats.

PubMed

Klippel, Brunella F; Duemke, Licia B; Leal, Marcos A; Friques, Andreia G F; Dantas, Eduardo M; Dalvi, Rodolfo F; Gava, Agata L; Pereira, Thiago M C; Andrade, Tadeu U; Meyrelles, Silvana S; Campagnaro, Bianca P; Vasquez, Elisardo C

2016-01-01

It has been previously shown that the probiotic kefir (a symbiotic matrix containing acid bacteria and yeasts) attenuated the hypertension and the endothelial dysfunction in spontaneously hypertensive rats (SHR). In the present study, the effect of chronic administration of kefir on the cardiac autonomic control of heart rate (HR) and baroreflex sensitivity (BRS) in SHR was evaluated. SHR were treated with kefir (0.3 mL/100 g body weight) for 60 days and compared with non-treated SHR and with normotensive Wistar-Kyoto rats. Cardiac autonomic vagal (VT) and sympathetic (ST) tones were estimated through the blockade of the cardiac muscarinic receptors (methylatropine) and the blockade of β1-adrenoceptor (atenolol). The BRS was evaluated by the tachycardia and bradycardia responses to vasoactive drug-induced decreases and increases in arterial blood pressure (BP), respectively. Additionally, spontaneous BRS was estimated by autoregressive spectral analysis. Kefir-treated SHR exhibited significant attenuation of basal BP, HR, and cardiac hypertrophy compared to non-treated SHR (12, 13, and 21%, respectively). Cardiac VT and ST were significantly altered in the SHR (~40 and ~90 bpm) compared with Wistar rats (~120 and ~30 bpm) and were partially recovered in SHR-kefir (~90 and ~25 bpm). SHR exhibited an impaired bradycardic BRS (~50%) compared with Wistar rats, which was reduced to ~40% in the kefir-treated SHR and abolished by methylatropine in all groups. SHR also exhibited a significant impairment of the tachycardic BRS (~23%) compared with Wistar rats and this difference was reduced to 8% in the SHR-kefir. Under the action of atenolol the residual reflex tachycardia was smaller in SHR than in Wistar rats and kefir attenuated this abnormality. Spectral analysis revealed increased low frequency components of BP (~3.5-fold) and pulse interval (~2-fold) compared with Wistar rats and these differences were reduced by kefir-treatment to ~1.6- and ~1.5-fold, respectively. Spectral analysis also showed an impairment of spontaneous BRS in SHR, but kefir-treatment caused only a tendency to reverse this result. The novelty of this study is that daily chronic consumption of a low dose of kefir reduced the impairment of the cardiac autonomic control of HR and of the impaired BRS in SHR.

Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function

PubMed Central

Saxena, Amit; Dobaczewski, Marcin; Rai, Vikrant; Haque, Zaffar; Chen, Wei; Li, Na

2014-01-01

Regulatory T cells (Tregs) play a pivotal role in suppressing immune responses regulating behavior and gene expression in effector T cells, macrophages, and dendritic cells. Tregs infiltrate the infarcted myocardium; however, their role the inflammatory and reparative response after myocardial infarction remains poorly understood. We used FoxP3EGFP reporter mice to study Treg trafficking in the infarcted heart and examined the effects of Treg depletion on postinfarction remodeling using an anti-CD25 antibody. Moreover, we investigated the in vitro effects of Tregs on cardiac fibroblast phenotype and function. Low numbers of Tregs infiltrated the infarcted myocardium after 24–72 h of reperfusion. Treg depletion had no significant effects on cardiac dysfunction and scar size after reperfused myocardial infarction but accelerated ventricular dilation and accentuated apical remodeling. Enhanced myocardial dilation in Treg-depleted animals was associated with increased expression of chemokine (C-C motif) ligand 2 and accentuated macrophage infiltration. In vitro, Tregs modulated the cardiac fibroblast phenotype, reducing expression of α-smooth muscle actin, decreasing expression of matrix metalloproteinase-3, and attenuating contraction of fibroblast-populated collagen pads. Our findings suggest that endogenous Tregs have modest effects on the inflammatory and reparative response after myocardial infarction. However, the anti-inflammatory and matrix-preserving properties of Tregs may suggest a role for Treg-based cell therapy in the attenuation of adverse postinfarction remodeling. PMID:25128167

Burden of Systolic and Diastolic Left Ventricular Dysfunction among Hispanics in the United States: Insights from the Echocardiographic Study of Latinos (ECHO-SOL)

PubMed Central

Mehta, Hardik; Armstrong, Anderson; Swett, Katrina; Shah, Sanjiv J.; Allison, Matthew A.; Hurwitz, Barry; Bangdiwala, Shrikant; Dadhania, Rupal; Kitzman, Dalane W.; Arguelles, William; Lima, Joao; Youngblood, Marston; Schneiderman, Neil; Daviglus, Martha L.; Spevack, Daniel; Talavera, Greg A.; Raisinghani, Ajit; Kaplan, Robert; Rodriguez, Carlos J.

2016-01-01

Background Population-based estimates of cardiac dysfunction and clinical heart failure (HF) remain undefined among Hispanics/Latino adults. Methods and Results Participants of Hispanic/Latino origin across the US, aged 45–74 years were enrolled into the Echocardiographic Study of Latinos (ECHO-SOL) and underwent a comprehensive echocardiography exam to define left ventricular systolic dysfunction (LVSD) and left ventricular diastolic dysfunction (LVDD). Clinical HF was defined according to self-report; and those with cardiac dysfunction but without clinical HF were characterized as having subclinical or unrecognized cardiac dysfunction. Of 1,818 ECHO-SOL participants (mean age 56.4 years; 42.6% male) , 49.7% had LVSD and/or LVDD. LVSD prevalence was 3.6%, while LVDD was detected in 50.3%. Participants with LVSD were more likely to be males and current smokers (all p<0.05). Female sex, hypertension, diabetes, higher body-mass index and renal dysfunction were more common among those with LVDD (all p<0.05). In age-sex adjusted models, individuals of Central American and Cuban backgrounds were almost two-fold more likely to have LVDD compared to those of Mexican backgrounds. Prevalence of clinical HF with LVSD (HF with reduced EF) was 7.3%; prevalence of clinical HF with LVDD (HF with preserved EF) was 3.6%. 96.1% of the cardiac dysfunction seen was subclinical or unrecognized. Compared to those with clinical cardiac dysfunction, prevalent coronary heart disease was the only factor independently associated with subclinical or unrecognized cardiac dysfunction (odds ratio: 0.1; 95% confidence interval: 0.1–0.4). Conclusions Among Hispanics/Latinos, most cardiac dysfunction is subclinical or unrecognized, with a high prevalence of diastolic dysfunction. This identifies a high-risk population for the development of clinical HF. PMID:27048764

Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

PubMed Central

He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

2014-01-01

Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias

NASA Technical Reports Server (NTRS)

Levine, Benjamin D.; Bungo, Michael W.; Platts, Steven H.; Hamilton, Douglas R.; Johnston, Smith L.

2009-01-01

Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias (Integrated Cardiovascular) will quantify the extent of long-duration space flightassociated cardiac atrophy (deterioration) on the International Space Station crewmembers.

Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

PubMed

Luo, Da; Hu, Huihui; Qin, Zhiliang; Liu, Shan; Yu, Xiaomei; Ma, Ruisong; He, Wenbo; Xie, Jing; Lu, Zhibing; He, Bo; Jiang, Hong

2017-12-01

Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing. Copyright © 2017 Elsevier B.V. All rights reserved.

Toll-like receptor 3 plays a role in myocardial infarction and ischemia/reperfusion injury.

PubMed

Lu, Chen; Ren, Danyang; Wang, Xiaohui; Ha, Tuanzhu; Liu, Li; Lee, Eric J; Hu, Jing; Kalbfleisch, John; Gao, Xiang; Kao, Race; Williams, David; Li, Chuanfu

2014-01-01

Innate immune and inflammatory responses mediated by Toll like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. This study examined the role of TLR3 in myocardial injury induced by two models, namely, myocardial infarction (MI) and I/R. First, we examined the role of TLR3 in MI. TLR3 deficient (TLR3(-/-)) and wild type (WT) mice were subjected to MI induced by permanent ligation of the left anterior descending (LAD) coronary artery for 21days. Cardiac function was measured by echocardiography. Next, we examined whether TLR3 contributes to myocardial I/R injury. TLR3(-/-) and WT mice were subjected to myocardial ischemia (45min) followed by reperfusion for up to 3days. Cardiac function and myocardial infarct size were examined. We also examined the effect of TLR3 deficiency on I/R-induced myocardial apoptosis and inflammatory cytokine production. TLR3(-/-) mice showed significant attenuation of cardiac dysfunction after MI or I/R. Myocardial infarct size and myocardial apoptosis induced by I/R injury were significantly attenuated in TLR3(-/-) mice. TLR3 deficiency increases B-cell lymphoma 2 (BCL2) levels and attenuates I/R-increased Fas, Fas ligand or CD95L (FasL), Fas-Associated protein with Death Domain (FADD), Bax and Bak levels in the myocardium. TLR3 deficiency also attenuates I/R-induced myocardial nuclear factor KappaB (NF-κB) binding activity, Tumor necrosis factor alpha (TNF-α) and Interleukin-1 beta (IL-1β) production as well as I/R-induced infiltration of neutrophils and macrophages into the myocardium. TLR3 plays an important role in myocardial injury induced by MI or I/R. The mechanisms involve activation of apoptotic signaling and NF-κB binding activity. Modulation of TLR3 may be an effective approach for ameliorating heart injury in heart attack patients. © 2013.

Tomato (Lycopersicon esculentum) or lycopene supplementation attenuates ventricular remodeling after myocardial infarction through different mechanistic pathways.

PubMed

Pereira, Bruna L B; Reis, Patrícia P; Severino, Fábio E; Felix, Tainara F; Braz, Mariana G; Nogueira, Flávia R; Silva, Renata A C; Cardoso, Ana C; Lourenço, Maria A M; Figueiredo, Amanda M; Chiuso-Minicucci, Fernanda; Azevedo, Paula S; Polegato, Bertha F; Okoshi, Katashi; Fernandes, Ana A H; Paiva, Sergio A R; Zornoff, Leonardo A M; Minicucci, Marcos F

2017-08-01

The objective of this study was to evaluate the influence of tomato or lycopene supplementation on cardiac remodeling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: the sham group (animals that underwent simulated surgery) that received a standard chow (S; n=18), the infarcted group that received a standard chow (MI; n=13), the infarcted group supplemented with lycopene (1 mg of lycopene/kg body weight/day) (MIL; n=16) and the infarcted group supplemented with tomato (MIT; n=16). After 3 months, morphological, functional and biochemical analyses were performed. The groups MIL and MIT showed decreased interstitial fibrosis induced by infarction. Tomato supplementation attenuated the hypertrophy induced by MI. In addition, tomato and lycopene improved diastolic dysfunction evaluated by echocardiographic and isolated heart studies, respectively. The MI group showed higher levels of cardiac TNF-α compared to the MIL and MIT groups. Decreased nuclear factor E2-related factor 2 was measured in the MIL group. Lipid hydroperoxide levels were higher in the infarcted groups; however, the MIT group had a lower concentration than did the MI group [S=223±20.8, MI=298±19.5, MIL=277±26.6, MIT=261±28.8 (nmol/g); n=8; P<.001]. We also examined left ventricle miRNA expression; when compared to the S group, the MIL group uniquely down-regulated the expression of eight miRNAs. No miRNA was found to be up-regulated uniquely in the MIT and MIL groups. In conclusion, tomato or lycopene supplementation attenuated the cardiac remodeling process and improved diastolic function after MI. However, the effect of lycopene and tomato supplementation occurred through different mechanistic pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary linoleate preserves cardiolipin and attenuates mitochondrial dysfunction in the failing rat heart

PubMed Central

Mulligan, Christopher M.; Sparagna, Genevieve C.; Le, Catherine H.; De Mooy, Anthony B.; Routh, Melissa A.; Holmes, Michael G.; Hickson-Bick, Diane L.; Zarini, Simona; Murphy, Robert C.; Xu, Fred Y.; Hatch, Grant M.; McCune, Sylvia A.; Moore, Russell L.; Chicco, Adam J.

2012-01-01

Aims Cardiolipin (CL) is a tetra-acyl phospholipid that provides structural and functional support to several proteins in the inner mitochondrial membrane. The majority of CL in the healthy mammalian heart contains four linoleic acid acyl chains (L4CL). A selective loss of L4CL is associated with mitochondrial dysfunction and heart failure in humans and animal models. We examined whether supplementing the diet with linoleic acid would preserve cardiac L4CL and attenuate mitochondrial dysfunction and contractile failure in rats with hypertensive heart failure. Methods and results Male spontaneously hypertensive heart failure rats (21 months of age) were administered diets supplemented with high-linoleate safflower oil (HLSO) or lard (10% w/w; 28% kilocalorie fat) or without supplemental fat (control) for 4 weeks. HLSO preserved L4CL and total CL to 90% of non-failing levels (vs. 61–75% in control and lard groups), and attenuated 17–22% decreases in state 3 mitochondrial respiration observed in the control and lard groups (P < 0.05). Left ventricular fractional shortening was significantly higher in HLSO vs. control (33 ± 2 vs. 29 ± 2%, P < 0.05), while plasma insulin levels were lower (5.4 ± 1.1 vs. 9.1 ± 2.3 ng/mL; P < 0.05), with no significant effect of lard supplementation. HLSO also increased serum concentrations of several eicosanoid species compared with control and lard diets, but had no effect on plasma glucose or blood pressure. Conclusion Moderate consumption of HLSO preserves CL and mitochondrial function in the failing heart and may be a useful adjuvant therapy for this condition. PMID:22411972

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart

PubMed Central

Desai, Moreshwar; Mathur, Bhoomika; Eblimit, Zeena; Vasquez, Hernan; Taegtmeyer, Heinrich; Karpen, Saul; Penny, Daniel J.; Moore, David D.; Anakk, Sayeepriyadarshini

2017-01-01

Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term Cholecardia. Fxr; Shp double knockout (DKO) mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, DKO mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of Pgc1α, a key regulator of fatty acid metabolism, and that Pgc1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the DKO mice. Conclusions Overall, we propose that decreased Pgc1α expression contributes to the metabolic dysfunction in Cholecardia, and that reducing serum bile acid concentrations will be beneficial against metabolic and pathological changes in the heart. PMID:27774647

The heart as an extravascular target of endothelin-1 in ...

EPA Pesticide Factsheets

Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease and cardiac dysfunction have been explored, though linkage with specific factors or genes remains limited. Given evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction, the present review highlights the emerging role of endothelins as mediators of cardiac dysfunction following particulate matter exposure. Endothelin-1 is a small multifunctional protein expressed in the pulmonary and cardiovascular system, known for its ability to constrict blood vessels. Although endothelin-1 can also directly and indirectly (via secondary signaling events) modulate cardiac contractility, heart rate, and rhythm, research on the role of endothelins in the context of air pollution has tended to focus on the vascular effects. The plausibility of endothelin as a mechanism underlying particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. Extravascular effects of endothelin on the heart could better explain one mechanism by which particulate matter exposure may lead to cardiac dysfunction. We propose and support the novel hypothesis that autocrine/paracrine signaling systems, such as endothelins, mediate cardiac

Decreased Autophagy Contributes to Myocardial Dysfunction in Rats Subjected to Nonlethal Mechanical Trauma

PubMed Central

Liang, Feng; Li, Xiaoyu; Wang, Li; Yang, Caihong; Yan, Zi; Zhang, Suli; Liu, Huirong

2013-01-01

Autophagy is important in cells for removing damaged organelles, such as mitochondria. Insufficient autophagy plays a critical role in tissue injury and organ dysfunction under a variety of pathological conditions. However, the role of autophagy in nonlethal traumatic cardiac damage remains unclear. The aims of the present study were to investigate whether nonlethal mechanical trauma may result in the change of cardiomyocyte autophagy, and if so, to determine whether the changed myocardial autophagy may contribute to delayed cardiac dysfunction. Male adult rats were subjected to nonlethal traumatic injury, and cardiomyocyte autophagy, cardiac mitochondrial function, and cardiac function in isolated perfused hearts were detected. Direct mechanical traumatic injury was not observed in the heart within 24 h after trauma. However, cardiomyocyte autophagy gradually decreased and reached a minimal level 6 h after trauma. Cardiac mitochondrial dysfunction was observed by cardiac radionuclide imaging 6 h after trauma, and cardiac dysfunction was observed 24 h after trauma in the isolated perfused heart. These were reversed when autophagy was induced by administration of the autophagy inducer rapamycin 30 min before trauma. Our present study demonstrated for the first time that nonlethal traumatic injury caused decreased autophagy, and decreased autophagy may contribute to post-traumatic organ dysfunction. Though our study has some limitations, it strongly suggests that cardiac damage induced by nonlethal mechanical trauma can be detected by noninvasive radionuclide imaging, and induction of autophagy may be a novel strategy for reducing posttrauma multiple organ failure. PMID:23977036

Cytoskeletal Role in the Contractile Dysfunction of Hypertrophied Myocardium

NASA Astrophysics Data System (ADS)

Tsutsui, Hiroyuki; Ishihara, Kazuaki; Cooper, George

1993-04-01

Cardiac hypertrophy in response to systolic pressure loading frequently results in contractile dysfunction of unknown cause. In the present study, pressure loading increased the microtubule component of the cardiac muscle cell cytoskeleton, which was responsible for the cellular contractile dysfunction observed. The linked microtubule and contractile abnormalities were persistent and thus may have significance for the deterioration of initially compensatory cardiac hypertrophy into congestive heart failure.

CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.

PubMed

Wang, Lei; Zhang, Yun-Long; Lin, Qiu-Yue; Liu, Yu; Guan, Xu-Min; Ma, Xiao-Lei; Cao, Hua-Jun; Liu, Ying; Bai, Jie; Xia, Yun-Long; Du, Jie; Li, Hui-Hua

2018-05-21

Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

Dietary salt restriction improves cardiac and adipose tissue pathology independently of obesity in a rat model of metabolic syndrome.

PubMed

Hattori, Takuya; Murase, Tamayo; Takatsu, Miwa; Nagasawa, Kai; Matsuura, Natsumi; Watanabe, Shogo; Murohara, Toyoaki; Nagata, Kohzo

2014-12-02

Metabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear. We investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which are derived from a cross between Dahl salt-sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal-salt (0.36% NaCl in chow) or low-salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean rats). DS/obese rats fed the normal-salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin-angiotensin-aldosterone system genes were increased in DS/obese rats fed the normal-salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats. Dietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.

PubMed

Wang, Wei; Zhang, Fuyang; Xia, Yunlong; Zhao, Shihao; Yan, Wenjun; Wang, Helin; Lee, Yan; Li, Congye; Zhang, Ling; Lian, Kun; Gao, Erhe; Cheng, Hexiang; Tao, Ling

2016-11-01

Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF. Copyright © 2016 the American Physiological Society.

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

PubMed Central

Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia del Giudice, Emanuele; Santoro, Nicola

2017-01-01

In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction. PMID:28144387

From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease.

PubMed

Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia Del Giudice, Emanuele; Santoro, Nicola

2017-01-18

In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction.

The relationship between physical performance and cardiac function in an elderly Russian cohort.

PubMed

Tadjibaev, Pulod; Frolova, Elena; Gurina, Natalia; Degryse, Jan; Vaes, Bert

2014-01-01

This study aims to determine the cardiac dysfunction prevalence, to investigate the relationship between the Short Physical Performance Battery (SPPB) test and structural and functional echocardiographic parameters and to determine whether SPPB scores and cardiac dysfunction are independent mortality predictors in an elderly Russian population. A random sample of 284 community-dwelling adults aged 65 and older were selected from a population-based register and divided into two age groups (65-74 and ≥75). The SPPB test, echocardiography and all-cause mortality were measured. The prevalence of cardiac dysfunction was 12% in the 65-74 group and 23% in the ≥75 group. The multivariate models could explain 15% and 23% of the SPPB score total variance for the 65-74 and ≥75 age groups, respectively. In the younger age group, the mean follow-up time was 2.6±0.46 years, and the adjusted hazard ratio (HR) for risk of mortality from cardiac dysfunction was 4.9. In the older age group, the mean follow-up time was 2.4±0.61 years, and both cardiac dysfunction and poor physical performance were found to be independent predictors of mortality (adjusted HR=3.4 and adjusted HR=4.2, respectively). The cardiac dysfunction prevalence in this elderly Russian population was found to be comparable to, or even lower than, reported prevalences for Western countries. Furthermore, the observed correlations between echocardiographic abnormalities and SPPB scores were limited. Cardiac dysfunction was shown to be a strong mortality predictor in both age groups, and poor physical performance was identified as an independent mortality predictor in the oldest subjects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.

PubMed

Kreusser, Michael M; Lehmann, Lorenz H; Keranov, Stanislav; Hoting, Marc-Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan-Christian; Neumann, Kay; Schneider, Michael D; Hill, Joseph A; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S; Gröne, Hermann-Josef; Katus, Hugo A; Olson, Eric N; Backs, Johannes

2014-10-07

Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure. © 2014 American Heart Association, Inc.

Apigenin Attenuates Experimental Autoimmune Myocarditis by Modulating Th1/Th2 Cytokine Balance in Mice.

PubMed

Zhang, Shouxin; Liu, Xiaoyan; Sun, Chengming; Yang, Jun; Wang, Lihong; Liu, Jie; Gong, Lei; Jing, Yanyan

2016-04-01

This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance.

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

Cardiac dysfunctions following spinal cord injury

PubMed Central

Sandu, AM; Popescu, M; Iacobini, MA; Stoian, R; Neascu, C; Popa, F

2009-01-01

The aim of this article is to analyze cardiac dysfunctions occurring after spinal cord injury (SCI). Cardiac dysfunctions are common complications following SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. We reviewed epidemiology of cardiac disturbances after SCI, and neuroanatomy and pathophysiology of autonomic nervous system, sympathetic and parasympathetic. SCI causes disruption of descendent pathways from central control centers to spinal sympathetic neurons, originating into intermediolateral nuclei of T1–L2 spinal cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant cardiac dysfunction. Impairment of autonomic nervous control system, mostly in patients with cervical or high thoracic SCI, causes cardiac dysrrhythmias, especially bradycardia and, rarely, cardiac arrest, or tachyarrhytmias and hypotension. Specific complication dependent on the period of time after trauma like spinal shock and autonomic dysreflexia are also reviewed. Spinal shock occurs during the acute phase following SCI and is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe bradycardia and hypotension. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Besides all this, additional cardiac complications, such as cardiac deconditioning and coronary heart disease may also occur. Proper prophylaxis, including nonpharmacologic and pharmacological strategies and cardiac rehabilitation diminish occurrence of the cardiac dysfunction following SCI. Each type of cardiac disturbance requires specific treatment. PMID:20108532

A core review of temperature regimens and neuroprotection during cardiopulmonary bypass: does rewarming rate matter?

PubMed

Grigore, Alina M; Murray, Catherine Friederich; Ramakrishna, Harish; Djaiani, George

2009-12-01

Despite a half century of research and the implementation of various risk-reduction strategies among clinicians and basic scientists, patients continue to experience strokes and cognitive dysfunction related to the use of cardiopulmonary bypass (CPB) for cardiac surgery. One strategy to reduce these detrimental effects has been the use of hypothermia. Although numerous studies have addressed the issue, the question of whether the use of hypothermia during CPB attenuates the impact of central nervous system consequences remains unresolved. However, data clearly demonstrate that hyperthermia is to be avoided in the perioperative period, necessitating careful rewarming strategies if hypothermia is used during CPB. Selecting and understanding the impact of the temperature-monitoring site is important to accurately estimate cerebral temperature and to avoid inadvertent surges in brain temperature. In this article, we review the literature regarding the impact of hypothermia and rewarming rates during cardiac surgery.

Cardiac-Specific IGF-1 Receptor Transgenic Expression Protects Against Cardiac Fibrosis and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

PubMed Central

Huynh, Karina; McMullen, Julie R.; Julius, Tracey L.; Tan, Joon Win; Love, Jane E.; Cemerlang, Nelly; Kiriazis, Helen; Du, Xiao-Jun; Ritchie, Rebecca H.

2010-01-01

OBJECTIVE Compelling epidemiological and clinical evidence has identified a specific cardiomyopathy in diabetes, characterized by early diastolic dysfunction and adverse structural remodeling. Activation of the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) promotes physiological cardiac growth and enhances contractile function. The aim of the present study was to examine whether cardiac-specific overexpression of IGF-1R prevents diabetes-induced myocardial remodeling and dysfunction associated with a murine model of diabetes. RESEARCH DESIGN AND METHODS Type 1 diabetes was induced in 7-week-old male IGF-1R transgenic mice using streptozotocin and followed for 8 weeks. Diastolic and systolic function was assessed using Doppler and M-mode echocardiography, respectively, in addition to cardiac catheterization. Cardiac fibrosis and cardiomyocyte width, heart weight index, gene expression, Akt activity, and IGF-1R protein content were also assessed. RESULTS Nontransgenic (Ntg) diabetic mice had reduced initial (E)-to-second (A) blood flow velocity ratio (E:A ratio) and prolonged deceleration times on Doppler echocardiography compared with nondiabetic counterparts, indicative markers of diastolic dysfunction. Diabetes also increased cardiomyocyte width, collagen deposition, and prohypertrophic and profibrotic gene expression compared with Ntg nondiabetic littermates. Overexpression of the IGF-1R transgene markedly reduced collagen deposition, accompanied by a reduction in the incidence of diastolic dysfunction. Akt phosphorylation was elevated ∼15-fold in IGF-1R nondiabetic mice compared with Ntg, and this was maintained in a setting of diabetes. CONCLUSIONS The current study suggests that cardiac overexpression of IGF-1R prevented diabetes-induced cardiac fibrosis and diastolic dysfunction. Targeting IGF-1R–Akt signaling may represent a therapeutic target for the treatment of diabetic cardiac disease. PMID:20215428

Right ventricular dysfunction after resuscitation predicts poor outcomes in cardiac arrest patients independent of left ventricular function.

PubMed

Ramjee, Vimal; Grossestreuer, Anne V; Yao, Yuan; Perman, Sarah M; Leary, Marion; Kirkpatrick, James N; Forfia, Paul R; Kolansky, Daniel M; Abella, Benjamin S; Gaieski, David F

2015-11-01

Determination of clinical outcomes following resuscitation from cardiac arrest remains elusive in the immediate post-arrest period. Echocardiographic assessment shortly after resuscitation has largely focused on left ventricular (LV) function. We aimed to determine whether post-arrest right ventricular (RV) dysfunction predicts worse survival and poor neurologic outcome in cardiac arrest patients, independent of LV dysfunction. A single-center, retrospective cohort study at a tertiary care university hospital participating in the Penn Alliance for Therapeutic Hypothermia (PATH) Registry between 2000 and 2012. 291 in- and out-of-hospital adult cardiac arrest patients at the University of Pennsylvania who had return of spontaneous circulation (ROSC) and post-arrest echocardiograms. Of the 291 patients, 57% were male, with a mean age of 59 ± 16 years. 179 (63%) patients had LV dysfunction, 173 (59%) had RV dysfunction, and 124 (44%) had biventricular dysfunction on the initial post-arrest echocardiogram. Independent of LV function, RV dysfunction was predictive of worse survival (mild or moderate: OR 0.51, CI 0.26-0.99, p<0.05; severe: OR 0.19, CI 0.06-0.65, p=0.008) and neurologic outcome (mild or moderate: OR 0.33, CI 0.17-0.65, p=0.001; severe: OR 0.11, CI 0.02-0.50, p=0.005) compared to patients with normal RV function after cardiac arrest. Echocardiographic findings of post-arrest RV dysfunction were equally prevalent as LV dysfunction. RV dysfunction was significantly predictive of worse outcomes in post-arrest patients after accounting for LV dysfunction. Post-arrest RV dysfunction may be useful for risk stratification and management in this high-mortality population. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction.

PubMed

Lang, Hongmei; Xiang, Yang; Ai, Zhihua; You, Zhiqing; Jin, Xiaolan; Wan, Yong; Yang, Yongjian

2018-04-20

Excessive salt intake and left ventricular hypertrophy (LVH) are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3) plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. UCP3-/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. Elevated blood pressure was only observed in HS-fed UCP3-/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3-/- mice. However, the cardiac lesions were more profound in HS-fed UCP3-/- mice. Furthermore, HS-fed UCP3-/-mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high-salt-induced cardiac hypertrophy and cardiac dysfunction. © 2018 The Author(s). Published by S. Karger AG, Basel.

Folic acid prevents cardiac dysfunction and reduces myocardial fibrosis in a mouse model of high-fat diet-induced obesity.

PubMed

Li, Wei; Tang, Renqiao; Ouyang, Shengrong; Ma, Feifei; Liu, Zhuo; Wu, Jianxin

2017-01-01

Folic acid (FA) is an antioxidant that can reduce reactive oxygen species generation and can blunt cardiac dysfunction during ischemia. We hypothesized that FA supplementation prevents cardiac fibrosis and cardiac dysfunction induced by obesity. Six-week-old C57BL6/J mice were fed a high-fat diet (HFD), normal diet (ND), or an HFD supplemented with folic acid (FAD) for 14 weeks. Cardiac function was measured using a transthoracic echocardiographic exam. Phenotypic analysis included measurements of body and heart weight, blood glucose and tissue homocysteine (Hcy) content, and heart oxidative stress status. HFD consumption elevated fasting blood glucose levels and caused obesity and heart enlargement. FA supplementation in HFD-fed mice resulted in reduced fasting blood glucose, heart weight, and heart tissue Hcy content. We also observed a significant cardiac systolic dysfunction when mice were subjected to HFD feeding as indicated by a reduction in the left ventricular ejection fraction and fractional shortening. However, FAD treatment improved cardiac function. FA supplementation protected against cardiac fibrosis induced by HFD. In addition, HFD increased malondialdehyde concentration of the heart tissue and reduced the levels of antioxidant enzyme, glutathione, and catalase. HFD consumption induced myocardial oxidant stress with amelioration by FA treatment. FA supplementation significantly lowers blood glucose levels and heart tissue Hcy content and reverses cardiac dysfunction induced by HFD in mice. These functional improvements of the heart may be mediated by the alleviation of oxidative stress and myocardial fibrosis.

Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway.

PubMed

Jin, Sheng; Teng, Xu; Xiao, Lin; Xue, Hongmei; Guo, Qi; Duan, Xiaocui; Chen, Yuhong; Wu, Yuming

2017-12-01

Reductions in hydrogen sulfide (H 2 S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N ω -nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt max and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and dysfunction. The cardioprotective effects of NaHS were counteracted by Gli which inhibited the Akt/eNOS/NO pathway. This suggests that the effects of hydrogen sulfide were mediated by the activation of the K ATP channels. In conclusion, hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease via the activation of the Akt/eNOS/NO pathway, which was mediated by K ATP channels. Impact statement 1. We found that H 2 S ameliorated L-NAME-induced cardiac remodeling and dysfunction, and played a protective role in L-NAME-induced hypertensive heart disease, which the existing studies have not reported. 2. H 2 S activated the Akt/eNOS/NO pathway, thereby playing a cardioprotective role in L-NAME-induced hypertensive heart disease. 3. The cardioprotective effect of H 2 S was mediated by ATP-sensitive potassium channels.

α-Enolase plays a catalytically independent role in doxorubicin-induced cardiomyocyte apoptosis and mitochondrial dysfunction.

PubMed

Gao, Si; Li, Hong; Feng, Xiao-jun; Li, Min; Liu, Zhi-ping; Cai, Yi; Lu, Jing; Huang, Xiao-yang; Wang, Jiao-jiao; Li, Qin; Chen, Shao-rui; Ye, Jian-tao; Liu, Pei-qing

2015-02-01

α-Enolase is a glycolytic enzyme with "second jobs" beyond its catalytic activity. However, its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the role of α-enolase in doxorubicin (Dox)-induced cardiomyopathy as well as the underlying mechanisms. The expression of α-enolase was detected in rat hearts and primary cultured rat cardiomyocytes with or without Dox administration. An adenovirus carrying short-hairpin interfering RNA targeting α-enolase was constructed and transduced specifically into the heart by intramyocardial injection. Heart function, cell apoptosis and mitochondrial function were measured following Dox administration. In addition, by using gain- and loss-of-function approaches to regulate α-enolase expression in primary cultured rat cardiomyocytes, we investigated the role of endogenous, wide type and catalytically inactive mutant α-enolase in cardiomyocyte apoptosis and ATP generation. Furthermore, the involvement of α-enolase in AMPK phosphorylation was also studied. The mRNA and protein expression of cardiac α-enolase was significantly upregulated by Dox. Genetic silencing of α-enolase in rat hearts and cultured cardiomyocytes attenuated Dox-induced apoptosis and mitochondrial dysfunction. In contrast, overexpression of wide-type or catalytically inactive α-enolase in cardiomyocytes mimicked the detrimental role of Dox in inducing apoptosis and ATP reduction. AMPK dephosphorylation was further demonstrated to be involved in the proapoptotic and ATP-depriving effects of α-enolase. Our findings provided the evidence that α-enolase has a catalytically independent role in inducing cardiomyocyte apoptosis and mitochondrial dysfunction, which could be at least partially contributed to the inhibition of AMPK phosphorylation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cardiac Dysfunction and Oxidative Stress in the Metabolic Syndrome: an Update on Antioxidant Therapies

PubMed Central

Ilkun, Olesya; Boudina, Sihem

2013-01-01

The metabolic syndrome (MetS) is a cluster of risk factors including obesity, insulin resistance, dyslipidemia, elevated blood pressure and glucose intolerance. The MetS increases the risk for cardiovascular disease (CVD) and type 2 diabetes. Each component of the MetS causes cardiac dysfunction and their combination carries additional risk. The mechanisms underlying cardiac dysfunction in the MetS are complex and might include lipid accumulation, increased fibrosis and stiffness, altered calcium homeostasis, abnormal autophagy, altered substrate utilization, mitochondrial dysfunction and increased oxidative stress. Mitochondrial and extra-mitochondrial sources of reactive oxygen species (ROS) and reduced antioxidant defense mechanisms characterize the myocardium of humans and animals with the MetS. The mechanisms for increased cardiac oxidative stress in the MetS are not fully understood but include increased fatty acid oxidation, mitochondrial dysfunction and enhanced NADPH oxidase activity. Therapies aimed to reduce oxidative stress and enhance antioxidant defense have been employed to reduce cardiac dysfunction in the MetS in animals. In contrast, large scale clinical trials using antioxidants therapies for the treatment of CVD have been disappointing because of the lack of efficacy and undesired side effects. The focus of this review is to summarize the current knowledge about the mechanisms underlying cardiac dysfunction in the MetS with a special interest in the role of oxidative stress. Finally, we will update the reader on the results obtained with natural antioxidant and mitochondria-targeted antioxidant therapies for the treatment of CVD in the MetS. PMID:23323621

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

PubMed Central

Wu, Mei-ping; Zhang, Yi-shuai; Xu, Xiangbin; Zhou, Qian

2017-01-01

Purpose Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Methods Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. Results We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Conclusions Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling. PMID:28321644

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

PubMed

Wu, Mei-Ping; Zhang, Yi-Shuai; Xu, Xiangbin; Zhou, Qian; Li, Jian-Dong; Yan, Chen

2017-04-01

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ.

PubMed

Vergeade, Aurélia; Mulder, Paul; Vendeville-Dehaudt, Cathy; Estour, François; Fortin, Dominique; Ventura-Clapier, Renée; Thuillez, Christian; Monteil, Christelle

2010-09-01

The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. Copyright 2010 Elsevier Inc. All rights reserved.

Thioredoxin-1 attenuates sepsis-induced cardiomyopathy after cecal ligation and puncture in mice.

PubMed

Wilson, Rickesha L; Selvaraju, Vaithinathan; Lakshmanan, Rajesh; Thirunavukkarasu, Mahesh; Campbell, Jacob; McFadden, David W; Maulik, Nilanjana

2017-12-01

Sepsis is a leading cause of mortality among patients in intensive care units across the USA. Thioredoxin-1 (Trx-1) is an essential 12 kDa cytosolic protein that, apart from maintaining the cellular redox state, possesses multifunctional properties. In this study, we explored the possibility of controlling adverse myocardial depression by overexpression of Trx-1 in a mouse model of severe sepsis. Adult C57BL/6J and Trx-1 Tg/+ mice were divided into wild-type sham (WTS), wild-type cecal ligation and puncture (WTCLP), Trx-1 Tg/+ sham (Trx-1 Tg/+ S), and Trx-1 Tg/+ CLP groups. Cardiac function was evaluated before surgery, 6 and 24 hours after CLP surgery. Immunohistochemical and Western blot analysis were performed after 24 hours in heart tissue sections. Echocardiography analysis showed preserved cardiac function in the Trx-1 Tg/+ CLP group compared with the WTCLP group. Similarly, Western blot analysis revealed increased expression of Trx-1, heme oxygenase-1 (HO-1), survivin (an inhibitor of apoptosis [IAP] protein family), and decreased expression of thioredoxin-interacting protein (TXNIP), caspase-3, and 3- nitrotyrosine in the Trx-1 Tg/+ CLP group compared with the WTCLP group. Immunohistochemical analysis showed reduced 4-hydroxynonenal, apoptosis, and vascular leakage in the cardiac tissue of Trx-1 Tg/+ CLP mice compared with mice in the WTCLP group. Our results indicate that overexpression of Trx-1 attenuates cardiac dysfunction during CLP. The mechanism of action may involve reduction of oxidative stress, apoptosis, and vascular permeability through activation of Trx-1/HO-1 and anti-apoptotic protein survivin. Copyright © 2017 Elsevier Inc. All rights reserved.

Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway.

PubMed

Liu, Hui; Jing, Xibo; Dong, Aiqiao; Bai, Baobao; Wang, Haiyan

2017-01-01

Myocardial ischemia/reperfusion (I/R) injury remains a great challenge in clinical therapy. Tissue inhibitor of metalloproteinases 3 (TIMP3) plays a crucial role in heart physiological and pathophysiological processes. However, the effects of TIMP3 on I/R injury remain unknown. C57BL/6 mice were infected with TIMP3 adenovirus by local delivery in myocardium followed by I/R operation or doxorubicin treatment. Neonatal rat cardiomyocytes were pretreated with TIMP3 adenovirus prior to anoxia/reoxygenation (A/R) treatment in vitro. Histology, echocardiography, in vivo phenotypical analysis, flow cytometry and western blotting were used to investigate the altered cardiac function and underlying mechanisms. The results showed that upregulation of TIMP3 in myocardium markedly inhibited myocardial infarct areas and the cardiac dysfunction induced by I/R or by doxorubicin treatment. TUNEL staining revealed that TIMP3 overexpression attenuated I/R-induced myocardial apoptosis, accompanied by decreased Bax/Bcl-2 ratio, Cleaved Caspase-3 and Cleaved Caspase-9 expression. In vitro, A/R-induced cardiomyocyte apoptosis was abrogated by pharmacological inhibition of reactive oxygen species (ROS) production or MAPKs signaling. Attenuation of ROS production reversed A/R-induced MAPKs activation, whereas MAPKs inhibitors showed on effect on ROS production. Furthermore, in vivo or in vitro overexpression of TIMP3 significantly inhibited I/R- or A/R-induced ROS production and MAPKs activation. Our findings demonstrate that TIMP3 upregulation protects against cardiac I/R injury through inhibiting myocardial apoptosis. The mechanism may be related to inhibition of ROS-initiated MAPKs pathway. This study suggests that TIMP3 may be a potential therapeutic target for the treatment of I/R injury. © 2017 The Author(s). Published by S. Karger AG, Basel.

Cellular apoptosis and cardiac dysfunction in STZ-induced diabetic rats attenuated by anthocyanins via activation of IGFI-R/PI3K/Akt survival signaling.

PubMed

Huang, Pei-Chen; Wang, Guei-Jane; Fan, Ming-Jen; Asokan Shibu, Marthandam; Liu, Yin-Tso; Padma Viswanadha, Vijaya; Lin, Yi-Lin; Lai, Chao-Hung; Chen, Yu-Feng; Liao, Hung-En; Huang, Chih-Yang

2017-12-01

Anthocyanins are known cyto-protective agents against various stress conditions. In this study cardio-protective effect of anthocyanins from black rice against diabetic mellitus (DM) was evaluated using a streptozotocin (STZ)-induced DM rat model. Five-week-old male Wistar rats were administered with STZ (55 mg kg -1 , IP) to induce DM; rats in the treatment group received 250 mg oral anthocyanin/kg/day during the 4-week treatment period. DM and the control rats received normal saline through oral gavage. The results reveal that STZ-induced DM elevates myocardial apoptosis and associated proapoptotic proteins but down-regulates the proteins of IGF1R mediated survival signaling mechanism. Furthermore, the functional parameters such as the ejection-fraction and fraction-shortening in the DM rat hearts declined considerably. However, the rats treated with anthocyanins significantly reduced apoptosis and the associated proapoptotic proteins and further increased the survival signals to restore the cardiac functions in DM rats. Anthocyanin supplementation enhances cardiomyocyte survival and restores cardiac function. © 2017 Wiley Periodicals, Inc.

MitoQ administration prevents endotoxin-induced cardiac dysfunction

PubMed Central

Murphy, M. P.; Callahan, L. A.

2009-01-01

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6′-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg·kg−1·day−1), saline + MitoQ (500 μM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction. PMID:19657095

MitoQ administration prevents endotoxin-induced cardiac dysfunction.

PubMed

Supinski, G S; Murphy, M P; Callahan, L A

2009-10-01

Sepsis elicits severe alterations in cardiac function, impairing cardiac mitochondrial and pressure-generating capacity. Currently, there are no therapies to prevent sepsis-induced cardiac dysfunction. We tested the hypothesis that administration of a mitochondrially targeted antioxidant, 10-(6'-ubiquinonyl)-decyltriphenylphosphonium (MitoQ), would prevent endotoxin-induced reductions in cardiac mitochondrial and contractile function. Studies were performed on adult rodents (n = 52) given either saline, endotoxin (8 mg x kg(-1) x day(-1)), saline + MitoQ (500 microM), or both endotoxin and MitoQ. At 48 h animals were killed and hearts were removed for determination of either cardiac mitochondrial function (using polarography) or cardiac pressure generation (using the Langendorf technique). We found that endotoxin induced reductions in mitochondrial state 3 respiration rates, the respiratory control ratio, and ATP generation. Moreover, MitoQ administration prevented each of these endotoxin-induced abnormalities, P < 0.001. We also found that endotoxin produced reductions in cardiac pressure-generating capacity, reducing the systolic pressure-diastolic relationship. MitoQ also prevented endotoxin-induced reductions in cardiac pressure generation, P < 0.01. One potential link between mitochondrial and contractile dysfunction is caspase activation; we found that endotoxin increased cardiac levels of active caspases 9 and 3 (P < 0.001), while MitoQ prevented this increase (P < 0.01). These data demonstrate that MitoQ is a potent inhibitor of endotoxin-induced mitochondrial and cardiac abnormalities. We speculate that this agent may prove a novel therapy for sepsis-induced cardiac dysfunction.

Cardiovascular dysfunction following spinal cord injury

PubMed Central

Partida, Elizabeth; Mironets, Eugene; Hou, Shaoping; Tom, Veronica J.

2016-01-01

Both sensorimotor and autonomic dysfunctions often occur after spinal cord injury (SCI). Particularly, a high thoracic or cervical SCI interrupts supraspinal vasomotor pathways and results in disordered hemodynamics due to deregulated sympathetic outflow. As a result of the reduced sympathetic activity, patients with SCI may experience hypotension, cardiac dysrhythmias, and hypothermia post-injury. In the chronic phase, changes within the CNS and blood vessels lead to orthostatic hypotension and life-threatening autonomic dysreflexia (AD). AD is characterized by an episodic, massive sympathetic discharge that causes severe hypertension associated with bradycardia. The syndrome is often triggered by unpleasant visceral or sensory stimuli below the injury level. Currently the only treatments are palliative – once a stimulus elicits AD, pharmacological vasodilators are administered to help reduce the spike in arterial blood pressure. However, a more effective means would be to mitigate AD development by attenuating contributing mechanisms, such as the reorganization of intraspinal circuits below the level of injury. A better understanding of the neuropathophysiology underlying cardiovascular dysfunction after SCI is essential to better develop novel therapeutic approaches to restore hemodynamic performance. PMID:27073353

Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging.

PubMed

Zhang, Yingmei; Wang, Cong; Zhou, Jingmin; Sun, Aijun; Hueckstaedt, Lindsay K; Ge, Junbo; Ren, Jun

2017-08-01

Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a cascade of biological processes including aging. A number of autophagy regulators have been identified. Here we demonstrated that mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with the most common single point mutation in humans, governs cardiac aging through regulation of autophagy. Myocardial mechanical and autophagy properties were examined in young (4months) and old (26-28months) wild-type (WT) and global ALDH2 transgenic mice. ALDH2 overexpression shortened lifespan by 7.7% without affecting aging-associated changes in plasma metabolic profiles. Myocardial function was compromised with aging associated with cardiac hypertrophy, the effects were accentuated by ALDH2. Aging overtly suppressed autophagy and compromised autophagy flux, the effects were exacerbated by ALDH2. Aging dampened phosphorylation of JNK, Bcl-2, IKKβ, AMPK and TSC2 while promoting phosphorylation of mTOR, the effects of which were exaggerated by ALDH2. Co-immunoprecipitation revealed increased dissociation between Bcl-2 and Beclin-1 (result of decreased Bcl-2 phosphorylation) in aging, the effect of which was exacerbated with ALDH2. Chronic treatment of the autophagy inducer rapamycin alleviated aging-induced cardiac dysfunction in both WT and ALDH2 mice. Moreover, activation of JNK and inhibition of either Bcl-2 or IKKβ overtly attenuated ALDH2 activation-induced accentuation of cardiomyocyte aging. Examination of the otherwise elderly individuals revealed a positive correlation between cardiac function/geometry and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may suppress myocardial autophagy possibly through a complex JNK-Bcl-2 and IKKβ-AMPK-dependent mechanism en route to accentuation of myocardial remodeling and contractile dysfunction in aging. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang. Copyright © 2017 Elsevier B.V. All rights reserved.

Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy.

PubMed

Bahrudin, Udin; Morisaki, Hiroko; Morisaki, Takayuki; Ninomiya, Haruaki; Higaki, Katsumi; Nanba, Eiji; Igawa, Osamu; Takashima, Seiji; Mizuta, Einosuke; Miake, Junichiro; Yamamoto, Yasutaka; Shirayoshi, Yasuaki; Kitakaze, Masafumi; Carrier, Lucie; Hisatome, Ichiro

2008-12-26

The ubiquitin-proteasome system is responsible for the disappearance of truncated cardiac myosin-binding protein C, and the suppression of its activity contributes to cardiac dysfunction. This study investigated whether missense cardiac myosin-binding protein C gene (MYBPC3) mutation in hypertrophic cardiomyopathy (HCM) leads to destabilization of its protein, causes UPS impairment, and is associated with cardiac dysfunction. Mutations were identified in Japanese HCM patients using denaturing HPLC and sequencing. Heterologous expression was investigated in COS-7 cells as well as neonatal rat cardiac myocytes to examine protein stability and proteasome activity. The cardiac function was measured using echocardiography. Five novel MYBPC3 mutations -- E344K, DeltaK814, Delta2864-2865GC, Q998E, and T1046M -- were identified in this study. Compared with the wild type and other mutations, the E334K protein level was significantly lower, it was degraded faster, it had a higher level of polyubiquination, and increased in cells pretreated with the proteasome inhibitor MG132 (50 microM, 6 h). The electrical charge of its amino acid at position 334 influenced its stability, but E334K did not affect its phosphorylation. The E334K protein reduced cellular 20 S proteasome activity, increased the proapoptotic/antiapoptotic protein ratio, and enhanced apoptosis in transfected Cos-7 cells and neonatal rat cardiac myocytes. Patients carrying the E334K mutation presented significant left ventricular dysfunction and dilation. The conclusion is the missense MYBPC3 mutation E334K destabilizes its protein through UPS and may contribute to cardiac dysfunction in HCM through impairment of the ubiquitin-proteasome system.

Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction

PubMed Central

2014-01-01

Introduction Elevated midkine (MK) expression may contribute to ventricular remodeling and ameliorate cardiac dysfunction after myocardial infarction (MI). Ex vivo modification of signaling mechanisms in mesenchymal stem cells (MSCs) with MK overexpression may improve the efficacy of cell-based therapy. This study sought to assess the safety and efficacy of MSCs with MK overexpression transplantation in a rat model of MI. Methods A pLenO-DCE vector lentivirus encoding MK was constructed and infected in MSCs. MSC migration activity and cytoprotection was examined in hypoxia-induced H9C2 cells using transwell insert in vitro. Rats were randomized into five groups: sham, MI plus injection of phosphate buffered saline (PBS), MSCs, MSCs-green fluorescent protein (MSCs-GFP) and MSCs-MK, respectively. Survival rates were compared among groups using log-rank test and left ventricular function was measured by echocardiography at baseline, 4, 8 and 12 weeks. Results Overexpression of MK partially prevented hypoxia-induced MSC apoptosis and exerted MSC cytoprotection to anoxia induced H9C2 cells. The underlying mechanisms may be associated with the increased mRNA and protein levels of vascular endothelial growth factor (VEGF), transformation growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and stromal cell-derived factor 1 (SDF-1a) in MSCs-MK compared with isolated MSCs and MSCs-GFP. Consistent with the qPCR results, the culture supernatant of MSCs-MK had more SDF-1a (9.23 ng/ml), VEGF (8.34 ng/ml) and TGF-β1 (17.88 ng/ml) expression. In vivo, a greater proportion of cell survival was observed in the MSCs-MK group than in the MSCs-GFP group. Moreover, MSCs-MK administration was related to a significant improvement of cardiac function compared with other control groups at 12 weeks. Conclusions Therapies employing MSCs with MK overexpression may represent an effective treatment for improving cardiac dysfunction and survival rate after MI. PMID:24635859

Cardiac DPP-4 inhibition by saxagliptin ameliorates isoproterenol-induced myocardial remodeling and cardiac diastolic dysfunction in rats.

PubMed

Ikeda, Junichi; Kimoto, Naoya; Kitayama, Tetsuya; Kunori, Shunji

2016-09-01

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure. Copyright © 2016 Kyowa Hakko Kirin Co.,Ltd. Production and hosting by Elsevier B.V. All rights reserved.

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

PubMed Central

Perry, Marie-Claude; Dufour, Catherine R.; Eichner, Lillian J.; Tsang, David W. K.; Deblois, Geneviève; Muller, William J.

2014-01-01

The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction. PMID:25246633

Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Xiao-Jing; Zhang, Dong-Mei; Jia, Lin-Lin

We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocytemore » diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines. • PVN inhibition of NF-κB attenuates PVN NF-κB p65 activity and oxidative stress.« less

The GSK-3 family as therapeutic target for myocardial diseases

PubMed Central

Lal, Hind; Ahmad, Firdos; Woodgett, James; Force, Thomas

2014-01-01

GSK-3 is one of the very few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in a number of diseases including heart failure, bipolar disorder, diabetes, Alzheimer’s disease, aging, inflammation and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review we will focus on its expanding role in the heart, concentrating primarily on recent studies that have employed cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction post-MI by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3β as a regulator of myocardial fibrosis will also be discussed. We will review our very recent findings that specific deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3β is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature. PMID:25552693

Role of adenosine A{sub 2A} receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; El-gowilly, Sahar M.; Fouda, Mohamed A.

Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16 {mu}g/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100 {mu}g/kg i.v.) dose-dependently reduced BRS{sub SNP} in contrast to no effect on BRS{submore » PE}. BRS{sub SNP} was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS{sub SNP} were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS{sub SNP} was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A{sub 2A} antagonist), or VUF5574 (A{sub 3} antagonist). In contrast, BRS{sub SNP} was preserved after blockade of A{sub 1} (DPCPX) or A{sub 2B} (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS{sub SNP} depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A{sub 2A} receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms. - Research Highlights: > The role of central adenosinergic sites in the nicotine-baroreflex interaction was investigated. > Inhibition of reflex sympathoinhibition mediates the BRS depressant action of nicotine. > Nicotine preferentially impairs reflex tachycardia via disruption of adenosine A{sub 2A} signaling. > The attenuation by nicotine of reflex sympathetic activity is clinically important.« less

Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels.

PubMed

Bidasee, Keshore R; Nallani, Karuna; Yu, Yongqi; Cocklin, Ross R; Zhang, Yinong; Wang, Mu; Dincer, U Deniz; Besch, Henry R

2003-07-01

Decrease in cardiac contractility is a hallmark of chronic diabetes. Previously we showed that this defect results, at least in part, from a dysfunction of the type 2 ryanodine receptor calcium-release channel (RyR2). The mechanism(s) underlying RyR2 dysfunction is not fully understood. The present study was designed to determine whether non-cross-linking advanced glycation end products (AGEs) on RyR2 increase with chronic diabetes and if formation of these post-translational complexes could be attenuated with insulin treatment. Overnight digestion of RyR2 from 8-week control animals (8C) with trypsin afforded 298 peptides with monoisotopic mass (M+H(+)) >or=500. Digestion of RyR2 from 8-week streptozotocin-induced diabetic animals (8D) afforded 21% fewer peptides, whereas RyR2 from 6-week diabetic/2-week insulin-treated animals generated 304 peptides. Using an in-house PERLscript algorithm, search of matrix-assisted laser desorption ionization-time of flight mass data files identified several M+H(+) peaks corresponding to theoretical RyR2 peptides with single N(epsilon)-(carboxymethyl)-lysine, imidazolone A, imidazone B, pyrraline, or 1-alkyl-2-formyl-3,4-glycosyl pyrrole modification that were present in 8D but not 8C. Insulin treatment minimized production of some of these nonenzymatic glycation products. These data show for the first time that AGEs are formed on intracellular RyR2 during diabetes. Because AGE complexes are known to compromise protein activity, these data suggest a potential mechanism for diabetes-induced RyR2 dysfunction.

Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet.

PubMed

Epp, Riley A; Susser, Shanel E; Morissette, Marc P; Kehler, D Scott; Jassal, Davinder S; Duhamel, Todd A

2013-01-01

This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum Ca(2 +)-transport proteins in the low-dose streptozotocin-induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague-Dawley rats (4 weeks old; 125-150 g) were made diabetic using a high-fat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg·(kg body mass)(-1)) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 ± 338 m·day(-1) of voluntary wheel running (mean ± SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 ± 29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 ± 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (-dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity (V(max)) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes.

Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction.

PubMed

Wang, Jiaxing; Lu, Songhe; Zheng, Qijun; Hu, Nan; Yu, Wenjun; Li, Na; Liu, Min; Gao, Beilei; Zhang, Guoyong; Zhang, Yingmei; Wang, Haichang

2016-07-01

Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteins for biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.

Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes*

PubMed Central

Xu, Xianmin; Kobayashi, Satoru; Chen, Kai; Timm, Derek; Volden, Paul; Huang, Yuan; Gulick, James; Yue, Zhenyu; Robbins, Jeffrey; Epstein, Paul N.; Liang, Qiangrong

2013-01-01

Cardiac autophagy is inhibited in type 1 diabetes. However, it remains unknown if the reduced autophagy contributes to the pathogenesis of diabetic cardiomyopathy. We addressed this question using mouse models with gain- and loss-of-autophagy. Autophagic flux was inhibited in diabetic hearts when measured at multiple time points after diabetes induction by streptozotocin as assessed by protein levels of microtubule-associated protein light chain 3 form 2 (LC3-II) or GFP-LC3 puncta in the absence and presence of the lysosome inhibitor bafilomycin A1. Autophagy in diabetic hearts was further reduced in beclin 1- or Atg16-deficient mice but was restored partially or completely by overexpression of beclin 1 to different levels. Surprisingly, diabetes-induced cardiac damage was substantially attenuated in beclin 1- and Atg16-deficient mice as shown by improved cardiac function as well as reduced levels of oxidative stress, interstitial fibrosis, and myocyte apoptosis. In contrast, diabetic cardiac damage was dose-dependently exacerbated by beclin 1 overexpression. The cardioprotective effects of autophagy deficiency were reproduced in OVE26 diabetic mice. These effects were associated with partially restored mitophagy and increased expression and mitochondrial localization of Rab9, an essential regulator of a non-canonical alternative autophagic pathway. Together, these findings demonstrate that the diminished autophagy is an adaptive response that limits cardiac dysfunction in type 1 diabetes, presumably through up-regulation of alternative autophagy and mitophagy. PMID:23658055

Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response

PubMed Central

Grogan, Martha; Dispenzieri, Angela; Gertz, Morie A

2017-01-01

Amyloid light chain (AL) amyloidosis is a systemic disease characterised by the aggregation of misfolded immunoglobulin light chain (LC), predominantly in the heart and kidneys, causing organ failure. If untreated, the median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Protracted time to establish a diagnosis, often lasting >1 year, is a frequent factor in poor treatment outcomes. Cardiologists, to whom patients are often referred, frequently miss the opportunity to diagnose cardiac AL amyloidosis. Nearly all typical cardiac support measures, with the exception of diuretics, are ineffective and may even worsen clinical symptoms, emphasising the need for accurate diagnosis. Patients with severe cardiac involvement face poor outcomes; heart transplantation is rarely an option because of multiorgan involvement, rapid clinical decline and challenges in predicting which patients will respond to treatment of the underlying plasma cell disorder. Early diagnosis and prompt treatment with ‘source therapies’ that limit the production of amyloidogenic LC are associated with better survival and improvement in organ function after a median of 2.4 months following haematological complete response. However, organ recovery is often incomplete because these source therapies do not directly target deposited amyloid. Emerging amyloid-directed therapies may attenuate, and potentially reverse, organ dysfunction by clearing existing amyloid and inhibiting fibril formation of circulating aggregates. Improved recognition of AL amyloidosis by cardiologists allows for earlier treatment and improved outcomes. PMID:28456755

Interferon Regulatory Factor 7 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

PubMed Central

Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng; Zhang, Yan; Zhang, Xiao-Dong; Zhang, Xiao-Fei; Chen, Ke; Gao, Lu; Peng, Juan; Gong, Hui; Chen, Yingjie; Yang, Qinglin; Liu, Peter P.; Fan, Guo-Chang; Zou, Yunzeng; Li, Hongliang

2017-01-01

Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBαS32A/S36A super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-βS177E/S181E (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy. PMID:24396025

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

PubMed Central

Ng, Hooi Hooi; Leo, Chen Huei; Prakoso, Darnel; Qin, Chengxue; Ritchie, Rebecca H.; Parry, Laura J.

2017-01-01

Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis. PMID:28067255

Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension

PubMed Central

Iliescu, Radu; Tudorancea, Ionut; Irwin, Eric D.

2013-01-01

The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation—current therapies in patients with resistant hypertension, who are commonly obese—restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1–4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and <20%, respectively, of control levels. Subsequently, both baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure. PMID:23913707

Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension.

PubMed

Fowler, Ewan D; Drinkhill, Mark J; Norman, Ruth; Pervolaraki, Eleftheria; Stones, Rachel; Steer, Emma; Benoist, David; Steele, Derek S; Calaghan, Sarah C; White, Ed

2018-07-01

Right heart failure is the major cause of death in Pulmonary Artery Hypertension (PAH) patients but is not a current, specific therapeutic target. Pre-clinical studies have shown that adrenoceptor blockade can improve cardiac function but the mechanisms of action within right ventricular (RV) myocytes are unknown. We tested whether the β 1 -adrenoceptor blocker metoprolol could improve RV myocyte function in an animal model of PAH, by attenuating adverse excitation-contraction coupling remodeling. PAH with RV failure was induced in rats by monocrotaline injection. When PAH was established, animals were given 10 mg/kg/day metoprolol (MCT + BB) or vehicle (MCT). The median time to the onset of heart failure signs was delayed from 23 days (MCT), to 31 days (MCT + BB). At 23 ± 1 days post-injection, MCT + BB showed improved in vivo cardiac function, measured by echocardiography. RV hypertrophy was reduced despite persistent elevated afterload. RV myocyte contractility during field stimulation was improved at higher pacing frequencies in MCT + BB. Preserved t-tubule structure, more uniform evoked Ca 2+ release, increased SERCA2a expression and faster ventricular repolarization (measured in vivo by telemetry) may account for the improved contractile function. Sarcoplasmic reticulum Ca 2+ overload was prevented in MCT + BB myocytes resulting in fewer spontaneous Ca 2+ waves, with a lower pro-arrhythmic potential. Our novel finding of attenuation of defects in excitation contraction coupling by β 1 -adrenoceptor blockade with delays in the onset of HF, identifies the RV as a promising therapeutic target in PAH. Moreover, our data suggest existing therapies for left ventricular failure may also be beneficial in PAH induced RV failure. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Milrinone ameliorates cardiac mechanical dysfunction after hypothermia in an intact rat model.

PubMed

Dietrichs, Erik Sveberg; Kondratiev, Timofei; Tveita, Torkjel

2014-12-01

Rewarming from hypothermia is often complicated by cardiac dysfunction, characterized by substantial reduction in stroke volume. Previously we have reported that inotropic agents, working via cardiac β-receptor agonism may exert serious side effects when applied to treat cardiac contractile dysfunction during rewarming. In this study we tested whether Milrinone, a phosphodiesterase III inhibitor, is able to ameliorate such dysfunction when given during rewarming. A rat model designed for circulatory studies during experimental hypothermia with cooling to a core temperature of 15°C, stable hypothermia at this temperature for 3h and subsequent rewarming was used, with a total of 3 groups: (1) a normothermic group receiving Milrinone, (2) a hypothermic group receiving Milrinone the last hour of hypothermia and during rewarming, and (3) a hypothermic saline control group. Hemodynamic function was monitored using a conductance catheter introduced to the left ventricle. After rewarming from 15°C, stroke volume and cardiac output returned to within baseline values in Milrinone treated animals, while these variables were significantly reduced in saline controls. Milrinone ameliorated cardiac dysfunction during rewarming from 15°C. The present results suggest that at low core temperatures and during rewarming from such temperatures, pharmacologic efforts to support cardiovascular function is better achieved by substances preventing cyclic AMP breakdown rather than increasing its formation via β-receptor stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation

PubMed Central

Li, Wenju; Li, Xiaoli; Zheng, Qiangsun; Niu, Xiaolin

2017-01-01

Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson’s trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway. PMID:28622359

Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via β3-AR-nNOS-NO activation.

PubMed

Wang, Bin; Xu, Ming; Li, Wenju; Li, Xiaoli; Zheng, Qiangsun; Niu, Xiaolin

2017-01-01

Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson's trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway.

A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design.

PubMed

Zangrillo, Alberto; Alvaro, Gabriele; Pisano, Antonio; Guarracino, Fabio; Lobreglio, Rosetta; Bradic, Nikola; Lembo, Rosalba; Gianni, Stefano; Calabrò, Maria Grazia; Likhvantsev, Valery; Grigoryev, Evgeny; Buscaglia, Giuseppe; Pala, Giovanni; Auci, Elisabetta; Amantea, Bruno; Monaco, Fabrizio; De Vuono, Giovanni; Corcione, Antonio; Galdieri, Nicola; Cariello, Claudia; Bove, Tiziana; Fominskiy, Evgeny; Auriemma, Stefano; Baiocchi, Massimo; Bianchi, Alessandro; Frontini, Mario; Paternoster, Gianluca; Sangalli, Fabio; Wang, Chew-Yin; Zucchetti, Maria Chiara; Biondi-Zoccai, Giuseppe; Gemma, Marco; Lipinski, Michael J; Lomivorotov, Vladimir V; Landoni, Giovanni

2016-07-01

Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. Double-blind, placebo-controlled, multicenter randomized trial. Tertiary care hospitals. Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours. The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement.

PubMed

Hao, Yuanyuan; Lu, Qun; Yang, Guodong; Ma, Aiqun

2016-10-28

Myocardial remodeling and cardiac dysfunction prevention may represent a therapeutic approach to reduce mortality in patients with myocardial infarction (MI). We investigated the effects of Lin28a in experimental MI models, as well as the mechanisms underlying these effects. Left anterior descending (LAD) coronary artery ligation was used to construct an MI-induced injury model. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of Lin28a against MI-induced injury. Lin28a significantly inhibited left ventricular remodeling and cardiac dysfunction after MI, as demonstrated via echocardiography and hemodynamic measurements. Lin28a reduced cardiac enzyme and inflammatory marker release in mice subjected to MI-induced injury. The mechanisms underlying the protective effects of Lin28a against MI-induced injury were associated with autophagy enhancements and apoptosis inhibition. Consistent with these findings, Lin28a knockdown aggravated cardiac remodeling and dysfunction after MI-induced injury. Lin28a knockdown also inhibited cardiomyocyte autophagy and increased cardiomyocyte apoptosis in mice subjected to MI-induced injury. Interestingly, Sirt1 knockdown abolished the protective effects of Lin28a against cardiac remodeling and dysfunction after MI, and Lin28a failed to increase the numbers of GFP-LC3-positive punctae and decrease aggresome and p62 accumulation in Sirt1-knockdown neonatal cardiomyocytes subjected to hypoxia-induced injury. Lin28a inhibits cardiac remodeling, improves cardiac function, and reduces cardiac enzyme and inflammatory marker release after MI. Lin28a also up-regulates cardiomyocyte autophagy and inhibits cardiomyocyte apoptosis through Sirt1 activation. Copyright © 2016 Elsevier Inc. All rights reserved.

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

PubMed

Hinze, Florian; Dieterich, Christoph; Radke, Michael H; Granzier, Henk; Gotthardt, Michael

2016-12-01

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction

PubMed Central

Pavillard, Luís E.; Cañadas-Lozano, Diego; Alcocer-Gómez, Elísabet; Marín-Aguilar, Fabiola; Pereira, Sheila; Robertson, Avril A.B.; Muntané, Jordi; Ryffel, Bernhard; Cooper, Matthew A.; Quiles, José L.; Bullón, Pedro; Ruiz-Cabello, Jesús; Cordero, Mario D.

2017-01-01

The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases. PMID:29245937

NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction.

PubMed

Pavillard, Luís E; Cañadas-Lozano, Diego; Alcocer-Gómez, Elísabet; Marín-Aguilar, Fabiola; Pereira, Sheila; Robertson, Avril A B; Muntané, Jordi; Ryffel, Bernhard; Cooper, Matthew A; Quiles, José L; Bullón, Pedro; Ruiz-Cabello, Jesús; Cordero, Mario D

2017-11-21

The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases.

Red Ginseng (Panax ginseng) Decreases Isoproterenol-Induced Cardiac Injury via Antioxidant Properties in Porcine

PubMed Central

Lim, Kyu Hee; Cho, Jae Youl; Kim, Bumseok; Bae, Bong-Seuk

2014-01-01

Abstract Red ginseng (RG, Panax ginseng) has been shown to possess various ginsenosides. These ginsenosides are widely used for treating cardiovascular diseases in Asian communities. The present study was designed to evaluate the cardioprotective potential of RG against isoproterenol (ISO)-induced myocardial infarction (MI), by assessing electrocardiographic, hemodynamic, and biochemical parameters. Male porcines were orally administered with RG (250 and 500 mg/kg) or with vehicle for 9 days, with concurrent intraperitoneal injections of ISO (20 mg/kg) on the 8th and 9th day. RG significantly attenuated ISO-induced cardiac dysfunctions as evidenced by improved ventricular hemodynamic functions and reduced ST segment and QRS complex intervals. Also, RG significantly ameliorated myocardial injury parameters such as antioxidants. Malonaldialdehyde formation was also inhibited by RG. Based on the results, it is concluded that RG possesses significant cardioprotective potential through the inhibition of oxidative stress and may serve as an adjunct in the treatment and prophylaxis of MI. PMID:24456361

The Correlation of Skeletal and Cardiac Muscle Dysfunction in Duchenne Muscular Dystrophy.

PubMed

Posner, Andrew D; Soslow, Jonathan H; Burnette, W Bryan; Bian, Aihua; Shintani, Ayumi; Sawyer, Douglas B; Markham, Larry W

2016-01-01

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle and cardiac dysfunction. While skeletal muscle dysfunction precedes cardiomyopathy, the relationship between the progressive decline in skeletal and cardiac muscle function is unclear. This relationship is especially important given that the myocardial effects of many developing DMD therapies are largely unknown. Our objective was to assess the relationship between progression of skeletal muscle weakness and onset of cardiac dysfunction in DMD. A total of 77 DMD subjects treated at a single referral center were included. Demographic information, quantitative muscle testing (QMT), subjective muscle strength, cardiac function, and current and retrospective medications were collected. A Spearman rank correlation was used to evaluate for an association between subjective strength and fractional shortening. The effects of total QMT and arm QMT on fractional shortening were examined in generalized least square with and without adjustments for age, ambulatory status, and duration of corticosteroids and cardiac specific medications. We found a significant correlation between maintained subjective skeletal muscle arm and leg strength and maintained cardiac function as defined by fractional shortening (rho=0.47, p=0.004 and rho=0.48, p=0.003, respectively). We also found a significant association between QMT and fractional shortening among non-ambulatory DMD subjects (p=0.03), while this association was not significant in ambulatory subjects. Our findings allow us to conclude that in this population, there exists a significant relationship between skeletal muscle and cardiac function in non-ambulatory DMD patients. While this does not imply a causal relationship, a possible association between skeletal and cardiac muscle function suggests that researchers should carefully monitor cardiac function, even when the primary outcome measures are not cardiac in nature.

Quantitative cardiac SPECT reconstruction with reduced image degradation due to patient anatomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsui, B.M.W.; Zhao, X.D.; Gregoriou, G.K.

1994-12-01

Patient anatomy has complicated effects on cardiac SPECT images. The authors investigated reconstruction methods which substantially reduced these effects for improved image quality. A 3D mathematical cardiac-torso (MCAT) phantom which models the anatomical structures in the thorax region were used in the study. The phantom was modified to simulate variations in patient anatomy including regions of natural thinning along the myocardium, body size, diaphragmatic shape, gender, and size and shape of breasts for female patients. Distributions of attenuation coefficients and Tl-201 uptake in different organs in a normal patient were also simulated. Emission projection data were generated from the phantomsmore » including effects of attenuation and detector response. The authors have observed the attenuation-induced artifacts caused by patient anatomy in the conventional FBP reconstructed images. Accurate attenuation compensation using iterative reconstruction algorithms and attenuation maps substantially reduced the image artifacts and improved quantitative accuracy. They conclude that reconstruction methods which accurately compensate for non-uniform attenuation can substantially reduce image degradation caused by variations in patient anatomy in cardiac SPECT.« less

The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery.

PubMed

Shahin, Jason; DeVarennes, Benoit; Tse, Chun Wing; Amarica, Dan-Alexandru; Dial, Sandra

2011-07-07

Acute haemodynamic complications are common after cardiac surgery and optimal perioperative use of inotropic agents, typically guided by haemodynamic variables, remains controversial. The aim of this study was to examine the relationship of inotrope use to hospital mortality and renal dysfunction. A retrospective cohort study of 1,326 cardiac surgery patients was carried out at two university-affiliated ICUs. Multivariable logistic regression analysis and propensity matching were performed to evaluate whether inotrope exposure was independently associated with mortality and renal dysfunction. Patients exposed to inotropes had a higher mortality rate than those not exposed. After adjusting for differences in Parsonnet score, left ventricular ejection fraction, perioperative intraaortic balloon pump use, bypass time, reoperation and cardiac index, inotrope exposure appeared to be independently associated with increased hospital mortality (adjusted odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.2 to 4.5) and renal dysfunction (adjusted OR 2.7, 95% CI 1.5 to 4.6). A propensity score-matched analysis similarly demonstrated that death and renal dysfunction were significantly more likely to occur in patients exposed to inotropes (P = 0.01). Postoperative inotrope exposure was independently associated with worse outcomes in this cohort study. Further research is needed to better elucidate the appropriate use of inotropes in cardiac surgery.

Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

PubMed Central

Yamaguchi, Osamu; Watanabe, Tetsuya; Nishida, Kazuhiko; Kashiwase, Kazunori; Higuchi, Yoshiharu; Takeda, Toshihiro; Hikoso, Shungo; Hirotani, Shinichi; Asahi, Michio; Taniike, Masayuki; Nakai, Atsuko; Tsujimoto, Ikuko; Matsumura, Yasushi; Miyazaki, Jun-ichi; Chien, Kenneth R.; Matsuzawa, Atsushi; Sadamitsu, Chiharu; Ichijo, Hidenori; Baccarini, Manuela; Hori, Masatsugu; Otsu, Kinya

2004-01-01

The Raf/MEK/extracellular signal–regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle–specific Raf-1–knockout (Raf CKO) mice with Cre-loxP–mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal–regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK–independent mechanism. PMID:15467832

Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions.

PubMed

Hamo, Carine E; Bloom, Michelle W; Cardinale, Daniela; Ky, Bonnie; Nohria, Anju; Baer, Lea; Skopicki, Hal; Lenihan, Daniel J; Gheorghiade, Mihai; Lyon, Alexander R; Butler, Javed

2016-02-01

Success with oncologic treatment has allowed cancer patients to experience longer cancer-free survival gains. Unfortunately, this success has been tempered by unintended and often devastating cardiac complications affecting overall patient outcomes. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction and cardiomyopathy, is an issue of growing concern. Although the pathophysiologic mechanisms behind cardiac toxicity have been characterized, there is currently no evidence-based approach for monitoring and management of these patients. In the first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In this second part, we discuss the prevention and treatment aspects in these patients and conclude with highlighting the evidence gaps and future directions for research in this area. © 2016 American Heart Association, Inc.

Cirrhotic cardiomyopathy

PubMed Central

Ruiz-del-Árbol, Luis; Serradilla, Regina

2015-01-01

During the course of cirrhosis, there is a progressive deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to a failure in heart function with decreased cardiac output. This is due to a deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy in the absence of other known cardiac disease. Other findings of this specific cardiomyopathy include impaired contractile responsiveness to stress stimuli and electrophysiological abnormalities with prolonged QT interval. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of the b-adrenergic receptor signalling, abnormal cardiomyocyte membrane lipid composition and biophysical properties, ion channel defects and overactivity of humoral cardiodepressant factors. Cirrhotic cardiomyopathy may be difficult to determine due to the lack of a specific diagnosis test. However, an echocardiogram allows the detection of the diastolic dysfunction and the E/e′ ratio may be used in the follow-up progression of the illness. Cirrhotic cardiomyopathy plays an important role in the pathogenesis of the impairment of effective arterial blood volume and correlates with the degree of liver failure. A clinical consequence of cardiac dysfunction is an inadequate cardiac response in the setting of vascular stress that may result in renal hypoperfusion leading to renal failure. The prognosis is difficult to establish but the severity of diastolic dysfunction may be a marker of mortality risk. Treatment is non-specific and liver transplantation may normalize the cardiac function. PMID:26556983

Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report.

PubMed

Ohara, Nobumasa; Yoneoka, Yuichiro; Seki, Yasuhiro; Akiyama, Katsuhiko; Arita, Masataka; Ohashi, Kazumasa; Suzuki, Kazuo; Takada, Toshinori

2017-08-24

Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. An 83-year-old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130 dependent manner accompanied by contractile dysfunction and ventricular arrhythmias

PubMed Central

Yajima, Toshitaka; Murofushi, Yoshiteru; Zhou, Hanbing; Park, Stanley; Housman, Jonathan; Zhong, Zhao-Hua; Nakamura, Michinari; Machida, Mitsuyo; Hwang, Kyung-Kuk; Gu, Yusu; Dalton, Nancy D.; Yajima, Tomoko; Yasukawa, Hideo; Peterson, Kirk L; Knowlton, Kirk U.

2011-01-01

Background Suppressor of cytokine signaling-3 (SOCS3) is a key negative-feedback regulator of gp130 receptor that provides crucial signaling for cardiac hypertrophy and survival; however, an in vivo role of SOCS3 regulation on cardiac gp130 signaling remains obscure. Methods and Results We generated cardiac-specific SOCS3 knockout (SOCS3 cKO) mice. These mice showed increased activation of gp130 downstream signaling targets (STAT3, ERK1/2, AKT and p38) from 15 weeks of age and developed cardiac dysfunction from around 25 weeks of age with signs of heart failure. Surprisingly, SOCS3 cKO failing hearts had minimal histological abnormalities with intact myofibril ultrastructure. In addition, Ca2+ transients were significantly increased in SOCS3 cKO failing hearts compared to wild-type (WT) hearts. We also found that Ser23/24 residues of troponin I were hypophosphorylated in SOCS3 cKO hearts before the manifestation of cardiac dysfunction. These data suggested the presence of abnormalities in myofilament Ca2+ sensitivity in SOCS3 cKO mice. In addition to the contractile dysfunction, we found various ventricular arrhythmias in SOCS3 cKO non-failing hearts accompanied by a sarcoplasmic reticulum Ca2+ overload. To determine the contribution of gp130 signaling to the cardiac phenotype that occurs with SOCS3 deficiency, we generated cardiac-specific gp130 and SOCS3 double knockout mice. Double KO mice lived significantly longer and had different histological abnormalities when compared to SOCS3 cKO mice; thus, demonstrating the importance of gp130 signaling in the SOCS3 cKO cardiac phenotype. Conclusions Our results demonstrate an important role of SOCS3 regulation on cardiac gp130 signaling in the pathogenesis of contractile dysfunction and ventricular arrhythmias. PMID:22082679

Inhibition of Receptor Interacting Protein Kinases Attenuates Cardiomyocyte Hypertrophy Induced by Palmitic Acid.

PubMed

Zhao, Mingyue; Lu, Lihui; Lei, Song; Chai, Hua; Wu, Siyuan; Tang, Xiaoju; Bao, Qinxue; Chen, Li; Wu, Wenchao; Liu, Xiaojing

2016-01-01

Palmitic acid (PA) is known to cause cardiomyocyte dysfunction. Cardiac hypertrophy is one of the important pathological features of PA-induced lipotoxicity, but the mechanism by which PA induces cardiomyocyte hypertrophy is still unclear. Therefore, our study was to test whether necroptosis, a receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3-) dependent programmed necrosis, was involved in the PA-induced cardiomyocyte hypertrophy. We used the PA-treated primary neonatal rat cardiac myocytes (NCMs) or H9c2 cells to study lipotoxicity. Our results demonstrated that cardiomyocyte hypertrophy was induced by PA treatment, determined by upregulation of hypertrophic marker genes and cell surface area enlargement. Upon PA treatment, the expression of RIPK1 and RIPK3 was increased. Pretreatment with the RIPK1 inhibitor necrostatin-1 (Nec-1), the PA-induced cardiomyocyte hypertrophy, was attenuated. Knockdown of RIPK1 or RIPK3 by siRNA suppressed the PA-induced myocardial hypertrophy. Moreover, a crosstalk between necroptosis and endoplasmic reticulum (ER) stress was observed in PA-treated cardiomyocytes. Inhibition of RIPK1 with Nec-1, phosphorylation level of AKT (Ser473), and mTOR (Ser2481) was significantly reduced in PA-treated cardiomyocytes. In conclusion, RIPKs-dependent necroptosis might be crucial in PA-induced myocardial hypertrophy. Activation of mTOR may mediate the effect of necroptosis in cardiomyocyte hypertrophy induced by PA.

Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents.

PubMed

Cuevas-Durán, Raúl Enrique; Medrano-Rodríguez, Juan Carlos; Sánchez-Aguilar, María; Soria-Castro, Elizabeth; Rubio-Ruíz, María Esther; Del Valle-Mondragón, Leonardo; Sánchez-Mendoza, Alicia; Torres-Narvaéz, Juan Carlos; Pastelín-Hernández, Gustavo; Ibarra-Lara, Luz

2017-11-14

Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha ( Co ) and Rosmarinus officinalis ( Ro ) extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); (c) Ro extract-treated myocardial infarction (MI- Ro ); (d) Co extract-treated myocardial infarction (MI- Co ); or (e) Ro+Co -treated myocardial infarction (MI- Ro+Co ). Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD)-Cu 2+ /Zn 2+ , SOD-Mn 2+ , and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1), increased vasodilators agents (angiotensin 1-7 and bradikinin) and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators.

Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

PubMed Central

Cuevas-Durán, Raúl Enrique; Medrano-Rodríguez, Juan Carlos; Sánchez-Aguilar, María; Soria-Castro, Elizabeth; Del Valle-Mondragón, Leonardo; Sánchez-Mendoza, Alicia; Torres-Narvaéz, Juan Carlos; Pastelín-Hernández, Gustavo; Ibarra-Lara, Luz

2017-01-01

Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co) and Rosmarinus officinalis (Ro) extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); (c) Ro extract-treated myocardial infarction (MI-Ro); (d) Co extract-treated myocardial infarction (MI-Co); or (e) Ro+Co-treated myocardial infarction (MI-Ro+Co). Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD)-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1), increased vasodilators agents (angiotensin 1–7 and bradikinin) and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators. PMID:29135932

Inhibition of Receptor Interacting Protein Kinases Attenuates Cardiomyocyte Hypertrophy Induced by Palmitic Acid

PubMed Central

Zhao, Mingyue; Lu, Lihui; Lei, Song; Chai, Hua; Wu, Siyuan; Tang, Xiaoju; Bao, Qinxue; Chen, Li; Wu, Wenchao; Liu, Xiaojing

2016-01-01

Palmitic acid (PA) is known to cause cardiomyocyte dysfunction. Cardiac hypertrophy is one of the important pathological features of PA-induced lipotoxicity, but the mechanism by which PA induces cardiomyocyte hypertrophy is still unclear. Therefore, our study was to test whether necroptosis, a receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3-) dependent programmed necrosis, was involved in the PA-induced cardiomyocyte hypertrophy. We used the PA-treated primary neonatal rat cardiac myocytes (NCMs) or H9c2 cells to study lipotoxicity. Our results demonstrated that cardiomyocyte hypertrophy was induced by PA treatment, determined by upregulation of hypertrophic marker genes and cell surface area enlargement. Upon PA treatment, the expression of RIPK1 and RIPK3 was increased. Pretreatment with the RIPK1 inhibitor necrostatin-1 (Nec-1), the PA-induced cardiomyocyte hypertrophy, was attenuated. Knockdown of RIPK1 or RIPK3 by siRNA suppressed the PA-induced myocardial hypertrophy. Moreover, a crosstalk between necroptosis and endoplasmic reticulum (ER) stress was observed in PA-treated cardiomyocytes. Inhibition of RIPK1 with Nec-1, phosphorylation level of AKT (Ser473), and mTOR (Ser2481) was significantly reduced in PA-treated cardiomyocytes. In conclusion, RIPKs-dependent necroptosis might be crucial in PA-induced myocardial hypertrophy. Activation of mTOR may mediate the effect of necroptosis in cardiomyocyte hypertrophy induced by PA. PMID:27057269

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy

PubMed Central

Stapel, Britta; Kohlhaas, Michael; Ricke-Hoch, Melanie; Haghikia, Arash; Erschow, Sergej; Knuuti, Juhani; Silvola, Johanna M. U.; Roivainen, Anne; Saraste, Antti; Nickel, Alexander G.; Saar, Jasmin A.; Sieve, Irina; Pietzsch, Stefan; Müller, Mirco; Bogeski, Ivan; Kappl, Reinhard; Jauhiainen, Matti; Thackeray, James T.; Scherr, Michaela; Bengel, Frank M.; Hagl, Christian; Tudorache, Igor; Bauersachs, Johann; Maack, Christoph; Hilfiker-Kleiner, Denise

2017-01-01

Abstract Aims The benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice. Methods and results Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The β-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir. Conclusions Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression. PMID:28201733

The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

EPA Science Inventory

Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease and cardiac dysfunction ha...

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.

PubMed

Hiemstra, Jessica A; Lee, Dong I; Chakir, Khalid; Gutiérrez-Aguilar, Manuel; Marshall, Kurt D; Zgoda, Pamela J; Cruz Rivera, Noelany; Dozier, Daniel G; Ferguson, Brian S; Heublein, Denise M; Burnett, John C; Scherf, Carolin; Ivey, Jan R; Minervini, Gianmaria; McDonald, Kerry S; Baines, Christopher P; Krenz, Maike; Domeier, Timothy L; Emter, Craig A

2016-04-20

Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation.

PubMed

Lamoureux, Lorissa; Radhakrishnan, Jeejabai; Mason, Thomas G; Kraut, Jeffrey A; Gazmuri, Raúl J

2016-11-01

Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO 2 accumulation-and activation of the Na + -H + exchanger isoform-1 (NHE-1). We hypothesized that a favorable interaction may result from NHE-1 inhibition during cardiac resuscitation followed by administration of a CO 2 -consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 min followed by defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Rats were randomized 1:1:1 to the NHE-1 inhibitor zoniporide or vehicle during CPR and disodium carbonate/sodium bicarbonate buffer or normal saline (30 ml/kg) after ROSC. Survival at 240 min declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (P = 0.004), explained by worsening postresuscitation myocardial dysfunction. Marked alkalemia occurred after buffer administration along with lactatemia that was maximal after Vehicle/Buffer, attenuated by Zoniporide/Buffer, and minimal with Zoniporide/Saline [13.3 ± 4.8 (SD), 9.2 ± 4.6, and 2.7 ± 1.0 mmol/l; P ≤ 0.001]. We attributed the intense postresuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened postresuscitation myocardial dysfunction also to severe alkalemia intensifying Na + entry via NHE-1 with consequent Ca 2+ overload injuring mitochondria, evidenced by increased plasma cytochrome c Both buffer-induced effects were ameliorated by zoniporide. Accordingly, buffer-induced alkalemia after ROSC worsened myocardial function and survival, likely through enhancing NHE-1 activity. Zoniporide attenuated these effects and uncovered a complex postresuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along with myocardial function and survival.

Amelioration of Cardiac Function and Activation of Anti-Inflammatory Vasoactive Peptides Expression in the Rat Myocardium by Low Level Laser Therapy

PubMed Central

Manchini, Martha Trindade; Serra, Andrey Jorge; Feliciano, Regiane dos Santos; Santana, Eduardo Tadeu; Antônio, Ednei Luis; de Tarso Camillo de Carvalho, Paulo; Montemor, Jairo; Crajoinas, Renato Oliveira; Girardi, Adriana Castello Costa; Tucci, Paulo José Ferreira; Silva, José Antônio

2014-01-01

Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation. PMID:24991808

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy

PubMed Central

Taglieri, Domenico M.; Johnson, Keven R.; Burmeister, Brian T.; Monasky, Michelle M.; Spindler, Matthew J.; DeSantiago, Jaime; Banach, Kathrin; Conklin, Bruce R.; Carnegie, Graeme K.

2014-01-01

The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAPLbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment. PMID:24161911

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy.

PubMed

Taglieri, Domenico M; Johnson, Keven R; Burmeister, Brian T; Monasky, Michelle M; Spindler, Matthew J; DeSantiago, Jaime; Banach, Kathrin; Conklin, Bruce R; Carnegie, Graeme K

2014-01-01

The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP-Lbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment. © 2013.

Serum bicarbonate and structural and functional cardiac abnormalities in CKD - A report from the CRIC study

PubMed Central

Dobre, Mirela; Roy, Jason; Tao, Kaixiang (Kelvin); Anderson, Amanda; Bansal, Nisha; Chen, Jing; Deo, Raj; Drawz, Paul; Feldman, Harold; Hamm, LL; Hostetter, Thomas; Kusek, John W; Lora, Claudia; Ojo, Akinlolu; Sharma, Kumar; Rahman, Mahboob

2016-01-01

Background Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. Methods The association between serum bicarbonate and left ventricular hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction and diastolic dysfunction were assessed in 3483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Results The mean eGFR was 42.5±17ml/min per 1.73m2. The overall prevalence of LVH was 51.2%, with 57.8%, 50.9% and 47.7% for bicarbonate categories <22, 22-26, and >26mmol/L, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95%CI 1.07–1.64, and 1.57; 95%CI 1.14–2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR1.07; 95%CI 0.66–1.72, and 1.27; 95%CI 0.64–2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up no significant changes in LV mass or EF were observed in any bicarbonate strata. Conclusions In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms. PMID:27241893

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.

PubMed

Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2015-01-06

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX's cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

PubMed Central

Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen-Shin; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2015-01-01

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury. PMID:25569804

Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF-α and TGF-β1/ERK1/2 signaling pathways

PubMed Central

Zhang, Changyi; Zhou, Guichi; Chen, Yezeng; Liu, Sizheng; Chen, Fen; Xie, Lichun; Wang, Wei; Zhang, Yonggang; Wang, Tianyou; Lai, Xiulan; Ma, Lian

2018-01-01

Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord-derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin-induced rat model of DCM. Male Lewis rats (aged 8-weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1×106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle-injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF-α, extracellular-signal regulated kinase 1/2 (ERK1/2) and TGF-β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF-α and the TGF-β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM. PMID:29115435

Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy.

PubMed

Liu, Xifu; Gu, Xinhua; Li, Zhaoming; Li, Xinyan; Li, Hui; Chang, Jianjie; Chen, Ping; Jin, Jing; Xi, Bing; Chen, Denghong; Lai, Donna; Graham, Robert M; Zhou, Mingdong

2006-10-03

We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta2a isoform) receptor-active peptide (rhNRG-1) in multiple animal models of heart disease. Activation of the erbB family of receptor tyrosine kinases by rhNRG-1 could provide a treatment option for heart failure, because neuregulin-stimulated erbB2/erbB4 heterodimerization is not only critical for myocardium formation in early heart development but prevents severe dysfunction of the adult heart and premature death. Disabled erbB-signaling is also implicated in the transition from compensatory hypertrophy to failure, whereas erbB receptor-activation promotes myocardial cell growth and survival and protects against anthracycline-induced cardiomyopathy. rhNRG-1 was administered IV to animal models of ischemic, dilated, and viral cardiomyopathy, and cardiac function and survival were evaluated. Short-term intravenous administration of rhNRG-1 to normal dogs and rats did not alter hemodynamics or cardiac contractility. In contrast, rhNRG-1 improved cardiac performance, attenuated pathological changes, and prolonged survival in rodent models of ischemic, dilated, and viral cardiomyopathy, with the survival benefits in the ischemic model being additive to those of angiotensin-converting enzyme inhibitor therapy. In addition, despite continued pacing, rhNRG-1 produced global improvements in cardiac function in a canine model of pacing-induced heart failure. These beneficial effects make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.

Protective effects of naringenin in cardiorenal syndrome.

PubMed

Liu, Yan; An, Wenjun; Gao, Aibao

2016-06-15

Cardiorenal syndrome is a complicated and bidirectional interrelationship between the heart and kidneys. Naringenin (NG) is a naturally occurring flavonoid possessing various biological and pharmacological properties. We tested whether NG could improve cardiac and renal function in a rat model of cardiorenal syndrome. The results showed that NG-attenuated cardiac remodeling and cardiac dysfunction in rats with cardiorenal syndrome, as evidenced by decrease of left ventricle weight (LVW), increase of body weight (BW), decrease of LVW/BW, decrease of concentrations of serum creatinine, blood urea nitrogen, type-B natriuretic peptide, aldosterone, angiotensin (Ang) II, C-reactive protein, and urine protein, increase of left ventricular systolic pressure and falling rates of left ventricular pressure (dp/dtmax), and decrease of left ventricular diastolic pressure, left ventricular end-diastolic pressure, and -dp/dtmax. NG significantly inhibited the increase of lipid profiles including low-density lipoprotein, TC, and TG in rats. In addition, NG significantly inhibited the increase of cardiac expression of IL-1β, IL-6, and interferon γ. Moreover, NG decreased malonaldehyde level, increased superoxide dismutase activity and glutathione content in rats, and increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunit of γ-glutamylcysteine ligase (GCLc) in rats and Ang II-treated cardiac fibroblasts. Inhibition of Nrf2 and glutathione synthesis significantly suppressed NG-induced decrease of ROS level. Inhibition of Nrf2 markedly suppressed NG-induced increase of GCLc expression in Ang II-treated cardiac fibroblasts. The data provide novel options for therapy of patients and new insights into the cardioprotective effects of NG in cardiorenal syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Controlled lung reperfusion to reduce pulmonary ischaemia/reperfusion injury after cardiopulmonary bypass in a porcine model.

PubMed

Slottosch, Ingo; Liakopoulos, Oliver; Kuhn, Elmar; Deppe, Antje; Lopez-Pastorini, Alberto; Schwarz, David; Neef, Klaus; Choi, Yeong-Hoon; Sterner-Kock, Anja; Jung, Kristina; Mühlfeld, Christian; Wahlers, Thorsten

2014-12-01

Ischaemia/reperfusion (I/R) injury of the lungs contributes to pulmonary dysfunction after cardiac surgery with cardiopulmonary bypass (CPB), leading to increased morbidity and mortality of patients. This study investigated the value of controlled lung reperfusion strategies on lung ischaemia-reperfusion injury in a porcine CPB model. Pigs were subjected to routine CPB for 120 min with 60 min of blood cardioplegic cardiac arrest (CCA). Following CCA, the uncontrolled reperfusion (UR, n = 6) group was conventionally weaned from CPB. Two groups underwent controlled lung reperfusion strategies (CR group: controlled reperfusion conditions, n = 6; MR group: controlled reperfusion conditions and modified reperfusate, n = 6) via the pulmonary artery before CPB weaning. Sham-operated pigs (n = 7) served as controls. Animals were followed up until 4 h after CPB. Pulmonary function, haemodynamics, markers of inflammation, endothelial injury and oxidative stress as well as morphological lung alterations were analysed. CPB (UR group) induced deterioration of pulmonary function (lung mechanics, oxygenation index and lung oedema). Also, controlled lung reperfusion groups (CR and MR) presented with pulmonary dysfunction after CPB. However, compared with UR, controlled lung reperfusion strategies (CR and MR) improved lung mechanics and reduced markers of oxidative stress, but without alteration of haemodynamics, oxygenation, inflammation, endothelial injury and lung morphology. Both controlled reperfusion groups were similar without relevant differences. Controlled lung reperfusion strategies attenuated a decrease in lung mechanics and an increase in oxidative stress, indicating an influence on CPB-related pulmonary injury. However, they failed to avoid completely CPB-related lung injury, implying the need for additional strategies given the multifactorial pathophysiology of postoperative pulmonary dysfunction. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Inhibiting Insulin-Mediated β2-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction.

PubMed

Wang, Qingtong; Liu, Yongming; Fu, Qin; Xu, Bing; Zhang, Yuan; Kim, Sungjin; Tan, Ruensern; Barbagallo, Federica; West, Toni; Anderson, Ethan; Wei, Wei; Abel, E Dale; Xiang, Yang K

2017-01-03

Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity. High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β 2 -adrenergic receptor (β 2 AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function. High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β 2 AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β 2 AR or GRK2, or genetic deletion of β 2 AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction. These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β 2 AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM. © 2016 American Heart Association, Inc.

Cardiac Impairment Evaluated by Transesophageal Echocardiography and Invasive Measurements in Rats Undergoing Sinoaortic Denervation

PubMed Central

Sirvente, Raquel A.; Irigoyen, Maria C.; Souza, Leandro E.; Mostarda, Cristiano; La Fuente, Raquel N.; Candido, Georgia O.; Souza, Pamella R. M.; Medeiros, Alessandra; Mady, Charles; Salemi, Vera M. C.

2014-01-01

Background Sympathetic hyperactivity may be related to left ventricular (LV) dysfunction and baro- and chemoreflex impairment in hypertension. However, cardiac function, regarding the association of hypertension and baroreflex dysfunction, has not been previously evaluated by transesophageal echocardiography (TEE) using intracardiac echocardiographic catheter. Methods and Results We evaluated exercise tests, baroreflex sensitivity and cardiovascular autonomic control, cardiac function, and biventricular invasive pressures in rats 10 weeks after sinoaortic denervation (SAD). The rats (n = 32) were divided into 4 groups: 16 Wistar (W) with (n = 8) or without SAD (n = 8) and 16 spontaneously hypertensive rats (SHR) with (n = 8) or without SAD (SHRSAD) (n = 8). Blood pressure (BP) and heart rate (HR) did not change between the groups with or without SAD; however, compared to W, SHR groups had higher BP levels and BP variability was increased. Exercise testing showed that SHR had better functional capacity compared to SAD and SHRSAD. Echocardiography showed left ventricular (LV) concentric hypertrophy; segmental systolic and diastolic biventricular dysfunction; indirect signals of pulmonary arterial hypertension, mostly evident in SHRSAD. The end-diastolic right ventricular (RV) pressure increased in all groups compared to W, and the end-diastolic LV pressure increased in SHR and SHRSAD groups compared to W, and in SHRSAD compared to SAD. Conclusions Our results suggest that baroreflex dysfunction impairs cardiac function, and increases pulmonary artery pressure, supporting a role for baroreflex dysfunction in the pathogenesis of hypertensive cardiac disease. Moreover, TEE is a useful and feasible noninvasive technique that allows the assessment of cardiac function, particularly RV indices in this model of cardiac disease. PMID:24828834

Association of morning blood pressure surge with carotid intima-media thickness and cardiac dysfunction in patients with cardiac syndrome-X.

PubMed

Mahfouz, Ragab A; Goda, Mohammad; Galal, Islam; Ghareb, Mohamed S

2018-05-23

Background & hypothesis: We hypothesized that exaggerated morning blood pressure surge, may contribute in cardiac dysfunction and arterial stiffness in patients with cardiac syndrome X. Thus we investigated the impact of morning blood pressure surge on cardiac function and carotid intima-media thickness in subjects with cardiac syndrome X. We studied patients with cardiac syndrome X using ambulatory blood pressure monitoring and investigated the association of morning blood pressure surge with carotid intima thickness, left atrial volume index and left ventricular filling (E/e'). Seventy patients with cardiac syndrome X were enrolled for the study and compared with 70 age and sex matched controls. Patients with cardiac syndrome X were stratified based on the systolic morning blood pressure surge value of control subjects to patients with exaggerated blood pressure surge (n = 42) and those with normal morning blood pressure surge (n = 28). Basal heart rate (p < .05), high sensitive C-reactive protein (p < .01), left atrial volume index (p < .01), E/e' (p < .01); carotid intima-media thickness (p < .001) and percentage of detected plaque (p < .005) were significantly higher in patients with exaggerated morning blood pressure surge group than those with morning blood pressure surge group. Morning blood pressure surge was significantly correlated with carotid intima-media thickness, high sensitive C-reactive protein, left atrial volume index and E/e' ratio in patients with cardiac syndrome X. In multivariate analysis, exaggerated morning blood pressure surge was the only independent predictor of increased carotid intima-media thickness (OR = 2.379; p < .001), and diastolic dysfunction (OR = 2.464; p < .001) in patients with cardiac syndrome X. Our data suggest that excessive morning blood pressure surge is an independent predictor for arterial stiffness and diastolic dysfunction in patients with cardiac syndrome X.

Serum from Diesel Exhaust-Exposed Rats with Cardiac Dysfunction Alters Aortic Endothelial Cell Function In Vitro: Circulating Mediators as Causative Factors?

EPA Science Inventory

Although circulating inflammatory mediators are strongly associated with adverse cardiovascular outcomes triggered by inhaled air pollution, direct cause-effect linkage has not been established. Given that endothelial toxicity often precedes and precipitates cardiac dysfunction, ...

The Effects of Steroids on Coagulation Dysfunction Induced by Cardiopulmonary Bypass: A Steroids in Cardiac Surgery (SIRS) Trial Substudy.

PubMed

Paparella, Domenico; Parolari, Alessandro; Rotunno, Crescenzia; Vincent, Jessica; Myasoedova, Veronica; Guida, Pietro; De Palo, Micaela; Margari, Vito; Devereaux, Philip J; Lamy, Andre; Alamanni, Francesco; Yusuf, Salim; Whitlock, Richard

2017-01-01

Cardiopulmonary bypass (CPB) surgery, despite heparin administration, elicits activation of coagulation system resulting in coagulopathy. Anti-inflammatory effects of steroid treatment have been demonstrated, but its effects on coagulation system are unknown. The primary objective of this study is to assess the effects of methylprednisolone on coagulation function by evaluating thrombin generation, fibrinolysis, and platelet activation in high-risk patients undergoing cardiac surgery with CPB. The Steroids In caRdiac Surgery study is a double-blind, randomized, controlled trial performed on 7507 patients worldwide who were randomized to receive either intravenous methylprednisolone, 250 mg at anesthetic induction and 250 mg at initiation of CPB (n = 3755), or placebo (n = 3752). A substudy was conducted in 2 sites to collect blood samples perioperatively to measure prothrombin fragment 1.2 (PF1+2, thrombin generation), plasmin-antiplasmin complex (PAP, fibrinolysis), platelet factor 4 (PF4 platelet activation), and fibrinogen. Eighty-one patients were enrolled in the substudy (37 placebo vs 44 in treatment group). No difference in clinical outcome was detected, including postoperative bleeding and need for blood products transfusion. All patients showed changes of all plasma biomarkers with greater values than baseline in both groups. This reaction was attenuated significantly in the treatment group for PF1.2 (P = 0.040) and PAP (P = 0.042) values at the first intraoperative measurement. No difference between groups was detected for PF4. Methylprednisolone treatment attenuates activation of coagulation system in high-risk patients undergoing CPB surgery. Reduction of thrombin generation and fibrinolysis activation may lead to reduced blood loss after surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat

PubMed Central

Grimes, Kelly M.; Reddy, Anilkumar K.; Lindsey, Merry L.

2014-01-01

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of >31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP. We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography (3 μg/g ip) revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age. NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening does not occur since there are no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs (P < 0.01). However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related increases in diastolic dysfunction in comparison with other species. Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans. PMID:24906918

Cardiac Overexpression of Antioxidant Catalase Attenuates Aging-Induced Cardiomyocyte Relaxation Dysfunction

PubMed Central

Ren, Jun; Li, Qun; Wu, Shan; Li, Shi-Yan; Babcock, Sara A.

2007-01-01

Catalase, an enzyme which detoxifies H2O2, may interfere with cardiac aging. To test this hypothesis, contractile and intracellular Ca2+ properties were evaluated in cardiomyocytes from young (3–4 mo) and old (26–28 mo) FVB and transgenic mice with cardiac overexpression of catalase. Contractile indices analyzed included peak shortening (PS), time-to-90% PS (TPS90), time-to-90% relengthening (TR90), half-width duration (HWD), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ levels or decay rate. Levels of advanced glycation endproduct (AGE), Na+/Ca2+ exchanger (NCX), sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), phospholamban (PLB), myosin heavy chain (MHC), membrane Ca2+ and K+ channels were measured by western blot. Catalase transgene prolonged survival while did not alter myocyte function by itself. Aging depressed ± dL/dt, prolonged HWD, TR90 and intracellular Ca2+ decay without affecting other indices in FVB myocytes. Aged FVB myocytes exhibited a stepper decline in PS in response to elevated stimulus or a dampened rise in PS in response to elevated extracellular Ca2+ levels. Interestingly, aging-induced defects were nullified or significantly attenuated by catalase. AGE level was elevated by 5-fold in aged FVB compared with young FVB mice, which was reduced by catalase. Expression of SERCA2a, NCX and Kv1.2 K+ channel was significantly reduced although levels of PLB, L-type Ca2+ channel dihydropyridine receptor and β-MHC isozyme remained unchanged in aged FVB hearts. Catalase restored NCX and Kv1.2 K+ channel but not SERCA2a level in aged mice. In summary, our data suggested that catalase protects cardiomyocytes from aging-induced contractile defect possibly via improved intracellular Ca2+ handling. PMID:17250874

Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation.

PubMed

Yang, Lifang; Gao, Jian-Yuan; Ma, Jipeng; Xu, Xihui; Wang, Qiurong; Xiong, Lize; Yang, Jian; Ren, Jun

2015-09-02

Hypertension is an independent risk factor for heart disease and is responsible for the increased cardiac morbidity and mortality. Oxidative stress plays a key role in hypertensive heart diseases although the precise mechanism remains unclear. This study was designed to examine the effect of cardiac-specific overexpression of metallothionein, a cysteine-rich antioxidant, on myocardial contractile and intracellular Ca(2+) anomalies in N(G)-nitro-l-arginine methyl ester (l-NAME)-induced experimental hypertension and the mechanism involved with a focus on autophagy. Our results revealed that l-NAME treatment (14 days) led to hypertension and myocardial anomalies evidenced by interstitial fibrosis, cardiomyocyte hypertrophy, increased LV end systolic and diastolic diameters (LVESD and LVEDD) along with suppressed fractional shortening. l-NAME compromised cardiomyocyte contractile and intracellular Ca(2+) properties manifested as depressed peak shortening, maximal velocity of shortening/relengthening, electrically-stimulated rise in intracellular Ca(2+), elevated baseline and peak intracellular Ca(2+). These l-NAME-induced histological and mechanical changes were attenuated or reconciled by metallothionein. Protein levels of autophagy markers LC3B and p62 were decreased and increased, respectively. Autophagy signaling molecules AMPK, TSC2 and ULK1 were inactivated while those of mTOR and p70s6K were activated by l-NAME, the effects of which were ablated by metallothionein. Autophagy induction mimicked whereas autophagy inhibition nullified the beneficial effect of metallothionein against l-NAME. These findings suggested that metallothionein protects against l-NAME-induced myocardial anomalies possibly through restoration of autophagy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The relationship between inotrope exposure, six-hour postoperative physiological variables, hospital mortality and renal dysfunction in patients undergoing cardiac surgery

PubMed Central

2011-01-01

Introduction Acute haemodynamic complications are common after cardiac surgery and optimal perioperative use of inotropic agents, typically guided by haemodynamic variables, remains controversial. The aim of this study was to examine the relationship of inotrope use to hospital mortality and renal dysfunction. Material and methods A retrospective cohort study of 1,326 cardiac surgery patients was carried out at two university-affiliated ICUs. Multivariable logistic regression analysis and propensity matching were performed to evaluate whether inotrope exposure was independently associated with mortality and renal dysfunction. Results Patients exposed to inotropes had a higher mortality rate than those not exposed. After adjusting for differences in Parsonnet score, left ventricular ejection fraction, perioperative intraaortic balloon pump use, bypass time, reoperation and cardiac index, inotrope exposure appeared to be independently associated with increased hospital mortality (adjusted odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.2 to 4.5) and renal dysfunction (adjusted OR 2.7, 95% CI 1.5 to 4.6). A propensity score-matched analysis similarly demonstrated that death and renal dysfunction were significantly more likely to occur in patients exposed to inotropes (P = 0.01). Conclusions Postoperative inotrope exposure was independently associated with worse outcomes in this cohort study. Further research is needed to better elucidate the appropriate use of inotropes in cardiac surgery. PMID:21736726

Effects of exercise training on pulmonary vessel muscularization and right ventricular function in an animal model of COPD.

PubMed

Hassel, Erlend; Berre, Anne Marie; Skjulsvik, Anne Jarstein; Steinshamn, Sigurd

2014-09-28

Right ventricular dysfunction in COPD is common, even in the absence of pulmonary hypertension. The aim of the present study was to examine the effects of high intensity interval training (HIIT) on right ventricular (RV) function, as well as pulmonary blood vessel remodeling in a mouse model of COPD. 42 female A/JOlaHsd mice were randomized to exposure to either cigarette smoke or air for 6 hours/day, 5 days/week for 14 weeks. Mice from both groups were further randomized to sedentariness or HIIT for 4 weeks. Cardiac function was evaluated by echocardiography and muscularization of pulmonary vessel walls by immunohistochemistry. Smoke exposure induced RV systolic dysfunction demonstrated by reduced tricuspid annular plane systolic excursion. HIIT in smoke-exposed mice reversed RV dysfunction. There were no significant effects on the left ventricle of neither smoke exposure nor HIIT. Muscularization of the pulmonary vessels was reduced after exercise intervention, but no significant effects on muscularization were observed from smoke exposure. RV function was reduced in mice exposed to cigarette smoke. No Increase in pulmonary vessel muscularization was observed in these mice, implying that other mechanisms caused the RV dysfunction. HIIT attenuated the RV dysfunction in the smoke exposed mice. Reduced muscularization of the pulmonary vessels due to HIIT suggests that exercise training not only affects the heart muscle, but also has important effects on the pulmonary vasculature.

Sinomenine prevents the development of cardiomyopathy in diabetic rats by inhibiting inflammatory responses and blocking activation of NF-κB.

PubMed

Jiang, Cheng; Tong, Yun-Long; Zhang, Dan; Liu, Li-Zhi; Wang, Ju-Fei

2017-01-01

Diabetic cardiomyopathy is a severe complication of diabetes mellitus (DM). The goal of current work was to study the effects of sinomenine on streptozotocin-induced cardiomyopathy in rats. DM in rats was induced by intraperitoneal injection of streptozotocin. Cardiac function was evaluated by measuring left ventricle end-diastolic diameter, left ventricle end-systolic diameter and ejection fraction. Cardiac inflammation was evaluated by the degree of infiltration of T lymphocytes and the levels of pro-inflammatory cytokines. Sinomenine attenuated diabetic symptoms without affecting plasma glucose. Cardiac dysfunction in the sinomenine-treated diabetic rats was significantly improved, as reflected by decreased levels of left ventricle end-diastolic diameter, left ventricle end systolic diameter and an increased level of ejection fraction. Sinomenine observably reduced cardiomyocyte hypertrophy in DM rats. Moreover, sinomenine reduced infiltration of CD3+ and CD68+ positive cells and decreased the levels of tumor necrosis factor-α, interlukin-1 and interlukin-6. Finally, sinomenine-treated rats showed a reduced expression of NF-κB and an increased expression of IκB in the myocardium compared with the myocardium of untreated diabetic rats. Our results indicate sinomenine significantly improves cardiac function in diabetic rats, which may be attributed to the deactivation of NF-κB and the blockade of inflammatory cytokine-mediated immune reactions.

Pathophysiology of Cardiopulmonary Bypass: Current Strategies for the Prevention and Treatment of Anemia, Coagulopathy, and Organ Dysfunction.

PubMed

Esper, Stephen A; Subramaniam, Kathirvel; Tanaka, Kenichi A

2014-06-01

The techniques and equipment of cardiopulmonary bypass (CPB) have evolved over the past 60 years, and numerous numbers of cardiac surgical procedures are conducted around the world using CPB. Despite more widespread applications of percutaneous coronary and valvular interventions, the need for cardiac surgery using CPB remains the standard approach for certain cardiac pathologies because some patients are ineligible for percutaneous procedures, or such procedures are unsuccessful in some. The ageing patient population for cardiac surgery poses a number of clinical challenges, including anemia, decreased cardiopulmonary reserve, chronic antithrombotic therapy, neurocognitive dysfunction, and renal insufficiency. The use of CPB is associated with inductions of systemic inflammatory responses involving both cellular and humoral interactions. Inflammatory pathways are complex and redundant, and thus, the reactions can be profoundly amplified to produce a multiorgan dysfunction that can manifest as capillary leak syndrome, coagulopathy, respiratory failure, myocardial dysfunction, renal insufficiency, and neurocognitive decline. In this review, pathophysiological aspects of CPB are considered from a practical point of view, and preventive strategies for hemodilutional anemia, coagulopathy, inflammation, metabolic derangement, and neurocognitive and renal dysfunction are discussed. © The Author(s) 2014.

Cardiac Dysautonomia in Huntington's Disease.

PubMed

Abildtrup, Mads; Shattock, Michael

2013-01-01

Huntington's disease is a fatal, hereditary, neurodegenerative disorder best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances. Although a disease of the central nervous system, mortality surveys indicate that heart disease is a leading cause of death. The nature of such cardiac abnormalities remains unknown. Clinical findings indicate a high prevalence of autonomic nervous system dysfunction - dysautonomia - which may be a result of pathology of the central autonomic network. Dysautonomia can have profound effects on cardiac health, and pronounced autonomic dysfunction can be associated with neurogenic arrhythmias and sudden cardiac death. Significant advances in the knowledge of neural mechanisms in cardiac disease have recently been made which further aid our understanding of cardiac mortality in Huntington's disease. Even so, despite the evidence of aberrant autonomic activity the potential cardiac consequences of autonomic dysfunction have been somewhat ignored. In fact, underlying cardiac abnormalities such as arrhythmias have been part of the exclusion criteria in clinical autonomic Huntington's disease research. A comprehensive analysis of cardiac function in Huntington's disease patients is warranted. Further experimental and clinical studies are needed to clarify how the autonomic nervous system is controlled and regulated in higher, central areas of the brain - and how these regions may be altered in neurological pathology, such as Huntington's disease. Ultimately, research will hopefully result in an improvement of management with the aim of preventing early death in Huntington's disease from cardiac causes.

Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase.

PubMed

Guerrero-Orriach, José Luis; Ariza-Villanueva, Daniel; Florez-Vela, Ana; Garrido-Sánchez, Lourdes; Moreno-Cortés, María Isabel; Galán-Ortega, Manuel; Ramírez-Fernández, Alicia; Alcaide Torres, Juan; Fernandez, Concepción Santiago; Navarro Arce, Isabel; Melero-Tejedor, José María; Rubio-Navarro, Manuel; Cruz-Mañas, José

2016-01-01

To evaluate if the preoperative administration of levosimendan in patients with right ventricular (RV) dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological functions, assessed using two biomarkers neutrophil gelatinase-associated lipocalin (N-GAL) and neuronal enolase. This is an observational study. Twenty-seven high-risk cardiac patients with RV dysfunction and pulmonary hypertension, scheduled for cardiac valve surgery, were prospectively followed after preoperative administration of levosimendan. Levosimendan was administered preoperatively on the day before surgery. All patients were considered high risk of cardiac and perioperative renal complications. Cardiac function was assessed by echocardiography, renal function by urinary N-GAL levels, and the acute kidney injury scale. Neuronal damage was assessed by neuron-specific enolase levels. After surgery, no significant variations were found in mean and SE levels of N-GAL (14.31 [28.34] ng/mL vs 13.41 [38.24] ng/mL), neuron-specific enolase (5.40 [0.41] ng/mL vs 4.32 [0.61] ng/mL), or mean ± SD creatinine (1.06±0.24 mg/dL vs 1.25±0.37 mg/dL at 48 hours). RV dilatation decreased from 4.23±0.7 mm to 3.45±0.6 mm and pulmonary artery pressure from 58±18 mmHg to 42±19 mmHg at 48 hours. Preoperative administration of levosimendan has shown a protective role against cardiac, renal, and neurological damage in patients with a high risk of multiple organ dysfunctions undergoing cardiac surgery.

Role of cytokine hemoadsorption in cardiopulmonary bypass-induced ventricular dysfunction in a porcine model.

PubMed

Vocelka, Craig R; Jones, Krystal M; Mikhova, Krasimira M; Ebisu, Ryan M; Shar, Ashley; Kellum, John A; Verrier, Edward D; Rabkin, David G

2013-12-01

Little is known about the effect of cardiopulmonary bypass alone on cardiac function; in an attempt to illuminate this relationship and test a possible mechanism, we used Cytosorb, a device capable of removing virtually all types of circulating cytokines to test the hypothesis that hemoadsorption of cytokines during bypass attenuates bypass-induced acute organ dysfunction. Twelve Yorkshire pigs (50-65 kg) were instrumented with a left ventricular conductance catheter. Baseline mechanics and cytokine expression (tumor necrosis factor [TNF], interleukin-6 [IL-6], and interleukin-10) were measured before and hourly after 1 hour of normothermic cardiopulmonary bypass. Animals underwent bypass without (cardiopulmonary bypass [CPB], n = 6) or with (CPB+HA, n = 6) the CytosorbTM device. Data were compared with "historical" controls (n = 6) that were similarly instrumented but underwent observation instead of bypass. Five hours after separation from bypass (or observation), animals were euthanized. Myocardial water content was determined postmortem. Neither TNF nor IL-6 was significantly elevated in either experimental group versus controls at any time point. Preload recruitable stroke work and dP/dtmax were significantly depressed immediately after separation from bypass in both CPB+HA and CPB and remained depressed for the duration of the experiment. Although Tau remained unchanged, dP/dTmin was significantly diminished in both bypass groups at all time points after separation from bypass. Cytokine hemoadsorption had no effect on any measurable index of function. Differences in postmortem data were not evident between groups. One hour of normothermic CPB results in a significant and sustained decline in left ventricular function that appears unrelated to changes in cytokine expression. Because we did not appreciate a significant change in cytokine concentrations postbypass, the capacity of cytokine hemoadsorption to attenuate CPB-induced ventricular dysfunction could not be assessed.

Is gut the "motor" for producing hepatocellular dysfunction after trauma and hemorrhagic shock?

PubMed

Wang, P; Ba, Z F; Cioffi, W G; Bland, K I; Chaudry, I H

1998-02-01

Although studies suggest that the gut may be the "motor" responsible for producing sepsis and multiple organ failure after injury, it is not known whether enterectomy prior to the onset of hemorrhage alters proinflammatory cytokines TNF and IL-6 and, if so, whether hepatocellular dysfunction and damage are prevented or attenuated under such conditions. Under methoxyflurane anesthesia, an enterectomy in the rat was performed by excision of the duodenum, jejunum, and ileum. The rats were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of shed blood with Ringer's lactate over 1 h. At 1.5 h after the completion of resuscitation, hepatocellular function [i.e., the maximal velocity (Vmax) and transport efficiency (Km) of indocyanine green (ICG) clearance] was assessed by an in vivo ICG clearance technique. Blood samples were taken for the measurement of TNF, IL-6, and liver enzymes (i.e., SGPT and SGOT). Cardiac output and microvascular blood flow were determined by ICG dilution and laser Doppler flowmetry, respectively. The increase in circulating levels of TNF but not IL-6 was prevented by enterectomy prior to hemorrhage. The reduced Vmax and K(m) and elevated SGPT and SGOT following hemorrhage and resuscitation, however, were not significantly affected by prior enterectomy. Moreover, enterectomy before hemorrhage further reduced hepatic perfusion. Since enterectomy prior to the onset of hemorrhage does not prevent or attenuate the reduced ICG clearance and elevated liver enzymes despite downregulation of TNF production, it appears that the small intestine does not play a significant role in producing hepatocellular dysfunction and injury following trauma and hemorrhagic shock.

Inhibition of Drp1 attenuates mitochondrial damage and myocardial injury in Coxsackievirus B3 induced myocarditis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Lin; Zhang, Ming; Yan, Rui

Viral myocarditis (VMC) is closely related to apoptosis, oxidative stress, innate immunity, and energy metabolism, which are all linked to mitochondrial dysfunction. A close nexus between mitochondrial dynamics and cardiovascular disease with mitochondrial dysfunction has been deeply researched, but there is still no relevant report in viral myocarditis. In this study, we aimed to explore the role of Dynamin-related protein 1 (Drp1)-linked mitochondrial fission in VMC. Mice were inoculated with the Coxsackievirus B3 (CVB3) and treated with mdivi1 (a Drp1 inhibitor). Protein expression of Drp1 was increased in mitochondria while decreased in cytoplasm and accompanied by excessive mitochondrial fission inmore » VMC mice. In addition, midivi1 treatment attenuate inflammatory cells infiltration in myocardium of the mice, serum Cardiac troponin I (CTnI) and Creatine kinase-MB (CK-MB) level. Mdivi1 also could improved the survival rate of mice and mitochondrial dysfunction reflected as the up-regulated mitochondrial marker enzymatic activities of succinate dehydrogenase (SDH), cytochrome c oxidase (COX) and mitochondrial membrane potential (MMP). At the same time, mdivi1 rescued the body weight loss, myocardial injury and apoptosis of cardiomyocyte. Furthermore, decease in LVEDs and increase in EF and FS were detected by echocardiogram, which indicated the improved myocardial function. Thus, Drp1-linked excessive mitochondrial fission contributed to VMC and midivi1 may be a potential therapeutic approach. - Highlights: • The expression of Drp1 is significantly increased in mitochondria while decreased in cytoplasm in VMC mice. • Drp1-linked excessive mitochondrial fission is involved in VMC. • Midivi1 treatment mitigate the mitochondrial damage, inflammation, apoptosis in VMC mice. • The disturbance of mitochondrial dynamics may be a new therapeutic target for VMC.« less

Valproic acid treatment attenuates caspase-3 activation and improves survival after lethal burn injury in a rodent model.

PubMed

Luo, Hong-Min; Hu, Sen; Bai, Hui-Ying; Wang, Hai-Bin; Du, Ming-Hua; Lin, Zhi-Long; Ma, Li; Wang, Huan; Lv, Yi; Sheng, Zhi-Yong

2014-01-01

Burn injury may result in multiple organ dysfunction partially because of apoptotic cell death. The authors have previously shown that valproic acid (VPA) improves survival in a dog burn model. The aim of this study is to examine whether a VPA improves survival in a rodent burn model and whether this was because of inhibition of cell apoptosis. Rats were subjected to third-degree 55% TBSA burns and randomized to treatment with a VPA (300 mg/kg) or normal saline. One group of animals was monitored for 12 hours for survival analysis; another group was killed at 6 hours after injury, and brains, hearts, and blood samples were harvested for examination. Plasma creatine kinase (CK)-MB activities and neuron-specific enolase (NSE) levels were measured to evaluate the cardiac and brain damages. The effects of a VPA on acetylation of histone H3 and caspase-3 activation were also evaluated. Major burn injury resulted in a significant decrease in the acetylation of histone H3, and there was an increase in plasma CK-MB activities, NSE concentrations, and tissue levels of activated caspase-3. A VPA treatment significantly increased the acetylation of histone H3 and survival of the animals after major burn injury. In addition, a VPA treatment significantly attenuated the plasma CK-MB activities, an NSE concentrations, and inhibited caspase-3 activation after major burn injury. These results indicate that a VPA can attenuate cardiac and brain injury, and can improve survival in a rodent model of lethal burn injury. These protective effects may be mediated in part through the inhibition of caspase-3 activation.

Evaluation of Right Ventricular Systolic Function in Chagas Disease Using Cardiac Magnetic Resonance Imaging.

PubMed

Moreira, Henrique T; Volpe, Gustavo J; Marin-Neto, José A; Ambale-Venkatesh, Bharath; Nwabuo, Chike C; Trad, Henrique S; Romano, Minna M D; Pazin-Filho, Antonio; Maciel, Benedito C; Lima, João A C; Schmidt, André

2017-03-01

Right ventricular (RV) impairment is postulated to be responsible for prominent systemic congestion in Chagas disease. However, occurrence of primary RV dysfunction in Chagas disease remains controversial. We aimed to study RV systolic function in patients with Chagas disease using cardiac magnetic resonance. This cross-sectional study included 158 individuals with chronic Chagas disease who underwent cardiac magnetic resonance. RV systolic dysfunction was defined as reduced RV ejection fraction based on predefined cutoffs accounting for age and sex. Multivariable logistic regression was used to verify the relationship of RV systolic dysfunction with age, sex, functional class, use of medications for heart failure, atrial fibrillation, and left ventricular systolic dysfunction. Mean age was 54±13 years, 51.2% men. RV systolic dysfunction was identified in 58 (37%) individuals. Although usually associated with reduced left ventricular ejection fraction, isolated RV systolic dysfunction was found in 7 (4.4%) patients, 2 of them in early stages of Chagas disease. Presence of RV dysfunction was not significantly different in patients with indeterminate/digestive form of Chagas disease (35.7%) compared with those with Chagas cardiomyopathy (36.8%) ( P =1.000). In chronic Chagas disease, RV systolic dysfunction is more commonly associated with left ventricular systolic dysfunction, although isolated and early RV dysfunction can also be identified. © 2017 American Heart Association, Inc.

ASSOCIATIONS OF MACRO- AND MICROVASCULAR ENDOTHELIAL DYSFUNCTION WITH SUBCLINICAL VENTRICULAR DYSFUNCTION IN END-STAGE RENAL DISEASE

PubMed Central

Dubin, Ruth F; Guajardo, Isabella; Ayer, Amrita; Mills, Claire; Donovan, Catherine; Beussink, Lauren; Scherzer, Rebecca; Ganz, Peter; Shah, Sanjiv J

2016-01-01

Patients with end-stage renal disease (ESRD) suffer high rates of heart failure and cardiovascular mortality, and we lack a thorough understanding of what, if any, modifiable factors contribute to cardiac dysfunction in these high-risk patients. In order to evaluate endothelial function as a potentially modifiable cause of cardiac dysfunction in ESRD, we investigated cross-sectional associations of macro- and microvascular dysfunction with left and right ventricular dysfunction in a well-controlled ESRD cohort. We performed comprehensive echocardiography, including tissue Doppler imaging and speckle tracking echocardiography of the left and right ventricle, in 149 ESRD patients enrolled in an ongoing prospective, observational study. Of these participants, 123 also underwent endothelium-dependent flow-mediated dilation (FMD) of the brachial artery (macrovascular function). Microvascular function was measured as the velocity time integral (VTI) of hyperemic blood flow following cuff deflation. Impaired FMD was associated with higher LV mass, independently of age and blood pressure: per two-fold lower FMD, LV mass was 4.1% higher (95%CI [0.49, 7.7], p=0.03). After adjustment for demographics, blood pressure, comorbidities and medications, a two-fold lower VTI was associated with 9.5% higher E/e’ ratio (95% CI [1.0, 16], p=0.03) and 6.7% lower absolute RV longitudinal strain (95% CI [2.0, 12], p=0.003). Endothelial dysfunction is a major correlate of cardiac dysfunction in ESRD, particularly diastolic and right ventricular dysfunction, in patients whose volume status is well-controlled. Future investigations are needed to determine whether therapies targeting the vascular endothelium could improve cardiac outcomes in ESRD. PMID:27550915

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

PubMed Central

Liu, Xiaoli; Hall, Sean R. R.; Wang, Zhihong; Huang, He; Ghanta, Sailaja; Di Sante, Moises; Leri, Annarosa; Anversa, Piero; Perrella, Mark A.

2015-01-01

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg−/− mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg−/− foetal hearts. CPCs harvested from Speg−/− mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg−/− mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg−/− mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases. PMID:26593099

[Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice].

PubMed

Zhang, Jian; Jin, Zhe; Li, Longhu; Gang, Li; Yu, Qin; Wang, Meilan; Song, Ailin; Hong, Bingzhe

2014-04-01

To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. Mice were randomly assigned to sham group (n = 6), PDE5shRNA group (n = 12), common adenovirus group (n = 15) and DMEM group (n = 8). Four weeks post-MI, the survival rate was evaluated. Cardiac function was examined by echocardiography. HE staining and Masson staining were used to evaluate the myocardial infarction size and fibrosis. The number of blood vessels was evaluated by immunohistochemistry, PDE5 protein expression in the left ventricular was detected using Western blot, level of cGMP or PKG activity in the left ventricle was evaluated with ELISA. Four weeks post-MI, all mice survived in the sham group, 3(37%) mice died in the DMEM group, 1 (8%) died in the PDE5shRNA group and 5 died in the common adenovirus group (33%). Infarct size was significantly reduced in PDE5shRNA group compared with the common adenovirus group and DMEM group [(25.4 ± 2.9)% vs. (42.0 ± 3.2)% and (43.4 ± 2.6) %, P < 0.05]. Cardiac function was significantly improved in PDE5shRNA group compared to common adenovirus group and DMEM group[LVFS: (21.1 ± 3.7)% vs. (14.2 ± 2.9)% and (14.22 ± 2.91)%, all P < 0.05; LVEF: (48.2 ± 7.1)% vs. (34.6 ± 6.2)% and (38.1 ± 2.8)%, all P < 0.05; LVESD: (3.87 ± 0.45) mm vs.(4.91 ± 0.62) mm and (4.63 ± 0.37) mm, all P < 0.05]. The blood vessel density was also higher in PDE5shRNA group compared with common adenovirus group (infarct area:14.3 ± 2.0 vs. 6.6 ± 1.2, P < 0.05; periinfarct area: 23.6 ± 2.1 vs. 13.7 ± 2.4, P < 0.05). Compared with common adenovirus group, level of PDE5 was significantly downregulated and level of cGMP or PKG was significantly upregulated in PDE5shRNA group (all P < 0.05). Present study suggests PDE5shRNA improves cardiac function and attenuates cardiac remodeling through reducing infarction size and cardiac fibrosis and these beneficial effects are possibly mediated by activating cGMP/PKG signaling pathway.

Regulation of Heat Shock Proteins 27 and 70, p-Akt/p-eNOS and MAPKs by Naringin Dampens Myocardial Injury and Dysfunction In Vivo after Ischemia/Reperfusion

PubMed Central

Rani, Neha; Bharti, Saurabh; Manchanda, Mansi; Nag, T. C.; Ray, Ruma; Chauhan, S. S.; Kumari, Santosh; Arya, Dharamvir Singh

2013-01-01

Naringin has antioxidant properties that could improve redox-sensitive myocardial ischemia reperfusion (IR) injury. This study was designed to investigate whether naringin restores the myocardial damage and dysfunction in vivo after IR and the mechanisms underlying its cardioprotective effects. Naringin (20–80 mg/kg/day, p.o.) or saline were administered to rats for 14 days and the myocardial IR injury was induced on 15th day by occluding the left anterior descending coronary artery for 45 min and subsequent reperfusion for 60 min. Post-IR rats exhibited pronounced cardiac dysfunction as evidenced by significantly decreased mean arterial pressure, heart rate, +LVdP/dt max (inotropic state), -LVdP/dt max (lusitropic state) and increased left ventricular end diastolic pressure as compared to sham group, which was improved by naringin. Further, on histopathological and ultrastructural assessments myocardium and myocytes appeared more normal in structure and the infarct size was reduced significantly in naringin 40 and 80 mg/kg/day group. This amelioration of post-IR-associated cardiac injury by naringin was accompanied by increased nitric oxide (NO) bioavailability, decreased NO inactivation to nitrotyrosine, amplified protein expressions of Hsp27, Hsp70, β-catenin and increased p-eNOS/eNOS, p-Akt/Akt, and p-ERK/ERK ratio. In addition, IR-induced TNF-α/IKK-β/NF-κB upregulation and JNK phosphorylation were significantly attenuated by naringin. Moreover, western blotting and immunohistochemistry analysis of apoptotic signaling pathway further established naringin cardioprotective potential as it upregulated Bcl-2 expression and downregulated Bax and Caspase-3 expression with reduced TUNEL positivity. Naringin also normalized the cardiac injury markers (lactate dehydrogenase and creatine kinase-MB), endogenous antioxidant activities (superoxide dismutase, reduced glutathione and glutathione peroxidase) and lipid peroxidation levels. Thus, naringin restored IR injury by preserving myocardial structural integrity and regulating Hsp27, Hsp70, p-eNOS/p-Akt/p-ERK signaling and inflammatory response. PMID:24324809

Biomechanics of Cardiac Function

PubMed Central

Voorhees, Andrew P.; Han, Hai-Chao

2015-01-01

The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments. PMID:26426462

Ca(2+) mishandling and cardiac dysfunction in obesity and insulin resistance: role of oxidative stress.

PubMed

Carvajal, Karla; Balderas-Villalobos, Jaime; Bello-Sanchez, Ma Dolores; Phillips-Farfán, Bryan; Molina-Muñoz, Tzindilu; Aldana-Quintero, Hugo; Gómez-Viquez, Norma L

2014-11-01

Obesity and insulin resistance (IR) are strongly connected to the development of subclinical cardiac dysfunction and eventually can lead to heart failure, which is the main cause of morbidity and death in patients having these metabolic diseases. It has been considered that excessive fat tissue may play a critical role in producing systemic IR and enhancing reactive oxygen species (ROS) generation. This oxidative stress (OS) may elicit or exacerbate IR. On the other hand, evidence suggests that some of the cellular mechanisms involved in the pathophysiology of obesity and IR-related cardiomyopathy are excessive myocardial ROS production and abnormal Ca(2+) homeostasis. In addition, emerging evidence suggests that augmented ROS production may contribute to Ca(2+) mishandling by affecting the redox state of key proteins implicated in this process. In this review, we focus on the role of Ca(2+) mishandling in the development of cardiac dysfunction in obesity and IR and address the evidence suggesting that OS might also contribute to cardiac dysfunction by affecting Ca(2+) handling. Copyright © 2014 Elsevier Ltd. All rights reserved.

Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.

PubMed

Zhang, Lei; Liu, Ming; Jiang, Hong; Yu, Ying; Yu, Peng; Tong, Rui; Wu, Jian; Zhang, Shuning; Yao, Kang; Zou, Yunzeng; Ge, Junbo

2016-03-01

Inflammation plays a key role in pressure overload-induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High-mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload-induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild-type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin-embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up-regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload-induced cardiac hypertrophy and cardiac dysfunction. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Cardiac Expression of Microsomal Triglyceride Transfer Protein Is Increased in Obesity and Serves to Attenuate Cardiac Triglyceride Accumulation

PubMed Central

Bartels, Emil D.; Nielsen, Jan M.; Hellgren, Lars I.; Ploug, Thorkil; Nielsen, Lars B.

2009-01-01

Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and β-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease. PMID:19390571

Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase.

PubMed

Dal-Secco, Daniela; DalBó, Silvia; Lautherbach, Natalia E S; Gava, Fábio N; Celes, Mara R N; Benedet, Patricia O; Souza, Adriana H; Akinaga, Juliana; Lima, Vanessa; Silva, Katiussia P; Kiguti, Luiz Ricardo A; Rossi, Marcos A; Kettelhut, Isis C; Pupo, André S; Cunha, Fernando Q; Assreuy, Jamil

2017-07-01

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore, G protein-coupled receptor kinase isoform 2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. Copyright © 2017 the American Physiological Society.

Attenuation-emission alignment in cardiac PET∕CT based on consistency conditions

PubMed Central

Alessio, Adam M.; Kinahan, Paul E.; Champley, Kyle M.; Caldwell, James H.

2010-01-01

Purpose: In cardiac PET and PET∕CT imaging, misaligned transmission and emission images are a common problem due to respiratory and cardiac motion. This misalignment leads to erroneous attenuation correction and can cause errors in perfusion mapping and quantification. This study develops and tests a method for automated alignment of attenuation and emission data. Methods: The CT-based attenuation map is iteratively transformed until the attenuation corrected emission data minimize an objective function based on the Radon consistency conditions. The alignment process is derived from previous work by Welch et al. [“Attenuation correction in PET using consistency information,” IEEE Trans. Nucl. Sci. 45, 3134–3141 (1998)] for stand-alone PET imaging. The process was evaluated with the simulated data and measured patient data from multiple cardiac ammonia PET∕CT exams. The alignment procedure was applied to simulations of five different noise levels with three different initial attenuation maps. For the measured patient data, the alignment procedure was applied to eight attenuation-emission combinations with initially acceptable alignment and eight combinations with unacceptable alignment. The initially acceptable alignment studies were forced out of alignment a known amount and quantitatively evaluated for alignment and perfusion accuracy. The initially unacceptable studies were compared to the proposed aligned images in a blinded side-by-side review. Results: The proposed automatic alignment procedure reduced errors in the simulated data and iteratively approaches global minimum solutions with the patient data. In simulations, the alignment procedure reduced the root mean square error to less than 5 mm and reduces the axial translation error to less than 1 mm. In patient studies, the procedure reduced the translation error by >50% and resolved perfusion artifacts after a known misalignment for the eight initially acceptable patient combinations. The side-by-side review of the proposed aligned attenuation-emission maps and initially misaligned attenuation-emission maps revealed that reviewers preferred the proposed aligned maps in all cases, except one inconclusive case. Conclusions: The proposed alignment procedure offers an automatic method to reduce attenuation correction artifacts in cardiac PET∕CT and provides a viable supplement to subjective manual realignment tools. PMID:20384256

The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.

PubMed

Calvier, Laurent; Martinez-Martinez, Ernesto; Miana, Maria; Cachofeiro, Victoria; Rousseau, Elodie; Sádaba, J Rafael; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

2015-01-01

This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside-binding lectin, is increased in heart failure and kidney injury. Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Cardiac-Specific Deletion of Pyruvate Dehydrogenase Impairs Glucose Oxidation Rates and Induces Diastolic Dysfunction.

PubMed

Gopal, Keshav; Almutairi, Malak; Al Batran, Rami; Eaton, Farah; Gandhi, Manoj; Ussher, John Reyes

2018-01-01

Obesity and type 2 diabetes (T2D) increase the risk for cardiomyopathy, which is the presence of ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. As myocardial energy metabolism is altered during obesity/T2D (increased fatty acid oxidation and decreased glucose oxidation), we hypothesized that restricting myocardial glucose oxidation in lean mice devoid of the perturbed metabolic milieu observed in obesity/T2D would produce a cardiomyopathy phenotype, characterized via diastolic dysfunction. We tested our hypothesis via producing mice with a cardiac-specific gene knockout for pyruvate dehydrogenase (PDH, gene name Pdha1 ), the rate-limiting enzyme for glucose oxidation. Cardiac-specific Pdha1 deficient ( Pdha1 Cardiac-/- ) mice were generated via crossing a tamoxifen-inducible Cre expressing mouse under the control of the alpha-myosin heavy chain (αMHC-MerCreMer) promoter with a floxed Pdha1 mouse. Energy metabolism and cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Tamoxifen administration produced an ~85% reduction in PDH protein expression in Pdha1 Cardiac-/- mice versus their control littermates, which resulted in a marked reduction in myocardial glucose oxidation and a corresponding increase in palmitate oxidation. This myocardial metabolism profile did not impair systolic function in Pdha1 Cardiac-/- mice, which had comparable left ventricular ejection fractions and fractional shortenings as their αMHC-MerCreMer control littermates, but did produce diastolic dysfunction as seen via the reduced mitral E/A ratio. Therefore, it does appear that forced restriction of glucose oxidation in the hearts of Pdha1 Cardiac-/- mice is sufficient to produce a cardiomyopathy-like phenotype, independent of the perturbed metabolic milieu observed in obesity and/or T2D.

Cardiac dysfunction and peri-weaning mortality in malonyl-coenzyme A decarboxylase (MCD) knockout mice as a consequence of restricting substrate plasticity.

PubMed

Aksentijević, Dunja; McAndrew, Debra J; Karlstädt, Anja; Zervou, Sevasti; Sebag-Montefiore, Liam; Cross, Rebecca; Douglas, Gillian; Regitz-Zagrosek, Vera; Lopaschuk, Gary D; Neubauer, Stefan; Lygate, Craig A

2014-10-01

Inhibition of malonyl-coenzyme A decarboxylase (MCD) shifts metabolism from fatty acid towards glucose oxidation, which has therapeutic potential for obesity and myocardial ischemic injury. However, ~40% of patients with MCD deficiency are diagnosed with cardiomyopathy during infancy. To clarify the link between MCD deficiency and cardiac dysfunction in early life and to determine the contributing systemic and cardiac metabolic perturbations. MCD knockout mice ((-/-)) exhibited non-Mendelian genotype ratios (31% fewer MCD(-/-)) with deaths clustered around weaning. Immediately prior to weaning (18days) MCD(-/-) mice had lower body weights, elevated body fat, hepatic steatosis and glycogen depletion compared to wild-type littermates. MCD(-/-) plasma was hyperketonemic, hyperlipidemic, had 60% lower lactate levels and markers of cellular damage were elevated. MCD(-/-) hearts exhibited hypertrophy, impaired ejection fraction and were energetically compromised (32% lower total adenine nucleotide pool). However differences between WT and MCD(-/-) converged with age, suggesting that, in surviving MCD(-/-) mice, early cardiac dysfunction resolves over time. These observations were corroborated by in silico modelling of cardiomyocyte metabolism, which indicated improvement of the MCD(-/-) metabolic phenotype and improved cardiac efficiency when switched from a high-fat diet (representative of suckling) to a standard post-weaning diet, independent of any developmental changes. MCD(-/-) mice consistently exhibited cardiac dysfunction and severe metabolic perturbations while on a high-fat, low carbohydrate diet of maternal milk and these gradually resolved post-weaning. This suggests that dysfunction is a common feature of MCD deficiency during early development, but that severity is dependent on composition of dietary substrates. Copyright © 2014. Published by Elsevier Ltd.

Milrinone for cardiac dysfunction in critically ill adult patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

PubMed

Koster, Geert; Bekema, Hanneke J; Wetterslev, Jørn; Gluud, Christian; Keus, Frederik; van der Horst, Iwan C C

2016-09-01

Milrinone is an inotrope widely used for treatment of cardiac failure. Because previous meta-analyses had methodological flaws, we decided to conduct a systematic review of the effect of milrinone in critically ill adult patients with cardiac dysfunction. This systematic review was performed according to The Cochrane Handbook for Systematic Reviews of Interventions. Searches were conducted until November 2015. Patients with cardiac dysfunction were included. The primary outcome was serious adverse events (SAE) including mortality at maximum follow-up. The risk of bias was evaluated and trial sequential analyses were conducted. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria. A total of 31 randomised clinical trials fulfilled the inclusion criteria, of which 16 provided data for our analyses. All trials were at high risk of bias, and none reported the primary composite outcome SAE. Fourteen trials with 1611 randomised patients reported mortality data at maximum follow-up (RR 0.96; 95% confidence interval 0.76-1.21). Milrinone did not significantly affect other patient-centred outcomes. All analyses displayed statistical and/or clinical heterogeneity of patients, interventions, comparators, outcomes, and/or settings and all featured missing data. The current evidence on the use of milrinone in critically ill adult patients with cardiac dysfunction suffers from considerable risks of both bias and random error and demonstrates no benefits. The use of milrinone for the treatment of critically ill patients with cardiac dysfunction can be neither recommended nor refuted. Future randomised clinical trials need to be sufficiently large and designed to have low risk of bias.

Cardiac dysfunction and peri-weaning mortality in malonyl-coenzyme A decarboxylase (MCD) knockout mice as a consequence of restricting substrate plasticity

PubMed Central

Aksentijević, Dunja; McAndrew, Debra J.; Karlstädt, Anja; Zervou, Sevasti; Sebag-Montefiore, Liam; Cross, Rebecca; Douglas, Gillian; Regitz-Zagrosek, Vera; Lopaschuk, Gary D.; Neubauer, Stefan; Lygate, Craig A.

2014-01-01

Inhibition of malonyl-coenzyme A decarboxylase (MCD) shifts metabolism from fatty acid towards glucose oxidation, which has therapeutic potential for obesity and myocardial ischemic injury. However, ~ 40% of patients with MCD deficiency are diagnosed with cardiomyopathy during infancy. Aim To clarify the link between MCD deficiency and cardiac dysfunction in early life and to determine the contributing systemic and cardiac metabolic perturbations. Methods and results MCD knockout mice (−/−) exhibited non-Mendelian genotype ratios (31% fewer MCD−/−) with deaths clustered around weaning. Immediately prior to weaning (18 days) MCD−/− mice had lower body weights, elevated body fat, hepatic steatosis and glycogen depletion compared to wild-type littermates. MCD−/− plasma was hyperketonemic, hyperlipidemic, had 60% lower lactate levels and markers of cellular damage were elevated. MCD−/− hearts exhibited hypertrophy, impaired ejection fraction and were energetically compromised (32% lower total adenine nucleotide pool). However differences between WT and MCD−/− converged with age, suggesting that, in surviving MCD−/− mice, early cardiac dysfunction resolves over time. These observations were corroborated by in silico modelling of cardiomyocyte metabolism, which indicated improvement of the MCD−/− metabolic phenotype and improved cardiac efficiency when switched from a high-fat diet (representative of suckling) to a standard post-weaning diet, independent of any developmental changes. Conclusions MCD−/− mice consistently exhibited cardiac dysfunction and severe metabolic perturbations while on a high-fat, low carbohydrate diet of maternal milk and these gradually resolved post-weaning. This suggests that dysfunction is a common feature of MCD deficiency during early development, but that severity is dependent on composition of dietary substrates. PMID:25066696

RNase alleviates neurological dysfunction in mice undergoing cardiac arrest and cardiopulmonary resuscitation

PubMed Central

Ma, Ye; Chen, Chan; Zhang, Shu; Wang, Qiao; Chen, Hai; Dong, Yuanlin; Zhang, Zheng; Li, Yan; Niu, Zhendong; Zhu, Tao; Yu, Hai; Liu, Bin

2017-01-01

Cardiac arrest (CA) is one of the leading lethal factors. Despite cardiopulmonary resuscitation (CPR) procedure has been consecutively improved and lots of new strategies have been developed, neurological outcome of the patients experienced CPR is still disappointing. Ribonuclease (RNase) has been demonstrated to have neuroprotective effects in acute stroke and postoperative cognitive impairment, possibly through acting against endogenous RNA that released from damaged tissue. However, the role of RNase in post-cardiac arrest cerebral injury is unknown. In the present study, we investigated the role of RNase in neurological outcome of mice undergoing 5 minutes of CA and followed by CPR. RNase or the same dosage of normal saline was administrated. We found that RNase administration could: 1) improve neurologic score on day 1 and day 3 after CA/CPR performance; 2) improve memory and learning ability on day 3 after training in contextual fear-conditioning test; 3) reduce extracellular RNA (exRNA) level in plasma and hippocampus tissue, and hippocampal cytokines mRNA production on day 3 after CA/CPR procedure; 4) attenuate autophagy levels in hippocampus tissue on day 3 after CA/CPR procedure. In conclusion, RNase could improve neurological function by reducing inflammation response and autophagy in mice undergoing CA/CPR. PMID:28881795

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation.

PubMed

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie; Yi, Qijian

2017-01-01

Background . This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods . Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results . The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions . The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281.

Modern nuclear cardiac imaging in diagnosis and clinical management of patients with left ventricular dysfunction.

PubMed

Abidov, A; Hachamovitch, R; Berman, D S

2004-12-01

Congestive heart failure (CHF) has become a large social burden in modern Western society, with very high morbidity and mortality and extremely large financial costs. The largest cause of CHF is coronary heart disease, with ventricular dysfunction that may or may not be reversible by revascularization. Thus, evaluation of the viable myocardial tissue in patients with ischemic left ventricular (LV) dysfunction has important clinical and therapeutic implications. Furthermore, since patients with ventricular dysfunction are at higher operative risk, cardiologists and cardiac surgeons are commonly faced with issues regarding the balance between the potential risk vs benefit of revascularization procedures. Cardiac nuclear imaging [myocardial perfusion SPECT (MPS) and positron emission tomography (PET)] provide objective information that augments standard clinical and angiographic assessments of patients with ventricular dysfunction with respect to diagnosis (etiology), prognosis, and potential benefit from intervention. Development of the technology and methodology of gated MPS, now the routine method for MPS, allows assessment of the extent and severity of inducible ischemia as well as hypoperfused but viable myocardium, and also provides measurements of LV ejection fraction, regional wall motion, LV volume measurements, diastolic function and LV geometry. With PET, myocardial metabolism and blood flow reserve can be added to the measurements provided by nuclear cardiology procedures. This paper provides insight into the current evidence regarding settings in which nuclear cardiac imaging procedures are helpful in assessment of patients in the setting of coronary artery disease with severe LV dysfunction. A risk-benefit approach to MPS results is proposed, with principal focus on identifying patients at risk for major cardiac events who may benefit from myocardial revascularization.

Effects of Age and Heart Failure on Human Cardiac Stem Cell Function

PubMed Central

Cesselli, Daniela; Beltrami, Antonio P.; D'Aurizio, Federica; Marcon, Patrizia; Bergamin, Natascha; Toffoletto, Barbara; Pandolfi, Maura; Puppato, Elisa; Marino, Laura; Signore, Sergio; Livi, Ugolino; Verardo, Roberto; Piazza, Silvano; Marchionni, Luigi; Fiorini, Claudia; Schneider, Claudio; Hosoda, Toru; Rota, Marcello; Kajstura, Jan; Anversa, Piero; Beltrami, Carlo A.; Leri, Annarosa

2011-01-01

Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21Cip1 and p16INK4a expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy. PMID:21703415

Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation

PubMed Central

Hasumi, Yukiko; Baba, Masaya; Hasumi, Hisashi; Huang, Ying; Lang, Martin; Reindorf, Rachel; Oh, Hyoung-bin; Sciarretta, Sebastiano; Nagashima, Kunio; Haines, Diana C.; Schneider, Michael D.; Adelstein, Robert S.; Schmidt, Laura S.; Sadoshima, Junichi; Marston Linehan, W.

2014-01-01

Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model. PMID:24908670

Cardiac oxidative stress following maternal separation stress was mitigated following adolescent voluntary exercise in adult male rat.

PubMed

Sahafi, Ehtramolsadat; Peeri, Maghsoud; Hosseini, Mir-Jamal; Azarbyjani, Mohammad Ali

2018-01-01

Early life stress (ELS) is known as a risk factor for the development of depression and its associated comorbidities, such as cardiomyopathy in depressed patients. Mitochondrial dysfunction plays a critical role in the pathophysiology of depression and cardiovascular diseases. Evidence indicates that regular physical activity has therapeutic effects on both mood and cardiovascular disorders. Therefore, the voluntary running wheel exercise (RW) during adolescence may be able to attenuate the negative impact of maternal separation stress (MS) as a valid animal model of depression on the behavior and cardiac mitochondrial function of adult rats. To do this, we applied MS to rat pups by separating them from their mothers for 180min during the postnatal day (PND) 2 to PND 14. Next, the animals were randomly divided into different treatment groups (fluoxetine [FLX] and RW) and received the treatments during adolescence, between PND 28 to PND 60. Then, we evaluated the effects of MS on the rat behaviors test, and finally, we assessed reactive oxygen species, mitochondrial glutathione, ATP and cytochrome c release in the cardiac tissue of animals. Our results showed that depressive-like behaviors following MS in adult male rats were associated with oxidative stress in cardiac tissue. Further, we found that treating animals with chronic FLX or RW during adolescence improved animal's behavior as well as cardiac mitochondrial function. The results of this study highlight the importance of adolescence as a period during which treating animals with non-pharmacological agents has significant protective effects against the negative influence of ELS on mood and cardiac energy hemostasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Carbachol inhibits TNF-α-induced endothelial barrier dysfunction through alpha 7 nicotinic receptors.

PubMed

Li, Yu-zhen; Liu, Xiu-hua; Rong, Fei; Hu, Sen; Sheng, Zhi-yong

2010-10-01

To test whether carbachol can influence endothelial barrier dysfunction induced by tumor necrosis factor (TNF)-α and whether the alpha 7 nicotinic receptor can mediate this process. Rat cardiac microvascular endothelial cells were exposed to carbachol followed by TNF-α treatment in the presence or the absence of α-bungarotoxin (an antagonist of the alpha 7 nicotinic receptor). Permeability of endothelial cells cultured on Transwell filters was assayed using FITC-albumin. F-actin was stained with FITC- phalloidin. Expression of vascular endothelial cadherin, intercellular adhesion molecule 1 (ICAM-1), phosphor-ERK1/2 and phosphor-JNK was detected using Western blot. Carbachol (2 μmol/L-2 mmol/L) prevented increase in endothelial cell permeability induced by TNF-α (500 ng/mL) in a dose-dependent manner. Further, it attenuated the down-regulation of vascular endothelial cadherin and the up-regulation of ICAM-1 induced by TNF-α. In addition, treatment of endothelial cells with carbachol decreased phosphor-ERK1/2 and phosphor-JNK. These effects of carbachol were blocked by α-bungarotoxin 3 μg/mL. These data suggest that the inhibitory effect of carbachol on TNF-α-induced endothelial barrier dysfunction mediated by the alpha 7 nicotinic receptor.

Carbachol inhibits TNF-α-induced endothelial barrier dysfunction through alpha 7 nicotinic receptors

PubMed Central

Li, Yu-zhen; Liu, Xiu-hua; Rong, Fei; Hu, Sen; Sheng, Zhi-yong

2010-01-01

Aim: To test whether carbachol can influence endothelial barrier dysfunction induced by tumor necrosis factor (TNF)-α and whether the alpha 7 nicotinic receptor can mediate this process. Methods: Rat cardiac microvascular endothelial cells were exposed to carbachol followed by TNF-α treatment in the presence or the absence of α-bungarotoxin (an antagonist of the alpha 7 nicotinic receptor). Permeability of endothelial cells cultured on Transwell filters was assayed using FITC-albumin. F-actin was stained with FITC- phalloidin. Expression of vascular endothelial cadherin, intercellular adhesion molecule 1 (ICAM-1), phosphor-ERK1/2 and phosphor-JNK was detected using Western blot. Results: Carbachol (2 μmol/L-2 mmol/L) prevented increase in endothelial cell permeability induced by TNF-α (500 ng/mL) in a dose-dependent manner. Further, it attenuated the down-regulation of vascular endothelial cadherin and the up-regulation of ICAM-1 induced by TNF-α. In addition, treatment of endothelial cells with carbachol decreased phosphor-ERK1/2 and phosphor-JNK. These effects of carbachol were blocked by α-bungarotoxin 3 μg/mL. Conclusion: These data suggest that the inhibitory effect of carbachol on TNF-α-induced endothelial barrier dysfunction mediated by the alpha 7 nicotinic receptor. PMID:20871620

Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1.

PubMed

Wu, Bing; Yu, Lu; Wang, Yishi; Wang, Hongtao; Li, Chen; Yin, Yue; Yang, Jingrun; Wang, Zhifa; Zheng, Qiangsun; Ma, Heng

2016-01-19

Cardiac aging is characterized by accumulation of damaged proteins and decline of autophagic efficiency. Here, by forestalling SIRT1 carbonylated inactivation in aged heart, we determined the benefits of activation of aldehyde dehydrogenase 2 (ALDH2) on the autophagy. In this study, the ALDH2 KO mice progressively developed age-related heart dysfunction and showed reduction in the life span, which strongly suggests that ALDH2 ablation leads to cardiac aging. What's more, aged hearts displayed a significant decrease ALDH2 activity, resulting in accumulation of 4-HNE-protein adducts and protein carbonyls, impairment in the autophagy flux, and, consequently, deteriorated cardiac function after starvation. Sustained Alda-1 (selective ALDH2 activator) treatment increased cardiac ALDH2 activity and abrogated these effects. Using SIRT1 deficient heterozygous (Sirt1+/-) mice, we found that SIRT1 was necessary for ALDH2 activation-induced autophagy. We further demonstrated that ALDH2 activation attenuated SIRT1 carbonylation and improved SIRT1 activity, thereby increasing the deacetylation of nuclear LC3 and FoxO1. Sequentially, ALDH2 enhanced SIRT1 regulates LC3-Atg7 interaction and FoxO1 increased Rab7 expression, which were both necessary and sufficient for restoring autophagy flux. These results highlight that both accumulation of proteotoxic carbonyl stress linkage with autophagy decline contribute to heart senescence. ALDH2 activation is adequate to improve the autophagy flux by reducing the carbonyl modification on SIRT1, which in turn plays an important role in maintaining cardiac health during aging.

Brain-Heart Interaction: Cardiac Complications After Stroke.

PubMed

Chen, Zhili; Venkat, Poornima; Seyfried, Don; Chopp, Michael; Yan, Tao; Chen, Jieli

2017-08-04

Neurocardiology is an emerging specialty that addresses the interaction between the brain and the heart, that is, the effects of cardiac injury on the brain and the effects of brain injury on the heart. This review article focuses on cardiac dysfunction in the setting of stroke such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage. The majority of post-stroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of post-stroke mortality. Accumulating clinical and experimental evidence suggests a causal relationship between brain damage and heart dysfunction. Thus, it is important to determine whether cardiac dysfunction is triggered by stroke, is an unrelated complication, or is the underlying cause of stroke. Stroke-induced cardiac damage may lead to fatality or potentially lifelong cardiac problems (such as heart failure), or to mild and recoverable damage such as neurogenic stress cardiomyopathy and Takotsubo cardiomyopathy. The role of location and lateralization of brain lesions after stroke in brain-heart interaction; clinical biomarkers and manifestations of cardiac complications; and underlying mechanisms of brain-heart interaction after stroke, such as the hypothalamic-pituitary-adrenal axis; catecholamine surge; sympathetic and parasympathetic regulation; microvesicles; microRNAs; gut microbiome, immunoresponse, and systemic inflammation, are discussed. © 2017 American Heart Association, Inc.

Inflammatory response and extracorporeal circulation.

PubMed

Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

2015-06-01

Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

PubMed Central

Shi, Qiang; Liu, Xiaoyan; Bai, Yuanyuan; Cui, Chuanjue; Li, Jun; Li, Yishi; Hu, Shengshou; Wei, Yingjie

2011-01-01

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling. PMID:22132230

Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

PubMed

Li, Chao; Zhang, Yu Yao; Frieler, Ryan A; Zheng, Xiao Jun; Zhang, Wu Chang; Sun, Xue Nan; Yang, Qing Zhen; Ma, Shu Min; Huang, Baozhuan; Berger, Stefan; Wang, Wang; Wu, Yong; Yu, Ying; Duan, Sheng Zhong; Mortensen, Richard M

2014-01-01

Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

Urocortin Treatment Improves Acute Hemodynamic Instability and Reduces Myocardial Damage in Post-Cardiac Arrest Myocardial Dysfunction

PubMed Central

Huang, Chien-Hua; Wang, Chih-Hung; Tsai, Min-Shan; Hsu, Nai-Tan; Chiang, Chih-Yen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

2016-01-01

Aims Hemodynamic instability occurs following cardiac arrest and is associated with high mortality during the post-cardiac period. Urocortin is a novel peptide and a member of the corticotrophin-releasing factor family. Urocortin has the potential to improve acute cardiac dysfunction, as well as to reduce the myocardial damage sustained after ischemia reperfusion injury. The effects of urocortin in post-cardiac arrest myocardial dysfunction remain unclear. Methods and Results We developed a preclinical cardiac arrest model and investigated the effects of urocortin. After cardiac arrest induced by 6.5 min asphyxia, male Wistar rats were resuscitated and randomized to either the urocortin treatment group or the control group. Urocortin (10 μg/kg) was administrated intravenously upon onset of resuscitation in the experimental group. The rate of return of spontaneous circulation (ROSC) was similar between the urocortin group (76%) and the control group (72%) after resuscitation. The left ventricular systolic (dP/dt40) and diastolic (maximal negative dP/dt) functions, and cardiac output, were ameliorated within 4 h after ROSC in the urocortin-treated group compared to the control group (P<0.01). The neurological function of surviving animals was better at 6 h after ROSC in the urocortin-treated group (p = 0.023). The 72-h survival rate was greater in the urocortin-treated group compared to the control group (p = 0.044 by log-rank test). Cardiomyocyte apoptosis was lower in the urocortin-treated group (39.9±8.6 vs. 17.5±4.6% of TUNEL positive nuclei, P<0.05) with significantly increased Akt, ERK and STAT-3 activation and phosphorylation in the myocardium (P<0.05). Conclusions Urocortin treatment can improve acute hemodynamic instability as well as reducing myocardial damage in post-cardiac arrest myocardial dysfunction. PMID:27832152

Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Xin-Ai; Jia, Lin-Lin; Cui, Wei

We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heartmore » weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of TNF-α attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of TNF-α attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of TNF-α attenuates hypertension-induced imbalance of cytokines. • PVN inhibition of TNF-α attenuates PVN NF-κB p65 activity and oxidative stress.« less

Comparison of purple carrot juice and β-carotene in a high-carbohydrate, high-fat diet-fed rat model of the metabolic syndrome.

PubMed

Poudyal, Hemant; Panchal, Sunil; Brown, Lindsay

2010-11-01

Anthocyanins, phenolic acids and carotenoids are the predominant phytochemicals present in purple carrots. These phytochemicals could be useful in treatment of the metabolic syndrome since anthocyanins improve dyslipidaemia, glucose tolerance, hypertension and insulin resistance; the phenolic acids may also protect against CVD and β-carotene may protect against oxidative processes. In the present study, we have compared the ability of purple carrot juice and β-carotene to reverse the structural and functional changes in rats fed a high-carbohydrate, high-fat diet as a model of the metabolic syndrome induced by diet. Cardiac structure and function were defined by histology, echocardiography and in isolated hearts and blood vessels; liver structure and function, oxidative stress and inflammation were defined by histology and plasma markers. High-carbohydrate, high-fat diet-fed rats developed hypertension, cardiac fibrosis, increased cardiac stiffness, endothelial dysfunction, impaired glucose tolerance, increased abdominal fat deposition, altered plasma lipid profile, liver fibrosis and increased plasma liver enzymes together with increased plasma markers of oxidative stress and inflammation as well as increased inflammatory cell infiltration. Purple carrot juice attenuated or reversed all changes while β-carotene did not reduce oxidative stress, cardiac stiffness or hepatic fat deposition. As the juice itself contained low concentrations of carotenoids, it is likely that the anthocyanins are responsible for the antioxidant and anti-inflammatory properties of purple carrot juice to improve glucose tolerance as well as cardiovascular and hepatic structure and function.

Cardiac structure and function in relation to cardiovascular risk factors in Chinese

PubMed Central

2012-01-01

Background Cardiac structure and function are well-studied in Western countries. However, epidemiological data is still scarce in China. Methods Our study was conducted in the framework of cardiovascular health examinations for the current and retired employees of a factory and their family members. According to the American Society of Echocardiography recommendations, we performed echocardiography to evaluate cardiac structure and function, including left atrial volume, left ventricular hypertrophy and diastolic dysfunction. Results The 843 participants (43.0 years) included 288 (34.2%) women, and 191 (22.7%) hypertensive patients, of whom 82 (42.9%) took antihypertensive drugs. The prevalence of left atrial enlargement, left ventricular hypertrophy and concentric remodeling was 2.4%, 5.0% and 12.7%, respectively. The prevalence of mild and moderate-to-severe left ventricular diastolic dysfunction was 14.2% and 3.3%, respectively. The prevalence of these cardiac abnormalities significantly (P ≤ 0.002) increased with age, except for the moderate-to-severe left ventricular diastolic dysfunction. After adjustment for age, gender, body height and body weight, left atrial enlargement was associated with plasma glucose (P = 0.009), and left ventricular hypertrophy and diastolic dysfunction were significantly associated with systolic and diastolic blood pressure (P ≤ 0.03), respectively. Conclusions The prevalence of cardiac structural and functional abnormalities increased with age in this Chinese population. Current drinking and plasma glucose had an impact on left atrial enlargement, whereas systolic and diastolic blood pressures were major correlates for left ventricular hypertrophy and diastolic dysfunction, respectively. PMID:23035836

C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway.

PubMed

Wu, Leiming; Gao, Lu; Zhang, Dianhong; Yao, Rui; Huang, Zhen; Du, Binbin; Wang, Zheng; Xiao, Lili; Li, Pengcheng; Li, Yapeng; Liang, Cui; Zhang, Yanzhou

2018-06-01

Complement C1q tumor necrosis factor related proteins (C1QTNFs) have been reported to have diverse biological influence on the cardiovascular system. C1QTNF1 is a member of the CTRP superfamily. C1QTNF1 is expressed in the myocardium; however, its function in myocytes has not yet been investigated. To systematically investigate the roles of C1QTNF1 in angiotensin II (Ang II)-induced cardiac hypertrophy. C1QTNF1 knock-out mice were used with the aim of determining the role of C1QTNF1 in cardiac hypertrophy in the adult heart. Data from experiments showed that C1QTNF1 was up-regulated during cardiac hypertrophic processes, which were triggered by increased reactive oxygen species. C1QTNF1 deficiency accelerated cardiac hypertrophy, fibrosis, inflammation responses, and oxidative stress with deteriorating cardiac dysfunction in the Ang II-induced cardiac hypertrophy mouse model. We identified C1QTNF1 as a negative regulator of cardiomyocyte hypertrophy in Ang II-stimulated neonatal rat cardiomyocytes using the recombinant human globular domain of C1QTNF1 and C1QTNF1 siRNA. Injection of the recombinant human globular domain of C1QTNF1 also suppressed the Ang II-induced cardiac hypertrophic response in vivo. The anti-hypertrophic effects of C1QTNF1 rely on AMPKa activation, which inhibits mTOR P70S6K phosphorylation. An AMPKa inhibitor abrogated the anti-hypertrophic effects of the recombinant human globular domain of C1QTNF1 both in vivo and vitro. Moreover, C1QTNF1-mediated AMPKa activation was triggered by the inhibition of PDE1-4, which subsequently activated the cAMP/PKA/LKB1 pathway. Our results demonstrated that C1QTNF1 improves cardiac function and inhibits cardiac hypertrophy and fibrosis by increasing and activating AMPKa, suggesting that C1QTNF1 could be a therapeutic target for cardiac hypertrophy and heart failure. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of Obesity on Cardiovascular Hemodynamics, Cardiac Morphology, and Ventricular Function.

PubMed

Alpert, Martin A; Omran, Jad; Bostick, Brian P

2016-12-01

Obesity produces a variety of hemodynamic alterations that may cause changes in cardiac morphology which predispose to left and right ventricular dysfunction. Various neurohormonal and metabolic alterations commonly associated with obesity may contribute to these abnormalities of cardiac structure and function. These changes in cardiovascular hemodynamics, cardiac morphology, and ventricular function may, in severely obese patients, predispose to heart failure, even in the absence of other forms of heart disease (obesity cardiomyopathy). In normotensive obese patients, cardiac involvement is commonly characterized by elevated cardiac output, low peripheral vascular resistance, and increased left ventricular (LV) end-diastolic pressure. Sleep-disordered breathing may lead to pulmonary arterial hypertension and, in association with left heart failure, may contribute to elevation of right heart pressures. These alterations, in association with various neurohormonal and metabolic abnormalities, may produce LV hypertrophy; impaired LV diastolic function; and less commonly, LV systolic dysfunction. Many of these alterations are reversible with substantial voluntary weight loss.

Evolution of echocardiography in subclinical detection of cancer therapy-related cardiac dysfunction.

PubMed

Moudgil, Rohit; Hassan, Saamir; Palaskas, Nicolas; Lopez-Mattei, Juan; Banchs, Jose; Yusuf, Syed Wamique

2018-05-11

Cancer therapies have resulted in increased survivorship in oncological patients. However, the benefits have been marred by the development of premature cardiovascular disease. The current definition outlines measurement of ejection fraction as a mean to diagnose cancer therapeutic-related cardiac dysfunction (CTRCD); however, up to 58% of the patients do not regain their cardiac function after the CTRCD diagnosis, despite therapeutic interventions. Therefore, there has been a growing interest in the markers for early myocardial changes (ie, changes with normal left ventricular ejection fraction [LVEF]) that may predict the development of subsequent left ventricular ejection fraction reduction or progression to heart failure. This review will highlight the use of diastolic parameters, tissue Doppler imaging (TDI), and speckle tracking echocardiogram (STE) as emerging technologies which can potentially detect cardiac dysfunction thereby stratifying patients for cardioprotective therapies. The goal of this manuscript was to highlight the concepts and discuss the current controversies surrounding these echocardiographic imaging modalities. © 2018 Wiley Periodicals, Inc.

The way to a man's heart is through his stomach: much 'diaphragmatic' attenuation is likely gastric, and effervescent granules enhance cardiac imaging.

PubMed

Munn, Samson

2004-12-01

Avoidance of falsely positive results depends on distinguishing reality from artifact, in turn depending on images of highest quality. In radionuclide cardiac imaging, an inferior wall artifactual defect, so called "diaphragmatic attenuation", is particularly common and vexing. Despite the historically held view, analysis and review of the literature suggest the defect is likely not diaphragmatic but rather primarily due to attenuation by nearby stomach wall. The explanation is based on gravity and anatomy. With this improved understanding, effervescent granules were given as a clinical, nonresearch measure to nine patients during myocardial scanning. It was observed that two-thirds demonstrated moderate or marked lessening of attenuation. An additional benefit is lessening of artifact by extracardiac activity. These benefits may also apply to other sorts of cardiac radionuclide imaging. The significance of this new imaging method is discussed and various avenues of research are proposed.

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

PubMed Central

Bakeer, Nihal; James, Jeanne; Roy, Swarnava; Wansapura, Janaka; Shanmukhappa, Shiva Kumar; Lorenz, John N.; Osinska, Hanna; Backer, Kurt; Huby, Anne-Cecile; Shrestha, Archana; Niss, Omar; Fleck, Robert; Quinn, Charles T.; Taylor, Michael D.; Purevjav, Enkhsaikhan; Aronow, Bruce J.; Towbin, Jeffrey A.; Malik, Punam

2016-01-01

Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA. PMID:27503873

Transesophageal Echocardiography, 3-Dimensional and Speckle Tracking Together as Sensitive Markers for Early Outcome in Patients With Left Ventricular Dysfunction Undergoing Cardiac Surgery.

PubMed

Kumar, Alok; Puri, Goverdhan Dutt; Bahl, Ajay

2017-10-01

Speckle tracking, when combined with 3-dimensional (3D) left ventricular ejection fraction, might prove to be a more sensitive marker for postoperative ventricular dysfunction. This study investigated early outcomes in a cohort of patients with left ventricular dysfunction undergoing cardiac surgery. Prospective, blinded, observational study. University hospital; single institution. The study comprised 73 adult patients with left ventricular ejection fraction <50% undergoing cardiac surgery using cardiopulmonary bypass. Routine transesophageal echocardiography before and after bypass. Global longitudinal strain using speckle tracking and 3D left ventricular ejection fraction were computed using transesophageal echocardiography. Mean prebypass global longitudinal strain and 3D left ventricle ejection fraction were significantly lower in patients with postoperative low-cardiac-output syndrome compared with patients who did not develop low cardiac output (global longitudinal strain -7.5% v -10.7% and 3D left ventricular ejection fraction 29% v 39%, respectively; p < 0.0001). The cut-off value of global longitudinal strain predicting postoperative low-cardiac-output syndrome was -6%, with 95% sensitivity and 68% specificity; and 3D left ventricular ejection fraction was 19% with 98% sensitivity and 81% specificity. Preoperative left ventricular global longitudinal strain (-6%) and 3D left ventricular ejection fraction (19%) together could act as predictor of postoperative low-cardiac-output states with high sensitivity (99.9%) in patients undergoing cardiac surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes.

PubMed

Sultana, Md Razia; Bagul, Pankaj K; Katare, Parameshwar B; Anwar Mohammed, Soheb; Padiya, Raju; Banerjee, Sanjay K

2016-11-01

Cardiac complications are major contributor in the mortality of diabetic people. Mitochondrial dysfunctioning is a crucial contributor for the cardiac complications in diabetes, and SIRT-3 remains the major mitochondrial deacetylase. We hypothesized whether garlic has any role on SIRT-3 to prevent mitochondrial dysfunction in diabetic heart. Rats with developed hyperglycemia after STZ injection were divided into two groups; diabetic (Dia) and diabetic+garlic (Dia+Garl). Garlic was administered at a dose of 250mg/kg/day, orally for four weeks. An additional group was maintained to evaluate the effect of raw garlic administration on control rat heart. We have observed altered functioning of cardiac mitochondrial enzymes involved in metabolic pathways, and increased levels of cardiac ROS with decreased activity of catalase and SOD in diabetic rats. Cardiac mRNA expression of TFAM, PGC-1α, and CO1 was also altered in diabetes. In addition, reduced levels of electron transport chain complexes that observed in Dia group were normalized with garlic administration. This indicates the presence of increased oxidative stress with mitochondrial dysfunctioning in diabetic heart. We have observed reduced activity of SIRT3 and increased acetylation of MnSOD. Silencing SIRT-3 in cells also revealed the same. However, administration of garlic improved the SIRT-3 and MnSOD activity, by deacetylating MnSOD. Increased SOD activity was correlated with reduced levels of ROS in garlic-administered rat hearts. Collectively, our results provide an insight into garlic's protection to T1DM heart through activation of SIRT3-MnSOD pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Erectile Dysfunction: A Sign of Heart Disease?

MedlinePlus

... e609. Cunningham GR, et al. Overview of male sexual dysfunction. http://www.uptodate.com/home. Accessed July 8, ... G, et al. The second Princeton consensus on sexual dysfunction and cardiac risk: New guidelines for sexual medicine. ...

Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart

PubMed Central

Croston, Tara L.; Thapa, Dharendra; Holden, Anthony A.; Tveter, Kevin J.; Lewis, Sara E.; Shepherd, Danielle L.; Nichols, Cody E.; Long, Dustin M.; Olfert, I. Mark; Jagannathan, Rajaganapathi

2014-01-01

The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P ≤ 0.05 for both), with a concomitant decline in their levels (P ≤ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels. PMID:24778174

Exercise through a cardiac rehabilitation program attenuates oxidative stress in patients submitted to coronary artery bypass grafting.

PubMed

Taty Zau, José Francisco; Costa Zeferino, Rodrigo; Sandrine Mota, Nádia; Fernandes Martins, Gerez; Manoel Serra, Salvador; Bonates da Cunha, Therezil; Medeiros Lima, Daniel; Bragança Pereira, Basilio de; Matos do Nascimento, Emília; Filho, Danilo Wilhelm; Curi Pedrosa, Rozangela; Pedrosa, Roberto Coury

2018-12-01

Cardiovascular disease is the main cause of morbidity and mortality in the world and oxidative stress has been implicated in the pathogenesis. Cardiac rehabilitation in patients with coronary artery disease submitted to coronary artery bypass grafting may prevent cardiovascular events probably through the attenuation of oxidative stress. The aim of this study was to evaluate the benefits of a cardiac rehabilitation program in the control of the systemic oxidative stress. The studied population consisted of 40 patients, with chronic stable coronary artery disease submitted to coronary artery bypass grafting, who attended a cardiac rehabilitation program. Biomarkers of oxidative stress were evaluated in the blood of these patients at different moments. After the onset of cardiac rehabilitation, there was a significant and progressive decrease in thiobarbituric acid reactive substances levels and protein carbonyls, an initial increase and subsequent decrease in superoxide dismutase, catalase and glutathione peroxidase activities. Also, a progressive increase of uric acid, while ferric reducing antioxidant power levels increased only at the end of the cardiac rehabilitation and a tendency to increase of glutathione contents. The results suggest that regular exercise through a cardiac rehabilitation program can attenuate oxidative stress in chronic coronary artery disease patients submitted to coronary artery bypass grafting.

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes

PubMed Central

Tae, Hyun-Jin; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2015-01-01

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/− mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2–4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6–14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS. PMID:26566724

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

PubMed

Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2016-01-15

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

Value of speckle tracking echocardiography for detection of clinically silent left ventricular dysfunction in patients with β-thalassemia.

PubMed

Parsaee, Mozhgan; Saedi, Sedigheh; Joghataei, Pegah; Azarkeivan, Azita; Alizadeh Sani, Zahra

2017-10-01

β-Thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia requiring chronic transfusion therapy. Cardiac involvement is the main cause of death in patients with thalassemia major. The narrow border is between overt myocardial dysfunction and clinically silent left ventricular (LV) dysfunction in patients with thalassemia. Therefore, we need novel parameters in different imaging techniques to discover cardiac involvement in an early and subtle stage. We explore to find a novel, straightforward and informative parameter in echocardiography as a noninvasive, economical and really routine in clinical practice. In this prospective study, 55 patients, who are known cases of β-thalassemia major, receiving long-term blood transfusions and undergoing iron chelation therapy were enrolled. Ferritin level, cardiac magnetic resonance (CMR) T2 * value, full conventional echocardiography and speckle tracking, LV regional circumferential and longitudinal strain values (%) and time-to-peak strain (ms) of 17 segments cardiac model in eyeball tomogram were measured. There was a significant reduction in global longitudinal strain (GLS) (-20.9% ± 1.9 vs. -22.2 ± 1.03) and also basal segments longitudinal strain compared to normal subjects group (-17.4% ± 2.7 vs. -19.6% ± 1.2). There was no significant difference in circumferential strain value between thalassemia patients and normal control group. Interestingly, there was no significant correlation between GLS and CMR T2 * values showing no association between cardiac iron load and longitudinal strain. Speckle tracking echocardiography could be used as a feasible method for evaluating subclinical myocardial dysfunction in patients with thalassemia major. Echocardiography, using GLS, could predict clinically silent myocardial dysfunction independent of CMR (T2 * value) and extension of iron deposition. Our study also puts forward other causes such as chronic tissue hypoxia resulting from chronic anemia as a root cause and initiating factor for subsequent injury by the iron deposition. Speckle tracking can recognize the cardiac involvement in really early stages.

A state of reversible compensated ventricular dysfunction precedes pathological remodelling in response to cardiomyocyte-specific activity of angiotensin II type-1 receptor in mice.

PubMed

Frentzou, Georgia A; Drinkhill, Mark J; Turner, Neil A; Ball, Stephen G; Ainscough, Justin F X

2015-08-01

Cardiac dysfunction is commonly associated with high-blood-pressure-induced cardiomyocyte hypertrophy, in response to aberrant renin-angiotensin system (RAS) activity. Ensuing pathological remodelling promotes cardiomyocyte death and cardiac fibroblast activation, leading to cardiac fibrosis. The initiating cellular mechanisms that underlie this progressive disease are poorly understood. We previously reported a conditional mouse model in which a human angiotensin II type-I receptor transgene (HART) was expressed in differentiated cardiomyocytes after they had fully matured, but not during development. Twelve-month-old HART mice exhibited ventricular dysfunction and cardiomyocyte hypertrophy with interstitial fibrosis following full receptor stimulation, without affecting blood pressure. Here, we show that chronic HART activity in young adult mice causes ventricular dysfunction without hypertrophy, fibrosis or cardiomyocyte death. Dysfunction correlated with reduced expression of pro-hypertrophy markers and increased expression of pro-angiogenic markers in the cardiomyocytes experiencing increased receptor load. This stimulates responsive changes in closely associated non-myocyte cells, including the downregulation of pro-angiogenic genes, a dampened inflammatory response and upregulation of Tgfβ. Importantly, this state of compensated dysfunction was reversible. Furthermore, increased stimulation of the receptors on the cardiomyocytes caused a switch in the secondary response from the non-myocyte cells. Progressive cardiac remodelling was stimulated through hypertrophy and death of individual cardiomyocytes, with infiltration, proliferation and activation of fibroblast and inflammatory cells, leading to increased angiogenic and inflammatory signalling. Together, these data demonstrate that a state of pre-hypertrophic compensated dysfunction can exist in affected individuals before common markers of heart disease are detectable. The data also suggest that there is an initial response from the housekeeping cells of the heart to signals emanating from distressed neighbouring cardiomyocytes to suppress those changes most commonly associated with progressive heart disease. We suggest that the reversible nature of this state of compensated dysfunction presents an ideal window of opportunity for personalised therapeutic intervention. © 2015. Published by The Company of Biologists Ltd.

PEG-coated gold nanoparticles attenuate β-adrenergic receptor-mediated cardiac hypertrophy.

PubMed

Qiao, Yuhui; Zhu, Baoling; Tian, Aiju; Li, Zijian

2017-01-01

Gold nanoparticles (AuNPs) are widely used as a drug delivery vehicle, which can accumulate in the heart through blood circulation. Therefore, it is very important to understand the effect of AuNPs on the heart, especially under pathological conditions. In this study, we found that PEG-coated AuNPs attenuate β-adrenergic receptor (β-AR)-mediated acute cardiac hypertrophy and inflammation. However, both isoproterenol, a non-selective β-AR agonist, and AuNPs did not induce cardiac function change or cardiac fibrosis. AuNPs exerted an anti-cardiac hypertrophy effect by decreasing β 1 -AR expression and its downstream ERK1/2 hypertrophic pathway. Our results indicated that AuNPs might be safe and have the potential to be used as multi-functional materials (drug carrier systems and anti-cardiac hypertrophy agents).

Biomarkers and echocardiography for evaluating the improvement of the ventricular diastolic function after surgical relief of hydronephrosis

PubMed Central

Yeh, Huei-Ming; Lin, Ting-Tse; Yeh, Chih-Fan; Huang, Ho-Shiang; Chang, Sheng-Nan; Lin, Jou-Wei; Tsai, Chia-Ti; Lai, Ling-Ping; Huang, Yi-You

2017-01-01

The pathophysiology of cardio-renal syndrome (CRS) is complex. Hydronephrosis caused by urolithiasis may cause cytokine release and lead to cardiac dysfunction. The aim of this study was to evaluate cardiac function changes observed in patients who received double J placement using feasible biomarkers and echocardiography. This was a prospective, single-center study. Eighty-seven patients who presented with acute unilateral hydronephrosis and received ureteroscope stone manipulation were enrolled. Echocardiography and cytokines were measured on the day of the operation and 24 hours after the procedure. Changes before and after surgery were assessed by the paired t-test and Wilcoxon test. Correlation analyses between echocardiographic diastolic indices and cytokine levels were performed using Pearson’s correlation coefficients. Patients with hydronephrosis showed a higher left atrium volume index (LAVI), decreased E', and increased E/ E' ratio, which indicated diastolic dysfunction. Patients with hydronephrosis also exhibited decreased global strain rates during isovolumetric relaxation (SRIVR) and E/ SRIVR, which confirmed the diastolic dysfunction. Significant reductions in LAVI, increases in SRIVR and decreases in E/ SRIVR were observed after the operation. Biomarkers, such as TGF-β and serum NT-proBNP, were significantly decreased after surgery. In addition, a significant correlation was observed between the post-surgical decrease in TGF-β1 and increase in SRIVR. Unilateral hydronephrosis causes cardiac diastolic dysfunction, and relieving hydronephrosis could improve diastolic function. Improvements in cardiac dysfunction can be evaluated by echocardiography and measuring cytokine levels. The results of this study will inform efforts to improve the early diagnosis of CRS and prevent further deterioration of cardiac function when treating patients with hydronephrosis. PMID:29161313

Biomarkers and echocardiography for evaluating the improvement of the ventricular diastolic function after surgical relief of hydronephrosis.

PubMed

Yeh, Huei-Ming; Lin, Ting-Tse; Yeh, Chih-Fan; Huang, Ho-Shiang; Chang, Sheng-Nan; Lin, Jou-Wei; Tsai, Chia-Ti; Lai, Ling-Ping; Huang, Yi-You; Chu, Chun-Lin

2017-01-01

The pathophysiology of cardio-renal syndrome (CRS) is complex. Hydronephrosis caused by urolithiasis may cause cytokine release and lead to cardiac dysfunction. The aim of this study was to evaluate cardiac function changes observed in patients who received double J placement using feasible biomarkers and echocardiography. This was a prospective, single-center study. Eighty-seven patients who presented with acute unilateral hydronephrosis and received ureteroscope stone manipulation were enrolled. Echocardiography and cytokines were measured on the day of the operation and 24 hours after the procedure. Changes before and after surgery were assessed by the paired t-test and Wilcoxon test. Correlation analyses between echocardiographic diastolic indices and cytokine levels were performed using Pearson's correlation coefficients. Patients with hydronephrosis showed a higher left atrium volume index (LAVI), decreased E', and increased E/ E' ratio, which indicated diastolic dysfunction. Patients with hydronephrosis also exhibited decreased global strain rates during isovolumetric relaxation (SRIVR) and E/ SRIVR, which confirmed the diastolic dysfunction. Significant reductions in LAVI, increases in SRIVR and decreases in E/ SRIVR were observed after the operation. Biomarkers, such as TGF-β and serum NT-proBNP, were significantly decreased after surgery. In addition, a significant correlation was observed between the post-surgical decrease in TGF-β1 and increase in SRIVR. Unilateral hydronephrosis causes cardiac diastolic dysfunction, and relieving hydronephrosis could improve diastolic function. Improvements in cardiac dysfunction can be evaluated by echocardiography and measuring cytokine levels. The results of this study will inform efforts to improve the early diagnosis of CRS and prevent further deterioration of cardiac function when treating patients with hydronephrosis.

Added value of cardiac computed tomography for evaluation of mechanical aortic valve: Emphasis on evaluation of pannus with surgical findings as standard reference.

PubMed

Suh, Young Joo; Lee, Sak; Im, Dong Jin; Chang, Suyon; Hong, Yoo Jin; Lee, Hye-Jeong; Hur, Jin; Choi, Byoung Wook; Chang, Byung-Chul; Shim, Chi Young; Hong, Geu-Ru; Kim, Young Jin

2016-07-01

The added value of cardiac computed tomography (CT) with transesophageal echocardiography (TEE) for evaluating mechanical aortic valve (AV) dysfunction has not yet been investigated. The purposes of this study were to investigate the added value of cardiac CT for evaluation of mechanical AVs and diagnoses of pannus compared to TEE, with surgical findings of redo-aortic valve replacement (AVR) used as a standard reference. 25 patients who underwent redo-AVR due to mechanical AV dysfunction and cardiac CT before redo-AVR were included. The presence of pannus, encroachment ratio by pannus, and limitation of motion (LOM) were evaluated on CT. The diagnostic performance of pannus detection was compared using TEE, CT, and CT+TEE, with surgical findings as a standard reference. The added value of CT for diagnosing the cause of mechanical AV dysfunction was assessed compared to TTE+TEE. In two patients, CT analysis was not feasible due to severe metallic artifacts. On CT, pannus and LOM were found in 100% (23/23) and 60.9% (14/23). TEE identified pannus in 48.0% of patients (12/25). CT, TEE, and CT+TEE correctly identified pannus with sensitivity of 92.0%, 48.0%, and 92.0%, respectively (P=0.002 for CT vs. TEE). In 11 of 13 cases (84.6%) with inconclusive or negative TEE results for pannus, CT detected the pannus. Among 13 inconclusive cases of TTE+TEE for the cause of mechanical AV dysfunction, CT suggested 6 prosthetic valve obstruction (PVO) by pannus, 4 low-flow low-gradient PVO, and one LOM without significant PVO. Cardiac CT showed added diagnostic value with TEE in the detection of pannus as the cause of mechanical AV dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Protective Roles of Interferon-γ in Cardiac Hypertrophy Induced by Sustained Pressure Overload.

PubMed

Kimura, Akihiko; Ishida, Yuko; Furuta, Machi; Nosaka, Mizuho; Kuninaka, Yumi; Taruya, Akira; Mukaida, Naofumi; Kondo, Toshikazu

2018-03-19

A clear understanding of the molecular mechanisms underlying hemodynamic stress-initiated cardiac hypertrophy is important for preventing heart failure. Interferon-γ (IFN-γ) has been suggested to play crucial roles in various diseases other than immunological disorders by modulating the expression of myriad genes. However, the involvement of IFN-γ in the pathogenesis of cardiac hypertrophy still remains unclear. In order to elucidate the roles of IFN-γ in pressure overload-induced cardiac pathology, we subjected Balb/c wild-type (WT) or IFN-γ-deficient ( Ifng -/- ) mice to transverse aortic constriction (TAC). Three weeks after TAC, Ifng -/- mice developed more severe cardiac hypertrophy, fibrosis, and dysfunction than WT mice. Bone marrow-derived immune cells including macrophages were a source of IFN-γ in hearts after TAC. The activation of PI3K/Akt signaling, a key signaling pathway in compensatory hypertrophy, was detected 3 days after TAC in the left ventricles of WT mice and was markedly attenuated in Ifng -/- mice. The administration of a neutralizing anti-IFN-γ antibody abrogated PI3K/Akt signal activation in WT mice during compensatory hypertrophy, while that of IFN-γ activated PI3K/Akt signaling in Ifng -/- mice. TAC also induced the phosphorylation of Stat5, but not Stat1 in the left ventricles of WT mice 3 days after TAC. Furthermore, IFN-γ induced Stat5 and Akt phosphorylation in rat cardiomyocytes cultured under stretch conditions. A Stat5 inhibitor significantly suppressed PI3K/Akt signaling activation in the left ventricles of WT mice, and aggravated pressure overload-induced cardiac hypertrophy. The IFN-γ/Stat5 axis may be protective against persistent pressure overload-induced cardiac hypertrophy by activating the PI3K/Akt pathway. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Geraniol alleviates diabetic cardiac complications: Effect on cardiac ischemia and oxidative stress.

PubMed

El-Bassossy, Hany M; Ghaleb, Hanna; Elberry, Ahmed A; Balamash, Khadijah S; Ghareib, Salah A; Azhar, Ahmad; Banjar, Zainy

2017-04-01

The present study was planned to assess the possible protective effect of geraniol on cardiovascular complications in an animal model with diabetes. Diabetes was induced in rats by a single streptozotocin injection. In the treated group, geraniol (150mgkg -1 day -1 ) was administered orally starting from the 15th day after induction of diabetes, and ending after 7 weeks; diabetic control rats were given vehicle for the same period. At the end of the study, cardiac contractility was assessed by using a Millar microtip catheter in anesthetised rats, and cardiac conductivity determined by a surface ECG. Serum levels of glucose, cholesterol, triglyceride and adiponectin as well as urine 8-isoprostane were determined. In addition, cardiac superoxide dismutase (SOD) and catalase activity were measured. Geraniol administration significantly alleviated the attenuated cardiac systolic function associated with diabetes as indicated by inhibiting the decrease in the rate of rise (dP/dt max ) in ventricular pressure and the increase in systolic duration observed in diabetic rats. In addition, geraniol alleviated impaired diastolic function as shown by inhibiting the decrease in the rate of fall (dP/dt min ) in ventricular pressure and increased isovolumic relaxation constant (Tau) observed in diabetic rats. ECG recordings showed that geraniol prevented any increase in QTc and T-peak-T-end intervals, and markers of LV ischemia and arrhythmogenesis, seen in diabetic animals. Geraniol suppressed the exaggerated oxidative stress as evidenced by preventing the increase in 8-isoprotane. In diabetic heart tissue, geraniol prevented the inhibition in catalase activity but did not affect the heart SOD. Geraniol partially reduced hyperglycemia, prevented the hypercholesterolemia, but did not affect the serum level of adiponectin in diabetic animals. Results obtained in this study suggest that geraniol provides a potent protective effect against cardiac dysfunction induced by diabetes. This ameliorative effect could be attributed to its suppression of oxidative stress. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Prenatal exposure to methyldopa leading to hypertensive crisis and cardiac failure in a neonate.

PubMed

Su, Jennifer A; Tang, William; Rivero, Niurka; Bar-Cohen, Yaniv

2014-05-01

A 2-week-old infant with normal intracardiac anatomy presented to the emergency department in a hypertensive crisis with acute cardiac failure. Despite extensive evaluation, no underlying disease was found. The patient's hypertension and cardiac dysfunction resolved after 1 week of supportive care in the PICU, and she was discharged within 2 weeks of presentation. The patient's history revealed transplacental exposure to the α-adrenergic agonist methyldopa for 10 weeks before delivery. Her age at presentation and the self-limited nature of cardiac sequelae with complete resolution of cardiac dysfunction suggest withdrawal effects from this exposure. Whereas the rebound hypertensive effects of α-adrenergic agonists are well established in the adult population, this report shows an unusual adverse outcome of in utero exposure to methyldopa. Copyright © 2014 by the American Academy of Pediatrics.

Cardiac microvascular rarefaction in hyperthyroidism-induced left ventricle dysfunction.

PubMed

Freitas, Felipe; Estato, Vanessa; Carvalho, Vinícius Frias; Torres, Rafael Carvalho; Lessa, Marcos Adriano; Tibiriçá, Eduardo

2013-10-01

The pathophysiology underlying hyperthyroidism-induced left ventricle (LV) dysfunction and hypertrophy directly involves the heart and indirectly involves the neuroendocrine systems. The effects of hyperthyroidism on the microcirculation are still controversial in experimental models. We investigated the effects of hyperthyroidism on the cardiac function and microcirculation of an experimental rat model. Male Wistar rats (170-250 g) were divided into two groups: the euthyroid group (n = 10), which was treated with 0.9% saline solution, and the hyperthyroid group (n = 10), which was treated with l-thyroxine (600 μg/kg/day, i.p.) during 14 days. An echocardiographic study was performed to evaluate the alterations in cardiac function, structure and geometry. The structural capillary density and the expression of angiotensin II AT1 receptor in the LV were analyzed using histochemistry and immunohistochemistry, respectively. Hyperthyroidism was found to induce profound cardiovascular alterations, such as systolic hypertension, tachycardia, LV dysfunction, cardiac hypertrophy, and myocardial fibrosis. This study demonstrates the existence of structural capillary rarefaction and the down-regulation of the cardiac angiotensin II AT1 receptor in the myocardium of hyperthyroid rats in comparison with euthyroid rats. Microvascular rarefaction may be involved in the pathophysiology of hyperthyroidism-induced cardiovascular alterations. © 2013 John Wiley & Sons Ltd.

Cardiac-specific overexpression of insulin-like growth factor I (IGF-1) rescues lipopolysaccharide-induced cardiac dysfunction and activation of stress signaling in murine cardiomyocytes.

PubMed

Zhao, Peng; Turdi, Subat; Dong, Feng; Xiao, Xiaoyan; Su, Guohai; Zhu, Xinglei; Scott, Glenda I; Ren, Jun

2009-07-01

Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, plays a key role in cardiac dysfunction in sepsis. Low circulating levels of insulin-like growth factor 1 (IGF-1) are found in sepsis, although the influence of IGF-1 on septic cardiac defect is unknown. This study was designed to examine the impact of IGF-1 on LPS-induced cardiac contractile and intracellular Ca2+ dysfunction, activation of stress signal and endoplasmic reticulum (ER) stress. Mechanical and intracellular Ca2+ properties were examined in cardiomyocytes from Fast Violet B and cardiac-specific IGF-1 overexpression mice treated with or without LPS (4 mg kg(-1), 6 h). Reactive oxygen species (ROS), protein carbonyl formation and apoptosis were measured. Activation of mitogen-activated protein kinase pathways (p38, c-jun N-terminal kinase [JNK] and extracellular signal-related kinase [ERK]), ER stress and apoptotic markers were evaluated using Western blot analysis. Our results revealed decreased peak shortening and maximal velocity of shortening/relengthening and prolonged duration of relengthening in LPS-treated Fast Violet B cardiomyocytes associated with reduced intracellular Ca2+ decay. Accumulation of ROS protein carbonyl and apoptosis were elevated after LPS treatment. Western blot analysis revealed activated p38 and JNK, up-regulated Bax, and the ER stress markers GRP78 and Gadd153 in LPS-treated mouse hearts without any change in ERK and Bcl-2. Total protein expression of p38, JNK, and ERK was unaffected by either LPS or IGF-1. Interestingly, these LPS-induced changes in mechanical and intracellular Ca2+ properties, ROS, protein carbonyl, apoptosis, stress signal activation, and ER stress markers were effectively ablated by IGF-1. In vitro LPS exposure (1 microg mL(-1)) produced cardiomyocyte mechanical dysfunction reminiscent of the in vivo setting, which was alleviated by exogenous IGF-1 (50 nM). These data collectively suggested a beneficial of IGF-1 in the management of cardiac dysfunction under sepsis.

Effect of perioperative sodium bicarbonate administration on renal function following cardiac surgery for infective endocarditis: a randomized, placebo-controlled trial.

PubMed

Cho, Jin Sun; Soh, Sarah; Shim, Jae-Kwang; Kang, Sanghwa; Choi, Haegi; Kwak, Young-Lan

2017-01-05

Patients with infective endocarditis (IE) have an elevated risk of renal dysfunction because of extensive systemic inflammation and use of nephrotoxic antibiotics. In this randomized, placebo-controlled trial, we investigated whether perioperative sodium bicarbonate administration could attenuate postoperative renal dysfunction in patients with IE undergoing cardiac surgery. Seventy patients randomly received sodium chloride (n = 35) or sodium bicarbonate (n = 35). Sodium bicarbonate was administered as a 0.5 mmol/kg loading dose for 1 h commencing with anesthetic induction, followed by a 0.15 mmol/kg/h infusion for 23 h. The primary outcome was peak serum creatinine (SCr) level during the first 48 h postoperatively. The incidence of acute kidney injury, SCr level, estimated glomerular filtration rate, and major morbidity endpoints were assessed postoperatively. The peak SCr during the first 48 h postoperatively (bicarbonate vs. 1.01 (0.74, 1.37) mg/dl vs. 0.88 (0.76, 1.27) mg/dl, P = 0.474) and the incidence of acute kidney injury (bicarbonate vs. 29% vs. 23%, P = 0.584) were similar in both groups. The postoperative increase in SCr above baseline was greater in the bicarbonate group than in the control group on postoperative day 2 (0.21 (0.07, 0.33) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P = 0.028) and postoperative day 5 (0.23 (0.08, 0.36) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P = 0.017). Perioperative sodium bicarbonate administration had no favorable impact on postoperative renal function and outcomes in patients with IE undergoing cardiac surgery. Instead, it was associated with possibly harmful renal effects, illustrated by a greater increase in SCr postoperatively, compared to control. ClinicalTrials.gov, NCT01920126 . Registered on 31 July 2013.

Serum Bicarbonate and Structural and Functional Cardiac Abnormalities in Chronic Kidney Disease - A Report from the Chronic Renal Insufficiency Cohort Study.

PubMed

Dobre, Mirela; Roy, Jason; Tao, Kaixiang; Anderson, Amanda H; Bansal, Nisha; Chen, Jing; Deo, Rajat; Drawz, Paul; Feldman, Harold I; Hamm, L Lee; Hostetter, Thomas; Kusek, John W; Lora, Claudia; Ojo, Akinlolu O; Shrama, Kumar; Rahman, Mahboob

2016-01-01

Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. The mean estimated glomerular filtration rate was 42.5 ± 17 ml/min/1.73 m2. The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories <22, 22-26 and >26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms. © 2016 Published by S. Karger AG, Basel.

CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy.

PubMed

Zhao, Gang; Wang, Shijun; Wang, Zhen; Sun, Aijun; Yang, Xiangdong; Qiu, Zhaohui; Wu, Chaoneng; Zhang, Wenbin; Li, Hua; Zhang, Youen; Zhao, Jingjing; Zou, Yunzeng; Ge, Junbo

2013-09-30

Emerging evidence shows that the chemokine CXCL16 plays an important role in the pathogenesis of myocardial remodeling and development of heart failure following ischemia/reperfusion (I/R) injury. CXCR6, the receptor for CXCL16, is also critically involved. However, the underlying mechanism remained uncertain, and the aim of this research was to investigate this mechanism in CXCR6 knockout (KO) mice. CXCR6 KO mice and wild type (WT) mice had no overt phenotype at baseline in the absence of injury, but difference was shown in response to I/R induction. Compared with WT mice, CXCR6 KO mice exhibited a lower infarction size (31.86 ± 1.808% vs. 43.09 ± 1.519%), and better cardiac function (measured by LVEF, LVFS, +dp/dt, LVEDP, and LVSP) following I/R. Moreover, cardiac levels of IFN-γ and IFN-γ-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-γ secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-γ and in vitro co-cultured cardiomyocytes with CD11b+ monocytes confirmed IFN-γ activated autophagic response, and induced cardiac dysfunction in a paracrine manner. The study suggested that since disruption of the CXCL16/CXCR6 signaling cascade had a cardio-protective effect against I/R injury, the underlying mechanism might be that I/R triggered the infiltration of monocytes into the myocardium, and induced cardiac autophagy through CXCL16/CXCR6-dependent paracrine secretion of IFN-γ. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω-3 Polyunsaturated Fatty Acids

PubMed Central

Xue, Hongyu; Ren, Wenhua; Denkinger, Melanie; Schlotzer, Ewald; Wischmeyer, Paul E.

2015-01-01

Background Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX-induced cardiotoxicity forms the major cumulative dose-limiting factor. Glutamine and ω-3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy. Methods Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor-bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω-3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50). Results Glutamine alone significantly prevented DOX-related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω-3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω-3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined. Conclusions Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω-3 PUFA treatments. The intriguing glutamine × ω-3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis. PMID:25888676

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω-3 Polyunsaturated Fatty Acids.

PubMed

Xue, Hongyu; Ren, Wenhua; Denkinger, Melanie; Schlotzer, Ewald; Wischmeyer, Paul E

2016-01-01

Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX-induced cardiotoxicity forms the major cumulative dose-limiting factor. Glutamine and ω-3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy. Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor-bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω-3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50). Glutamine alone significantly prevented DOX-related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω-3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω-3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined. Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω-3 PUFA treatments. The intriguing glutamine × ω-3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis. © 2015 American Society for Parenteral and Enteral Nutrition.

A novel apparatus for non-contact measurement of heart rate variability: a system to prevent secondary exposure of medical personnel to toxic materials under biochemical hazard conditions, in monitoring sepsis or in predicting multiple organ dysfunction syndrome.

PubMed

Matsui, T; Arai, I; Gotoh, S; Hattori, H; Takase, B; Kikuchi, M; Ishihara, M

2005-10-01

The impaired balance of the low-frequency/high-frequency ratio obtained from spectral components of RR intervals can be a diagnostic test for sepsis. In addition, it is known that a reduction of heart rate variability (HRV) is useful in identifying septic patients at risk of the development of multiple organ dysfunction syndrome (MODS). We have reported a non-contact method using a microwave radar to monitor the heart and respiratory rates of a healthy person placed inside an isolator or of experimental animals exposed to toxic materials. With the purpose of preventing secondary exposure of medical personnel to toxic materials under biochemical hazard conditions, we designed a novel apparatus for non-contact measurement of HRV using a 1215 MHz microwave radar, a high-pass filter, and a personal computer. The microwave radar monitors only the small reflected waves from the subject's chest wall, which are modulated by the cardiac and respiratory motion. The high-pass filter enhances the cardiac signal and attenuates the respiratory signal. In a human trial, RR intervals derived from the non-contact apparatus significantly correlated with those derived from ECG (r=0.98, P<0.0001). The non-contact apparatus showed a similar power spectrum of RR intervals to that of ECG. Our non-contact HRV measurement apparatus appears promising for future pre-hospital monitoring of septic patients or for predicting MODS patients, inside isolators or in the field for mass casualties under biochemical hazard circumstances.

Role of bone marrow-derived CD11c+ dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy.

PubMed

Wang, Huan; Kwak, Dongmin; Fassett, John; Liu, Xiaohong; Yao, Wu; Weng, Xinyu; Xu, Xin; Xu, Yawei; Bache, Robert J; Mueller, Daniel L; Chen, Yingjie

2017-05-01

Inflammatory responses play an important role in the development of left ventricular (LV) hypertrophy and dysfunction. Recent studies demonstrated that increased T-cell infiltration and T-cell activation contribute to LV hypertrophy and dysfunction. Dendritic cells (DCs) are professional antigen-presenting cells that orchestrate immune responses, especially by modulating T-cell function. In this study, we investigated the role of bone marrow-derived CD11c + DCs in transverse aortic constriction (TAC)-induced LV fibrosis and hypertrophy in mice. We observed that TAC increased the number of CD11c + cells and the percentage of CD11c + MHCII + (major histocompatibility complex class II molecule positive) DCs in the LV, spleen and peripheral blood in mice. Using bone marrow chimeras and an inducible CD11c + DC ablation model, we found that depletion of bone marrow-derived CD11c + DCs significantly attenuated LV fibrosis and hypertrophy in mice exposed to 24 weeks of moderate TAC. CD11c + DC ablation significantly reduced TAC-induced myocardial inflammation as indicated by reduced myocardial CD45 + cells, CD11b + cells, CD8 + T cells and activated effector CD8 + CD44 + T cells in LV tissues. Moreover, pulsing of autologous DCs with LV homogenates from TAC mice promoted T-cell proliferation. These data indicate that bone marrow-derived CD11c + DCs play a maladaptive role in hemodynamic overload-induced cardiac inflammation, hypertrophy and fibrosis through the presentation of cardiac self-antigens to T cells.

Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

PubMed

Hong, Seul-Ki; Choo, Eun-Ho; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

2017-11-01

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Cardiac Protection of Valsartan on Juvenile Rats with Heart Failure by Inhibiting Activity of CaMKII via Attenuating Phosphorylation

PubMed Central

Wu, Yao; Si, Feifei; Ji, Xiaojuan; Jiang, Kunfeng; Song, Sijie

2017-01-01

Background. This study was undertaken to determine relative contributions of phosphorylation and oxidation to the increased activity of calcium/calmodulin-stimulated protein kinase II (CaMKII) in juveniles with cardiac myocyte dysfunction due to increased pressure overload. Methods. Juvenile rats underwent abdominal aortic constriction to induce heart failure. Four weeks after surgery, rats were then randomly divided into two groups: one group given valsartan (HF + Val) and the other group given placebo (HF + PBO). Simultaneously, the sham-operated rats were randomly given valsartan (Sham + Val) or placebo (Sham + PBO). After 4 weeks of treatment, Western blot analysis was employed to quantify CaMKII and relative calcium handling proteins (RyR2 and PLN) in all groups. Results. The deteriorated cardiac function was reversed by valsartan treatment. In ventricular muscle cells of group HF + PBO, Thr287 phosphorylation of CaMKII and S2808 phosphorylation of RyR2 and PLN were increased and S16 phosphorylation of PLN was decreased compared to the other groups, while Met281 oxidation was not significantly elevated. In addition, these changes in the expression of calcium handling proteins were ameliorated by valsartan administration. Conclusions. The phosphorylation of Thr286 is associated with the early activation of CaMKII rather than the oxidation of Met281. PMID:28536695

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury

PubMed Central

Weinreuter, Martin; Kreusser, Michael M; Beckendorf, Jan; Schreiter, Friederike C; Leuschner, Florian; Lehmann, Lorenz H; Hofmann, Kai P; Rostosky, Julia S; Diemert, Nathalie; Xu, Chang; Volz, Hans Christian; Jungmann, Andreas; Nickel, Alexander; Sticht, Carsten; Gretz, Norbert; Maack, Christoph; Schneider, Michael D; Gröne, Hermann-Josef; Müller, Oliver J; Katus, Hugo A; Backs, Johannes

2014-01-01

CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes. PMID:25193973

Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction.

PubMed

Lee, Heow Won; Ahmad, Monir; Wang, Hong-Wei; Leenen, Frans H H

2017-03-01

What is the central question of this study? Exercise training increases brain-derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain-containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied. What is the main finding and its importance? Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non-infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training. Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed-MI) or an exercise group (ExT-MI). Exercise training was done for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non-, peri- and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end-diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non-infarct area of the LV. The mBDNF protein in the non-infarct area correlated positively with ejection fraction and inversely with LV end-diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non-infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction.

PubMed

Cappetta, Donato; Esposito, Grazia; Coppini, Raffaele; Piegari, Elena; Russo, Rosa; Ciuffreda, Loreta Pia; Rivellino, Alessia; Santini, Lorenzo; Rafaniello, Concetta; Scavone, Cristina; Rossi, Francesco; Berrino, Liberato; Urbanek, Konrad; De Angelis, Antonella

2017-11-01

Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg -1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg -1 , daily) for the following 4 weeks. While diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. Ranolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc. © 2017 The British Pharmacological Society.

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Tomoyuki; Saotome, Masao, E-mail: msaotome@hama-med.ac.jp; Nobuhara, Mamoru

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}),more » they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS failed to improve palmitate-induced insulin-resistance. • Mitochondrial dysfunction by lipid metabolites would induce insulin-resistance.« less

Role of Extracellular RNA and TLR3‐Trif Signaling in Myocardial Ischemia–Reperfusion Injury

PubMed Central

Chen, Chan; Feng, Yan; Zou, Lin; Wang, Larry; Chen, Howard H.; Cai, Jia‐Yan; Xu, Jun‐Mei; Sosnovik, David E.; Chao, Wei

2014-01-01

Background Toll‐like receptor 3 (TLR3) was originally identified as the receptor for viral RNA and represents a major host antiviral defense mechanism. TLR3 may also recognize extracellular RNA (exRNA) released from injured tissues under certain stress conditions. However, a role for exRNA and TLR3 in the pathogenesis of myocardial ischemic injury has not been tested. This study examined the role of exRNA and TLR3 signaling in myocardial infarction (MI), apoptosis, inflammation, and cardiac dysfunction during ischemia‐reperfusion (I/R) injury. Methods and Results Wild‐type (WT), TLR3−/−, Trif−/−, and interferon (IFN) α/β receptor‐1 deficient (IFNAR1−/−) mice were subjected to 45 minutes of coronary artery occlusion and 24 hours of reperfusion. Compared with WT, TLR3−/− or Trif−/− mice had smaller MI and better preserved cardiac function. Surprisingly, unlike TLR(2/4)‐MyD88 signaling, lack of TLR3‐Trif signaling had no impact on myocardial cytokines or neutrophil recruitment after I/R, but myocardial apoptosis was significantly attenuated in Trif−/− mice. Deletion of the downstream IFNAR1 had no effect on infarct size. Importantly, hypoxia and I/R led to release of RNA including microRNA from injured cardiomyocytes and ischemic heart, respectively. Necrotic cardiomyocytes induced a robust and dose‐dependent cytokine response in cultured cardiomyocytes, which was markedly reduced by RNase but not DNase, and partially blocked in TLR3‐deficient cardiomyocytes. In vivo, RNase administration reduced serum RNA level, attenuated myocardial cytokine production, leukocytes infiltration and apoptosis, and conferred cardiac protection against I/R injury. Conclusion TLR3‐Trif signaling represents an injurious pathway during I/R. Extracellular RNA released during I/R may contribute to myocardial inflammation and infarction. PMID:24390148

AMPK attenuates microtubule proliferation in cardiac hypertrophy.

PubMed

Fassett, John T; Hu, Xinli; Xu, Xin; Lu, Zhongbing; Zhang, Ping; Chen, Yingjie; Bache, Robert J

2013-03-01

Cell hypertrophy requires increased protein synthesis and expansion of the cytoskeletal networks that support cell enlargement. AMPK limits anabolic processes, such as protein synthesis, when energy supply is insufficient, but its role in cytoskeletal remodeling is not known. Here, we examined the influence of AMPK in cytoskeletal remodeling during cardiomyocyte hypertrophy, a clinically relevant condition in which cardiomyocytes enlarge but do not divide. In neonatal cardiomyocytes, activation of AMPK with 5-aminoimidazole carboxamide ribonucleotide (AICAR) or expression of constitutively active AMPK (CA-AMPK) attenuated cell area increase by hypertrophic stimuli (phenylephrine). AMPK activation had little effect on intermediate filaments or myofilaments but dramatically reduced microtubule stability, as measured by detyrosinated tubulin levels and cytoskeletal tubulin accumulation. Importantly, low-level AMPK activation limited cell expansion and microtubule growth independent of mTORC1 or protein synthesis repression, identifying a new mechanism by which AMPK regulates cell growth. Mechanistically, AICAR treatment increased Ser-915 phosphorylation of microtubule-associated protein 4 (MAP4), which reduces affinity for tubulin and prevents stabilization of microtubules (MTs). RNAi knockdown of MAP4 confirmed its critical role in cardiomyocyte MT stabilization. In support of a pathophysiological role for AMPK regulation of cardiac microtubules, AMPK α2 KO mice exposed to pressure overload (transverse aortic constriction; TAC) demonstrated reduced MAP4 phosphorylation and increased microtubule accumulation that correlated with the severity of contractile dysfunction. Together, our data identify the microtubule cytoskeleton as a sensitive target of AMPK activity, and the data suggest a novel role for AMPK in limiting accumulation and densification of microtubules that occurs in response to hypertrophic stress.

AMPK attenuates microtubule proliferation in cardiac hypertrophy

PubMed Central

Fassett, John T.; Hu, Xinli; Xu, Xin; Lu, Zhongbing; Zhang, Ping; Chen, Yingjie

2013-01-01

Cell hypertrophy requires increased protein synthesis and expansion of the cytoskeletal networks that support cell enlargement. AMPK limits anabolic processes, such as protein synthesis, when energy supply is insufficient, but its role in cytoskeletal remodeling is not known. Here, we examined the influence of AMPK in cytoskeletal remodeling during cardiomyocyte hypertrophy, a clinically relevant condition in which cardiomyocytes enlarge but do not divide. In neonatal cardiomyocytes, activation of AMPK with 5-aminoimidazole carboxamide ribonucleotide (AICAR) or expression of constitutively active AMPK (CA-AMPK) attenuated cell area increase by hypertrophic stimuli (phenylephrine). AMPK activation had little effect on intermediate filaments or myofilaments but dramatically reduced microtubule stability, as measured by detyrosinated tubulin levels and cytoskeletal tubulin accumulation. Importantly, low-level AMPK activation limited cell expansion and microtubule growth independent of mTORC1 or protein synthesis repression, identifying a new mechanism by which AMPK regulates cell growth. Mechanistically, AICAR treatment increased Ser-915 phosphorylation of microtubule-associated protein 4 (MAP4), which reduces affinity for tubulin and prevents stabilization of microtubules (MTs). RNAi knockdown of MAP4 confirmed its critical role in cardiomyocyte MT stabilization. In support of a pathophysiological role for AMPK regulation of cardiac microtubules, AMPK α2 KO mice exposed to pressure overload (transverse aortic constriction; TAC) demonstrated reduced MAP4 phosphorylation and increased microtubule accumulation that correlated with the severity of contractile dysfunction. Together, our data identify the microtubule cytoskeleton as a sensitive target of AMPK activity, and the data suggest a novel role for AMPK in limiting accumulation and densification of microtubules that occurs in response to hypertrophic stress. PMID:23316058

High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss.

PubMed

Zeng, Heng; Vaka, Venkata Ramana; He, Xiaochen; Booz, George W; Chen, Jian-Xiong

2015-08-01

Mitochondrial dysfunction plays an important role in obesity-induced cardiac impairment. SIRT3 is a mitochondrial protein associated with increased human life span and metabolism. This study investigated the functional role of SIRT3 in obesity-induced cardiac dysfunction. Wild-type (WT) and SIRT3 knockout (KO) mice were fed a normal diet (ND) or high-fat diet (HFD) for 16 weeks. Body weight, fasting glucose levels, reactive oxygen species (ROS) levels, myocardial capillary density, cardiac function and expression of hypoxia-inducible factor (HIF)-1α/-2α were assessed. HFD resulted in a significant reduction in SIRT3 expression in the heart. Both HFD and SIRT3 KO mice showed increased ROS formation, impaired HIF signalling and reduced capillary density in the heart. HFD induced cardiac hypertrophy and impaired cardiac function. SIRT3 KO mice fed HFD showed greater ROS production and a further reduction in cardiac function compared to SIRT3 KO mice on ND. Thus, the adverse effects of HFD on cardiac function were not attributable to SIRT3 loss alone. However, HFD did not further reduce capillary density in SIRT3 KO hearts, implicating SIRT3 loss in HFD-induced capillary rarefaction. Our study demonstrates the importance of SIRT3 in preserving heart function and capillary density in the setting of obesity. Thus, SIRT3 may be a potential therapeutic target for obesity-induced heart failure. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress

PubMed Central

Koncsos, Gábor; Varga, Zoltán V.; Boengler, Kerstin; Rohrbach, Susanne; Li, Ling; Schlüter, Klaus-Dieter; Schreckenberg, Rolf; Radovits, Tamás; Oláh, Attila; Mátyás, Csaba; Lux, Árpád; Al-Khrasani, Mahmoud; Komlódi, Tímea; Bukosza, Nóra; Máthé, Domokos; Deres, László; Barteková, Monika; Rajtík, Tomáš; Adameová, Adriana; Szigeti, Krisztián; Helyes, Zsuzsanna; Tretter, László; Pacher, Pál; Merkely, Béla; Schulz, Rainer; Ferdinandy, Péter

2016-01-01

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. PMID:27521417

Cardiac and renal function in a large cohort of amateur marathon runners.

PubMed

Hewing, Bernd; Schattke, Sebastian; Spethmann, Sebastian; Sanad, Wasiem; Schroeckh, Sabrina; Schimke, Ingolf; Halleck, Fabian; Peters, Harm; Brechtel, Lars; Lock, Jürgen; Baumann, Gert; Dreger, Henryk; Borges, Adrian C; Knebel, Fabian

2015-03-21

Participation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners. A total of 167 participants of the Berlin-Marathon (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT-proBNP and cystatin C). Among the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon. The increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function.

IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

PubMed Central

Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

2012-01-01

Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation

PubMed Central

Veltri, Tiago; Landim-Vieira, Maicon; Parvatiyar, Michelle S.; Gonzalez-Martinez, David; Dieseldorff Jones, Karissa M.; Michell, Clara A.; Dweck, David; Landstrom, Andrew P.; Chase, P. Bryant; Pinto, Jose R.

2017-01-01

Mutations in TNNC1—the gene encoding cardiac troponin C (cTnC)—that have been associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction may also affect Ca2+-regulation and function of slow skeletal muscle since the same gene is expressed in both cardiac and slow skeletal muscle. Therefore, we reconstituted rabbit soleus fibers and bovine masseter myofibrils with mutant cTnCs (A8V, C84Y, E134D, and D145E) associated with HCM to investigate their effects on contractile force and ATPase rates, respectively. Previously, we showed that these HCM cTnC mutants, except for E134D, increased the Ca2+ sensitivity of force development in cardiac preparations. In the current study, an increase in Ca2+ sensitivity of isometric force was only observed for the C84Y mutant when reconstituted in soleus fibers. Incorporation of cTnC C84Y in bovine masseter myofibrils reduced the ATPase activity at saturating [Ca2+], whereas, incorporation of cTnC D145E increased the ATPase activity at inhibiting and saturating [Ca2+]. We also tested whether reconstitution of cardiac fibers with troponin complexes containing the cTnC mutants and slow skeletal troponin I (ssTnI) could emulate the slow skeletal functional phenotype. Reconstitution of cardiac fibers with troponin complexes containing ssTnI attenuated the Ca2+ sensitization of isometric force when cTnC A8V and D145E were present; however, it was enhanced for C84Y. In summary, although the A8V and D145E mutants are present in both muscle types, their functional phenotype is more prominent in cardiac muscle than in slow skeletal muscle, which has implications for the protein-protein interactions within the troponin complex. The C84Y mutant warrants further investigation since it drastically alters the properties of both muscle types and may account for the earlier clinical onset in the proband. PMID:28473771

Ibrolipim attenuates high glucose-induced endothelial dysfunction in cultured human umbilical vein endothelial cells via PI3K/Akt pathway.

PubMed

Xiao, Guohua; Wang, Zongbao; Zeng, Huaicai; Yu, Jian; Yin, Weidong; Zhang, Sujun; Wang, Yueting; Zhang, Yali

2011-10-01

Endothelial dysfunction is a key event in the onset and progression of atherosclerosis associated with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction and contribute to vascular complications. Therefore, we aimed to elucidate the possible role and mechanism of ibrolipim in preventing endothelial dysfunction induced by high glucose. Human umbilical vein endothelial cells (HUVECs) were cultured respectively under normal glucose level (5.5mM), high glucose level (33mM), and high glucose level with ibrolipim treatment. Endothelial dysfunction was identified by the expression of ET-1 and vWF through reverse transcription PCR (RT-PCR). HUVECs apoptosis was assessed by fluorescent staining with Hoechst 33258. Akt activity was analyzed by western blot. High glucose condition significantly increased the rate of apoptotic cells, weakened cell viability, and decreased the expression of ET-1 and vWF. Ibrolipim treatment significantly attenuated these alterations of endothelial dysfunction. The lower concentrations (2, 4, 8 microM) of ibrolipim inhibited apoptosis of cultured HUVECs, improved cell viability, down-regulated the mRNA levels of ET-1, vWF, and attenuated the cytotoxicity; however, higher concentration (16, 32 microM) of ibrolipim aggravated the damage of HUVECs cultured under high glucose level. Meanwhile, high glucose induced a decrease of Akt activity which led to apoptosis, and ibrolipim prevented the decrease and attenuated apoptotic effect induced by high glucose. Furthermore, the PI3K inhibitor LY294002 significantly abolished the anti-apoptotic effect of ibrolipim, and decreased Akt phosphorylation. Although, the expression of Akt mRNA and total protein were not altered in cultured HUVECs. Ibrolipim at lower concentrations can inhibit high glucose-induced apoptosis in cultured HUVECs, which might be related to the alternation of Akt activity. Ibrolipim has the potential to attenuate endothelial dysfunction and lower the risk of diabetes-associated vascular diseases. And it might be a therapeutic agent for diabetic vascular complications.

Reversible preoperative renal dysfunction does not add to the risk of postoperative acute kidney injury after cardiac valve surgery

PubMed Central

Xu, Jia-Rui; Zhuang, Ya-Min; Liu, Lan; Shen, Bo; Wang, Yi-Mei; Luo, Zhe; Teng, Jie; Wang, Chun-Sheng; Ding, Xiao-Qiang

2017-01-01

Objective To evaluate the impact of the renal dysfunction (RD) type and change of postoperative cardiac function on the risk of developing acute kidney injury (AKI) in patients who underwent cardiac valve surgery. Method Reversible renal dysfunction (RRD) was defined as preoperative RD in patients who had not been initially diagnosed with chronic kidney disease (CKD). Cardiac function improvement (CFI) was defined as postoperative left ventricular ejection function – preoperative left ventricular ejection function (ΔEF) >0%, and cardiac function not improved (CFNI) as ΔEF ≤0%. Results Of the 4,805 (94%) cardiac valve surgery patients, 301 (6%) were RD cases. The AKI incidence in the RRD group (n=252) was significantly lower than in the CKD group (n=49) (36.5% vs 63.3%, P=0.018). The AKI and renal replacement therapy incidences in the CFI group (n=174) were significantly lower than in the CFNI group (n=127) (33.9% vs 50.4%, P=0.004; 6.3% vs 13.4%, P=0.037). After adjustment for age, gender, and other confounding factors, CKD and CKD + CFNI were identified as independent risk factors for AKI in all patients after cardiac valve surgery. Multivariate logistic regression analysis showed that the risk factors for postoperative AKI in preoperative RD patients were age, gender (male), hypertension, diabetes, chronic heart failure, cardiopulmonary bypass time (every 1 min added), and intraoperative hypotension, while CFI after surgery could reduce the risk. Conclusion For cardiac valve surgery patients, preoperative CKD was an independent risk factor for postoperative AKI, but RRD did not add to the risk. Improved postoperative cardiac function can significantly reduce the risk of postoperative AKI. PMID:29184415

Exercise Training Reverses Extrapulmonary Impairments in Smoke-exposed Mice.

PubMed

Bowen, T Scott; Aakerøy, Lars; Eisenkolb, Sophia; Kunth, Patricia; Bakkerud, Fredrik; Wohlwend, Martin; Ormbostad, Anne Marie; Fischer, Tina; Wisloff, Ulrik; Schuler, Gerhard; Steinshamn, Sigurd; Adams, Volker; Bronstad, Eivind

2017-05-01

Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease and emphysema. However, evidence on the extrapulmonary effects of smoke exposure that precede lung impairments remains unclear at present, as are data on nonpharmacological treatments such as exercise training. Three groups of mice, including control (n = 10), smoking (n = 10), and smoking with 6 wk of high-intensity interval treadmill running (n = 11), were exposed to 20 wk of fresh air or whole-body cigarette smoke. Exercise capacity (peak oxygen uptake) and lung destruction (histology) were subsequently measured, whereas the heart, peripheral endothelium (aorta), and respiratory (diaphragm) and limb (extensor digitorum longus and soleus) skeletal muscles were assessed for in vivo and in vitro function, in situ mitochondrial respiration, and molecular alterations. Smoking reduced body weight by 26% (P < 0.05) without overt airway destruction (P > 0.05). Smoking impaired exercise capacity by 15% while inducing right ventricular dysfunction by ~20%, endothelial dysfunction by ~20%, and diaphragm muscle weakness by ~15% (all P < 0.05), but these were either attenuated or reversed by exercise training (P < 0.05). Compared with controls, smoking mice had normal limb muscle and mitochondrial function (cardiac and skeletal muscle fibers); however, diaphragm measures of oxidative stress and protein degradation were increased by 111% and 65%, respectively (P < 0.05), but these were attenuated by exercise training (P < 0.05). Prolonged cigarette smoking reduced exercise capacity concomitant with functional impairments to the heart, peripheral endothelium, and respiratory muscle that preceded the development of overt emphysema. However, high-intensity exercise training was able to reverse these smoke-induced extrapulmonary impairments.

Cardiac abnormalities in Parkinson's disease and Parkinsonism.

PubMed

Scorza, Fulvio A; Fiorini, Ana C; Scorza, Carla A; Finsterer, Josef

2018-07-01

Though there is increasing evidence for primary cardiac disease in Parkinson's disease (PD) and Parkinsonism (PS), this evidence is hardly included in the general management of these patients. Literature review. PD is one of the most common age-related neurodegenerative disorders. Epidemiological studies have shown that PD is accompanied by high rates of premature death compared with the general population. In general, death in PD/PS is usually caused by determinant factors such as pneumonia, cerebrovascular, and cardiovascular disease. There is a significant body of literature demonstrating involvement of the heart in PD/PS. Cardiac involvement in PD/PS includes cardiac autonomic dysfunction, cardiomyopathy, coronary heart disease, arrhythmias, conduction defects, and sudden cardiac death (SCD), and sudden unexpected death in Parkinson's disease (SUDPAR). Cardiac abnormalities found in PD/PS are manifold but the most prominent is cardiac autonomic dysfunction. The frequency of coronary heart disease in PD is a matter of debate. Only rarely reported in PD/PS are cardiomyopathies, arrhythmias, and sudden cardiac death, and SUDPAR. It is particularly recommended that PD/PS patients are more intensively investigated cardiologically as soon as the diagnosis is established. Early recognition of cardiac involvement is important for preventing SCD and SUDPAR. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ketorolac as an analgesic agent for infants and children after cardiac surgery: safety profile and appropriate patient selection.

PubMed

Jalkut, Meredith K

2014-01-01

Ketorolac has been used safely as an analgesic agent for children following cardiac surgery in selected populations. Controversy exists among institutions about the risks involved with this medication in this patient group. This article reviews the current literature regarding the safety of ketorolac for postoperative pain management in children after cardiac surgery. Specifically, concerns about renal dysfunction and increased bleeding risk are addressed. Additionally, the article details pharmacokinetics and potential benefits of ketorolac, such as its opioid-sparing effect. The literature reflects that the use of this medication is not well studied in certain pediatric cardiac patients such as neonates and those with single-ventricle physiology, and the safety of this medication in regards to these special populations is reviewed. In conclusion, ketorolac can be used in specific pediatric patients after cardiac surgery with minimal risk of bleeding or renal dysfunction with appropriate dosing and duration of use.

Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration.

PubMed

Missinato, Maria A; Saydmohammed, Manush; Zuppo, Daniel A; Rao, Krithika S; Opie, Graham W; Kühn, Bernhard; Tsang, Michael

2018-03-06

Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in dusp6 mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair. © 2018. Published by The Company of Biologists Ltd.

Effects of testosterone supplementation on clinical and rehabilitative outcomes in older men undergoing on-pump CABG.

PubMed

Maggio, Marcello; Nicolini, Francesco; Cattabiani, Chiara; Beghi, Cesare; Gherli, Tiziano; Schwartz, Robert S; Valenti, Giorgio; Ceda, Gian Paolo

2012-07-01

Testosterone levels decrease with age. This decline is steeper during "critical illnesses". Cardiac surgery is a particular representative model of major clinical condition producing stress responses similar to those observed during severe nonsurgical illness. Cardiac revascularization with extracorporeal circulation is characterized by marked postoperative complications such as insulin resistance, a pro-inflammatory state, acute anemia and renal dysfunction. These phenomena are more evident in older subjects, who are particularly vulnerable in the post-operative state, a condition that has been recently termed as "acute postoperative frailty". We recently showed that in older men with low ejection fraction undergoing cardiac revascularization with extracorporeal circulation, there is a profound decline in anabolic hormones, including testosterone. After surgery testosterone concentration frequently declines to less than 200 ng/dl, a situation suggestive of overt hypogonadism. Since men with low testosterone levels have a high probability of developing mobility limitations, we considered this a rationale for the perioperative use of testosterone treatment in older men undergoing cardiac revasularization surgery. We hypothesized that testosterone supplementation at this time might attenuate the impressive post-surgical catabolic hormonal milieu. The aim of this manuscript is to elucidate an ongoing randomized clinical trial in older men (70+ years old) undergoing elective cardiovascular revascularization with extracorporeal circulation. This randomized clinical trial will evaluate the effects of intramuscular testosterone administration on clinical and functional outcomes in this population. The study will also address potential mechanisms underlying the expected beneficial effects of testosterone supplementation including improvement of insulin sensitivity, markers of inflammatory status and improved hemoglobin levels. Copyright © 2012 Elsevier Inc. All rights reserved.

Cardiac arrhythmia and thyroid dysfunction: a novel genetic link

PubMed Central

Purtell, Kerry; Roepke, Torsten K.; Abbott, Geoffrey W.

2010-01-01

Inherited Long QT Syndrome, a cardiac arrhythmia that predisposes to the often lethal ventricular fibrillation, is commonly linked to mutations in KCNQ1. The KCNQ1 voltage-gated K+ channel α subunit passes ventricular myocyte K+ current that helps bring a timely end to each heart-beat. KCNQ1, like many K+ channel α subunits, is regulated by KCNE β subunits, inherited mutations in which also associate with Long QT Syndrome. KCNQ1 and KCNE mutations are also associated with atrial fibrillation. It has long been known that thyroid status strongly influences cardiac function, and that thyroid dysfunction causes abnormal cardiac structure and rhythm. We recently discovered that KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated K+ channel in the thyroid that is required for normal thyroid hormone biosynthesis. Here, we review this novel genetic link between cardiac and thyroid physiology and pathology, and its potential influence upon future therapeutic strategies in cardiac and thyroid disease. PMID:20688187

Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion.

PubMed

Maity, Sangeeta; Kar, Dipak; De, Kakali; Chander, Vivek; Bandyopadhyay, Arun

2013-05-01

This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 μg/100 g BW, oral) and were found to improve in the Bzf co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration. Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction.

Evaluation of cerebral-cardiac syndrome using echocardiography in a canine model of acute traumatic brain injury.

PubMed

Qian, Rong; Yang, Weizhong; Wang, Xiumei; Xu, Zhen; Liu, Xiaodong; Sun, Bing

2015-01-01

Previous studies have confirmed that traumatic brain injury (TBI) can induce general adaptation syndrome (GAS), which subsequently results in myocardial dysfunction and damage in some patients with acute TBI; this condition is also termed as cerebral-cardiac syndrome. However, most clinicians ignore the detection and treatment of myocardial dysfunction, and instead concentrate only on the serious neural damage that is observed in acute TBI, which is one of the most important fatal factors. Therefore, clarification is urgently needed regarding the relationship between TBI and myocardial dysfunction. In the present study, we evaluated 18 canine models of acute TBI, by using real-time myocardial contrast echocardiography and strain rate imaging to accurately evaluate myocardial function and regional microcirculation, including the strain rate of the different myocardial segments, time-amplitude curves, mean ascending slope of the curve, and local myocardial blood flow. Our results suggest that acute TBI often results in cerebral-cardiac syndrome, which rapidly progresses to the serious stage within 3 days. This study is the first to provide comprehensive ultrasonic characteristics of cerebral-cardiac syndrome in an animal model of TBI.

Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats.

PubMed

Barman, Susmita; Srinivasan, Krishnapura

2017-02-01

Oxidative stress plays a major role in the pathogenesis of diabetes mellitus, which further exacerbates damage of cardiac, hepatic and other tissues. We have recently reported that Zn supplementation beneficially modulates hyperglycaemia and hypoinsulinaemia, with attendant reduction of associated metabolic abnormalities in diabetic rats. The present study assessed the potential of Zn supplementation in modulating oxidative stress and cardioprotective effects in diabetic rats. Diabetes was induced in Wistar rats with streptozotocin, and groups of diabetic rats were treated with 5- and 10-fold dietary Zn interventions (0·19 and 0·38 g Zn/kg diet) for 6 weeks. The markers of oxidative stress, antioxidant enzyme activities and concentrations of antioxidant molecules, lipid profile, and expressions of fibrosis and pro-apoptotic factors in the cardiac tissue were particularly assessed. Supplemental Zn showed significant attenuation of diabetes-induced oxidative stress in terms of altered antioxidant enzyme activities and increased the concentrations of antioxidant molecules. Hypercholesterolaemia and hyperlipidaemia were also significantly countered by Zn supplementation. Along with attenuated oxidative stress, Zn supplementation also showed significant cardioprotective effects by altering the mRNA expressions of fibrosis and pro-apoptotic factors (by >50 %). The expression of lipid oxidative marker 4-hydroxy-2-nonenal (4-HNE) protein in cardiac tissue of diabetic animals was rectified (68 %) by Zn supplementation. Elevated cardiac and hepatic markers in circulation and pathological abnormalities in cardiac and hepatic tissue architecture of diabetic animals were ameliorated by dietary Zn intervention. The present study indicates that Zn supplementation can attenuate diabetes-induced oxidative stress in circulation as well as in cardiac and hepatic tissues.

Assessing the effect of preoperative levosimendan on renal function in patients with right ventricular dysfunction.

PubMed

Guerrero Orriach, Jose L; Galán Ortega, M; Ramírez Fernandez, A; Ariza Villanueva, D; Florez Vela, A; Moreno Cortés, I; Rubio Navarro, M; Cruz Mañas, J

2017-02-01

The Acute Kidney Injury Network (AKIN) classification considers SCr values, urea and urine output in order to improve timely diagnose ARF and improve patient prognosis by early treatment. Preoperative levosimendan is a new way for cardiac and kidney protection, we try to evaluate this drug in fifteen patients comparing values of AKIN scale parameters pre and post cardiac surgery in patients with right ventricle dysfunction.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn; Zhang, Dong-Mei; Yu, Xiao-Jing

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiacmore » atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE attenuates ANG II-induced hypertension and cardiac hypertrophy. • PVN inhibition of ACE attenuates ANG II-induced imbalance of PVN neurotransmitters. • PVN inhibition of ACE attenuates ANG II-induced imbalance of cytokines in the PVN. • PVN blockade of AT1-R attenuates ANG II-induced imbalance of cytokines in the PVN.« less

p53-PGC-1α Pathway Mediates Oxidative Mitochondrial Damage and Cardiomyocyte Necrosis Induced by Monoamine Oxidase-A Upregulation: Role in Chronic Left Ventricular Dysfunction in Mice

PubMed Central

Villeneuve, Christelle; Guilbeau-Frugier, Céline; Sicard, Pierre; Lairez, Olivier; Ordener, Catherine; Duparc, Thibaut; De Paulis, Damien; Couderc, Bettina; Spreux-Varoquaux, Odile; Tortosa, Florence; Garnier, Anne; Knauf, Claude; Valet, Philippe; Borchi, Elisabetta; Nediani, Chiara; Gharib, Abdallah; Ovize, Michel; Delisle, Marie-Bernadette; Mialet-Perez, Jeanne

2013-01-01

Abstract Aims: Oxidative stress and mitochondrial dysfunction participate together in the development of heart failure (HF). mRNA levels of monoamine oxidase-A (MAO-A), a mitochondrial enzyme that produces hydrogen peroxide (H2O2), increase in several models of cardiomyopathies. Therefore, we hypothesized that an increase in cardiac MAO-A could cause oxidative stress and mitochondrial damage, leading to cardiac dysfunction. In the present study, we evaluated the consequences of cardiac MAO-A augmentation on chronic oxidative damage, cardiomyocyte survival, and heart function, and identified the intracellular pathways involved. Results: We generated transgenic (Tg) mice with cardiac-specific MAO-A overexpression. Tg mice displayed cardiac MAO-A activity levels similar to those found in HF and aging. As expected, Tg mice showed a significant decrease in the cardiac amounts of the MAO-A substrates serotonin and norepinephrine. This was associated with enhanced H2O2 generation in situ and mitochondrial DNA oxidation. As a consequence, MAO-A Tg mice demonstrated progressive loss of cardiomyocytes by necrosis and ventricular failure, which were prevented by chronic treatment with the MAO-A inhibitor clorgyline and the antioxidant N-acetyl-cystein. Interestingly, Tg hearts exhibited p53 accumulation and downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial function. This was concomitant with cardiac mitochondrial ultrastructural defects and ATP depletion. In vitro, MAO-A adenovirus transduction of neonatal cardiomyocytes mimicked the results in MAO-A Tg mice, triggering oxidative stress-dependent p53 activation, leading to PGC-1α downregulation, mitochondrial impairment, and cardiomyocyte necrosis. Innovation and Conclusion: We provide the first evidence that MAO-A upregulation in the heart causes oxidative mitochondrial damage, p53-dependent repression of PGC-1α, cardiomyocyte necrosis, and chronic ventricular dysfunction. Antioxid. Redox Signal. 18, 5–18. PMID:22738191

Alcoholic cardiomyopathy

PubMed Central

Guzzo-Merello, Gonzalo; Cobo-Marcos, Marta; Gallego-Delgado, Maria; Garcia-Pavia, Pablo

2014-01-01

Alcohol is the most frequently consumed toxic substance in the world. Low to moderate daily intake of alcohol has been shown to have beneficial effects on the cardiovascular system. In contrast, exposure to high levels of alcohol for a long period could lead to progressive cardiac dysfunction and heart failure. Cardiac dysfunction associated with chronic and excessive alcohol intake is a specific cardiac disease known as alcoholic cardiomyopathy (ACM). In spite of its clinical importance, data on ACM and how alcohol damages the heart are limited. In this review, we evaluate available evidence linking excessive alcohol consumption with heart failure and dilated cardiomyopathy. Additionally, we discuss the clinical presentation, prognosis and treatment of ACM. PMID:25228956

Short-term exercise worsens cardiac oxidative stress and fibrosis in 8-month-old db/db mice by depleting cardiac glutathione.

PubMed

Laher, Ismail; Beam, Julianne; Botta, Amy; Barendregt, Rebekah; Sulistyoningrum, Dian; Devlin, Angela; Rheault, Mark; Ghosh, Sanjoy

2013-01-01

Moderate exercise improves cardiac antioxidant status in young humans and animals with Type-2 diabetes (T2D). Given that both diabetes and advancing age synergistically decrease antioxidant expression in most tissues, it is unclear whether exercise can upregulate cardiac antioxidants in chronic animal models of T2D. To this end, 8-month-old T2D and normoglycemic mice were exercised for 3 weeks, and cardiac redox status was evaluated. As expected, moderate exercise increased cardiac antioxidants and attenuated oxidative damage in normoglycemic mice. In contrast, similar exercise protocol in 8-month-old db/db mice worsened cardiac oxidative damage, which was associated with a specific dysregulation of glutathione (GSH) homeostasis. Expression of enzymes for GSH biosynthesis [γ-glutamylcysteine synthase, glutathione reductase] as well as for GSH-mediated detoxification (glutathione peroxidase, glutathione-S-transferase) was lower, while toxic metabolites dependent on GSH for clearance (4-hydroxynonenal) were increased in exercised diabetic mice hearts. To validate GSH loss as an important factor for such aggravated damage, daily administration of GSH restored cardiac GSH levels in exercised diabetic mice. Such supplementation attenuated both oxidative damage and fibrotic changes in the myocardium. Expression of transforming growth factor beta (TGF-β) and its regulated genes which are responsible for such profibrotic changes were also attenuated with GSH supplementation. These novel findings in a long-term T2D animal model demonstrate that short-term exercise by itself can deplete cardiac GSH and aggravate cardiac oxidative stress. As GSH administration conferred protection in 8-month-old diabetic mice undergoing exercise, supplementation with GSH-enhancing agents may be beneficial in elderly diabetic patients undergoing exercise.

Depression and Cardiac Disease: Epidemiology, Mechanisms, and Diagnosis

PubMed Central

Huffman, Jeff C.; Celano, Christopher M.; Beach, Scott R.; Motiwala, Shweta R.; Januzzi, James L.

2013-01-01

In patients with cardiovascular disease (CVD), depression is common, persistent, and associated with worse health-related quality of life, recurrent cardiac events, and mortality. Both physiological and behavioral factors—including endothelial dysfunction, platelet abnormalities, inflammation, autonomic nervous system dysfunction, and reduced engagement in health-promoting activities—may link depression with adverse cardiac outcomes. Because of the potential impact of depression on quality of life and cardiac outcomes, the American Heart Association has recommended routine depression screening of all cardiac patients with the 2- and 9-item Patient Health Questionnaires. However, despite the availability of these easy-to-use screening tools and effective treatments, depression is underrecognized and undertreated in patients with CVD. In this paper, we review the literature on epidemiology, phenomenology, comorbid conditions, and risk factors for depression in cardiac disease. We outline the associations between depression and cardiac outcomes, as well as the mechanisms that may mediate these links. Finally, we discuss the evidence for and against routine depression screening in patients with CVD and make specific recommendations for when and how to assess for depression in this high-risk population. PMID:23653854

Right Ventricular Ejection Fraction Is Incremental to Left Ventricular Ejection Fraction for the Prediction of Future Arrhythmic Events in Patients With Systolic Dysfunction.

PubMed

Mikami, Yoko; Jolly, Umjeet; Heydari, Bobak; Peng, Mingkai; Almehmadi, Fahad; Zahrani, Mohammed; Bokhari, Mahmoud; Stirrat, John; Lydell, Carmen P; Howarth, Andrew G; Yee, Raymond; White, James A

2017-01-01

Left ventricular ejection fraction remains the primary risk stratification tool used in the selection of patients for implantable cardioverter defibrillator therapy. However, this solitary marker fails to identify a substantial portion of patients experiencing sudden cardiac arrest. In this study, we examined the incremental value of considering right ventricular ejection fraction for the prediction of future arrhythmic events in patients with systolic dysfunction using the gold standard of cardiovascular magnetic resonance. Three hundred fourteen consecutive patients with ischemic cardiomyopathy or nonischemic dilated cardiomyopathy undergoing cardiovascular magnetic resonance were followed for the primary outcome of sudden cardiac arrest or appropriate implantable cardioverter defibrillator therapy. Blinded quantification of left ventricular and right ventricular (RV) volumes was performed from standard cine imaging. Quantification of fibrosis from late gadolinium enhancement imaging was incrementally performed. RV dysfunction was defined as right ventricular ejection fraction ≤45%. Among all patients (164 ischemic cardiomyopathy, 150 nonischemic dilated cardiomyopathy), the mean left ventricular ejection fraction was 32±12% (range, 6-54%) with mean right ventricular ejection fraction of 48±15% (range, 7-78%). At a median of 773 days, 49 patients (15.6%) experienced the primary outcome (9 sudden cardiac arrest, 40 appropriate implantable cardioverter defibrillator therapies). RV dysfunction was independently predictive of the primary outcome (hazard ratio=2.98; P=0.002). Among those with a left ventricular ejection fraction >35% (N=121; mean left ventricular ejection fraction, 45±6%), RV dysfunction provided an adjusted hazard ratio of 4.2 (P=0.02). RV dysfunction is a strong, independent predictor of arrhythmic events. Among patients with mild to moderate LV dysfunction, a cohort greatly contributing to global sudden cardiac arrest burden, this marker provides robust discrimination of high- versus low-risk subjects. © 2017 American Heart Association, Inc.

Nitric Oxide Bioavailability and Adiponectin Production in Chronic Systolic Heart Failure: Relation to Severity of Cardiac Dysfunction

PubMed Central

Tang, W.H. Wilson; Shrestha, Kevin; Tong, Wilson; Wang, Zeneng; Troughton, Richard W.; Borowski, Allen G.; Klein, Allan L.; Hazen, Stanley L.

2013-01-01

Adiponectin is an anti-inflammatory, anti-atherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailablity. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association [NYHA] class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA) and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman’s r=0.41, p<0.001) and NT-proBNP levels (r=0.55, p<0.001), inversely correlated with GABR (r= −0.39, p<0.001), and were not associated with hsCRP (p=0.81) or MPO (p=0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33, p=0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums p=0.002), RV systolic dysfunction (rank sums p=0.002), and RV diastolic dysfunction (rank sums p=0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (HR [95% CI]: 1.45 [1.02–2.07], p=0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels. PMID:23499315

Aconitine "challenge" test reveals a single whole-body exposure to diesel exhaust increases cardiac arrhythmia risk in hypertensive rats

EPA Science Inventory

Epidemiological studies demonstrate a significant association between cardiac electrical dysfunction, arrhythmias and air pollution exposure. Sensitivity to aconitine-induced arrhythmia has been used repeatedly to examine the factors that increase the risk of such cardiac electri...

CD28/B7 deficiency attenuates systolic overload-induced congestive heart failure, myocardial and pulmonary inflammation, and activated T-cell accumulation in the heart and lungs

PubMed Central

Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J.; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-bo; Shimizu, Yoji; Bache, Robert J.; Chen, Yingjie

2017-01-01

The inflammatory response regulates congestive heart failure (CHF) development. T-cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T-cell activation and attenuates CHF development by reducing systemic, cardiac and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T-cells (CD3+CD44high cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout (KO) mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction (TAC). CD28 or B7 KO significantly attenuated TAC-induced CHF development, as indicated by less increase of heart and lung weight, and less reduction of LV contractility. CD28 or B7 KO also significantly reduced TAC-induced CD45+ leukocyte, T-cell and macrophage infiltration in hearts and lungs, lowered pro-inflammatory cytokine expression (such as TNF-α and IL-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250μg/mouse every 3 days) attenuated TAC-induced T cell activation, LV hypertrophy, and LV dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T-cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T-cell activation may be useful in treating CHF. PMID:27432861

5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection.

PubMed

Iskandar, Muhammad Zaid; Quasem, Wahid; El-Omar, Magdi

2015-05-02

A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5-FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. 2015 BMJ Publishing Group Ltd.

5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection

PubMed Central

Iskandar, Muhammad Zaid; Quasem, Wahid; El-Omar, Magdi

2015-01-01

A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5-FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. PMID:25935919

Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.

PubMed

Patten, Ian S; Rana, Sarosh; Shahul, Sajid; Rowe, Glenn C; Jang, Cholsoon; Liu, Laura; Hacker, Michele R; Rhee, Julie S; Mitchell, John; Mahmood, Feroze; Hess, Philip; Farrell, Caitlin; Koulisis, Nicole; Khankin, Eliyahu V; Burke, Suzanne D; Tudorache, Igor; Bauersachs, Johann; del Monte, Federica; Hilfiker-Kleiner, Denise; Karumanchi, S Ananth; Arany, Zoltan

2012-05-09

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

Low molecular weight fucoidan alleviates cardiac dysfunction in diabetic Goto-Kakizaki rats by reducing oxidative stress and cardiomyocyte apoptosis.

PubMed

Yu, Xinfeng; Zhang, Quanbin; Cui, Wentong; Zeng, Zheng; Yang, Wenzhe; Zhang, Chao; Zhao, Hongwei; Gao, Weidong; Wang, Xiaomin; Luo, Dali

2014-01-01

Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte apoptosis. Oxidative stress is suggested to be the major contributor to the development of DCM. This study was intended to evaluate the protective effect of low molecular weight fucoidan (LMWF) against cardiac dysfunction in diabetic rats. Type 2 diabetic goto-kakizaki rats were untreated or treated with LMWF (50 and 100 mg/kg/day) for three months. The establishment of DCM model and the effects of LMWF on cardiac function were evaluated by echocardiography and isolated heart perfusion. Ventricle staining with H-E or Sirius Red was performed to investigate the structural changes in myocardium. Functional evaluation demonstrated that LMWF has a beneficial effect on DCM by enhancing myocardial contractility and mitigating cardiac fibrosis. Additionally, LMWF exerted significant inhibitory effects on the reactive oxygen species production and myocyte apoptosis in diabetic hearts. The depressed activity of superoxide dismutase in diabetic heart was also improved by intervention with LMWF. Moreover, LMWF robustly inhibited the enhanced expression of protein kinase C β, an important contributor to oxidative stress, in diabetic heart and high glucose-treated cardiomyocytes. In conclusion, LMWF possesses a protective effect against DCM through ameliorations of PKCβ-mediated oxidative stress and subsequent cardiomyocyte apoptosis in diabetes.

Cardiac Angiogenic Imbalance Leads to Peri-partum Cardiomyopathy

PubMed Central

Patten, Ian S.; Rana, Sarosh; Shahul, Sajid; Rowe, Glenn C; Jang, Cholsoon; Liu, Laura; Hacker, Michele R.; Rhee, Julie S.; Mitchell, John; Mahmood, Feroze; Hess, Phil; Farrell, Caitlin; Koulisis, Nicole; Khankin, Eliyahu V; Burke, Suzanne D.; Tudorache, Igor; Bauersachs, Johann; del Monte, Federica; Hilfiker-Kleiner, Denise; Karumanchi, S. Ananth; Arany, Zoltan

2012-01-01

Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM. PMID:22596155

Complications of Transfusion-Dependent β-Thalassemia Patients in Sistan and Baluchistan, South-East of Iran.

PubMed

Yaghobi, Maryam; Miri-Moghaddam, Ebrahim; Majid, Naderi; Bazi, Ali; Navidian, Ali; Kalkali, Asiyeh

2017-10-01

Background : Thalassemia syndromes are among prevalent hereditary disorders imposing high expenses on health-care system worldwide and in Iran. Organ failure represents a life-threatening challenge in transfusion- dependent β-thalassemia (TDT) patients. The purpose of the present study was to determine the frequency of organ dysfunctions among TDT patients in Sistan and Baluchistan province in South-East of Iran. Materials and Methods: Laboratory and clinical data were extracted from medical records as well as by interviews. Standard criteria were applied to recognize cardiac, gonadal, endocrine and renal dysfunctions. The collected data were analyzed using the SPSS statistics software (Ver.19). Results: A total of 613 TDT patients (54.3% males and 45.7% females) were included in this study. The mean age of patients was 13.3 ±7.7 years old. Cardiac events comprised the most encountered complications (76.4%), following by hypogonadism (46.8%), parathyroid dysfunction (22%), thyroid abnormalities (8.3%), diabetes (7.8%) and renal disease (1.8%). Hypogonadism comprised the most identified complication in patient <15 years old, while the cardiac complications were the most frequent sequela in patients >15 years old (P<0.01). Conclusion: As cardiac events are significantly more common among TDT patients, close monitoring of the heart function is recommended for identifying patients with cardiac problems.

Phantom evaluation of a cardiac SPECT/VCT system that uses a common set of solid-state detectors for both emission and transmission scans.

PubMed

Bai, Chuanyong; Conwell, Richard; Kindem, Joel; Babla, Hetal; Gurley, Mike; De Los Santos, Romer; Old, Rex; Weatherhead, Randy; Arram, Samia; Maddahi, Jamshid

2010-06-01

We developed a cardiac SPECT system (X-ACT) with low dose volume CT transmission-based attenuation correction (AC). Three solid-state detectors are configured to form a triple-head system for emission scans and reconfigured to form a 69-cm field-of-view detector arc for transmission scans. A near mono-energetic transmission line source is produced from the collimated fluorescence x-ray emitted from a lead target when the target is illuminated by a narrow polychromatic x-ray beam from an x-ray tube. Transmission scans can be completed in 1 min with insignificant patient dose (deep dose equivalent <5 muSv). We used phantom studies to evaluate (1) the accuracy of the reconstructed attenuation maps, (2) the effect of AC on image uniformity, and (3) the effect of AC on defect contrast (DC). The phantoms we used included an ACR phantom, an anthropomorphic phantom with a uniform cardiac insert, and an anthropomorphic phantom with two defects in the cardiac insert. The reconstructed attenuation coefficient of water at 140 keV was .150 +/- .003/cm in the uniform region of the ACR phantom, .151 +/- .003/cm and .151 +/- .002/cm in the liver and cardiac regions of the anthropomorphic phantom. The ACR phantom images with AC showed correction of the bowing effect due to attenuation in the images without AC (NC). The 17-segment scores of the images of the uniform cardiac insert were 78.3 +/- 6.5 before and 87.9 +/- 3.3 after AC (average +/- standard deviation). The inferior-to-anterior wall ratio and the septal-to-lateral wall ratio were .99 and 1.16 before and 1.02 and 1.00 after AC. The DC of the two defects was .528 and .156 before and .628 and .173 after AC. The X-ACT system generated accurate attenuation maps with 1-minute transmission scans. AC improved image quality and uniformity over NC.

Employing Extracellular Volume Cardiovascular Magnetic Resonance Measures of Myocardial Fibrosis to Foster Novel Therapeutics.

PubMed

Schelbert, Erik B; Sabbah, Hani N; Butler, Javed; Gheorghiade, Mihai

2017-06-01

Quantifying myocardial fibrosis (MF) with myocardial extracellular volume measures acquired during cardiovascular magnetic resonance promises to transform clinical care by advancing pathophysiologic understanding and fostering novel therapeutics. Extracellular volume quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma. MF is a key domain of dysfunctional but viable myocardium among others (eg, microvascular dysfunction and cardiomyocyte/mitochondrial dysfunction). Although anatomically distinct, these domains may functionally interact. MF represents pathological remodeling in the heart associated with cardiac dysfunction and adverse outcomes likely mediated by interactions with the microvasculature and the cardiomyocyte. Reversal of MF improves key measures of cardiac dysfunction, so reversal of MF represents a likely mechanism for improved outcomes. Instead of characterizing the myocardium as homogenous tissue and using important yet still generic descriptors, such as thickness (hypertrophy) and function (diastolic or systolic), which lack mechanistic specificity, paradigms of cardiac disease have evolved to conceptualize myocardial disease and patient vulnerability based on the extent of disease involving its various compartments. Specifying myocardial compartmental involvement may then implicate cellular/molecular disease pathways for treatment and targeted pharmaceutical development and above all highlight the role of the cardiac-specific pathology in heart failure among myriad other changes in the heart and beyond. The cardiology community now requires phase 2 and 3 clinical trials to examine strategies for the regression/prevention of MF and eventually biomarkers to identify MF without reliance on cardiovascular magnetic resonance. It seems likely that efficacious antifibrotic therapy will improve outcomes, but definitive data are needed. © 2017 American Heart Association, Inc.

Systemic inflammation is associated with myocardial fibrosis, diastolic dysfunction, and cardiac hypertrophy in patients with hypertrophic cardiomyopathy

PubMed Central

Fang, Lu; Ellims, Andris H; Beale, Anna L; Taylor, Andrew J; Murphy, Andrew; Dart, Anthony M

2017-01-01

Background: Regional or diffuse fibrosis is an early feature of hypertrophic cardiomyopathy (HCM) and is related to poor prognosis. Previous studies have documented low-grade inflammation in HCM. The aim of this study was to examine the relationships between circulating inflammatory markers and myocardial fibrosis, systolic and diastolic dysfunction, and the degree of cardiac hypertrophy in HCM patients. Methods and results: Fifty HCM patients were recruited while 20 healthy subjects served as the control group. Seventeen inflammatory cytokines/chemokines were measured in plasma. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac phenotypes. Tumour necrosis factor (TNF)-α, interleukin (IL)-6 and serum amyloid P (SAP) were significantly increased in HCM patients compared to controls. IL-6, IL-4, and monocyte chemotactic protein (MCP)-1 were correlated with regional fibrosis while stromal cell-derived factor-1 and MCP-1 were correlated with diffuse fibrosis. Fractalkine and interferon-γ were associated with left ventricular wall thickness. The above associations remained significant in a linear regression model including age, gender, body mass index and family history. TNF-α, IL-6, SAP, MCP-1 and IL-10 were associated with parameters of diastolic dysfunction. White blood cells were also increased in HCM patients and correlated with diffuse fibrosis and diastolic dysfunction. However the associations between parameters of systemic inflammation and diastolic dysfunction were weakened in the linear regression analysis. Conclusions: Systemic inflammation is associated with parameters of the disease severity of HCM patients, particularly regional and diffuse fibrosis. Modifying inflammation may reduce myocardial fibrosis in HCM patients. PMID:29218105

mTOR drives cerebral blood flow and memory deficits in LDLR-/- mice modeling atherosclerosis and vascular cognitive impairment.

PubMed

Jahrling, Jordan B; Lin, Ai-Ling; DeRosa, Nicholas; Hussong, Stacy A; Van Skike, Candice E; Girotti, Milena; Javors, Martin; Zhao, Qingwei; Maslin, Leigh Ann; Asmis, Reto; Galvan, Veronica

2018-01-01

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR -/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload.

PubMed

Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A; Cummins, Timothy D; McNally, Lindsey A; Brittian, Kenneth R; Jagatheesan, Ganapathy; Audam, Timothy N; Long, Bethany W; Brainard, Robert E; Jones, Steven P; Hill, Bradford G

2018-06-01

Pathological cardiac remodeling during heart failure is associated with higher levels of lipid peroxidation products and lower abundance of several aldehyde detoxification enzymes, including aldehyde dehydrogenase 2 (ALDH2). An emerging idea that could explain these findings concerns the role of electrophilic species in redox signaling, which may be important for adaptive responses to stress or injury. The purpose of this study was to determine whether genetically increasing ALDH2 activity affects pressure overload-induced cardiac dysfunction. Mice subjected to transverse aortic constriction (TAC) for 12 weeks developed myocardial hypertrophy and cardiac dysfunction, which were associated with diminished ALDH2 expression and activity. Cardiac-specific expression of the human ALDH2 gene in mice augmented myocardial ALDH2 activity but did not improve cardiac function in response to pressure overload. After 12 weeks of TAC, ALDH2 transgenic mice had larger hearts than their wild-type littermates and lower capillary density. These findings show that overexpression of ALDH2 augments the hypertrophic response to pressure overload and imply that downregulation of ALDH2 may be an adaptive response to certain forms of cardiac pathology. Copyright © 2018. Published by Elsevier B.V.

Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress.

PubMed

Koncsos, Gábor; Varga, Zoltán V; Baranyai, Tamás; Boengler, Kerstin; Rohrbach, Susanne; Li, Ling; Schlüter, Klaus-Dieter; Schreckenberg, Rolf; Radovits, Tamás; Oláh, Attila; Mátyás, Csaba; Lux, Árpád; Al-Khrasani, Mahmoud; Komlódi, Tímea; Bukosza, Nóra; Máthé, Domokos; Deres, László; Barteková, Monika; Rajtík, Tomáš; Adameová, Adriana; Szigeti, Krisztián; Hamar, Péter; Helyes, Zsuzsanna; Tretter, László; Pacher, Pál; Merkely, Béla; Giricz, Zoltán; Schulz, Rainer; Ferdinandy, Péter

2016-10-01

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca 2+ /calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. Copyright © 2016 the American Physiological Society.

The cardiovascular system in growth hormone excess and growth hormone deficiency.

PubMed

Lombardi, G; Di Somma, C; Grasso, L F S; Savanelli, M C; Colao, A; Pivonello, R

2012-12-01

The clinical conditions associated with GH excess and GH deficiency (GHD) are known to be associated with an increased risk for the cardiovascular morbidity and mortality, suggesting that either an excess or a deficiency in GH and/or IGF-I is deleterious for cardiovascular system. In patients with acromegaly, chronic GH and IGF-I excess commonly causes a specific cardiomyopathy characterized by a concentric cardiac hypertrophy associated with diastolic dysfunction and, in later stages, with systolic dysfunction ending in heart failure if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and anomalies of cardiac valves can also occur. Moreover, the increased prevalence of cardiovascular risk factors, such as hypertension, diabetes mellitus, and insulin resistance, as well as dyslipidemia, confer an increased risk for vascular atherosclerosis. Successful control of the disease is accompanied by a decrease of the cardiac mass and improvement of cardiac function and an improvement in cardiovascular risk factors. In patients with hypopituitarism, GHD has been considered the under- lying factor of the increased mortality when appropriate standard replacement of the pituitary hormones deficiencies is given. Either childhood-onset or adulthood-onset GHD are characterized by a cluster of abnormalities associated with an increased cardiovascular risk, including altered body composition, unfavorable lipid profile, insulin resistance, endothelial dysfunction and vascular atherosclerosis, a decrease in cardiac mass together with an impairment of systolic function mainly after exercise. Treatment with recombinant GH in patients with GHD is followed by an improvement of the cardiovascular risk factors and an increase in cardiac mass together with an improvement in cardiac performance. In conclusion, acromegaly and GHD are associated with an increased risk for cardiovascular morbidity and mortality, but the control of GH/IGF-I secretion reverses cardiovascular abnormalities and restores the normal life expectancy.

Attenuation correction for flexible magnetic resonance coils in combined magnetic resonance/positron emission tomography imaging.

PubMed

Eldib, Mootaz; Bini, Jason; Calcagno, Claudia; Robson, Philip M; Mani, Venkatesh; Fayad, Zahi A

2014-02-01

Attenuation correction for magnetic resonance (MR) coils is a new challenge that came about with the development of combined MR and positron emission tomography (PET) imaging. This task is difficult because such coils are not directly visible on either PET or MR acquisitions with current combined scanners and are therefore not easily localized in the field of view. This issue becomes more evident when trying to localize flexible MR coils (eg, cardiac or body matrix coil) that change position and shape from patient to patient and from one imaging session to another. In this study, we proposed a novel method to localize and correct for the attenuation and scatter of a flexible MR cardiac coil, using MR fiducial markers placed on the surface of the coil to allow for accurate registration of a template computed tomography (CT)-based attenuation map. To quantify the attenuation properties of the cardiac coil, a uniform cylindrical water phantom injected with 18F-fluorodeoxyglucose (18F-FDG) was imaged on a sequential MR/PET system with and without the flexible cardiac coil. After establishing the need to correct for the attenuation of the coil, we tested the feasibility of several methods to register a precomputed attenuation map to correct for the attenuation. To accomplish this, MR and CT visible markers were placed on the surface of the cardiac flexible coil. Using only the markers as a driver for registration, the CT image was registered to the reference image through a combination of rigid and deformable registration. The accuracy of several methods was compared for the deformable registration, including B-spline, thin-plate spline, elastic body spline, and volume spline. Finally, we validated our novel approach both in phantom and patient studies. The findings from the phantom experiments indicated that the presence of the coil resulted in a 10% reduction in measured 18F-FDG activity when compared with the phantom-only scan. Local underestimation reached 22% in regions of interest close to the coil. Various registration methods were tested, and the volume spline was deemed to be the most accurate, as measured by the Dice similarity metric. The results of our phantom experiments showed that the bias in the 18F-FDG quantification introduced by the presence of the coil could be reduced by using our registration method. An overestimation of only 1.9% of the overall activity for the phantom scan with the coil attenuation map was measured when compared with the baseline phantom scan without coil. A local overestimation of less than 3% was observed in the ROI analysis when using the proposed method to correct for the attenuation of the flexible cardiac coil. Quantitative results from the patient study agreed well with the phantom findings. We presented and validated an accurate method to localize and register a CT-based attenuation map to correct for the attenuation and scatter of flexible MR coils. This method may be translated to clinical use to produce quantitatively accurate measurements with the use of flexible MR coils during MR/PET imaging.

Pitx2c attenuation results in cardiac defects and abnormalities of intestinal orientation in developing Xenopus laevis.

PubMed

Dagle, John M; Sabel, Jaime L; Littig, Jennifer L; Sutherland, Lillian B; Kolker, Sandra J; Weeks, Daniel L

2003-10-15

The experimental manipulation of early embryologic events, resulting in the misexpression of the homeobox transcription factor pitx2, is associated with subsequent defects of laterality in a number of vertebrate systems. To clarify the role of one pitx2 isoform, pitx2c, in determining the left-right axis of amphibian embryos, we examined the heart and gut morphology of Xenopus laevis embryos after attenuating pitx2c mRNA levels using chemically modified antisense oligonucleotides. We demonstrate that the partial depletion of pitx2c mRNA in these embryos results in alteration of both cardiac morphology and intestinal coiling. The most common cardiac abnormality seen was a failure of rightward migration of the outflow tract, while the most common intestinal laterality phenotype seen was a full reversal in the direction of coiling, each present in 23% of embryos injected with the pitx2c antisense oligonucleotide. An abnormality in either the heart or gut further predisposed to a malformation in the other. In addition, a number of other cardiac anomalies were observed after pitx2c mRNA attenuation, including abnormalities of atrial septation, extracellular matrix restriction, relative atrial-ventricular chamber positioning, and restriction of ventricular development. Many of these findings correlate with cardiac defects previously reported in pitx2 null and hypomorphic mice, but can now be assigned specifically to attenuation of the pitx2c isoform in Xenopus.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system.

PubMed

Thomas, Candice M; Yong, Qian Chen; Rosa, Rodolfo M; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E; Jones, W Keith; Gupta, Sudhiranjan; Baker, Kenneth M; Kumar, Rajesh

2014-10-01

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.

Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

PubMed Central

Thomas, Candice M.; Yong, Qian Chen; Rosa, Rodolfo M.; Seqqat, Rachid; Gopal, Shanthi; Casarini, Dulce E.; Jones, W. Keith; Gupta, Sudhiranjan; Baker, Kenneth M.

2014-01-01

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system. PMID:25085967

The Prevalence, Correlates, and Impact on Cardiac Mortality of Right Ventricular Dysfunction in Nonischemic Cardiomyopathy.

PubMed

Pueschner, Andreas; Chattranukulchai, Pairoj; Heitner, John F; Shah, Dipan J; Hayes, Brenda; Rehwald, Wolfgang; Parker, Michele A; Kim, Han W; Judd, Robert M; Kim, Raymond J; Klem, Igor

2017-10-01

This study sought to determine the prevalence, correlates, and impact on cardiac mortality of right ventricular (RV) dysfunction in nonischemic cardiomyopathy. Current heart failure guidelines place little emphasis on RV assessment due to limited available data on determinants of RV function, mechanisms leading to its failure, and relation to outcomes. We prospectively studied 423 patients with cardiac magnetic resonance (CMR). The pre-specified study endpoint was cardiac mortality. In 100 patients, right heart catheterization was performed as clinically indicated. During a median follow-up time of 6.2 years (interquartile range: 2.9 to 7.6 years), 101 patients (24%) died of cardiac causes. CMR right ventricular ejection fraction (RVEF) was a strong independent predictor of cardiac mortality after adjustment for age, heart failure-functional class, blood pressure, heart rate, serum sodium, serum creatinine, myocardial scar, and left ventricular ejection fraction (LVEF). Patients with the lowest quintile of RVEF had a nearly 5-fold higher cardiac mortality risk than did patients with the highest quintile (hazard ratio: 4.68; 95% confidence interval [CI]: 2.43 to 9.02; p < 0.0001). RVEF was positively correlated with LVEF (r = 0.60; p < 0.0001), and inversely correlated with right atrial pressure (r = -0.32; p = 0.001), pulmonary artery pressure (r = -0.34; p = 0.0005), transpulmonary gradient (r = -0.28; p = 0.006) but not with pulmonary wedge pressure (r = -0.15; p = 0.13). In multivariable logistic regression analysis of CMR, clinical, and hemodynamic data the strongest predictors of right ventricular dysfunction were LVEF (odds ratio [OR]: 0.85; 95% CI: 0.78 to 0.92; p < 0.0001), transpulmonary gradient (OR: 1.20; 95% CI: 1.09 to 1.32; p = 0.0003), and systolic blood pressure (OR: 0.97; 95% CI: 0.94 to 0.99; p = 0.02). CMR assessment of RVEF provides important prognostic information independent of established risk factors and LVEF in heart failure patients with nonischemic cardiomyopathy. Right ventricular dysfunction is strongly associated with both indices of intrinsic myocardial contractility and increased afterload from pulmonary vascular dysfunction. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Cumulative Burden of Myocardial Dysfunction in Cardiac Amyloidosis Assessed Using Four-Chamber Cardiac Strain.

PubMed

Kado, Yuichiro; Obokata, Masaru; Nagata, Yasufumi; Ishizu, Tomoko; Addetia, Karima; Aonuma, Kazutaka; Kurabayashi, Masahiko; Lang, Roberto M; Takeuchi, Masaaki; Otsuji, Yutaka

2016-11-01

The aim of this study was to test the hypothesis that prognosis in patients with cardiac amyloidosis is closely coupled with amyloid burden in all four cardiac chambers. The goal was to evaluate longitudinal strain (LS) in each cardiac chamber and to determine whether LS in specific cardiac chambers is preferentially associated with prognosis over conventional two-dimensional echocardiographic parameters in patients with cardiac amyloidosis. Patients with two phenotypes of left ventricular (LV) hypertrophy (cardiac amyloidosis in 55 patients and nonobstructive hypertrophic cardiomyopathy in 40 patients) and 55 healthy subjects were retrospectively enrolled for the simultaneous assessment of LS of all four cardiac chambers in the apical four-chamber view. Patients with cardiac amyloidosis were followed up to record major adverse cardiovascular events, including cardiac death, heart transplantation, nonfatal myocardial infarction, ventricular tachyarrhythmia, and exacerbation of heart failure requiring hospitalization. LS in each chamber was significantly depressed in patients with both LV hypertrophy phenotypes compared with healthy subjects. Right atrial LS was significantly lower in patients with cardiac amyloidosis than those with nonobstructive hypertrophic cardiomyopathy after adjusting for LV ejection fraction and LV mass index. During a median follow-up period of 10 months, major adverse cardiovascular events developed in 22 patients with cardiac amyloidosis. Four-chamber LS were significantly associated with major adverse cardiovascular events, with incremental value over traditional echocardiographic parameters. Cardiac amyloidosis involves all cardiac chambers, and thus, chamber-specific strain analysis may be useful to assess the total cumulative burden of cardiac dysfunction. Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

PubMed

Meybohm, Patrick; Kohlhaas, Madeline; Stoppe, Christian; Gruenewald, Matthias; Renner, Jochen; Bein, Berthold; Albrecht, Martin; Cremer, Jochen; Coburn, Mark; Schaelte, Gereon; Boening, Andreas; Niemann, Bernd; Sander, Michael; Roesner, Jan; Kletzin, Frank; Mutlak, Haitham; Westphal, Sabine; Laufenberg-Feldmann, Rita; Ferner, Marion; Brandes, Ivo F; Bauer, Martin; Stehr, Sebastian N; Kortgen, Andreas; Wittmann, Maria; Baumgarten, Georg; Meyer-Treschan, Tanja; Kienbaum, Peter; Heringlake, Matthias; Schoen, Julika; Treskatsch, Sascha; Smul, Thorsten; Wolwender, Ewa; Schilling, Thomas; Fuernau, Georg; Bogatsch, Holger; Brosteanu, Oana; Hasenclever, Dirk; Zacharowski, Kai

2018-03-26

Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure).

PubMed

AbouEzzeddine, Omar F; Haines, Phillip; Stevens, Susanna; Nativi-Nicolau, Jose; Felker, G Michael; Borlaug, Barry A; Chen, Horng H; Tracy, Russell P; Braunwald, Eugene; Redfield, Margaret M

2015-03-01

This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Pulmonary Vascular Congestion: A Mechanism for Distal Lung Unit Dysfunction in Obesity.

PubMed

Oppenheimer, Beno W; Berger, Kenneth I; Ali, Saleem; Segal, Leopoldo N; Donnino, Robert; Katz, Stuart; Parikh, Manish; Goldring, Roberta M

2016-01-01

Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

Mitochondrial Dynamics in Diabetic Cardiomyopathy

PubMed Central

Galloway, Chad A.

2015-01-01

Abstract Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545–1562. PMID:25738230

Mediastinal Bronchogenic Cyst With Acute Cardiac Dysfunction: Two-Stage Surgical Approach.

PubMed

Smail, Hassiba; Baste, Jean Marc; Melki, Jean; Peillon, Christophe

2015-10-01

We describe a two-stage surgical approach in a patient with cardiac dysfunction and hemodynamic compromise resulting from a massive and compressive mediastinal bronchogenic cyst. To drain this cyst, video-assisted mediastinoscopy was performed as an emergency procedure, which immediately improved the patient's cardiac function. Five days later and under video thoracoscopy, resection of the cyst margins was impossible because the cyst was tightly adherent to the left atrium. We performed deroofing of this cyst through a right thoracotomy. The patient had an uncomplicated postoperative recovery, and no recurrence was observed at the long-term follow-up visit. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Edaravone Improves Septic Cardiac Function by Inducing an HIF-1α/HO-1 Pathway

PubMed Central

He, Chao; Zhang, Wei; Li, Suobei; Ruan, Wei; Xu, Junmei

2018-01-01

Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction. PMID:29765498

A comparison of toxicities in acute myeloid leukemia patients with and without renal impairment treated with decitabine.

PubMed

Levine, Lauren B; Roddy, Julianna Vf; Kim, Miryoung; Li, Junan; Phillips, Gary; Walker, Alison R

2018-06-01

Purpose There are limited data regarding the clinical use of decitabine for the treatment of acute myeloid leukemia in patients with a serum creatinine of 2 mg/dL or greater. Methods We retrospectively evaluated 111 patients with acute myeloid leukemia who had been treated with decitabine and compared the development of toxicities during cycle 1 in those with normal renal function (creatinine clearance greater than or equal to 60 mL/min) to those with renal dysfunction (creatinine clearance less than 60 mL/min). Results Notable differences in the incidence of grade ≥3 cardiotoxicity (33% of renal dysfunction patients vs. 16% of normal renal function patients, p = 0.042) and respiratory toxicity (40% of renal dysfunction patients vs. 14% of normal renal function patients, p = 0.0037) were observed. The majority of heart failure, myocardial infarction, and atrial fibrillation cases occurred in the renal dysfunction group. The odds of developing grade ≥3 cardiotoxicity did not differ significantly between patients with and without baseline cardiac comorbidities (OR 1.43, p = 0.43). Conclusions This study noted a higher incidence of grade ≥3 cardiac and respiratory toxicities in decitabine-treated acute myeloid leukemia patients with renal dysfunction compared to normal renal function. This may prompt closer monitoring, regardless of baseline cardiac comorbidities. Further evaluation of decitabine in patients with renal dysfunction is needed.

Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death.

PubMed

Hakeem, Abdul; Bhatti, Sabha; Dillie, Kathryn Sullivan; Cook, Jeffrey R; Samad, Zainab; Roth-Cline, Michelle D; Chang, Su Min

2008-12-09

Patients with chronic kidney disease (CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT (MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated. We followed up 1652 consecutive patients who underwent stress MPS (32% exercise, 95% gated) for cardiac death for a mean of 2.15+/-0.8 years. MPS defects were defined with a summed stress score (normal summed stress score <4, abnormal summed stress score>or=4). Ischemia was defined as a summed stress score >or=4 plus a summed difference score >or=2, and scar was defined as a summed difference score <2 plus a summed stress score >or=4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD (estimated glomerular filtration rate <60 mL . min(-1) . 1.73 m(-2)) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS (2.7% versus 0.8%, P=0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects (hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD (hazard ratio 1.96, 95% CI 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction (global chi(2) 207.5 versus 169.3, P<0.0001). MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan.

Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity.

PubMed

Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang; Sun, Zhongjie

2016-11-01

The objective of this study is to investigate whether stem cell delivery of secreted Klotho (SKL), an aging-suppressor protein, attenuates monocrotaline-induced pulmonary vascular dysfunction and remodeling. Overexpression of SKL in mesenchymal stem cells (MSCs) was achieved by transfecting MSCs with lentiviral vectors expressing SKL-green fluorescent protein (GFP). Four groups of rats were treated with monocrotaline, whereas an additional group was given saline (control). Three days later, 4 monocrotaline-treated groups received intravenous delivery of nontransfected MSCs, MSC-GFP, MSC-SKL-GFP, and PBS, respectively. Ex vivo vascular relaxing responses to acetylcholine were diminished in small pulmonary arteries (PAs) in monocrotaline-treated rats, indicating pulmonary vascular endothelial dysfunction. Interestingly, delivery of MSCs overexpressing SKL (MSC-SKL-GFP) abolished monocrotaline-induced pulmonary vascular endothelial dysfunction and PA remodeling. Monocrotaline significantly increased right ventricular systolic blood pressure, which was attenuated significantly by MSC-SKL-GFP, indicating improved PA hypertension. MSC-SKL-GFP also attenuated right ventricular hypertrophy. Nontransfected MSCs slightly, but not significantly, improved PA hypertension and pulmonary vascular endothelial dysfunction. MSC-SKL-GFP attenuated monocrotaline-induced inflammation, as evidenced by decreased macrophage infiltration around PAs. MSC-SKL-GFP increased SKL levels, which rescued the downregulation of SIRT1 (Sirtuin 1) expression and endothelial NO synthase (eNOS) phosphorylation in the lungs of monocrotaline-treated rats. In cultured endothelial cells, SKL abolished monocrotaline-induced downregulation of eNOS activity and NO levels and enhanced cell viability. Therefore, stem cell delivery of SKL is an effective therapeutic strategy for pulmonary vascular endothelial dysfunction and PA remodeling. SKL attenuates monocrotaline-induced PA remodeling and PA smooth muscle cell proliferation, likely by reducing inflammation and restoring SIRT1 levels and eNOS activity. © 2016 American Heart Association, Inc.

Cardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone.

PubMed

Granata, Riccarda; Isgaard, Jörgen; Alloatti, Giuseppe; Ghigo, Ezio

2011-05-01

In 1976, small peptide growth hormone secretagogues (GHSs) were discovered and found to promote growth hormone (GH) release from the pituitary. The GHS receptor (GHS-R) was subsequently cloned, and its endogenous ligand ghrelin was later isolated from the stomach. Ghrelin is a 28-amino acid peptide, whose acylation is essential for binding to GHS-R type 1a and for the endocrine functions, including stimulation of GH secretion and subsequent food intake. Unacylated ghrelin, the other ghrelin form, although devoid of GHS-R binding is an active peptide, sharing many peripheral effects with acylated ghrelin (AG). The ghrelin system is broadly expressed in myocardial tissues, where it exerts different functions. Indeed, ghrelin inhibits cardiomyocyte and endothelial cell apoptosis, and improves left ventricular (LV) function during ischemia-reperfusion (I/R) injury. In rats with heart failure (HF), ghrelin improves LV dysfunction and attenuates the development of cardiac cachexia. Similarly, ghrelin exerts vasodilatory effects in humans, improves cardiac function and decreases systemic vascular resistance in patients with chronic HF. Obestatin is a recently identified ghrelin gene peptide. The physiological role of obestatin and its binding to the putative GPR39 receptor are still unclear, although protective effects have been demonstrated in the pancreas and heart. Similarly to AG, the hypothalamic peptide growth hormone-releasing hormone (GHRH) stimulates GH release from the pituitary, through binding to the GHRH-receptor. Besides its proliferative effects in different cell types, at the cardiovascular level GHRH inhibits cardiomyocyte apoptosis, and reduces infarct size in both isolated rat heart after I/R and in vivo after myocardial infarction. Therefore, both ghrelin and GHRH exert cardioprotective effects, which make them candidate targets for therapeutic intervention in cardiovascular dysfunctions.

L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat.

PubMed

Brooks, Wesley W; Conrad, Chester H; Robinson, Kathleen G; Colucci, Wilson S; Bing, Oscar H L

2009-02-01

The effects of long-term oral administration of L-arginine, a substrate for nitric oxide (NO) production, on left ventricular (LV) remodeling, myocardial function and the prevention of heart failure (HF) was compared to the angiotensin-converting enzyme (ACE) inhibitor captopril in a rat model of hypertensive HF (aged spontaneously hypertensive rat (SHR)). SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats were assigned to either no treatment, treatment with L-arginine (7.5 g/l in drinking water) or captopril (1 g/l in drinking water) beginning at 14 months of age, a time when SHRs exhibit stable compensated hypertrophy with no hemodynamic impairment; animals were studied at 23 months of age or at the time of HF. In untreated SHR, relative to WKY, there was significant LV hypertrophy, myocardial fibrosis, and isolated LV muscle performance and response to isoproterenol (ISO) were depressed; and, 7 of 10 SHRs developed HF. Captopril administration to six SHRs attenuated hypertrophy and prevented impaired inotropic responsiveness to ISO, contractile dysfunction, fibrosis, increased passive stiffness, and HF. In contrast, L-arginine administration to SHR increased LV hypertrophy and myocardial fibrosis while cardiac performance was depressed; and 7 of 9 SHRs developed HF. In WKY, L-arginine treatment but not captopril resulted in increased LV weight and the contractile response to ISO was blunted. Neither L-arginine nor captopril treatment of WKY changed fibrosis and HF did not occur. These data demonstrate that in contrast to captopril, long-term treatment with L-arginine exacerbates age-related cardiac hypertrophy, fibrosis, and did not prevent contractile dysfunction or the development of HF in aging SHR.

B-vitamin Supplementation Mitigates Effects of Fine Particles on Cardiac Autonomic Dysfunction and Inflammation: A Pilot Human Intervention Trial

NASA Astrophysics Data System (ADS)

Zhong, Jia; Trevisi, Letizia; Urch, Bruce; Lin, Xinyi; Speck, Mary; Coull, Brent A.; Liss, Gary; Thompson, Aaron; Wu, Shaowei; Wilson, Ander; Koutrakis, Petros; Silverman, Frances; Gold, Diane R.; Baccarelli, Andrea A.

2017-04-01

Ambient fine particle (PM2.5) pollution triggers acute cardiovascular events. Individual-level preventions are proposed to complement regulation in reducing the global burden of PM2.5-induced cardiovascular diseases. We determine whether B vitamin supplementation mitigates PM2.5 effects on cardiac autonomic dysfunction and inflammation in a single-blind placebo-controlled crossover pilot trial. Ten healthy adults received two-hour controlled-exposure-experiment to sham under placebo, PM2.5 (250 μg/m3) under placebo, and PM2.5 (250 μg/m3) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. At pre-, post-, 24 h-post-exposure, we measured resting heart rate (HR) and heart rate variability (HRV) with electrocardiogram, and white blood cell (WBC) counts with hematology analyzer. Compared to sham, PM2.5 exposure increased HR (3.8 bpm, 95% CI: 0.3, 7.4; P = 0.04), total WBC count (11.5%, 95% CI: 0.3%, 24.0%; P = 0.04), lymphocyte count (12.9%, 95% CI: 4.4%, 22.1%; P = 0.005), and reduced low-frequency power (57.5%, 95% CI: 2.5%, 81.5%; P = 0.04). B-vitamin supplementation attenuated PM2.5 effect on HR by 150% (P = 0.003), low-frequency power by 90% (P = 0.01), total WBC count by 139% (P = 0.006), and lymphocyte count by 106% (P = 0.02). In healthy adults, two-hour PM2.5 exposure substantially increases HR, reduces HRV, and increases WBC. These effects are reduced by B vitamin supplementation.

OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling.

PubMed

Ogino, Atsushi; Takemura, Genzou; Hashimoto, Ayako; Kanamori, Hiromitsu; Okada, Hideshi; Nakagawa, Munehiro; Tsujimoto, Akiko; Goto, Kazuko; Kawasaki, Masanori; Nagashima, Kenshi; Miyakoda, Goro; Fujiwara, Takako; Yabuuchi, Youichi; Fujiwara, Hisayoshi; Minatoguchi, Shinya

2015-07-01

Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction. Copyright © 2015 the American Physiological Society.

Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

PubMed Central

Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

2014-01-01

Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Haipeng; Zhang, Xin; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan

Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It wasmore » demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and β-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. - Highlights: • We focus on the protective effect of taxifolin on cardiac remodeling. • Taxifolin inhibited cardiac hypertrophy and attenuated ventricular fibrosis. • Taxifolin suppressed oxidative stress and the excess production of ROS. • Taxifolin blocked ERK1/2, JNK1/2 and Smad signaling pathways. • We reported that taxifolin had the potential to be a candidate for cardiac hypertrophy treatment.« less

Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure.

PubMed

Koyani, Chintan N; Kolesnik, Ewald; Wölkart, Gerald; Shrestha, Niroj; Scheruebel, Susanne; Trummer, Christopher; Zorn-Pauly, Klaus; Hammer, Astrid; Lang, Petra; Reicher, Helga; Maechler, Heinrich; Groschner, Klaus; Mayer, Bernd; Rainer, Peter P; Sourij, Harald; Sattler, Wolfgang; Malle, Ernst; Pelzmann, Brigitte; von Lewinski, Dirk

2017-12-01

Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca 2+ /calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca 2+ -ATPase 2a axis and Na + -Ca 2+ exchanger function in Ca 2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca 2+ content, diastolic Ca 2+ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K + current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Muscular, cardiac, ventilatory and metabolic dysfunction in patients with multiple sclerosis: Implications for screening, clinical care and endurance and resistance exercise therapy, a scoping review.

PubMed

Wens, Inez; Eijnde, Bert O; Hansen, Dominique

2016-08-15

In the treatment of multiple sclerosis (MS), exercise training is now considered a cornerstone. However, most clinicians tend to focus on neurologic deficits only, and thus prefer to prescribe rehabilitation programs specifically to counteract these deficits. However, the present comprehensive review shows that patients with MS (pwMS) also experience significant muscular, cardiac, ventilatory and metabolic dysfunction, which significantly contribute, next to neurologic deficits, to exercise intolerance. In addition, these anomalies also might increase the risk for frequent hospitalization and morbidity and can reduce life expectancy. Unfortunately, the impact of exercise intervention on these anomalies in pwMS are mostly unknown. Therefore, it is suggested that pwMS should be screened systematically for muscular, cardiac, ventilatory and metabolic function during exercise testing. The detection of such anomalies should lead to adaptations and optimisation of exercise training prescription and clinical care/medical treatment of pwMS. In addition, future studies should focus on the impact of exercise intervention on muscular, cardiac, ventilatory and metabolic (dys)function in pwMS, to contribute to improved treatment and care. Copyright © 2016. Published by Elsevier B.V.

Diesel Exhaust-Induced Cardiac Dysfunction Is Mediated by Sympathetic Dominance in Heart Failure-Prone Rats

EPA Science Inventory

Short-term exposure to vehicular emissions is associated with adverse cardiac events. Diesel exhaust (DE) may provoke cardiac events through defective co-ordination of the two main autonomic nervous system (ANS) branches. We exposed heart failure-prone rats once to DE (500 g/m3 ...

Evaluation of corrective reconstruction methods using a 3D cardiac-torso phantom and bull's-eye plots

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, X.D.; Tsui, B.M.W.; Gregoriou, G.K.

The goal of the investigation was to study the effectiveness of the corrective reconstruction methods in cardiac SPECT using a realistic phantom and to qualitatively and quantitatively evaluate the reconstructed images using bull's-eye plots. A 3D mathematical phantom which realistically models the anatomical structures of the cardiac-torso region of patients was used. The phantom allows simulation of both the attenuation distribution and the uptake of radiopharmaceuticals in different organs. Also, the phantom can be easily modified to simulate different genders and variations in patient anatomy. Two-dimensional projection data were generated from the phantom and included the effects of attenuation andmore » detector response blurring. The reconstruction methods used in the study included the conventional filtered backprojection (FBP) with no attenuation compensation, and the first-order Chang algorithm, an iterative filtered backprojection algorithm (IFBP), the weighted least square conjugate gradient algorithm and the ML-EM algorithm with non-uniform attenuation compensation. The transaxial reconstructed images were rearranged into short-axis slices from which bull's-eye plots of the count density distribution in the myocardium were generated.« less

Discrete microstructural cues for the attenuation of fibrosis following myocardial infarction.

PubMed

Pinney, James R; Du, Kim T; Ayala, Perla; Fang, Qizhi; Sievers, Richard E; Chew, Patrick; Delrosario, Lawrence; Lee, Randall J; Desai, Tejal A

2014-10-01

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pathophysiologic Mechanisms in Heart Failure: Role of the Sympathetic Nervous System.

PubMed

Antoine, Steve; Vaidya, Gaurang; Imam, Haider; Villarreal, Daniel

2017-01-01

The syndrome of heart failure involves complex pathophysiologic mechanisms and is associated with extremely high-morbidity, mortality and economic costs. This growing global epidemic has diverse etiologies and is fundamentally characterized by dyshomeostasis between heart and kidneys, leading to development and progression of the cardiorenal syndrome. Excessive and sustained sympathoexcitation has emerged as a single prominent factor involved in the structural and functional dysfunction of multiple organ systems during this disease. Studies in experimental models of heart failure indicate that ablation of the renal nerves may help restore renal sodium and water equilibrium as well as the attenuation of adverse cardiac remodeling. With the recent development of minimally invasive endovascular renal denervation in humans, it is anticipated that this technology would become a novel and important paradigm shift in the management of heart failure. Copyright © 2017. Published by Elsevier Inc.

Enhanced Skeletal Muscle Expression of EcSOD Mitigates Streptozotocin-Induced Diabetic Cardiomyopathy by Reducing Oxidative Stress and Aberrant Cell Signaling

PubMed Central

Call, Jarrod A.; Chain, Kristopher H.; Martin, Kyle S.; Lira, Vitor A.; Okutsu, Mitsuharu; Zhang, Mei; Yan, Zhen

2015-01-01

Background Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM). Methods and Results Exercise training promotes EcSOD expression in skeletal muscle and provides protection against DCM; however, it is not known if enhanced EcSOD expression in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice (TG) are protected from cardiac hypertrophy, fibrosis and dysfunction under the condition of type-1 diabetes induced by STZ injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in TG mice displayed significantly reduced oxidative stress, aberrant cell signaling and inflammatory cytokine expression compared with wild type mice under the same diabetic condition. Conclusions Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate STZ-induced DCM through attenuation of oxidative stress, aberrant cell signaling and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes. PMID:25504759

DOE Office of Scientific and Technical Information (OSTI.GOV)

Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-inducedmore » increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.« less

Decreased brain sigma-1 receptor contributes to the relationship between heart failure and depression.

PubMed

Ito, Koji; Hirooka, Yoshitaka; Matsukawa, Ryuichi; Nakano, Masatsugu; Sunagawa, Kenji

2012-01-01

Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression. Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 weeks to accelerate cardiac dysfunction (AB-H). Compared with sham-operated controls (Sham), AB-H showed augmented sympathetic activity, decreased per cent fractional shortening, increased left ventricular dimensions, and significantly lower brain S1R expression. Intracerebroventricular (ICV) infusion of S1R agonist PRE084 increased brain S1R expression, lowered sympathetic activity, and improved cardiac function in AB-H. ICV infusion of S1R antagonist BD1063 increased sympathetic activity and decreased cardiac function in Sham. Tail suspension test was used to evaluate the index of depression-like behaviour, with immobility time and strain amplitude recorded as markers of struggle activity using a force transducer. Immobility time increased and strain amplitude decreased in AB-H compared with Sham, and these changes were attenuated by ICV infusion of PRE084. These results indicate that decreased brain S1R contributes to the relationship between heart failure and depression in a mouse model of pressure overload.

Zero-order metoprolol pharmacokinetics after therapeutic doses: severe toxicity and cardiogenic shock.

PubMed

Isbister, Geoffrey K; Ang, Karyn; Gorman, Kieron; Cooper, Joyce; Mostafa, Ahmed; Roberts, Michael S

2016-11-01

Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment. A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m 2 ). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX ® vs 4.3 ( www.lixoft.com ). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035-0.5 μg/mL). Data best fitted a one compartmental model with Michaelis-Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [V m ], 9.57 mg h -1 , Michaelis constant [K m ], 1.97 mg L -1 . Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h. The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes.

Left ventricular diastolic dysfunction in type 2 diabetes patients: a novel 2D strain analysis based on cardiac magnetic resonance imaging.

PubMed

Chen, Qiang; Gan, Yan; Li, Zhi-Yong

2016-09-01

This study was to develop a strain analysis method to evaluate the left ventricular (LV) functions in type 2 diabetic patients with an asymptomatic LV diastolic dysfunction. Two groups (10 asymptomatic type 2 diabetic subjects and 10 control ones) were considered. All of the subjects had normal ejection fraction values but impaired diastolic functions assessed by the transmitral blood flow velocity. For each subject, based on cardiac MRI, global indexes including LV volume, LV myocardial mass, cardiac index (CI), and transmitral peak velocity, were measured, and regional indexes (i.e., LV deformation, strain and strain rate) were calculated through an image-registration technology. Most of the global indexes did not differentiate between the two groups, except for the CI, LV myocardial mass and transmitral peak velocity. While for the regional indexes, the global LV diastolic dysfunction of the diabetic indicated an increased strain (0.08 ± 0.044 vs. -0.031 ± 0.077, p = 0.001) and a reduced strain rate (1.834 ± 0.909 vs. 3.791 ± 2.394, p = 0.033) compared to the controls, moreover, the local LV diastolic dysfunction reflected by the strain and strain rate varied, and the degree of dysfunction gradually decreased from the basal level to the apical level. The results showed that the strain and strain rates are effective to capture the subtle alterations of the LV functions, and the proposed method can be used to estimate the LV myocardial function based on cardiac MRI.

Increased LDL electronegativity in chronic kidney disease disrupts calcium homeostasis resulting in cardiac dysfunction.

PubMed

Chang, Kuan-Cheng; Lee, An-Sheng; Chen, Wei-Yu; Lin, Yen-Nien; Hsu, Jing-Fang; Chan, Hua-Chen; Chang, Chia-Ming; Chang, Shih-Sheng; Pan, Chia-Chi; Sawamura, Tatsuya; Chang, Chi-Tzong; Su, Ming-Jai; Chen, Chu-Huang

2015-07-01

Chronic kidney disease (CKD), an independent risk factor for cardiovascular disease, is associated with abnormal lipoprotein metabolism. We examined whether electronegative low-density lipoprotein (LDL) is mechanistically linked to cardiac dysfunction in patients with early CKD. We compared echocardiographic parameters between patients with stage 2 CKD (n = 88) and normal controls (n = 89) and found that impaired relaxation was more common in CKD patients. Reduction in estimated glomerular filtration rate was an independent predictor of left ventricular relaxation dysfunction. We then examined cardiac function in a rat model of early CKD induced by unilateral nephrectomy (UNx) by analyzing pressure-volume loop data. The time constant of isovolumic pressure decay was longer and the maximal velocity of pressure fall was slower in UNx rats than in controls. When we investigated the mechanisms underlying relaxation dysfunction, we found that LDL from CKD patients and UNx rats was more electronegative than LDL from their respective controls and that LDL from UNx rats induced intracellular calcium overload in H9c2 cardiomyocytes in vitro. Furthermore, chronic administration of electronegative LDL, which signals through lectin-like oxidized LDL receptor-1 (LOX-1), induced relaxation dysfunction in wild-type but not LOX-1(-/-) mice. In in vitro and in vivo experiments, impaired cardiac relaxation was associated with increased calcium transient resulting from nitric oxide (NO)-dependent nitrosylation of SERCA2a due to increases in inducible NO synthase expression and endothelial NO synthase uncoupling. In conclusion, LDL becomes more electronegative in early CKD. This change disrupts SERCA2a-regulated calcium homeostasis, which may be the mechanism underlying cardiorenal syndrome. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ramipril restores PPARβ/δ and PPARγ expressions and reduces cardiac NADPH oxidase but fails to restore cardiac function and accompanied myosin heavy chain ratio shift in severe anthracycline-induced cardiomyopathy in rat.

PubMed

Cernecka, Hana; Doka, Gabriel; Srankova, Jasna; Pivackova, Lenka; Malikova, Eva; Galkova, Kristina; Kyselovic, Jan; Krenek, Peter; Klimas, Jan

2016-11-15

We hypothesized that peroxisome proliferator-activated receptors (PPARs) might be involved in a complex protective action of ACE inhibitors (ACEi) in anthracyclines-induced cardiomyopathy. For purpose of study, we compared effects of ramipril on cardiac dysfunction, cardiac failure markers and PPAR isoforms in moderate and severe chronic daunorubicin-induced cardiomyopathy. Male Wistar rats were administered with a single intravenous injection of daunorubicin: 5mg/kg (moderate cardiomyopathy), or 15mg/kg (severe cardiomyopathy) or co-administered with daunorubicin and ramipril (1mg/kg/d, orally) or vehicle for 8 weeks. Left ventricular function was measured invasively under anesthesia. Cardiac mRNA levels of heart failure markers (ANP, Myh6, Myh7, Myh7b) and PPARs (alpha, beta/delta and gama) were measured by qRT-PCR. Protein expression of NADPH subunit (gp91phox) was measured by Western blot. Moderate cardiomyopathy exhibited only minor cardiac dysfunction what was corrected by ramipril. In severe cardiomyopathy, hemodynamic dysfunction remained unaltered upon ramipril although it decreased the significantly up-regulated cardiac ANP mRNA expression. Simultaneously, while high-dose daunorubicin significantly decreased PPARbeta/delta and PPARgama mRNA, ramipril normalized these abnormalities. Similarly, ramipril reduced altered levels of oxidative stress-related gp91phox. On the other hand, ramipril was unable to correct both the significantly decreased relative abundance of Myh6 and increased Myh7 mRNA levels, respectively. In conclusion, ramipril had a protective effect on cardiac function exclusively in moderate chronic daunorubicin-induced cardiomyopathy. Although it normalized abnormal PPARs expression and exerted also additional protective effects also in severe cardiomyopathy, it was insufficient to influence impaired cardiac function probably because of a shift in myosin heavy chain isoform content. Copyright © 2016 Elsevier B.V. All rights reserved.

Long-term outcomes and management of the heart transplant recipient.

PubMed

McCartney, Sharon L; Patel, Chetan; Del Rio, J Mauricio

2017-06-01

Cardiac transplantation remains the gold standard in the treatment of advanced heart failure. With advances in immunosuppression, long-term outcomes continue to improve despite older and higher risk recipients. The median survival of the adult after heart transplantation is currently 10.7 years. While early graft failure and multiorgan system dysfunction are the most important causes of early mortality, malignancy, rejection, infection, and cardiac allograft vasculopathy contribute to late mortality. Chronic renal dysfunction is common after heart transplantation and occurs in up to 68% of patients by year 10, with 6.2% of patients requiring dialysis and 3.7% undergoing renal transplant. Functional outcomes after heart transplantation remain an area for improvement, with only 26% of patients working at 1-year post-transplantation, and are likely related to the high incidence of depression after cardiac transplantation. Areas of future research include understanding and managing primary graft dysfunction and reducing immunosuppression-related complications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Is plasma N-BNP a good indicator of the functional reserve of failing hearts? The FRESH-BNP study.

PubMed

Williams, Simon G; Ng, Leong L; O'Brien, Russell J; Taylor, Steve; Wright, D Jay; Tan, Lip-Bun

2004-12-01

Whether plasma N-terminal brain natriuretic peptide (N-BNP) is useful in the diagnosis of heart failure (HF) depends traditionally on whether it is as good as the putative 'gold-standard', left ventricular ejection fraction (LVEF), in indicating cardiac dysfunction. However, since HF is primarily an impairment of function of the cardiac pump, we explored the relationship between N-BNP and direct and indirect indicators of cardiac pump dysfunction. Eighty-six HF patients (mean age 56 years) with a range of LVEF's (mean 36.9+/-15.2%, range 15-66%) and 10 age-matched healthy controls were recruited into the study and had resting N-BNP measured. Cardiopulmonary exercise testing was performed to assess peak oxygen consumption (Vo(2)). A subgroup of 23 subjects underwent further exercise haemodynamic assessment to evaluate peak cardiac power output (CPO). The CHF group had significantly higher N-BNP (median [interquartile range]) levels (299 [705] fmol/ml) than the control group (7 [51] fmol/ml, P<0.005). Significant correlations between N-BNP and peak Vo(2), and N-BNP and peak CPO were observed (R> or =0.5, P<0.005). Although significant correlation was observed between N-BNP and LVEF (R=0.34, P=0.01), the correlations between LVEF and peak Vo(2) or peak CPO (all R<0.3, P>0.3) were not significant. Multivariate analysis identified plasma N-BNP and NYHA class, but not LVEF, as independent predictors of peak Vo(2). We have found that N-BNP was surprisingly good as a simple indicator of cardiac pump dysfunction. Since heart failure is an inadequacy of function, these results strongly support the notion that N-BNP is a useful blood test in estimating the extent of cardiac pump dysfunction and helpful in establishing positive diagnosis of heart failure.

Complications of Transfusion-Dependent β-Thalassemia Patients in Sistan and Baluchistan, South-East of Iran

PubMed Central

Yaghobi, Maryam; Miri-Moghaddam, Ebrahim; Majid, Naderi; Bazi, Ali; Navidian, Ali; Kalkali, Asiyeh

2017-01-01

Background: Thalassemia syndromes are among prevalent hereditary disorders imposing high expenses on health-care system worldwide and in Iran. Organ failure represents a life-threatening challenge in transfusion- dependent β-thalassemia (TDT) patients. The purpose of the present study was to determine the frequency of organ dysfunctions among TDT patients in Sistan and Baluchistan province in South-East of Iran. Materials and Methods: Laboratory and clinical data were extracted from medical records as well as by interviews. Standard criteria were applied to recognize cardiac, gonadal, endocrine and renal dysfunctions. The collected data were analyzed using the SPSS statistics software (Ver.19). Results: A total of 613 TDT patients (54.3% males and 45.7% females) were included in this study. The mean age of patients was 13.3 ±7.7 years old. Cardiac events comprised the most encountered complications (76.4%), following by hypogonadism (46.8%), parathyroid dysfunction (22%), thyroid abnormalities (8.3%), diabetes (7.8%) and renal disease (1.8%). Hypogonadism comprised the most identified complication in patient <15 years old, while the cardiac complications were the most frequent sequela in patients >15 years old (P<0.01). Conclusion: As cardiac events are significantly more common among TDT patients, close monitoring of the heart function is recommended for identifying patients with cardiac problems. PMID:29340121

Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis.

PubMed

Kim, Jin Sug; Kim, Weon; Park, Ji Yoon; Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyun; Moon, Ju-Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2017-01-01

Lipid lowering therapy is widely used for the prevention of cardiovascular complications after acute myocardial infarction (AMI). However, some studies show that this benefit is uncertain in patients with renal dysfunction, and the role of statins is based on the severity of renal dysfunction. In this study, we investigated the impact of statin therapy on major adverse cardiac events (MACEs) and all-cause mortality in patients with advanced renal dysfunction undergoing percutaneous coronary intervention (PCI) after AMI. This study was based on the Korea Acute Myocardial Infarction Registry database. We included 861 patients with advanced renal dysfunction from among 33,205 patients who underwent PCI after AMI between November 2005 and July 2012. Patients were divided into two groups: a statin group (n = 537) and a no-statin group (n = 324). We investigated the 12-month MACEs (cardiac death, myocardial infarction, repeated PCI or coronary artery bypass grafting) and all-cause mortality of each group. Subsequently, a propensity score-matched analysis was performed. In the total population studied, no significant differences were observed between the two groups with respect to the rate of recurrent MI, repeated PCI, coronary artery bypass grafting (CABG), or all-cause mortality. However, the cardiac death rate was significantly lower in the statin group (p = 0.009). Propensity score-matched analysis yielded 274 pairs demonstrating, results similar to those obtained from the total population. However, there was no significant difference in the cardiac death rate in the propensity score-matched population (p = 0.103). Cox-regression analysis revealed only left ventricular ejection fraction to be an independent predictor of 12-month MACEs (Hazard ratio [HR] of 0.979, 95% confidence interval [CI], 0962-0.996, p = 0.018). Statin therapy was not significantly associated with a reduction in the 12-month MACEs or all-cause mortality in patients with advanced renal dysfunction undergoing PCI after AMI.

Endothelin-1 and ET receptors impair left ventricular function by mediated coronary arteries dysfunction in chronic intermittent hypoxia rats.

PubMed

Wang, Jin-Wei; Li, Ai-Ying; Guo, Qiu-Hong; Guo, Ya-Jing; Weiss, James W; Ji, En-Sheng

2017-01-01

Obstructive sleep apnea (OSA) results in cardiac dysfunction and vascular endothelium injury. Chronic intermittent hypoxia (CIH), the main characteristic of OSAS, is considered to be mainly responsible for cardiovascular system impairment. This study is aimed to evaluate the role of endothelin-1(ET-1) system in coronary injury and cardiac dysfunction in CIH rats. In our study, Sprague-Dawley rats were exposed to CIH (FiO 2 9% for 1.5 min, repeated every 3 min for 8 h/d, 7 days/week for 3 weeks). After 3 weeks, the left ventricular developed pressure (LVDP) and coronary resistance (CR) were measured with the langendorff mode in isolated hearts. Meanwhile, expressions of ET-1 and ET receptors were detected by immunohistochemical and western blot, histological changes were also observed to determine effects of CIH on coronary endothelial cells. Results suggested that decreased LVDP level combined with augmented coronary resistance was exist in CIH rats. CIH could induce endothelial injury and endothelium-dependent vasodilatation dysfunction in the coronary arteries. Furthermore, ET-1 and ET A receptor expressions in coronary vessels were increased after CIH exposure, whereas ET B receptors expression was decreased. Coronary contractile response to ET-1 in both normoxia and CIH rats was inhibited by ET A receptor antagonist BQ123. However, ET B receptor antagonist BQ788 enhanced ET-1-induced contractile in normoxia group, but had no significant effects on CIH group. These results indicate that CIH-induced cardiac dysfunction may be associated with coronary injury. ET-1 plays an important role in coronary pathogenesis of CIH through ET A receptor by mediating a potent vasoconstrictor response. Moreover, decreased ET B receptor expression that leads to endothelium-dependent vasodilatation decline, might be also participated in coronary and cardiac dysfunction. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart.

PubMed

Osadchii, Oleg E

2016-01-01

Flecainide is class Ic antiarrhythmic agent that was found to increase the risk of sudden cardiac death. Arrhythmic responses to flecainide could be precipitated by exercise, suggesting a role played by inappropriate rate adaptation of ventricular repolarization. This study therefore examined flecainide effect on adaptation of the QT interval and ventricular action potential duration (APD) to abrupt reductions of the cardiac cycle length. ECG and ventricular epicardial and endocardial monophasic APD were recorded in isolated, perfused guinea-pig heart preparations upon a sustained cardiac acceleration (rapid pacing for 30 s), and following a single perturbation of the cycle length evoked by extrasystolic stimulation. Sustained increase in heart rate was associated with progressive bi-exponential shortening of the QT interval and APD. Flecainide prolonged ventricular repolarization, delayed its rate adaptation, and decreased the amplitude of QT interval and APD shortening upon rapid cardiac pacing. During extrasystolic stimulation, flecainide attenuated APD shortening in premature ventricular beats, with effect being greater upon using a longer basic drive cycle length (S1-S1=550 ms versus S1-S1=300 ms). Flecainide-induced arrhythmia may be partly accounted for by attenuated adaptation of ventricular repolarization to sudden changes in cardiac cycle length provoked by transient tachycardia or ectopic beats.

Transplantation of mesenchymal stem cells overexpressing IL10 attenuates cardiac impairments in rats with myocardial infarction.

PubMed

Meng, Xin; Li, Jianping; Yu, Ming; Yang, Jian; Zheng, Minjuan; Zhang, Jinzhou; Sun, Chao; Liang, Hongliang; Liu, Liwen

2018-01-01

Mesenchymal stem cell (MSC) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). In addition, interleukin-10 (IL10) could attenuate MI through suppressing inflammation. Thus, the combination of MSC implantation with IL10 delivery may extend health benefits to ameliorate cardiac injury after MI. Here we established overexpression of IL10 in bone marrow-derived MSC through adenoviral transduction. Cell viability, apoptosis, and IL10 secretion under ischemic challenge in vitro were examined. In addition, MSC was transplanted into the injured hearts in a rat model of MI. Four weeks after the MI induction, MI, cardiac functions, apoptotic cells, and inflammation cytokines were assessed. In response to in vitro oxygen-glucose deprivation (OGD), IL10 overexpression in MSC (Ad.IL10-MSC) enhanced cell viability, decreased apoptosis, and increased IL10 secretion. Consistently, the implantation of Ad.IL10-MSCs into MI animals resulted in more reductions in myocardial infarct size, cardiac impairment, and cell apoptosis, compared to the individual treatments of either MSC or IL10 administration. Moreover, the attenuation of both systemic and local inflammations was most prominent for Ad.IL10-MSC treatment. IL10 overexpression and MSC may exert a synergistic anti-inflammatory effect to alleviate cardiac injury after MI. © 2017 Wiley Periodicals, Inc.

Right ventricular dysfunction in the R6/2 transgenic mouse model of Huntington's disease is unmasked by dobutamine.

PubMed

Buonincontri, Guido; Wood, Nigel I; Puttick, Simon G; Ward, Alex O; Carpenter, T Adrian; Sawiak, Stephen J; Morton, A Jennifer

2014-01-01

Increasingly, evidence from studies in both animal models and patients suggests that cardiovascular dysfunction is important in HD. Previous studies measuring function of the left ventricle (LV) in the R6/2 model have found a clear cardiac abnormality, albeit with preserved LV systolic function. It was hypothesized that an impairment of RV function might play a role in this condition via mechanisms of ventricular interdependence. To investigate RV function in the R6/2 mouse model of Huntington's disease (HD). Cardiac cine-magnetic resonance imaging (MRI) was used to determine functional parameters in R6/2 mice. In a first experiment, these parameters were derived longitudinally to determine deterioration of cardiac function with disease progression. A second experiment compared the response to a stress test (using dobutamine) of wildtype and early-symptomatic R6/2 mice. There was progressive deterioration of RV systolic function with age in R6/2 mice. Furthermore, beta-adrenergic stimulation with dobutamine revealed RV dysfunction in R6/2 mice before any overt symptoms of the disease were apparent. This work adds to accumulating evidence of cardiovascular dysfunction in R6/2 mice, describing for the first time the involvement of the right ventricle. Cardiovascular dysfunction should be considered, both when treatment strategies are being designed, and when searching for biomarkers for HD.

Cluster Differentiating 36 (CD36) Deficiency Attenuates Obesity-Associated Oxidative Stress in the Heart.

PubMed

Gharib, Mohamed; Tao, Huan; Fungwe, Thomas V; Hajri, Tahar

2016-01-01

Obesity is often associated with a state of oxidative stress and increased lipid deposition in the heart. More importantly, obesity increases lipid influx into the heart and induces excessive production of reactive oxygen species (ROS) leading to cell toxicity and metabolic dysfunction. Cluster differentiating 36 (CD36) protein is highly expressed in the heart and regulates lipid utilization but its role in obesity-associated oxidative stress is still not clear. The aim of this study was to determine the impact of CD36 deficiency on cardiac steatosis, oxidative stress and lipotoxicity associated with obesity. Studies were conducted in control (Lean), obese leptin-deficient (Lepob/ob) and leptin-CD36 double null (Lepob/obCD36-/-) mice. Compared to lean mice, cardiac steatosis, and fatty acid (FA) uptake and oxidation were increased in Lepob/ob mice, while glucose uptake and oxidation was reduced. Moreover, insulin resistance, oxidative stress markers and NADPH oxidase-dependent ROS production were markedly enhanced. This was associated with the induction of NADPH oxidase expression, and increased membrane-associated p47phox, p67phox and protein kinase C. Silencing CD36 in Lepob/ob mice prevented cardiac steatosis, increased insulin sensitivity and glucose utilization, but reduced FA uptake and oxidation. Moreover, CD36 deficiency reduced NADPH oxidase activity and decreased NADPH oxidase-dependent ROS production. In isolated cardiomyocytes, CD36 deficiency reduced palmitate-induced ROS production and normalized NADPH oxidase activity. CD36 deficiency prevented obesity-associated cardiac steatosis and insulin resistance, and reduced NADPH oxidase-dependent ROS production. The study demonstrates that CD36 regulates NADPH oxidase activity and mediates FA-induced oxidative stress.

PPARβ/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.

PubMed

Alvarez-Guardia, David; Palomer, Xavier; Coll, Teresa; Serrano, Lucía; Rodríguez-Calvo, Ricardo; Davidson, Mercy M; Merlos, Manuel; El Kochairi, Ilhem; Michalik, Liliane; Wahli, Walter; Vázquez-Carrera, Manuel

2011-02-01

Owing to its high fat content, the classical Western diet has a range of adverse effects on the heart, including enhanced inflammation, hypertrophy, and contractile dysfunction. Proinflammatory factors secreted by cardiac cells, which are under the transcriptional control of nuclear factor-κB (NF-κB), may contribute to heart failure and dilated cardiomyopathy. The underlying mechanisms are complex, since they are linked to systemic metabolic abnormalities and changes in cardiomyocyte phenotype. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolism and are capable of limiting myocardial inflammation and hypertrophy via inhibition of NF-κB. Since PPARβ/δ is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPARβ/δ agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-κB in the heart of mice. GW501516 abrogated this enhanced proinflammatory profile. Similar results were obtained when human cardiac AC16 cells exposed to palmitate were coincubated with GW501516. PPARβ/δ activation by GW501516 enhanced the physical interaction between PPARβ/δ and p65, which suggests that this mechanism may also interfere NF-κB transactivation capacity in the heart. GW501516-induced PPARβ/δ activation can attenuate the inflammatory response induced in human cardiac AC16 cells exposed to the saturated fatty acid palmitate and in mice fed a high-fat diet. This is relevant, especially taking into account that PPARβ/δ has been postulated as a potential target in the treatment of obesity and the insulin resistance state. Copyright © 2010 Elsevier B.V. All rights reserved.

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling.

PubMed

Hang, Pengzhou; Zhao, Jing; Su, Zhenli; Sun, Hanqi; Chen, Tingting; Zhao, Lihui; Du, Zhimin

2018-01-01

Backgroud/Aims: Growing evidence suggests that both cardiomyocyte apoptosis and excessive autophagy exacerbates cardiac dysfunction during myocardial ischemia-reperfusion (IR). As a precursor of acetylcholine, choline has been found to protect the heart by repressing ischemic cardiomyocyte apoptosis. However, the relationship between choline and cardiomyocyte autophagy is unclear. The present study aimed to investigate whether autophagy was involved in the cardioprotection of choline during IR. Rats were subjected to 30 min reversible ischemia by ligation of left anterior descending coronary artery followed by reperfusion for 2 h. Choline (5 mg/kg, i.v.) alone or along with rapamycin (5 mg/ kg, i.p.) were injected 30 min before ischemia. Transmission electron microscopy, hematoxylin and eosin (HE) and TUNEL staining were conducted to evaluate the effect of choline on cardiac apoptosis and autophagy. Protein levels of autophagic markers including LC3, beclin-1 and p62 as well as Akt and mammalian target of rapamycin (mTOR) were examined by Western blotting. Myocardial IR-induced cardiac apoptosis and accumulation of autophagosomes was attenuated by choline. Choline treatment significantly ameliorated myocardial IR-induced autophagic activity characterized by repression of beclin-1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, and p62 protein abundance. In addition, IR-induced downregulation of p-Akt/mTOR cascade was increased by choline. However, the above functions of choline were abolished by rapamycin. These findings suggest that choline plays a protective role against myocardial IR injury by inhibiting excessive autophagy, which might be associated with the activation of Akt/mTOR pathway. This study provides new mechanistic understanding of cardioprotective effect of choline and suggests novel potential therapeutic targets for cardiac IR injury. © 2018 The Author(s). Published by S. Karger AG, Basel.

Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

PubMed

Mohammed, Selma F; Hussain, Saad; Mirzoyev, Sultan A; Edwards, William D; Maleszewski, Joseph J; Redfield, Margaret M

2015-02-10

Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF. © 2014 American Heart Association, Inc.

Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function.

PubMed

Li, Zi-Lun; Ebrahimi, Behzad; Zhang, Xin; Eirin, Alfonso; Woollard, John R; Tang, Hui; Lerman, Amir; Wang, Shen-Ming; Lerman, Lilach O

2014-04-01

Obesity associated with metabolic derangements (ObM) worsens the prognosis of patients with coronary artery stenosis (CAS), but the underlying cardiac pathophysiologic mechanisms remain elusive. We tested the hypothesis that ObM exacerbates cardiomyocyte loss distal to moderate CAS. Obesity-prone pigs were randomized to four groups (n = 6 each): lean-sham, ObM-sham, lean-CAS, and ObM-CAS. Lean and ObM pigs were maintained on a 12-wk standard or atherogenic diet, respectively, and left circumflex CAS was then induced by placing local-irritant coils. Cardiac structure, function, and myocardial oxygenation were assessed 4 wk later by computed-tomography and blood oxygenation level dependent (BOLD) MRI, the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. ObM pigs showed obesity, dyslipidemia, and insulin resistance. The degree of CAS (range, 50-70%) was similar in lean and ObM pigs, and resting myocardial perfusion and global cardiac function remained unchanged. Increased angiogenesis distal to the moderate CAS observed in lean was attenuated in ObM pigs, which also showed microvascular dysfunction and increased inflammation (M1-macrophages, TNF-α expression), oxidative stress (gp91), hypoxia (BOLD-MRI), and fibrosis (Sirius-red and trichrome). Furthermore, lean-CAS showed increased myocardial autophagy, which was blunted in ObM pigs (downregulated expression of unc-51-like kinase-1 and autophagy-related gene-12; P < 0.05 vs. lean CAS) and associated with marked apoptosis. The interaction diet xstenosis synergistically inhibited angiogenic, autophagic, and fibrogenic activities. ObM exacerbates structural and functional myocardial injury distal to moderate CAS with preserved myocardial perfusion, possibly due to impaired cardiomyocyte turnover.

Involvement of vascular peroxidase 1 in angiotensin II-induced hypertrophy of H9c2 cells.

PubMed

Yang, Wei; Liu, Zhaoya; Xu, Qian; Peng, Haiyang; Chen, Luyao; Huang, Xiao; Yang, Tianlun; Yu, Zaixin; Cheng, Guangjie; Zhang, Guogang; Shi, Ruizheng

2017-08-01

Oxidative stress has been implicated in cardiac hypertrophy and heart failure. Vascular peroxidase 1 (VPO1), a peroxidase in the cardiovascular system, uses the hydrogen peroxide (H 2 O 2 ) derived from co-expressed NADPH oxidases (NOX) to produce hypochlorous acid (HOCl) and catalyze peroxidative reactions. Our previous studies showed that VPO1 contributes to the vascular smooth muscle cell proliferation and endothelial dysfunction in spontaneous hypertensive rats (SHRs); however, the role of VPO1 in cardiomyocytes hypertrophy is still uninvestigated. The present study was therefore undertaken to examine the role of VPO1 in the angiotensin II-induced cardiac hypertrophy, and the underlying mechanism by which VPO1 regulates the redox signaling. As compared to WKY rats, the SHRs exhibited increased myocyte cross sectional area, enhanced Nox2 and VPO1 expression level in cardiac tissue, and an increased Ang II level in plasma. In cultured H9c2 cell line, Ang II increased the hypertrophy-related gene (BNP/ANF) expression and the cellular surface area, which was attenuated by knocking down of VPO1 via VPO1 siRNA or pharmacological inhibition of NOX/VPO1 pathway. Moreover, the enhanced hypochlorous acid (HOCl) production and phosphorylation of ERK1/2 was suppressed by VPO1 knockdown. Furthermore, the protective role of VPO1 siRNA transfection on H9c2 cardiomyocytes hypertrophy was abrogated on the HOCl stimulation, and the phosphorylated ERK1/2 expression level was found also upregulated after HOCl stimulation. In conclusion, these results suggest that the Nox2/VPO1/HOCl/ERK1/2 redox signaling pathway was implicated in the pathogenesis of Ang II-induced cardiac hypertrophy. Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Liposome encapsulated berberine treatment attenuates cardiac dysfunction after myocardial infarction.

PubMed

Allijn, Iris E; Czarny, Bertrand M S; Wang, Xiaoyuan; Chong, Suet Yen; Weiler, Marek; da Silva, Acarilia Eduardo; Metselaar, Josbert M; Lam, Carolyn Su Ping; Pastorin, Giorgia; de Kleijn, Dominique P V; Storm, Gert; Wang, Jiong-Wei; Schiffelers, Raymond M

2017-02-10

Inflammation is a known mediator of adverse ventricular remodeling after myocardial infarction (MI) that may lead to reduction of ejection fraction and subsequent heart failure. Berberine is a isoquinoline quarternary alkaloid from plants that has been associated with anti-inflammatory, anti-oxidative, and cardioprotective properties. Its poor solubility in aqueous buffers and its short half-life in the circulation upon injection, however, have been hampering the extensive usage of this natural product. We hypothesized that encapsulation of berberine into long circulating liposomes could improve its therapeutic availability and efficacy by protecting cardiac function against MI in vivo. Berberine-loaded liposomes were prepared by ethanol injection and characterized. They contained 0.3mg/mL of the drug and were 0.11μm in diameter. Subsequently they were tested for IL-6 secretion inhibition in RAW 264.7 macrophages and for cardiac function protection against adverse remodeling after MI in C57BL/6J mice. In vitro, free berberine significantly inhibited IL-6 secretion (IC 50 =10.4μM), whereas encapsulated berberine did not as it was not released from the formulation in the time frame of the in vitro study. In vivo, berberine-loaded liposomes significantly preserved the cardiac ejection fraction at day 28 after MI by 64% as compared to control liposomes and free berberine. In conclusion, liposomal encapsulation enhanced the solubility of berberine in buffer and preserves ejection fraction after MI. This shows that delivery of berberine-loaded liposomes significantly improves its therapeutic availability and identifies berberine-loaded liposomes as potential treatment of adverse remodeling after MI. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial Approaches to Protect Against Cardiac Ischemia and Reperfusion Injury

PubMed Central

Camara, Amadou K. S.; Bienengraeber, Martin; Stowe, David F.

2011-01-01

The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury. PMID:21559063

Cardiac Dysfunction in a Porcine Model of Pediatric Malnutrition

PubMed Central

Fabiansen, Christian; Lykke, Mikkel; Hother, Anne-Louise; Koch, Jørgen; Nielsen, Ole Bækgaard; Hunter, Ingrid; Goetze, Jens P.; Friis, Henrik; Thymann, Thomas

2015-01-01

Background Half a million children die annually of severe acute malnutrition and cardiac dysfunction may contribute to the mortality. However, cardiac function remains poorly examined in cases of severe acute malnutrition. Objective To determine malnutrition-induced echocardiographic disturbances and longitudinal changes in plasma pro-atrial natriuretic peptide and cardiac troponin-T in a pediatric porcine model. Methods and Results Five-week old piglets (Duroc-x-Danish Landrace-x-Yorkshire) were fed a nutritionally inadequate maize-flour diet to induce malnutrition (MAIZE, n = 12) or a reference diet (AGE-REF, n = 12) for 7 weeks. Outcomes were compared to a weight-matched reference group (WEIGHT-REF, n = 8). Pro-atrial natriuretic peptide and cardiac troponin-T were measured weekly. Plasma pro-atrial natriuretic peptide decreased in both MAIZE and AGE-REF during the first 3 weeks but increased markedly in MAIZE relative to AGE-REF during week 5–7 (p≤0.001). There was overall no difference in plasma cardiac troponin-T between groups. However, further analysis revealed that release of cardiac troponin-T in plasma was more frequent in AGE-REF compared with MAIZE (OR: 4.8; 95%CI: 1.2–19.7; p = 0.03). However, when release occurred, cardiac troponin-T concentration was 6.9-fold higher (95%CI: 3.0–15.9; p<0.001) in MAIZE compared to AGE-REF. At week 7, the mean body weight in MAIZE was lower than AGE-REF (8.3 vs 32.4 kg, p<0.001), whereas heart-weight relative to body-weight was similar across the three groups. The myocardial performance index was 86% higher in MAIZE vs AGE-REF (p<0.001) and 27% higher in MAIZE vs WEIGHT-REF (p = 0.025). Conclusions Malnutrition associates with cardiac dysfunction in a pediatric porcine model by increased myocardial performance index and pro-atrial natriuretic peptide and it associates with cardiac injury by elevated cardiac troponin-T. Clinical studies are needed to see if the same applies for children suffering from malnutrition. PMID:26473958

Prognostic value of depressed midwall systolic function in cardiac light-chain amyloidosis.

PubMed

Perlini, Stefano; Salinaro, Francesco; Musca, Francesco; Mussinelli, Roberta; Boldrini, Michele; Raimondi, Ambra; Milani, Paolo; Foli, Andrea; Cappelli, Francesco; Perfetto, Federico; Palladini, Giovanni; Rapezzi, Claudio; Merlini, Giampaolo

2014-05-01

Cardiac amyloidosis represents an archetypal form of restrictive heart disease, characterized by profound diastolic dysfunction. As ejection fraction is preserved until the late stage of the disease, the majority of patients do fulfill the definition of diastolic heart failure, that is, heart failure with preserved ejection fraction (HFpEF). In another clinical model of HFpEF, that is, pressure-overload hypertrophy, depressed midwall fractional shortening (mFS) has been shown to be a powerful prognostic factor. To assess the potential prognostic role of mFS in cardiac light-chain amyloidosis with preserved ejection fraction, we enrolled 221 consecutive untreated patients, in whom a first diagnosis of cardiac light-chain amyloidosis was concluded between 2008 and 2010. HFpEF was present in 181 patients. Patients in whom cardiac involvement was excluded served as controls (n = 121). Prognosis was assessed after a median follow-up of 561 days. When compared with light-chain amyloidosis patients without myocardial involvement, cardiac light-chain amyloidosis was characterized by increased wall thickness (P <0.001), reduced end-diastolic left ventricular volumes (P <0.001), and diastolic dysfunction (P <0.001). In patients with preserved ejection fraction, mFS was markedly depressed [10.6% (8.7-13.5) vs. 17.8% (15.9-19.5) P <0.001]. At multivariable analysis, mFS, troponin I, and NT-pro-brain natriuretic peptide were the only significant prognostic determinants (P <0.001), whereas other indices of diastolic (E/E' ratio, transmitral and pulmonary vein flow velocities) and systolic function (tissue Doppler systolic indices, ejection fraction), or the presence/absence of congestive heart failure did not enter the model. In cardiac light-chain amyloidosis with normal ejection fraction, depressed circumferential mFS, a marker of myocardial contractile dysfunction, is a powerful predictor of survival.

Subject-specific left ventricular dysfunction modeling using composite material mechanics approach

NASA Astrophysics Data System (ADS)

Haddad, Seyed Mohammad Hassan; Karami, Elham; Samani, Abbas

2017-03-01

Diverse cardiac conditions such as myocardial infarction and hypertension can lead to diastolic dysfunction as a prevalent cardiac condition. Diastolic dysfunctions can be diagnosed through different adverse mechanisms such as abnormal left ventricle (LV) relaxation, filling, and diastolic stiffness. This paper is geared towards evaluating diastolic stiffness and measuring the LV blood pressure non-invasively. Diastolic stiffness is an important parameter which can be exploited for more accurate diagnosis of diastolic dysfunction. For this purpose, a finite element (FE) LV mechanical model, which works based on a novel composite material model of the cardiac tissue, was utilized. Here, this model was tested for inversion-based applications where it was applied for estimating the cardiac tissue passive stiffness mechanical properties as well as diastolic LV blood pressure. To this end, the model was applied to simulate diastolic inflation of the human LV. The start-diastolic LV geometry was obtained from MR image data segmentation of a healthy human volunteer. The obtained LV geometry was discretized into a FE mesh before FE simulation was conducted. The LV tissue stiffness and diastolic LV blood pressure were adjusted through optimization to achieve the best match between the calculated LV geometry and the one obtained from imaging data. The performance of the LV mechanical simulations using the optimal values of tissue stiffness and blood pressure was validated by comparing the geometrical parameters of the dilated LV model as well as the stress and strain distributions through the LV model with available measurements reported on the LV dilation.

Febuxostat attenuates paroxysmal atrial fibrillation-induced regional endothelial dysfunction.

PubMed

Li, YanGuang; Chen, FuKun; Deng, Long; Lin, Kun; Shi, Xiangmin; Zhaoliang, Shan; Wang, YuTang

2017-01-01

Paroxysmal atrial fibrillation (PAF) can increase thrombogenesis risk, especially in the left atrium (LA). The exact mechanism is still unclear. We assessed the effects of PAF on endothelial function, and investigated if febuxostat (FX) can attenuate endothelial dysfunction by inhibition of xanthine oxidase (XO). Eighteen male New Zealand white rabbits were divided randomly into sham-operated (S), PAF (P) or FX+pacing (FP) groups. Group P and group FP received rapid atrial pacing (RAP). Group FP was administered febuxostat (FX) for 7days before RAP. Post-procedure, blood samples were collected from the LA, right atrium (RA) and peripheral circulation. Tissues from the LA and RA were obtained. Endothelial dysfunction (thrombomodulin [TM], von Willebrand factor [VWF], asymmetric dimethylarginine [ADMA]), and indirect thrombin generation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1.2]) and oxidative stress in atrial tissue (xanthine oxidase [XO], superoxide dismutase [SOD], malondialdehyde [MDA]) were measured using an Enzyme-linked immunosorbent assay. Atrial endothelial expression of TM and VWF was measured by histology/western blotting. Endothelial dysfunction (TM, VWF, ADMA), TAT generation and oxidative stress (XO, SOD, MDA) in group P were more significant compared with that in group S (p<0.05, respectively). In group P, all of these changes occurred to a greater extent in the LA compared with those in the RA or peripheral circulation. In group FP, FX attenuated endothelial dysfunction and reduced TAT levels by inhibition of XO-mediated oxidative stress. PAF can lead to endothelial dysfunction and TAT generation by XO-mediated oxidative stress. The LA is more susceptible to these effects. FX can attenuate these changes by inhibition XO and XO-mediated oxidative stress. Copyright © 2016. Published by Elsevier Ltd.

Mitochondria and Cardiovascular Aging

PubMed Central

Dai, Dao-Fu; Ungvari, Zoltan

2013-01-01

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (e.g. renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics and exercise training. PMID:22499901

Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients.

PubMed

Kim, Bong-Sung; Jacobs, Denise; Emontzpohl, Christoph; Goetzenich, Andreas; Soppert, Josefin; Jarchow, Mareike; Schindler, Lisa; Averdunk, Luisa; Kraemer, Sandra; Marx, Gernot; Bernhagen, Jürgen; Pallua, Norbert; Schlemmer, Heinz-Peter; Simons, David; Stoppe, Christian

2016-06-01

In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients.

Longstanding Hyperthyroidism Is Associated with Normal or Enhanced Intrinsic Cardiomyocyte Function despite Decline in Global Cardiac Function

PubMed Central

Redetzke, Rebecca A.; Gerdes, A. Martin

2012-01-01

Thyroid hormones (THs) play a pivotal role in cardiac homeostasis. TH imbalances alter cardiac performance and ultimately cause cardiac dysfunction. Although short-term hyperthyroidism typically leads to heightened left ventricular (LV) contractility and improved hemodynamic parameters, chronic hyperthyroidism is associated with deleterious cardiac consequences including increased risk of arrhythmia, impaired cardiac reserve and exercise capacity, myocardial remodeling, and occasionally heart failure. To evaluate the long-term consequences of chronic hyperthyroidism on LV remodeling and function, we examined LV isolated myocyte function, chamber function, and whole tissue remodeling in a hamster model. Three-month-old F1b hamsters were randomized to control or 10 months TH treatment (0.1% grade I desiccated TH). LV chamber remodeling and function was assessed by echocardiography at 1, 2, 4, 6, 8, and 10 months of treatment. After 10 months, terminal cardiac function was assessed by echocardiography and LV hemodynamics. Hyperthyroid hamsters exhibited significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and increased LV interstitial fibrotic deposition. Importantly, hyperthyroid hamsters demonstrated significant LV systolic and diastolic dysfunction. Despite the aforementioned remodeling and global cardiac decline, individual isolated cardiac myocytes from chronically hyperthyroid hamsters had enhanced function when compared with myocytes from untreated age-matched controls. Thus, it appears that long-term hyperthyroidism may impair global LV function, at least in part by increasing interstitial ventricular fibrosis, in spite of normal or enhanced intrinsic cardiomyocyte function. PMID:23056390

HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Tongyi; Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai; Zhang, Ben

Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague–Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction.more » Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation. - Highlights: • EP could effectively reduce the cardiac hypertrophic responses induced by TAC. • EP may play a protective role by upregulating the expressions of HSF1 and HSP70 and then activating HSF1. • EP may play a protective role by inhibiting the expression of NF-κB p65 and nuclear translocation.« less

GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Zhuo; Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, 105 Jiefang Road, Jinan, 250013; Wang, Hao

2015-03-27

Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, andmore » immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression.« less

Contribution of serum FGF21 level to the identification of left ventricular systolic dysfunction and cardiac death.

PubMed

Shen, Yun; Zhang, Xueli; Pan, Xiaoping; Xu, Yiting; Xiong, Qin; Lu, Zhigang; Ma, Xiaojing; Bao, Yuqian; Jia, Weiping

2017-08-18

The relationship between fibroblast growth factor 21 (FGF21) and cardiovascular disease has been well established in recent studies. This study aimed to investigate the relationship between FGF21 and left ventricular systolic dysfunction and cardiac death. Two-dimensional echocardiography was used to measure the left ventricular ejection fraction (LVEF) to estimate left ventricular systolic function. The optimal cutoff of FGF21 for identifying left ventricular systolic dysfunction at baseline was analyzed via receiver operating characteristic (ROC) curves. The identification of different serum levels of FGF21 and their association with cardiac death was analyzed via Kaplan-Meier survival curves. Serum FGF21 level was measured by an enzyme-linked immunosorbent assay kit, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level was determined by a chemiluminescent immunoassay. A total of 253 patients were recruited for this study at baseline. Patients were excluded if they lacked echocardiography or laboratory measurement data, and there were 218 patients enrolled in the final analysis. The average age was 66.32 ± 10.10 years. The optimal cutoff values of FGF21 and NT-pro-BNP for identifying left ventricular systolic dysfunction at baseline were 321.5 pg/mL and 131.3 ng/L, respectively, determined separately via ROC analysis. The areas under the curves were non-significant among FGF21, NT-pro-BNP and FGF21 + NT-pro-BNP as determined by pairwise comparisons. Both a higher serum level of FGF21 and a higher serum level of NT-pro-BNP were independent risk factors for left ventricular systolic dysfunction at baseline (odd ratio (OR) 3.138 [1.037-9.500], P = 0.043, OR 9.207 [2.036-41.643], P = 0.004, separately). Further Kaplan-Meier survival analysis indicated an association between both a higher serum level of FGF21 and a higher serum level of NT-pro-BNP with cardiac death in 5 years [RR 5.000 (1.326-18.861), P = 0.026; RR 9.643 (2.596-35.825), P = 0.009, respectively]. Serum FGF21 level was significantly correlated with left ventricular systolic dysfunction at baseline. Patients with higher serum levels of FGF21 tended to suffer greater risks of cardiac death than patients with lower serum levels of FGF21. The identification of FGF21 and its relationship with left ventricular systolic function and cardiac death were non-inferior to NT-pro-BNP.

Targeted Gene Silencing of Tumor Necrosis Factor Attenuates the Negative Inotropic Effects of Lipopolysaccharide in Isolated Contracting Cardiac Myocytes

PubMed Central

Ramabadran, R. S.; Chancey, Amanda; Vallejo, Jesus G.; Barger, Philip M.; Sivasubramanian, Natarajan; Mann, Douglas L.

2008-01-01

Bacterial endotoxin (lipopolysaccharide) depresses cardiovascular function; however, the mediators and signaling pathways that are responsible for the negative inotropic effects of lipopolysaccharide are not fully known. We used RNA interference to determine the relative role of tumor necrosis factor with respect to mediating the negative inotropic effects of lipopolysaccharide in isolated cardiac myocytes. Cardiac myocyte cultures were treated with lipopolysaccharide in the presence or absence of small interfering RNAs (siRNA) for tumor necrosis factor. We examined the effects of tumor necrosis factor siRNA on lipopolysaccharide-induced tumor necrosis factor messenger RNA (mRNA) and protein biosynthesis, as well as the negative inotropic effects of lipopolysaccharide in isolated contracting cardiac myocytes. Treatment of adult cardiac myocyte cultures with tumor necrosis factor siRNA significantly attenuated lipopolysaccharide-induced tumor necrosis factor mRNA and protein biosynthesis, whereas transfection with a double-stranded RNA that does not target mammalian mRNA had no effect. Pretreatment with tumor necrosis factor siRNA significantly attenuated, but did not abrogate, the lipopolysaccharide-induced decrease in sarcomere shortening in isolated contracting cardiac myocytes. In contrast, tumor necrosis factor siRNA had a comparatively smaller effect on improving sarcomere shortening once the negative inotropic effects of lipopolysaccharide were fully established. These results suggest that tumor necrosis factor plays an important upstream role in lipopolysaccharide-induced negative inotropic effects in isolated contracting cardiac myocytes and that other molecular mechanisms are responsible for the decrease in sarcomere shortening after sustained lipopolysaccharide signaling. PMID:18427645

Right ventricular systolic dysfunction and vena cava dilatation precede alteration of renal function in adult patients undergoing cardiac surgery: An observational study.

PubMed

Guinot, Pierre Grégoire; Abou-Arab, Osama; Longrois, Dan; Dupont, Herve

2015-08-01

Several authors have suggested that right ventricular dysfunction (RVd) may contribute to renal dysfunction in nonsurgical patients. We tested the hypothesis that RVd diagnosed immediately after cardiac surgery may be associated with subsequent development of renal dysfunction and tried to identify the possible mechanisms. A single-centre, prospective observational study. Amiens University Hospital, France. All adult patients undergoing cardiac surgery were considered eligible for participation. Patients who had undergone pulmonary or tricuspid valve surgery, repeat surgery or who underwent immediate postoperative renal replacement therapy were excluded. Data from 74 patients were analysed. Left ventricular and right ventricular function were assessed before surgery and on admission to ICU by transthoracic echocardiography (TTE): left ventricular and right ventricular ejection fractions (LVEF/RVEF), tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (Sr(t)) and right ventricular dilatation. RVd was defined as values in the lowest quartile of at least two echocardiographic variables. Renal dysfunction was defined as an increase in serum creatinine concentration (sCr) on postoperative day 1. All right ventricular TTE variables decreased (P < 0.05) after surgery: RVEF from 50% (49 to 60) to 40% (35 to 50); TAPSE from 22.3 mm (19.4 to 25.3) to 12.2 mm (8.8 to 14.8); and Sr(t) from 15.0 cm s(-1) (12.0 to 18.0) to 8.1 cm s(-1) (6.3 to 9.2). Fourteen (19%) patients had right ventricular dilatation and RVd was present in 23 (31%) patients. Forty patients had a positive variation in sCr. In multivariate analysis, patients with RVd had an odds ratio (OR) of 12.7 [95% confidence interval (95% CI) 2.6 to 63.4, P = 0.02] for development of renal dysfunction. Renal dysfunction was associated with increased central venous pressure but was not associated with cardiac index (CI). These results suggest that early postoperative RVd is associated with a subsequent increase of sCr and that the mechanism involved is congestion (vena cava dilatation/elevated CVP) rather than decreased CI.

Low multiple electrode aggregometry platelet responses are not associated with non-synonymous variants in G-protein coupled receptor genes.

PubMed

Norman, Jane E; Lee, Kurtis R; Walker, Mary E; Murden, Sherina L; Harris, Jessica; Mundell, Stuart; J Murphy, Gavin; Mumford, Andrew D

2015-10-01

Multiple electrode aggregometry (MEA) improves prediction of thrombosis and bleeding in cardiac patients. However, the causes of inter-individual variation in MEA results are incompletely understood. We explore whether low MEA results are associated with platelet G-protein coupled receptor (GPCR) gene variants. The effects of P2Y12 receptor (P2Y12), thromboxane A2 receptor (TPα) and protease-activated receptor 1 (PAR1) dysfunction on the MEA ADP-test, ASPI-test and TRAP-test were determined using receptor antagonists. Cardiac surgery patients with pre-operative MEA results suggesting GPCR dysfunction were selected for P2Y12 (P2RY12), TPα (TBXA2R) and PAR1 (F2R) sequencing. In control blood samples, P2Y12, TPα or PAR1 antagonists markedly reduced ADP-test, ASPI-test and TRAP-test results respectively. In the 636 patients from a cohort of 2388 cardiac surgery patients who were not receiving aspirin or a P2Y12 blocker, the median ADP-test result was 75.1 U (range 4.8-153.2), ASPI-test 83.7 U (1.4-157.3) and TRAP-test 117.7 U (2.4-194.1), indicating a broad range of results unexplained by anti-platelet drugs. In 238 consenting patients with unexplained low MEA results, three P2RY12 variants occurred in 70/107 (65%) with suspected P2Y12 dysfunction and four TBXA2R variants occurred in 19/22 (86%) with suspected TPα dysfunction although the later group was too small to draw meaningful conclusions about variant frequency. All the variants were synonymous and unlikely to cause GPCR dysfunction. There were no F2R variants in the 109 cases with suspected PAR1 dysfunction. MEA results suggesting isolated platelet GPCR dysfunction were common in cardiac surgery patients, but were not associated with non-synonymous variants in P2RY12 or F2R. Copyright © 2015 Elsevier Ltd. All rights reserved.

[RyR-bound FKBP12.6 and the modulation].

PubMed

Yano, M; Matsuzaki, M

2001-06-01

In the pathogenesis of cardiac dysfunction in heart failure, a decrease in the activity of the sarcoplasmic reticulum (SR) Ca(2+) -ATPase is believed to be a major determinant. Recently, a novel mechanism of cardiac dysfunction in heart failure has been reported on the basis of the following findings:1) PKA hyperphosphorylation of RyR causes a dissociation of FKBP12.6 from RyR, resulting in the abnormal single-channel properties (increased Ca(2+) sensitivity for activation and elevated channel activity associated with destabilization of RyR (Marx et al, Cell 101:365, 2000), 2) a prominent abnormal Ca(2+) leak occurs through RyR, following a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR (Yano M et al, Circulation 102:2131, 2000). This abnormal Ca(2+) leak might possibly cause Ca(2+) overload and consequent diastolic dysfunction, as well as systolic dysfunction.

Intratracheal Milrinone Bolus Administration During Acute Right Ventricular Dysfunction After Cardiopulmonary Bypass.

PubMed

Gebhard, Caroline Eva; Desjardins, Georges; Gebhard, Cathérine; Gavra, Paul; Denault, André Y

2017-04-01

To evaluate intratracheal milrinone (tMil) administration for rapid treatment of right ventricular (RV) dysfunction as a novel route after cardiopulmonary bypass. Retrospective analysis. Single-center study. The study comprised 7 patients undergoing cardiac surgery who exhibited acute RV dysfunction after cardiopulmonary bypass. After difficult weaning caused by cardiopulmonary bypass-induced acute RV dysfunction, milrinone was administered as a 5-mg bolus inside the endotracheal tube. RV function improvement, as indicated by decreasing pulmonary artery pressure and changes of RV waveforms, was observed in all 7 patients. Adverse effects of tMil included dynamic RV outflow tract obstruction (2 patients) and a decrease in systemic mean arterial pressure (1 patient). tMil may be an effective, rapid, and easily applicable therapeutic alternative to inhaled milrinone for the treatment of acute RV failure during cardiac surgery. However, sufficiently powered clinical trials are needed to confirm these findings. Copyright © 2017 Elsevier Inc. All rights reserved.

Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT)

DTIC Science & Technology

2013-10-01

proceed with the formal Department of the Army review. 15. SUBJECT TERMS Trauma, hemorrhagic shock, cardiac arrest, cardiopulmonary resuscitation ...n/a Introduction Cardiopulmonary resuscitation (CPR) can save victims of normovolemic cardiac arrest (CA), e.g., ventricular...delayed resuscitation with cardiopulmonary bypass. The primary outcome variable will be survival to hospital discharge with minimal neurologic dysfunction

Cardiac diastolic and autonomic dysfunction are aggravated by central chemoreflex activation in heart failure with preserved ejection fraction rats

PubMed Central

Toledo, Camilo; Andrade, David C.; Lucero, Claudia; Arce‐Alvarez, Alexis; Díaz, Hugo S.; Aliaga, Valentín; Schultz, Harold D.; Marcus, Noah J.; Manríquez, Mónica; Faúndez, Marcelo

2017-01-01

Key points Heart failure with preserved ejection fraction (HFpEF) is associated with disordered breathing patterns, and sympatho‐vagal imbalance.Although it is well accepted that altered peripheral chemoreflex control plays a role in the progression of heart failure with reduced ejection fraction (HFrEF), the pathophysiological mechanisms underlying deterioration of cardiac function in HFpEF are poorly understood.We found that central chemoreflex is enhanced in HFpEF and neuronal activation is increased in pre‐sympathetic regions of the brainstem.Our data showed that activation of the central chemoreflex pathway in HFpEF exacerbates diastolic dysfunction, worsens sympatho‐vagal imbalance and markedly increases the incidence of cardiac arrhythmias in rats with HFpEF. Abstract Heart failure (HF) patients with preserved ejection fraction (HFpEF) display irregular breathing, sympatho‐vagal imbalance, arrhythmias and diastolic dysfunction. It has been shown that tonic activation of the central and peripheral chemoreflex pathway plays a pivotal role in the pathophysiology of HF with reduced ejection fraction. In contrast, no studies to date have addressed chemoreflex function or its effect on cardiac function in HFpEF. Therefore, we tested whether peripheral and central chemoreflexes are hyperactive in HFpEF and if chemoreflex activation exacerbates cardiac dysfunction and autonomic imbalance. Sprague‐Dawley rats (n = 32) were subjected to sham or volume overload to induce HFpEF. Resting breathing variability, chemoreflex gain, cardiac function and sympatho‐vagal balance, and arrhythmia incidence were studied. HFpEF rats displayed [mean ± SD; chronic heart failure (CHF) vs. Sham, respectively] a marked increase in the incidence of apnoeas/hypopnoeas (20.2 ± 4.0 vs. 9.7 ± 2.6 events h−1), autonomic imbalance [0.6 ± 0.2 vs. 0.2 ± 0.1 low/high frequency heart rate variability (LF/HFHRV)] and cardiac arrhythmias (196.0 ± 239.9 vs. 19.8 ± 21.7 events h−1). Furthermore, HFpEF rats showed increase central chemoreflex sensitivity but not peripheral chemosensitivity. Accordingly, hypercapnic stimulation in HFpEF rats exacerbated increases in sympathetic outflow to the heart (229.6 ± 43.2% vs. 296.0 ± 43.9% LF/HFHRV, normoxia vs. hypercapnia, respectively), incidence of cardiac arrhythmias (196.0 ± 239.9 vs. 576.7 ± 472.9 events h−1) and diastolic dysfunction (0.008 ± 0.004 vs. 0.027 ± 0.027 mmHg μl−1). Importantly, the cardiovascular consequences of central chemoreflex activation were related to sympathoexcitation since these effects were abolished by propranolol. The present results show that the central chemoreflex is enhanced in HFpEF and that acute activation of central chemoreceptors leads to increases of cardiac sympathetic outflow, cardiac arrhythmogenesis and impairment in cardiac function in rats with HFpEF. PMID:28181258

Phantom evaluation of a cardiac SPECT/VCT system that uses a common set of solid-state detectors for both emission and transmission scans

PubMed Central

Conwell, Richard; Kindem, Joel; Babla, Hetal; Gurley, Mike; De Los Santos, Romer; Old, Rex; Weatherhead, Randy; Arram, Samia; Maddahi, Jamshid

2010-01-01

Background We developed a cardiac SPECT system (X-ACT) with low dose volume CT transmission-based attenuation correction (AC). Three solid-state detectors are configured to form a triple-head system for emission scans and reconfigured to form a 69-cm field-of-view detector arc for transmission scans. A near mono-energetic transmission line source is produced from the collimated fluorescence x-ray emitted from a lead target when the target is illuminated by a narrow polychromatic x-ray beam from an x-ray tube. Transmission scans can be completed in 1 min with insignificant patient dose (deep dose equivalent <5 μSv). Methods We used phantom studies to evaluate (1) the accuracy of the reconstructed attenuation maps, (2) the effect of AC on image uniformity, and (3) the effect of AC on defect contrast (DC). The phantoms we used included an ACR phantom, an anthropomorphic phantom with a uniform cardiac insert, and an anthropomorphic phantom with two defects in the cardiac insert. Results The reconstructed attenuation coefficient of water at 140 keV was .150 ± .003/cm in the uniform region of the ACR phantom, .151 ± .003/cm and .151 ± .002/cm in the liver and cardiac regions of the anthropomorphic phantom. The ACR phantom images with AC showed correction of the bowing effect due to attenuation in the images without AC (NC). The 17-segment scores of the images of the uniform cardiac insert were 78.3 ± 6.5 before and 87.9 ± 3.3 after AC (average ± standard deviation). The inferior-to-anterior wall ratio and the septal-to-lateral wall ratio were .99 and 1.16 before and 1.02 and 1.00 after AC. The DC of the two defects was .528 and .156 before and .628 and .173 after AC. Conclusion The X-ACT system generated accurate attenuation maps with 1-minute transmission scans. AC improved image quality and uniformity over NC. PMID:20169476

Cardio-oncology: a multidisciplinary approach for detection, prevention and management of cardiac dysfunction in cancer patients.

PubMed

Tajiri, Kazuko; Aonuma, Kazutaka; Sekine, Ikuo

2017-08-01

Cardiac dysfunction that develops during or after completion of cancer therapy is a growing health concern that should be addressed in a multidisciplinary setting. Cardio-oncology is a new discipline that focuses on screening, monitoring and treating cardiovascular disease during and after cancer treatment. A baseline cardiovascular risk assessment is essential. For high-risk patients, a tailored and detailed plan for cardiovascular management throughout treatment and beyond should also be established. Anthracycline and/or trastuzumab-containing chemotherapy and chest-directed radiation therapy are well known cardiotoxic cancer therapies. Monitoring for the development of subclinical cardiotoxicity is crucial for the prevention of clinical heart failure. Detecting a decreased left ventricular ejection fraction after cancer therapy might be a late finding; therefore, earlier markers of cardiac injury are being actively explored. Abnormal myocardial strain and increased serum cardiac biomarkers (e.g. troponins and natriuretic peptides) are possible candidates for this purpose. An important method for preventing heart failure is the avoidance or minimization of the use of cardiotoxic therapies. Decisions must balance the anti-tumor efficacy of the treatment with its potential cardiotoxicity. If patients develop cardiac dysfunction or heart failure, they should be treated in accordance with established guidelines for heart failure. Cancer survivors who have been exposed to cardiotoxic cancer therapies are at high risk of developing heart failure. The management of cardiovascular risk factors and periodic screening with cardiac imaging and biomarkers should be considered in high-risk survivors. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Diastolic dysfunction characterizes cirrhotic cardiomyopathy

PubMed Central

Somani, Piyush O.; contractor, Qais; Chaurasia, Ajay S.; Rathi, Pravin M.

2014-01-01

Aim Present study aims to study the occurrence of cirrhotic cardiomyopathy and its correlation to hepatorenal syndrome by assessing the cardiac status in patients with cirrhosis of liver and healthy controls. Methods Thirty alcoholic cirrhotic, thirty non-alcoholic cirrhotic and thirty controls were enrolled for the study. Cardiac parameters were assessed by color doppler echocardiography. Patients were followed up for twelve months period for development of hepatorenal syndrome. Results Mild diastolic dysfunction was present in 18 cirrhotic patients (30%): grade I in fifteen patients and grade II in three. Diastolic dysfunction was unrelated to age; sex and etiology of cirrhosis. Among all the echocardiographic parameters, only deceleration time was found to be statistically significant. Echocardiographic parameters in systolic and diastolic function were not different in compensated vs decompensated patients in different Child-Pugh classes or cirrhosis aetiologies. At one year follow-up, no significant differences were found in survival between patients with or without diastolic dysfunction. Hepatorenal syndrome developed in only two patients and its correlation with diastolic dysfunction was not statistically significant. Conclusions Present study shows that although diastolic dysfunction is a frequent event in cirrhosis, it is usually of mild degree and does not correlate with severity of liver dysfunction. There are no significant differences in echocardiographic parameters between alcoholic and non-alcoholic cirrhosis. HRS is not correlated to diastolic dysfunction in cirrhotic patients. There is no difference in survival at one year between patients with or without diastolic dysfunction. Diastolic dysfunction in cirrhosis is unrelated to circulatory dysfunction, ascites and HRS. PMID:25634400

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism.

PubMed

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-11-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease.

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism

PubMed Central

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-01-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease. PMID:28924131

Shikonin ameliorates isoproterenol (ISO)-induced myocardial damage through suppressing fibrosis, inflammation, apoptosis and ER stress.

PubMed

Yang, Jun; Wang, Zhao; Chen, Dong-Lin

2017-09-01

Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future. Copyright © 2017. Published by Elsevier Masson SAS.

Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

PubMed

Lee, Tsung-Ming; Chang, Nen-Chung; Lin, Shinn-Zong

2017-03-01

During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling. Copyright © 2017 Elsevier Inc. All rights reserved.

Postinfarction Functional Recovery Driven by a Three-Dimensional Engineered Fibrin Patch Composed of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

PubMed

Roura, Santiago; Soler-Botija, Carolina; Bagó, Juli R; Llucià-Valldeperas, Aida; Férnandez, Marco A; Gálvez-Montón, Carolina; Prat-Vidal, Cristina; Perea-Gil, Isaac; Blanco, Jerónimo; Bayes-Genis, Antoni

2015-08-01

Considerable research has been dedicated to restoring myocardial cell slippage and limiting ventricular remodeling after myocardial infarction (MI). We examined the ability of a three-dimensional (3D) engineered fibrin patch filled with human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to induce recovery of cardiac function after MI. The UCBMSCs were modified to coexpress luciferase and fluorescent protein reporters, mixed with fibrin, and applied as an adhesive, viable construct (fibrin-cell patch) over the infarcted myocardium in mice (MI-UCBMSC group). The patch adhered well to the heart. Noninvasive bioluminescence imaging demonstrated early proliferation and differentiation of UCBMSCs within the construct in the postinfarct mice in the MI-UCBMSC group. The implanted cells also participated in the formation of new, functional microvasculature that connected the fibrin-cell patch to both the subjacent myocardial tissue and the host circulatory system. As revealed by echocardiography, the left ventricular ejection fraction and fractional shortening at sacrifice were improved in MI-UCBMSC mice and were markedly reduced in mice treated with fibrin alone and untreated postinfarction controls. In conclusion, a 3D engineered fibrin patch composed of UCBMSCs attenuated infarct-derived cardiac dysfunction when transplanted locally over a myocardial wound. ©AlphaMed Press.

Mangiferin protect myocardial insults through modulation of MAPK/TGF-β pathways.

PubMed

Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N; Ojha, Shreesh; Kumari, Santosh; Bhatia, Jagriti; Arya, Dharamvir Singh

2016-04-05

Mangiferin, a xanthone glycoside isolated from leaves of Mangifera indica (Anacardiaceae) is known to modulate many biological targets in inflammation and oxidative stress. The present study was designed to investigate whether mangiferin exerts protection against myocardial ischemia-reperfusion (IR) injury and possible role of Mitogen Activated Protein Kinase (MAPKs) and Transforming Growth Factor-β (TGF-β) pathways in its cardioprotection. Male albino Wistar rats were treated with mangiferin (40 mg/kg, i.p.) for 15 days. At the end of the treatment protocol, rats were subjected to IR injury consisting of 45 min ischemia followed by 1h reperfusion. IR-control rats caused significant cardiac dysfunction, increased serum cardiac injury markers, lipid peroxidation and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats revealed myocardial necrosis, edema and infiltration of inflammatory cells. However, pretreatment with mangiferin significantly restored myocardial oxidant-antioxidant status, maintained membrane integrity, and attenuated the levels of proinflammatory cytokines, pro-apoptotic proteins and TGF-β. Furthermore, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. These results suggest that mangiferin protects against myocardial IR injury by modulating MAPK mediated inflammation and apoptosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.

PubMed

da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho

2015-10-01

The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.

Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1-mediated autophagy regulation.

PubMed

Ren, Jun; Yang, Lifang; Zhu, Li; Xu, Xihui; Ceylan, Asli F; Guo, Wei; Yang, Jian; Zhang, Yingmei

2017-10-01

Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulation of Akt and autophagy. This study examined the impact of Akt2 ablation on life span and cardiac aging as well as the mechanisms involved with a focus on autophagy and mitochondrial integrity. Cardiac geometry, contractile, and intracellular Ca 2+ properties were evaluated using echocardiography, IonOptix ® edge-detection and fura-2 techniques. Levels of Sirt1, mitochondrial integrity, autophagy, and mitophagy markers were evaluated using Western blot. Our results revealed that Akt2 ablation prolonged life span (by 9.1%) and alleviated aging (24 months)-induced unfavorable changes in myocardial function and intracellular Ca 2+ handling (SERCA2a oxidation) albeit with more pronounced cardiac hypertrophy (58.1%, 47.8%, and 14.5% rises in heart weight, wall thickness, and cardiomyocyte cross-sectional area). Aging downregulated levels of Sirt1, increased phosphorylation of Akt, and the nuclear transcriptional factor Foxo1, as well as facilitated acetylation of Foxo1, the effects of which (except Sirt1 and Foxo1 acetylation) were significantly attenuated or negated by Akt2 ablation. Advanced aging disturbed autophagy, mitophagy, and mitochondrial integrity as evidenced by increased p62, decreased levels of beclin-1, Atg7, LC3B, BNIP3, PTEN-induced putative kinase 1 (PINK1), Parkin, UCP-2, PGC-1α, and aconitase activity, the effects of which were reversed by Akt2 ablation. Aging-induced cardiomyocyte contractile dysfunction and loss of mitophagy were improved by rapamycin and the Sirt1 activator SRT1720. Activation of Akt using insulin or Parkin deficiency prevented SRT1720-induced beneficial effects against aging. In conclusion, our data indicate that Akt2 ablation protects against cardiac aging through restored Foxo1-related autophagy and mitochondrial integrity. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Positive effect of combined exercise training in a model of metabolic syndrome and menopause: autonomic, inflammatory, and oxidative stress evaluations.

PubMed

Conti, Filipe Fernandes; Brito, Janaina de Oliveira; Bernardes, Nathalia; Dias, Danielle da Silva; Malfitano, Christiane; Morris, Mariana; Llesuy, Susana Francisca; Irigoyen, Maria-Cláudia; De Angelis, Kátia

2015-12-15

It is now well established that after menopause cardiometabolic disorders become more common. Recently, resistance exercise has been recommended as a complement to aerobic (combined training, CT) for the treatment of cardiometabolic diseases. The aim of this study was to evaluate the effects of CT in hypertensive ovariectomized rats undergoing fructose overload in blood pressure variability (BPV), inflammation, and oxidative stress parameters. Female rats were divided into the following groups (n = 8/group): sedentary normotensive Wistar rats (C), and sedentary (FHO) or trained (FHOT) ovariectomized spontaneously hypertensive rats undergoing and fructose overload. CT was performed on a treadmill and ladder adapted to rats in alternate days (8 wk; 40-60% maximal capacity). Arterial pressure (AP) was directly measured. Oxidative stress and inflammation were measured on cardiac and renal tissues. The association of risk factors (hypertension + ovariectomy + fructose) promoted increase in insulin resistance, mean AP (FHO: 174 ± 4 vs. C: 108 ± 1 mmHg), heart rate (FHO: 403 ± 12 vs. C: 352 ± 11 beats/min), BPV, cardiac inflammation (tumor necrosis factor-α-FHO: 65.8 ± 9.9 vs. C: 23.3 ± 4.3 pg/mg protein), and oxidative stress cardiac and renal tissues. However, CT was able to reduce mean AP (FHOT: 158 ± 4 mmHg), heart rate (FHOT: 303 ± 5 beats/min), insulin resistance, and sympathetic modulation. Moreover, the trained rats presented increased nitric oxide bioavailability, reduced tumor necrosis factor-α (FHOT: 33.1 ± 4.9 pg/mg protein), increased IL-10 in cardiac tissue and reduced lipoperoxidation, and increased antioxidant defenses in cardiac and renal tissues. In conclusion, the association of risk factors promoted an additional impairment in metabolic, cardiovascular, autonomic, inflammatory, and oxidative stress parameters and combined exercise training was able to attenuate these dysfunctions. Copyright © 2015 the American Physiological Society.

TRPA1 mediates changes in heart rate variability and cardiac mechanical function in mice exposed to acrolein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kurhanewicz, Nicole

Short-term exposure to ambient air pollution is linked with adverse cardiovascular effects. While previous research focused primarily on particulate matter-induced responses, gaseous air pollutants also contribute to cause short-term cardiovascular effects. Mechanisms underlying such effects have not been adequately described, however the immediate nature of the response suggests involvement of irritant neural activation and downstream autonomic dysfunction. Thus, this study examines the role of TRPA1, an irritant sensory receptor found in the airways, in the cardiac response of mice to acrolein and ozone. Conscious unrestrained wild-type C57BL/6 (WT) and TRPA1 knockout (KO) mice implanted with radiotelemeters were exposed once tomore » 3 ppm acrolein, 0.3 ppm ozone, or filtered air. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure. Analysis of ECG morphology, incidence of arrhythmia and heart rate variability (HRV) were performed. Cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 h post-exposure. Acrolein exposure increased HRV independent of HR, as well as incidence of arrhythmia. Acrolein also increased left ventricular developed pressure in WT mice at 24 h post-exposure. Ozone did not produce any changes in cardiac function. Neither gas produced ECG effects, changes in HRV, arrhythmogenesis, or mechanical function in KO mice. These data demonstrate that a single exposure to acrolein causes cardiac dysfunction through TRPA1 activation and autonomic imbalance characterized by a shift toward parasympathetic modulation. Furthermore, it is clear from the lack of ozone effects that although gaseous irritants are capable of eliciting immediate cardiac changes, gas concentration and properties play important roles. - Highlights: • Acute acrolein exposure causes autonomic imbalance and altered CV function in mice. • TRPA1 mediates acrolein-induced autonomic nervous system cardiac effects. • Sensory irritation contributes to acrolein-induced cardiac arrhythmia & dysfunction.« less

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.

PubMed

Pillai, Indulekha C L; Li, Shen; Romay, Milagros; Lam, Larry; Lu, Yan; Huang, Jie; Dillard, Nathaniel; Zemanova, Marketa; Rubbi, Liudmilla; Wang, Yibin; Lee, Jason; Xia, Ming; Liang, Owen; Xie, Ya-Hong; Pellegrini, Matteo; Lusis, Aldons J; Deb, Arjun

2017-02-02

Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development. Copyright © 2017 Elsevier Inc. All rights reserved.

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

PubMed Central

Froese, Alexander; Breher, Stephanie S.; Waldeyer, Christoph; Schindler, Roland F.R.; Nikolaev, Viacheslav O.; Rinné, Susanne; Wischmeyer, Erhard; Schlueter, Jan; Becher, Jan; Simrick, Subreena; Vauti, Franz; Kuhtz, Juliane; Meister, Patrick; Kreissl, Sonja; Torlopp, Angela; Liebig, Sonja K.; Laakmann, Sandra; Müller, Thomas D.; Neumann, Joachim; Stieber, Juliane; Ludwig, Andreas; Maier, Sebastian K.; Decher, Niels; Arnold, Hans-Henning; Kirchhof, Paulus; Fabritz, Larissa; Brand, Thomas

2012-01-01

Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention. PMID:22354168

Prolongation of heart rate-corrected QT interval is a predictor of cardiac autonomic dysfunction in patients with systemic lupus erythematosus.

PubMed

Nomura, Atsushi; Kishimoto, Mitsumasa; Takahashi, Osamu; Deshpande, Gautam A; Yamaguchi, Kenichi; Okada, Masato

2014-05-01

Heart rate-corrected QT interval duration (QTc) has been shown to be related to cardiac autonomic dysfunction in patients with diabetes mellitus, although this association has not been previously described in patients with systemic lupus erythematosus (SLE). We retrospectively reviewed the medical records of 91 SLE patients and 144 non-SLE connective tissue disease patients visiting our clinic from November 2010 to April 2011. We compared ambulatory heart rate identified by pulse measured by automated machine in an outpatient waiting area versus resting heart rate identified on prior screening electrocardiogram. Heart rate differences were analyzed in relation to QTc interval and other characteristics. Ambulatory and resting heart rate differences were larger among SLE patients with QTc prolongation (QTc > 430 ms) than those without QTc prolongation (mean difference, 15.9 vs. 9.6, p = 0.001). In multivariate analysis, differences in heart rate were associated with QTc prolongation (OR 1.10, 95 % CI 1.01-1.21; p = 0.038), independent of age, duration of disease, immunosuppressant use, hydroxychloroquine use, diabetes mellitus, cardiac abnormality, anti-Ro/SS-A antibody positivity, or resting heart rate. Cardiac autonomic dysfunction is a common manifestation of SLE and may be related to QTc prolongation.

Impedance cardiography: a comparison of cardiac output vs waveform analysis for assessing left ventricular systolic dysfunction.

PubMed

DeMarzo, Arthur P; Kelly, Russell F; Calvin, James E

2007-01-01

Early detection of asymptomatic left ventricular systolic dysfunction (LVSD) is beneficial in managing heart failure. Recent studies have cast doubt on the usefulness of cardiac output as an indicator of LVSD. In impedance cardiography (ICG), the dZ/dt waveform has a systolic wave called the E wave. This study looked at measurements of the amplitude and area of the E wave compared with ICG-derived cardiac output, stroke volume, cardiac index, and stroke index as methods of assessing LVSD. ICG data were obtained from patients (n=26) admitted to a coronary care unit. Clinical LVSD severity was stratified into 4 groups (none, mild, moderate, and severe) based on echocardiography data and standard clinical assessment by a cardiologist blinded to ICG data. Statistical analysis showed that the E wave amplitude and area were better indicators of the level of LVSD than cardiac output, stroke volume, cardiac index, or stroke index. ICG waveform analysis has potential as a simple point-of-care test for detecting LVSD in asymptomatic patients at high risk for developing heart failure and for monitoring LVSD in patients being treated for heart failure.

3D cardiac wall thickening assessment for acute myocardial infarction

NASA Astrophysics Data System (ADS)

Khalid, A.; Chan, B. T.; Lim, E.; Liew, Y. M.

2017-06-01

Acute myocardial infarction (AMI) is the most severe form of coronary artery disease leading to localized myocardial injury and therefore irregularities in the cardiac wall contractility. Studies have found very limited differences in global indices (such as ejection fraction, myocardial mass and volume) between healthy subjects and AMI patients, and therefore suggested regional assessment. Regional index, specifically cardiac wall thickness (WT) and thickening is closely related to cardiac function and could reveal regional abnormality due to AMI. In this study, we developed a 3D wall thickening assessment method to identify regional wall contractility dysfunction due to localized myocardial injury from infarction. Wall thickness and thickening were assessed from 3D personalized cardiac models reconstructed from cine MRI images by fitting inscribed sphere between endocardial and epicardial wall. The thickening analysis was performed in 5 patients and 3 healthy subjects and the results were compared against the gold standard 2D late-gadolinium-enhanced (LGE) images for infarct localization. The notable finding of this study is the highly accurate estimation and visual representation of the infarct size and location in 3D. This study provides clinicians with an intuitive way to visually and qualitatively assess regional cardiac wall dysfunction due to infarction in AMI patients.

Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure

PubMed Central

Fu, Feng; Zhao, Kun; Li, Jia; Xu, Jie; Zhang, Yuan; Liu, Chengfeng; Yang, Weidong; Gao, Chao; Li, Jun; Zhang, Haifeng; Li, Yan; Cui, Qin; Wang, Haichang; Tao, Ling; Wang, Jing; Quon, Michael J; Gao, Feng

2015-01-01

A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF. PMID:26659007

LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG.

PubMed

Wu, Bing; Zhang, Chunping; Zou, Lifang; Ma, Yucheng; Huang, Kangyu; Lv, Qiulan; Zhang, Xi; Wang, Shouyu; Xue, Yun; Yi, Zhihua; Jia, Tianyu; Zhao, Shanhong; Liu, Shuangmei; Xu, Hong; Li, Guilin; Liang, Shangdong

2016-05-01

Diabetic autonomic neuropathy includes the sympathetic ganglionic dysfunction. P2X7 receptor in superior cervical ganglia (SCG) participated in the pathological changes of cardiac dysfunction. Abnormal expression of long noncoding RNAs (lncRNAs) was reported to be involved in nervous system diseases. Our preliminary results obtained from rat lncRNA array profiling revealed that the expression of the uc.48+ was significantly increased in the rat SCG in response to diabetic sympathetic pathology. In this study, we found that lncRNAuc.48+ and P2X7 receptor in the SCG were increased in type 2 diabetic rats and were associated with the cardiac dysfunction. The uc.48+ small interference RNA (siRNA) improved the cardiac autonomic dysfunction and decreased the up-regulation P2X7 and the ratio of phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2) to ERK1/2 in SCG of type 2 diabetic rats. In conclusion, lncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats through regulating the expression of P2X7 and ERK signaling in SCG. Copyright © 2016 Elsevier B.V. All rights reserved.

Amelioration of High Fructose-Induced Cardiac Hypertrophy by Naringin.

PubMed

Park, Jung Hyun; Ku, Hyeong Jun; Kim, Jae Kyeom; Park, Jeen-Woo; Lee, Jin Hyup

2018-06-21

Heart failure is a frequent unfavorable outcome of pathological cardiac hypertrophy. Recent increase in dietary fructose consumption mirrors the rise in prevalence of cardiovascular diseases such as cardiac hypertrophy leading to concerns raised by public health experts. Mitochondria, comprising 30% of cardiomyocyte volume, play a central role in modulating redox-dependent cellular processes such as metabolism and apoptosis. Furthermore, mitochondrial dysfunction is a key cause of pathogenesis of fructose-induced cardiac hypertrophy. Naringin, a major flavanone glycoside in citrus species, has displayed strong antioxidant potential in models of oxidative stress. In this study, we evaluated protective effects of naringin against fructose-induced cardiac hypertrophy and associated mechanisms of action, using in vitro and in vivo models. We found that naringin suppressed mitochondrial ROS production and mitochondrial dysfunction in cardiomyocytes exposed to fructose and consequently reduced cardiomyocyte hypertrophy by regulating AMPK-mTOR signaling axis. Furthermore, naringin counteracted fructose-induced cardiomyocyte apoptosis, and this function of naringin was linked to its ability to inhibit ROS-dependent ATM-mediated p53 signaling. This result was supported by observations in in vivo mouse model of cardiac hypertrophy. These findings indicate a novel role for naringin in protecting against fructose-induced cardiac hypertrophy and suggest unique therapeutic strategies for prevention of cardiovascular diseases.

Artificial aortic valve dysfunction due to pannus and thrombus – different methods of cardiac surgical management

PubMed Central

Marcinkiewicz, Anna; Kośmider, Anna; Walczak, Andrzej; Zwoliński, Radosław; Jaszewski, Ryszard

2015-01-01

Introduction Approximately 60 000 prosthetic valves are implanted annually in the USA. The risk of prosthesis dysfunction ranges from 0.1% to 4% per year. Prosthesis valve dysfunction is usually caused by a thrombus obstructing the prosthetic discs. However, 10% of prosthetic valves are dysfunctional due to pannus formation, and 12% of prostheses are damaged by both fibrinous and thrombotic components. The authors present two patients with dysfunctional aortic prostheses who were referred for cardiac surgery. Different surgical solutions were used in the treatment of each case. Case study 1 The first patient was a 71-year-old woman whose medical history included arterial hypertension, stable coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and hypercholesterolemia; she had previously undergone left-sided mastectomy and radiotherapy. The patient was admitted to the Cardiac Surgery Department due to aortic prosthesis dysfunction. Transthoracic echocardiography revealed complete obstruction of one disc and a severe reduction in the mobility of the second. The mean transvalvular gradient was very high. During the operation, pannus covering the discs’ surface was found. A biological aortic prosthesis was reimplanted without complications. Case study 2 The second patient was an 87-year-old woman with arterial hypertension, persistent atrial fibrillation, and COPD, whose past medical history included gastric ulcer disease and ischemic stroke. As in the case of the first patient, she was admitted due to valvular prosthesis dysfunction. Preoperative transthoracic echocardiography revealed an obstruction of the posterior prosthetic disc and significant aortic regurgitation. Transesophageal echocardiography and fluoroscopy confirmed the prosthetic dysfunction. During the operation, a thrombus growing around a minor pannus was found. The thrombus and pannus were removed, and normal functionality of the prosthetic valve was restored. Conclusions Precise and modern diagnostic methods facilitated selection of the treatment method. However, the intraoperative view also seems to be crucial in individualizing the surgical approach. PMID:26702274

Artificial aortic valve dysfunction due to pannus and thrombus - different methods of cardiac surgical management.

PubMed

Ostrowski, Stanisław; Marcinkiewicz, Anna; Kośmider, Anna; Walczak, Andrzej; Zwoliński, Radosław; Jaszewski, Ryszard

2015-09-01

Approximately 60 000 prosthetic valves are implanted annually in the USA. The risk of prosthesis dysfunction ranges from 0.1% to 4% per year. Prosthesis valve dysfunction is usually caused by a thrombus obstructing the prosthetic discs. However, 10% of prosthetic valves are dysfunctional due to pannus formation, and 12% of prostheses are damaged by both fibrinous and thrombotic components. The authors present two patients with dysfunctional aortic prostheses who were referred for cardiac surgery. Different surgical solutions were used in the treatment of each case. The first patient was a 71-year-old woman whose medical history included arterial hypertension, stable coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and hypercholesterolemia; she had previously undergone left-sided mastectomy and radiotherapy. The patient was admitted to the Cardiac Surgery Department due to aortic prosthesis dysfunction. Transthoracic echocardiography revealed complete obstruction of one disc and a severe reduction in the mobility of the second. The mean transvalvular gradient was very high. During the operation, pannus covering the discs' surface was found. A biological aortic prosthesis was reimplanted without complications. The second patient was an 87-year-old woman with arterial hypertension, persistent atrial fibrillation, and COPD, whose past medical history included gastric ulcer disease and ischemic stroke. As in the case of the first patient, she was admitted due to valvular prosthesis dysfunction. Preoperative transthoracic echocardiography revealed an obstruction of the posterior prosthetic disc and significant aortic regurgitation. Transesophageal echocardiography and fluoroscopy confirmed the prosthetic dysfunction. During the operation, a thrombus growing around a minor pannus was found. The thrombus and pannus were removed, and normal functionality of the prosthetic valve was restored. Precise and modern diagnostic methods facilitated selection of the treatment method. However, the intraoperative view also seems to be crucial in individualizing the surgical approach.

Cardiac emergencies and problems of the critical care patient.

PubMed

Marr, Celia M

2004-04-01

Cardiac disease and dysfunction can occur as a primary disorder(ie, with pathology situated in one or more of the cardiac structures) or can be classified as a secondary problem when it occurs in patients with another primary problem that has affected the heart either directly or indirectly. Primary cardiac problems are encountered in horses presented to emergency clinics; however,this occurs much less frequently in equine critical patients than cardiac problems arising secondary to other conditions. Nevertheless,if primary or secondary cardiac problems are not identified and addressed, they certainly contribute to the morbidity and mortality of critical care patients.

Pyridostigmine protects against cardiomyopathy associated with adipose tissue browning and improvement of vagal activity in high-fat diet rats.

PubMed

Lu, Yi; Wu, Qing; Liu, Long-Zhu; Yu, Xiao-Jiang; Liu, Jin-Jun; Li, Man-Xiang; Zang, Wei-Jin

2018-04-01

Obesity, a major contributor to the development of cardiovascular diseases, is associated with an autonomic imbalance characterized by sympathetic hyperactivity and diminished vagal activity. Vagal activation plays important roles in weight loss and improvement of cardiac function. Pyridostigmine is a reversible acetylcholinesterase inhibitor, but whether it ameliorates cardiac lipid accumulation and cardiac remodeling in rats fed a high-fat diet has not been determined. This study investigated the effects of pyridostigmine on high-fat diet-induced cardiac dysfunction and explored the potential mechanisms. Rats were fed a normal or high-fat diet and treated with pyridostigmine. Vagal discharge was evaluated using the BL-420S system, and cardiac function by echocardiograms. Lipid deposition and cardiac remodeling were determined histologically. Lipid utility was assessed by qPCR. A high-fat diet led to a significant reduction in vagal discharge and lipid utility and a marked increase in lipid accumulation, cardiac remodeling, and cardiac dysfunction. Pyridostigmine improved vagal activity and lipid metabolism disorder and cardiac remodeling, accompanied by an improvement of cardiac function in high-fat diet-fed rats. An increase in the browning of white adipose tissue in pyridostigmine-treated rats was also observed and linked to the expression of UCP-1 and CIDEA. Additionally, pyridostigmine facilitated activation of brown adipose tissue via activation of the SIRT-1/AMPK/PGC-1α pathway. In conclusion, a high-fat diet resulted in cardiac lipid accumulation, cardiac remodeling, and a significant decrease in vagal discharge. Pyridostigmine ameliorated cardiomyopathy, an effect related to reduced cardiac lipid accumulation, and facilitated the browning of white adipose tissue while activating brown adipose tissue. Copyright © 2018 Elsevier B.V. All rights reserved.

Beta blocker infusion decreases the magnitude of core hypothermia after anesthesia induction.

PubMed

Inoue, S; Abe, R; Kawaguchi, M; Kobayashi, H; Furuya, H

2010-12-01

Beta-1-receptor blockade reduces heart rate, cardiac output, and arterial pressure while increasing peripheral vascular resistance. It is possible that beta blockers not only inhibit the core-to-peripheral re-distribution of body heat and cutaneous heat loss due to vasodilation after anesthesia induction but also reduce the convective transfer of heat from the core to peripheral tissues by decreasing cardiac output. The authors investigated whether the co-administration of esmolol or landiolol, ultra-short-acting beta blockers, attenuates the magnitude of initial re-distribution hypothermia after anesthesia induction and tracheal intubation. Immediately prior to the induction of anesthesia, patients were randomly assigned to receive 0.2 mg kg-1 of landiolol (landiolol group; N=30), 1 mg kg-1 of esmolol (esmolol group; N=30), or 0.1 mL kg-1 of saline (control group; N=30). Heart rate, blood pressure, cardiac output, and tympanic, forearm, and digit temperatures were recorded. Forearm minus fingertip skin-surface temperature gradients (temperature gradient) were calculated. Tympanic membrane temperatures 15 to 60 min after the induction of anesthesia were significantly higher in the esmolol group than in the control group although the temperature gradient was similar among the three groups. Both esmolol and landiolol inhibited the increase in HR and MAP after the induction of anesthesia and tracheal intubation. The cardiac index in the esmolol group was significantly lower than in the control group. The degree of hemodynamic attenuation after induction by esmolol was larger than that of landiolol. The co-administration of esmolol, but not landiolol, attenuated the magnitude of initial re-distribution hypothermia after anesthesia induction and tracheal intubation. Esmolol likely prevented initial hypothermia because it attenuated the convective transfer of heat from the core to peripheral tissues by decreasing cardiac output.

Development and Implementation of Discrete Polymeric Microstructural Cues for Applications in Cardiac Tissue Engineering

NASA Astrophysics Data System (ADS)

Pinney, James Richardson

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. Despite care in the acute setting of MI, subsequent development of scar tissue and a lack of treatments for this maladaptive response lead to a poor prognosis. This has increased burdens on the cost of healthcare due to chronic disability. Here a novel therapeutic strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructural cues to attenuate the fibrotic response and improve functional outcomes is presented. Additionally, applications of integrated chemical functionalizations into discrete, micro-scale polymer structures are discussed in the realm of tissue engineering in order to impart enhancements in in vivo localization, three-dimensional manipulation and drug delivery. Polymeric microstructures, termed "microrods" and "microcubes", were fabricated using photolithographic techniques and studied in three-dimensional culture models of the fibrotic environment and by direct injection into the infarct zone of adult Sprague-Dawley rats. In vitro gene expression and functional and histological results were analyzed, showing a dose-dependent down-regulation fibrotic indicators and improvement in cardiac function. Furthermore, iron oxide nanoparticles and functionalized fluorocarbons were incorporated into the polymeric microdevices to promote in situ visualization by magnetic resonance imaging as well as to facilitate the manipulation and alignment of microstructural cues in a tissue-realistic environment. Lastly, successful encapsulation of native MGF peptide within microrods is demonstrated with release over two weeks as a proof of concept in the ability to locally deliver myogenic or supportive pharmacotherapeutics to the injured myocardium. This work demonstrates the efficacy and versatility of discrete microtopographical cues to attenuate the fibrotic response after MI and suggests a novel therapeutic strategy for combatting the chronic sequelae of pathologic fibrosis that is biocompatible, localizable, functionalizable, and biologically, mechanically, and chemically active. By integrating this multifunctional strategy into post-infarctive care, as well as a wide range of other fibrotic and mechanically sensitive disease processes, more directed and effective therapeutics could be developed to aid in combatting these complex and challenging pathologies.

Estimation of cardiac left ventricular ejection fraction in transfusional cardiac iron overload by R2* magnetic resonance.

PubMed

Sakuta, Juri; Ito, Yoshikazu; Kimura, Yukihiko; Park, Jinho; Tokuuye, Koichi; Ohyashiki, Kazuma

2010-12-01

Cardiac dysfunction due to transfusional iron overload is one of the most critical complications for patients with transfusion-dependent hematological disorders. Clinical parameters such as total red blood cell (RBC) transfusion units and serum ferritin level are usually considered as indicators for initiation of iron chelation therapy. We used MRI-T2*, MRI-R2* values, and left ventricular ejection fraction in 19 adult patients with blood transfusion-dependent hematological disorders without consecutive oral iron chelation therapy, and propose possible formulae of cardiac function using known parameters, such as total RBC transfusion units and serum ferritin levels. We found a positive correlation in all patients between both R2* values (reciprocal values of T2*) and serum ferritin levels (r = 0.81) and also total RBC transfusion volume (r = 0.90), but not when we analyzed subgroups of patients whose T2* values were over 30 ms (0.52). From the formulae of the R2*, we concluded that approximately 50 Japanese units or 2,900 pmol/L ferritin might be the cutoff value indicating possible future cardiac dysfunction.

Thyroid gland and cerebella lesions: New risk factors for sudden cardiac death in schizophrenia?

PubMed

Scorza, Fulvio A; Cavalheiro, Esper A; de Albuquerque, Marly; de Albuquerque, Juliana; Cysneiros, Roberta M; Terra, Vera C; Arida, Ricardo M

2011-02-01

People with schizophrenia show a two to threefold increased risk to die prematurely than those without schizophrenia. Patients' life style, suicide, premature development of cardiovascular disease, high prevalence of metabolic syndrome and sudden cardiac death are well-known causes of the excess mortality. The exact pathophysiological cause of sudden death in schizophrenia is unknown, but it is likely that cardiac arrhythmia and respiratory abnormalities play potential role. Some antipsychotics may be associated with cardiovascular adverse events (e.g., QT interval prolongation) and lesions in specific brain regions, such as cerebella may be associated with respiratory abnormalities, suggesting that metabolic and brain dysfunction could lead to sudden cardiac death in patients with schizophrenia. However, exact knowledge regarding the association of these findings and schizophrenia is lacking. As subclinical hyperthyroidism has been linked with increased risk of cardiovascular disease and cerebella progressive atrophy has been observed in patients with schizophrenia, we propose in this paper that subclinical thyroid dysfunction and cerebella volume loss could be considered as new risk factor for sudden cardiac death in schizophrenia. Copyright © 2010 Elsevier Ltd. All rights reserved.

New angiotensin II type 1 receptor blocker, azilsartan, attenuates cardiac remodeling after myocardial infarction.

PubMed

Nakamura, Yuichi; Suzuki, Satoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

2013-01-01

After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.

Computational Modeling of Pathophysiologic Responses to Exercise in Fontan Patients

PubMed Central

Kung, Ethan; Perry, James C.; Davis, Christopher; Migliavacca, Francesco; Pennati, Giancarlo; Giardini, Alessandro; Hsia, Tain-Yen; Marsden, Alison

2014-01-01

Reduced exercise capacity is nearly universal among Fontan patients. Although many factors have emerged as possible contributors, the degree to which each impacts the overall hemodynamics is largely unknown. Computational modeling provides a means to test hypotheses of causes of exercise intolerance via precisely controlled virtual experiments and measurements. We quantified the physiological impacts of commonly encountered, clinically relevant dysfunctions introduced to the exercising Fontan system via a previously developed lumped-parameter model of Fontan exercise. Elevated pulmonary arterial pressure was observed in all cases of dysfunction, correlated with lowered cardiac output, and often mediated by elevated atrial pressure. Pulmonary vascular resistance was not the most significant factor affecting exercise performance as measured by cardiac output. In the absence of other dysfunctions, atrioventricular valve insufficiency alone had significant physiological impact, especially under exercise demands. The impact of isolated dysfunctions can be linearly summed to approximate the combined impact of several dysfunctions occurring in the same system. A single dominant cause of exercise intolerance was not identified, though several hypothesized dysfunctions each led to variable decreases in performance. Computational predictions of performance improvement associated with various interventions should be weighed against procedural risks and potential complications, contributing to improvements in routine patient management protocol. PMID:25260878

Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications.

PubMed

Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C Ronald

2014-10-01

Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications. © FASEB.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy.

PubMed

Toczek, Marta; Zielonka, Daniel; Zukowska, Paulina; Marcinkowski, Jerzy T; Slominska, Ewa; Isalan, Mark; Smolenski, Ryszard T; Mielcarek, Michal

2016-11-01

Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings. Copyright © 2016 Elsevier B.V. All rights reserved.

Low molecular weight fibroblast growth factor-2 signals via protein kinase C and myofibrillar proteins to protect against postischemic cardiac dysfunction.

PubMed

Manning, Janet R; Perkins, Sarah O; Sinclair, Elizabeth A; Gao, Xiaoqian; Zhang, Yu; Newman, Gilbert; Pyle, W Glen; Schultz, Jo El J

2013-05-15

Among its many biological roles, fibroblast growth factor-2 (FGF2) acutely protects the heart from dysfunction associated with ischemia/reperfusion (I/R) injury. Our laboratory has demonstrated that this is due to the activity of the low molecular weight (LMW) isoform of FGF2 and that FGF2-mediated cardioprotection relies on the activity of protein kinase C (PKC); however, which PKC isoforms are responsible for LMW FGF2-mediated cardioprotection, and their downstream targets, remain to be elucidated. To identify the PKC pathway(s) that contributes to postischemic cardiac recovery by LMW FGF2, mouse hearts expressing only LMW FGF2 (HMWKO) were bred to mouse hearts not expressing PKCα (PKCαKO) or subjected to a selective PKCε inhibitor (εV(1-2)) before and during I/R. Hearts only expressing LMW FGF2 showed significantly improved postischemic recovery of cardiac function following I/R (P < 0.05), which was significantly abrogated in the absence of PKCα (P < 0.05) or presence of PKCε inhibition (P < 0.05). Hearts only expressing LMW FGF2 demonstrated differences in actomyosin ATPase activity as well as increases in the phosphorylation of troponin I and T during I/R compared with wild-type hearts; several of these effects were dependent on PKCα activity. This evidence indicates that both PKCα and PKCε play a role in LMW FGF2-mediated protection from cardiac dysfunction and that PKCα signaling to the contractile apparatus is a key step in the mechanism of LMW FGF2-mediated protection against myocardial dysfunction.

Cardioactive and vasoactive effects of natural wild honey against cardiac malperformance induced by hyperadrenergic activity.

PubMed

Rakha, Miran K; Nabil, Zohour I; Hussein, Aida A

2008-03-01

Induction of hyperadrenergic activity was experimentally achieved in urethane-anesthetized rats using epinephrine (adrenaline). Acute administration of epinephrine (100 microg/kg) for 2 hours induced several cardiac disorders and vasomotor dysfunction. Pretreatment with natural wild honey (5 g/kg) for 1 hour prior to the injection with epinephrine (100 mug/kg) protected the anesthetized normal rats from the incidence of epinephrine-induced cardiac disorders and vasomotor dysfunction. Moreover, posttreatment with natural wild honey (5 g/kg) following the injection with epinephrine (100 microg/kg) for 1 hour showed several ameliorative outcomes to the electrocardiographic parameters and vasomotor dysfunction of anesthetized stressed rats. Furthermore, natural wild honey preserved the positive inotropic effect of epinephrine in both cases. Also, the total antioxidant capacity (AOC) of natural wild honey was found to be very pronounced. Levels of both reduced glutathione and ascorbic acid (vitamin C) were considered relatively high in natural wild honey. Activity of superoxide dismutase (SOD) was also high, whereas catalase activity was relatively low, especially when compared to the value of SOD activity. It would appear from the results of the present study that natural wild honey may exert its cardioprotective and therapeutic effects against epinephrine-induced cardiac disorders and vasomotor dysfunction directly, via its very pronounced total AOC and its great wealth of both enzymatic and nonenzymatic antioxidants involved in cardiovascular defense mechanisms, besides its substantial quantities of mineral elements such as magnesium, sodium, and chlorine, and/or indirectly, via the enhancement of the endothelium-derived relaxing factor nitric oxide release through the influence of ascorbic acid (vitamin C).

Mesenchymal stem cells and cardiac repair

PubMed Central

Nesselmann, Catharina; Ma, Nan; Bieback, Karen; Wagner, Wolfgang; Ho, Anthony; Konttinen, Yrjö T; Zhang, Hao; Hinescu, Mihail E; Steinhoff, Gustav

2008-01-01

Accumulating clinical and experimental evidence indicates that mesenchymal stem cells (MSCs) are promising cell types in the treatment of cardiac dysfunction. They may trigger production of reparative growth factors, replace damaged cells and create an environment that favours endogenous cardiac repair. However, identifying mechanisms which regulate the role of MSCs in cardiac repair is still at work. To achieve the maximal clinical benefits, ex vivo manipulation can further enhance MSC therapeutic potential. This review focuses on the mechanism of MSCs in cardiac repair, with emphasis on ex vivo manipulation. PMID:18684237

Modulation of Hypercholesterolemia-Induced Oxidative/Nitrative Stress in the Heart

PubMed Central

Sárközy, Márta; Pipicz, Márton; Dux, László; Csont, Tamás

2016-01-01

Hypercholesterolemia is a frequent metabolic disorder associated with increased risk for cardiovascular morbidity and mortality. In addition to its well-known proatherogenic effect, hypercholesterolemia may exert direct effects on the myocardium resulting in contractile dysfunction, aggravated ischemia/reperfusion injury, and diminished stress adaptation. Both preclinical and clinical studies suggested that elevated oxidative and/or nitrative stress plays a key role in cardiac complications induced by hypercholesterolemia. Therefore, modulation of hypercholesterolemia-induced myocardial oxidative/nitrative stress is a feasible approach to prevent or treat deleterious cardiac consequences. In this review, we discuss the effects of various pharmaceuticals, nutraceuticals, some novel potential pharmacological approaches, and physical exercise on hypercholesterolemia-induced oxidative/nitrative stress and subsequent cardiac dysfunction as well as impaired ischemic stress adaptation of the heart in hypercholesterolemia. PMID:26788247

The left heart can only be as good as the right heart: determinants of function and dysfunction of the right ventricle.

PubMed

Magder, Sheldon

2007-12-01

Discussions of cardiac physiology and pathophysiology most often emphasise the function of the left heart. However, right heart dysfunction plays an important role in critically ill patients and is often not recognised. This is probably because the role of the right ventricle is for generating flow more than pressure, and flow is not easy to evaluate. Of importance, when right ventricular function limits cardiac output, assessing left ventricular function gives little indication of overall cardiac performance. It has recently become evident that the right ventricle also has different genetic origins and characteristics from the left ventricle. The right and left ventricles interact through series effects, diastolic interactions and systolic interactions. The mechanisms of these, and their physiological and pathological significance are discussed.

N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure.

PubMed

Giam, Beverly; Chu, Po-Yin; Kuruppu, Sanjaya; Smith, A Ian; Horlock, Duncan; Kiriazis, Helen; Du, Xiao-Jun; Kaye, David M; Rajapakse, Niwanthi W

2016-04-01

Oxidative stress plays a central role in the pathogenesis of heart failure. We aimed to determine whether the antioxidantN-acetylcysteine can attenuate cardiac fibrosis and remodeling in a mouse model of heart failure. Minipumps were implanted subcutaneously in wild-type mice (n = 20) and mice with cardiomyopathy secondary to cardiac specific overexpression of mammalian sterile 20-like kinase 1 (MST-1;n = 18) to administerN-acetylcysteine (40 mg/kg per day) or saline for a period of 8 weeks. At the end of this period, cardiac remodeling and function was assessed via echocardiography. Fibrosis, oxidative stress, and expression of collagen types I andIIIwere quantified in heart tissues. Cardiac perivascular and interstitial fibrosis were greater by 114% and 209%, respectively, inMST-1 compared to wild type (P ≤ 0.001). InMST-1 mice administeredN-acetylcysteine, perivascular and interstitial fibrosis were 40% and 57% less, respectively, compared to those treated with saline (P ≤ 0. 03). Cardiac oxidative stress was 119% greater inMST-1 than in wild type (P < 0.001) andN-acetylcysteine attenuated oxidative stress inMST-1 by 42% (P = 0.005). These data indicate thatN-acetylcysteine can blunt cardiac fibrosis and related remodeling in the setting of heart failure potentially by reducing oxidative stress. This study provides the basis to investigate the role ofN-acetylcysteine in chronic heart failure. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Dual ACE-inhibition and angiotensin II AT1 receptor antagonism with curcumin attenuate maladaptive cardiac repair and improve ventricular systolic function after myocardial infarctionin rat heart.

PubMed

Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Ijaz Shah, Ahmed; Garner, Ron; Zhao, Zhi-Qing

2015-01-05

Curcumin has been shown to improve cardiac function by reducing degradation of extracellular matrix and inhibiting synthesis of collagen after ischemia. This study tested the hypothesis that attenuation of maladaptive cardiac repair with curcumin is associated with a dual ACE-inhibition and angiotensin II AT1 receptor antagonism after myocardial infarction. Sprague-Dawley rats were subjected to 45min ischemia followed by 7 and 42 days of reperfusion, respectively. Curcumin was fed orally at a dose of 150mg/kg/day only during reperfusion. Relative to the control animals, dietary treatment with curcumin significantly reduced levels of ACE and AT1 receptor protein as determined by Western blot assay, coincident with less locally-expressed ACE and AT1 receptor in myocardium and coronary vessels as identified by immunohistochemistry. Along with this inhibition, curcumin significantly increased protein level of AT2 receptor and its expression compared with the control. As evidenced by less collagen deposition in fibrotic myocardium, curcumin also reduced the extent of collagen-rich scar and increased mass of viable myocardium detected by Masson׳s trichrome staining. Echocardiography showed that the wall thickness of the infarcted anterior septum in the curcumin group was significantly greater than that in the control group. Cardiac contractile function was improved in the curcumin treated animals as measured by fraction shortening and ejection fraction. In cultured cardiac muscle cells, curcumin inhibited oxidant-induced AT1 receptor expression and promoted cell survival. These results suggest that curcumin attenuates maladaptive cardiac repair and enhances cardiac function, primarily mediated by a dual ACE-inhibition and AT1 receptor antagonism after myocardial infarction. Copyright © 2014 Elsevier B.V. All rights reserved.

A Green Algae Mixture of Scenedesmus and Schroederiella Attenuates Obesity-Linked Metabolic Syndrome in Rats

PubMed Central

Kumar, Senthil Arun; Magnusson, Marie; Ward, Leigh C.; Paul, Nicholas A.; Brown, Lindsay

2015-01-01

This study investigated the responses to a green algae mixture of Scenedesmus dimorphus and Schroederiella apiculata (SC) containing protein (46.1% of dry algae), insoluble fibre (19.6% of dry algae), minerals (3.7% of dry algae) and omega-3 fatty acids (2.8% of dry algae) as a dietary intervention in a high carbohydrate, high fat diet-induced metabolic syndrome model in four groups of male Wistar rats. Two groups were fed with a corn starch diet containing 68% carbohydrates as polysaccharides, while the other two groups were fed a diet high in simple carbohydrates (fructose and sucrose in food, 25% fructose in drinking water, total 68%) and fats (saturated and trans fats from beef tallow, total 24%). High carbohydrate, high fat-fed rats showed visceral obesity with hypertension, insulin resistance, cardiovascular remodelling, and nonalcoholic fatty liver disease. SC supplementation (5% of food) lowered total body and abdominal fat mass, increased lean mass, and attenuated hypertension, impaired glucose and insulin tolerance, endothelial dysfunction, infiltration of inflammatory cells into heart and liver, fibrosis, increased cardiac stiffness, and nonalcoholic fatty liver disease in the high carbohydrate, high fat diet-fed rats. This study suggests that the insoluble fibre or protein in SC helps reverse diet-induced metabolic syndrome. PMID:25875119

Examining a role for PKG Iα oxidation in the pathogenesis of cardiovascular dysfunction during diet-induced obesity.

PubMed

Rudyk, Olena; Eaton, Philip

2017-09-01

Protein kinase G (PKG) Iα is the end-effector kinase that mediates nitric oxide (NO)-dependent and oxidant-dependent vasorelaxation to maintain blood pressure during health. A hallmark of cardiovascular disease is attenuated NO production, which in part is caused by NO Synthase (NOS) uncoupling, which in turn increases oxidative stress because of superoxide generation. NOS uncoupling promotes PKG Iα oxidation to the interprotein disulfide state, likely mediated by superoxide-derived hydrogen peroxide, and because the NO-cyclic guanosine monophosphate (cGMP) pathway otherwise negatively regulates oxidation of the kinase to its active disulfide dimeric state. Diet-induced obesity is associated with NOS uncoupling, which may in part contribute to the associated cardiovascular dysfunction due to exacerbated PKG Iα disulfide oxidation to the disulfide state. This is a rational hypothesis because PKG Iα oxidation is known to significantly contribute to heart failure that arises from chronic myocardial oxidative stress. Bovine arterial endothelial cells (BAECs) or smooth muscle cells (SMCs) were exposed to drugs that uncouple NOS. These included 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) which promotes its S-glutathiolation, 4-diamino-6-hydroxy-pyrimidine (DAHP) which inhibits guanosine-5'-triphosphate-cyclohydrolase 2 to prevent BH 4 synthesis or methotrexate (MTX) which inhibits the regeneration of BH 4 from BH 2 by dihydrofolate reductase. While all the drugs mentioned above induced robust PKG Iα disulfide dimerization in cells, exposure of BAECs to NOS inhibitor L-NMMA did not. Increased PKG Iα disulfide formation occurred in hearts and aortae from mice treated in vivo with DAHP (10mM in a drinking water for 3 weeks). Redox-dead C42S PKG Iα knock-in (KI) mice developed less pronounced cardiac posterior wall hypertrophy and did not develop cardiac dysfunction, assessed by echocardiography, compared to the wild-type (WT) mice after chronic DAHP treatment. WT or KI mice were then subjected to a diet-induced obesity protocol by feeding them with a high fat Western-type diet (RM 60% AFE) for 27 weeks, which increased body mass, adiposity, plasma leptin, resistin and glucagon levels comparably in each genotype. Obesity-induced hypertension, assessed by radiotelemetry, was mild and transient in the WT, while the basally hypertensive KI mice were resistant to further increases in blood pressure following high fat feeding. Although the obesogenic diet caused mild cardiac dysfunction in the WT but not the KI mice, gross changes in myocardial structure monitored by echocardiography were not apparent in either genotype. The level of cyclic guanosine monophosphate (cGMP) was decreased in the aortae of WT and KI mice following high fat feeding. PKG Iα oxidation was not evident in the hearts of WT mice fed a high fat diet. Despite robust evidence for PKG Iα oxidation during NOS uncoupling in cell models, it is unlikely that PKG Iα oxidation occurs to a significant extent in vivo during diet-induced obesity and so is unlikely to mediate the associated cardiovascular dysfunction. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Combined atorvastatin and coenzyme Q10 improve the left ventricular function in isoproterenol-induced heart failure in rat.

PubMed

Garjani, Alireza; Andalib, Sina; Biabani, Sajjad; Soraya, Hamid; Doustar, Yousef; Garjani, Afagh; Maleki-Dizaji, Nasrin

2011-09-01

The effect of atorvastatin on cardiac remodeling, function, and homodynamic parameters in isoproterenol-induced heart failure was evaluated in the present study. A subcutaneous injection of isoproterenol (5mg/kg/day) for 10 days was used for the induction of heart failure. Isoproterenol administration produced intensive myocardial necrosis and fibrosis with a significant decrease in the arterial pressure indices, heart rate, contractility (LVdP/dt(max)) and relaxation (LVdP/dt(min)), but an increase in the left ventricular end-diastolic pressure. Rats were randomly assigned to control, treatment with only atorvastatin, and treatment with atorvastatin plus coenzyme Q10. Histopathological analysis showed a marked attenuation of myocyte necrosis and interstitial fibrosis in all atorvastatin treated groups (P<0.001). A low dose of atorvastatin (5mg/kg/day) significantly improved the left ventricular systolic pressure, contractility and relaxation (P<0.01). On the contrary, a high dose of atorvastatin (20mg/kg/day) worsened the isoproterenol-induced left ventricular dysfunction by a further reduction of LVdP/dt(max) from +2780 ± 94 to +1588 ± 248 (mmHg/s; P<0.01) and LVdP/dt(min) from -2007 ± 190 to -2939 ± 291 (mmHg/s; P<0.05). Co-administration of coenzyme Q10 with atorvastatin reversed the hemodynamic depression and the left ventricular dysfunction to a high level (P<0.001). There was a lower level of LVEDPs in the atorvastatin+coenzyme Q10 treated groups (3 ± 1 and 4 ± 1.4 versus 8 ± 3.5 and 14 ± 3.6 mmHg, respectively), thereby suggesting improvement in the myocardial stiffness by the combined coenzyme Q10 and atorvastatin treatment. The atorvastatin therapy attenuated myocardial necrosis and fibrosis in isoproterenol-induced heart failure. However, a high dose of the drug considerably worsened the left ventricular dysfunction and hemodynamic depression, which was reversed by coenzyme Q10 co-administration. Copyright © 2011 Elsevier B.V. All rights reserved.

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

PubMed Central

Lee, Eunjo; Song, Min-ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung

2016-01-01

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats. PMID:27610034

Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

PubMed

Lee, Eunjo; Song, Min-Ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

2016-09-01

CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1

PubMed Central

Gomes, Katia M.S.; Bechara, Luiz R.G.; Lima, Vanessa M.; Ribeiro, Márcio A.C.; Campos, Juliane C.; Dourado, Paulo M.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

2015-01-01

Background/Objectives We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy is unknown and should be established to determine the optimal time window for drug treatment. Methods Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H2O2 release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats. Results We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H2O2 release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy. PMID:25464432

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

PubMed Central

Chung, Ha-Yeun; Kollmey, Anna S.; Schrepper, Andrea; Kohl, Matthias; Bläss, Markus F.; Stehr, Sebastian N.; Lupp, Amelie; Gräler, Markus H.; Claus, Ralf A.

2017-01-01

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine. PMID:28420138

Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction.

PubMed

Chung, Ha-Yeun; Kollmey, Anna S; Schrepper, Andrea; Kohl, Matthias; Bläss, Markus F; Stehr, Sebastian N; Lupp, Amelie; Gräler, Markus H; Claus, Ralf A

2017-04-15

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid sphingomyelinase (SMPD1)-the principal regulator for rapid and transient generation of the lipid mediator ceramide-is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1 +/+ as well as SMPD1 -/- animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1 -/- littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.

Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy.

PubMed

Guo, Rui; Zhang, Yingmei; Turdi, Subat; Ren, Jun

2013-08-01

Adiponectin (APN), an adipose-derived adipokine, offers cardioprotective effects although the precise mechanism of action remains unclear. This study was designed to examine the role of APN in high fat diet-induced obesity and cardiac pathology. Adult C57BL/6 wild-type and APN knockout mice were fed a low or high fat diet for 22weeks. After 40day feeding, mice were treated with 2mg/kg rapamycin or vehicle every other day for 42days on respective fat diet. Cardiomyocyte contractile and Ca(2+) transient properties were evaluated. Myocardial function was evaluated using echocardiography. Dual energy X-ray absorptiometry was used to evaluate adiposity. Energy expenditure, metabolic rate and physical activity were monitored using a metabolic cage. Lipid deposition, serum triglyceride, glucose tolerance, markers of autophagy and fatty acid metabolism including LC3, p62, Beclin-1, AMPK, mTOR, fatty acid synthase (FAS) were evaluated. High fat diet intake induced obesity, systemic glucose intolerance, cardiac hypertrophy, dampened metabolic ability, cardiac and intracellular Ca(2+) derangements, the effects of which were accentuated by APN knockout. Furthermore, APN deficiency augmented high fat diet-induced upregulation in the autophagy adaptor p62 and the decline in AMPK without affecting high fat diet-induced decrease in LC3II and LC3II-to-LC3I ratio. Neither high fat diet nor APN deficiency altered Beclin-1. Interestingly, rapamycin negated high fat diet-induced/APN-deficiency-accentuated obesity, cardiac hypertrophy and contractile dysfunction as well as AMPK dephosphorylation, mTOR phosphorylation and p62 buildup. Our results collectively revealed that APN deficiency may aggravate high fat diet-induced obesity, metabolic derangement, cardiac hypertrophy and contractile dysfunction possibly through decreased myocardial autophagy. Copyright © 2013 Elsevier B.V. All rights reserved.

Cardiac Auscultation for Noncardiologists: Application in Cardiac Rehabilitation Programs: PART I: PATIENTS AFTER ACUTE CORONARY SYNDROMES AND HEART FAILURE.

PubMed

Compostella, Leonida; Compostella, Caterina; Russo, Nicola; Setzu, Tiziana; Iliceto, Sabino; Bellotto, Fabio

2017-09-01

During outpatient cardiac rehabilitation after an acute coronary syndrome or after an episode of congestive heart failure, a careful, periodic evaluation of patients' clinical and hemodynamic status is essential. Simple and traditional cardiac auscultation could play a role in providing useful prognostic information.Reduced intensity of the first heart sound (S1), especially when associated with prolonged apical impulse and the appearance of added sounds, may help identify left ventricular (LV) dysfunction or conduction disturbances, sometimes associated with transient myocardial ischemia. If both S1 and second heart sound (S2) are reduced in intensity, a pericardial effusion may be suspected, whereas an increased intensity of S2 may indicate increased pulmonary artery pressure. The persistence of a protodiastolic sound (S3) after an acute coronary syndrome is an indicator of severe LV dysfunction and a poor prognosis. In patients with congestive heart failure, the association of an S3 and elevated heart rate may indicate impending decompensation. A presystolic sound (S4) is often associated with S3 in patients with LV failure, although it could also be present in hypertensive patients and in patients with an LV aneurysm. Careful evaluation of apical systolic murmurs could help identifying possible LV dysfunction or mitral valve pathology, and differentiate them from a ruptured papillary muscle or ventricular septal rupture. Friction rubs after an acute myocardial infarction, due to reactive pericarditis or Dressler syndrome, are often associated with a complicated clinical course.During cardiac rehabilitation, periodic cardiac auscultation may provide useful information about the clinical-hemodynamic status of patients and allow timely detection of signs, heralding possible complications in an efficient and low-cost manner.

Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine

PubMed Central

Faller, Kiterie M E; Atzler, Dorothee; McAndrew, Debra J; Zervou, Sevasti; Whittington, Hannah J; Simon, Jillian N; Aksentijevic, Dunja; ten Hove, Michiel; Choe, Chi-un; Isbrandt, Dirk; Casadei, Barbara; Schneider, Jurgen E; Neubauer, Stefan; Lygate, Craig A

2018-01-01

Abstract Aims Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases. PMID:29236952

Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: Role of autophagy

PubMed Central

Guo, Rui; Zhang, Yingmei; Turdi, Subat; Ren, Jun

2013-01-01

Adiponectin (APN), an adipose-derived adipokine, offers cardioprotective effects although the precise mechanism of action remains unclear. This study was designed to examine the role of APN in high fat diet-induced obesity and cardiac pathology. Adult C57BL/6 wild-type and APN knockout mice were fed a low or high fat diet for 22 weeks. After 40 day feeding, mice were treated with 2 mg/kg rapamycin or vehicle every other day for 42 days on respective fat diet. Cardiomyocyte contractile and Ca2+ transient properties were evaluated. Myocardial function was evaluated using echocardiography. Dual energy X-ray absorptiometry was used to evaluate adiposity. Energy expenditure, metabolic rate and physical activity were monitored using a metabolic cage. Lipid deposition, serum triglyceride, glucose tolerance, markers of autophagy and fatty acid metabolism including LC3, p62, Beclin-1, AMPK, mTOR, fatty acid synthase (FAS) were evaluated. High fat diet intake induced obesity, systemic glucose intolerance, cardiac hypertrophy, dampened metabolic ability, cardiac and intracellular Ca2+ derangements, the effects of which were accentuated by APN knockout. Furthermore, APN deficiency augmented high fat diet-induced upregulation in the autophagy adaptor p62 and the decline in AMPK without affecting high fat diet-induced decrease in LC3II and LC3II-to-LC3I ratio. Neither high fat diet nor APN deficiency altered Beclin-1. Interestingly, rapamycin negated high fat diet-induced/APN-deficiency-accentuated obesity, cardiac hypertrophy and contractile dysfunction as well as AMPK dephosphorylation, mTOR phosphorylation and p62 buildup. Our results collectively revealed that APN deficiency may aggravate high fat diet-induced obesity, metabolic derangement, cardiac hypertrophy and contractile dysfunction possibly through decreased myocardial autophagy. PMID:23524376

Biomarkers of Myocardial Stress and Fibrosis as Predictors of Mode of Death in Patients with Chronic Heart Failure

PubMed Central

Ahmad, Tariq; Fiuzat, Mona; Neely, Ben; Neely, Megan; Pencina, Michael J.; Kraus, William E.; Zannad, Faiez; Whellan, David J.; Donahue, Mark; Piña, Ileana L.; Adams, Kirkwood; Kitzman, Dalane W.; O’Connor, Christopher M.; Felker, G. Michael

2014-01-01

Objective To determine whether biomarkers of myocardial stress and fibrosis improve prediction of mode of death in patients with chronic heart failure. Background The two most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of mode of death may facilitate treatment decisions. The relationship between NT-proBNP, galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown. Methods HF-ACTION was a randomized controlled trial of exercise training vs. usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (LVEF<35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause-specific Cox-proportional hazards modeling, and interaction testing was used to measure differential association between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP. Results After a median follow up of 2.5 years, there were 155 deaths: 49 from pump failure 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk of both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure. Conclusions Clinical predictors along with NT-proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers. PMID:24952693

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants.

PubMed

Fernandes, T; Soci, U P R; Oliveira, E M

2011-09-01

Among the molecular, biochemical and cellular processes that orchestrate the development of the different phenotypes of cardiac hypertrophy in response to physiological stimuli or pathological insults, the specific contribution of exercise training has recently become appreciated. Physiological cardiac hypertrophy involves complex cardiac remodeling that occurs as an adaptive response to static or dynamic chronic exercise, but the stimuli and molecular mechanisms underlying transduction of the hemodynamic overload into myocardial growth are poorly understood. This review summarizes the physiological stimuli that induce concentric and eccentric physiological hypertrophy, and discusses the molecular mechanisms, sarcomeric organization, and signaling pathway involved, also showing that the cardiac markers of pathological hypertrophy (atrial natriuretic factor, β-myosin heavy chain and α-skeletal actin) are not increased. There is no fibrosis and no cardiac dysfunction in eccentric or concentric hypertrophy induced by exercise training. Therefore, the renin-angiotensin system has been implicated as one of the regulatory mechanisms for the control of cardiac function and structure. Here, we show that the angiotensin II type 1 (AT1) receptor is locally activated in pathological and physiological cardiac hypertrophy, although with exercise training it can be stimulated independently of the involvement of angiotensin II. Recently, microRNAs (miRs) have been investigated as a possible therapeutic approach since they regulate the translation of the target mRNAs involved in cardiac hypertrophy; however, miRs in relation to physiological hypertrophy have not been extensively investigated. We summarize here profiling studies that have examined miRs in pathological and physiological cardiac hypertrophy. An understanding of physiological cardiac remodeling may provide a strategy to improve ventricular function in cardiac dysfunction.

Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity

PubMed Central

Lovelock, Joshua D.; Monasky, Michelle M.; Jeong, Euy-Myoung; Lardin, Harvey A.; Liu, Hong; Patel, Bindiya G.; Taglieri, Domenico M.; Gu, Lianzhi; Kumar, Praveen; Pokhrel, Narayan; Zeng, Dewan; Belardinelli, Luiz; Sorescu, Dan; Solaro, R. John; Dudley, Samuel C.

2012-01-01

Rationale Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (INa), reducing the net cytosolic Ca2+ efflux. Objective Oxidative stress in the DOCA-salt model may increase late INa resulting in diastolic dysfunction amenable to treatment with ranolazine. Methods and Results Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E′, sham 31.9 ± 2.8, sham+ranolazine 30.2 ± 1.9, DOCA-salt 41.8 ± 2.6, and DOCA-salt+ranolazine 31.9 ± 2.6, p = 0.018). The end diastolic pressure volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham 0.16 ± 0.01 vs. sham+ranolazine 0.18 ± 0.01 vs. DOCA-salt 0.23 ± 0.2 vs. DOCA-salt+ranolazine 0.17 ± 0.01 mm Hg/L, p < 0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt 0.18 ± 0.02, DOCA-salt + ranolazine 0.13 ± 0.01, Sham 0.11 ± 0.01, Sham + ranolazine 0.09 ± 0.02 s, p = 0.0004). Neither late INa nor the Ca2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca2+ response and cross-bridge kinetics. Conclusions Therefore, diastolic dysfunction could be reversed by ranolazine, likely resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus. PMID:22343711

Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.

PubMed

Lovelock, Joshua D; Monasky, Michelle M; Jeong, Euy-Myoung; Lardin, Harvey A; Liu, Hong; Patel, Bindiya G; Taglieri, Domenico M; Gu, Lianzhi; Kumar, Praveen; Pokhrel, Narayan; Zeng, Dewan; Belardinelli, Luiz; Sorescu, Dan; Solaro, R John; Dudley, Samuel C

2012-03-16

Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (I(Na)), reducing the net cytosolic Ca(2+) efflux. Oxidative stress in the DOCA-salt model may increase late I(Na), resulting in diastolic dysfunction amenable to treatment with ranolazine. Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E':sham, 31.9 ± 2.8, sham+ranolazine, 30.2 ± 1.9, DOCA-salt, 41.8 ± 2.6, and DOCA-salt+ranolazine, 31.9 ± 2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16 ± 0.01 versus sham+ranolazine, 0.18 ± 0.01 versus DOCA-salt, 0.23 ± 0.2 versus DOCA-salt+ranolazine, 0.17 ± 0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18 ± 0.02, DOCA-salt+ranolazine, 0.13 ± 0.01, sham, 0.11 ± 0.01, sham+ranolazine, 0.09 ± 0.02 seconds; P=0.0004). Neither late I(Na) nor the Ca(2+) transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca(2+) with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca(2+) response and cross-bridge kinetics. Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.

Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model.

PubMed

Hsu, Yu-Juei; Hsu, Shih-Che; Hsu, Chiao-Po; Chen, Yen-Hui; Chang, Yung-Lung; Sadoshima, Junichi; Huang, Shih-Ming; Tsai, Chien-Sung; Lin, Chih-Yuan

2017-02-01

The longevity regulator Sirtuin 1 is an NAD + -dependent histone deacetylase that regulates endoplasmic reticulum stress and influences cardiomyocyte apoptosis during cardiac contractile dysfunction induced by aging. The mechanism underlying Sirtuin 1 function in cardiac contractile dysfunction related to aging has not been completely elucidated. We evaluated cardiac contractile function, endoplasmic reticulum stress, apoptosis, and oxidative stress in 6- and 12month-old cardiac-specific Sirtuin 1 knockout (Sirt1 -/- ) and control (Sirt1 f/f ) mice using western blotting and immunohistochemistry. Mice were injected with a protein disulphide isomerase inhibitor. For in vitro analysis, cultured H9c2 cardiomyocytes were exposed to either a Sirtuin 1 inhibitor or activator, with or without a mitochondrial inhibitor, to evaluate the effects of Sirtuin 1 on endoplasmic reticulum stress, nitric oxide synthase expression, and apoptosis. The effects of protein disulphide isomerase inhibition on oxidative stress and ER stress-related apoptosis were also investigated. Compared with 6-month-old Sirt1 f/f mice, marked impaired contractility was observed in 12-month-old Sirt1 -/- mice. These findings were consistent with increased endoplasmic reticulum stress and apoptosis in the myocardium. Measures of oxidative stress and nitric oxide synthase expression were significantly higher in Sirt1 -/- mice compared with those in Sirt1 f/f mice at 6months. In vitro experiments revealed increased endoplasmic reticulum stress-mediated apoptosis in H9c2 cardiomyocytes treated with a Sirtuin 1 inhibitor; the effects were ameliorated by a Sirtuin 1 activator. Moreover, consistent with the in vitro findings, impaired cardiac contractility was demonstrated in Sirt1 -/- mice injected with a protein disulphide isomerase inhibitor. The present study demonstrates that the aging heart is characterized by contractile dysfunction associated with increased oxidative stress and endoplasmic reticulum stress and Sirtuin 1 might have the ability to protect the aging hearts from the inhibition of endoplasmic reticulum-mediated apoptosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Double valve replacement in a patient with implantable cardioverter defibrillator with severe left ventricular dysfunction.

PubMed

Manjunath, Girish; Rao, Prakash; Prakash, Nagendra; Shivaram, B K

2016-01-01

Recent data from landmark trials suggest that the indications for cardiac pacing and implantable cardioverter defibrillators (ICDs) are set to expand to include heart failure, sleep-disordered breathing, and possibly routine implantation in patients with myocardial infarction and poor ventricular function.[1] This will inevitably result in more patients with cardiac devices undergoing surgeries. Perioperative electromagnetic interference and their potential effects on ICDs pose considerable challenges to the anesthesiologists.[2] We present a case of a patient with automatic ICD with severe left ventricular dysfunction posted for double valve replacement.

Mitochondrial proteome disruption in the diabetic heart through targeted epigenetic regulation at the mitochondrial heat shock protein 70 (mtHsp70) nuclear locus.

PubMed

Shepherd, Danielle L; Hathaway, Quincy A; Nichols, Cody E; Durr, Andrya J; Pinti, Mark V; Hughes, Kristen M; Kunovac, Amina; Stine, Seth M; Hollander, John M

2018-06-01

>99% of the mitochondrial proteome is nuclear-encoded. The mitochondrion relies on a coordinated multi-complex process for nuclear genome-encoded mitochondrial protein import. Mitochondrial heat shock protein 70 (mtHsp70) is a key component of this process and a central constituent of the protein import motor. Type 2 diabetes mellitus (T2DM) disrupts mitochondrial proteomic signature which is associated with decreased protein import efficiency. The goal of this study was to manipulate the mitochondrial protein import process through targeted restoration of mtHsp70, in an effort to restore proteomic signature and mitochondrial function in the T2DM heart. A novel line of cardiac-specific mtHsp70 transgenic mice on the db/db background were generated and cardiac mitochondrial subpopulations were isolated with proteomic evaluation and mitochondrial function assessed. MicroRNA and epigenetic regulation of the mtHsp70 gene during T2DM were also evaluated. MtHsp70 overexpression restored cardiac function and nuclear-encoded mitochondrial protein import, contributing to a beneficial impact on proteome signature and enhanced mitochondrial function during T2DM. Further, transcriptional repression at the mtHsp70 genomic locus through increased localization of H3K27me3 during T2DM insult was observed. Our results suggest that restoration of a key protein import constituent, mtHsp70, provides therapeutic benefit through attenuation of mitochondrial and contractile dysfunction in T2DM. Copyright © 2018 Elsevier Ltd. All rights reserved.

RhoA/ROCK may involve in cardiac hypertrophy induced by experimental hyperthyroidism.

PubMed

Na, Wang; Peng, Guan; Jianping, Zhang; Yanzhong, Chang; Shengjiang, Guan; Li, Chu

2012-10-01

In this study, the role of the RhoA/Rho-kinase (RhoA/ROCK)-signaling pathway in cardiovascular dysfunction associated with hyperthyroidism was examined with the use of fasudil, a Rho-kinase inhibitor. Male Spraque-Dawley rats were treated with l-thyroxine (T(4)) alone, T(4) + low-dose fasudil (2 mg/kg/day) or T(4) + high-dose fasudil (10 mg/kg/day) and compared with control animals. Rats in the T(4) group showed an increase in the ratio of heart weight to body weight, which was ameliorated by fasudil at both low and high doses. Morphometric and hemodynamic parameters were also evaluated and confirmed that fasudil attenuated the cardiac hypertrophy induced by T(4). The extent of phosphorylation of the myosin phosphatase targeting subunit was quantified by Western blotting to evaluate the activity of Rho-kinase in the heart tissue. Both Western blotting and reverse transcriptase-polymerase chain reaction analyses revealed enhancement of Rho-kinase and activator protein 1 activity and reduction of c-FLIP(L) expression in the T(4) group, and this response was inhibited by fasudil in a dose-dependent manner. Furthermore, fasudil inhibited apoptosis induced by T(4) as evidenced by the detection of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and the expressions of bax and bcl-2. These results suggested that the RhoA/ROCK pathway is involved in the cardiac hypertrophy induced by experimental hyperthyroidism. The antagonism of this pathway may thus be useful as an alternative target in the treatment of hyperthyroid heart disease.

Atorvastatin reduces cardiac and adipose tissue inflammation in rats with metabolic syndrome.

PubMed

Yamada, Yuichiro; Takeuchi, Shino; Yoneda, Mamoru; Ito, Shogo; Sano, Yusuke; Nagasawa, Kai; Matsuura, Natsumi; Uchinaka, Ayako; Murohara, Toyoaki; Nagata, Kohzo

2017-08-01

Statins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS). DS/obese rats were treated with atorvastatin (6 or 20mgkg -1 day -1 ) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator-activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obese rats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor-κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obese rats was attenuated and further enhanced, respectively, by atorvastatin treatment. The present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS. Copyright © 2017 Elsevier B.V. All rights reserved.

Intracranial pancreatic islet transplantation increases islet hormone expression in the rat brain and attenuates behavioral dysfunctions induced by MK-801 (dizocilpine).

PubMed

Bloch, Konstantin; Gil-Ad, Irit; Tarasenko, Igor; Vanichkin, Alexey; Taler, Michal; Hornfeld, Shay Henry; Vardi, Pnina; Weizman, Abraham

2015-06-01

The treatment of rodents with non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, MK-801 (dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling. We examined the capacity of syngeneic islets grafted into the cranial subarachnoid cavity to attenuate behavioral dysfunctions in rats exposed to MK-801. Animals were examined in the open field (OF) and the Morris Water Maze (MWM) tests following acute or subchronic administration of MK-801. We found well-vascularized grafted islets expressing insulin, glucagon and somatostatin onto the olfactory bulb and prefrontal cortex. Significantly higher levels of insulin were detected in the hippocampus and prefrontal cortex of transplanted animals compared to the non-transplanted rats. All animals expressed normal peripheral glucose homeostasis for two months after transplantation. OF tests revealed that rats exposed to MK-801 treatment, showed hyper-responsiveness in motility parameters and augmented center field exploration compared to intact controls and these effects were attenuated by the grafted islets. Moreover, in the MWM, the rats treated with MK-801 showed impairment of spatial memory that were partially corrected by the grafted islets. In conclusion, intracranial islet transplantation leads to the expression of islet hormones in the brain and attenuates behavioral and cognitive dysfunctions in rats exposed to MK-801 administration without altering the peripheral glucose homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.