Exercise training improves cardiac function in infarcted rabbits: involvement of autophagic function and fatty acid utilization.

PubMed

Chen, Ching-Yi; Hsu, Hsiu-Ching; Lee, Bai-Chin; Lin, Hung-Ju; Chen, Ying-Hsien; Huang, Hui-Chun; Ho, Yi-Lwun; Chen, Ming-Fong

2010-04-01

To explore whether exercise can improve cardiac function in a post-myocardial infarction (MI) rabbit model and to determine contributing factors in the left ventricle (LV). Adult male New Zealand White rabbits (2.5-3 kg) underwent MI by ligation of the left anterior descending coronary artery. For 8 weeks after surgery, sham-operated, and post-MI rabbits were housed under sedentary conditions or assigned to a 4-week treadmill exercise protocol at a speed of 1.0 km/h for 30 min 5 days per week, then sacrificed. The non-infarcted region of the LV was harvested for further analysis. MI decreased left ventricular ejection fraction (LVEF) and increased thiobarbituric acid reactive substances (TBARS) generation in the LV. Exercise improved the cardiac function of MI rabbits. Left ventricular LC3II/LC3I (microtubule-associated protein light chain 3) in the MI group was 2.1-fold higher than that of the sham group, exercise significantly decreased LC3II/LC3I in the MI group. MI down-regulated the expression of heart-type fatty acid binding protein (h-FABP), and exercise up-regulated h-FABP. In addition, LVEF had a significantly positive correlation with h-FABP and a negative correlation with LC3II/LC3I. Exercise induced change in autophagic function and fatty acid utilization may contribute to the improvement in ventricular function in the infarcted heart.

Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism.

PubMed

Sun, Dan; Yang, Fei

2017-04-29

To investigate whether metformin can improve the cardiac function through improving the mitochondrial function in model of heart failure after myocardial infarction. Male C57/BL6 mice aged about 8 weeks were selected and the anterior descending branch was ligatured to establish the heart failure model after myocardial infarction. The cardiac function was evaluated via ultrasound after 3 days to determine the modeling was successful, and the mice were randomly divided into two groups. Saline group (Saline) received the intragastric administration of normal saline for 4 weeks, and metformin group (Met) received the intragastric administration of metformin for 4 weeks. At the same time, Shame group (Sham) was set up. Changes in cardiac function in mice were detected at 4 weeks after operation. Hearts were taken from mice after 4 weeks, and cell apoptosis in myocardial tissue was detected using TUNEL method; fresh mitochondria were taken and changes in oxygen consumption rate (OCR) and respiratory control rate (RCR) of mitochondria in each group were detected using bio-energy metabolism tester, and change in mitochondrial membrane potential (MMP) of myocardial tissue was detected via JC-1 staining; the expressions and changes in Bcl-2, Bax, Sirt3, PGC-1α and acetylated PGC-1α in myocardial tissue were detected by Western blot. RT-PCR was used to detect mRNA levels in Sirt3 in myocardial tissues. Metformin improved the systolic function of heart failure model rats after myocardial infarction and reduced the apoptosis of myocardial cells after myocardial infarction. Myocardial mitochondrial respiratory function and membrane potential were decreased after myocardial infarction, and metformin treatment significantly improved the mitochondrial respiratory function and mitochondrial membrane potential; Metformin up-regulated the expression of Sirt3 and the activity of PGC-1α in myocardial tissue of heart failure after myocardial infarction. Metformin decreases the

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

Simvastatin reduces wasting and improves cardiac function as well as outcome in experimental cancer cachexia.

PubMed

Palus, Sandra; von Haehling, Stephan; Flach, Valerie C; Tschirner, Anika; Doehner, Wolfram; Anker, Stefan D; Springer, Jochen

2013-10-09

Chronic inflammation is common in cancer cachexia (CC) and directly involved in the atrophy seen in this condition. Recently, several groups have described a form of cardiomyopathy in CC animal models. Hence, we investigated the effect of simvastatin with its known anti-inflammatory and cardioprotective effects in a rat model of CC. Juvenile Wister Han rats (weight approx. 200 g) were inoculated with Yoshida AH-130 hepatoma cells and treated once daily with 0.1, 1, 10 or 20 mg/kg/d simvastatin or placebo for 14 days. Body weight and body composition (NMR) were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and day 11. Tumour-bearing, placebo-treated rats lost 47.9±3.8 g of their initial body weight. Treatment with 0.1, 1, 10 or 20 mg/kg/d simvastatin significantly reduced wasting by 39.6%, 47.6%, 28.5% and 35.4%, respectively (all p<0.05 vs. placebo). This was mainly due to reduced atrophy of lean mass, i.e. muscle mass. Cardiac function was significantly improved, e.g. cardiac output (untreated sham: 78.9 mL/min) was severely impaired in tumour-bearing rats (42.4 mL/min) and improved by 1, 10 or 20 mg/kg/d simvastatin (62.2, 59.0 and 57.0 mL/min, respectively, all p<0.05 vs. placebo). Most importantly, 10 or 20 mg/kg/d simvastatin reduced mortality (HR:0.16, 95%CI:0.04-0.76, p=0.021 and HR:0.16, 95%CI:0.03-0.72, p=0.017 vs placebo, respectively). Simvastatin attenuated loss of body weight as well as muscle mass and improved cardiac function leading to improved survival in this CC model. Simvastatin may be beneficial in a clinical setting to treat CC. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Long-term wheel running compromises diaphragm function but improves cardiac and plantarflexor function in the mdx mouse

PubMed Central

Acosta, Pedro; Sleeper, Meg M.; Barton, Elisabeth R.; Sweeney, H. Lee

2013-01-01

Dystrophin-deficient muscles suffer from free radical injury, mitochondrial dysfunction, apoptosis, and inflammation, among other pathologies that contribute to muscle fiber injury and loss, leading to wheelchair confinement and death in the patient. For some time, it has been appreciated that endurance training has the potential to counter many of these contributing factors. Correspondingly, numerous investigations have shown improvements in limb muscle function following endurance training in mdx mice. However, the effect of long-term volitional wheel running on diaphragm and cardiac function is largely unknown. Our purpose was to determine the extent to which long-term endurance exercise affected dystrophic limb, diaphragm, and cardiac function. Diaphragm specific tension was reduced by 60% (P < 0.05) in mice that performed 1 yr of volitional wheel running compared with sedentary mdx mice. Dorsiflexor mass (extensor digitorum longus and tibialis anterior) and function (extensor digitorum longus) were not altered by endurance training. In mice that performed 1 yr of volitional wheel running, plantarflexor mass (soleus and gastrocnemius) was increased and soleus tetanic force was increased 36%, while specific tension was similar in wheel-running and sedentary groups. Cardiac mass was increased 15%, left ventricle chamber size was increased 20% (diastole) and 18% (systole), and stroke volume was increased twofold in wheel-running compared with sedentary mdx mice. These data suggest that the dystrophic heart may undergo positive exercise-induced remodeling and that limb muscle function is largely unaffected. Most importantly, however, as the diaphragm most closely recapitulates the human disease, these data raise the possibility of exercise-mediated injury in dystrophic skeletal muscle. PMID:23823150

Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress

PubMed Central

Liu, Li; Goldberg, Ira J.

2015-01-01

Elevated cardiac triacylglycerol (TAG) content is traditionally equated with cardiolipotoxicity and suggested to be a culprit in cardiac dysfunction. However, previous work demonstrated that myosin heavy-chain–mediated cardiac-specific overexpression of diacylglycerol transferase 1 (MHC-DGAT1), the primary enzyme for TAG synthesis, preserved cardiac function in two lipotoxic mouse models despite maintaining high TAG content. Therefore, we examined whether increased cardiomyocyte TAG levels due to DGAT1 overexpression led to changes in cardiac TAG turnover rates under normoxia and ischemia-reperfusion conditions. MHC-DGAT1 mice had elevated TAG content and synthesis rates, which did not alter cardiac function, substrate oxidation, or myocardial energetics. MHC-DGAT1 hearts had ischemia-induced lipolysis; however, when a physiologic mixture of long-chain fatty acids was provided, enhanced TAG turnover rates were associated with improved functional recovery from low-flow ischemia. Conversely, exogenous supply of palmitate during reperfusion suppressed elevated TAG turnover rates and impaired recovery from ischemia in MHC-DGAT1 hearts. Collectively, this study shows that elevated TAG content, accompanied by enhanced turnover, does not adversely affect cardiac function and, in fact, provides cardioprotection from ischemic stress. In addition, the results highlight the importance of exogenous supply of fatty acids when assessing cardiac lipid metabolism and its relationship with cardiac function. PMID:25858561

Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction.

PubMed

Miyamoto, Kazutaka; Akiyama, Mizuha; Tamura, Fumiya; Isomi, Mari; Yamakawa, Hiroyuki; Sadahiro, Taketaro; Muraoka, Naoto; Kojima, Hidenori; Haginiwa, Sho; Kurotsu, Shota; Tani, Hidenori; Wang, Li; Qian, Li; Inoue, Makoto; Ide, Yoshinori; Kurokawa, Junko; Yamamoto, Tsunehisa; Seki, Tomohisa; Aeba, Ryo; Yamagishi, Hiroyuki; Fukuda, Keiichi; Ieda, Masaki

2018-01-04

Direct cardiac reprogramming holds great promise for regenerative medicine. We previously generated directly reprogrammed induced cardiomyocyte-like cells (iCMs) by overexpression of Gata4, Mef2c, and Tbx5 (GMT) using retrovirus vectors. However, integrating vectors pose risks associated with insertional mutagenesis and disruption of gene expression and are inefficient. Here, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

N-acetylcysteine neither lowers plasma homocysteine concentrations nor improves brachial artery endothelial function in cardiac transplant recipients.

PubMed

Miner, S E S; Cole, D E C; Evrovski, J; Forrest, Q; Hutchison, S J; Holmes, K; Ross, H J

2002-05-01

N-acetylcysteine is a novel antioxidant that has been reported to reduce plasma homocysteine concentrations and improve endothelial function. Cardiac transplant recipients have a high incidence of coronary endothelial dysfunction and hyperhomocysteinemia, both of which may lead to the development of transplantation coronary artery disease. It was hypothesized that N-acetylcysteine would reduce plasma homocysteine concentrations and improve brachial endothelial function in cardiac transplant recipients. A cohort of stable cardiac transplant recipients was recruited from the outpatient clinic at the Toronto General Hospital, Toronto, Ontario. Brachial artery endothelial functions were studied according to standard techniques to determine flow-mediated dilation of the brachial artery. Plasma homocysteine concentrations were assayed using high performance liquid chromatography with electrochemical detection and pulsed integrated amperometry. After baseline testing, patients were treated in an unblinded fashion with N-acetylcysteine 500 mg/day. After 10 weeks of therapy, patients returned for follow-up endothelial function and homocysteine testing. Thirty-one patients were initially enrolled. Two patients withdrew due to excessive gastrointestinal upset. Two patients did not return for follow-up testing. The remaining 27 patients tolerated the treatment well. At baseline, 85% of the patients had hyperhomocysteinemia (greater than 15 mol/L) with a mean plasma concentration of 18.6 4.7 mol/L. No changes in homocysteine concentrations were seen at follow-up. At baseline, the average flow-mediated dilation was only 4.7 6.3%. No changes were seen at follow-up. Hyperhomocysteinemia and brachial endothelial dysfunction are common in stable cardiac transplant recipients and are unaffected by supplementation with N-acetylcysteine.

Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

PubMed Central

Tolonen, Anna-Maria; Magga, Johanna; Szabó, Zoltán; Viitala, Pirkko; Gao, Erhe; Moilanen, Anne-Mari; Ohukainen, Pauli; Vainio, Laura; Koch, Walter J; Kerkelä, Risto; Ruskoaho, Heikki; Serpi, Raisa

2014-01-01

The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2–positive fibroblasts, while the number of c-kit+ cardiac stem cells and Ki-67+ proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure. PMID:25505600

Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression.

PubMed

Szalay, László; Shimizu, Tomoharu; Suzuki, Takao; Yu, Huang-Ping; Choudhry, Mashkoor A; Schwacha, Martin G; Rue, Loring W; Bland, Kirby I; Chaudry, Irshad H

2006-03-01

Although studies indicate that 17beta-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats ( approximately 300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for approximately 90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-alpha, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-alpha, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17beta-estradiol on organ functions after T-H.

Albumin fiber scaffolds for engineering functional cardiac tissues.

PubMed

Fleischer, Sharon; Shapira, Assaf; Regev, Omri; Nseir, Nora; Zussman, Eyal; Dvir, Tal

2014-06-01

In recent years attempts to engineer contracting cardiac patches were focused on recapitulation of the myocardium extracellular microenvironment. We report here on our work, where for the first time, a three-dimensional cardiac patch was fabricated from albumin fibers. We hypothesized that since albumin fibers' mechanical properties resemble those of cardiac tissue extracellular matrix (ECM) and their biochemical character enables their use as protein carriers, they can support the assembly of cardiac tissues capable of generating strong contraction forces. Here, we have fabricated aligned and randomly oriented electrospun albumin fibers and investigated their structure, mechanical properties, and chemical nature. Our measurements showed that the scaffolds have improved elasticity as compared to synthetic electrospun PCL fibers, and that they are capable of adsorbing serum proteins, such as laminin leading to strong cell-matrix interactions. Moreover, due to the functional groups on their backbone, the fibers can be chemically modified with essential biomolecules. When seeded with rat neonatal cardiac cells the engineered scaffolds induced the assembly of aligned cardiac tissues with high aspect ratio cardiomyocytes and massive actinin striation. Compared to synthetic fibrous scaffolds, cardiac cells cultured within aligned or randomly oriented scaffolds formed functional tissues, exhibiting significantly improved function already on Day 3, including higher beating rate (P = 0.0002 and P < 0.0001, respectively), and higher contraction amplitude (P = 0.009 and P = 0.003, respectively). Collectively, our results suggest that albumin electrospun scaffolds can play a key role in contributing to the ex vivo formation of a contracting cardiac muscle tissue. © 2014 Wiley Periodicals, Inc.

Cardiac function and cognition in older community-dwelling cardiac patients.

PubMed

Eggermont, Laura H P; Aly, Mohamed F A; Vuijk, Pieter J; de Boer, Karin; Kamp, Otto; van Rossum, Albert C; Scherder, Erik J A

2017-11-01

Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies. © 2017 Japanese Psychogeriatric Society.

Nanotized PPARα Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3β-Mediated Mitochondrial Death Pathway.

PubMed

Rana, Santanu; Datta, Ritwik; Chaudhuri, Ratul Datta; Chatterjee, Emeli; Chawla-Sarkar, Mamta; Sarkar, Sagartirtha

2018-05-09

Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPARα). Thereby, we hypothesized that a cardiac-specific induction of PPARα might restore the FAO-related protein expression and resultant energy deficit. In the present study, consequences of PPARα augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. Nanotized PPARα overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPARα ameliorated pathological hypertrophy and improved cardiac function. Augmented PPARα in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPARα with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3β (GSK3β), which upregulated inactive phospho-GSK3β (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPARα-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. Cardiomyocyte-targeted overexpression of a protein of interest (PPARα) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPARα-overexpressed myocardium. PPARα-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPARα during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac

Functional cardiac magnetic resonance microscopy

NASA Astrophysics Data System (ADS)

Brau, Anja Christina Sophie

2003-07-01

The study of small animal models of human cardiovascular disease is critical to our understanding of the origin, progression, and treatment of this pervasive disease. Complete analysis of disease pathophysiology in these animal models requires measuring structural and functional changes at the level of the whole heart---a task for which an appropriate non-invasive imaging method is needed. The purpose of this work was thus to develop an imaging technique to support in vivo characterization of cardiac structure and function in rat and mouse models of cardiovascular disease. Whereas clinical cardiac magnetic resonance imaging (MRI) provides accurate assessment of the human heart, the extension of cardiac MRI from humans to rodents presents several formidable scaling challenges. Acquiring images of the mouse heart with organ definition and fluidity of contraction comparable to that achieved in humans requires an increase in spatial resolution by a factor of 3000 and an increase in temporal resolution by a factor of ten. No single technical innovation can meet the demanding imaging requirements imposed by the small animal. A functional cardiac magnetic resonance microscopy technique was developed by integrating improvements in physiological control, imaging hardware, biological synchronization of imaging, and pulse sequence design to achieve high-quality images of the murine heart with high spatial and temporal resolution. The specific methods and results from three different sets of imaging experiments are presented: (1) 2D functional imaging in the rat with spatial resolution of 175 mum2 x 1 mm and temporal resolution of 10 ms; (2) 3D functional imaging in the rat with spatial resolution of 100 mum 2 x 500 mum and temporal resolution of 30 ms; and (3) 2D functional imaging in the mouse with spatial resolution down to 100 mum2 x 1 mm and temporal resolution of 10 ms. The cardiac microscopy technique presented here represents a novel collection of technologies capable

Intramuscular injection of human umbilical cord-derived mesenchymal stem cells improves cardiac function in dilated cardiomyopathy rats.

PubMed

Mao, Chenggang; Hou, Xu; Wang, Benzhen; Chi, Jingwei; Jiang, Yanjie; Zhang, Caining; Li, Zipu

2017-01-28

Stem cells provide a promising candidate for the treatment of the fatal pediatric dilated cardiomyopathy (DCM). This study aimed to investigate the effects of intramuscular injection of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) on the cardiac function of a DCM rat model. A DCM model was established by intraperitoneal injections of doxorubicin in Sprague-Dawley rats. hUCMSCs at different concentrations or cultured medium were injected via limb skeletal muscles, with blank medium injected as the control. The rats were monitored for 4 weeks, meanwhile BNP, cTNI, VEGF, HGF, GM-CSF, and LIF in the peripheral blood were examined by ELISA, and cardiac function was monitored by echocardiography (Echo-CG). Finally, the expression of IGF-1, HGF, and VEGF in the myocardium was examined by histoimmunochemistry and real-time PCR, and the ultrastructure of the myocardium was examined by electron microscopy. Injection of hUCMSCs markedly improved cardiac function in the DCM rats by significantly elevating left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS). The BNP and cTNI levels in the peripheral blood were reduced by hUCMSCs, while HGF, LIF, GM-CSF, and VEGF were increased by hUCMSCs. Expression of IGF-1, HGF, and VEGF in the myocardium from the DCM rats was significantly increased by hUCMSC injection. Furthermore, hUCMSCs protected the ultrastructure of cardiomyocytes by attenuating mitochondrial swelling and maintaining sarcolemma integrity. Intramuscular injection of UCMSCs can improve DCM-induced cardiac function impairment and protect the myocardium. These effects may be mediated by regulation of relevant cytokines in serum and the myocardium.

Improvement of cardiac function persists long term with medical therapy for left ventricular systolic dysfunction.

PubMed

Chen, David; Chang, Richard; Umakanthan, Branavan; Stoletniy, Liset N; Heywood, J Thomas

2007-09-01

In certain patients with left ventricular (LV) systolic dysfunction, improvements in cardiac function are seen after initiation of medical therapy; however, the long-term stability of ventricular function in such patients is not well described. We retrospectively analyzed 171 patients who had a baseline ejection fraction of 45% or less, a follow-up echocardiogram at 2 to 12 months after initiation of medical therapy, and a final echocardiogram. We found that 48.5% of the patients demonstrated initial improvements in LV function after initiation of medical therapy, and the improvements appear to be sustained (88% of patients) at 44 +/- 21 months follow-up. A nonischemic etiology and younger age were the only independent predictors of change of LV ejection fraction of 10 or more at a mean 8.4 +/- 3.4 months after optimal medical therapy. Our study revealed a trend toward improved long-term survival in individuals with an early improvement in LV ejection fraction with medical therapy, especially in those with sustained improvement.

Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure

PubMed Central

Xu, Bin; Xu, Hao; Cao, Heng; Liu, Xiaoxiao; Qin, Chunhuan; Zhao, Yanzhou; Han, Xiaolin; Li, Hongli

2017-01-01

Emerging evidence has suggested that intermedin (IMD), a novel member of the calcitonin gene-related peptide (CGRP) family, has a wide range of cardioprotective effects. The present study investigated the effects of long-term administration of IMD on cardiac function and sympathetic neural remodeling in heart failure (HF) rats, and studied potential underlying mechanism. HF was induced in rats by myocardial infarction (MI). Male Sprague Dawley rats were randomly assigned to either saline or IMD (0.6 µg/kg/h) treatment groups for 4 weeks post-MI. Another group of sham-operated rats served as controls. Cardiac function was assessed by echocardiography, cardiac catheterization and plasma level of B-type natriuretic peptide (BNP). Cardiac sympathetic neural remodeling was assessed by immunohistochemistical study of tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) immunoreactive nerve fibers. The protein expression levels of nerve growth factor (NGF), TH and GAP43 in the ventricular myocardium were studied by western blotting. Ventricular fibrillation threshold (VFT) was determined to evaluate the incidence of ventricular arrhythmia. Oxidative stress was assessed by detecting the activity of superoxide dismutase and the level of malondialdehyde. Compared with rats administrated with saline, IMD significantly improved cardiac function, decreased the plasma BNP level, attenuated sympathetic neural remodeling, increased VFT and suppressed oxidative stress. In conclusion, these results indicated that IMD prevents ventricle remodeling and improves the performance of a failing heart. In addition, IMD attenuated sympathetic neural remodeling and reduced the incidence of ventricular arrhythmia, which may contribute to its anti-oxidative property. These results implicate IMD as a potential therapeutic agent for the treatment of HF. PMID:28627670

Improved cardiac function and exercise capacity following correction of pectus excavatum: a review of current literature.

PubMed

Maagaard, Marie; Heiberg, Johan

2016-09-01

Patients with pectus excavatum (PE) often describe improvements in exercise stamina following corrective surgery. Studies have investigated the surgical effect on physiological parameters; still, no consensus has yet been reached. Therefore, the aim of this literature review was to describe the cardiac outcome after surgical correction, both at rest and during exercise. In February 2016, a detailed search of the databases PubMed, Medline, and EMBASE was performed. We assessed clinical studies that described cardiac outcomes both before and after surgical correction of PE. We only included studies reporting either pre-defined echocardiographic or exercise test parameters. No exclusion criteria or statistical analyses were applied. Twenty-one full-text articles, published between 1972 and 2016, were selected, with cohort-ranges of 3-168 patients, mean age-ranges of 5-33 years, and mean follow-up-ranges from immediately to 4 years after surgery. Twelve studies described resting cardiac parameters. Four studies measured cardiac output, where one described 36% immediate increase after surgery, one reported 15% increase after Nuss-bar removal and two found no difference. Three studies demonstrated improvement in mean stroke volume ranges of 22-34% and two studies found no difference. Fifteen studies investigated exercise capacity, with 11 considering peak O 2 pr. kg, where five studies demonstrated improvements with the mean ranging from 8% to 15% after surgery, five studies demonstrated no difference, and one saw a decrease of 19% 3 months after Nuss-bar implantation. A measurable increase in exercise capacity exists following surgery, which may be caused by multiple factors. This may be owed to the relief of compressed cardiac chambers with the increased anterior-posterior thoracic dimensions, which could facilitate an improved filling of the heart. With these results, the positive physiological impact of the surgery is emphasized and the potential gain in cardiac

Improved cardiac function and exercise capacity following correction of pectus excavatum: a review of current literature

PubMed Central

Heiberg, Johan

2016-01-01

Patients with pectus excavatum (PE) often describe improvements in exercise stamina following corrective surgery. Studies have investigated the surgical effect on physiological parameters; still, no consensus has yet been reached. Therefore, the aim of this literature review was to describe the cardiac outcome after surgical correction, both at rest and during exercise. In February 2016, a detailed search of the databases PubMed, Medline, and EMBASE was performed. We assessed clinical studies that described cardiac outcomes both before and after surgical correction of PE. We only included studies reporting either pre-defined echocardiographic or exercise test parameters. No exclusion criteria or statistical analyses were applied. Twenty-one full-text articles, published between 1972 and 2016, were selected, with cohort-ranges of 3–168 patients, mean age-ranges of 5–33 years, and mean follow-up-ranges from immediately to 4 years after surgery. Twelve studies described resting cardiac parameters. Four studies measured cardiac output, where one described 36% immediate increase after surgery, one reported 15% increase after Nuss-bar removal and two found no difference. Three studies demonstrated improvement in mean stroke volume ranges of 22–34% and two studies found no difference. Fifteen studies investigated exercise capacity, with 11 considering peak O2 pr. kg, where five studies demonstrated improvements with the mean ranging from 8% to 15% after surgery, five studies demonstrated no difference, and one saw a decrease of 19% 3 months after Nuss-bar implantation. A measurable increase in exercise capacity exists following surgery, which may be caused by multiple factors. This may be owed to the relief of compressed cardiac chambers with the increased anterior-posterior thoracic dimensions, which could facilitate an improved filling of the heart. With these results, the positive physiological impact of the surgery is emphasized and the potential gain in cardiac

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.

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.

Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study.

PubMed

Legallois, Damien; Belin, Annette; Nesterov, Sergey V; Milliez, Paul; Parienti, J-J; Knuuti, Juhani; Abbas, Ahmed; Tirel, Olivier; Agostini, Denis; Manrique, Alain

2016-01-01

Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 ± 0.38 mL/min/g vs. 1.16 ± 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 ± 0.22 mL/min/g to 0.19 ± 0.22 mL/min/g, p < 0.001 and from 101.5 ± 16.5% to 118.3 ± 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion. © The European Society of Cardiology 2014.

The cardiac regenerative potential of myoblasts remains limited despite improving their survival via antioxidant treatment.

PubMed

Beckman, Sarah A; Sekiya, Naosumi; Chen, William C W; Mlakar, Logan; Tobita, Kimimassa; Huard, Johnny

2014-01-01

Since myoblasts have been limited by poor cell survival after cellular myoplasty, the major goal of the current study was to determine whether improving myoblast survival with an antioxidant could improve cardiac function after the transplantation of the myoblasts into an acute myocardial infarction. We previously demonstrated that early myogenic progenitors such as muscle-derived stem cells (MDSCs) exhibited superior cell survival and improved cardiac repair after transplantation into infarcted hearts compared to myoblasts, which we partially attributed to MDSC's higher antioxidant levels. To determine if antioxidant treatment could increase myoblast survival, subsequently improving cardiac function after myoblast transplantation into infarcted hearts. Myoblasts were pre-treated with the antioxidant N-acetylcysteine (NAC) or the glutathione depleter, diethyl maleate (DEM), and injected into infarcted murine hearts. Regenerative potential was monitored by cell survival and cardiac function. At early time points, hearts injected with NAC-treated myoblasts exhibited increased donor cell survival, greater cell proliferation, and decreased cellular apoptosis, compared to untreated myoblasts. NAC-treated myoblasts significantly improved cardiac contractility, reduced fibrosis, and increased vascular density compared to DEM-treated myoblasts, but compared to untreated myoblasts, no difference was noted. While early survival of myoblasts transplanted into infarcted hearts was augmented by NAC pre-treatment, cardiac function remained unchanged compared to non-treated myoblasts. Despite improving cell survival with NAC treated myoblast transplantation in a MI heart, cardiac function remained similar to untreated myoblasts. These results suggest that the reduced cardiac regenerative potential of myoblasts, when compared to MDSCs, is not only attributable to cell survival but is probably also related to the secretion of paracrine factors by the MDSCs.

Heme Oxygenase-1 Induction Improves Cardiac Function following Myocardial Ischemia by Reducing Oxidative Stress

PubMed Central

Issan, Yossi; Kornowski, Ran; Aravot, Dan; Shainberg, Asher; Laniado-Schwartzman, Michal; Sodhi, Komal; Abraham, Nader G.; Hochhauser, Edith

2014-01-01

Background Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation. Methods In vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP) and tin protoporphyrin (SnPP) prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured. Results HO-1 induction lowered release of lactate dehydrogenase (LDH) and creatine phospho kinase (CK), decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS) was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05). CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01), reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively). CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05). The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05). CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05) in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPP's cardioprotective effects. Conclusions HO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart as proved by

Matrine pretreatment improves cardiac function in rats with diabetic cardiomyopathy via suppressing ROS/TLR-4 signaling pathway.

PubMed

Liu, Zhong-wei; Wang, Jun-kui; Qiu, Chuan; Guan, Gong-chang; Liu, Xin-hong; Li, Shang-jian; Deng, Zheng-rong

2015-03-01

Matrine is an alkaloid from Sophora alopecuroides L, which has shown a variety of pharmacological activities and potential therapeutic value in cardiovascular diseases. In this study we examined the protective effects of matrine against diabetic cardiomyopathy (DCM) in rats. Male SD rats were injected with streptozotocin (STZ) to induce DCM. One group of DCM rats was pretreated with matrine (200 mg·kg(-1)·d(-1), po) for 10 consecutive days before STZ injection. Left ventricular function was evaluated using invasive hemodynamic examination, and myocardiac apoptosis was assessed. Primary rat myocytes were used for in vitro experiments. Intracellular ROS generation, MDA content and GPx activity were determined. Real-time PCR and Western blotting were performed to detect the expression of relevant mRNAs and proteins. DCM rats exhibited abnormally elevated non-fasting blood glucose levels at 4 weeks after STZ injection, and LV function impairment at 16 weeks. The cardiac tissues of DCM rats showed markedly increased apoptosis, excessive ROS production, and activation of TLR-4/MyD-88/caspase-8/caspase-3 signaling. Pretreatment with matrine significantly decreased non-fasting blood glucose levels and improved LV function in DCM rats, which were associated with reducing apoptosis and ROS production, and suppressing TLR-4/MyD-88/caspase-8/caspase-3 signaling in cardiac tissues. Incubation in a high-glucose medium induced oxidative stress and activation of TLR-4/MyD-88 signaling in cultured myocytes in vitro, which were significantly attenuated by pretreatment with N-acetylcysteine. Excessive ROS production in DCM activates the TLR-4/MyD-88 signaling, resulting in cardiomyocyte apoptosis, whereas pretreatment with matrine improves cardiac function via suppressing ROS/TLR-4 signaling pathway.

The cardiac regenerative potential of myoblasts remains limited despite improving their survival via antioxidant treatment

PubMed Central

Beckman, Sarah A.; Sekiya, Naosumi; Chen, William C.W.; Mlakar, Logan; Tobita, Kimimassa; Huard, Johnny

2017-01-01

Introduction Since myoblasts have been limited by poor cell survival after cellular myoplasty, the major goal of the current study was to determine whether improving myoblast survival with an antioxidant could improve cardiac function after the transplantation of the myoblasts into an acute myocardial infarction. Background We previously demonstrated that early myogenic progenitors such as muscle-derived stem cells (MDSCs) exhibited superior cell survival and improved cardiac repair after transplantation into infarcted hearts compared to myoblasts, which we partially attributed to MDSC’s higher antioxidant levels. Aim To determine if antioxidant treatment could increase myoblast survival, subsequently improving cardiac function after myoblast transplantation into infarcted hearts. Materials and Methods Myoblasts were pre-treated with the antioxidant N-acetylcysteine (NAC) or the glutathione depleter, diethyl maleate (DEM), and injected into infarcted murine hearts. Regenerative potential was monitored by cell survival and cardiac function. Results At early time points, hearts injected with NAC-treated myoblasts exhibited increased donor cell survival, greater cell proliferation, and decreased cellular apoptosis, compared to untreated myoblasts. NAC-treated myoblasts significantly improved cardiac contractility, reduced fibrosis, and increased vascular density compared to DEM-treated myoblasts, but compared to untreated myoblasts, no difference was noted. Discussion While early survival of myoblasts transplanted into infarcted hearts was augmented by NAC pre-treatment, cardiac function remained unchanged compared to non-treated myoblasts. Conclusion Despite improving cell survival with NAC treated myoblast transplantation in a MI heart, cardiac function remained similar to untreated myoblasts. These results suggest that the reduced cardiac regenerative potential of myoblasts, when compared to MDSCs, is not only attributable to cell survival but is probably also

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

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

Can a Home-based Cardiac Physical Activity Program Improve the Physical Function Quality of Life in Children with Fontan Circulation?

PubMed

Jacobsen, Roni M; Ginde, Salil; Mussatto, Kathleen; Neubauer, Jennifer; Earing, Michael; Danduran, Michael

2016-01-01

Patients after Fontan operation for complex congenital heart disease (CHD) have decreased exercise capacity and report reduced health-related quality of life (HRQOL). Studies suggest hospital-based cardiac physical activity programs can improve HRQOL and exercise capacity in patients with CHD; however, these programs have variable adherence rates. The impact of a home-based cardiac physical activity program in Fontan survivors is unclear. This pilot study evaluated the safety, feasibility, and benefits of an innovative home-based physical activity program on HRQOL in Fontan patients. A total of 14 children, 8-12 years, with Fontan circulation enrolled in a 12-week moderate/high intensity home-based cardiac physical activity program, which included a home exercise routine and 3 formalized in-person exercise sessions at 0, 6, and 12 weeks. Subjects and parents completed validated questionnaires to assess HRQOL. The Shuttle Test Run was used to measure exercise capacity. A Fitbit Flex Activity Monitor was used to assess adherence to the home activity program. Of the 14 patients, 57% were male and 36% had a dominant left ventricle. Overall, 93% completed the program. There were no adverse events. Parents reported significant improvement in their child's overall HRQOL (P < .01), physical function (P < .01), school function (P = .01), and psychosocial function (P < .01). Patients reported no improvement in HRQOL. Exercise capacity, measured by total shuttles and exercise time in the Shuttle Test Run and calculated VO2 max, improved progressively from baseline to the 6 and 12 week follow up sessions. Monthly Fitbit data suggested adherence to the program. This 12-week home-based cardiac physical activity program is safe and feasible in preteen Fontan patients. Parent proxy-reported HRQOL and objective measures of exercise capacity significantly improved. A 6-month follow up session is scheduled to assess sustainability. A larger study is needed to determine the

Electromechanical Conditioning of Adult Progenitor Cells Improves Recovery of Cardiac Function After Myocardial Infarction

PubMed Central

Llucià‐Valldeperas, Aida; Soler‐Botija, Carolina; Gálvez‐Montón, Carolina; Roura, Santiago; Prat‐Vidal, Cristina; Perea‐Gil, Isaac; Sanchez, Benjamin; Bragos, Ramon; Vunjak‐Novakovic, Gordana

2016-01-01

Abstract Cardiac cells are subjected to mechanical and electrical forces, which regulate gene expression and cellular function. Therefore, in vitro electromechanical stimuli could benefit further integration of therapeutic cells into the myocardium. Our goals were (a) to study the viability of a tissue‐engineered construct with cardiac adipose tissue‐derived progenitor cells (cardiac ATDPCs) and (b) to examine the effect of electromechanically stimulated cardiac ATDPCs within a myocardial infarction (MI) model in mice for the first time. Cardiac ATDPCs were electromechanically stimulated at 2‐millisecond pulses of 50 mV/cm at 1 Hz and 10% stretching during 7 days. The cells were harvested, labeled, embedded in a fibrin hydrogel, and implanted over the infarcted area of the murine heart. A total of 39 animals were randomly distributed and sacrificed at 21 days: groups of grafts without cells and with stimulated or nonstimulated cells. Echocardiography and gene and protein analyses were also carried out. Physiologically stimulated ATDPCs showed increased expression of cardiac transcription factors, structural genes, and calcium handling genes. At 21 days after implantation, cardiac function (measured as left ventricle ejection fraction between presacrifice and post‐MI) increased up to 12% in stimulated grafts relative to nontreated animals. Vascularization and integration with the host blood supply of grafts with stimulated cells resulted in increased vessel density in the infarct border region. Trained cells within the implanted fibrin patch expressed main cardiac markers and migrated into the underlying ischemic myocardium. To conclude, synchronous electromechanical cell conditioning before delivery may be a preferred alternative when considering strategies for heart repair after myocardial infarction. Stem Cells Translational Medicine 2017;6:970–981 PMID:28297585

Soccer training improves cardiac function in men with type 2 diabetes.

PubMed

Schmidt, Jakob Friis; Andersen, Thomas Rostgaard; Horton, Joshua; Brix, Jonathan; Tarnow, Lise; Krustrup, Peter; Andersen, Lars Juel; Bangsbo, Jens; Hansen, Peter Riis

2013-12-01

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease, which is worsened by physical inactivity. Subclinical myocardial dysfunction is associated with increased risk of heart failure and impaired prognosis in T2DM; however, it is not clear if exercise training can counteract the early signs of diabetic heart disease. This study aimed to evaluate the effects of soccer training on cardiac function, exercise capacity, and blood pressure in middle-age men with T2DM. Twenty-one men age 49.8 ± 1.7 yr with T2DM and no history of cardiovascular disease participated in a soccer training group (n = 12) that trained 1 h twice a week or a control group (n = 9) with no change in lifestyle. Examinations included comprehensive transthoracic echocardiography, measurements of blood pressure, maximal oxygen consumption (V(˙)O(2max)), and intermittent endurance capacity before and after 12 and 24 wk. Two-way repeated-measures ANOVA was applied. After 24 wk of soccer training, left ventricular (LV) end-diastolic diameter and volume were increased (P < 0.001) compared to baseline. LV longitudinal systolic displacement was augmented by 23% (P < 0.001) and global longitudinal two-dimensional strain increased by 10% (P < 0.05). LV diastolic function, determined by mitral inflow (E/A ratio) and peak diastolic velocity E', was increased by 18% (P < 0.01) and 29% (P < 0.001), respectively, whereas LV filling pressure E/E' was reduced by 15% (P = 0.05). Systolic, diastolic, and mean arterial pressures were all reduced by 8 mm Hg (P < 0.01, P < 0.001, and P < 0.001, respectively). V(˙)O(2max) and intermittent endurance capacity was 12% and 42% (P < 0.001) higher, respectively. No changes in any of the measured parameters were observed in control group. Regular soccer training improves cardiac function, increases exercise capacity, and lowers blood pressure in men with T2DM.

[Effect of formula of removing both phlegm and blood stasis in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome].

PubMed

Li, Lei; Lin, Cheng-Ren; Ren, Jian-Xun; Miao, Lan; Yao, Ming-Jiang; Li, Dan; Shi, Yue; Ma, Yan-Lei; Fu, Jian-Hua; Liu, Jian-Xun

2014-02-01

To evaluate that the effect of formula of removing both phlegm and blood stasis in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome. Totally 36 Chinese mini-swine were randomly divided to six groups: the normal control group, the model group, the Danlou tablet group, and Tanyu Tonzhi Fang(TYTZ) groups with doses of 2. 0, 1. 0 and 0. 5 g kg-1, with six in each group. Except for the normal control group, all of other groups were fed with high-fat diet for 2 weeks. Interventional balloons are adopted to injure their left anterior descending artery endothelium. After the operation, they were fed with high-fat diet for 8 weeks to prepare the coronary heart disease model of phlegm-stasis cementation syndrome. After the operation, they were administered with drugs for 8 weeks. The changes in the myocardial ischemia were observed. The changes in the cardiac function and structure were detected by cardiac ultrasound and noninvasive hemodynamic method. Compared with the normal control group, the model group showed significant increase in myocardial ischemia and SVR and obvious decrease in CO, SV and LCW in noninvasive hemodynamic parameters (P <0.05 or P <0.01). The ultrasonic cardiogram indicated notable decrease in IVSd, LVPWs, EF and FS, and remarkable increase in LVIDs (P<0. 05 orP<0.01). Compared with the model group, TYTZ could reduce the myocardial ischemia, strengthen cardiac function, and improve the abnormal cardiac structure and function induced by ischemia (P <0. 05 or P <0. 01). TYTZ shows a significant effect in improving cardiac function of Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome. The clinical cardiac function detection method could be adopted to correctly evaluate the changes in the post-myocardial ischemia cardiac function, and narrow the gap between clinical application and basic experimental studies.

Cortistatin Improves Cardiac Function After Acute Myocardial Infarction in Rats by Suppressing Myocardial Apoptosis and Endoplasmic Reticulum Stress.

PubMed

Shi, Zhi-Yu; Liu, Yue; Dong, Li; Zhang, Bo; Zhao, Meng; Liu, Wen-Xiu; Zhang, Xin; Yin, Xin-Hua

2016-04-18

The endoplasmic reticulum (ER) stress-induced apoptotic pathway is associated with the development of acute myocardial infarction (AMI). Cortistatin (CST) is a novel bioactive peptide that inhibits apoptosis-related injury. Therefore, we investigated the cardioprotective effects and potential mechanisms of CST in a rat model of AMI. Male Wistar rats were randomly divided into sham, AMI, and AMI + CST groups. Cardiac function and the degree of infarction were evaluated by echocardiography, cardiac troponin I activity, and 2,3,5-triphenyl-2H-tetrazolium chloride staining after 7 days. The expression of CST, ER stress markers, and apoptotic markers was examined using immunohistochemistry and Western blotting. Compared to the AMI group, the AMI + CST group exhibited markedly better cardiac function and a lower degree of infarction. Electron microscopy and terminal deoxynucleotidyl transferase dUTP nick end labeling confirmed that myocardial apoptosis occurred after AMI. Cortistatin treatment reduced the expression of caspase 3, cleaved caspase 3, and Bax (proapoptotic proteins) and promoted the expression of Bcl-2 (antiapoptotic protein). In addition, the reduced expression of glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding proteins homologous protein, and caspase 12 indicated that ER stress and the apoptotic pathway associated with ER stress were suppressed. Exogenous CST has a notable cardioprotective effect after AMI in a rat model in that it improves cardiac function by suppressing ER stress and myocardial apoptosis. © The Author(s) 2016.

Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction

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

Guo, Hai-dong; Cui, Guo-hong; Yang, Jia-jun

Highlights: Black-Right-Pointing-Pointer The designer peptide LRKKLGKA could self-assemble into nanofibers. Black-Right-Pointing-Pointer Injection of LRKKLGKA peptides could promote the sustained delivery of VEGF. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides lead to sufficient angiogenesis. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides improves heart function. -- Abstract: Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self-assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. Thismore » designer self-assembling peptide self-assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function.« less

Clinical significance of automatic warning function of cardiac remote monitoring systems in preventing acute cardiac episodes

PubMed Central

Chen, Shou-Qiang; Xing, Shan-Shan; Gao, Hai-Qing

2014-01-01

Objective: In addition to ambulatory Holter electrocardiographic recording and transtelephonic electrocardiographic monitoring (TTM), a cardiac remote monitoring system can provide an automatic warning function through the general packet radio service (GPRS) network, enabling earlier diagnosis, treatment and improved outcome of cardiac diseases. The purpose of this study was to estimate its clinical significance in preventing acute cardiac episodes. Methods: Using 2 leads (V1 and V5 leads) and the automatic warning mode, 7160 patients were tested with a cardiac remote monitoring system from October 2004 to September 2007. If malignant arrhythmias or obvious ST-T changes appeared in the electrocardiogram records was automatically transferred to the monitoring center, the patient and his family members were informed, and the corresponding precautionary or therapeutic measures were implemented immediately. Results: In our study, 274 cases of malignant arrhythmia, including sinus standstill and ventricular tachycardia, and 43 cases of obvious ST-segment elevation were detected and treated. Because of early detection, there was no death or deformity. Conclusions: A cardiac remote monitoring system providing an automatic warning function can play an important role in preventing acute cardiac episodes. PMID:25674124

Electromechanical Conditioning of Adult Progenitor Cells Improves Recovery of Cardiac Function After Myocardial Infarction.

PubMed

Llucià-Valldeperas, Aida; Soler-Botija, Carolina; Gálvez-Montón, Carolina; Roura, Santiago; Prat-Vidal, Cristina; Perea-Gil, Isaac; Sanchez, Benjamin; Bragos, Ramon; Vunjak-Novakovic, Gordana; Bayes-Genis, Antoni

2017-03-01

Cardiac cells are subjected to mechanical and electrical forces, which regulate gene expression and cellular function. Therefore, in vitro electromechanical stimuli could benefit further integration of therapeutic cells into the myocardium. Our goals were (a) to study the viability of a tissue-engineered construct with cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs) and (b) to examine the effect of electromechanically stimulated cardiac ATDPCs within a myocardial infarction (MI) model in mice for the first time. Cardiac ATDPCs were electromechanically stimulated at 2-millisecond pulses of 50 mV/cm at 1 Hz and 10% stretching during 7 days. The cells were harvested, labeled, embedded in a fibrin hydrogel, and implanted over the infarcted area of the murine heart. A total of 39 animals were randomly distributed and sacrificed at 21 days: groups of grafts without cells and with stimulated or nonstimulated cells. Echocardiography and gene and protein analyses were also carried out. Physiologically stimulated ATDPCs showed increased expression of cardiac transcription factors, structural genes, and calcium handling genes. At 21 days after implantation, cardiac function (measured as left ventricle ejection fraction between presacrifice and post-MI) increased up to 12% in stimulated grafts relative to nontreated animals. Vascularization and integration with the host blood supply of grafts with stimulated cells resulted in increased vessel density in the infarct border region. Trained cells within the implanted fibrin patch expressed main cardiac markers and migrated into the underlying ischemic myocardium. To conclude, synchronous electromechanical cell conditioning before delivery may be a preferred alternative when considering strategies for heart repair after myocardial infarction. Stem Cells Translational Medicine 2017;6:970-981. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Carbon nanotube-incorporated collagen hydrogels improve cell alignment and the performance of cardiac constructs

PubMed Central

Sun, Hongyu; Zhou, Jing; Huang, Zhu; Qu, Linlin; Lin, Ning; Liang, Chengxiao; Dai, Ruiwu; Tang, Lijun; Tian, Fuzhou

2017-01-01

Carbon nanotubes (CNTs) provide an essential 2-D microenvironment for cardiomyocyte growth and function. However, it remains to be elucidated whether CNT nanostructures can promote cell–cell integrity and facilitate the formation of functional tissues in 3-D hydrogels. Here, single-walled CNTs were incorporated into collagen hydrogels to fabricate (CNT/Col) hydrogels, which improved mechanical and electrical properties. The incorporation of CNTs (up to 1 wt%) exhibited no toxicity to cardiomyocytes and enhanced cell adhesion and elongation. Through the use of immunohistochemical staining, transmission electron microscopy, and intracellular calcium-transient measurement, the incorporation of CNTs was found to improve cell alignment and assembly remarkably, which led to the formation of engineered cardiac tissues with stronger contraction potential. Importantly, cardiac tissues based on CNT/Col hydrogels were noted to have better functionality. Collectively, the incorporation of CNTs into the Col hydrogels improved cell alignment and the performance of cardiac constructs. Our study suggests that CNT/Col hydrogels offer a promising tissue scaffold for cardiac constructs, and might serve as injectable biomaterials to deliver cell or drug molecules for cardiac regeneration following myocardial infarction in the near future. PMID:28450785

Bundled Postconditioning Therapies Improve Hemodynamics and Neurologic Recovery after 17 Minutes of Untreated Cardiac Arrest

PubMed Central

Bartos, Jason A.; Matsuura, Timothy R.; Sarraf, Mohammad; Youngquist, Scott T.; McKnite, Scott H.; Rees, Jennifer N.; Sloper, Daniel T.; Bates, Frank S.; Segal, Nicolas; Debaty, Guillaume; Lurie, Keith G.; Neumar, Robert W.; Metzger, Joseph M.; Riess, Matthias L.; Yannopoulos, Demetris

2014-01-01

Objective Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15 minutes of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. Methods Following 17 minutes of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR + ITD + sevoflurane + P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. Results Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48 hours), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48 hours). Conclusions Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17 minutes of untreated cardiac arrest in pigs. PMID:25447036

Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study.

PubMed

Madathil, Asgar; Hollingsworth, Kieren G; Blamire, Andrew M; Razvi, Salman; Newton, Julia L; Taylor, Roy; Weaver, Jolanta U

2015-04-01

It is well established that subclinical hypothyroidism (SCH) is associated with mild cardiac dysfunction, but it is unknown whether there is an underlying impairment of cardiac bioenergetic function. The objective of the study was to quantify the cardiac phosphocreatine to adenosine triphosphate ratio (PCr to ATP) in SCH, compared with healthy controls, and to measure the effect of 6 months of levothyroxine treatment. This was a 6-month, prospective, case-controlled interventional study. The PCr to ATP ratio was measured using phosphorus-31 magnetic resonance spectroscopy in subjects with SCH at baseline and after levothyroxine therapy (1.6 μg/kg · d) and compared with age- and gender-matched euthyroid controls. All subjects were free of overt heart disease. Twenty-one subjects with SCH (normal free T4 and serum TSH between 4.1 and 10 mIU/L) and 17 controls were matched for age (mean age 40.5 vs 43.3 y) and sex (females 81% vs 82%) but differed in mean TSH (6.5 vs 2.1 mIU/L, P < .001). At baseline the mean (± SD) PCr to ATP ratio in SCH was lower than in controls (1.80 ± 0.26 vs 2.07 ± 0.20, P = .001). In the 16 subjects studied after levothyroxine treatment, the PCr to ATP ratio improved (from 1.74 ± 0.24 to 1.91 ± 0.26, P = .004) and approached controls (borderline loss of significance, P = .051). On multivariate analysis, SCH was independently associated with a reduced PCr to ATP ratio, even after adjusting for confounding variables (body mass index and fasting glucose) (P = .001). Our results demonstrate early cardiac bioenergetic impairment in SCH, which is reversible with levothyroxine therapy. This mechanistic insight provides justification for longitudinal trials to determine whether improvement in bioenergetic function improves cardiovascular outcome.

Cardiorespiratory Fitness and Cardiac Autonomic Function in Diabetes.

PubMed

Röhling, Martin; Strom, Alexander; Bönhof, Gidon J; Roden, Michael; Ziegler, Dan

2017-10-23

This review summarizes the current knowledge on the relationship of physical activity, exercise, and cardiorespiratory fitness (CRF) with cardiovascular autonomic neuropathy (CAN) based on epidemiological, clinical, and interventional studies. The prevalence of CAN increases with age and duration of diabetes. Further risk factors for CAN comprise poor glycemic control, dyslipidemia, abdominal obesity, hypertension, and the presence of diabetic complications. CAN has been also linked to reduced CRF. We recently showed that CRF parameters (e.g., maximal oxidative capacity or oxidative capacity at the anaerobic threshold) are associated with cardiac autonomic function in patients recently diagnosed with type 1 or type 2 diabetes. Exercise interventions have shown that physical activity can increase cardiovagal activity and reduce sympathetic overactivity. In particular, long-term and regularly, but also supervised, performed endurance and high-intense and high-volume exercise improves cardiac autonomic function in patients with type 2 diabetes. By contrast, the evidence in those with type 1 diabetes and also in individuals with prediabetes or metabolic syndrome is weaker. Overall, the studies reviewed herein addressing the question whether favorably modulating the autonomic nervous system may improve CRF during exercise programs support the therapeutic concept to promote physical activity and to achieve physical fitness. However, high-quality exercise interventions, especially in type 1 diabetes and metabolic syndrome including prediabetes, are further required to better understand the relationship between physical activity, fitness, and cardiac autonomic function.

Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation.

PubMed

Musolino, Vincenzo; Palus, Sandra; Tschirner, Anika; Drescher, Cathleen; Gliozzi, Micaela; Carresi, Cristina; Vitale, Cristiana; Muscoli, Carolina; Doehner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Mollace, Vincenzo; Springer, Jochen

2016-12-01

Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant megestrol acetate (MA) has been discussed as a treatment for cachexia. In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 ± 12%, P  < 0.05) and the wasting of lean and fat mass (-7.0 ± 6% and -22.4 ± 3 %, P  < 0.001 and P  < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 ± 30 mg vs. placebo 474 ± 13 mg, P  < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular

Relationship between cardiac autonomic function and cognitive function in Alzheimer's disease.

PubMed

Nonogaki, Zen; Umegaki, Hiroyuki; Makino, Taeko; Suzuki, Yusuke; Kuzuya, Masafumi

2017-01-01

Alzheimer's disease (AD) affects many central nervous structures and neurotransmitter systems. These changes affect not only cognitive function, but also cardiac autonomic function. However, the functional relationship between cardiac autonomic function and cognition in AD has not yet been investigated. The objective of the present study was to evaluate the association between cardiac autonomic function measured by heart rate variability and cognitive function in AD. A total of 78 AD patients were recruited for this study. Cardiac autonomic function was evaluated using heart rate variability analysis. Multiple linear regression analysis was used to model the association between heart rate variability and cognitive function (global cognitive function, memory, executive function and processing speed), after adjustment for covariates. Global cognitive function was negatively associated with sympathetic modulation (low-to-high frequency power ratio). Memory performance was positively associated with parasympathetic modulation (high frequency power) and negatively associated with sympathetic modulation (low-to-high frequency power ratio). These associations were independent of age, sex, educational years, diabetes, hypertension and cholinesterase inhibitor use. Cognitive function, especially in the areas of memory, is associated with cardiac autonomic function in AD. Specifically, lower cognitive performance was found to be associated with significantly higher cardiac sympathetic and lower parasympathetic function in AD. Geriatr Gerontol Int 2017; 17: 92-98. © 2015 Japan Geriatrics Society.

Myocardial Adeno-Associated Virus Serotype 6–βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure

PubMed Central

Rengo, Giuseppe; Lymperopoulos, Anastasios; Zincarelli, Carmela; Donniacuo, Maria; Soltys, Stephen; Rabinowitz, Joseph E.; Koch, Walter J.

2009-01-01

Background The upregulation of G protein–coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function. The peptide βARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve βAR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term βARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). Methods and Results In HF rats, we delivered βARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the β-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. βARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac βAR signaling. Addition of metoprolol neither enhanced nor decreased βARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. Conclusions Long-term cardiac AAV6-βARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, βARKct alone improves outcomes more than a β-blocker alone, whereas both treatments are compatible. These findings show that βARKct gene therapy can be of long-term therapeutic value in HF. PMID:19103992

Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI

NASA Astrophysics Data System (ADS)

Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

2017-02-01

Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver DCE MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7  ±  1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n  =  9) measured at 7 d. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and 7 d reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p  =  0.066), total liver blood flow (TLBF) (p  =  0.101), hepatic arterial (HA) fraction (p  =  0.895), mean transit time (MTT) (p  =  0.646), distribution volume (DV) (p  =  0.890) were not significantly different. Seven day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% limits-of-agreement (BA95%LoA)  ±27.9%, coefficient of variation (CoV) 61.4% versus 9.3%, ±35.5%, 81.7% respectively without correction). Seven day uncorrected PV perfusion was also improved (mean difference 9.3 ml min-1/100 g, BA95%LoA  ±506.1 ml min-1/100 g, CoV 64.1% versus 0.9 ml min-1/100 g, ±562.8 ml min-1/100 g, 65.1% respectively with correction) as was uncorrected TLBF (mean difference 43.8 ml min-1/100 g, BA95%LoA  ±586.7 ml min-1/ 100 g, CoV 58.3% versus 13.3 ml min-1/100 g, ±661.5 ml min-1/100 g, 60.9% respectively with correction

Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy.

PubMed

Graham, Delyth; Huynh, Ngan N; Hamilton, Carlene A; Beattie, Elisabeth; Smith, Robin A J; Cochemé, Helena M; Murphy, Michael P; Dominiczak, Anna F

2009-08-01

Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ(10). Eight-week-old male stroke-prone spontaneously hypertensive rats were treated with MitoQ(10) (500 mumol/L; n=16), control compound decyltriphenylphosphonium (decylTPP; 500 mumol/L; n=8), or vehicle (n=9) in drinking water for 8 weeks. Systolic blood pressure was significantly reduced by approximately 25 mm Hg over the 8-week MitoQ(10) treatment period compared with decylTPP (F=5.94; P=0.029) or untreated controls (F=65.6; P=0.0001). MitoQ(10) treatment significantly improved thoracic aorta NO bioavailability (1.16+/-0.03 g/g; P=0.002, area under the curve) compared with both untreated controls (0.68+/-0.02 g/g) and decylTPP-treated rats (0.60+/-0.06 g/g). Cardiac hypertrophy was significantly reduced by MitoQ(10) treatment compared with untreated control and decylTPP treatment (MitoQ(10): 4.01+/-0.05 mg/g; control: 4.42+/-0.11 mg/g; and decylTPP: 4.40+/-0.09 mg/g; ANOVA P=0.002). Total MitoQ(10) content was measured in liver, heart, carotid artery, and kidney harvested from MitoQ(10)-treated rats by liquid chromatography-tandem mass spectrometry. All of the organs analyzed demonstrated detectable levels of MitoQ(10), with comparable accumulation in vascular and cardiac tissues. Administration of the mitochondria-targeted antioxidant MitoQ(10) protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats. MitoQ(10) provides a novel

Non-invasive imaging of global and regional cardiac function in pulmonary hypertension

PubMed Central

Crowe, Tim; Jayasekera, Geeshath

2017-01-01

Pulmonary hypertension (PH) is a progressive illness characterized by elevated pulmonary artery pressure; however, the main cause of mortality in PH patients is right ventricular (RV) failure. Historically, improving the hemodynamics of pulmonary circulation was the focus of treatment; however, it is now evident that cardiac response to a given level of pulmonary hemodynamic overload is variable but plays an important role in the subsequent prognosis. Non-invasive tests of RV function to determine prognosis and response to treatment in patients with PH is essential. Although the right ventricle is the focus of attention, it is clear that cardiac interaction can cause left ventricular dysfunction, thus biventricular assessment is paramount. There is also focus on the atrial chambers in their contribution to cardiac function in PH. Furthermore, there is evidence of regional dysfunction of the two ventricles in PH, so it would be useful to understand both global and regional components of dysfunction. In order to understand global and regional cardiac function in PH, the most obvious non-invasive imaging techniques are echocardiography and cardiac magnetic resonance imaging (CMRI). Both techniques have their advantages and disadvantages. Echocardiography is widely available, relatively inexpensive, provides information regarding RV function, and can be used to estimate RV pressures. CMRI, although expensive and less accessible, is the gold standard of biventricular functional measurements. The advent of 3D echocardiography and techniques including strain analysis and stress echocardiography have improved the usefulness of echocardiography while new CMRI technology allows the measurement of strain and measuring cardiac function during stress including exercise. In this review, we have analyzed the advantages and disadvantages of the two techniques and discuss pre-existing and novel forms of analysis where echocardiography and CMRI can be used to examine atrial

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.

PubMed

Zang, Qun S; Sadek, Hesham; Maass, David L; Martinez, Bobbie; Ma, Lisha; Kilgore, Jessica A; Williams, Noelle S; Frantz, Doug E; Wigginton, Jane G; Nwariaku, Fiemu E; Wolf, Steven E; Minei, Joseph P

2012-05-01

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 μmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during

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.

Mathematical Models of Cardiac Pacemaking Function

NASA Astrophysics Data System (ADS)

Li, Pan; Lines, Glenn T.; Maleckar, Mary M.; Tveito, Aslak

2013-10-01

Over the past half century, there has been intense and fruitful interaction between experimental and computational investigations of cardiac function. This interaction has, for example, led to deep understanding of cardiac excitation-contraction coupling; how it works, as well as how it fails. However, many lines of inquiry remain unresolved, among them the initiation of each heartbeat. The sinoatrial node, a cluster of specialized pacemaking cells in the right atrium of the heart, spontaneously generates an electro-chemical wave that spreads through the atria and through the cardiac conduction system to the ventricles, initiating the contraction of cardiac muscle essential for pumping blood to the body. Despite the fundamental importance of this primary pacemaker, this process is still not fully understood, and ionic mechanisms underlying cardiac pacemaking function are currently under heated debate. Several mathematical models of sinoatrial node cell membrane electrophysiology have been constructed as based on different experimental data sets and hypotheses. As could be expected, these differing models offer diverse predictions about cardiac pacemaking activities. This paper aims to present the current state of debate over the origins of the pacemaking function of the sinoatrial node. Here, we will specifically review the state-of-the-art of cardiac pacemaker modeling, with a special emphasis on current discrepancies, limitations, and future challenges.

Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment.

PubMed

Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

2016-01-01

Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. Copyright © 2015 Elsevier Inc. All rights reserved.

Inspiratory Muscle Training and Functional Capacity in Patients Undergoing Cardiac Surgery.

PubMed

Cordeiro, André Luiz Lisboa; de Melo, Thiago Araújo; Neves, Daniela; Luna, Julianne; Esquivel, Mateus Souza; Guimarães, André Raimundo França; Borges, Daniel Lago; Petto, Jefferson

2016-04-01

Cardiac surgery is a highly complex procedure which generates worsening of lung function and decreased inspiratory muscle strength. The inspiratory muscle training becomes effective for muscle strengthening and can improve functional capacity. To investigate the effect of inspiratory muscle training on functional capacity submaximal and inspiratory muscle strength in patients undergoing cardiac surgery. This is a clinical randomized controlled trial with patients undergoing cardiac surgery at Instituto Nobre de Cardiologia. Patients were divided into two groups: control group and training. Preoperatively, were assessed the maximum inspiratory pressure and the distance covered in a 6-minute walk test. From the third postoperative day, the control group was managed according to the routine of the unit while the training group underwent daily protocol of respiratory muscle training until the day of discharge. 50 patients, 27 (54%) males were included, with a mean age of 56.7±13.9 years. After the analysis, the training group had significant increase in maximum inspiratory pressure (69.5±14.9 vs. 83.1±19.1 cmH2O, P=0.0073) and 6-minute walk test (422.4±102.8 vs. 502.4±112.8 m, P=0.0031). We conclude that inspiratory muscle training was effective in improving functional capacity submaximal and inspiratory muscle strength in this sample of patients undergoing cardiac surgery.

Time Course of Atrophic Remodeling: Effects of Exercise on Cardiac Morpology and Function

NASA Technical Reports Server (NTRS)

Scott, J. M.; Martin, D.; Caine, T.; Matz, T.; Ploutz-Snyder, L. L.

2014-01-01

Early and consistent evaluation of cardiac morphology and function throughout an atrophic stimulus is critically important for the design and optimization of interventions. Exercise training is one intervention that has been shown to confer favorable improvements in LV mass and function during unloading. However, the format and intensity of exercise required to induce optimal cardiac improvements has not been investigated. PURPOSE: This randomized, controlled trial was designed to 1) comprehensively characterize the time course of unloading-induced morpho-functional remodeling, and 2) examine the effects of high intensity exercise training on cardiac structural and functional parameters during unloading. METHODS: Twenty six subjects completed 70 days of head down tilt bed rest (HDBR): 17 were randomized to exercise training (ExBR) and 9 remained sedentary. Exercise consisted of integrated high intensity, continuous, and resistance exercise. We assessed cardiac morphology (left ventricular mass; LVM) and function (speckle-tracking assessment of longitudinal, radial, and circumferential strain and twist) before (BR-2), during (BR7,21,31,70), and following (BR+0, +3) HDBR. Cardiorespiratory fitness (VO2max) was evaluated before (BR- 3), during (BR4,25,46,68) and following (BR+0) HDBR. RESULTS: Sedentary HDBR resulted in a progressive decline in LVM, longitudinal, radial, and circumferential strain, and an increase in twist. ExBR mitigated decreases in LVM and function. Change in twist was significantly related to change in VO2max (R=0.68, p<0.01). CONCLUSIONS: Alterations in cardiac morphology and function begin early during unloading. High-intensity exercise attenuates atrophic morphological and functional remodeling.

Assessment of Cardiac Function in Fetuses of Gestational Diabetic Mothers During the Second Trimester.

PubMed

Atiq, Mehnaz; Ikram, Anum; Hussain, Batool M; Saleem, Bakhtawar

2017-06-01

Fetuses of diabetic mothers may have structural or functional cardiac abnormalities which increase morbidity and mortality. Isolated functional abnormalities have been identified in the third trimester. The aim of the present study was to assess fetal cardiac function (systolic, diastolic, and global myocardial performance) in the second trimester in mothers with gestational diabetes, and also to relate cardiac function with glycemic control. Mothers with gestational diabetes mellitus referred for fetal cardiac evaluation in the second trimester (between 19 and 24 weeks) from March 2015 to February 2016 were enrolled as case subjects in this study. Non-diabetic mothers who had a fetal echocardiogram done between 19 and 24 weeks for other indications were enrolled as controls. Functional cardiac variables showed a statistically significant difference in isovolumetric relaxation and contraction times and the myocardial performance index and mitral E/A ratios in the gestational diabetic group (p = 0.003). Mitral annular plane systolic excursion was significantly less in the diabetic group (p = 0.01). The only functional cardiac variable found abnormal in mothers with poor glycemic control was the prolonged isovolumetric relaxation time. Functional cardiac abnormalities can be detected in the second trimester in fetuses of gestational diabetic mothers and timely intervention can improve postnatal outcomes.

Yoga respiratory training improves respiratory function and cardiac sympathovagal balance in elderly subjects: a randomised controlled trial

PubMed Central

Santaella, Danilo F; Devesa, Cesar R S; Rojo, Marcos R; Amato, Marcelo B P; Drager, Luciano F; Casali, Karina R; Montano, Nicola

2011-01-01

Objectives Since ageing is associated with a decline in pulmonary function, heart rate variability and spontaneous baroreflex, and recent studies suggest that yoga respiratory exercises may improve respiratory and cardiovascular function, we hypothesised that yoga respiratory training may improve respiratory function and cardiac autonomic modulation in healthy elderly subjects. Design 76 healthy elderly subjects were enrolled in a randomised control trial in Brazil and 29 completed the study (age 68±6 years, 34% males, body mass index 25±3 kg/m2). Subjects were randomised into a 4-month training program (2 classes/week plus home exercises) of either stretching (control, n=14) or respiratory exercises (yoga, n=15). Yoga respiratory exercises (Bhastrika) consisted of rapid forced expirations followed by inspiration through the right nostril, inspiratory apnoea with generation of intrathoracic negative pressure, and expiration through the left nostril. Pulmonary function, maximum expiratory and inspiratory pressures (PEmax and PImax, respectively), heart rate variability and blood pressure variability for spontaneous baroreflex determination were determined at baseline and after 4 months. Results Subjects in both groups had similar demographic parameters. Physiological variables did not change after 4 months in the control group. However, in the yoga group, there were significant increases in PEmax (34%, p<0.0001) and PImax (26%, p<0.0001) and a significant decrease in the low frequency component (a marker of cardiac sympathetic modulation) and low frequency/high frequency ratio (marker of sympathovagal balance) of heart rate variability (40%, p<0.001). Spontaneous baroreflex did not change, and quality of life only marginally increased in the yoga group. Conclusion Respiratory yoga training may be beneficial for the elderly healthy population by improving respiratory function and sympathovagal balance. Trial Registration CinicalTrials.gov identifier: NCT

[Sodium hydrosulfide improves cardiac functions and structures in rats with chronic heart failure].

PubMed

Li, Xiao-hui; Zhang, Chao-ying; Zhang, Ting

2011-11-22

an amelioration of myocardial damage, an alleviation of myocardial fiber changes and a decrease in myocardial collagen content (particularly type-I collagen). Compared with the sham operation and shunt + NaHS groups, the shunt group displayed increased right ventricular hydroxyproline (mg×g(-1)·pro: 1.32 ± 0.25 vs 0.89 ± 0.18 and 0.83 ± 0.19, all P < 0.05). H(2)S may improve cardiac functions and ameliorate cardiac structures in rats with chronic heart failure probably through dilating the blood vessels and affecting the extracellular collagen metabolism.

Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

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

Ray, Aramita, E-mail: aramitaray@yahoo.co.in; Rana, Santanu, E-mail: rana.santanu@gmail.com; Banerjee, Durba, E-mail: durba.research@gmail.com

Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showedmore » higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug. �

Genetic modification of embryonic stem cells with VEGF enhances cell survival and improves cardiac function.

PubMed

Xie, Xiaoyan; Cao, Feng; Sheikh, Ahmad Y; Li, Zongjin; Connolly, Andrew J; Pei, Xuetao; Li, Ren-Ke; Robbins, Robert C; Wu, Joseph C

2007-01-01

Cardiac stem cell therapy remains hampered by acute donor cell death posttransplantation and the lack of reliable methods for tracking cell survival in vivo. We hypothesize that cells transfected with inducible vascular endothelial growth factor 165 (VEGF(165)) can improve their survival as monitored by novel molecular imaging techniques. Mouse embryonic stem (ES) cells were transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF(165) and renilla luciferase (Rluc). Addition of doxycycline induced Bi-Tet expression of VEGF(165) and Rluc significantly compared to baseline (p<0.05). Expression of VEGF(165) enhanced ES cell proliferation and inhibited apoptosis as determined by Annexin-V staining. For noninvasive imaging, ES cells were transduced with a double fusion (DF) reporter gene consisting of firefly luciferase and enhanced green fluorescence protein (Fluc-eGFP). There was a robust correlation between cell number and Fluc activity (R(2)=0.99). Analysis by immunostaining, histology, and RT-PCR confirmed that expression of Bi-Tet and DF systems did not affect ES cell self-renewal or pluripotency. ES cells were differentiated into beating embryoid bodies expressing cardiac markers such as troponin, Nkx2.5, and beta-MHC. Afterward, 5 x 10(5) cells obtained from these beating embryoid bodies or saline were injected into the myocardium of SV129 mice (n=36) following ligation of the left anterior descending (LAD) artery. Bioluminescence imaging (BLI) and echocardiography showed that VEGF(165) induction led to significant improvements in both transplanted cell survival and cardiac function (p<0.05). This is the first study to demonstrate imaging of embryonic stem cell-mediated gene therapy targeting cardiovascular disease. With further validation, this platform may have broad applications for current basic research and further clinical studies.

Inhibition of the Mitochondrial Fission Protein Drp1 Improves Survival in a Murine Cardiac Arrest Model

PubMed Central

Sharp, Willard W.; Beiser, David G.; Fang, Yong Hu; Han, Mei; Piao, Lin; Varughese, Justin; Archer, Stephen L.

2015-01-01

Objectives Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation (CPR) and the use of therapeutic hypothermia. Dynamin related protein 1 (Drp1), a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that Drp1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest. Design Laboratory investigation. Setting University laboratory Interventions Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-min KCl induced cardiac arrest followed by 90 seconds of CPR. Mice were then blindly randomized to a single intravenous injection of Mdivi-1 (0.24 mg/kg), a small molecule Drp1 inhibitor or vehicle (DMSO). Measurements and Main Results Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by Drp1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during CPR inhibited Drp1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (ROSC) 116±4 vs. 143±7 sec (p<. 001) during CPR and enhanced myocardial performance post-ROSC. These improvements were associated with significant increases in survival (65% vs. 33%) and improved neurological scores up to 72 hours post cardiac arrest. Conclusions Post cardiac arrest inhibition of Drp1 improves time to ROSC and myocardial hemodynamics resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest. PMID:25599491

Qishen Yiqi Drop Pill improves cardiac function after myocardial ischemia.

PubMed

JianXin, Chen; Xue, Xu; ZhongFeng, Li; Kuo, Gao; FeiLong, Zhang; ZhiHong, Li; Xian, Wang; HongCai, Shang

2016-04-14

Myocardial ischemia (MI) is one of the leading causes of death, while Qishen Yiqi Drop Pill (QYDP) is a representative traditional Chinese medicine to treat this disease. Unveiling the pharmacological mechanism of QYDP will provide a great opportunity to promote the development of novel drugs to treat MI. 64 male Sprague-Dawley (SD) rats were divided into four groups: MI model group, sham operation group, QYDP treatment group and Fosinopril treatment group. Echocardiography results showed that QYDP exhibited significantly larger LV end-diastolic dimension (LVEDd) and LV end-systolic dimension (LVEDs), compared with the MI model group, indicating the improved cardiac function by QYDP. (1)H-NMR based metabonomics further identify 9 significantly changed metabolites in the QYDP treatment group, and the QYDP-related proteins based on the protein-metabolite interaction networks and the corresponding pathways were explored, involving the pyruvate metabolism pathway, the retinol metabolism pathway, the tyrosine metabolism pathway and the purine metabolism pathway, suggesting that QYDP was closely associated with blood circulation. ELISA tests were further employed to identify NO synthase (iNOS) and cathepsin K (CTSK) in the networks. For the first time, our work combined experimental and computational methods to study the mechanism of the formula of traditional Chinese medicine.

Single-Dose Intracardiac Injection of Pro-Regenerative MicroRNAs Improves Cardiac Function After Myocardial Infarction.

PubMed

Lesizza, Pierluigi; Prosdocimo, Giulia; Martinelli, Valentina; Sinagra, Gianfranco; Zacchigna, Serena; Giacca, Mauro

2017-04-14

Recent evidence indicates that a few human microRNAs (miRNAs), in particular hsa-miR-199a-3p and hsa-miR-590-3p, stimulate proliferation of cardiomyocytes and, once expressed in the mouse heart using viral vectors, induce cardiac regeneration after myocardial infarction. Viral vectors, however, are not devoid of safety issues and, more notably, drive expression of the encoded miRNAs for indefinite periods of time, which might not be desirable in light of human therapeutic application. As an alternative to the use of viral vectors, we wanted to assess the efficacy of synthetic miRNA mimics in inducing myocardial repair after single intracardiac injection using synthetic lipid formulations. We comparatively analyzed the efficacy of different lipid formulations in delivering hsa-miR-199a-3p and hsa-miR-590-3p both in primary neonatal mouse cardiomyocytes and in vivo. We established a transfection protocol allowing persistence of these 2 mimics for at least 12 days after a single intracardiac injection, with minimal dispersion to other organs and long-term preservation of miRNA functional activity, as assessed by monitoring the expression of 2 mRNA targets. Administration of this synthetic formulation immediately after myocardial infarction in mice resulted in marked reduction of infarct size and persistent recovery of cardiac function. A single administration of synthetic miRNA-lipid formulations is sufficient to stimulate cardiac repair and restoration of cardiac function. © 2017 American Heart Association, Inc.

Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration.

PubMed

Yoshihisa, Akiomi; Shimizu, Takeshi; Owada, Takashi; Nakamura, Yuichi; Iwaya, Shoji; Yamauchi, Hiroyuki; Miyata, Makiko; Hoshino, Yasuto; Sato, Takamasa; Suzuki, Satoshi; Sugimoto, Koichi; Yamaki, Takayoshi; Kunii, Hiroyuki; Nakazato, Kazuhiko; Suzuki, Hitoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

2011-01-01

Cheyne-Stokes respiration (CSR) is often observed in patients with chronic heart failure (CHF). Although adaptive servo ventilation (ASV) is effective for CSR, it remains unclear whether ASV improves the cardiac function and prognosis of patients with CHF and CSR.Sixty patients with CHF and CSR (mean left ventricular ejection fraction 38.7%, mean apnea hypopnea index 36.8 times/hour, mean central apnea index 19.1 times/hour) were enrolled in this study. Patients were divided into two groups: 23 patients treated with ASV (ASV group) and 37 patients treated without ASV (Non-ASV group). Measurement of plasma B-type natriuretic peptide (BNP) levels and echocardiography were performed before, 3 and 6 months after treatments in each group. Patients were followed-up for cardiac events (cardiac death and re-hospitalization) after discharge. In the ASV group, NYHA functional class, BNP levels, cardiac systolic and diastolic function were significantly improved with ASV treatment for 6 months. In contrast, none of these parameters changed in the Non-ASV group. Importantly, Kaplan-Meier analysis clearly demonstrated that the event-free rate was significantly higher in the ASV group than in the Non-ASV group.Adaptive servo ventilation improves cardiac function and prognosis in patients with chronic heart failure and Cheyne-Stokes respiration.

[Cardiac Synchronization Function Estimation Based on ASM Level Set Segmentation Method].

PubMed

Zhang, Yaonan; Gao, Yuan; Tang, Liang; He, Ying; Zhang, Huie

At present, there is no accurate and quantitative methods for the determination of cardiac mechanical synchronism, and quantitative determination of the synchronization function of the four cardiac cavities with medical images has a great clinical value. This paper uses the whole heart ultrasound image sequence, and segments the left & right atriums and left & right ventricles of each frame. After the segmentation, the number of pixels in each cavity and in each frame is recorded, and the areas of the four cavities of the image sequence are therefore obtained. The area change curves of the four cavities are further extracted, and the synchronous information of the four cavities is obtained. Because of the low SNR of Ultrasound images, the boundary lines of cardiac cavities are vague, so the extraction of cardiac contours is still a challenging problem. Therefore, the ASM model information is added to the traditional level set method to force the curve evolution process. According to the experimental results, the improved method improves the accuracy of the segmentation. Furthermore, based on the ventricular segmentation, the right and left ventricular systolic functions are evaluated, mainly according to the area changes. The synchronization of the four cavities of the heart is estimated based on the area changes and the volume changes.

Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats

PubMed Central

Dolinsky, Vernon W; Jones, Kelvin E; Sidhu, Robinder S; Haykowsky, Mark; Czubryt, Michael P; Gordon, Tessa; Dyck, Jason R B

2012-01-01

Exercise training (ET) improves endurance capacity by increasing both skeletal muscle mitochondrial number and function, as well as contributing to favourable cardiac remodelling. Interestingly, some of the benefits of regular exercise can also be mimicked by the naturally occurring polyphenol, resveratrol (RESV). However, it is not known whether RESV enhances physiological adaptations to ET. To investigate this, male Wistar rats were randomly assigned to a control chow diet or a chow diet that contained RESV (4 g kg−1 of diet) and subsequently subjected to a programme of progressive treadmill running for 12 weeks. ET-induced improvements in exercise performance were enhanced by 21% (P < 0.001) by the addition of RESV to the diet. In soleus muscle, ET + RESV increased both the twitch (1.8-fold; P < 0.05) and tetanic (1.2-fold; P < 0.05) forces generated during isometric contraction, compared to ET alone. In vivo echocardiography demonstrated that ET + RESV also increased the resting left ventricular ejection fraction by 10% (P < 0.05), and reduced left ventricular wall stress compared to ET alone. These functional changes were accompanied by increased cardiac fatty acid oxidation (1.2-fold; P < 0.05) and favourable changes in cardiac gene expression and signal transduction pathways that optimized the utilization of fatty acids in ET + RESV compared to ET alone. Overall, our findings provide evidence that the capacity for fatty acid oxidation is augmented by the addition of RESV to the diet during ET, and that this may contribute to the improved physical performance of rats following ET. PMID:22473781

Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury

PubMed Central

West, Christopher R; Crawford, Mark A; Poormasjedi-Meibod, Malihe-Sadat; Currie, Katharine D; Fallavollita, Andre; Yuen, Violet; McNeill, John H; Krassioukov, Andrei V

2014-01-01

Spinal cord injury (SCI) causes altered autonomic control and severe physical deconditioning that converge to drive maladaptive cardiac remodelling. We used a clinically relevant experimental model to investigate the cardio-metabolic responses to SCI and to establish whether passive hind-limb cycling elicits a cardio-protective effect. Initially, 21 male Wistar rats were evenly assigned to three groups: uninjured control (CON), T3 complete SCI (SCI) or T3 complete SCI plus passive hind-limb cycling (SCI-EX; 2 × 30 min day−1, 5 days week−1 for 4 weeks beginning 6 days post-SCI). On day 32, cardio-metabolic function was assessed using in vivo echocardiography, ex vivo working heart assessments, cardiac histology/molecular biology and blood lipid profiles. Twelve additional rats (n = 6 SCI and n = 6 SCI-EX) underwent in vivo echocardiography and basal haemodynamic assessments pre-SCI and at days 7, 14 and 32 post-SCI to track temporal cardiovascular changes. Compared with CON, SCI exhibited a rapid and sustained reduction in left ventricular dimensions and function that ultimately manifested as reduced contractility, increased myocardial collagen deposition and an up-regulation of transforming growth factor beta-1 (TGFβ1) and mothers against decapentaplegic homolog 3 (Smad3) mRNA. For SCI-EX, the initial reduction in left ventricular dimensions and function at day 7 post-SCI was completely reversed by day 32 post-SCI, and there were no differences in myocardial contractility between SCI-EX and CON. Collagen deposition was similar between SCI-EX and CON. TGFβ1 and Smad3 were down-regulated in SCI-EX. Blood lipid profiles were improved in SCI-EX versus SCI. We provide compelling novel evidence that passive hind-limb cycling prevents cardiac dysfunction and reduces cardiovascular disease risk in experimental SCI. PMID:24535438

Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury.

PubMed

West, Christopher R; Crawford, Mark A; Poormasjedi-Meibod, Malihe-Sadat; Currie, Katharine D; Fallavollita, Andre; Yuen, Violet; McNeill, John H; Krassioukov, Andrei V

2014-04-15

Spinal cord injury (SCI) causes altered autonomic control and severe physical deconditioning that converge to drive maladaptive cardiac remodelling. We used a clinically relevant experimental model to investigate the cardio-metabolic responses to SCI and to establish whether passive hind-limb cycling elicits a cardio-protective effect. Initially, 21 male Wistar rats were evenly assigned to three groups: uninjured control (CON), T3 complete SCI (SCI) or T3 complete SCI plus passive hind-limb cycling (SCI-EX; 2 × 30 min day(-1), 5 days week(-1) for 4 weeks beginning 6 days post-SCI). On day 32, cardio-metabolic function was assessed using in vivo echocardiography, ex vivo working heart assessments, cardiac histology/molecular biology and blood lipid profiles. Twelve additional rats (n = 6 SCI and n = 6 SCI-EX) underwent in vivo echocardiography and basal haemodynamic assessments pre-SCI and at days 7, 14 and 32 post-SCI to track temporal cardiovascular changes. Compared with CON, SCI exhibited a rapid and sustained reduction in left ventricular dimensions and function that ultimately manifested as reduced contractility, increased myocardial collagen deposition and an up-regulation of transforming growth factor beta-1 (TGFβ1) and mothers against decapentaplegic homolog 3 (Smad3) mRNA. For SCI-EX, the initial reduction in left ventricular dimensions and function at day 7 post-SCI was completely reversed by day 32 post-SCI, and there were no differences in myocardial contractility between SCI-EX and CON. Collagen deposition was similar between SCI-EX and CON. TGFβ1 and Smad3 were down-regulated in SCI-EX. Blood lipid profiles were improved in SCI-EX versus SCI. We provide compelling novel evidence that passive hind-limb cycling prevents cardiac dysfunction and reduces cardiovascular disease risk in experimental SCI.

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.

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.

Anisotropic Reinforcement of Acute Anteroapical Infarcts Improves Pump Function

PubMed Central

Fomovsky, Gregory M.; Clark, Samantha A.; Parker, Katherine M.; Ailawadi, Gorav; Holmes, Jeffrey W.

2012-01-01

Background We hypothesize that a therapy that improves LV pump function early after infarction should decrease the need for compensation through sympathetic activation and dilation, thereby reducing the risk of developing heart failure. The mechanical properties of healing myocardial infarcts are an important determinant of left ventricular (LV) function, yet improving function by altering infarct properties has proven unexpectedly difficult. Using a computational model, we recently predicted that stiffening a large anterior infarct anisotropically (in only one direction) would improve LV function, while isotropic stiffening, the focus of previous studies and therapies, would not. The goal of this study was to test the novel strategy of anisotropic infarct reinforcement. Methods and Results We tested the effects of anisotropic infarct reinforcement in 10 open-chest dogs with large anteroapical infarcts that depressed LV pump function. We measured regional mechanics, LV volumes, and cardiac output at a range of preloads at Baseline, 45 minutes after coronary ligation (Ischemia), and 30 minutes later, following surgical reinforcement in the longitudinal direction (Anisotropic). Ischemia shifted the end-systolic pressure-volume relationship (ESPVR) and cardiac output curves rightward, decreasing cardiac output at matched end-diastolic pressure (EDP) by 44%. Anisotropic reinforcement significantly improved systolic function without impairing diastolic function, recovering half the deficit in overall LV function. Conclusions We conclude that anisotropic reinforcement is a promising new approach to improving LV function following a large myocardial infarction. PMID:22665716

Transjugular intrahepatic portosystemic shunt: impact on systemic hemodynamics and renal and cardiac function in patients with cirrhosis.

PubMed

Busk, Troels M; Bendtsen, Flemming; Poulsen, Jørgen H; Clemmesen, Jens O; Larsen, Fin S; Goetze, Jens P; Iversen, Jens S; Jensen, Magnus T; Møgelvang, Rasmus; Pedersen, Erling B; Bech, Jesper N; Møller, Søren

2018-02-01

Transjugular intrahepatic portosystemic shunt (TIPS) alleviates portal hypertension and possibly increases central blood volume (CBV). Moreover, renal function often improves; however, its effects on cardiac function are unclear. The aims of our study were to examine the effects of TIPS on hemodynamics and renal and cardiac function in patients with cirrhosis. In 25 cirrhotic patients, we analyzed systemic, cardiac, and splanchnic hemodynamics by catheterization of the liver veins and right heart chambers before and 1 wk after TIPS. Additionally, we measured renal and cardiac markers and performed advanced echocardiography before, 1 wk after, and 4 mo after TIPS. CBV increased significantly after TIPS (+4.6%, P < 0.05). Cardiac output (CO) increased (+15.3%, P < 0.005) due to an increase in stroke volume (SV) (+11.1%, P < 0.005), whereas heart rate (HR) was initially unchanged. Cardiopulmonary pressures increased after TIPS, whereas copeptin, a marker of vasopressin, decreased (-18%, P < 0.005) and proatrial natriuretic peptide increased (+52%, P < 0.0005) 1 wk after TIPS and returned to baseline 4 mo after TIPS. Plasma neutrophil gelatinase-associated lipocalin, renin, aldosterone, and serum creatinine decreased after TIPS (-36%, P < 0.005; -65%, P < 0.05; -90%, P < 0.005; and -13%, P < 0.005, respectively). Echocardiography revealed subtle changes in cardiac function after TIPS, although these were within the normal range. TIPS increases CBV by increasing CO and SV, whereas HR is initially unaltered. These results indicate an inability to increase the heart rate in response to a hemodynamic challenge that only partially increases CBV after TIPS. These changes, however, are sufficient for improving renal function. NEW & NOTEWORTHY For the first time, we have combined advanced techniques to study the integrated effects of transjugular intrahepatic portosystemic shunt (TIPS) in cirrhosis. We showed that TIPS increases central blood volume (CBV) through improved

[Improvement and the mechanism of cardiac function by knockdown of ADAM10 in adriamycin-induced cardiomyopathy rats].

PubMed

Li, Xiaoou; Xie, Lili; He, Bing; Huang, Wei

2018-01-01

Objective To study the role of a disintegrin and metalloproteinase10 (ADAM10) in shedding neural cadherin (N-cadherin) and develop an approach to interfere the process of ventricular remodeling in adriamycin-induced cardiomyopathy (ACM) rats. Methods In a rat model of ACM, the effects of intraperitoneal injection of the lentiviral RNAi vector of ADAM10 on the morphology of cardiomyocytes and contractile function were observed by HE staining and color Doppler echocardiography. The expressions of N-cadherin and C-terminal fragment 1 (CTF1) were detected by Western blotting and immunohistochemistry. Results In the in vivo experiment, a large amount of fluorescence was seen in the isolated primary cardiomyocytes, which indicated that the transfection in the rat model was successful. In the treatment group, the morphology of cardiomyocytes and function of the heart were evidently improved, N-cadherin protein expression was remarkably up-regulated and CTF1 protein was obviously down-regulated compared with the model group. Conclusion Knock-down of ADAM10 increases N-cadherin expression and decreases CTF1 expression, thus improves cardiac function in the rat model of ACM.

Cardiac structure and function in Cushing's syndrome: a cardiac magnetic resonance imaging study.

PubMed

Kamenický, Peter; Redheuil, Alban; Roux, Charles; Salenave, Sylvie; Kachenoura, Nadjia; Raissouni, Zainab; Macron, Laurent; Guignat, Laurence; Jublanc, Christel; Azarine, Arshid; Brailly, Sylvie; Young, Jacques; Mousseaux, Elie; Chanson, Philippe

2014-11-01

Patients with Cushing's syndrome have left ventricular (LV) hypertrophy and dysfunction on echocardiography, but echo-based measurements may have limited accuracy in obese patients. No data are available on right ventricular (RV) and left atrial (LA) size and function in these patients. The objective of the study was to evaluate LV, RV, and LA structure and function in patients with Cushing's syndrome by means of cardiac magnetic resonance, currently the reference modality in assessment of cardiac geometry and function. Eighteen patients with active Cushing's syndrome and 18 volunteers matched for age, sex, and body mass index were studied by cardiac magnetic resonance. The imaging was repeated in the patients 6 months (range 2-12 mo) after the treatment of hypercortisolism. Compared with controls, patients with Cushing's syndrome had lower LV, RV, and LA ejection fractions (P < .001 for all) and increased end-diastolic LV segmental thickness (P < .001). Treatment of hypercortisolism was associated with an improvement in ventricular and atrial systolic performance, as reflected by a 15% increase in the LV ejection fraction (P = .029), a 45% increase in the LA ejection fraction (P < .001), and an 11% increase in the RV ejection fraction (P = NS). After treatment, the LV mass index and end-diastolic LV mass to volume ratio decreased by 17% (P < .001) and 10% (P = .002), respectively. None of the patients had late gadolinium myocardial enhancement. Cushing's syndrome is associated with subclinical biventricular and LA systolic dysfunctions that are reversible after treatment. Despite skeletal muscle atrophy, Cushing's syndrome patients have an increased LV mass, reversible upon correction of hypercortisolism.

Regular Football Practice Improves Autonomic Cardiac Function in Male Children

PubMed Central

Fernandes, Luis; Oliveira, Jose; Soares-Miranda, Luisa; Rebelo, Antonio; Brito, Joao

2015-01-01

Background: The role of the autonomic nervous system (ANS) in the cardiovascular regulation is of primal importance. Since it has been associated with adverse conditions such as cardiac arrhythmias, sudden death, sleep disorders, hypertension and obesity. Objectives: The present study aimed to investigate the impact of recreational football practice on the autonomic cardiac function of male children, as measured by heart rate variability. Patients and Methods: Forty-seven male children aged 9 - 12 years were selected according to their engagement with football oriented practice outside school context. The children were divided into a football group (FG; n = 22) and a control group (CG; n = 25). The FG had regular football practices, with 2 weekly training sessions and occasional weekend matches. The CG was not engaged with any physical activity other than complementary school-based physical education classes. Data from physical activity, physical fitness, and heart rate variability measured in time and frequency domains were obtained. Results: The anthropometric and body composition characteristics were similar in both groups (P > 0.05). The groups were also similar in time spent daily on moderate-to-vigorous physical activities (FG vs. CG: 114 ± 64 vs. 87 ± 55 minutes; P > 0.05). However, the FG performed better (P < 0.05) in Yo-Yo intermittent endurance test (1394 ± 558 vs. 778 ± 408 m) and 15-m sprint test (3.06 ± 0.17 vs. 3.20 ± 0.23 s). Also, the FG presented enhanced autonomic function. Significant differences were detected (P < 0.05) between groups for low frequency normalized units (38.0 ± 15.2 vs. 47.3 ± 14.2 n.u (normalized units)), high frequency normalized units (62.1 ± 15.2 vs. 52.8 ± 14.2 n.u.), and LF:HF ratio (0.7 ± 0.4 vs. 1.1 ± 0.6 ms2). Conclusions: Children engaged with regular football practice presented enhanced physical fitness and autonomic function, by increasing vagal tone at rest. PMID:26448848

Regular Football Practice Improves Autonomic Cardiac Function in Male Children.

PubMed

Fernandes, Luis; Oliveira, Jose; Soares-Miranda, Luisa; Rebelo, Antonio; Brito, Joao

2015-09-01

The role of the autonomic nervous system (ANS) in the cardiovascular regulation is of primal importance. Since it has been associated with adverse conditions such as cardiac arrhythmias, sudden death, sleep disorders, hypertension and obesity. The present study aimed to investigate the impact of recreational football practice on the autonomic cardiac function of male children, as measured by heart rate variability. Forty-seven male children aged 9 - 12 years were selected according to their engagement with football oriented practice outside school context. The children were divided into a football group (FG; n = 22) and a control group (CG; n = 25). The FG had regular football practices, with 2 weekly training sessions and occasional weekend matches. The CG was not engaged with any physical activity other than complementary school-based physical education classes. Data from physical activity, physical fitness, and heart rate variability measured in time and frequency domains were obtained. The anthropometric and body composition characteristics were similar in both groups (P > 0.05). The groups were also similar in time spent daily on moderate-to-vigorous physical activities (FG vs. CG: 114 ± 64 vs. 87 ± 55 minutes; P > 0.05). However, the FG performed better (P < 0.05) in Yo-Yo intermittent endurance test (1394 ± 558 vs. 778 ± 408 m) and 15-m sprint test (3.06 ± 0.17 vs. 3.20 ± 0.23 s). Also, the FG presented enhanced autonomic function. Significant differences were detected (P < 0.05) between groups for low frequency normalized units (38.0 ± 15.2 vs. 47.3 ± 14.2 n.u (normalized units)), high frequency normalized units (62.1 ± 15.2 vs. 52.8 ± 14.2 n.u.), and LF:HF ratio (0.7 ± 0.4 vs. 1.1 ± 0.6 ms(2)). Children engaged with regular football practice presented enhanced physical fitness and autonomic function, by increasing vagal tone at rest.

Chronic resuscitation after trauma-hemorrhage and acute fluid replacement improves hepatocellular function and cardiac output.

PubMed

Remmers, D E; Wang, P; Cioffi, W G; Bland, K I; Chaudry, I H

1998-01-01

To determine whether prolonged (chronic) resuscitation has any beneficial effects on cardiac output and hepatocellular function after trauma-hemorrhage and acute fluid replacement. Acute fluid resuscitation after trauma-hemorrhage restores but does not maintain the depressed hepatocellular function and cardiac output. Male Sprague-Dawley rats underwent a 5-cm laparotomy (i.e., trauma was induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer's lactate (RL). The animals were acutely resuscitated with RL using 4 times the volume of maximum bleed-out over 60 minutes, followed by chronic resuscitation of 0, 5, or 10 mL/kg/hr RL for 20 hours. Hepatocellular function was determined by an in vivo indocyanine green clearance technique. Hepatic microvascular blood flow was assessed by laser Doppler flowmetry. Plasma levels of interleukin-6 (IL-6) were determined by bioassay. Chronic resuscitation with 5 mL/kg/hr RL, but not with 0 or 10 mL/kg/hr RL, restored cardiac output, hepatocellular function, and hepatic microvascular blood flow at 20 hours after hemorrhage. The regimen above also reduced plasma IL-6 levels. Because chronic resuscitation with 5 mL/kg/hr RL after trauma-hemorrhage and acute fluid replacement restored hepatocellular function and hepatic microvascular blood flow and decreased plasma levels of IL-6, we propose that chronic fluid resuscitation in addition to acute fluid replacement should be routinely used in experimental studies of trauma-hemorrhage.

Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.

PubMed

Byrne, Nikole J; Levasseur, Jody; Sung, Miranda M; Masson, Grant; Boisvenue, Jamie; Young, Martin E; Dyck, Jason R B

2016-05-15

Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Older Adults in Cardiac Rehabilitation: A New Strategy for Enhancing Physical Function.

ERIC Educational Resources Information Center

Rejeski, W. Jack; Foy, Capri Gabrielle; Brawley, Lawrence R.; Brubaker, Peter H.; Focht, Brian C.; Norris, James L., III; Smith, Marci L.

2002-01-01

Contrasted the effect of a group-mediated cognitive- behavioral intervention (GMCB) versus traditional cardiac rehabilitation (CRP) upon changes in objective and self-reported physical function of older adults after 3 months of exercise therapy. Both groups improved significantly. Adults with lower function at the outset of the intervention…

Conversion from cyclosporine to tacrolimus improves renal function and lipid profile after cardiac transplantation.

PubMed

Garlicki, Mirosław; Czub, Paweł; Labuś, Krzysztof; Ehrlich, Marek P; Rdzanek, Hanna

2006-01-01

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. The impact on renal function after conversion from cyclosporine (CsA) to tacrolimus (TAC) is reported. Fifteen patients (men age 42 +/- 11 years) after cardiac transplantation (HTX) were switched from CsA to TAC (mean time after HTX 21 +/- 6 months). There were 13 male and 2 female patients. Mean cholesterol and LDL level at the time of conversion were 217 +/- 65 ml/dl and and 136 +/- 51 mg/100 ml respectively. Indication for HTX was ischemic cardiomyopathy (CMP) in 8, congenital in 3 and dilatative CMP in the remaining 4 patients. Mean tacrolimus level (microg/dl) at 1, 3, 6 and 12 months were 8.6 +/- 3.3, 8.6 +/- 1.4, 9.2 +/- 2.8 and 9.8 +/- 2.5 respectively. There was a statistically significant improvement in creatinine levels at 1, 3, 6 and 12 months after conversion from baseline 1.9 +/- 0.7 mg/dl to 1.4 +/- 0.5 mg/dl, 1.4 +/- 0.4 mg/dl, 1.3 +/- 0.4 mg/dl and 1.2 +/- 0.4 mg/dl, respectively (p < 0.05). Furthermore, TAC decreased cholesterol as well as LDL-levels during this one-year time frame. This study shows that conversion from CsA to tacrolimus after orthotopic heart transplantation improves renal function.

Relationship between improvement in left ventricular dyssynchrony and contractile function and clinical outcome with cardiac resynchronization therapy: the MADIT-CRT trial.

PubMed

Pouleur, Anne-Catherine; Knappe, Dorit; Shah, Amil M; Uno, Hajime; Bourgoun, Mikhail; Foster, Elyse; McNitt, Scott; Hall, W Jackson; Zareba, Wojciech; Goldenberg, Ilan; Moss, Arthur J; Pfeffer, Marc A; Solomon, Scott D

2011-07-01

To assess long-term effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) dyssynchrony and contractile function, by two-dimensional speckle-tracking echocardiography, compared with implantable cardioverter defibrillator (ICD) only in MADIT-CRT. We studied 761 patients in New York Heart Association I/II, ejection fraction ≤30%, and QRS ≥130 ms [n = 434, CRT-defibrillator (CRT-D), n = 327, ICD] with echocardiographic studies available at baseline and 12 months. Dyssynchrony was determined as the standard deviation of time to peak transverse strain between 12 segments of apical four- and two-chamber views, and contractile function as global longitudinal strain (GLS) by averaging longitudinal strain over these 12 segments. We compared changes in LV dyssynchrony and contractile function between treatment groups and assessed relationships between these changes over the first year and subsequent outcomes (median post 1-year follow-up = 14.9 months). Mean changes in LV dyssynchrony and contractile function measured by GLS in the overall population were, respectively, -29 ± 83 ms and -1 ± 2.9%. However, both LV dyssynchrony (CRT-D: -47 ± 83 ms vs. ICD: -6 ± 76 ms, P < 0.001) and contractile function (CRT-D: -1.4 ± 3.1% vs. ICD: -0.4 ± 2.5%, P < 0.001) improved to a greater extent in the CRT-D group compared with the ICD-only group. A greater improvement in dyssynchrony and contractile function at 1 year was associated with lower rates of the subsequent primary outcome of death or heart failure, adjusting for baseline dyssynchrony and contractile function, treatment arm, ischaemic status, and change in LV end-systolic volume. Each 20 ms decrease in LV dyssynchrony was associated with a 7% reduction in the primary outcome (P = 0.047); each 1% improvement in GLS over the 12-month period was associated with a 24% reduction in the primary outcome (P < 0.001). Cardiac resynchronization therapy resulted in a significant improvement in both LV

Novel All-Extremity High-Intensity Interval Training Improves Aerobic Fitness, Cardiac Function and Insulin Resistance in Healthy Older Adults

PubMed Central

Hwang, Chueh-Lung; Yoo, Jeung-Ki; Kim, Han-Kyul; Hwang, Moon-Hyon; Handberg, Eileen M.; Petersen, John W.; Christou, Demetra D.

2016-01-01

Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1 years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4 minutes 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4x/week for 8 weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001) respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance. PMID:27346646

Novel all-extremity high-intensity interval training improves aerobic fitness, cardiac function and insulin resistance in healthy older adults.

PubMed

Hwang, Chueh-Lung; Yoo, Jeung-Ki; Kim, Han-Kyul; Hwang, Moon-Hyon; Handberg, Eileen M; Petersen, John W; Christou, Demetra D

2016-09-01

Aging is associated with decreased aerobic fitness and cardiac remodeling leading to increased risk for cardiovascular disease. High-intensity interval training (HIIT) on the treadmill has been reported to be more effective in ameliorating these risk factors compared with moderate-intensity continuous training (MICT) in patients with cardiometabolic disease. In older adults, however, weight-bearing activities are frequently limited due to musculoskeletal and balance problems. The purpose of this study was to examine the feasibility and safety of non-weight-bearing all-extremity HIIT in older adults. In addition, we tested the hypothesis that all-extremity HIIT will be more effective in improving aerobic fitness, cardiac function, and metabolic risk factors compared with all-extremity MICT. Fifty-one healthy sedentary older adults (age: 65±1years) were randomized to HIIT (n=17), MICT (n=18) or non-exercise control (CONT; n=16). HIIT (4×4min 90% of peak heart rate; HRpeak) and isocaloric MICT (70% of HRpeak) were performed on a non-weight-bearing all-extremity ergometer, 4×/week for 8weeks under supervision. All-extremity HIIT was feasible in older adults and resulted in no adverse events. Aerobic fitness (peak oxygen consumption; VO2peak) and ejection fraction (echocardiography) improved by 11% (P<0.0001) and 4% (P=0.001), respectively in HIIT, while no changes were observed in MICT and CONT (P≥0.1). Greater improvements in ejection fraction were associated with greater improvements in VO2peak (r=0.57; P<0.0001). Insulin resistance (homeostatic model assessment) decreased only in HIIT by 26% (P=0.016). Diastolic function, body composition, glucose and lipids were unaffected (P≥0.1). In conclusion, all-extremity HIIT is feasible and safe in older adults. HIIT, but not MICT, improved aerobic fitness, ejection fraction, and insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac Structure and Function in Cushing's Syndrome: A Cardiac Magnetic Resonance Imaging Study

PubMed Central

Roux, Charles; Salenave, Sylvie; Kachenoura, Nadjia; Raissouni, Zainab; Macron, Laurent; Guignat, Laurence; Jublanc, Christel; Azarine, Arshid; Brailly, Sylvie; Young, Jacques; Mousseaux, Elie; Chanson, Philippe

2014-01-01

Background: Patients with Cushing's syndrome have left ventricular (LV) hypertrophy and dysfunction on echocardiography, but echo-based measurements may have limited accuracy in obese patients. No data are available on right ventricular (RV) and left atrial (LA) size and function in these patients. Objectives: The objective of the study was to evaluate LV, RV, and LA structure and function in patients with Cushing's syndrome by means of cardiac magnetic resonance, currently the reference modality in assessment of cardiac geometry and function. Methods: Eighteen patients with active Cushing's syndrome and 18 volunteers matched for age, sex, and body mass index were studied by cardiac magnetic resonance. The imaging was repeated in the patients 6 months (range 2–12 mo) after the treatment of hypercortisolism. Results: Compared with controls, patients with Cushing's syndrome had lower LV, RV, and LA ejection fractions (P < .001 for all) and increased end-diastolic LV segmental thickness (P < .001). Treatment of hypercortisolism was associated with an improvement in ventricular and atrial systolic performance, as reflected by a 15% increase in the LV ejection fraction (P = .029), a 45% increase in the LA ejection fraction (P < .001), and an 11% increase in the RV ejection fraction (P = NS). After treatment, the LV mass index and end-diastolic LV mass to volume ratio decreased by 17% (P < .001) and 10% (P = .002), respectively. None of the patients had late gadolinium myocardial enhancement. Conclusion: Cushing's syndrome is associated with subclinical biventricular and LA systolic dysfunctions that are reversible after treatment. Despite skeletal muscle atrophy, Cushing's syndrome patients have an increased LV mass, reversible upon correction of hypercortisolism. PMID:25093618

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

Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study

PubMed Central

Kume, Satoshi; Nishimura, Yukako; Mizuno, Kei; Sakimoto, Nae; Hori, Hiroshi; Tamura, Yasuhisa; Yamato, Masanori; Mitsuhashi, Rika; Akiba, Keigo; Koizumi, Jun-ichi; Watanabe, Yasuyoshi; Kataoka, Yosky

2017-01-01

It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension–Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes

Music Improves Subjective Feelings Leading to Cardiac Autonomic Nervous Modulation: A Pilot Study.

PubMed

Kume, Satoshi; Nishimura, Yukako; Mizuno, Kei; Sakimoto, Nae; Hori, Hiroshi; Tamura, Yasuhisa; Yamato, Masanori; Mitsuhashi, Rika; Akiba, Keigo; Koizumi, Jun-Ichi; Watanabe, Yasuyoshi; Kataoka, Yosky

2017-01-01

It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension-Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes

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

Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy

PubMed Central

Niu, Youguo; Herrera, Emilio A; Evans, Rhys D; Giussani, Dino A

2013-01-01

Glucocorticoids are widely used to treat chronic lung disease in premature infants but their longer-term adverse effects on the cardiovascular system raise concerns. We reported that neonatal dexamethasone treatment in rats induced in the short term molecular indices of cardiac oxidative stress and cardiovascular tissue remodelling at weaning, and that neonatal combined antioxidant and dexamethasone treatment was protective at this time. In this study, we investigated whether such effects of neonatal dexamethasone have adverse consequences for NO bioavailability and cardiovascular function at adulthood, and whether neonatal combined antioxidant and dexamethasone treatment is protective in the adult. Newborn rat pups received daily i.p. injections of a human-relevant tapering dose of dexamethasone (D; n= 8; 0.5, 0.3, 0.1 μg g−1) or D with vitamins C and E (DCE; n= 8; 200 and 100 mg kg−1, respectively) on postnatal days 1–3 (P1–3); vitamins were continued from P4 to P6. Controls received equal volumes of vehicle from P1 to P6 (C; n= 8). A fourth group received vitamins alone (CCE; n= 8). At P100, plasma NO metabolites (NOx) was measured and isolated hearts were assessed under both Working and Langendorff preparations. Relative to controls, neonatal dexamethasone therapy increased mortality by 18% (P < 0.05). Surviving D pups at adulthood had lower plasma NOx concentrations (10.6 ± 0.8 vs. 28.0 ± 1.5 μm), an increased relative left ventricular (LV) mass (70 ± 2 vs. 63 ± 1%), enhanced LV end-diastolic pressure (14 ± 2 vs. 8 ± 1 mmHg) and these hearts failed to adapt output with increased preload (Δcardiac output: 2.9 ± 2.0 vs. 10.6 ± 1.2 ml min−1) or afterload (Δcardiac output: −5.3 ± 2.0 vs.1.4 ± 1.2 ml min−1); all P < 0.05. Combined neonatal dexamethasone with antioxidant vitamins improved postnatal survival, restored plasma NOx and protected against cardiac dysfunction at adulthood. In conclusion, neonatal dexamethasone therapy promotes

Low-dose β-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure.

PubMed

Kobayashi, Shigeki; Susa, Takehisa; Tanaka, Takeo; Murakami, Wakako; Fukuta, Seiko; Okuda, Shinichi; Doi, Masahiro; Wada, Yasuaki; Nao, Tomoko; Yamada, Jutaro; Okamura, Takayuki; Yano, Masafumi; Matsuzaki, Masunori

2012-01-01

The purpose of this study was to determine whether a low-dose β-blocker, in combination with milrinone, improves cardiac function in acute decompensated heart failure (ADHF) with tachycardia. Twenty ADHF patients (New York Heart Association classification III, n=1, and IV, n=19; heart rate [HR], 107±12 beats/min; left ventricular ejection fraction, 24±7%; cardiac index [CI], 2.2±0.6 L·min(-1)·m(-2); pulmonary capillary wedge pressure [PCWP], 26±8 mmHg) were enrolled in this study. The patients first underwent conventional therapy with milrinone, vasodilators and diuretics; landiolol (1.5-6.0 µg·kg(-1)·min(-1); i.v.), which is an ultra-short-acting β(1)-selective blocker, was then added to the treatment regimen to study its effect on hemodynamics. Low-dose landiolol (1.5 µg·kg(-1)·min(-1)) significantly reduced HR by 11% without changing blood pressure (BP) and CI, whereas higher doses (≥3.0 µg·kg(-1)·min(-1)) tended to decrease BP and CI while increasing PCWP and systemic vascular resistance. After treatment with landiolol (1.5 µg·kg(-1)·min(-1)), hemodynamic parameters such as PCWP, stroke volume index, SvO(2), rate pressure product, filling time/RR, E/e', and Tei index were significantly improved. A low-dose β-blocker in combination with milrinone improved cardiac function in ADHF patients with tachycardia; therefore, it may be considered as an adjunct therapy for use when standard therapy with milrinone is not effective at slowing HR.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats.

PubMed

Luck, Christian; DeMarco, Vincent G; Mahmood, Abuzar; Gavini, Madhavi P; Pulakat, Lakshmi

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750  μ g/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters ( E / E ', E '/ A ', E / Vp ) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFN γ , and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes.

Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

PubMed Central

Luck, Christian; DeMarco, Vincent G.; Mahmood, Abuzar; Gavini, Madhavi P.

2017-01-01

Diabetes is comorbid with cardiovascular disease and impaired immunity. Rapamycin improves cardiac functions and extends lifespan by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1). However, in diabetic murine models, Rapamycin elevates hyperglycemia and reduces longevity. Since Rapamycin is an immunosuppressant, we examined whether Rapamycin (750 μg/kg/day) modulates intracardiac cytokines, which affect the cardiac immune response, and cardiac function in male lean (ZL) and diabetic obese Zucker (ZO) rats. Rapamycin suppressed levels of fasting triglycerides, insulin, and uric acid in ZO but increased glucose. Although Rapamycin improved multiple diastolic parameters (E/E′, E′/A′, E/Vp) initially, these improvements were reversed or absent in ZO at the end of treatment, despite suppression of cardiac fibrosis and phosphoSer473Akt. Intracardiac cytokine protein profiling and Ingenuity® Pathway Analysis indicated suppression of intracardiac immune defense in ZO, in response to Rapamycin treatment in both ZO and ZL. Rapamycin increased fibrosis in ZL without increasing phosphoSer473Akt and differentially modulated anti-fibrotic IL-10, IFNγ, and GM-CSF in ZL and ZO. Therefore, fundamental difference in intracardiac host defense between diabetic ZO and healthy ZL, combined with differential regulation of intracardiac cytokines by Rapamycin in ZO and ZL hearts, underlies differential cardiac outcomes of Rapamycin treatment in health and diabetes. PMID:28408970

High intensity intermittent exercise improves cardiac structure and function and reduces liver fat in patients with type 2 diabetes: a randomised controlled trial.

PubMed

Cassidy, Sophie; Thoma, Christian; Hallsworth, Kate; Parikh, Jehill; Hollingsworth, Kieren G; Taylor, Roy; Jakovljevic, Djordje G; Trenell, Michael I

2016-01-01

Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated. Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (n = 14) or standard care (n = 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by 1H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK. Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs. 107 ± 25 g to 105 ± 25 g, p < 0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs. 79 ± 14 ml to 75 ± 15 ml, p < 0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs. 250 ± 44 ml/s to 251 ± 47 ml/s, p < 0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs. 7.1 ± 2.2° to 7.6 ± 1.9°, p < 0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (p < 0.05) and a reduction in HbA1c (7.1 ± 1.0% [54.5 mmol/mol] to 6.8 ± 0.9% [51.3 mmol/mol] vs. 7.2 ± 0.5% [54.9 mmol/mol] to 7.4 ± 0.7% [57.0 mmol/mol], p < 0.05). Changes in liver fat correlated with changes in HbA1c (r = 0.70, p < 0.000) and 2 h glucose

Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice.

PubMed

Dobrzyn, Pawel; Dobrzyn, Agnieszka; Miyazaki, Makoto; Ntambi, James M

2010-08-01

The heart of leptin-deficient ob/ob mice is characterized by pathologic left ventricular hypertrophy along with elevated triglyceride (TG) content, increased stearoyl-CoA desaturase (SCD) activity, and increased myocyte apoptosis. In the present study, using an ob/ob;SCD1(-/-) mouse model, we tested the hypothesis that lack of SCD1 could improve steatosis and left ventricle (LV) function in leptin deficiency. We show that disruption of the SCD1 gene improves cardiac function in ob/ob mice by correcting systolic and diastolic dysfunction without affecting levels of plasma TG and FFA. The improvement is associated with reduced expression of genes involved in FA transport and lipid synthesis in the heart, as well as reduction in cardiac FFA, diacylglycerol, TG, and ceramide levels. The rate of FA beta-oxidation is also significantly lower in the heart of ob/ob;SCD1(-/-) mice compared with ob/ob controls. Moreover, SCD1 deficiency reduces cardiac apoptosis in ob/ob mice due to increased expression of antiapoptotic factor Bcl-2 and inhibition of inducible nitric oxide synthase and caspase-3 activities. Reduction in myocardial lipid accumulation and inhibition of apoptosis appear to be one of the main mechanisms responsible for improved LV function in ob/ob mice caused by SCD1 deficiency.

3D bioprinted functional and contractile cardiac tissue constructs

PubMed Central

Wang, Zhan; Lee, Sang Jin; Cheng, Heng-Jie; Yoo, James J.; Atala, Anthony

2018-01-01

Bioengineering of a functional cardiac tissue composed of primary cardiomyocytes has great potential for myocardial regeneration and in vitro tissue modeling. However, its applications remain limited because the cardiac tissue is a highly organized structure with unique physiologic, biomechanical, and electrical properties. In this study, we undertook a proof-of-concept study to develop a contractile cardiac tissue with cellular organization, uniformity, and scalability by using three-dimensional (3D) bioprinting strategy. Primary cardiomyocytes were isolated from infant rat hearts and suspended in a fibrin-based bioink to determine the priting capability for cardiac tissue engineering. This cell-laden hydrogel was sequentially printed with a sacrificial hydrogel and a supporting polymeric frame through a 300-μm nozzle by pressured air. Bioprinted cardiac tissue constructs had a spontaneous synchronous contraction in culture, implying in vitro cardiac tissue development and maturation. Progressive cardiac tissue development was confirmed by immunostaining for α-actinin and connexin 43, indicating that cardiac tissues were formed with uniformly aligned, dense, and electromechanically coupled cardiac cells. These constructs exhibited physiologic responses to known cardiac drugs regarding beating frequency and contraction forces. In addition, Notch signaling blockade significantly accelerated development and maturation of bioprinted cardiac tissues. Our results demonstrated the feasibility of bioprinting functional cardiac tissues that could be used for tissue engineering applications and pharmaceutical purposes. PMID:29452273

Cardiac and peripheral adjustments induced by early exercise training intervention were associated with autonomic improvement in infarcted rats: role in functional capacity and mortality.

PubMed

Jorge, Luciana; Rodrigues, Bruno; Rosa, Kaleizu Teodoro; Malfitano, Christiane; Loureiro, Tatiana Carolina Alba; Medeiros, Alessandra; Curi, Rui; Brum, Patricia Chakur; Lacchini, Silvia; Montano, Nicola; De Angelis, Kátia; Irigoyen, Maria-Cláudia

2011-04-01

To test the effects of early exercise training (ET) on left ventricular (LV) and autonomic functions, haemodynamics, tissues blood flows (BFs), maximal oxygen consumption (VO(2) max), and mortality after myocardial infarction (MI) in rats. Male Wistar rats were divided into: control (C), sedentary-infarcted (SI), and trained-infarcted (TI). One week after MI, TI group underwent an ET protocol (90 days, 50-70% VO(2) max). Left ventricular function was evaluated non-invasively and invasively. Baroreflex sensitivity, heart rate variability, and pulse interval were measured. Cardiac output (CO) and regional BFs were determined using coloured microspheres. Infarcted area was reduced in TI (19 ± 6%) compared with SI (34 ± 5%) after ET. Exercise training improved the LV and autonomic functions, the CO and regional BF changes induced by MI, as well as increased SERCA2 expression and mRNA vascular endothelial growth factor levels. These changes brought about by ET resulted in mortality rate reduction in the TI (13%) group compared with the SI (54%) group. Early aerobic ET reduced cardiac and peripheral dysfunctions and preserved cardiovascular autonomic control after MI in trained rats. Consequently, these ET-induced changes resulted in improved functional capacity and survival after MI.

Cardiac Function in Young and Old Little Mice

PubMed Central

Reddy, Anilkumar K.; Amador-Noguez, Daniel; Darlington, Gretchen J.; Scholz, Beth A.; Michael, Lloyd H.; Hartley, Craig J.; Entman, Mark L.; Taffet, George E.

2009-01-01

We studied cardiac function in young and old, wild-type (WT), and longer-living Little mice using cardiac flow velocities, echocardiographic measurements, and left ventricular (LV) pressure (P) to determine if enhanced reserves were in part responsible for longevity in these mice. Resting/baseline cardiac function, as measured by velocities, LV dimensions, +dP/dtmax, and −dP/dtmax, was significantly lower in young Little mice versus young WT mice. Fractional shortening (FS) increased significantly, and neither +dP/dtmax nor −dP/dtmax declined with age in Little mice. In contrast, old WT mice had no change in FS but had significantly lower +dP/dtmax and −dP/dtmax versus young WT mice. Significant decreases were observed in the velocity indices of old Little mice versus old WT mice, but other parameters were unchanged. The magnitude of dobutamine stress response remained unchanged with age in Little mice, while that in WT mice decreased. These data suggest that while resting cardiac function in Little mice versus WT mice is lower at young age, it is relatively unaltered with aging. Additionally, cardiac function in response to stress was maintained with age in Little mice but not in their WT counterparts. Thus, some mouse models of increased longevity may not be associated with enhanced reserves. PMID:18166681

Stem Cell Therapy with Overexpressed VEGF and PDGF Genes Improves Cardiac Function in a Rat Infarct Model

PubMed Central

Das, Hiranmoy; George, Jon C.; Joseph, Matthew; Das, Manjusri; Abdulhameed, Nasreen; Blitz, Anna; Khan, Mahmood; Sakthivel, Ramasamy; Mao, Hai-Quan; Hoit, Brian D.; Kuppusamy, Periannan; Pompili, Vincent J.

2009-01-01

Background Therapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+/CD34+) genetically modified with VEGF plus PDGF genes (VIP). Methods and Findings Myocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue velocity, wall motion score index, strain and strain rate in animals treated with VEGF plus PDGF overexpressed stem cells (VIP) compared to nanofiber expanded cells (Exp), freshly isolated cells (FCB) or media control (Media). Improvement observed was as follows: VIP>Exp> FCB>media. Similar trend was noticed in the exercise capacity of rats on a treadmill. These findings correlated with significantly increased neovascularization in ischemic tissue and markedly reduced infarct area in animals in the VIP group. Stem cells in addition to their usual homing sites such as lung, spleen, bone marrow and liver, also migrated to sites of myocardial ischemia. The improvement of cardiac function correlated with expression of heart tissue connexin 43, a gap junctional protein, and heart tissue angiogenesis related protein molecules like VEGF, pNOS3, NOS2 and GSK3. There was no evidence of upregulation in the molecules of oncogenic potential in genetically modified or other stem cell therapy groups. Conclusion Regenerative therapy using nanofiber-expanded hematopoietic stem cells with overexpression of VEGF and PDGF has a favorable impact on the improvement of rat myocardial function accompanied by upregulation of tissue connexin 43 and pro-angiogenic molecules after infarction. PMID:19809493

TRPV2 is critical for the maintenance of cardiac structure and function in mice

PubMed Central

Katanosaka, Yuki; Iwasaki, Keiichiro; Ujihara, Yoshihiro; Takatsu, Satomi; Nishitsuji, Koki; Kanagawa, Motoi; Sudo, Atsushi; Toda, Tatsushi; Katanosaka, Kimiaki; Mohri, Satoshi; Naruse, Keiji

2014-01-01

The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2+ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2+-dependent intracellular Ca2+ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function. PMID:24874017

TRPV2 is critical for the maintenance of cardiac structure and function in mice.

PubMed

Katanosaka, Yuki; Iwasaki, Keiichiro; Ujihara, Yoshihiro; Takatsu, Satomi; Nishitsuji, Koki; Kanagawa, Motoi; Sudo, Atsushi; Toda, Tatsushi; Katanosaka, Kimiaki; Mohri, Satoshi; Naruse, Keiji

2014-05-29

The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca(2+) handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca(2+)-dependent intracellular Ca(2+) increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function.

Defining the Intrinsic Cardiac Risks of Operations to Improve Preoperative Cardiac Risk Assessments.

PubMed

Liu, Jason B; Liu, Yaoming; Cohen, Mark E; Ko, Clifford Y; Sweitzer, Bobbie J

2018-02-01

Current preoperative cardiac risk stratification practices group operations into broad categories, which might inadequately consider the intrinsic cardiac risks of individual operations. We sought to define the intrinsic cardiac risks of individual operations and to demonstrate how grouping operations might lead to imprecise estimates of perioperative cardiac risk. Elective operations (based on Common Procedural Terminology codes) performed from January 1, 2010 to December 31, 2015 at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program were studied. A composite measure of perioperative adverse cardiac events was defined as either cardiac arrest requiring cardiopulmonary resuscitation or acute myocardial infarction. Operations' intrinsic cardiac risks were derived from mixed-effects models while controlling for patient mix. Resultant risks were sorted into low-, intermediate-, and high-risk categories, and the most commonly performed operations within each category were identified. Intrinsic operative risks were also examined using a representative grouping of operations to portray within-group variation. Sixty-six low, 30 intermediate, and 106 high intrinsic cardiac risk operations were identified. Excisional breast biopsy had the lowest intrinsic cardiac risk (overall rate, 0.01%; odds ratio, 0.11; 95% CI, 0.02 to 0.25) relative to the average, whereas aorto-bifemoral bypass grafting had the highest (overall rate, 4.1%; odds ratio, 6.61; 95% CI, 5.54 to 7.90). There was wide variation in the intrinsic cardiac risks of operations within the representative grouping (median odds ratio, 1.40; interquartile range, 0.88 to 2.17). A continuum of intrinsic cardiac risk exists among operations. Grouping operations into broad categories inadequately accounts for the intrinsic cardiac risk of individual operations.

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.

Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling

PubMed Central

Rines, Amy K.; Chang, Hsiang-Chun; Wu, Rongxue; Sato, Tatsuya; Khechaduri, Arineh; Kouzu, Hidemichi; Shapiro, Jason; Shang, Meng; Burke, Michael A.; Abdelwahid, Eltyeb; Jiang, Xinghang; Chen, Chunlei; Rawlings, Tenley A.; Lopaschuk, Gary D.; Schumacker, Paul T.; Abel, E. Dale; Ardehali, Hossein

2017-01-01

Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection. PMID:28117339

Evaluation of cardiac function in active and hibernating grizzly bears.

PubMed

Nelson, O Lynne; McEwen, Margaret-Mary; Robbins, Charles T; Felicetti, Laura; Christensen, William F

2003-10-15

To evaluate cardiac function parameters in a group of active and hibernating grizzly bears. Prospective study. 6 subadult grizzly bears. Indirect blood pressure, a 12-lead ECG, and a routine echocardiogram were obtained in each bear during the summer active phase and during hibernation. All measurements of myocardial contractility were significantly lower in all bears during hibernation, compared with the active period. Mean rate of circumferential left ventricular shortening, percentage fractional shortening, and percentage left ventricular ejection fraction were significantly lower in bears during hibernation, compared with the active period. Certain indices of diastolic function appeared to indicate enhanced ventricular compliance during the hibernation period. Mean mitral inflow ratio and isovolumic relaxation time were greater during hibernation. Heart rate was significantly lower for hibernating bears, and mean cardiac index was lower but not significantly different from cardiac index during the active phase. Contrary to results obtained in hibernating rodent species, cardiac index was not significantly correlated with heart rate. Cardiac function parameters in hibernating bears are opposite to the chronic bradycardic effects detected in nonhibernating species, likely because of intrinsic cardiac muscle adaptations during hibernation. Understanding mechanisms and responses of the myocardium during hibernation could yield insight into mechanisms of cardiac function regulation in various disease states in nonhibernating species.

Health-Related Quality of Life, Functional Status, and Cardiac Event-Free Survival in Patients With Heart Failure.

PubMed

Wu, Jia-Rong; Lennie, Terry A; Frazier, Susan K; Moser, Debra K

2016-01-01

Health-related quality of life (HRQOL), functional status, and cardiac event-free survival are outcomes used to assess the effectiveness of interventions in patients with heart failure (HF). However, the nature of the relationships among HRQOL, functional status, and cardiac event-free survival remains unclear. The purpose of this study is to examine the nature of the relationships among HRQOL, functional status, and cardiac event-free survival in patients with HF. This was a prospective, observational study of 313 patients with HF that was a secondary analysis from a registry. At baseline, patient demographic and clinical data were collected. Health-related quality of life was assessed using the Minnesota Living With Heart Failure Questionnaire and functional status was measured using the Duke Activity Status Index. Cardiac event-free survival data were obtained by patient interview, hospital database, and death certificate review. Multiple linear and Cox regressions were used to explore the relationships among HRQOL, functional status, and cardiac event-free survival while adjusting for demographic and clinical factors. Participants (n = 313) were men (69%), white (79%), and aged 62 ± 11 years. Mean left ventricular ejection fraction was 35% ± 14%. The mean HRQOL score of 32.3 ± 20.6 indicated poor HRQOL. The mean Duke Activity Status Index score of 16.2 ± 12.9 indicated poor functional status. Cardiac event-free survival was significantly worse in patients who had worse HRQOL or poorer functional status. Patients who had better functional status had better HRQOL (P < .001). Health-related quality of life was not a significant predictor of cardiac event-free survival after entering functional status in the model (P = .54), demonstrating that it was a mediator of the relationship between HRQOL and outcome. Functional status was a mediator between HRQOL and cardiac event-free survival. These data suggest that intervention studies to improve functional status

3D bioprinted functional and contractile cardiac tissue constructs.

PubMed

Wang, Zhan; Lee, Sang Jin; Cheng, Heng-Jie; Yoo, James J; Atala, Anthony

2018-04-01

Bioengineering of a functional cardiac tissue composed of primary cardiomyocytes has great potential for myocardial regeneration and in vitro tissue modeling. However, its applications remain limited because the cardiac tissue is a highly organized structure with unique physiologic, biomechanical, and electrical properties. In this study, we undertook a proof-of-concept study to develop a contractile cardiac tissue with cellular organization, uniformity, and scalability by using three-dimensional (3D) bioprinting strategy. Primary cardiomyocytes were isolated from infant rat hearts and suspended in a fibrin-based bioink to determine the priting capability for cardiac tissue engineering. This cell-laden hydrogel was sequentially printed with a sacrificial hydrogel and a supporting polymeric frame through a 300-µm nozzle by pressured air. Bioprinted cardiac tissue constructs had a spontaneous synchronous contraction in culture, implying in vitro cardiac tissue development and maturation. Progressive cardiac tissue development was confirmed by immunostaining for α-actinin and connexin 43, indicating that cardiac tissues were formed with uniformly aligned, dense, and electromechanically coupled cardiac cells. These constructs exhibited physiologic responses to known cardiac drugs regarding beating frequency and contraction forces. In addition, Notch signaling blockade significantly accelerated development and maturation of bioprinted cardiac tissues. Our results demonstrated the feasibility of bioprinting functional cardiac tissues that could be used for tissue engineering applications and pharmaceutical purposes. Cardiovascular disease remains a leading cause of death in the United States and a major health-care burden. Myocardial infarction (MI) is a main cause of death in cardiovascular diseases. MI occurs as a consequence of sudden blocking of blood vessels supplying the heart. When occlusions in the coronary arteries occur, an immediate decrease in nutrient and

Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats

PubMed Central

Chen, Yung-wu; Wessale, Jerry L.

2014-01-01

Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg, P < 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD. PMID:25503724

Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes

PubMed Central

Okazaki, Tatsuma; Ebihara, Satoru; Asada, Masanori; Yamanda, Shinsuke; Saijo, Yoshifumi; Shiraishi, Yasuyuki; Ebihara, Takae; Niu, Kaijun; Mei, He; Arai, Hiroyuki; Yambe, Tomoyuki

2007-01-01

Macrophage colony-stimulating factor (M-CSF), known as a hematopoietic growth factor, induces vascular endothelial growth factor (VEGF) production from skeletal muscles. However, the effects of M-CSF on cardiomyocytes have not been reported. Here, we show M-CSF increases VEGF production from cardiomyocytes, protects cardiomyocytes and myotubes from cell death, and improves cardiac function after ischemic injury. In mice, M-CSF increased VEGF production in hearts and in freshly isolated cardiomyocytes, which showed M-CSF receptor expression. In rat cell line H9c2 cardiomyocytes and myotubes, M-CSF induced VEGF production via the Akt signaling pathway, and M-CSF pretreatment protected these cells from H2O2-induced cell death. M-CSF activated Akt and extracellular signal-regulated kinase signaling pathways and up-regulated downstream anti-apoptotic Bcl-xL expression in these cells. Using goats as a large animal model of myocardial infarction, we found that M-CSF treatment after the onset of myocardial infarction by permanent coronary artery ligation promoted angiogenesis in ischemic hearts but did not reduce the infarct area. M-CSF pretreatment of the goat myocardial infarction model by coronary artery occlusion-reperfusion improved cardiac function, as assessed by hemodynamic parameters and echocardiography. These results suggest M-CSF might be a novel therapeutic agent for ischemic heart disease. PMID:17717142

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

PubMed Central

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

Combining computer modelling and cardiac imaging to understand right ventricular pump function.

PubMed

Walmsley, John; van Everdingen, Wouter; Cramer, Maarten J; Prinzen, Frits W; Delhaas, Tammo; Lumens, Joost

2017-10-01

Right ventricular (RV) dysfunction is a strong predictor of outcome in heart failure and is a key determinant of exercise capacity. Despite these crucial findings, the RV remains understudied in the clinical, experimental, and computer modelling literature. This review outlines how recent advances in using computer modelling and cardiac imaging synergistically help to understand RV function in health and disease. We begin by highlighting the complexity of interactions that make modelling the RV both challenging and necessary, and then summarize the multiscale modelling approaches used to date to simulate RV pump function in the context of these interactions. We go on to demonstrate how these modelling approaches in combination with cardiac imaging have improved understanding of RV pump function in pulmonary arterial hypertension, arrhythmogenic right ventricular cardiomyopathy, dyssynchronous heart failure and cardiac resynchronization therapy, hypoplastic left heart syndrome, and repaired tetralogy of Fallot. We conclude with a perspective on key issues to be addressed by computational models of the RV in the near future. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Myocardin-related transcription factors are required for cardiac development and function

PubMed Central

Mokalled, Mayssa H.; Carroll, Kelli J.; Cenik, Bercin K.; Chen, Beibei; Liu, Ning; Olson, Eric N.; Bassel-Duby, Rhonda

2016-01-01

Myocardin-Related Transcription Factors A and B (MRTF-A and MRTF-B) are highly homologous proteins that function as powerful coactivators of serum response factor (SRF), a ubiquitously expressed transcription factor essential for cardiac development. The SRF/MRTF complex binds to CArG boxes found in the control regions of genes that regulate cytoskeletal dynamics and muscle contraction, among other processes. While SRF is required for heart development and function, the role of MRTFs in the developing or adult heart has not been explored. Through cardiac-specific deletion of MRTF alleles in mice, we show that either MRTF-A or MRTF-B is dispensable for cardiac development and function, whereas deletion of both MRTF-A and MRTF-B causes a spectrum of structural and functional cardiac abnormalities. Defects observed in MRTF-A/B null mice ranged from reduced cardiac contractility and adult onset heart failure to neonatal lethality accompanied by sarcomere disarray. RNA-seq analysis on neonatal hearts identified the most altered pathways in MRTF double knockout hearts as being involved in cytoskeletal organization. Together, these findings demonstrate redundant but essential roles of the MRTFs in maintenance of cardiac structure and function and as indispensible links in cardiac cytoskeletal gene regulatory networks. PMID:26386146

Pulmonary function and health-related quality of life 1-year follow up after cardiac surgery.

PubMed

Westerdahl, Elisabeth; Jonsson, Marcus; Emtner, Margareta

2016-07-08

Pulmonary function is severely reduced in the early period after cardiac surgery, and impairments have been described up to 4-6 months after surgery. Evaluation of pulmonary function in a longer perspective is lacking. In this prospective study pulmonary function and health-related quality of life were investigated 1 year after cardiac surgery. Pulmonary function measurements, health-related quality of life (SF-36), dyspnoea, subjective breathing and coughing ability and pain were evaluated before and 1 year after surgery in 150 patients undergoing coronary artery bypass grafting, valve surgery or combined surgery. One year after surgery the forced vital capacity and forced expiratory volume in 1 s were significantly decreased (by 4-5 %) compared to preoperative values (p < 0.05). Saturation of peripheral oxygen was unchanged 1 year postoperatively compared to baseline. A significantly improved health-related quality of life was found 1 year after surgery, with improvements in all eight aspects of SF-36 (p < 0.001). Sternotomy-related pain was low 1 year postoperatively at rest (median 0 [min-max; 0-7]), while taking a deep breath (0 [0-4]) and while coughing (0 [0-8]). A more pronounced decrease in pulmonary function was associated with dyspnoea limitations and impaired subjective breathing and coughing ability. One year after cardiac surgery static and dynamic lung function measurements were slightly decreased, while health-related quality of life was improved in comparison to preoperative values. Measured levels of pain were low and saturation of peripheral oxygen was same as preoperatively.

Does Lifestyle Exercise After a Cardiac Event Improve Metabolic Syndrome Profile in Older Adults?

PubMed

Wright, Kathy D; Moore-Schiltz, Laura; Sattar, Abdus; Josephson, Richard; Moore, Shirley M

Exercise is a common recommendation to reduce the risk factors of metabolic syndrome, yet there are limited data on the influence of lifestyle exercise after cardiac events on metabolic syndrome factors. The purpose of this study was to determine whether lifestyle exercise improves metabolic syndrome profile in older adults after a cardiac event. Participants were from a post-cardiac-event lifestyle exercise study. Five metabolic syndrome factors were assessed: waist circumference, triglycerides, high-density lipids, glucose, and systolic and diastolic blood pressure. Objective measures of exercise were obtained from heart rate monitors over a year. Logistic regression was used to determine whether participants who engaged in the minimum recommendation of 130 hours of exercise or greater during the 12-month period improved their metabolic syndrome profile by improving at least 1 metabolic syndrome factor. In the sample of 116 participants (74% men; average age, 67.5 years), 43% exercised at the recommended amount (≥130 h/y) and 28% (n = 33) improved their metabolic syndrome profile. After controlling for confounding factors of age, gender, race, diabetes, functional ability, and employment, subjects who exercised at least 130 hours a year were 3.6 times more likely to improve at least 1 metabolic syndrome factor (95% confidence interval, 1.24-10.49). Of the 28% who improved their metabolic syndrome profile, 72% increased their high-density lipoprotein and 60.6% reduced their waist circumference and glucose. After a cardiac event, older patients who engage in lifestyle exercise at the recommended amount have improvement in their metabolic syndrome profile.

Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction.

PubMed

Xiong, Liang; Liu, Yu; Zhou, Mingmin; Wang, Guangji; Quan, Dajun; Shen, Caijie; Shuai, Wei; Kong, Bin; Huang, Congxin; Huang, He

2018-05-31

The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

Intra coronary freshly isolated bone marrow cells transplantation improve cardiac function in patients with ischemic heart disease

PubMed Central

2012-01-01

Background Autologous bone marrow cell transplantation (BMCs-Tx) is a promising novel option for treatment of cardiovascular disease. In this study we analyzed whether intracoronary autologous freshly isolated BMCs-Tx have beneficial effects on cardiac function in patients with ischemic heart disease (IHD). Results In this prospective nonrandomized study we treated 12 patients with IHD by freshly isolated BMCs-Tx by use of point of care system and compared them with a representative 12 control group without cell therapy. Global ejection fraction (EF) and infarct size area were determined by left ventriculography. Intracoronary transplantation of autologous freshly isolated BMCs led to a significant reduction of infarct size (p < 0.001) and an increase of global EF (p = 0.003) as well as infarct wall movement velocity (p < 0.001) after 6 months follow-up compared to control group. In control group there were no significant differences of global EF, infarct size and infarct wall movement velocity between baseline and 6 months after coronary angiography. Furthermore, we found significant decrease in New York Heart Association (NYHA) as well as significant decrease of B-type natriuretic peptide (BNP) level 6 months after intracoronary cell therapy (p < 0.001), whereas there were no significant differences in control group 6 months after coronary angiography. Conclusions These results demonstrate that intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system is safe and may lead to improvement of cardiac function in patients with IHD. Trial registration Registration number: ISRCTN54510226 PMID:22534049

Autonomic control of cardiac function and myocardial oxygen consumption during hypoxic hypoxia.

NASA Technical Reports Server (NTRS)

Erickson, H. H.; Stone, H. L.

1972-01-01

Investigation in 19 conscious dogs of the importance of the sympathetic nervous system in the coronary and cardiac response to altitude (hypoxic) hypoxia. Beta-adrenergic blockade was used to minimize the cardiac effect associated with sympathetic receptors. It is shown that the autonomic nervous system, and particularly the sympathetic nervous system, is responsible for the increase in ventricular function and myocardial oxygen consumption that occurs during hypoxia. Minimizing this response through appropriate conditioning and training may improve the operating efficiency of the heart and reduce the hazard of hypoxia and other environmental stresses, such as acceleration, which are encountered in advanced aircraft systems.

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

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2.

PubMed

Grubb, Søren; Aistrup, Gary L; Koivumäki, Jussi T; Speerschneider, Tobias; Gottlieb, Lisa A; Mutsaers, Nancy A M; Olesen, Søren-Peter; Calloe, Kirstine; Thomsen, Morten B

2015-08-01

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K(+) current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca(2+) current (ICa,L). Anesthetized KChIP2(-/-) mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ₂ protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca(2+) entry into the cell, thereby augmenting Ca(2+)-induced Ca(2+) release. Ca(2+) transients in disaggregated KChIP2(-/-) cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca(2+)-induced Ca(2+) release event. We next functionally probed dyad structure, ryanodine receptor Ca(2+) sensitivity, and sarcoplasmic reticulum Ca(2+) load and found that increased temporal synchronicity of the Ca(2+) release in KChIP2(-/-) cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2(-/-) mice. Copyright © 2015 the American Physiological Society.

Simultaneous determination of dynamic cardiac metabolism and function using PET/MRI.

PubMed

Barton, Gregory P; Vildberg, Lauren; Goss, Kara; Aggarwal, Niti; Eldridge, Marlowe; McMillan, Alan B

2018-05-01

Cardiac metabolic changes in heart disease precede overt contractile dysfunction. However, metabolism and function are not typically assessed together in clinical practice. The purpose of this study was to develop a cardiac positron emission tomography/magnetic resonance (PET/MR) stress test to assess the dynamic relationship between contractile function and metabolism in a preclinical model. Following an overnight fast, healthy pigs (45-50 kg) were anesthetized and mechanically ventilated. 18 F-fluorodeoxyglucose ( 18 F-FDG) solution was administered intravenously at a constant rate of 0.01 mL/s for 60 minutes. A cardiac PET/MR stress test was performed using normoxic gas (F I O 2  = .209) and hypoxic gas (F I O 2  = .12). Simultaneous cardiac imaging was performed on an integrated 3T PET/MR scanner. Hypoxic stress induced a significant increase in heart rate, cardiac output, left ventricular (LV) ejection fraction (EF), and peak torsion. There was a significant decline in arterial SpO 2 , LV end-diastolic and end-systolic volumes in hypoxia. Increased LV systolic function was coupled with an increase in myocardial FDG uptake (Ki) during hypoxic stress. PET/MR with continuous FDG infusion captures dynamic changes in both cardiac metabolism and contractile function. This technique warrants evaluation in human cardiac disease for assessment of subtle functional and metabolic abnormalities.

Cardiac telomere length in heart development, function, and disease.

PubMed

Booth, S A; Charchar, F J

2017-07-01

Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. Copyright © 2017 the American Physiological Society.

Protecting Mitochondrial Bioenergetic Function during Resuscitation from Cardiac Arrest

PubMed Central

Gazmuri, Raúl J.; Radhakrishnan, Jeejabai

2012-01-01

Synopsis Successful resuscitation from cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been deprived of oxygen for variables periods of time. However, reperfusion concomitantly activates pathogenic mechanisms known as “reperfusion injury.” At the core of reperfusion injury are mitochondria, playing a critical role as effectors and targets of such injury. Mitochondrial injury compromises oxidative phosphorylation and also prompts release of cytochrome c to the cytosol and bloodstream where it correlates with severity of injury. Main drivers of such injury include Ca2+ overload and oxidative stress. Preclinical work shows that limiting myocardial cytosolic Na+ overload at the time of reperfusion attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation yielding functional myocardial benefits that include preservation of left ventricular distensibility. Preservation of left ventricular distensibility enables hemodynamically more effective chest compression. Similar myocardial effect have been reported using erythropoietin hypothesized to protect mitochondrial bioenergetic function presumably through activation of pathways similar to those activated during preconditioning. Incorporation of novel and clinical relevant strategies to protect mitochondrial bioenergetic function are expected to attenuate injury at the time of reperfusion and enhance organ viability ultimately improving resuscitation and survival from cardiac arrest. PMID:22433486

Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

PubMed Central

Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

2016-01-01

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials. PMID:27184924

Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

NASA Astrophysics Data System (ADS)

Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

2016-05-01

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

Injectable biodegradable hydrogels for embryonic stem cell transplantation: improved cardiac remodelling and function of myocardial infarction

PubMed Central

Wang, Haibin; Liu, Zhiqiang; Li, Dexue; Guo, Xuan; Kasper, F Kurtis; Duan, Cuimi; Zhou, Jin; Mikos, Antonios G; Wang, Changyong

2012-01-01

Abstract In this study, an injectable, biodegradable hydrogel composite of oligo[poly(ethylene glycol) fumarate] (OPF) was investigated as a carrier of mouse embryonic stem cells (mESCs) for the treatment of myocardial infarction (MI). The OPF hydrogels were used to encapsulate mESCs. The cell differentiation in vitro over 14 days was determined via immunohistochemical examination. Then, mESCs encapsulated in OPF hydrogels were injected into the LV wall of a rat MI model. Detailed histological analysis and echocardiography were used to determine the structural and functional consequences after 4 weeks of transplantation. With ascorbic acid induction, mESCs could differentiate into cardiomyocytes and other cell types in all three lineages in the OPF hydrogel. After transplantation, both the 24-hr cell retention and 4-week graft size were significantly greater in the OPF + ESC group than that of the PBS + ESC group (P < 0.01). Four weeks after transplantation, OPF hydrogel alone significantly reduced the infarct size and collagen deposition and improved the cardiac function. The heart function and revascularization improved significantly, while the infarct size and fibrotic area decreased significantly in the OPF + ESC group compared with that of the PBS + ESC, OPF and PBS groups (P < 0.01). All treatments had significantly reduced MMP2 and MMP9 protein levels compared to the PBS control group, and the OPF + ESC group decreased most by Western blotting. Transplanted mESCs expressed cardiovascular markers. This study suggests the potential of a method for heart regeneration involving OPF hydrogels for stem cell encapsulation and transplantation. PMID:21838774

Aerobic exercise training delays cardiac dysfunction and improves autonomic control of circulation in diabetic rats undergoing myocardial infarction.

PubMed

Rodrigues, Bruno; Jorge, Luciana; Mostarda, Cristiano T; Rosa, Kaleizu T; Medeiros, Alessandra; Malfitano, Christiane; de Souza, Alcione L; Viegas, Katia Aparecida da Silva; Lacchini, Silvia; Curi, Rui; Brum, Patricia C; De Angelis, Kátia; Irigoyen, Maria Cláudia

2012-09-01

Exercise training (ET) has been used as a nonpharmacological strategy for treatment of diabetes and myocardial infarction (MI) separately. We evaluated the effects ET on functional and molecular left ventricular (LV) parameters as well as on autonomic function and mortality in diabetics after MI. Male Wistar rats were divided into control (C), sedentary-diabetic infarcted (SDI), and trained-diabetic infarcted (TDI) groups. MI was induced after 15 days of streptozotocin-diabetes induction. Seven days after MI, the trained group underwent ET protocol (90 days, 50-70% maximal oxygen consumption-VO(2)max). LV function was evaluated noninvasively and invasively; baroreflex sensitivity, pulse interval variability, cardiac output, tissue blood flows, VEGF mRNA and protein, HIF1-α mRNA, and Ca(2+) handling proteins were measured. MI area was reduced in TDI (21 ± 4%) compared with SDI (38 ± 4%). ET induced improvement in cardiac function, hemodynamics, and tissue blood flows. These changes were probable consequences of a better expression of Ca(2+) handling proteins, increased VEGF mRNA and protein expression as well as improvement in autonomic function, that resulted in reduction of mortality in TDI (33%) compared with SDI (68%) animals. ET reduced cardiac and peripheral dysfunction and preserved autonomic control in diabetic infarcted rats. Consequently, these changes resulted in improved VO(2)max and survival after MI. Copyright © 2012 Elsevier Inc. All rights reserved.

Biomimetic perfusion and electrical stimulation applied in concert improved the assembly of engineered cardiac tissue

PubMed Central

Lee, Eun Jung; Luo, Jianwen; Duan, Yi; Yeager, Keith; Konofagou, Elisa; Vunjak-Novakovic, Gordana

2012-01-01

Maintenance of normal myocardial function depends intimately on synchronous tissue contraction driven by electrical activation and on adequate nutrient perfusion in support thereof. Bioreactors have been used to mimic aspects of these factors in vitro to engineer cardiac tissue, but due to design limitations, previous bioreactor systems have yet to simultaneously support nutrient perfusion, electrical stimulation, and unconstrained (i.e., not isometric) tissue contraction. To the best of our knowledge, the bioreactor system described herein is the first to integrate in concert these three key factors. We present the design of our bioreactor and characterize its capability in integrated experimental and mathematical modeling studies. We then culture cardiac cells obtained from neonatal rats in porous, channeled elastomer scaffolds with the simultaneous application of perfusion and electrical stimulation, with controls excluding either one or both of these two conditions. After eight days of culture, constructs grown with the simultaneous perfusion and electrical stimulation exhibited substantially improved functional properties, as evidenced by a significant increase in contraction amplitude (0.23±0.10% vs. 0.14±0.05, 0.13±0.08, or 0.09±0.02% in control constructs grown without stimulation, without perfusion, or either stimulation or perfusion, respectively). Consistently, these constructs had significantly improved DNA contents, cell distribution throughout the scaffold thickness, cardiac protein expression, cell morphology and overall tissue organization than either control group. Thus, the simultaneous application of medium perfusion and electrical conditioning enabled by the use of the novel bioreactor system may accelerate the generation of fully functional, clinically sized cardiac tissue constructs. PMID:22170772

Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine.

PubMed

Gao, Ling; Gregorich, Zachery R; Zhu, Wuqiang; Mattapally, Saidulu; Oduk, Yasin; Lou, Xi; Kannappan, Ramaswamy; Borovjagin, Anton V; Walcott, Gregory P; Pollard, Andrew E; Fast, Vladimir G; Hu, Xinyang; Lloyd, Steven G; Ge, Ying; Zhang, Jianyi

2018-04-17

Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform. In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch. The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that

Functional screening identifies miRNAs inducing cardiac regeneration.

PubMed

Eulalio, Ana; Mano, Miguel; Dal Ferro, Matteo; Zentilin, Lorena; Sinagra, Gianfranco; Zacchigna, Serena; Giacca, Mauro

2012-12-20

In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

PubMed Central

Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

2017-01-01

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats. PMID:28287621

An injectable silk sericin hydrogel promotes cardiac functional recovery after ischemic myocardial infarction.

PubMed

Song, Yu; Zhang, Cheng; Zhang, Jinxiang; Sun, Ning; Huang, Kun; Li, Huili; Wang, Zheng; Huang, Kai; Wang, Lin

2016-09-01

Acute myocardial infarction (MI) leads to morbidity and mortality due to cardiac dysfunction. Here we identify sericin, a silk-derived protein, as an injectable therapeutic biomaterial for the minimally invasive MI repair. For the first time, sericin prepared in the form of an injectable hydrogel has been utilized for cardiac tissue engineering and its therapeutical outcomes evaluated in a mouse MI model. The injection of this sericin hydrogel into MI area reduces scar formation and infarct size, increases wall thickness and neovascularization, and inhibits the MI-induced inflammatory responses and apoptosis, thereby leading to a significant functional improvement. The potential therapeutical mechanisms have been further analyzed in vitro. Our results indicate that sericin downregulates pro-inflammatory cytokines (TNF-α and IL-18) and chemokine (CCL2) and reduces TNF-α expression by suppressing the TLR4-MAPK/NF-κB pathways. Moreover, sericin exhibits angiogenic activity by promoting migration and tubular formation of human umbilical vessel endothelial cells (HUVECs). Also, sericin stimulates VEGFa expression via activating ERK phosphorylation. Further, sericin protects endothelial cells and cardiomyocytes from apoptosis by inhibiting the activation of caspase 3. Together, these diverse biochemical activities of sericin protein lead to a significant recovery of cardiac function. This work represents the first study reporting sericin as an effective therapeutic biomaterial for ischemic myocardial repair in vivo. Intramyocardial biomaterial injection is thought to be a potential therapeutic approach to improve cardiac performance after ischemic myocardial infarction. In this study, we report the successful fabrication and in vivo application of an injectable sericin hydrogel for ischemic heart disease. We for the first time show that the injection of in situ forming crosslinked sericin hydrogel promotes heart functional recovery accompanied with reduced

Cardiac dimensions and function in female handball players.

PubMed

Malmgren, A; Dencker, M; Stagmo, M; Gudmundsson, P

2015-04-01

Long-term intensive endurance training leads to increased left ventricular mass and increased left ventricular end-diastolic and left atrial end-systolic diameters. Different types of sports tend to give rise to distinct morphological forms of the athlete's heart. However, the sport-specific aspects have not been fully investigated in female athletes. The purpose of the present study was to investigate differences in left and right cardiac dimensions, cardiac volumes, and systolic and diastolic function in elite female handball players compared to sedentary controls. A cross-sectional study of 33 elite female handball players was compared to 33 matched sedentary controls. Mean age was 21.5±2 years. The subjects underwent echocardiography examinations, both 2-dimensional (2DE) and 3-dimensional (3DE). Cardiac dimensions and volumes were quantified using M-mode, 2DE and 3DE. Systolic and diastolic left ventricular functions were also evaluated. All cardiac dimensions and volumes were adjusted for body surface area (BSA). Left atrium and left ventricle volumes were significantly (P<0.001) larger in elite female handball players compared with sedentary controls. Even right atrium area as well as right ventricular end-diastolic and end-systolic area were significantly (P<0.001) larger in elite female handball players. Significant differences were observed in three out of five systolic parameters. Most diastolic function parameters did not differ between the two groups. The findings from the present study suggest that similar cardiac remodeling takes place in elite female handball players as it does in athletes pursuing endurance or team game sports.

Chronic clenbuterol administration negatively alters cardiac function.

PubMed

Sleeper, Margaret M; Kearns, Charles F; McKeever, Kenneth H

2002-04-01

Chronic administration of pharmacological levels of beta2-agonists have been shown to have toxic effects on the heart; however, no data exist on cardiac function after chronic clenbuterol administration. The purpose of this study was to examine the effect of therapeutic levels of clenbuterol on cardiac performance. Twenty unfit Standardbred mares were divided into four experimental groups: clenbuterol (2.4 microg.kg(-1) twice daily 5 d.wk(-1)) plus exercise (20 min at 50% .VO(2max)) (CLENEX; N = 6), clenbuterol (CLEN; N = 6), exercise (EX; N = 4), and control (CON; N = 4). M-mode and two-dimensional echocardiography (2.5-MHz sector scanner transducer) were used to measure cardiac size and function before and immediately after an incremental exercise test, before and after 8 wk of drug and/or exercise treatments. After treatment, CLENEX and CLEN demonstrated significantly higher left ventricular internal dimension (LVD) at end diastole (+23.7 +/- 4.8%; +25.6 +/- 4.1%), LVD at end systole (+29.2 +/- 8.7%; +40.1 +/- 7.9%), interventricular septal wall thickness (IVS) at end diastole (+28.9 +/- 11.0%; +30.7 +/- 7.0%), IVS at end systole (+29.2 +/- 8.7%; +40.1 +/- 7.9%), and left ventricular posterior wall systolic thickness (+43.1 +/- 14.%; +45.8 +/- 14.1%). CLENEX and CLEN had significantly increased aortic root dimensions (+29.9 +/- 6.1%; +24.0 +/- 1.7%), suggesting increased risk of aortic rupture. Taken together, these data indicate that chronic clenbuterol administration may negatively alter cardiac function.

Digoxin Induces Cardiac Hypertrophy Without Negative Effects on Cardiac Function and Physical Performance in Trained Normotensive Rats.

PubMed

Neves, Claodete Hasselstrom; Tibana, Ramires Alsamir; Prestes, Jonato; Voltarelli, Fabricio Azevedo; Aguiar, Andreo Fernando; Ferreira Mota, Gustavo Augusto; de Sousa, Sergio Luiz Borges; Leopoldo, Andre Soares; Leopoldo, Ana Paula Lima; Mueller, Andre; Aguiar, Danilo Henrique; Navalta, James Wilfred; Sugizaki, Mario Mateus

2017-04-01

Cardiotonic drugs and exercise training promote cardiac inotropic effects, which may affect training-induced cardiac adaptations. This study investigated the effects of long-term administration of digoxin on heart structure and function, and physical performance of rats submitted to high-intensity interval training (HIIT). Male Wistar rats, 60 days old, were divided into control (C), digoxin (DIGO), trained (T), and trained with digoxin (TDIGO). Digoxin was administered by gavage (30 µg/kg/day) for 75 days. The HIIT program consisted of treadmill running 60 min/day (8 min at 80% of the maximum speed (MS) and 2 min at 20% of the MS), 5 days per week during 60 days. The main cardiac parameters were evaluated by echocardiograph and cardiomyocyte area was determined by histology. There were no group x time effects of digoxin, HIIT or interactions (digoxin and HIIT) on functional echocardiographic parameters (heart rate; ejection fraction) or in the maximum exercise test. There was a group x time interaction, as evidenced by observed cardiac hypertrophy in the TDIGO group evaluated by ratio of left ventricle weight to body weight (p<0.002) and cardiomyocyte area (p<0.000002). Long-term administration of digoxin promoted cardiac hypertrophy without affecting cardiac function and physical performance in rats submitted to HIIT. © Georg Thieme Verlag KG Stuttgart · New York.

Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

PubMed Central

Quattrocelli, Mattia; Swinnen, Melissa; Giacomazzi, Giorgia; Camps, Jordi; Barthélemy, Ines; Ceccarelli, Gabriele; Caluwé, Ellen; Grosemans, Hanne; Thorrez, Lieven; Pelizzo, Gloria; Muijtjens, Manja; Verfaillie, Catherine M.; Blot, Stephane; Janssens, Stefan; Sampaolesi, Maurilio

2015-01-01

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. PMID:26571398

Improved Estimation of Cardiac Function Parameters Using a Combination of Independent Automated Segmentation Results in Cardiovascular Magnetic Resonance Imaging.

PubMed

Lebenberg, Jessica; Lalande, Alain; Clarysse, Patrick; Buvat, Irene; Casta, Christopher; Cochet, Alexandre; Constantinidès, Constantin; Cousty, Jean; de Cesare, Alain; Jehan-Besson, Stephanie; Lefort, Muriel; Najman, Laurent; Roullot, Elodie; Sarry, Laurent; Tilmant, Christophe; Frouin, Frederique; Garreau, Mireille

2015-01-01

This work aimed at combining different segmentation approaches to produce a robust and accurate segmentation result. Three to five segmentation results of the left ventricle were combined using the STAPLE algorithm and the reliability of the resulting segmentation was evaluated in comparison with the result of each individual segmentation method. This comparison was performed using a supervised approach based on a reference method. Then, we used an unsupervised statistical evaluation, the extended Regression Without Truth (eRWT) that ranks different methods according to their accuracy in estimating a specific biomarker in a population. The segmentation accuracy was evaluated by estimating six cardiac function parameters resulting from the left ventricle contour delineation using a public cardiac cine MRI database. Eight different segmentation methods, including three expert delineations and five automated methods, were considered, and sixteen combinations of the automated methods using STAPLE were investigated. The supervised and unsupervised evaluations demonstrated that in most cases, STAPLE results provided better estimates than individual automated segmentation methods. Overall, combining different automated segmentation methods improved the reliability of the segmentation result compared to that obtained using an individual method and could achieve the accuracy of an expert.

Improved Estimation of Cardiac Function Parameters Using a Combination of Independent Automated Segmentation Results in Cardiovascular Magnetic Resonance Imaging

PubMed Central

Lebenberg, Jessica; Lalande, Alain; Clarysse, Patrick; Buvat, Irene; Casta, Christopher; Cochet, Alexandre; Constantinidès, Constantin; Cousty, Jean; de Cesare, Alain; Jehan-Besson, Stephanie; Lefort, Muriel; Najman, Laurent; Roullot, Elodie; Sarry, Laurent; Tilmant, Christophe

2015-01-01

This work aimed at combining different segmentation approaches to produce a robust and accurate segmentation result. Three to five segmentation results of the left ventricle were combined using the STAPLE algorithm and the reliability of the resulting segmentation was evaluated in comparison with the result of each individual segmentation method. This comparison was performed using a supervised approach based on a reference method. Then, we used an unsupervised statistical evaluation, the extended Regression Without Truth (eRWT) that ranks different methods according to their accuracy in estimating a specific biomarker in a population. The segmentation accuracy was evaluated by estimating six cardiac function parameters resulting from the left ventricle contour delineation using a public cardiac cine MRI database. Eight different segmentation methods, including three expert delineations and five automated methods, were considered, and sixteen combinations of the automated methods using STAPLE were investigated. The supervised and unsupervised evaluations demonstrated that in most cases, STAPLE results provided better estimates than individual automated segmentation methods. Overall, combining different automated segmentation methods improved the reliability of the segmentation result compared to that obtained using an individual method and could achieve the accuracy of an expert. PMID:26287691

Physical activity and cardiac function in the oldest old.

PubMed

Stessman-Lande, Irit; Jacobs, Jeremy M; Gilon, Dan; Leibowitz, David

2012-02-01

The relationship of physical activity (PA) and cardiac function in the oldest old remains unclear. The objective of this study was to evaluate the relationship between PA and cardiac structure and function, in the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study that was initiated in 1990 and has followed an age homogeneous cohort of Jerusalem residents born in 1920-1921. A total of 496 of the subjects from the most recent set of data collection in 2005-2006 underwent echocardiography at their place of residence in addition to structured interviews and physical examination. Standard echocardiographic assessment of cardiac structure and function including ejection fraction (EF) and diastolic function as assessed by E:E' measurements was performed. PA was defined as a dichotomous (≥4 hr of light exercise weekly) and as a categorical variable (<4 hr weekly/4 hours weekly/at least 1 hr daily/sport at least twice weekly). On bivariate analysis, mean EF was lower among sedentary versus active women (55.5%±8.5% vs. 58.4%±8.3, p=0.021). No other significant differences were observed between sedentary and active subjects, for either systolic or diastolic function. After adjusting for sex, education, diabetes, ischemic heart disease, hypertension, dependence in activities of daily living, and body mass index (BMI), no significant associations were found between systolic or diastolic function, or left ventricular structure and PA. Gender-specific analyses yielded similar findings. Our study of the oldest old did not demonstrate an association between PA and cardiac structure or function.

[Experimental therapy of cardiac remodeling with quercetin-containing drugs].

PubMed

Kuzmenko, M A; Pavlyuchenko, V B; Tumanovskaya, L V; Dosenko, V E; Moybenko, A A

2013-01-01

It was shown that continuous beta-adrenergic hyperstimulation resulted in cardiac function disturbances and fibrosis of cardiac tissue. Treatment with quercetin-containing drugs, particularly, water-soluble corvitin and tableted quertin exerted favourable effect on cardiac hemodynamics, normalized systolic and diastolic function in cardiac remodeling, induced by sustained beta-adrenergic stimulation. It was estimated that conducted experimental therapy limited cardiac fibrosis area almost three-fold, that could be associated with first and foremost improved cardiac distensibility, characteristics of diastolic and also pump function in cardiac remodeling.

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.

Qiliqiangxin Rescues Mouse Cardiac Function by Regulating AGTR1/TRPV1-Mediated Autophagy in STZ-Induced Diabetes Mellitus.

PubMed

Tong, Jing; Lai, Yan; Yao, Yi-An; Wang, Xue-Jun; Shi, Yu-Shuang; Hou, Han-Jin; Gu, Jian-Yun; Chen, Fei; Liu, Xue-Bo

2018-06-19

To explore the potential role of qiliqiangxin (QLQX) A traditional Chinese medicine and the involvement of angiotensin II receptor type 1 (AGTR1) and transient receptor potential vanilloid 1 (TRPV1) in diabetic mouse cardiac function. Intragastric QLQX was administered for 5 weeks after streptozotocin (STZ) treatment. Additionally, Intraperitoneal injections of angiotensin II (Ang II) or intragastric losartan (Los) were administered to assess the activities of AGTR1 and TRPV1. Two-dimensional echocardiography and tissue histopathology were used to assess cardiac function Western blot was used to detect the autophagic biomarkers Such as light chain 3 P62 and lysosomal-associated membrane protein 2 And transmission electron microscopy was used to count the number of autophagosomes. Decreased expression of TRPV1 and autophagic hallmarks and reduced numbers of autophagolysosomes as well as increased expression of angiotensin converting enzyme 1 and AGTR1 were observed in diabetic hearts. Blocking AGTR1 with Los mimicked the QLQX-mediated improvements in cardiac function Alleviated myocardial fibrosis and enabled autophagy Whereas Ang II abolished the beneficial effects of QLQX in wild type diabetic mice but not in TRPV1-/- diabetic mice. QLQX may improve diabetic cardiac function by regulating AGTR1/ TRPV1-mediated autophagy in STZ-induced diabetic mice. © 2018 The Author(s). Published by S. Karger AG, Basel.

Simulation-based Mastery Learning Improves Cardiac Auscultation Skills in Medical Students

PubMed Central

McGaghie, William C.; Cohen, Elaine R.; Kaye, Marsha; Wayne, Diane B.

2010-01-01

Background Cardiac auscultation is a core clinical skill. However, prior studies show that trainee skills are often deficient and that clinical experience is not a proxy for competence. Objective To describe a mastery model of cardiac auscultation education and evaluate its effectiveness in improving bedside cardiac auscultation skills. Design Untreated control group design with pretest and posttest. Participants Third-year students who received a cardiac auscultation curriculum and fourth year students who did not. Intervention A cardiac auscultation curriculum consisting of a computer tutorial and a cardiac patient simulator. All third-year students were required to meet or exceed a minimum passing score (MPS) set by an expert panel at posttest. Measurements Diagnostic accuracy with simulated heart sounds and actual patients. Results Trained third-year students (n = 77) demonstrated significantly higher cardiac auscultation accuracy compared to untrained fourth year students (n = 31) in assessment of simulated heart sounds (93.8% vs. 73.9%, p < 0.001) and with real patients (81.8% vs. 75.1%, p = 0.003). USMLE scores correlated modestly with a computer-based multiple choice assessment using simulated heart sounds but not with bedside skills on real patients. Conclusions A cardiac auscultation curriculum consisting of deliberate practice with a computer-based tutorial and a cardiac patient simulator resulted in improved assessment of simulated heart sounds and more accurate examination of actual patients. PMID:20339952

Biomimetic perfusion and electrical stimulation applied in concert improved the assembly of engineered cardiac tissue.

PubMed

Maidhof, Robert; Tandon, Nina; Lee, Eun Jung; Luo, Jianwen; Duan, Yi; Yeager, Keith; Konofagou, Elisa; Vunjak-Novakovic, Gordana

2012-11-01

Maintenance of normal myocardial function depends intimately on synchronous tissue contraction, driven by electrical activation and on adequate nutrient perfusion in support thereof. Bioreactors have been used to mimic aspects of these factors in vitro to engineer cardiac tissue but, due to design limitations, previous bioreactor systems have yet to simultaneously support nutrient perfusion, electrical stimulation and unconstrained (i.e. not isometric) tissue contraction. To the best of our knowledge, the bioreactor system described herein is the first to integrate these three key factors in concert. We present the design of our bioreactor and characterize its capability in integrated experimental and mathematical modelling studies. We then cultured cardiac cells obtained from neonatal rats in porous, channelled elastomer scaffolds with the simultaneous application of perfusion and electrical stimulation, with controls excluding either one or both of these two conditions. After 8 days of culture, constructs grown with simultaneous perfusion and electrical stimulation exhibited substantially improved functional properties, as evidenced by a significant increase in contraction amplitude (0.23 ± 0.10% vs 0.14 ± 0.05%, 0.13 ± 0.08% or 0.09 ± 0.02% in control constructs grown without stimulation, without perfusion, or either stimulation or perfusion, respectively). Consistently, these constructs had significantly improved DNA contents, cell distribution throughout the scaffold thickness, cardiac protein expression, cell morphology and overall tissue organization compared to control groups. Thus, the simultaneous application of medium perfusion and electrical conditioning enabled by the use of the novel bioreactor system may accelerate the generation of fully functional, clinically sized cardiac tissue constructs. Copyright © 2011 John Wiley & Sons, Ltd.

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.

Characterization and functionality of cardiac progenitor cells in congenital heart patients.

PubMed

Mishra, Rachana; Vijayan, Kalpana; Colletti, Evan J; Harrington, Daniel A; Matthiesen, Thomas S; Simpson, David; Goh, Saik Kia; Walker, Brandon L; Almeida-Porada, Graça; Wang, Deli; Backer, Carl L; Dudley, Samuel C; Wold, Loren E; Kaushal, Sunjay

2011-02-01

Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration. Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, <30 days), infants (age, 1 month to 2 years), and children (age, >2 to ≤13 years). C-kit(+) hCPCs were 3-fold higher in neonates than in children >2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit(+) Ki67(+) expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit(+), NKX2-5(+), NOTCH1(+), and NUMB(+) expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium-derived CPCs from all patients (n=103) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit(+), Islet-1, and supporting cells. The number of c-kit(+)-expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts. Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair.

EPAC expression and function in cardiac fibroblasts and myofibroblasts

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

Olmedo, Ivonne; Muñoz, Claudia; Guzmán, Nancy

In the heart, cardiac fibroblasts (CF) and cardiac myofibroblasts (CMF) are the main cells responsible for wound healing after cardiac insult. Exchange protein activated by cAMP (EPAC) is a downstream effector of cAMP, and it has been not completely studied on CF. Moreover, in CMF, which are the main cells responsible for cardiac healing, EPAC expression and function are unknown. We evaluated in both CF and CMF the effect of transforming growth factor β1 (TGF-β1) on EPAC-1 expression. We also studied the EPAC involvement on collagen synthesis, adhesion, migration and collagen gel contraction. Method: Rat neonatal CF and CMF weremore » treated with TGF-β1 at different times and concentrations. EPAC-1 protein levels and Rap1 activation were measured by western blot and pull down assay respectively. EPAC cellular functions were determined by adhesion, migration and collagen gel contraction assay; and collagen expression was determined by western blot. Results: TGF-β1 through Smad and JNK significantly reduced EPAC-1 expression in CF, while in CMF this cytokine increased EPAC-1 expression through ERK1/2, JNK, p38, AKT and Smad3. EPAC activation was able to induce higher Rap1-GTP levels in CMF than in CF. EPAC and PKA, both cAMP effectors, promoted CF and CMF adhesion on fibronectin, as well as CF migration; however, this effect was not observed in CMF. EPAC but not PKA activation mediated collagen gel contraction in CF, while in CMF both PKA and EPAC mediated collagen gel contraction. Finally, the EPAC and PKA activation reduced collagen synthesis in CF and CMF. Conclusion: TGF-β1 differentially regulates the expression of EPAC in CF and CMF; and EPAC regulates differentially CF and CMF functions associated with cardiac remodeling. - Highlights: • TGF-β1 regulates EPAC-1 expression in cardiac fibroblast and myofibroblast. • Rap-1GTP levels are higher in cardiac myofibroblast than fibroblast. • EPAC-1 controls adhesion, migration and collagen synthesis in

The effects of malnutrition on cardiac function in African children.

PubMed

Silverman, Jonathan A; Chimalizeni, Yamikani; Hawes, Stephen E; Wolf, Elizabeth R; Batra, Maneesh; Khofi, Harriet; Molyneux, Elizabeth M

2016-02-01

Cardiac dysfunction may contribute to high mortality in severely malnourished children. Our objective was to assess the effect of malnutrition on cardiac function in hospitalised African children. Prospective cross-sectional study. Public referral hospital in Blantyre, Malawi. We enrolled 272 stable, hospitalised children ages 6-59 months, with and without WHO-defined severe acute malnutrition. Cardiac index, heart rate, mean arterial pressure, stroke volume index and systemic vascular resistance index were measured by the ultrasound cardiac output monitor (USCOM, New South Wales, Australia). We used linear regression with generalised estimating equations controlling for age, sex and anaemia. Our primary outcome, cardiac index, was similar between those with and without severe malnutrition: difference=0.22 L/min/m(2) (95% CI -0.08 to 0.51). No difference was found in heart rate or stroke volume index. However, mean arterial pressure and systemic vascular resistance index were lower in children with severe malnutrition: difference=-8.6 mm Hg (95% CI -12.7 to -4.6) and difference=-200 dyne s/cm(5)/m(2) (95% CI -320 to -80), respectively. In this largest study to date, we found no significant difference in cardiac function between hospitalised children with and without severe acute malnutrition. Further study is needed to determine if cardiac function is diminished in unstable malnourished children. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Design and formulation of functional pluripotent stem cell-derived cardiac microtissues

PubMed Central

Thavandiran, Nimalan; Dubois, Nicole; Mikryukov, Alexander; Massé, Stéphane; Beca, Bogdan; Simmons, Craig A.; Deshpande, Vikram S.; McGarry, J. Patrick; Chen, Christopher S.; Nanthakumar, Kumaraswamy; Keller, Gordon M.; Radisic, Milica; Zandstra, Peter W.

2013-01-01

Access to robust and information-rich human cardiac tissue models would accelerate drug-based strategies for treating heart disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. We used computational modeling of tissue contraction and assembly mechanics in conjunction with microfabricated constraints to guide the design of aligned and functional 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues that we term cardiac microwires (CMWs). Miniaturization of the platform circumvented the need for tissue vascularization and enabled higher-throughput image-based analysis of CMW drug responsiveness. CMW tissue properties could be tuned using electromechanical stimuli and cell composition. Specifically, controlling self-assembly of 3D tissues in aligned collagen, and pacing with point stimulation electrodes, were found to promote cardiac maturation-associated gene expression and in vivo-like electrical signal propagation. Furthermore, screening a range of hPSC-derived cardiac cell ratios identified that 75% NKX2 Homeobox 5 (NKX2-5)+ cardiomyocytes and 25% Cluster of Differentiation 90 OR (CD90)+ nonmyocytes optimized tissue remodeling dynamics and yielded enhanced structural and functional properties. Finally, we demonstrate the utility of the optimized platform in a tachycardic model of arrhythmogenesis, an aspect of cardiac electrophysiology not previously recapitulated in 3D in vitro hPSC-derived cardiac microtissue models. The design criteria identified with our CMW platform should accelerate the development of predictive in vitro assays of human heart tissue function. PMID:24255110

Cardiac surgical outcomes improvement led by a physician champion working with a nurse clinical coordinator.

PubMed

Stanford, John R; Swaney-Berghoff, Laurie; Recht, Kimberly

2012-01-01

Cardiac surgical outcomes improvement in a community hospital was driven by a physician champion working with a nurse clinical coordinator. Specific system improvements implemented were (1) nurse checklists of vital signs, cardiovascular function parameters, and life support appliance operation; (2) use of the EuroSCORE system of preoperative patient risk assessment; (3) monthly morbidity and mortality conferences; and (4) daily patient progress tracking. The hospital received 1 star (bottom 12% of hospitals for quality outcomes) from the Society of Thoracic Surgeons Adult Cardiac Database in 2006 prior to program inception, 2 stars (middle 76% of hospitals for quality outcomes) in 2007 and 2008, and 3 stars (top 12% of hospitals) in 2009. The physician and nurse together combined a strategy for clinical improvement with the cultural practices at the hospital to ensure that system improvements approved at the strategic level were implemented at the point of care. Both strategy and culture must be addressed to ensure patient outcomes improvement.

Cardiac Biomarkers: a Focus on Cardiac Regeneration

PubMed Central

Forough, Reza; Scarcello, Catherine; Perkins, Matthew

2011-01-01

Historically, biomarkers have been used in two major ways to maintain and improve better health status: first, for diagnostic purposes, and second, as specific targets to treat various diseases. A new era in treatment and even cure for the some diseases using reprograming of somatic cells is about to be born. In this approach, scientists are successfully taking human skin cells (previously considered terminally-differentiated cells) and re-programming them into functional cardiac myocytes and other cell types in vitro. A cell reprograming approach for treatment of cardiovascular diseases will revolutionize the field of medicine and significantly expand the human lifetime. Availability of a comprehensive catalogue for cardiac biomarkers is necessary for developing cell reprograming modalities to treat cardiac diseases, as well as for determining the progress of reprogrammed cells as they become cardiac cells. In this review, we present a comprehensive survey of the cardiac biomarkers currently known. PMID:23074366

The effect of time to defibrillation and targeted temperature management on functional survival after out-of-hospital cardiac arrest.

PubMed

Drennan, Ian R; Lin, Steve; Thorpe, Kevin E; Morrison, Laurie J

2014-11-01

Cardiac arrest physiology has been proposed to occur in three distinct phases: electrical, circulatory and metabolic. There is limited research evaluating the relationship of the 3-phase model of cardiac arrest to functional survival at hospital discharge. Furthermore, the effect of post-cardiac arrest targeted temperature management (TTM) on functional survival during each phase is unknown. To determine the effect of TTM on the relationship between the time of initial defibrillation during each phase of cardiac arrest and functional survival at hospital discharge. This was a retrospective observational study of consecutive adult (≥18 years) out-of-hospital cardiac arrest (OHCA) patients with initial shockable rhythms. Included patients obtained a return of spontaneous circulation (ROSC) and were eligible for TTM. Multivariable logistic regression was used to determine predictors of functional survival at hospital discharge. There were 20,165 OHCA treated by EMS and 871 patients were eligible for TTM. Of these patients, 622 (71.4%) survived to hospital discharge and 487 (55.9%) had good functional survival. Good functional survival was associated with younger age (OR 0.94; 95% CI 0.93-0.95), shorter times from collapse to initial defibrillation (OR 0.73; 95% CI 0.65-0.82), and use of post-cardiac arrest TTM (OR 1.49; 95% CI 1.07-2.30). Functional survival decreased during each phase of the model (65.3% vs. 61.7% vs. 50.2%, P<0.001). Functional survival at hospital discharge was associated with shorter times to initial defibrillation and was decreased during each successive phase of the 3-phase model. Post-cardiac arrest TTM was associated with improved functional survival. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Improving Cardiac Action Potential Measurements: 2D and 3D Cell Culture.

PubMed

Daily, Neil J; Yin, Yue; Kemanli, Pinar; Ip, Brian; Wakatsuki, Tetsuro

2015-11-01

Progress in the development of assays for measuring cardiac action potential is crucial for the discovery of drugs for treating cardiac disease and assessing cardiotoxicity. Recently, high-throughput methods for assessing action potential using induced pluripotent stem cell (iPSC) derived cardiomyocytes in both two-dimensional monolayer cultures and three-dimensional tissues have been developed. We describe an improved method for assessing cardiac action potential using an ultra-fast cost-effective plate reader with commercially available dyes. Our methods improve dramatically the detection of the fluorescence signal from these dyes and make way for the development of more high-throughput methods for cardiac drug discovery and cardiotoxicity.

Biophysical stimulation for in vitro engineering of functional cardiac tissues.

PubMed

Korolj, Anastasia; Wang, Erika Yan; Civitarese, Robert A; Radisic, Milica

2017-07-01

Engineering functional cardiac tissues remains an ongoing significant challenge due to the complexity of the native environment. However, our growing understanding of key parameters of the in vivo cardiac microenvironment and our ability to replicate those parameters in vitro are resulting in the development of increasingly sophisticated models of engineered cardiac tissues (ECT). This review examines some of the most relevant parameters that may be applied in culture leading to higher fidelity cardiac tissue models. These include the biochemical composition of culture media and cardiac lineage specification, co-culture conditions, electrical and mechanical stimulation, and the application of hydrogels, various biomaterials, and scaffolds. The review will also summarize some of the recent functional human tissue models that have been developed for in vivo and in vitro applications. Ultimately, the creation of sophisticated ECT that replicate native structure and function will be instrumental in advancing cell-based therapeutics and in providing advanced models for drug discovery and testing. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Inspiration from heart development: Biomimetic development of functional human cardiac organoids.

PubMed

Richards, Dylan J; Coyle, Robert C; Tan, Yu; Jia, Jia; Wong, Kerri; Toomer, Katelynn; Menick, Donald R; Mei, Ying

2017-10-01

Recent progress in human organoids has provided 3D tissue systems to model human development, diseases, as well as develop cell delivery systems for regenerative therapies. While direct differentiation of human embryoid bodies holds great promise for cardiac organoid production, intramyocardial cell organization during heart development provides biological foundation to fabricate human cardiac organoids with defined cell types. Inspired by the intramyocardial organization events in coronary vasculogenesis, where a diverse, yet defined, mixture of cardiac cell types self-organizes into functional myocardium in the absence of blood flow, we have developed a defined method to produce scaffold-free human cardiac organoids that structurally and functionally resembled the lumenized vascular network in the developing myocardium, supported hiPSC-CM development and possessed fundamental cardiac tissue-level functions. In particular, this development-driven strategy offers a robust, tunable system to examine the contributions of individual cell types, matrix materials and additional factors for developmental insight, biomimetic matrix composition to advance biomaterial design, tissue/organ-level drug screening, and cell therapy for heart repair. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Mesenchymal-endothelial-transition contributes to cardiac neovascularization

PubMed Central

Ubil, Eric; Duan, Jinzhu; Pillai, Indulekha C.L.; Rosa-Garrido, Manuel; Wu, Yong; Bargiacchi, Francesca; Lu, Yan; Stanbouly, Seta; Huang, Jie; Rojas, Mauricio; Vondriska, Thomas M.; Stefani, Enrico; Deb, Arjun

2014-01-01

Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal-transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial cell like phenotype after acute ischemic cardiac injury. Fibroblast derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast derived endothelial cells, reduces post infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal to endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial-transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair. PMID:25317562

Chronic Cardiac-Targeted RNA Interference for the Treatment of Heart Failure Restores Cardiac Function and Reduces Pathological Hypertrophy

PubMed Central

Suckau, Lennart; Fechner, Henry; Chemaly, Elie; Krohn, Stefanie; Hadri, Lahouaria; Kockskämper, Jens; Westermann, Dirk; Bisping, Egbert; Ly, Hung; Wang, Xiaomin; Kawase, Yoshiaki; Chen, Jiqiu; Liang, Lifan; Sipo, Isaac; Vetter, Roland; Weger, Stefan; Kurreck, Jens; Erdmann, Volker; Tschope, Carsten; Pieske, Burkert; Lebeche, Djamel; Schultheiss, Heinz-Peter; Hajjar, Roger J.; Poller, Wolfgang Ch.

2009-01-01

Background RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. We report on targeted RNAi for the treatment of heart failure (HF), an important disorder in humans resulting from multiple etiologies. Successful treatment of HF is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban (PLB), a key regulator of cardiac Ca2+ homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy employs regulatory RNAs to achieve its effect. Methods and Results We describe structural requirements to obtain high RNAi activity from adenoviral (AdV) and adeno-associated virus (AAV9) vectors and show that an AdV short hairpin RNA vector (AdV-shRNA) silenced PLB in cardiomyocytes (NRCMs) and improved hemodynamics in HF rats 1 month after aortic root injection. For simplified long-term therapy we developed a dimeric cardiotropic AAV vector (rAAV9-shPLB) delivering RNAi activity to the heart via intravenous injection. Cardiac PLB protein was reduced to 25% and SERCA2a suppression in the HF groups was rescued. In contrast to traditional vectors rAAV9 shows high affinity for myocardium, but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (LVEDP, dp/dtmin, Tau) and systolic (fractional shortening) functional parameters to normal range. The massive cardiac dilation was normalized and the cardiac hypertrophy, cardiomyocyte diameter and cardiac fibrosis significantly reduced. Importantly, there was no evidence of microRNA deregulation or hepatotoxicity during these RNAi therapies. Conclusion Our data show, for the first time, high efficacy of an RNAi therapeutic strategy in a cardiac disease. PMID:19237664

Effects of a Structured Discharge Planning Program on Perceived Functional Status, Cardiac Self-efficacy, Patient Satisfaction, and Unexpected Hospital Revisits Among Filipino Cardiac Patients: A Randomized Controlled Study.

PubMed

Cajanding, Ruff Joseph

Cardiovascular diseases remain the leading cause of morbidity and mortality among Filipinos and are responsible for a very large number of hospital readmissions. Comprehensive discharge planning programs have demonstrated positive benefits among various populations of patients with cardiovascular disease, but the clinical and psychosocial effects of such intervention among Filipino patients with acute myocardial infarction (AMI) have not been studied. In this study we aimed to determine the effectiveness of a nurse-led structured discharge planning program on perceived functional status, cardiac self-efficacy, patient satisfaction, and unexpected hospital revisits among Filipino patients with AMI. A true experimental (randomized control) 2-group design with repeated measures and data collected before and after intervention and at 1-month follow-up was used in this study. Participants were assigned to either the control (n = 68) or the intervention group (n = 75). Intervention participants underwent a 3-day structured discharge planning program implemented by a cardiovascular nurse practitioner, which is comprised of a series of individualized lecture-discussion, provision of feedback, integrative problem solving, goal setting, and action planning. Control participants received standard routine care. Measures of functional status, cardiac self-efficacy, and patient satisfaction were measured at baseline; cardiac self-efficacy and patient satisfaction scores were measured prior to discharge, and perceived functional status and number of revisits were measured 1 month after discharge. Participants in the intervention group had significant improvement in functional status, cardiac self-efficacy, and patient satisfaction scores at baseline and at follow-up compared with the control participants. Furthermore, participants in the intervention group had significantly fewer hospital revisits compared with those who received only standard care. The results demonstrate that a

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.

Systematic Characterization of the Murine Mitochondrial Proteome Using Functionally Validated Cardiac Mitochondria

PubMed Central

Zhang, Jun; Li, Xiaohai; Mueller, Michael; Wang, Yueju; Zong, Chenggong; Deng, Ning; Vondriska, Thomas M.; Liem, David A.; Yang, Jeong-In; Korge, Paavo; Honda, Henry; Weiss, James N.; Apweiler, Rolf; Ping, Peipei

2009-01-01

Mitochondria play essential roles in cardiac pathophysiology and the murine model has been extensively used to investigate cardiovascular diseases. In the present study, we characterized murine cardiac mitochondria using an LC/MS/MS approach. We extracted and purified cardiac mitochondria; validated their functionality to ensure the final preparation contains necessary components to sustain their normal function; and subjected these validated organelles to LC/MS/MS-based protein identification. A total of 940 distinct proteins were identified from murine cardiac mitochondria, among which, 480 proteins were not previously identified by major proteomic profiling studies. The 940 proteins consist of functional clusters known to support oxidative phosphorylation, metabolism and biogenesis. In addition, there are several other clusters--including proteolysis, protein folding, and reduction/oxidation signaling-which ostensibly represent previously under-appreciated tasks of cardiac mitochondria. Moreover, many identified proteins were found to occupy other subcellular locations, including cytoplasm, ER, and golgi, in addition to their presence in the mitochondria. These results provide a comprehensive picture of the murine cardiac mitochondrial proteome and underscore tissue- and species-specification. Moreover, the use of functionally intact mitochondria insures that the proteomic observations in this organelle are relevant to its normal biology and facilitates decoding the interplay between mitochondria and other organelles. PMID:18348319

Randomised controlled trial of a 12 week yoga intervention on negative affective states, cardiovascular and cognitive function in post-cardiac rehabilitation patients.

PubMed

Yeung, Alan; Kiat, Hosen; Denniss, A Robert; Cheema, Birinder S; Bensoussan, Alan; Machliss, Bianca; Colagiuri, Ben; Chang, Dennis

2014-10-24

Negative affective states such as anxiety, depression and stress are significant risk factors for cardiovascular disease, particularly in cardiac and post-cardiac rehabilitation populations.Yoga is a balanced practice of physical exercise, breathing control and meditation that can reduce psychosocial symptoms as well as improve cardiovascular and cognitive function. It has the potential to positively affect multiple disease pathways and may prove to be a practical adjunct to cardiac rehabilitation in further reducing cardiac risk factors as well as improving self-efficacy and post-cardiac rehabilitation adherence to healthy lifestyle behaviours. This is a parallel arm, multi-centre, randomised controlled trial that will assess the outcomes of post- phase 2 cardiac rehabilitation patients assigned to a yoga intervention in comparison to a no-treatment wait-list control group. Participants randomised to the yoga group will engage in a 12 week yoga program comprising of two group based sessions and one self-administered home session each week. Group based sessions will be led by an experienced yoga instructor. This will involve teaching beginner students a hatha yoga sequence that incorporates asana (poses and postures), pranayama (breathing control) and meditation. The primary outcomes of this study are negative affective states of anxiety, depression and stress assessed using the Depression Anxiety Stress Scale. Secondary outcomes include measures of quality of life, and cardiovascular and cognitive function. The cardiovascular outcomes will include blood pressure, heart rate, heart rate variability, pulse wave velocity, carotid intima media thickness measurements, lipid/glucose profiles and C-reactive protein assays. Assessments will be conducted prior to (week 0), mid-way through (week 6) and following the intervention period (week 12) as well as at a four week follow-up (week 16). This study will determine the effect of yoga practice on negative affective states

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.

High intensity interval training (HIIT) improves resting blood pressure, metabolic (MET) capacity and heart rate reserve without compromising cardiac function in sedentary aging men.

PubMed

Grace, Fergal; Herbert, Peter; Elliott, Adrian D; Richards, Jo; Beaumont, Alexander; Sculthorpe, Nicholas F

2017-05-13

This study examined a programme of pre-conditioning exercise with subsequent high intensity interval training (HIIT) on blood pressure, echocardiography, cardiac strain mechanics and maximal metabolic (MET) capacity in sedentary (SED) aging men compared with age matched masters athletes (LEX). Using a STROBE compliant observational design, 39 aging male participants (SED; n=22, aged 62.7±5.2yrs) (LEX; n=17, aged=61.1±5.4yrs) were recruited to a study that necessitated three distinct assessment phases; enrolment (Phase A), following pre-conditioning exercise in SED (Phase B), then following 6weeks of HIIT performed once every five days by both groups before reassessment (Phase C). Hemodynamic, echocardiographic and cardiac strain mechanics were obtained at rest and maximal cardiorespiratory and chronotropic responses were obtained at each measurement phase. The training intervention improved systolic, mean arterial blood pressure, rate pressure product and heart rate reserve (each P<0.05) in SED and increased MET capacity in both SED and LEX (P<0.01) which was amplified by HIIT. Echocardiography and cardiac strain measures were unremarkable apart from trivial increase to intra-ventricular septum diastole (IVSd) (P<0.05) and decrease to left ventricular internal dimension diastole (LVId) (P<0.05) in LEX following HIIT. A programme of preconditioning exercise with HIIT induces clinically relevant improvements in blood pressure, rate pressure product and encourages recovery of heart rate reserve in SED, while improving maximal MET capacity in both SED and LEX without inducing any pathological cardiovascular remodeling. These data add to the emerging repute of HIIT as a safe and promising exercise prescription to improve cardiovascular function and metabolic capacity in sedentary aging. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Thioredoxin-2 Inhibits Mitochondrial ROS Generation and ASK1 Activity to Maintain Cardiac Function

PubMed Central

Huang, Qunhua; Zhou, Huanjiao Jenny; Zhang, Haifeng; Huang, Yan; Hinojosa-Kirschenbaum, Ford; Fan, Peidong; Yao, Lina; Belardinelli, Luiz; Tellides, George; Giordano, Frank J.; Budas, Grant R.; Min, Wang

2015-01-01

Background Thioredoxin 2 (Trx2) is a key mitochondrial protein which regulates cellular redox and survival by suppressing mitochondrial ROS generation and by inhibiting apoptosis stress kinase-1 (ASK1)-dependent apoptotic signaling. To date, the role of the mitochondrial Trx2 system in heart failure pathogenesis has not been investigated. Methods and Results Western blot and histological analysis revealed that Trx2 protein expression levels were reduced in hearts from patients with dilated cardiomyopathy (DCM), with a concomitant increase in increased ASK1 phosphorylation/activity. Cardiac-specific Trx2 knockout mice (Trx2-cKO). Trx2-cKO mice develop spontaneous DCM at 1 month of age with increased heart size, reduced ventricular wall thickness, and a progressive decline in left ventricular (LV) contractile function, resulting in mortality due to heart failure by ~4 months of age. The progressive decline in cardiac function observed in Trx2-cKO mice was accompanied by disruption of mitochondrial ultrastructure, mitochondrial membrane depolarization, increased mitochondrial ROS generation and reduced ATP production, correlating with increased ASK1 signaling and increased cardiomyocyte apoptosis. Chronic administration of a highly selective ASK1 inhibitor improved cardiac phenotype and reduced maladaptive LV remodeling with significant reductions in oxidative stress, apoptosis, fibrosis and cardiac failure. Cellular data from Trx2-deficient cardiomyocytes demonstrated that ASK1 inhibition reduced apoptosis and reduced mitochondrial ROS generation. Conclusions Our data support an essential role for mitochondrial Trx2 in preserving cardiac function by suppressing mitochondrial ROS production and ASK1-dependent apoptosis. Inhibition of ASK1 represents a promising therapeutic strategy for the treatment of dilated cardiomyopathy and heart failure. PMID:25628390

Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function

PubMed Central

Beaumont, Eric; Salavatian, Siamak; Southerland, E Marie; Vinet, Alain; Jacquemet, Vincent; Armour, J Andrew; Ardell, Jeffrey L

2013-01-01

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias. PMID:23818689

Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study.

PubMed

Chung, T; Kelleher, S; Liu, P Y; Conway, A J; Kritharides, L; Handelsman, D J

2007-02-01

Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. To assess the effects of testosterone and nandrolone, a non-amplifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. Ambulatory care research centre. Healthy young men randomized into three groups of 10 men. Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167

Detraining Differentially Preserved Beneficial Effects of Exercise on Hypertension: Effects on Blood Pressure, Cardiac Function, Brain Inflammatory Cytokines and Oxidative Stress

PubMed Central

Agarwal, Deepmala; Dange, Rahul B.; Vila, Jorge; Otamendi, Arturo J.; Francis, Joseph

2012-01-01

Aims This study sought to investigate the effects of physical detraining on blood pressure (BP) and cardiac morphology and function in hypertension, and on pro- and anti-inflammatory cytokines (PICs and AIC) and oxidative stress within the brain of hypertensive rats. Methods and Results Hypertension was induced in male Sprague-Dawley rats by delivering AngiotensinII for 42 days using implanted osmotic minipumps. Rats were randomized into sedentary, trained, and detrained groups. Trained rats underwent moderate-intensity exercise (ExT) for 42 days, whereas, detrained groups underwent 28 days of exercise followed by 14 days of detraining. BP and cardiac function were evaluated by radio-telemetry and echocardiography, respectively. At the end, the paraventricular nucleus (PVN) was analyzed by Real-time RT-PCR and Western blot. ExT in AngII-infused rats caused delayed progression of hypertension, reduced cardiac hypertrophy, and improved diastolic function. These results were associated with significantly reduced PICs, increased AIC (interleukin (IL)-10), and attenuated oxidative stress in the PVN. Detraining did not abolish the exercise-induced attenuation in MAP in hypertensive rats; however, detraining failed to completely preserve exercise-mediated improvement in cardiac hypertrophy and function. Additionally, detraining did not reverse exercise-induced improvement in PICs in the PVN of hypertensive rats; however, the improvements in IL-10 were abolished. Conclusion These results indicate that although 2 weeks of detraining is not long enough to completely abolish the beneficial effects of regular exercise, continuing cessation of exercise may lead to detrimental effects. PMID:23285093

Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

PubMed

Thomas, Julia D J; Dattani, Abhishek; Zemrak, Filip; Burchell, Thomas; Akker, Scott A; Kaplan, Felicity J L; Khoo, Bernard; Aylwin, Simon; Grossman, Ashley B; Davies, L Ceri; Korbonits, Márta

2017-06-01

Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m 2 , ANOVA p=0.034, B vs. C p<0.01). Groups A and B had EDVi and ESVi values at the top of published reference range values; Group C had values in the middle of the range.Acromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension. © Georg Thieme Verlag KG Stuttgart · New York.

Unexpected and rapid recovery of left ventricular function in patients with peripartum cardiomyopathy: impact of cardiac resynchronization therapy.

PubMed

Mouquet, Frederic; Mostefa Kara, Meriem; Lamblin, Nicolas; Coulon, Capucine; Langlois, Stephane; Marquie, Christelle; de Groote, Pascal

2012-05-01

Aim Peripartum cardiomyopathy (PPCM) is a rare cause of dilated cardiomyopathy responsible for heart failure toward the end of pregnancy, which can lead to chronic heart failure in 50% of cases. In this short report, we assessed the benefit of cardiac resynchronization in patients with PPCM and chronic systolic dysfunction despite optimal medical treatment. For the last 10 years, we managed eight patients diagnosed with PPCM. Two of them presented severe systolic dysfunction, and medical treatment resulted in limited improvement from 10% to 25% and from 25% to 28% despite optimal treatment for 9 and 6 years, respectively. These two patients were porposed to receive an implantatable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT). Six months after ICD-CRT treatment, we observed a significant improvement in systolic function from 25% to 45% and 28% to 50%, respectively, and positive remodelling with reduction of left ventricular end-diastolic volume from 216 to 144 mL and from 354 to 105 mL, which represent a 34% and a 70% reduction, respectively. Physicians in charge of patients with PPCM should offer the opportunity of CRT for patients whose cardiac function has not significantly improved under standard medical treatment.

Improved Accuracy of Automated Estimation of Cardiac Output Using Circulation Time in Patients with Heart Failure.

PubMed

Dajani, Hilmi R; Hosokawa, Kazuya; Ando, Shin-Ichi

2016-11-01

Lung-to-finger circulation time of oxygenated blood during nocturnal periodic breathing in heart failure patients measured using polysomnography correlates negatively with cardiac function but possesses limited accuracy for cardiac output (CO) estimation. CO was recalculated from lung-to-finger circulation time using a multivariable linear model with information on age and average overnight heart rate in 25 patients who underwent evaluation of heart failure. The multivariable model decreased the percentage error to 22.3% relative to invasive CO measured during cardiac catheterization. This improved automated noninvasive CO estimation using multiple variables meets a recently proposed performance criterion for clinical acceptability of noninvasive CO estimation, and compares very favorably with other available methods. Copyright © 2016 Elsevier Inc. All rights reserved.

Performance of Automated Software in the Assessment of Segmental Left Ventricular Function in Cardiac CT: Comparison with Cardiac Magnetic Resonance.

PubMed

Wang, Rui; Meinel, Felix G; Schoepf, U Joseph; Canstein, Christian; Spearman, James V; De Cecco, Carlo N

2015-12-01

To evaluate the accuracy, reliability and time saving potential of a novel cardiac CT (CCT)-based, automated software for the assessment of segmental left ventricular function compared to visual and manual quantitative assessment of CCT and cardiac magnetic resonance (CMR). Forty-seven patients with suspected or known coronary artery disease (CAD) were enrolled in the study. Wall thickening was calculated. Segmental LV wall motion was automatically calculated and shown as a colour-coded polar map. Processing time for each method was recorded. Mean wall thickness in both systolic and diastolic phases on polar map, CCT, and CMR was 9.2 ± 0.1 mm and 14.9 ± 0.2 mm, 8.9 ± 0.1 mm and 14.5 ± 0.1 mm, 8.3 ± 0.1 mm and 13.6 ± 0.1 mm, respectively. Mean wall thickening was 68.4 ± 1.5 %, 64.8 ± 1.4 % and 67.1 ± 1.4 %, respectively. Agreement for the assessment of LV wall motion between CCT, CMR and polar maps was good. Bland-Altman plots and ICC indicated good agreement between CCT, CMR and automated polar maps of the diastolic and systolic segmental wall thickness and thickening. The processing time using polar map was significantly decreased compared with CCT and CMR. Automated evaluation of segmental LV function with polar maps provides similar measurements to manual CCT and CMR evaluation, albeit with substantially reduced analysis time. • Cardiac computed tomography (CCT) can accurately assess segmental left ventricular wall function. • A novel automated software permits accurate and fast evaluation of wall function. • The software may improve the clinical implementation of segmental functional analysis.

Acupuncture Effects on Cardiac Functions Measured by Cardiac Magnetic Resonance Imaging in a Feline Model

PubMed Central

Lin, Jen-Hsou; Shih, Chen-Haw; Kaphle, Krishna; Wu, Leang-Shin; Tseng, Weng-Yih; Chiu, Jen-Hwey; Lee, Tzu-chi

2010-01-01

The usefulness of acupuncture (AP) as a complementary and/or alternative therapy in animals is well established but more research is needed on its clinical efficacy relative to conventional therapy, and on the underlying mechanisms of the effects of AP. Cardiac magnetic resonance imaging (CMRI), an important tool in monitoring cardiovascular diseases, provides a reliable method to monitor the effects of AP on the cardiovascular system. This controlled experiment monitored the effect electro-acupuncture (EA) at bilateral acupoint Neiguan (PC6) on recovery time after ketamine/xylazine cocktail anesthesia in healthy cats. The CMRI data established the basic feline cardiac function index (CFI), including cardiac output and major vessel velocity. To evaluate the effect of EA on the functions of the autonomic nervous and cardiovascular systems, heart rate, respiration rate, electrocardiogram and pulse rate were also measured. Ketamine/xylazine cocktail anesthesia caused a transient hypertension in the cats; EA inhibited this anesthetic-induced hypertension and shortened the post-anesthesia recovery time. Our data support existing knowledge on the cardiovascular benefits of EA at PC6, and also provide strong evidence for the combination of anesthesia and EA to shorten post-anesthesia recovery time and counter the negative effects of anesthetics on cardiac physiology. PMID:18955311

The effects of pleural fluid drainage on respiratory function in mechanically ventilated patients after cardiac surgery

PubMed Central

Brims, Fraser J H; Davies, Michael G; Elia, Andy; Griffiths, Mark J D

2015-01-01

Background Pleural effusions occur commonly after cardiac surgery and the effects of drainage on gas exchange in this population are not well established. We examined pulmonary function indices following drainage of pleural effusions in cardiac surgery patients. Methods We performed a retrospective study examining the effects of pleural fluid drainage on the lung function indices of patients recovering from cardiac surgery requiring mechanical ventilation for more than 7 days. We specifically analysed patients who had pleural fluid removed via an intercostal tube (ICT: drain group) compared with those of a control group (no effusion, no ICT). Results In the drain group, 52 ICTs were sited in 45 patients. The mean (SD) volume of fluid drained was 1180 (634) mL. Indices of oxygenation were significantly worse in the drain group compared with controls prior to drainage. The arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) (P/F) ratio improved on day 1 after ICT placement (mean (SD), day 0: 31.01 (8.92) vs 37.18 (10.7); p<0.05) and both the P/F ratio and oxygenation index (OI: kPa/cm H2O=PaO2/mean airway pressure×FiO2) demonstrated sustained improvement to day 5 (P/F day 5: 39.85 (12.8); OI day 0: 2.88 (1.10) vs day 5: 4.06 (1.73); both p<0.01). The drain group patients were more likely to have an improved mode of ventilation on day 1 compared with controls (p=0.028). Conclusions Pleural effusion after cardiac surgery may impair oxygenation. Drainage of pleural fluid is associated with a rapid and sustained improvement in oxygenation. PMID:26339492

Novel MRI-derived quantitative biomarker for cardiac function applied to classifying ischemic cardiomyopathy within a Bayesian rule learning framework

NASA Astrophysics Data System (ADS)

Menon, Prahlad G.; Morris, Lailonny; Staines, Mara; Lima, Joao; Lee, Daniel C.; Gopalakrishnan, Vanathi

2014-03-01

index (LV-ESVI). This improved to 91.9% with inclusion of the RMS-P2PD biomarker and was congruent with improvements in both sensitivity for classifying patients and specificity for identifying asymptomatic controls from 82.6% up to 95.7%. RMS-P2PD, when contrasted against a collective normal reference, is a promising biomarker to investigate further in its utility for identifying quantitative signs of pathological endocardial function which may boost standard image makers as precursors of declining cardiac performance.

Triptolide improves systolic function and myocardial energy metabolism of diabetic cardiomyopathy in streptozotocin-induced diabetic rats.

PubMed

Liang, Zhongshu; Leo, Sunnar; Wen, Helin; Ouyang, Mao; Jiang, Weihong; Yang, Kan

2015-05-13

Triptolide treatment leads to an improvement in Diabetic Cardiomyopathy (DCM) in streptozotocin-induced diabetic rat model. DCM is characterized by abnormal cardiac energy metabolism. We hypothesized that triptolide ameliorated cardiac metabolic abnormalities in DCM. We proposed (31)P nuclear magnetic resonance ((31)P NMR) spectrometry method for assessing cardiac energy metabolism in vivo and evaluating the effect of triptolide treatment in DCM rats. Six weeks triptolide treatment was conducted on streptozotocin-induced diabetic rats with dose of 100, 200 or 400 μg/kg/day respectively. Sex- and age-matched non-diabetic rats were used as control group. Cardiac chamber dimension and function were determined with echocardiography. Whole heart preparations were perfused with Krebs-Henseleit buffer and (31)P NMR spectroscopy was performed. Cardiac p38 Mitogen Activating Protein Kinase (MAPK) was measured using real time PCR and western blot analysis. In diabetic rats, cardiac mass index was significantly higher, where as cardiac EF was lower than control group. (31)P NMR spectroscopy showed that ATP and pCr concentrations in diabetic groups were also remarkably lower than control group. Compared to non-treated diabetic rats, triptolide-treated diabetic groups showed remarkable lower cardiac mass index and higher EF, ATP, pCr concentrations, and P38 MAPK expressions. Best improvement was seen in group treated with Triptolide with dose 200 μg/kg/day. (31)P NMR spectroscopy enables assessment of cardiac energy metabolism in whole heart preparations. It detects energy metabolic abnormalities in DCM hearts. Triptolide therapy improves cardiac function and increases cardiac energy metabolism at least partly through upregulation of MAPK signaling transduction.

Open lung ventilation improves functional residual capacity after extubation in cardiac surgery.

PubMed

Reis Miranda, Dinis; Struijs, Ard; Koetsier, Peter; van Thiel, Robert; Schepp, Ronald; Hop, Wim; Klein, Jan; Lachmann, Burkhard; Bogers, Ad J J C; Gommers, Diederik

2005-10-01

After cardiac surgery, functional residual capacity (FRC) after extubation is reduced significantly. We hypothesized that ventilation according to the open lung concept (OLC) attenuates FRC reduction after extubation. A prospective, single-center, randomized, controlled clinical study. Cardiothoracic operating room and intensive care unit of a university hospital. Sixty-nine patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Before surgery, patients were randomly assigned to three groups: (1) conventional ventilation (CV); (2) OLC, started after arrival in the intensive care unit (late open lung); and (3) OLC, started directly after intubation (early open lung). In both OLC groups, recruitment maneuvers were applied until Pao2/Fio2 was >375 Torr (50 kPa). No recruitment maneuvers were applied in the CV group. FRC was measured preoperatively and 1, 3, and 5 days after extubation. Peripheral hemoglobin saturation (Spo2) was measured daily till the third day after extubation while the patient was breathing room air. Hypoxemia was defined by an Spo2 value < or =90%. Averaged over the 5 postoperative days, FRC was significantly higher in the early open lung group and tended to be higher in the late open lung group, in comparison with the CV group (mean +/- sem: CV, 1.8 +/- 0.1; late open lung,1.9 +/- 0.1; and early open lung, 2.2 +/- 0.1l). In the CV group, 37% of the patients were hypoxic on the third day after extubation, compared with none of the patients in both OLC groups. After cardiac surgery, earlier application of OLC resulted in a significantly higher FRC and fewer episodes of hypoxemia than with CV after extubation.

Vascularisation to improve translational potential of tissue engineering systems for cardiac repair.

PubMed

Dilley, Rodney J; Morrison, Wayne A

2014-11-01

Cardiac tissue engineering is developing as an alternative approach to heart transplantation for treating heart failure. Shortage of organ donors and complications arising after orthotopic transplant remain major challenges to the modern field of heart transplantation. Engineering functional myocardium de novo requires an abundant source of cardiomyocytes, a biocompatible scaffold material and a functional vasculature to sustain the high metabolism of the construct. Progress has been made on several fronts, with cardiac cell biology, stem cells and biomaterials research particularly promising for cardiac tissue engineering, however currently employed strategies for vascularisation have lagged behind and limit the volume of tissue formed. Over ten years we have developed an in vivo tissue engineering model to construct vascularised tissue from various cell and tissue sources, including cardiac tissue. In this article we review the progress made with this approach and others, together with their potential to support a volume of engineered tissue for cardiac tissue engineering where contractile mass impacts directly on functional outcomes in translation to the clinic. It is clear that a scaled-up cardiac tissue engineering solution required for clinical treatment of heart failure will include a robust vascular supply for successful translation. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pulmonary function and adverse cardiovascular outcomes: Can cardiac function explain the link?

PubMed

Burroughs Peña, Melissa S; Dunning, Allison; Schulte, Phillip J; Durheim, Michael T; Kussin, Peter; Checkley, William; Velazquez, Eric J

2016-12-01

The complex interaction between pulmonary function, cardiac function and adverse cardiovascular events has only been partially described. We sought to describe the association between pulmonary function with left heart structure and function, all-cause mortality and incident cardiovascular hospitalization. This study is a retrospective analysis of patients evaluated in a single tertiary care medical center. We used multivariable linear regression analyses to examine the relationship between FVC and FEV1 with left ventricular ejection fraction (LVEF), left ventricular internal dimension in systole and diastole (LVIDS, LVIDD) and left atrial diameter, adjusting for baseline characteristics, right ventricular function and lung hyperinflation. We also used Cox proportional hazards models to examine the relationship between FVC and FEV1 with all-cause mortality and cardiac hospitalization. A total of 1807 patients were included in this analysis with a median age of 61 years and 50% were female. Decreased FVC and FEV1 were both associated with decreased LVEF. In individuals with FVC less than 2.75 L, decreased FVC was associated with increased all-cause mortality after adjusting for left and right heart echocardiographic variables (hazard ratio [HR] 0.49, 95% CI 0.29, 0.82, respectively). Decreased FVC was associated with increased cardiac hospitalization after adjusting for left heart size (HR 0.80, 95% CI 0.67, 0.96), even in patients with normal LVEF (HR 0.75, 95% CI 0.57, 0.97). In a tertiary care center reduced pulmonary function was associated with adverse cardiovascular events, a relationship that is not fully explained by left heart remodeling or right heart dysfunction. Copyright © 2016 Elsevier Ltd. All rights reserved.

The CD4(+) AT2R(+) T cell subpopulation improves post-infarction remodelling and restores cardiac function.

PubMed

Skorska, Anna; von Haehling, Stephan; Ludwig, Marion; Lux, Cornelia A; Gaebel, Ralf; Kleiner, Gabriela; Klopsch, Christian; Dong, Jun; Curato, Caterina; Altarche-Xifró, Wassim; Slavic, Svetlana; Unger, Thomas; Steinhoff, Gustav; Li, Jun; David, Robert

2015-08-01

Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4(+) AT2R(+) cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4(+) AT2R(+) T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4(+) cells. CD4(+) AT2R(+) T cells within blood CD4(+) T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4(+) AT2R(+) T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4(+) AT2R(+) T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4(+) AT2R(+) cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4(+) AT2R(+) cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

The CD4+AT2R+ T cell subpopulation improves post-infarction remodelling and restores cardiac function

PubMed Central

Skorska, Anna; von Haehling, Stephan; Ludwig, Marion; Lux, Cornelia A; Gaebel, Ralf; Kleiner, Gabriela; Klopsch, Christian; Dong, Jun; Curato, Caterina; Altarche-Xifró, Wassim; Slavic, Svetlana; Unger, Thomas; Steinhoff, Gustav; Li, Jun; David, Robert

2015-01-01

Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4+ AT2R+ cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4+ AT2R+ T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4+ cells. CD4+ AT2R+ T cells within blood CD4+ T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4+ AT2R+ T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4+ AT2R+ T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4+ AT2R+ cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4+ AT2R+ cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof. PMID:25991381

Mammalian enabled (Mena) is a critical regulator of cardiac function.

PubMed

Aguilar, Frédérick; Belmonte, Stephen L; Ram, Rashmi; Noujaim, Sami F; Dunaevsky, Olga; Protack, Tricia L; Jalife, Jose; Todd Massey, H; Gertler, Frank B; Blaxall, Burns C

2011-05-01

Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena(-/-)) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena(-/-) mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena(-/-) hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena(-/-) mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction.

Modified high-intensity interval training reduces liver fat and improves cardiac function in non-alcoholic fatty liver disease: a randomized controlled trial.

PubMed

Hallsworth, Kate; Thoma, Christian; Hollingsworth, Kieren G; Cassidy, Sophie; Anstee, Quentin M; Day, Christopher P; Trenell, Michael I

2015-12-01

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481. © 2015 Authors; published by Portland Press Limited.

The treatment with pyridostigmine improves the cardiocirculatory function in rats with chronic heart failure.

PubMed

Sabino, João Paulo J; da Silva, Carlos Alberto Aguiar; de Melo, Rubens Fernando; Fazan, Rubens; Salgado, Helio C

2013-01-01

Sympathetic hyperactivity and its outcome in heart failure have been thoroughly investigated to determine the focus of pharmacologic approaches targeting the sympathetic nervous system in the treatment of this pathophysiological condition. On the other hand, therapeutic approaches aiming to protect the reduced cardiac parasympathetic function have not received much attention. The present study evaluated rats with chronic heart failure (six to seven weeks after coronary artery ligation) and the effects of an increased parasympathetic function by pyridostigmine (an acetylcholinesterase inhibitor) on the following aspects: arterial pressure (AP), heart rate (HR), baroreceptor and Bezold-Jarisch reflex, pulse interval (PI) and AP variability, cardiac sympathetic and parasympathetic tonus, intrinsic heart rate (i-HR) and cardiac function. Conscious rats with heart failure exhibited no change in HR, Bezold-Jarisch reflex, PI variability and cardiac sympathetic tonus. On the other hand, these animals presented hypotension and reduced baroreflex sensitivity, power in the low frequency (LF) band of the systolic AP spectrum, cardiac parasympathetic tonus and i-HR, while anesthetized rats exhibited reduced cardiac performance. Pyridostigmine prevented the attenuation of all the parameters examined, except basal AP and cardiac performance. In conclusion, the blockade of acetylcholinesterase with pyridostigmine was revealed to be an important pharmacological approach, which could be used to increase parasympathetic function and to improve a number of cardiocirculatory parameters in rats with heart failure. Copyright © 2012 Elsevier B.V. All rights reserved.

Evaluation of platelet function in dogs with cardiac disease using the PFA-100 platelet function analyzer.

PubMed

Clancey, Noel; Burton, Shelley; Horney, Barbara; Mackenzie, Allan; Nicastro, Andrea; Côté, Etienne

2009-09-01

Cardiac disease has the potential to alter platelet function in dogs. Evaluation of platelet function using the PFA-100 analyzer in dogs of multiple breeds and with a broad range of cardiac conditions would help clarify the effect of cardiac disease on platelets. The objective of this study was to assess differences in closure time (CT) in dogs with cardiac disease associated with murmurs, when compared with that of healthy dogs. Thirty-nine dogs with cardiac murmurs and turbulent blood flow as determined echocardiographically were included in the study. The dogs represented 23 different breeds. Dogs with murmurs were further divided into those with atrioventricular valvular insufficiency (n=23) and subaortic stenosis (n=9). Fifty-eight clinically healthy dogs were used as controls. CTs were determined in duplicate on a PFA-100 analyzer using collagen/ADP cartridges. Compared with CTs in the control group (mean+/-SD, 57.6+/-5.9 seconds; median, 56.5 seconds; reference interval, 48.0-77.0 seconds), dogs with valvular insufficiency (mean+/-SD, 81.9+/-26.3 seconds; median, 78.0 seconds; range, 52.5-187 seconds), subaortic stenosis (71.4+/-16.5 seconds; median, 66.0 seconds; range, 51.5-95.0 seconds), and all dogs with murmurs combined (79.6+/-24.1 seconds; median, 74.0 seconds; range, 48.0-187 seconds) had significantly prolonged CTs (P<.01). The PFA-100 analyzer is useful in detecting platelet function defects in dogs with cardiac murmurs, most notably those caused by mitral and/or tricuspid valvular insufficiency or subaortic stenosis. The form of turbulent blood flow does not appear to be an important factor in platelet hypofunction in these forms of cardiac disease.

A Novel Human Tissue-Engineered 3-D Functional Vascularized Cardiac Muscle Construct

PubMed Central

Valarmathi, Mani T.; Fuseler, John W.; Davis, Jeffrey M.; Price, Robert L.

2017-01-01

Organ tissue engineering, including cardiovascular tissues, has been an area of intense investigation. The major challenge to these approaches has been the inability to vascularize and perfuse the in vitro engineered tissue constructs. Attempts to provide oxygen and nutrients to the cells contained in the biomaterial constructs have had varying degrees of success. The aim of this current study is to develop a three-dimensional (3-D) model of vascularized cardiac tissue to examine the concurrent temporal and spatial regulation of cardiomyogenesis in the context of postnatal de novo vasculogenesis during stem cell cardiac regeneration. In order to achieve the above aim, we have developed an in vitro 3-D functional vascularized cardiac muscle construct using human induced pluripotent stem cell-derived embryonic cardiac myocytes (hiPSC-ECMs) and human mesenchymal stem cells (hMSCs). First, to generate the prevascularized scaffold, human cardiac microvascular endothelial cells (hCMVECs) and hMSCs were co-cultured onto a 3-D collagen cell carrier (CCC) for 7 days under vasculogenic culture conditions. In this milieu, hCMVECs/hMSCs underwent maturation, differentiation, and morphogenesis characteristic of microvessels, and formed extensive plexuses of vascular networks. Next, the hiPSC-ECMs and hMSCs were co-cultured onto this generated prevascularized CCCs for further 7 or 14 days in myogenic culture conditions. Finally, the vascular and cardiac phenotypic inductions were analyzed at the morphological, immunological, biochemical, molecular, and functional levels. Expression and functional analyses of the differentiated cells revealed neo-angiogenesis and neo-cardiomyogenesis. Thus, our unique 3-D co-culture system provided us the apt in vitro functional vascularized 3-D cardiac patch that can be utilized for cellular cardiomyoplasty. PMID:28194397

Multicomponent cardiac rehabilitation in patients after transcatheter aortic valve implantation: Predictors of functional and psychocognitive recovery.

PubMed

Eichler, Sarah; Salzwedel, Annett; Reibis, Rona; Nothroff, Jörg; Harnath, Axel; Schikora, Martin; Butter, Christian; Wegscheider, Karl; Völler, Heinz

2017-02-01

Background In the last decade, transcatheter aortic valve implantation has become a promising treatment modality for patients with aortic stenosis and a high surgical risk. Little is known about influencing factors of function and quality of life during multicomponent cardiac rehabilitation. Methods From October 2013 to July 2015, patients with elective transcatheter aortic valve implantation and a subsequent inpatient cardiac rehabilitation were enrolled in the prospective cohort multicentre study. Frailty-Index (including cognition, nutrition, autonomy and mobility), Short Form-12 (SF-12), six-minute walk distance (6MWD) and maximum work load in bicycle ergometry were performed at admission and discharge of cardiac rehabilitation. The relation between patient characteristics and improvements in 6MWD, maximum work load or SF-12 scales were studied univariately and multivariately using regression models. Results One hundred and thirty-six patients (80.6 ± 5.0 years, 47.8% male) were enrolled. 6MWD and maximum work load increased by 56.3 ± 65.3 m ( p < 0.001) and 8.0 ± 14.9 watts ( p < 0.001), respectively. An improvement in SF-12 (physical 2.5 ± 8.7, p = 0.001, mental 3.4 ± 10.2, p = 0.003) could be observed. In multivariate analysis, age and higher education were significantly associated with a reduced 6MWD, whereas cognition and obesity showed a positive predictive value. Higher cognition, nutrition and autonomy positively influenced the physical scale of SF-12. Additionally, the baseline values of SF-12 had an inverse impact on the change during cardiac rehabilitation. Conclusions Cardiac rehabilitation can improve functional capacity as well as quality of life and reduce frailty in patients after transcatheter aortic valve implantation. An individually tailored therapy with special consideration of cognition and nutrition is needed to maintain autonomy and empower octogenarians in coping with challenges of everyday

Cardiac Amyloidosis Shows Decreased Diastolic Function as Assessed by Echocardiographic Parameterized Diastolic Filling.

PubMed

Salman, Katrin; Cain, Peter A; Fitzgerald, Benjamin T; Sundqvist, Martin G; Ugander, Martin

2017-07-01

Cardiac amyloidosis is a rare but serious condition with poor survival. One of the early findings by echocardiography is impaired diastolic function, even before the development of cardiac symptoms. Early diagnosis is important, permitting initiation of treatment aimed at improving survival. The parameterized diastolic filling (PDF) formalism entails describing the left ventricular filling pattern during early diastole using the mathematical equation for the motion of a damped harmonic oscillator. We hypothesized that echocardiographic PDF analysis could detect differences in diastolic function between patients with amyloidosis and controls. Pulsed-wave Doppler echocardiography of transmitral flow was measured in 13 patients with amyloid heart disease and 13 age- and gender matched controls. E- waves (2 to 3 per subject) were analyzed using in-house developed software. Nine PDF-derived parameters were obtained in addition to conventional echocardiographic parameters of diastolic function. Compared to controls, cardiac amyloidosis patients had a larger left atrial area (23.7 ± 7.5 cm 2 vs. 18.5 ± 4.8 cm 2 , p = 0.04), greater interventricular septum wall thickness (14.4 ± 2.6 mm vs. 9.3 ± 1.3 mm, p < 0.001), lower e' (0.06 ± 0.02 m/s vs. 0.09 ± 0.02 m/s, p < 0.001) and higher E/e' (18.0 ± 12.9 vs. 7.7 ± 1.3, p = 0.001). The PDF parameter peak resistive force was greater in cardiac amyloidosis patients compared to controls (17.9 ± 5.7 mN vs. 13.1 ± 3.1 mN, p = 0.03), and other PDF parameters did not differ. PDF analysis revealed that patients with cardiac amyloidosis had a greater peak resistive force compared to controls, consistent with a greater degree of diastolic dysfunction. PDF analysis may be useful in characterizing diastolic function in amyloid heart disease. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Acute Alcohol Modulates Cardiac Function as PI3K/Akt Regulates Oxidative Stress

PubMed Central

Umoh, Nsini A.; Walker, Robin K.; Al-Rubaiee, Mustafa; Jeffress, Miara A.; Haddad, Georges E.

2015-01-01

Background Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low-dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure. Methods Thus, acutely exposed rat cardiac tissue and cardiocytes to low (LA: 5 mM), moderate (MA: 25 mM), and high (HA: 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI3K/Akt activators (IGF-1 0.1 μM or constitutively active PI3K: Ad.BD110 transfection) or inhibitor (LY294002 1 μMor Akt-negative construct Ad.Akt(K179M) transfection). Results Acute LA reduced Akt, superoxide dismutase (SOD-3) and NFκB, ERK1, and p38 MAPK gene expression. Acute HA only increased that of SOD-3 and NFκB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad.BD110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF-1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI3K/Akt activation. This translated into reduced viability with HA, with no effect with LA. On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end-systolic pressure–volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA. LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF-1 treatment

Mammalian enabled (Mena) is a critical regulator of cardiac function

PubMed Central

Aguilar, Frédérick; Belmonte, Stephen L.; Ram, Rashmi; Noujaim, Sami F.; Dunaevsky, Olga; Protack, Tricia L.; Jalife, Jose; Todd Massey, H.; Gertler, Frank B.

2011-01-01

Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena−/−) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena−/− mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena−/− hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena−/− mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction. PMID:21335464

Skeletal and cardiac muscle pericytes: Functions and therapeutic potential

PubMed Central

Murray, Iain R.; Baily, James E.; Chen, William C.W.; Dar, Ayelet; Gonzalez, Zaniah N.; Jensen, Andrew R.; Petrigliano, Frank A.; Deb, Arjun; Henderson, Neil C.

2017-01-01

Pericytes are periendothelial mesenchymal cells residing within the microvasculature. Skeletal muscle and cardiac pericytes are now recognized to fulfill an increasing number of functions in normal tissue homeostasis, including contributing to microvascular function by maintaining vessel stability and regulating capillary flow. In the setting of muscle injury, pericytes contribute to a regenerative microenvironment through release of trophic factors and by modulating local immune responses. In skeletal muscle, pericytes also directly enhance tissue healing by differentiating into myofibers. Conversely, pericytes have also been implicated in the development of disease states, including fibrosis, heterotopic ossication and calcification, atherosclerosis, and tumor angiogenesis. Despite increased recognition of pericyte heterogeneity, it is not yet clear whether specific subsets of pericytes are responsible for individual functions in skeletal and cardiac muscle homeostasis and disease. PMID:27595928

Critical Care Management Focused on Optimizing Brain Function After Cardiac Arrest.

PubMed

Nakashima, Ryuta; Hifumi, Toru; Kawakita, Kenya; Okazaki, Tomoya; Egawa, Satoshi; Inoue, Akihiko; Seo, Ryutaro; Inagaki, Nobuhiro; Kuroda, Yasuhiro

2017-03-24

The discussion of neurocritical care management in post-cardiac arrest syndrome (PCAS) has generally focused on target values used for targeted temperature management (TTM). There has been less attention paid to target values for systemic and cerebral parameters to minimize secondary brain damage in PCAS. And the neurologic indications for TTM to produce a favorable neurologic outcome remain to be determined. Critical care management of PCAS patients is fundamental and essential for both cardiologists and general intensivists to improve neurologic outcome, because definitive therapy of PCAS includes both special management of the cause of cardiac arrest, such as coronary intervention to ischemic heart disease, and intensive management of the results of cardiac arrest, such as ventilation strategies to avoid brain ischemia. We reviewed the literature and the latest research about the following issues and propose practical care recommendations. Issues are (1) prediction of TTM candidate on admission, (2) cerebral blood flow and metabolism and target value of them, (3) seizure management using continuous electroencephalography, (4) target value of hemodynamic stabilization and its method, (5) management and analysis of respiration, (6) sedation and its monitoring, (7) shivering control and its monitoring, and (8) glucose management. We hope to establish standards of neurocritical care to optimize brain function and produce a favorable neurologic outcome.

Connecting Teratogen-Induced Congenital Heart Defects to Neural Crest Cells and Their Effect on Cardiac Function

PubMed Central

Karunamuni, Ganga H.; Ma, Pei; Gu, Shi; Rollins, Andrew M.; Jenkins, Michael W.; Watanabe, Michiko

2014-01-01

Neural crest cells play many key roles in embryonic development, as demonstrated by the abnormalities that result from their specific absence or dysfunction. Unfortunately, these key cells are particularly sensitive to abnormalities in various intrinsic and extrinsic factors, such as genetic deletions or ethanol-exposure that lead to morbidity and mortality for organisms. This review discusses the role identified for a segment of neural crest is in regulating the morphogenesis of the heart and associated great vessels. The paradox is that their derivatives constitute a small proportion of cells to the cardiovascular system. Findings supporting that these cells impact early cardiac function raises the interesting possibility that they indirectly control cardiovascular development at least partially through regulating function. Making connections between insults to the neural crest, cardiac function, and morphogenesis is more approachable with technological advances. Expanding our understanding of early functional consequences could be useful in improving diagnosis and testing therapies. PMID:25220155

STRUCTURAL AND FUNCTIONAL BASES OF CARDIAC FIBRILLATION. DIFFERENCES AND SIMILARITIES BETWEEN ATRIA AND VENTRICLES

PubMed Central

Filgueiras-Rama, David; Jalife, José

2016-01-01

Evidence accumulated over the last 25 years suggests that, whether in the atria or ventricles, fibrillation may be explained by the self-organization of the cardiac electrical activity into rapidly spinning rotors giving way to spiral waves that break intermittently and result in fibrillatory conduction. The dynamics and frequency of such rotors depend on the ion channel composition, excitability and refractory properties of the tissues involved, as well as on the thickness and respective three-dimensional fiber structure of the atrial and ventricular chambers. Therefore, improving the understanding of fibrillation has required the use of multidisciplinary research approaches, including optical mapping, patch clamping and molecular biology, and the application of concepts derived from the theory of wave propagation in excitable media. Moreover, translation of such concepts to the clinic has recently opened new opportunities to apply novel mechanistic approaches to therapy, particularly during atrial fibrillation ablation. Here we review the current understanding of the manner in which the underlying myocardial structure and function influence rotor initiation and maintenance during cardiac fibrillation. We also examine relevant underlying differences and similarities between atrial fibrillation and ventricular fibrillation and evaluate the latest clinical mapping technologies used to identify rotors in either arrhythmia. Altogether, the data being discussed have significantly improved our understanding of the cellular and structural bases of cardiac fibrillation and pointed toward potentially exciting new avenues for more efficient and effective identification and therapy of the most complex cardiac arrhythmias. PMID:27042693

Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome

PubMed Central

Tang, Junnan; Shen, Deliang; Caranasos, Thomas George; Wang, Zegen; Vandergriff, Adam C.; Allen, Tyler A.; Hensley, Michael Taylor; Dinh, Phuong-Uyen; Cores, Jhon; Li, Tao-Sheng; Zhang, Jinying; Kan, Quancheng; Cheng, Ke

2017-01-01

Stem cell therapy represents a promising strategy in regenerative medicine. However, cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries immunogenicity and/or tumourigenicity risks. Mounting lines of evidence indicate that stem cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based cell–cell interaction with the injured cells. Here, we fabricate a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not stimulate T-cell infiltration in immuno-competent mice. In conclusion, CMMPs act as ‘synthetic stem cells’ which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration. PMID:28045024

Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry).

PubMed

Tuzovic, Mirela; Kobayashi, Yukari; Wheeler, Matthew; Barrett, Christopher; Liedtke, Michaela; Lafayette, Richard; Schrier, Stanley; Haddad, Francois; Witteles, Ronald

2017-10-15

Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography. Copyright © 2017 Elsevier Inc. All rights reserved.

Anti-thymocyte globulin induces neoangiogenesis and preserves cardiac function after experimental myocardial infarction.

PubMed

Lichtenauer, Michael; Mildner, Michael; Werba, Gregor; Beer, Lucian; Hoetzenecker, Konrad; Baumgartner, Andrea; Hasun, Matthias; Nickl, Stefanie; Mitterbauer, Andreas; Zimmermann, Matthias; Gyöngyösi, Mariann; Podesser, Bruno Karl; Klepetko, Walter; Ankersmit, Hendrik Jan

2012-01-01

Acute myocardial infarction (AMI) followed by ventricular remodeling is the major cause of congestive heart failure and death in western world countries. Of relevance are reports showing that infusion of apoptotic leucocytes or anti-lymphocyte serum after AMI reduces myocardial necrosis and preserves cardiac function. In order to corroborate this therapeutic mechanism, the utilization of an immunosuppressive agent with a comparable mechanism, such as anti-thymocyte globulin (ATG) was evaluated in this study. AMI was induced in rats by ligation of the left anterior descending artery. Initially after the onset of ischemia, rabbit ATG (10 mg/rat) was injected intravenously. In vitro and in vivo experiments showed that ATG induced a pronounced release of pro-angiogenic and chemotactic factors. Moreover, paracrine factors released from ATG co-incubated cell cultures conferred a down-regulation of p53 in cardiac myocytes. Rats that were injected with ATG evidenced higher numbers of CD68+ macrophages in the ischemic myocardium. Animals injected with ATG evidenced less myocardial necrosis, showed a significant reduction of infarct dimension and an improvement of post-AMI remodeling after six weeks (infarct dimension 24.9% vs. 11.4%, p<0.01). Moreover, a higher vessel density in the peri-infarct region indicated a better collateralization in rats that were injected with ATG. These data indicate that ATG, a therapeutic agent successfully applied in clinical transplant immunology, triggered cardioprotective effects after AMI that salvaged ischemic myocardium by down-regulation of p53. This might have raised the resistance against apoptotic cell death during ischemia. The combination of these mechanisms seems to be causative for improved cardiac function and less ventricular remodeling after experimental AMI.

Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals.

PubMed

Byrne, M J; Power, J M; Preovolos, A; Mariani, J A; Hajjar, R J; Kaye, D M

2008-12-01

Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max); low dose -220+/-70, P>0.05; medium dose 125+/-53, P<0.05; high dose 287+/-104, P<0.05) and echocardiographically (fractional shortening: low dose -3+/-2, P>0.05; medium dose 1+/-2, P>0.05; high dose 6.5+/-3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.

Temporal resolution improvement using PICCS in MDCT cardiac imaging

PubMed Central

Chen, Guang-Hong; Tang, Jie; Hsieh, Jiang

2009-01-01

The current paradigm for temporal resolution improvement is to add more source-detector units and∕or increase the gantry rotation speed. The purpose of this article is to present an innovative alternative method to potentially improve temporal resolution by approximately a factor of 2 for all MDCT scanners without requiring hardware modification. The central enabling technology is a most recently developed image reconstruction method: Prior image constrained compressed sensing (PICCS). Using the method, cardiac CT images can be accurately reconstructed using the projection data acquired in an angular range of about 120°, which is roughly 50% of the standard short-scan angular range (∼240° for an MDCT scanner). As a result, the temporal resolution of MDCT cardiac imaging can be universally improved by approximately a factor of 2. In order to validate the proposed method, two in vivo animal experiments were conducted using a state-of-the-art 64-slice CT scanner (GE Healthcare, Waukesha, WI) at different gantry rotation times and different heart rates. One animal was scanned at heart rate of 83 beats per minute (bpm) using 400 ms gantry rotation time and the second animal was scanned at 94 bpm using 350 ms gantry rotation time, respectively. Cardiac coronary CT imaging can be successfully performed at high heart rates using a single-source MDCT scanner and projection data from a single heart beat with gantry rotation times of 400 and 350 ms. Using the proposed PICCS method, the temporal resolution of cardiac CT imaging can be effectively improved by approximately a factor of 2 without modifying any scanner hardware. This potentially provides a new method for single-source MDCT scanners to achieve reliable coronary CT imaging for patients at higher heart rates than the current heart rate limit of 70 bpm without using the well-known multisegment FBP reconstruction algorithm. This method also enables dual-source MDCT scanner to achieve higher temporal resolution

Temporal resolution improvement using PICCS in MDCT cardiac imaging.

PubMed

Chen, Guang-Hong; Tang, Jie; Hsieh, Jiang

2009-06-01

The current paradigm for temporal resolution improvement is to add more source-detector units and/or increase the gantry rotation speed. The purpose of this article is to present an innovative alternative method to potentially improve temporal resolution by approximately a factor of 2 for all MDCT scanners without requiring hardware modification. The central enabling technology is a most recently developed image reconstruction method: Prior image constrained compressed sensing (PICCS). Using the method, cardiac CT images can be accurately reconstructed using the projection data acquired in an angular range of about 120 degrees, which is roughly 50% of the standard short-scan angular range (approximately 240 degrees for an MDCT scanner). As a result, the temporal resolution of MDCT cardiac imaging can be universally improved by approximately a factor of 2. In order to validate the proposed method, two in vivo animal experiments were conducted using a state-of-the-art 64-slice CT scanner (GE Healthcare, Waukesha, WI) at different gantry rotation times and different heart rates. One animal was scanned at heart rate of 83 beats per minute (bpm) using 400 ms gantry rotation time and the second animal was scanned at 94 bpm using 350 ms gantry rotation time, respectively. Cardiac coronary CT imaging can be successfully performed at high heart rates using a single-source MDCT scanner and projection data from a single heart beat with gantry rotation times of 400 and 350 ms. Using the proposed PICCS method, the temporal resolution of cardiac CT imaging can be effectively improved by approximately a factor of 2 without modifying any scanner hardware. This potentially provides a new method for single-source MDCT scanners to achieve reliable coronary CT imaging for patients at higher heart rates than the current heart rate limit of 70 bpm without using the well-known multisegment FBP reconstruction algorithm. This method also enables dual-source MDCT scanner to achieve higher

Erythropoietin improves cardiac wasting and outcomes in a rat model of liver cancer cachexia.

PubMed

Saitoh, Masakazu; Hatanaka, Michiyoshi; Konishi, Masaaki; Ishida, Junichi; Palus, Sandra; Ebner, Nicole; Döhner, Wolfram; von Haehling, Stephan; Anker, Stefan D; Springer, Jochen

2016-09-01

Erythropoietin administration, which is clinically used in cancer patients with cancer-induced anemia, has also potentially beneficial effects on nonhematopoietic organs. We assessed the effects of erythropoietin on cancer cachexia progression and cardiac wasting compared with placebo using the Yoshida hepatoma model. Wistar rats were divided in a sham group (n=10) and a tumor-bearing group (n=60). The tumor-bearing group was further randomized to placebo (n=28), 500Unit/kg/day (n=16) or 5000Unit/kg/day of erythropoietin (n=16). Body composition was measured using nuclear magnetic resonance spectroscopy, cardiac function using echocardiography, physical activity using infrared monitoring system. Tumor-bearing rats with high dose erythropoietin led to a significant improvement on survival compared with placebo (hazard ratio: 0.43, 95%CI: 0.20-0.92, p=0.030), though low dose erythropoietin did not reach significance (hazard ratio: 0.46, 95%CI: 0.22-1.02, p=0.056). Loss of body weight, wasting of lean mass, fat mass, and reduced physical activity were ameliorated in rats treated with both low and high doses of erythropoietin (p<0.05, all). Moreover, reduced left ventricular mass and left ventricular systolic function were also ameliorated in rats treated with low and high doses of erythropoietin (p<0.05, respectively). Overall, the present data support that cardiac wasting induced by cancer cachexia plays an important role which leads to impaired survival, provided that the erythropoietin could be an effective therapeutic approach for cancer cachexia progression and cardiac wasting. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

ADAPTIVE REAL-TIME CARDIAC MRI USING PARADISE: VALIDATION BY THE PHYSIOLOGICALLY IMPROVED NCAT PHANTOM

PubMed Central

Sharif, Behzad; Bresler, Yoram

2013-01-01

Patient-Adaptive Reconstruction and Acquisition Dynamic Imaging with Sensitivity Encoding (PARADISE) is a dynamic MR imaging scheme that optimally combines parallel imaging and model-based adaptive acquisition. In this work, we propose the application of PARADISE to real-time cardiac MRI. We introduce a physiologically improved version of a realistic four-dimensional cardiac-torso (NCAT) phantom, which incorporates natural beat-to-beat heart rate and motion variations. Cardiac cine imaging using PARADISE is simulated and its performance is analyzed by virtue of the improved phantom. Results verify the effectiveness of PARADISE for high resolution un-gated real-time cardiac MRI and its superiority over conventional acquisition methods. PMID:24398475

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.

Short-term supervised inpatient physiotherapy exercise protocol improves cardiac autonomic function after coronary artery bypass graft surgery--a randomised controlled trial.

PubMed

Mendes, Renata Gonçalves; Simões, Rodrigo Polaquini; De Souza Melo Costa, Fernando; Pantoni, Camila Bianca Falasco; Di Thommazo, Luciana; Luzzi, Sérgio; Catai, Aparecida Maria; Arena, Ross; Borghi-Silva, Audrey

2010-01-01

Coronary artery bypass grafting (CABG) is accompanied by severe impairment of cardiac autonomous regulation (CAR). This study aimed to determine whether a short-term physiotherapy exercise protocol post-CABG, during inpatient cardiac rehabilitation (CR), might improve CAR. Seventy-four patients eligible for CABG were recruited and randomised into physiotherapy exercise group (EG) or physiotherapy usual care group (UCG). EG patients underwent a short-term supervised inpatient physiotherapy exercise protocol consisting of an early mobilisation with progressive exercises plus usual care (respiratory exercises). UCG only received respiratory exercises. Forty-seven patients (24 EG and 23 UGC) completed the study. Outcome measures of CAR included linear and non-linear measures of heart rate variability (HRV) assessed before discharge. By hospital discharge, EG presented significantly higher parasympathetic HRV values [rMSSD, high frequency (HF), SD1)], global power (STD RR, SD2), non-linear HRV indexes [detrended fluctuation analysis (DFA)alpha1, DFAalpha2, approximate entropy (ApEn)] and mean RR compared to UCG (p<0.05). Conversely, higher values of mean HR, low frequency (LF) (sympathetic activity) and the LF/HF (global sympatho-vagal balance) were found in the UCG. A short-term supervised physiotherapy exercise protocol during inpatient CR improves CAR at the time of discharge. Thus, exercise-based inpatient CR might be an effective non-pharmacological tool to improve autonomic cardiac tone in patient's post-CABG.

Relationship between cardiac function and resting cerebral blood flow: MRI measurements in healthy elderly subjects.

PubMed

Henriksen, Otto M; Jensen, Lars T; Krabbe, Katja; Larsson, Henrik B W; Rostrup, Egill

2014-11-01

Although both impaired cardiac function and reduced cerebral blood flow are associated with ageing, current knowledge of the influence of cardiac function on resting cerebral blood flow (CBF) is limited. The aim of this study was to investigate the potential effects of cardiac function on CBF. CBF and cardiac output were measured in 31 healthy subjects 50-75 years old using magnetic resonance imaging techniques. Mean values of CBF, cardiac output and cardiac index were 43.6 ml per 100 g min(-1), 5.5 l min(-1) and 2.7 l min(-1) m(-2), respectively, in males, and 53.4 ml per 100 g min(-1), 4.3 l min(-1) and 2.4 l min(-1) m(-2), respectively, in females. No effects of cardiac output or cardiac index on CBF or structural signs of brain ageing were observed. However, fractional brain flow defined as the ratio of total brain flow to cardiac output was inversely correlated with cardiac index (r(2) = 0.22, P = 0.008) and furthermore lower in males than in females (8.6% versus 12.5%, P = 0.003). Fractional brain flow was also inversely correlated with cerebral white matter lesion grade, although this effect was not significant when adjusted for age. Frequency analysis of heart rate variability showed a gender-related inverse association of increased low-to-high-frequency power ratio with CBF and fractional brain flow. The findings do not support a direct effect of cardiac function on CBF, but demonstrates gender-related differences in cardiac output distribution. We propose fractional brain flow as a novel index that may be a useful marker of adequate brain perfusion in the context of ageing as well as cardiovascular disease. © 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia.

PubMed

Nehra, Sarita; Bhardwaj, Varun; Bansal, Anju; Saraswat, Deepika

2017-09-26

Chronic hypobaric hypoxia (cHH) mediated cardiac insufficiencies are associated with pathological damage. Sustained redox stress and work load are major causative agents of cardiac insufficiencies under cHH. Despite the advancements made in pharmacological (anti-oxidants, vasodilators) and non-pharmacological therapeutics (acclimatization strategies and schedules), only partial success has been achieved in improving cardiac acclimatization to cHH. This necessitates the need for potent combinatorial therapies to improve cardiac acclimatization at high altitudes. We hypothesize that a combinatorial therapy comprising preconditioning to mild aerobic treadmill exercise and supplementation with nanocurcumin formulation (NCF) consisting of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) might improve cardiac adaptation at high altitudes. Adult Sprague-Dawley rats pre-conditioned to treadmill exercise and supplemented with NCF were exposed to cHH (7620 m altitude corresponding to pO2~8% at 28±2°C, relative humidity 55%±1%) for 3 weeks. The rat hearts were analyzed for changes in markers of oxidative stress (free radical leakage, lipid peroxidation, manganese-superoxide dismutase [MnSOD] activity), cardiac injury (circulating cardiac troponin I [TnI] and T [cTnT], myocardial creatine kinase [CK-MB]), metabolic damage (lactate dehydrogenase [LDH] and acetyl-coenzyme A levels, lactate and pyruvate levels) and bio-energetic insufficiency (ATP, p-AMPKα). Significant modulations (p≤0.05) in cardiac redox status, metabolic damage, cardiac injury and bio-energetics were observed in rats receiving both NCF supplementation and treadmill exercise-preconditioning compared with rats receiving only one of the treatments. The combinatorial therapeutic strategy showed a tremendous improvement in cardiac acclimatization to cHH compared to either exercise-preconditioning or NCF supplementation alone which was evident from the effective modulation in redox, metabolic, contractile

Sex differences in cardiac function after prolonged strenuous exercise.

PubMed

Cote, Anita T; Phillips, Aaron A; Foulds, Heather J; Charlesworth, Sarah A; Bredin, Shannon S D; Burr, Jamie F; Koehle, Michael S; Warburton, Darren E R

2015-05-01

To evaluate sex differences in left ventricular (LV) function after an ultramarathon, and the association of vascular and training indices with the magnitude of exercise-induced cardiac fatigue. Descriptive field study. Fat Dog 100 Ultramarathon Trail Race, Canada. Thirty-four (13 women) recreational runners (aged 28-56 years). A 100-km or 160-km mountain marathon. Baseline baroreceptor sensitivity, heart rate variability, and arterial compliance; Pre-exercise and postexercise echocardiographic evaluations of LV dimensions, volumes, Doppler flow velocities, tissue velocities, strain, and strain rate. Finishers represented 17 men (44.8 ± 6.6 years) and 8 women (45.9 ± 10.2 years; P = 0.758). After ultraendurance exercise, significant reductions (P < 0.05) in fractional shortening (men: 40.9 ± 6.9 to 34.1 ± 7.6%; women: 42.5 ± 6.5 to 34.6 ± 7.9%) diastolic filling (E/A, men: 1.28 ± 0.68 to 1.26 ± 0.33; women: 1.55 ± 0.51 to 1.30 ± 0.27), septal and lateral tissue velocities (E'), and longitudinal strain (men: -21.02 ± 1.98 to -18.44 ± 0.34; women: -20.28 ± 1.90 to -18.44 ± 2.34) were observed. Sex differences were found for baseline cardiac structure and global function, peak late transmitral flow velocity, and estimates of LV filling pressures (P < 0.05). Regression analysis found that higher baseline arterial compliance was associated with lower reductions in cardiac function postexercise, to which sex was a significant factor for E' of the lateral wall. Faster race pace and greater lifetime ultramarathons were associated with lower reductions in LV longitudinal strain (P < 0.05). Cardiac responses after an ultramarathon were similar between men and women. Greater evidence of exercise-induced cardiac fatigue was found to be associated with lower baseline arterial compliance and training status/experience. These findings suggest that vascular health is an important contributor to the degree of cardiovascular strain incurred as the result of an acute

Heart repair by reprogramming non-myocytes with cardiac transcription factors

PubMed Central

Song, Kunhua; Nam, Young-Jae; Luo, Xiang; Qi, Xiaoxia; Tan, Wei; Huang, Guo N.; Acharya, Asha; Smith, Christopher L.; Tallquist, Michelle D.; Neilson, Eric G.; Hill, Joseph A.; Bassel-Duby, Rhonda; Olson, Eric N.

2012-01-01

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodeling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, Hand2, MEF2C and Tbx5 can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodeling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules. PMID:22660318

[Salubrinal improves cardiac function in rats with heart failure post myocardial infarction through reducing endoplasmic reticulum stress-associated apoptosis].

PubMed

Liu, Y; Qi, S Y; Ru, L S; Ding, C; Wang, H J; Li, A Y; Xu, B Y; Zhang, G H; Wang, D M

2016-06-24

results suggest that reduction of ER stress and myocardial apoptosis through inhibition of eIF2α dephosphorylation may serve as the potential mechanisms for the improved cardiac function and attenuated cardiac remodeling post Sal treatment in this heart failure rat model.

A high-sugar and high-fat diet impairs cardiac systolic and diastolic function in mice.

PubMed

Carbone, Salvatore; Mauro, Adolfo G; Mezzaroma, Eleonora; Kraskauskas, Donatas; Marchetti, Carlo; Buzzetti, Raffaella; Van Tassell, Benjamin W; Abbate, Antonio; Toldo, Stefano

2015-11-01

Heart failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, exercise intolerance and cardiac dysfunction. Unhealthy diet has been associated with increased risk of obesity and heart disease, but whether it directly affects cardiac function, and promotes the development and progression of HF is unknown. We fed 8-week old male or female CD-1 mice with a standard diet (SD) or a diet rich in saturated fat and sugar, resembling a "Western" diet (WD). Cardiac systolic and diastolic function was measured at baseline and 4 and 8 weeks by Doppler echocardiography, and left ventricular (LV) end-diastolic pressure (EDP) by cardiac catheterization prior to sacrifice. An additional group of mice received WD for 4 weeks followed by SD (wash-out) for 8 weeks. WD-fed mice experienced a significant decreased in LV ejection fraction (LVEF), reflecting impaired systolic function, and a significant increase in isovolumetric relaxation time (IRT), myocardial performance index (MPI), and LVEDP, showing impaired diastolic function, without any sex-related differences. Switching to a SD after 4 weeks of WD partially reversed the cardiac systolic and diastolic dysfunction. A diet rich in saturated fat and sugars (WD) impairs cardiac systolic and diastolic function in the mouse. Further studies are required to define the mechanism through which diet affects cardiac function, and whether dietary interventions can be used in patients with, or at risk for, HF. Published by Elsevier Ireland Ltd.

Functional significance of cardiac reinnervation in heart transplant recipients.

PubMed

Schwaiblmair, M; von Scheidt, W; Uberfuhr, P; Ziegler, S; Schwaiger, M; Reichart, B; Vogelmeier, C

1999-09-01

There is accumulating evidence of structural sympathetic reinnervation after human cardiac transplantation. However, the functional significance of reinnervation in terms of exercise capacity has not been established as yet; we therefore investigated the influence of reinnervation on cardiopulmonary exercise testing. After orthotopic heart transplantation 35 patients (mean age, 49.1 +/- 8.4 years) underwent positron emission tomography with scintigraphically measured uptake of C11-hydroxyephedrine (HED), lung function testing, and cardiopulmonary exercise testing. Two groups were defined based on scintigraphic findings, indicating a denervated group (n = 15) with a HED uptake of 5.45%/min and a reinnervated group (n = 20) with a HED uptake of 10.59%/min. The two study groups did not show significant differences with regard to anthropometric data, number of rejection episodes, preoperative hemodynamics, and postoperative lung function data. The reinnervated group had a significant longer time interval from transplantation (1625 +/- 1069 versus 800 +/- 1316 days, p < .05). In transplant recipients with reinnervation, heart rate at maximum exercise (137 +/- 15 versus 120 +/- 20 beats/min, p = .012), peak oxygen uptake (21.0 +/- 4 versus 16.1 +/- 5 mL/min/kg, p = .006), peak oxygen pulse (12.4 +/- 2.9 versus 10.2 +/- 2.7 mL/min/beat, p = .031), and anaerobic threshold (11.2 +/- 1.8 versus 9.5 +/- 2.1 mL/min, p = .046) were significantly increased in comparison to denervated transplant recipients. Additionally, a decreased functional dead space ventilation (0.24 +/- 0.05 versus 0.30 +/- 0.05, p = .004) was observed in the reinnervated group. Our study results support the hypothesis that partial sympathetic reinnervation after cardiac transplantation is of functional significance. Sympathetic reinnervation enables an increased peak oxygen uptake. This is most probably due to partial restoration of the chronotropic and inotropic competence of the heart as well as an

Cardiac function, myocardial mechano-energetic efficiency, and ventricular-arterial coupling in normal pregnancy.

PubMed

Iacobaeus, Charlotte; Andolf, Ellika; Thorsell, Malin; Bremme, Katarina; Östlund, Eva; Kahan, Thomas

2018-04-01

To assess cardiac function, myocardial mechanoenergetic efficiency (MEE), and ventricular-arterial coupling (VAC) longitudinally during normal pregnancy, and to study if there was an association between cardiac structure and function, and fetal growth. Cardiac structure and function, MEE, and ventricular-arterial coupling was assessed longitudinally in 52 healthy nulliparous women at 14, 24, and 34 weeks' gestation and 9-month postpartum. Left atrial diameter increased during pregnancy (30.41 ± 3.59 mm in the nonpregnant state and 31.02 ± 3.91, 34.06 ± 3.58, and 33.9 ± 2.97 mm in the first, second, and third trimesters, P < 0.001). Left ventricular mass increased 117.12 ± 45.0 g in the nonpregnant state and 116.5 ± 33.0, 126.9 ± 34.5, 128.4 ± 36 g in the first, second, and third trimesters (P < 0.001). Cardiac output increased from 3.4 ± 1.2 l/min to 4.3 ± 0.7 l/min in the second and third trimesters (P < 0.001). Diastolic function decreased as both E/A and e'/a' decreased during pregnancy (P < 0.05 and P < 0.001, respectively). MEE and VAC were retained during pregnancy. Heart rate was associated with birth weight centile in the first (r = 0.41, P = 0.002) and second (r = 0.46, P = 0.002) trimester. The increase in cardiac output during normal pregnancy is obtained by an increase in heart rate, followed by structural cardiac changes. The impaired systolic function is accomplished by a deteriorated diastolic function. Despite these rapid changes, the myocardium manages to work efficient with a preserved MEE. Cardiac and arterial adaption to pregnancy seems to appear parallel as evidenced by a preserved VAC.

Cardiac structure and function predicts functional decline in the oldest old.

PubMed

Leibowitz, David; Jacobs, Jeremy M; Lande-Stessman, Irit; Gilon, Dan; Stessman, Jochanan

2018-02-01

Background This study examined the association between cardiac structure and function and the deterioration in activities of daily living (ADLs) in an age-homogenous, community-dwelling population of patients born in 1920-1921 over a five-year follow-up period. Design Longitudinal cohort study. Methods Patients were recruited from the Jerusalem Longitudinal Cohort Study, which has followed an age-homogenous cohort of Jerusalem residents born in 1920-1921. Patients underwent home echocardiography and were followed up for five years. Dependence was defined as needing assistance with one or more basic ADL. Standard echocardiographic assessment of cardiac structure and function, including systolic and diastolic function, was performed. Reassessment of ADLs was performed at the five-year follow-up. Results A total of 459 patients were included in the study. Of these, 362 (79%) showed a deterioration in at least one ADL at follow-up. Patients with functional deterioration had a significantly higher left ventricular mass index and left atrial volume with a lower ejection fraction. There was no significant difference between the diastolic parameters the groups in examined. When the data were examined categorically, a significantly larger percentage of patients with functional decline had an abnormal left ventricular ejection fraction and left ventricular hypertrophy. The association between left ventricular mass index and functional decline remained significant in all multivariate models. Conclusions In this cohort of the oldest old, an elevated left ventricular mass index, higher left atrial volumes and systolic, but not diastolic dysfunction, were predictive of functional disability.

Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function

PubMed Central

Feiner, Ron; Engel, Leeya; Fleischer, Sharon; Malki, Maayan; Gal, Idan; Shapira, Assaf; Shacham-Diamand, Yosi; Dvir, Tal

2016-01-01

In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, free-standing electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular electrical activities and the on-demand provision of electrical stimulation for synchronizing cell contraction. We also show that electroactive polymers containing biological factors can be deposited on designated electrodes to release drugs in the patch microenvironment on-demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function. PMID:26974408

Changes in cardiac function after pedicle subtraction osteotomy in patients with a kyphosis due to ankylosing spondylitis.

PubMed

Fu, J; Song, K; Zhang, Y G; Zheng, G Q; Zhang, G Y; Liu, C; Wang, Y

2015-10-01

Cardiac disease in patients with ankylosing spondylitis (AS) has previously been studied but not in patients with a kyphosis or in those who have undergone an operation to correct it. The aim of this study was to measure the post-operative changes in cardiac function of patients with an AS kyphosis after pedicle subtraction osteotomy (PSO). The original cohort consisted of 39 patients (33 men, six women). Of these, four patients (two men, two women) were lost to follow-up leaving 35 patients (31 men, four women) to study. The mean age of the remaining patients was 37.4 years (22.3 to 47.8) and their mean duration of AS was 17.0 years (4.6 to 26.4). Echocardiographic measurements, resting heart rate (RHR), physical function score (PFS), and full-length standing spinal radiographs were obtained before surgery and at the two-year follow-up. The mean pre-operative RHR was 80.2 bpm (60.6 to 112.3) which dropped to a mean of 73.7 bpm (60.7 to 90.6) at the two-year follow-up (p = 0.0000). Of 15 patients with normal ventricular function pre-operatively, two developed mild left ventricular diastolic dysfunction (LVDD) at the two-year follow-up. Of 20 patients with mild LVDD pre-operatively only five had this post-operatively. Overall, 15 patients had normal LV diastolic function before their operation and 28 patients had normal LV function at the two-year follow-up. The clinical improvement was 15 out of 20 (75.0%): cardiac function in patients with AS whose kyphosis was treated by PSO was significantly improved. ©2015 The British Editorial Society of Bone & Joint Surgery.

Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology

PubMed Central

Roncaglia, Paola; Howe, Douglas G.; Laulederkind, Stanley J.F.; Khodiyar, Varsha K.; Berardini, Tanya Z.; Tweedie, Susan; Foulger, Rebecca E.; Osumi-Sutherland, David; Campbell, Nancy H.; Huntley, Rachael P.; Talmud, Philippa J.; Blake, Judith A.; Breckenridge, Ross; Riley, Paul R.; Lambiase, Pier D.; Elliott, Perry M.; Clapp, Lucie; Tinker, Andrew; Hill, David P.

2018-01-01

Background: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. Methods and Results: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. Conclusions: We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects. PMID:29440116

Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology.

PubMed

Lovering, Ruth C; Roncaglia, Paola; Howe, Douglas G; Laulederkind, Stanley J F; Khodiyar, Varsha K; Berardini, Tanya Z; Tweedie, Susan; Foulger, Rebecca E; Osumi-Sutherland, David; Campbell, Nancy H; Huntley, Rachael P; Talmud, Philippa J; Blake, Judith A; Breckenridge, Ross; Riley, Paul R; Lambiase, Pier D; Elliott, Perry M; Clapp, Lucie; Tinker, Andrew; Hill, David P

2018-02-01

A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects. © 2018 The Authors.

Impact of early initiation of corticosteroid therapy on cardiac function and rhythm in patients with cardiac sarcoidosis.

PubMed

Padala, Santosh K; Peaslee, Samuel; Sidhu, Mandeep S; Steckman, David A; Judson, Marc A

2017-01-15

There is limited data on the effect of corticosteroid therapy in patients with cardiac sarcoidosis (CS). We sought to examine the impact of early initiation of corticosteroid therapy, within a month of CS diagnosis, on left ventricular ejection fraction (LVEF), ventricular arrhythmias (VAs), and atrioventricular (AV) block. We retrospectively identified 30 CS patients from a large university sarcoidosis clinic. The effect of early initiation of corticosteroid therapy on LVEF was assessed by serial echocardiography, and on VAs and AV block was assessed by Holter monitoring and/or device interrogations. The median time from diagnosis of extra-cardiac sarcoidosis to CS was 40months. 90% (27/30) of the CS patients received corticosteroid therapy and 85% percent (23/27) had early initiation of corticosteroid therapy. Fourteen patients (47%) had reduced EF<50%. 9/14 patients who had early initiation of corticosteroid therapy had improvement in mean EF (25% to 46%, P<0.001); 5/14 patients who had a delay in initiation or who did not receive corticosteroids had no improvement in mean EF (41% to 37%, P=0.47). Fourteen patients (47%) had VAs and 5 patients (17%) had advanced AV block. Early initiation of corticosteroid therapy resulted in no VA recurrences in 8/11 patients (72%), and complete recovery of AV conduction in 2/3 patients (67%). Patients with VAs (n=3) or advanced AV block (n=2) who failed to receive early corticosteroid therapy did not show improvement. There is often a delay in manifestation of cardiac sarcoidosis for several years from the diagnosis of extra-cardiac sarcoidosis. Prompt initiation of corticosteroid therapy in CS patients may improve outcomes whereas delayed initiation of corticosteroids or failure to use corticosteroids may be associated with worse outcomes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cardiac auscultation in sports medicine: strategies to improve clinical care.

PubMed

Barrett, Michael J; Ayub, Bilal; Martinez, Matthew W

2012-01-01

Cardiac auscultation is an important part of the preparticipation physical examination of athletes. Sudden death remains a rare but tragic event among athletes. The most common cause of sudden death among young athletes in the United States continues to be hypertrophic cardiomyopathy, which may or may not present with a typical heart murmur. Many clinicians do not possess sufficient proficiency in recognizing abnormal heart murmurs. New insights in the field of auditory learning suggest that cardiac auscultation is more of a technical skill than an intellectual one. Intensive repetition of abnormal heart murmurs has been shown to improve proficiency in cardiac auscultation markedly. Sample audio files of two important murmurs, i.e., an innocent murmur and hypertrophic cardiomyopathy, are provided online with this review.

Interoception across Modalities: On the Relationship between Cardiac Awareness and the Sensitivity for Gastric Functions

PubMed Central

Herbert, Beate M.; Muth, Eric R.; Pollatos, Olga; Herbert, Cornelia

2012-01-01

The individual sensitivity for ones internal bodily signals (“interoceptive awareness”) has been shown to be of relevance for a broad range of cognitive and affective functions. Interoceptive awareness has been primarily assessed via measuring the sensitivity for ones cardiac signals (“cardiac awareness”) which can be non-invasively measured by heartbeat perception tasks. It is an open question whether cardiac awareness is related to the sensitivity for other bodily, visceral functions. This study investigated the relationship between cardiac awareness and the sensitivity for gastric functions in healthy female persons by using non-invasive methods. Heartbeat perception as a measure for cardiac awareness was assessed by a heartbeat tracking task and gastric sensitivity was assessed by a water load test. Gastric myoelectrical activity was measured by electrogastrography (EGG) and subjective feelings of fullness, valence, arousal and nausea were assessed. The results show that cardiac awareness was inversely correlated with ingested water volume and with normogastric activity after water load. However, persons with good and poor cardiac awareness did not differ in their subjective ratings of fullness, nausea and affective feelings after drinking. This suggests that good heartbeat perceivers ingested less water because they subjectively felt more intense signals of fullness during this lower amount of water intake compared to poor heartbeat perceivers who ingested more water until feeling the same signs of fullness. These findings demonstrate that cardiac awareness is related to greater sensitivity for gastric functions, suggesting that there is a general sensitivity for interoceptive processes across the gastric and cardiac modality. PMID:22606278

Heterogeneous response of cardiac sympathetic function to cardiac resynchronization therapy in heart failure documented by 11[C]-hydroxy-ephedrine and PET/CT.

PubMed

Capitanio, Selene; Nanni, Cristina; Marini, Cecilia; Bonfiglioli, Rachele; Martignani, Cristian; Dib, Bassam; Fuccio, Chiara; Boriani, Giuseppe; Picori, Lorena; Boschi, Stefano; Morbelli, Silvia; Fanti, Stefano; Sambuceti, Gianmario

2015-11-01

Cardiac resynchronization therapy (CRT) is an accepted treatment in patients with end-stage heart failure. PET permits the absolute quantification of global and regional homogeneity in cardiac sympathetic innervation. We evaluated the variation of cardiac adrenergic activity in patients with idiopathic heart failure (IHF) disease (NYHA III-IV) after CRT using (11)C-hydroxyephedrine (HED) PET/CT. Ten IHF patients (mean age = 68; range = 55-81; average left ventricular ejection fraction 26 ± 4%) implanted with a resynchronization device underwent three HED PET/CT studies: PET 1 one week after inactive device implantation; PET 2, one week after PET 1 under stimulated rhythm; PET 3, at 3 months under active CRT. A dedicated software (PMOD 3.4 version) was used to estimate global and regional cardiac uptake of HED through 17 segment polar maps. At baseline, HED uptake was heterogeneously distributed throughout the left ventricle with a variation coefficient of 18 ± 5%. This variable markedly decreased after three months CRT (12 ± 5%, p < 0.01). Interestingly, subdividing the 170 myocardial segments (17 segments of each patient multiplied by the number of patients) into two groups, according to the median value of tracer uptake expressed as % of maximal myocardial uptake (76%), we observed a different behaviour depending on baseline innervation: HED uptake significantly increased only in segments with "impaired innervation" (SUV 2.61 ± 0.92 at PET1 and 3.05 ± 1.67 at three months, p < 0.01). As shown by HED PET/CT uptake and distribution, improvement in homogeneity of myocardial neuronal function reflected a selective improvement of tracer uptake in regions with more severe neuronal damage. These finding supported the presence of a myocardial regional variability in response of cardiac sympathetic system to CRT and a systemic response involving remote tissues with rich adrenergic innervation. This work might contribute to identify imaging parameters that could

Cardiac iron load and function in transfused patients treated with deferasirox (the MILE study).

PubMed

Ho, P Joy; Tay, Lay; Teo, Juliana; Marlton, Paula; Grigg, Andrew; St Pierre, Tim; Brown, Greg; Badcock, Caro-Anne; Traficante, Robert; Gervasio, Othon L; Bowden, Donald K

2017-02-01

To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608). © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Structure and functional organization of integrated cardiac intensive care].

PubMed

Scherillo, Marino; Miceli, Domenico; Tubaro, Marco; Guiducci, Umberto

2007-05-01

The early invasive strategy for the treatment of acute coronary syndromes and the increasing number of older and sicker patients requiring prolonged and more complex intensive care have induced many changes in the function of the intensive care units. These changes include the statement that specially trained cardiologists and cardiac nurses who can manage patients with acute cardiac conditions should staff the intensive care units. This document indicates the structure of the units and specific recommendations for the number of beds, monitoring system, respirators, pacemaker/defibrillators and additional equipment.

The Role of Diacylglycerol Acyltransferase (DGAT) 1 and 2 in Cardiac Metabolism and Function.

PubMed

Roe, Nathan D; Handzlik, Michal K; Li, Tao; Tian, Rong

2018-03-21

It is increasingly recognized that synthesis and turnover of cardiac triglyceride (TG) play a pivotal role in the regulation of lipid metabolism and function of the heart. The last step in TG synthesis is catalyzed by diacylglycerol:acyltransferase (DGAT) which esterifies the diacylglycerol with a fatty acid. Mammalian heart has two DGAT isoforms, DGAT1 and DGAT2, yet their roles in cardiac metabolism and function remain poorly defined. Here, we show that inactivation of DGAT1 or DGAT2 in adult mouse heart results in a moderate suppression of TG synthesis and turnover. Partial inhibition of DGAT activity increases cardiac fatty acid oxidation without affecting PPARα signaling, myocardial energetics or contractile function. Moreover, coinhibition of DGAT1/2 in the heart abrogates TG turnover and protects the heart against high fat diet-induced lipid accumulation with no adverse effects on basal or dobutamine-stimulated cardiac function. Thus, the two DGAT isoforms in the heart have partially redundant function, and pharmacological inhibition of one DGAT isoform is well tolerated in adult hearts.

Cardiac Trauma.

PubMed

Gosavi, Sucheta; Tyroch, Alan H; Mukherjee, Debabrata

2016-11-01

Cardiac trauma is a leading cause of death in the United States and occurs mostly due to motor vehicle accidents. Blunt cardiac trauma and penetrating chest injuries are most common, and both can lead to aortic injuries. Timely diagnosis and early management are the key to improve mortality. Cardiac computed tomography and cardiac ultrasound are the 2 most important diagnostic modalities. Mortality related to cardiac trauma remains high despite improvement in diagnosis and management.

Effects of vildagliptin versus sitagliptin, on cardiac function, heart rate variability and mitochondrial function in obese insulin-resistant rats

PubMed Central

Apaijai, Nattayaporn; Pintana, Hiranya; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2013-01-01

Background and Purpose Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. Experimental Approach Male Wistar rats weighing 180–200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg−1·day−1), sitagliptin (30 mg·kg−1·day−1) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined. Key Results Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV. Conclusions and Implications Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats. PMID:23488656

Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial.

PubMed

Dor-Haim, Horesh; Barak, Sharon; Horowitz, Michal; Yaakobi, Eldad; Katzburg, Sara; Swissa, Moshe; Lotan, Chaim

2018-01-01

Exercise is considered a valuable nonpharmacological intervention modality in cardiac rehabilitation (CR) programs in patients with ischemic heart disease. The effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac patients' with reduced left ventricular function, post-myocardial infarction (MI) has not been thoroughly investigated. to improve cardiac function with a novel method of combined aerobic-resistance circuit training in a randomized control trial by way of comparing the effectiveness of continuous aerobic training (CAT) to SCT on mechanical cardiac function. Secondary to compare their effect on aerobic fitness, manual strength, and quality of life in men post MI. Finally, to evaluate the safety and feasibility of SCT. 29 men post-MI participants were randomly assigned to either 12-weeks of CAT (n = 15) or SCT (n = 14). Both groups, CAT and SCT exercised at 60%-70% and 75-85% of their heart rate reserve, respectively. The SCT group also engaged in intermittently combined resistance training. Primary outcome measure was echocardiography. Secondary outcome measures were aerobic fitness, strength, and quality of life (QoL). The effectiveness of the two training programs was examined via paired t-tests and Cohen's d effect size (ES). Post-training, only the SCT group presented significant changes in echocardiography (a reduction in E/e' and an increase in ejection fraction, P<0.05). Similarly, only the SCT group presented significant changes in aerobic fitness (an increase in maximal metabolic equivalent, P<0.05). In addition, SCT improvement in the physical component of QoL was greater than this observed in the CAT group. In both training programs, no adverse events were observed. Men post-MI stand to benefit from both CAT and SCT. However, in comparison to CAT, as assessed by echocardiography, SCT may yield greater benefits to the left ventricle mechanical function as well as to the

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

Resveratrol-Mediated Expression of KLF15 in the Ischemic Myocardium is Associated with an Improved Cardiac Phenotype.

PubMed

Rogers, Russell G; Otis, Jeffrey S

2017-02-01

Myocardial infarction results in physiological derangements that lead to structural and functional alterations to the myocardium. In addition, oxidative stress potentiates cardiac remodeling and drives disease progression. Unfortunately, treatment with antioxidants in clinical trials have failed to show any therapeutic benefits despite the positive results reported in animal studies, which warrants further investigation into their mechanism(s) of action. Accordingly, the aim of this study was to elucidate a previously unknown mechanism of action for the antioxidant, resveratrol, in the treatment of the ischemic heart. Male Sprague-Dawley rats underwent four weeks of chronic myocardial ischemia with or without daily resveratrol treatment (10 mg/kg/day). The expression and signaling of Krüppel-like factor 15 (KLF15) were determined by immunoblot and qPCR analyses, respectively. Chronic myocardial ischemia reduced the protein expression of KLF15. In parallel, mRNA transcripts of KLF15 gene targets actively involved in cardiac remodeling were robustly increased in untreated hearts. Importantly, daily treatment with resveratrol stimulated KLF15 expression, which was associated with attenuated gene expression and an improved cardiac phenotype. Additionally, we describe a novel role for KLF15 in the regulation of redox homeostasis. Based on our current findings, it appears that resveratrol treatment induces KLF15 expression, which may, in part, explain its therapeutic efficacy to improve the cardiac phenotype following ischemic injury.

Childhood obesity and cardiac remodeling: from cardiac structure to myocardial mechanics.

PubMed

Tadic, Marijana; Cuspidi, Cesare

2015-08-01

Epidemic of obesity, especially morbid obesity, among children and adolescents, is a key factor associated with the dramatic increase in prevalence of type 2 diabetes mellitus, arterial hypertension, and metabolic syndrome in this population. Furthermore, childhood obesity represents a very important predictor of obesity in adulthood that is related to cardiovascular and cerebrovascular diseases. Overweight and obesity in children and adolescents are associated with impairment of cardiac structure and function. The majority of studies investigated the influence of obesity on left ventricular remodeling. However, the impact of obesity on the right ventricle, both the atria, and myocardial mechanics has been insufficiently studied. The aim of this review article is to summarize all data about heart remodeling in childhood, from cardiac size, throughout systolic and diastolic function, to myocardial mechanics, using a wide range of mainly echocardiographic techniques and parameters. Additionally, we sought to present current knowledge about the influence of weight loss, achieved by various therapeutic approaches, on the improvement of cardiac geometry, structure, and function in obese children and adolescents.

Long-term administration of pyridostigmine attenuates pressure overload-induced cardiac hypertrophy by inhibiting calcineurin signalling.

PubMed

Lu, Yi; Zhao, Ming; Liu, Jin-Jun; He, Xi; Yu, Xiao-Jiang; Liu, Long-Zhu; Sun, Lei; Chen, Li-Na; Zang, Wei-Jin

2017-09-01

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload-induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4

Estrogen-Related Receptor α (ERRα) and ERRγ Are Essential Coordinators of Cardiac Metabolism and Function

PubMed Central

Wang, Ting; McDonald, Caitlin; Petrenko, Nataliya B.; Leblanc, Mathias; Wang, Tao; Giguere, Vincent; Evans, Ronald M.; Patel, Vickas V.

2015-01-01

Almost all cellular functions are powered by a continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors estrogen-related receptor α (ERRα) and ERRγ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERRα and ERRγ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERRα and ERRγ influence major cardiomyocyte energy consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis, and conduction genes. Mice lacking both ERRα and cardiac ERRγ develop severe bradycardia, lethal cardiomyopathy, and heart failure featuring metabolic, contractile, and conduction dysfunctions. These results illustrate that the ERR transcriptional pathway is essential to couple cellular energy metabolism with energy consumption processes in order to maintain normal cardiac function. PMID:25624346

Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs

PubMed Central

Wang, Bo; Patnaik, Sourav S.; Brazile, Bryn; Butler, J. Ryan; Claude, Andrew; Zhang, Ge; Guan, Jianjun; Hong, Yi; Liao, Jun

2016-01-01

Myocardial infarction (MI) causes massive heart muscle death and remains a leading cause of death in the world. Cardiac tissue engineering aims to replace the infarcted tissues with functional engineered heart muscles or revitalize the infarcted heart by delivering cells, bioactive factors, and/or biomaterials. One major challenge of cardiac tissue engineering and regeneration is the establishment of functional perfusion and structure to achieve timely angiogenesis and effective vascularization, which are essential to the survival of thick implants and the integration of repaired tissue with host heart. In this paper, we review four major approaches to promoting angiogenesis and vascularization in cardiac tissue engineering and regeneration: delivery of pro-angiogenic factors/molecules, direct cell implantation/cell sheet grafting, fabrication of prevascularized cardiac constructs, and the use of bioreactors to promote angiogenesis and vascularization. We further provide a detailed review and discussion on the early perfusion design in nature-derived biomaterials, synthetic biodegradable polymers, tissue-derived acellular scaffolds/whole hearts, and hydrogel derived from extracellular matrix. A better understanding of the current approaches and their advantages, limitations, and hurdles could be useful for developing better materials for future clinical applications. PMID:27480586

Establishing Early Functional Perfusion and Structure in Tissue Engineered Cardiac Constructs.

PubMed

Wang, Bo; Patnaik, Sourav S; Brazile, Bryn; Butler, J Ryan; Claude, Andrew; Zhang, Ge; Guan, Jianjun; Hong, Yi; Liao, Jun

2015-01-01

Myocardial infarction (MI) causes massive heart muscle death and remains a leading cause of death in the world. Cardiac tissue engineering aims to replace the infarcted tissues with functional engineered heart muscles or revitalize the infarcted heart by delivering cells, bioactive factors, and/or biomaterials. One major challenge of cardiac tissue engineering and regeneration is the establishment of functional perfusion and structure to achieve timely angiogenesis and effective vascularization, which are essential to the survival of thick implants and the integration of repaired tissue with host heart. In this paper, we review four major approaches to promoting angiogenesis and vascularization in cardiac tissue engineering and regeneration: delivery of pro-angiogenic factors/molecules, direct cell implantation/cell sheet grafting, fabrication of prevascularized cardiac constructs, and the use of bioreactors to promote angiogenesis and vascularization. We further provide a detailed review and discussion on the early perfusion design in nature-derived biomaterials, synthetic biodegradable polymers, tissue-derived acellular scaffolds/whole hearts, and hydrogel derived from extracellular matrix. A better understanding of the current approaches and their advantages, limitations, and hurdles could be useful for developing better materials for future clinical applications.

Renal perfusion index reflects cardiac systolic function in chronic cardio-renal syndrome.

PubMed

Lubas, Arkadiusz; Ryczek, Robert; Kade, Grzegorz; Niemczyk, Stanisław

2015-04-17

Cardiac dysfunction can modify renal perfusion, which is crucial to maintain sufficient kidney tissue oxygenation. Renal cortex perfusion assessed by dynamic ultrasound method is related both to renal function and cardiac hemodynamics. The aim of the study was to test the hypothesis that Renal Perfusion Index (RPI) can more closely reflect cardiac hemodynamics and differentiate etiology of chronic cardio-renal syndrome. Twenty-four patients with hypertension and chronic kidney disease (CKD) at 2-4 stage (12 with hypertensive nephropathy and 12 with CKD prior to hypertension) were enrolled in the study. Blood tests, 24-h ABPM, echocardiography, and ultrasonography with estimation of Total renal Cortical Perfusion intensity and Renal Perfusion Index (RPI) were performed. In the group of all patients, RPI correlated with left ventricular stoke volume (LVSV), and cardiac index, but not with markers of renal function. In multiple stepwise regression analysis CKD-EPI(Cys-Cr) (b=-0.360), LVSV (b=0.924) and MAP (b=0.376) together independently influenced RPI (R2=0.74; p<0.0001). RPI<0.567 allowed for the identification of patients with chronic cardio-renal syndrome with sensitivity of 41.7% and specificity of 83.3%. Renal perfusion index relates more strongly to cardiac output than to renal function, and could be helpful in recognizing chronic cardio-renal syndrome. Applicability of RPI in diagnosing early abnormalities in the cardio-renal axis requires further investigation.

Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function.

PubMed

Feiner, Ron; Engel, Leeya; Fleischer, Sharon; Malki, Maayan; Gal, Idan; Shapira, Assaf; Shacham-Diamand, Yosi; Dvir, Tal

2016-06-01

In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, freestanding electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular electrical activities and the on-demand provision of electrical stimulation for synchronizing cell contraction. We also show that electroactive polymers containing biological factors can be deposited on designated electrodes to release drugs in the patch microenvironment on demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function.

Delivery of Nox2-NADPH oxidase siRNA with polyketal nanoparticles for improving cardiac function following myocardial infarction.

PubMed

Somasuntharam, Inthirai; Boopathy, Archana V; Khan, Raffay S; Martinez, Mario D; Brown, Milton E; Murthy, Niren; Davis, Michael E

2013-10-01

Myocardial infarction (MI) is the most common cause of heart failure (HF), the leading cause of death in the developed world. Oxidative stress due to excessive production of reactive oxygen species (ROS) plays a key role in the pathogenesis of cardiac remodeling leading to HF. NADPH oxidase with Nox2 as the catalytic subunit is a major source for cardiac ROS production. Nox2-NADPH expression is significantly increased in the infarcted myocardium, primarily in neutrophils, macrophages and myocytes. Moreover, mice lacking the Nox2 gene are protected from ischemic injury, implicating Nox2 as a potential therapeutic target. RNAi-mediated gene silencing holds great promise as a therapeutic owing to its high specificity and potency. However, in vivo delivery hurdles have limited its effective clinical use. Here, we demonstrate acid-degradable polyketal particles as delivery vehicles for Nox2-siRNA to the post-MI heart. In vitro, Nox2-siRNA particles are effectively taken up by macrophages and significantly knockdown Nox2 expression and activity. Following in vivo intramyocardial injection in experimental mice models of MI, Nox2-siRNA particles prevent upregulation of Nox2 and significantly recovered cardiac function. This study highlights the potential of polyketals as siRNA delivery vehicles to the MI heart and represents a viable therapeutic approach for targeting oxidative stress. Copyright © 2013 Elsevier Ltd. All rights reserved.

Cardiac sarcoidosis: challenges in clinical practice.

PubMed

Bakker, Anne L; Grutters, Jan C; Keijsers, Ruth G; Post, Martijn C

2017-09-01

To address the current recommendations for screening, diagnosis, and treatment of cardiac sarcoidosis and the difficulties to put these recommendations into clinical practice. The incidence of cardiac sarcoidosis appears to be higher than earlier reported, probably because of improved imaging techniques. Late gadolinium enhancement with cardiac MRI (LGE-CMR) and fluorodeoxyglucose positron emission tomography obtained a central role in the diagnostic algorithm and monitoring of disease activity. New techniques are being investigated: T1 and T2 mapping for early detection in CMR, a sarcoid-specific tracer in PET, integrated positron emission tomography/MRI scanners, and assessment of scar with LGE in cardiac computed tomography. Isolated cardiac sarcoidosis is an increasingly recognized phenotype, but still an enormous challenge in clinical practice. The prognostic value of (and extent of) LGE-CMR should be taken into account for risk assessment and internal cardiac defbrillator therapy, even in patients with preserved left ventricular function. Unfortunately, randomized controlled trials to guide immunosuppressive therapy are still lacking. A multidisciplinary approach to diagnose and treat cardiac sarcoidosis patients in specialized centers is strongly recommendable. Cardiac sarcoidosis is increasingly recognized because of improved imaging techniques; however, treatment of cardiac sarcoidosis is still mainly based on expert opinion.

Hemodynamic Improvement in Cardiac Resynchronization Does Not Require Improvement in Left Ventricular Rotation Mechanics

PubMed Central

Ashikaga, Hiroshi; Leclercq, Christophe; Wang, Jiangxia; Kass, David A.; McVeigh, Elliot R.

2010-01-01

Background Earlier studies have yielded conflicting evidence on whether or not cardiac resynchronization therapy (CRT) improves left ventricular (LV) rotation mechanics. Methods and Results In dogs with left bundle branch block and pacing-induced heart failure (n=7), we studied the effects of CRT on LV rotation mechanics in vivo by 3-dimensional tagged magnetic resonance imaging with a temporal resolution of 14 ms. CRT significantly improved hemodynamic parameters but did not significantly change the LV rotation or rotation rate. LV torsion, defined as LV rotation of each slice with respect to that of the most basal slice, was not significantly changed by CRT. CRT did not significantly change the LV torsion rate. There was no significant circumferential regional heterogeneity (anterior, lateral, inferior, and septal) in LV rotation mechanics in either left bundle branch block with pacing-induced heart failure or CRT, but there was significant apex-to-base regional heterogeneity. Conclusions CRT acutely improves hemodynamic parameters without improving LV rotation mechanics. There is no significant circumferential regional heterogeneity of LV rotation mechanics in the mechanically dyssynchronous heart. These results suggest that LV rotation mechanics is an index of global LV function, which requires coordination of all regions of the left ventricle, and improvement in LV rotation mechanics appears to be a specific but insensitive index of acute hemodynamic response to CRT. PMID:20478988

SIRT1 activation rescues doxorubicin-induced loss of functional competence of human cardiac progenitor cells.

PubMed

De Angelis, Antonella; Piegari, Elena; Cappetta, Donato; Russo, Rosa; Esposito, Grazia; Ciuffreda, Loreta Pia; Ferraiolo, Fiorella Angelica Valeria; Frati, Caterina; Fagnoni, Francesco; Berrino, Liberato; Quaini, Federico; Rossi, Francesco; Urbanek, Konrad

2015-01-01

The search for compounds able to counteract chemotherapy-induced heart failure is extremely important at the age of global cancer epidemic. The role of SIRT1 in the maintenance of progenitor cell homeostasis may contribute to its cardioprotective effects. SIRT1 activators, by preserving progenitor cells, could have a clinical relevance for the prevention of doxorubicin (DOXO)-cardiotoxicity. To determine whether SIRT1 activator, resveratrol (RES), interferes with adverse effects of DOXO on cardiac progenitor cells (CPCs): 1) human CPCs (hCPCs) were exposed in vitro to DOXO or DOXO+RES and their regenerative potential was tested in vivo in an animal model of DOXO-induced heart failure; 2) the in vivo effects of DOXO+RES co-treatment on CPCs were studied in a rat model. In contrast to healthy cells, DOXO-exposed hCPCs were ineffective in a model of anthracycline cardiomyopathy. The in vitro activation of SIRT1 decreased p53 acetylation, overcame suppression of the IGF-1/Akt pro-survival and anti-apoptotic signaling, enhanced oxidative stress defense and prevented senescence and growth arrest of hCPCs. Priming with RES counterbalanced the onset of dysfunctional phenotype in DOXO-exposed hCPCs, partly restoring their ability to repair the damage with improvement in cardiac function and animal survival. The in vivo co-treatment DOXO+RES prevented the anthracycline-induced alterations in CPCs, partly preserving cardiac function. SIRT1 activation protects DOXO-exposed CPCs and re-establishes their proper function. Pharmacological intervention at the level of tissue-specific progenitor cells may provide cardiac benefits for the growing population of long-term cancer survivors that are at risk of chemotherapy-induced cardiovascular toxicity. Copyright © 2015. Published by Elsevier Ireland Ltd.

Impact of metoprolol treatment on cardiac function and exercise tolerance in heart failure patients with neuropsychiatric disorders.

PubMed

Huang, Jingjing; Zhang, Ran; Liu, Xuelu; Meng, Yong

2018-01-01

To investigate the impact of neuropsychiatric disorders on the effect of metoprolol on cardiac and motor function in chronic heart failure (CHF) patients. From February 2013 to April 2016, CHF patients with clinical mental disorders received metoprolol (23.75 or 47.5 mg, once daily, orally) at the Second Affiliated Hospital of Kunming Medical University. Mental status was confirmed by means of the Hospital Anxiety and Depression Scale (HADS) and the Copenhagen Burnout Inventory (CBI) scale. Cardiac function parameters such as systolic blood pressure (SBP), ejection fraction (EF) and cardiac index (CI) as well as motor function including the 6 meter walk test (6MWT) and the Veteran's Specific Activity Questionnaire (VSAQ) were assessed as primary outcomes of the study. A total of 154 patients (median age, 66.39 years; men, n = 101) were allocated into eight groups based on their mental status. There were no significant differences in heart rate (HR) or SBP control achieved by metoprolol in any groups compared with the control (patients with normal mental status). Furthermore, biphasic ejection fraction (EF) changes were observed in all the groups with a decrease in the first month and increase from the sixth month. However, this increase was significantly lower (p < .001) than the EF achieved with metoprolol treatment in the control group except for the anxiety group. A similar pattern was seen for CI, 6MWT and VSAQ changes in all the groups. Patients in the anxiety group responded similarly to the patients with normal mental status. Depressive and high burnout symptoms, but not anxiety, lower the improvement of cardiac and motor function by metoprolol treatment in CHF.

Low-dose dasatinib rescues cardiac function in Noonan syndrome

PubMed Central

Yi, Jae-Sung; Huang, Yan; Kwaczala, Andrea T.; Kuo, Ivana Y.; Ehrlich, Barbara E.; Campbell, Stuart G.; Giordano, Frank J.; Bennett, Anton M.

2016-01-01

Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies. PMID:27942593

c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction

PubMed Central

Ledee, Dolena; Smith, Lincoln; Bruce, Margaret; Kajimoto, Masaki; Isern, Nancy; Portman, Michael A.; Olson, Aaron K.

2015-01-01

Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes. PMID:26266538

Current trends in cardiac rehabilitation

PubMed Central

Dafoe, W; Huston, P

1997-01-01

Cardiac rehabilitation can reduce mortality and morbidity for patients with many types of cardiac disease cost-effectively, yet is generally underutilized. Rehabilitation is helpful not only for patients who have had a myocardial infarction but also for those with stable angina or congestive heart failure or those who have undergone myocardial revascularization procedures, a heart transplant or heart valve surgery. The beneficial effects of rehabilitation include a reduction in the rate of death from cardiovascular disease, improved exercise tolerance, fewer cardiac symptoms, improved lipid levels, decreased cigarette smoking, improvement in psychosocial well-being and increased likelihood of return to work. Rehabilitation involves a multidisciplinary team that focuses on education, individually tailored exercise, risk-factor modification and the optimization of functional status and mental health. Current research trends in this area include the evaluation of new secondary-prevention modalities and alternative program options, such as home-based rehabilitation. PMID:9054823

Long-term functional and echocardiographic assessment after penetrating cardiac injury: 5-year follow-up results.

PubMed

Carr, John Alfred; Buterakos, Roxanne; Bowling, William M; Janson, Lisa; Kralovich, Kurt A; Copeland, Craig; Link, Renee; Roiter, Cecilia; Casey, Gregory; Wagner, James W

2011-03-01

There is almost no data describing the long-term functional outcome of patients after penetrating cardiac injury. A retrospective study at a Level I trauma center from 2000 to 2009. Sixty-three patients had penetrating cardiac injuries from 28 stabbings and 35 gunshots. Men comprised 89% (56) of the patients. Overall, there were 21 survivors (33%) and 42 died in the emergency room or perioperative period. The mean age did not significantly differ between survivors (36 years ± 12 years) compared with those who died (30 years ± 11 years; p=0.07). There was an increased chance of survival after being stabbed compared with being shot (17 patients vs. 4 patients; odds ratio=12; p=0.002). Thirteen (62%) had injuries to the right ventricle only. Three patients died during follow-up: one from lung cancer and two other patients died from myocardial infarctions, one 9 years later at the age of 45 years and the other 8 years later at the age of 55 years. The survivors had functional follow-up evaluations from 2 months to 114 months (median, 71; interquartile range, 34-92 months) and echocardiographic follow-up from 2 months to 107 months (median, 64; interquartile range, 31-84 months) after their injuries. Functionally, all patients were in NYHA class 1 status, except one patient in class II who was 54 years old and had a mild exertional limitation. The previously injured area could only be identified by echocardiogram in one patient who had a patch repair of a ventricular septal defect (VSD). The mean ejection fraction improved over time from a mean of 51% ± 8% in the immediate postoperative period to 60% ± 9% after a mean follow-up of 59 months (p=0.01). After surgery, 43% of patients had a mild to moderate pericardial effusion; however, the long-term follow-up studies showed that all these had resolved. Wall motion abnormalities occurred in 33% of patients in the immediate postoperative period and, again, all these resolved during long-term follow-up. Patients who

Prognostic role of coronary flow reserve for left ventricular functional improvement after cardiac resynchronization therapy in patients with dilated cardiomyopathy.

PubMed

Djordjevic Dikic, Ana; Nikcevic, Gabrijela; Raspopovic, Srdjan; Jovanovic, Velibor; Tesic, Milorad; Beleslin, Branko; Stepanovic, Jelena; Giga, Vojislav; Milasinovic, Goran

2014-12-01

The aim of the study was to assess the value of coronary flow reserve (CFR) for predicting improvement of left ventricular function after cardiac resynchronization therapy (CRT). Study population included 40 patients (mean age 58 ± 9 years) with heart failure (ejection fraction 25, 7 ± 5, 4%) and QRS duration of 158 ± 22 ms, planned for CRT. Before and after CRT implantation, CFR was measured non-invasively during hyperaemia induced with adenosine. Responders were defined by decrease in end-systolic volume ≥15%. Follow-up echocardiography and CFR measurements were obtained after 6 months. At baseline there was no significant difference in left ventricular ejection fraction (LVEF), QRS duration, 6 min walk test distance and coronary flow velocity at rest between responder (n = 26) vs. non-responder group (n = 14, P = ns). Before CRT implantation, responders compared with non-responders, showed a greater increase in coronary flow velocity during hyperaemia, and consequently higher CFR: 2.41 ± 0.60 vs. 1.61 ± 0.45 (P = 0.001). There was significant correlation between CFR before CRT implantation and LVEF after 6 months (r = 0.545, P = 0.001). End-diastolic, end-systolic left ventricular diameter, and CFR before CRT were predictors of LV functional improvement. By multivariate analysis, only CFR before CRT was independent predictor of left ventricular recovery in the follow-up period (P = 0.001). Our results demonstrate that preserved CFR in patients with dilated cardiomyopathy is predictive of left ventricular improvement after CRT implantation. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

PubMed

Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

2012-12-01

IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

SiSSR: Simultaneous subdivision surface registration for the quantification of cardiac function from computed tomography in canines.

PubMed

Vigneault, Davis M; Pourmorteza, Amir; Thomas, Marvin L; Bluemke, David A; Noble, J Alison

2018-05-01

Recent improvements in cardiac computed tomography (CCT) allow for whole-heart functional studies to be acquired at low radiation dose (<2mSv) and high-temporal resolution (<100ms) in a single heart beat. Although the extraction of regional functional information from these images is of great clinical interest, there is a paucity of research into the quantification of regional function from CCT, contrasting with the large body of work in echocardiography and cardiac MR. Here we present the Simultaneous Subdivision Surface Registration (SiSSR) method: a fast, semi-automated image analysis pipeline for quantifying regional function from contrast-enhanced CCT. For each of thirteen adult male canines, we construct an anatomical reference mesh representing the left ventricular (LV) endocardium, obviating the need for a template mesh to be manually sculpted and initialized. We treat this generated mesh as a Loop subdivision surface, and adapt a technique previously described in the context of 3-D echocardiography to register these surfaces to the endocardium efficiently across all cardiac frames simultaneously. Although previous work performs the registration at a single resolution, we observe that subdivision surfaces naturally suggest a multiresolution approach, leading to faster convergence and avoiding local minima. We additionally make two notable changes to the cost function of the optimization, explicitly encouraging plausible biological motion and high mesh quality. Finally, we calculate an accepted functional metric for CCT from the registered surfaces, and compare our results to an alternate state-of-the-art CCT method. Published by Elsevier B.V.

Effects of depth and chest volume on cardiac function during breath-hold diving.

PubMed

Marabotti, Claudio; Scalzini, Alessandro; Cialoni, Danilo; Passera, Mirko; Ripoli, Andrea; L'Abbate, Antonio; Bedini, Remo

2009-07-01

Cardiac response to breath-hold diving in human beings is primarily characterized by the reduction of both heart rate and stroke volume. By underwater Doppler-echocardiography we observed a "restrictive/constrictive" left ventricular filling pattern compatible with the idea of chest squeeze and heart compression during diving. We hypothesized that underwater re-expansion of the chest would release heart constriction and normalize cardiac function. To this aim, 10 healthy male subjects (age 34.2 +/- 10.4) were evaluated by Doppler-echocardiography during breath-hold immersion at a depth of 10 m, before and after a single maximal inspiration from a SCUBA device. During the same session, all subjects were also studied at surface (full-body immersion) and at 5-m depth in order to better characterize the relationship of echo-Doppler pattern with depth. In comparison to surface immersion, 5-m deep diving was sufficient to reduce cardiac output (P = 0.042) and increase transmitral E-peak velocity (P < 0.001). These changes remained unaltered at a 10-m depth. Chest expansion at 10 m decreased left ventricular end-systolic volume (P = 0.024) and increased left ventricular stroke volume (P = 0.024). In addition, it decreased transmitral E-peak velocity (P = 0.012) and increased deceleration time of E-peak (P = 0.021). In conclusion the diving response, already evident during shallow diving (5 m) did not progress during deeper dives (10 m). The rapid improvement in systolic and diastolic function observed after lung volume expansion is congruous with the idea of a constrictive effect on the heart exerted by chest squeeze.

Comparison of yoga and walking-exercise on cardiac time intervals as a measure of cardiac function in elderly with increased pulse pressure.

PubMed

Patil, Satish Gurunathrao; Patil, Shankargouda S; Aithala, Manjunatha R; Das, Kusal Kanti

Arterial aging along with increased blood pressure(BP) has become the major cardiovascular(CV) risk in elderly. The aim of the study was to compare the effects of yoga program and walking-exercise on cardiac function in elderly with increased pulse pressure (PP). An open label, parallel-group randomized controlled study design was adopted. Elderly individuals aged ≥60 years with PP≥60mmHg were recruited for the study. Yoga (study) group (n=30) was assigned for yoga training and walking (exercise) group (n=30) for walking with loosening practices for one hour in the morning for 6days in a week for 3 months. The outcome measures were cardiac time intervals derived from pulse wave analysis and ECG: resting heart rate (RHR), diastolic time(DT), ventricular ejection time(LVET), upstroke time(UT), ejection duration index (ED%), pre-ejection period (PEP), rate pressure product (RPP) and percentage of mean arterial pressure (%MAP). The mean within-yoga group change in RHR(bpm) was 4.41 (p=0.031), PD(ms): -50.29 (p=0.042), DT(ms): -49.04 (p=0.017), ED%: 2.107 (p=0.001), ES(mmHg/ms): 14.62 (p=0.118), ET(ms): -0.66 (p=0.903), UT(ms): -2.54 (p=0.676), PEP(ms): -1.25 (p=0.11) and %MAP: 2.08 (p=0.04). The mean within-control group change in HR (bpm) was 0.35 (p=0.887), PD (ms): 11.15(p=0.717), DT (ms): 11.3 (p=0.706), ED%: -0.101 (p=0.936), ES (mmHg/ms): 0.75 (p=0.926), ET(ms): 2.2 (p=0.721), UT(ms):4.7(p=455), PEP (ms): 2.1(p=0.11), %MAP: 0.65 (p=0.451). A significant difference between-group was found in RHR (p=0.036), PD (p=0.02), ED% (p=0.049), LVET (p=0.048), DT (p=0.02) and RPP (p=0.001). Yoga practice for 3 months showed a significant improvement in diastolic function with a minimal change in systolic function. Yoga is more effective than walking in improving cardiac function in elderly with high PP. Copyright © 2017 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Proangiogenic scaffolds as functional templates for cardiac tissue engineering.

PubMed

Madden, Lauran R; Mortisen, Derek J; Sussman, Eric M; Dupras, Sarah K; Fugate, James A; Cuy, Janet L; Hauch, Kip D; Laflamme, Michael A; Murry, Charles E; Ratner, Buddy D

2010-08-24

We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30-40 microm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.

Proangiogenic scaffolds as functional templates for cardiac tissue engineering

PubMed Central

Madden, Lauran R.; Mortisen, Derek J.; Sussman, Eric M.; Dupras, Sarah K.; Fugate, James A.; Cuy, Janet L.; Hauch, Kip D.; Laflamme, Michael A.; Murry, Charles E.; Ratner, Buddy D.

2010-01-01

We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into host myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30–40 μm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response. PMID:20696917

Functional Cardiac Magnetic Resonance Imaging (MRI) in the Assessment of Myocardial Viability and Perfusion

PubMed Central

2003-01-01

extent of hyperenhancement was significantly related to the likelihood of improvement in contractility after revascularization. However, the LVEF in the patient population was 43% prior to revascularization. It is important to know whether the technique has the same degree of accuracy in patients who have more severe LV dysfunction and who would most benefit from an assessment of myocardial viability. “Substantial” viability used as a measure of a patient’s ability to recover after revascularization has not been definitively reported (how much viability is enough?). Patients with severe LV dysfunction are more likely to have mixtures of surviving myocardium, including normal, infarcted, stunned and hibernating myocardium (Cowley et al., 1999). This may lead to a lack of homogeneity of response to testing and to revascularization and contribute to inter- and intra-study differences. There is a need for a large prospective study with adequate follow-up time for patients with CAD and LV dysfunction (LVEF<35%) comparing MRI and an alternate imaging technique. There is some evidence that MRI has comparable sensitivity, specificity and accuracy to PET for determining myocardial viability. However, there is a lack of evidence comparing the accuracy of these two techniques to predict LV function recovery. In addition, some studies refer to PET as the gold standard for the assessment of myocardial viability. Therefore, PET may be an ideal noninvasive imaging comparator to MRI for a prospective study with follow-up. To date, there is a lack of cost-effectiveness analyses (or any economic analyses) of functional cardiac MRI versus an alternate noninvasive imaging method for the assessment of myocardial viability/perfusion. Conclusion There is some evidence that the accuracy of functional cardiac MRI compares favourably with alternate imaging techniques for the assessment of myocardial viability and perfusion. There is insufficient evidence whether functional cardiac MRI can

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.

One year of high-intensity interval training improves exercise capacity, but not left ventricular function in stable heart transplant recipients: a randomised controlled trial.

PubMed

Rustad, Lene A; Nytrøen, Kari; Amundsen, Brage H; Gullestad, Lars; Aakhus, Svend

2014-02-01

Heart transplant recipients have lower exercise capacity and impaired cardiac function compared with the normal population. High-intensity interval training (HIIT) improves exercise capacity and cardiac function in patients with heart failure and hypertension, but the effect on cardiac function in stable heart transplant recipients is not known. Thus, we investigated whether HIIT improved cardiac function and exercise capacity in stable heart transplant recipients by use of comprehensive rest- and exercise-echocardiography and cardiopulmonary exercise testing. Fifty-two clinically stable heart transplant recipients were randomised either to HIIT (4 × 4 minutes at 85-95% of peak heart rate three times per week for eight weeks) or to control. Three such eight-week periods were distributed throughout one year. Echocardiography (rest and submaximal exercise) and cardiopulmonary exercise testing were performed at baseline and follow-up. One year of HIIT increased VO 2peak from 27.7 ± 5.5 at baseline to 30.9 ± 5.0 ml/kg/min at follow-up, while the control group remained unchanged (28.5 ± 7.0 vs. 28.0 ± 6.7 ml/kg per min, p < 0.001 for difference between the groups). Systolic and diastolic left ventricular functions at rest and during exercise were generally unchanged by HIIT. Whereas HIIT is feasible in heart transplant recipients and effectively improves exercise capacity, it does not alter cardiac systolic and diastolic function significantly. Thus, the observed augmentation in exercise capacity is best explained by extra-cardiac adaptive mechanisms.

Clinical benefit of cardiac resynchronization therapy with a defibrillator in patients with an ejection fraction > 35% estimated by cardiac magnetic resonance.

PubMed

Fabregat-Andrés, Oscar; García-González, Pilar; Valle-Muñoz, Alfonso; Estornell-Erill, Jordi; Pérez-Boscá, Leandro; Palanca-Gil, Victor; Payá-Serrano, Rafael; Quesada-Dorador, Aurelio; Morell, Salvador; Ridocci-Soriano, Francisco

2014-02-01

Cardiac resynchronization therapy with a defibrillator prolongs survival and improves quality of life in advanced heart failure. Traditionally, patients with ejection fraction > 35 estimated by echocardiography have been excluded. We assessed the prognostic impact of this therapy in a group of patients with severely depressed systolic function as assessed by echocardiography but with an ejection fraction > 35% as assessed by cardiac magnetic resonance. We analyzed consecutive patients admitted for decompensated heart failure between 2004 and 2011. The patients were in functional class II-IV, with a QRS ≥ to 120 ms, ejection fraction ≤ 35% estimated by echocardiography, and a cardiac magnetic resonance study. We included all patients (n=103) who underwent device implantation for primary prevention. Ventricular arrhythmia, all-cause mortality and readmission for heart failure were considered major cardiac events. The patients were divided into 2 groups according to systolic function assessed by magnetic resonance. The 2 groups showed similar improvements in functional class and ejection fraction at 6 months. We found a nonsignificant trend toward a higher risk of all-cause mortality in patients with systolic function ≤ 35% at long-term follow-up. The presence of a pattern of necrosis identified patients with a worse prognosis for ventricular arrhythmias and mortality in both groups. We conclude that cardiac resynchronization therapy with a defibrillator leads to a similar clinical benefit in patients with an ejection fraction ≤ 35% or > 35% estimated by cardiac magnetic resonance. Analysis of the pattern of late gadolinium enhancement provides additional information on arrhythmic risk and long-term prognosis. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Sulforaphane, a Natural Isothiocyanate Compound, Improves Cardiac Function and Remodeling by Inhibiting Oxidative Stress and Inflammation in a Rabbit Model of Chronic Heart Failure.

PubMed

Ma, Tongliang; Zhu, Decai; Chen, Duoxue; Zhang, Qiaoyun; Dong, Huifang; Wu, Wenwu; Lu, Huihe; Wu, Guangfu

2018-03-12

BACKGROUND The aim of this study was to investigate the effects of sulforaphane (SFN), a natural isothiocyanate compound, in a rabbit ascending aortic cerclage model of chronic heart failure (CHF). MATERIAL AND METHODS Thirty New Zealand White rabbits were divided into the sham operation group (n=10), the CHF group (n=10), and the CHF + SFN group (n=10) treated with subcutaneous SFN (0.5 mg/kg) for five days per week for 12 weeks. After 12 weeks, echocardiography and biometric analysis were performed, followed by the examination of the rabbit hearts. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used to detect levels of inflammatory cytokines, superoxide dismutase (SOD), and malondialdehyde (MDA). RESULTS In the CHF group, compared with the sham operation group, there was an increase in the heart weight to body weight ratio (HW/BW), the left ventricular weight to body weight ratio (LVW/BW), the left ventricular end diastolic diameter (LVEDD), the left ventricular end systolic diameter (LVESD), plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels, the cardiac collagen volume fraction (CVF), apoptotic index, expression levels of collagen I, collagen III, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA) in the myocardial tissue, and a decrease in the left ventricular shortening fraction (LVFS) and left ventricular ejection fraction (LVEF), and cardiac superoxide dismutase (SOD) activity. These changes were corrected in the SFN-treated group. CONCLUSIONS In a rabbit model of CHF, treatment with SFN improved cardiac function and remodeling by inhibiting oxidative stress and inflammation.

The effect of childhood obesity on cardiac functions.

PubMed

Üner, Abdurrahman; Doğan, Murat; Epcacan, Zerrin; Epçaçan, Serdar

2014-03-01

Obesity is a metabolic disorder defined as excessive accumulation of body fat, which is made up of genetic, environmental, and hormonal factors and has various social, psychological, and medical complications. Childhood obesity is a major indicator of adult obesity. The aim of this study is to evaluate the cardiac functions via electrocardiography (ECG), echocardiography (ECHO), and treadmill test in childhood obesity. A patient group consisting of 30 obese children and a control group consisting of 30 non-obese children were included in the study. The age range was between 8 and 17 years. Anthropometric measurements, physical examination, ECG, ECHO, and treadmill test were done in all patients. P-wave dispersion (PD) was found to be statistically significantly high in obese patients. In ECHO analysis, we found that end-diastolic diameter, end-systolic diameter, left ventricle posterior wall thickness, and interventricular septum were significantly greater in obese children. In treadmill test, exercise capacity was found to be significantly lower and the hemodynamic response to exercise was found to be defective in obese children. Various cardiac structural and functional changes occur in childhood obesity and this condition includes important cardiovascular risks. PD, left ventricle end-systolic and end-diastolic diameter, left ventricle posterior wall thickness, interventricular septum thickness, exercise capacity, and hemodynamic and ECG measurements during exercise testing are useful tests to determine cardiac dysfunctions and potential arrhythmias even in early stages of childhood obesity. Early recognition and taking precautions for obesity during childhood is very important to intercept complications that will occur in adulthood.

Respiratory motion compensated overlay of surface models from cardiac MR on interventional x-ray fluoroscopy for guidance of cardiac resynchronization therapy procedures

NASA Astrophysics Data System (ADS)

Manzke, R.; Bornstedt, A.; Lutz, A.; Schenderlein, M.; Hombach, V.; Binner, L.; Rasche, V.

2010-02-01

Various multi-center trials have shown that cardiac resynchronization therapy (CRT) is an effective procedure for patients with end-stage drug invariable heart failure (HF). Despite the encouraging results of CRT, at least 30% of patients do not respond to the treatment. Detailed knowledge of the cardiac anatomy (coronary venous tree, left ventricle), functional parameters (i.e. ventricular synchronicity) is supposed to improve CRT patient selection and interventional lead placement for reduction of the number of non-responders. As a pre-interventional imaging modality, cardiac magnetic resonance (CMR) imaging has the potential to provide all relevant information. With functional information from CMR optimal implantation target sites may be better identified. Pre-operative CMR could also help to determine whether useful vein target segments are available for lead placement. Fused with X-ray, the mainstay interventional modality, improved interventional guidance for lead-placement could further help to increase procedure outcome. In this contribution, we present novel and practicable methods for a) pre-operative functional and anatomical imaging of relevant cardiac structures to CRT using CMR, b) 2D-3D registration of CMR anatomy and functional meshes with X-ray vein angiograms and c) real-time capable breathing motion compensation for improved fluoroscopy mesh overlay during the intervention based on right ventricular pacer lead tracking. With these methods, enhanced interventional guidance for left ventricular lead placement is provided.

Changes in parameters of right ventricular function with cardiac resynchronization therapy.

PubMed

Sharma, Abhishek; Lavie, Carl J; Vallakati, Ajay; Garg, Akash; Goel, Sunny; Lazar, Jason; Fonarow, Gregg C

2017-11-01

Studies have shown that cardiac resynchronization therapy (CRT) significantly improves right ventricle (RV) size and function in patients with heart failure (HF). CRT does not lead to improvement in RV function independent of baseline clinical variables. A systematic search of studies published between 1966 to August 31, 2015 was conducted using Pub Med, CINAHL, Cochrane CENTRAL and the Web of Science databases. Studies reporting tricuspid annular plane systolic excursion (TAPSE) or RV basal strain or RV long axis diameter or RV short axis diameter or RV fractional area change (FAC), before and after CRT, were identified. A meta-analysis was performed using random effects with inverse variance method to determine the pooled mean difference in various parameters of RV function after CRT. Meta-regression analysis was performed to test the relationship between change in various parameters of RV functions after CRT and covariates- age, QRS duration, and left ventricular ejection fraction (LVEF). Thirteen studies (N=1541) were selected for final analysis. CRT therapy led to statistically significant increases in TAPSE [1.21 (95% CI 0.55-1.86; p<0.001)], RV FAC [2.26 (95% CI 0.50-4.01; p<0.001)] and basal strain [2.82 (95% CI 0.59-5.05; p<0.001)] and statistically significant decreases in mean RV long axis diameter [-2.94 (95% CI -5.07- -0.82; p=0.005)] and short axis diameter [-1.39 (95% CI -2.10- -0.67; p=0.876)] after a mean follow up period of 9 months. However, after meta-regression analysis for age, QRS duration, and baseline LVEF as covariates, there was no significant improvement in any of the parameters of RV function after CRT. There was a statistically significant improvement in TAPSE, RV basal strain, RV fractional area, RV long axis and short axis with CRT. However, improvement in these echocardiographic parameters of RV function after CRT was not independent of baseline clinical variables but statistically dependent on age, QRS duration and baseline LVEF. �

Hypoxic exercise training improves cardiac/muscular hemodynamics and is associated with modulated circulating progenitor cells in sedentary men.

PubMed

Wang, Jong-Shyan; Lee, Mei-Yi; Lien, Hen-Yu; Weng, Tzu-Pin

2014-01-01

Circulating progenitor cells (CPCs) improve cardiovascular function and organ perfusion by enhancing the capacities of endothelial repair and neovasculogenesis. This study investigates whether exercise regimens with/without hypoxia affect cardiac and muscular hemodynamics by modulating CPCs and angiogenic factors. Forty sedentary males were randomly divided into hypoxic (HT, n=20) and normoxic (NT, n=20) training groups. The subjects were trained on a bicycle ergometer at 60%VO(2max) under 15% (HT) or 21% (NT) O2 conditions for 30 min daily, five days weekly for five weeks. After the five-week interventions, the HT group exhibited a larger improvement in aerobic capacity than the NT group. Furthermore, the HT regimen (i) enhanced cardiac output (Q(H)) and perfusion (Q(M))/oxygenation of vastus lateralis during exercise; (ii) increased levels of CD34(+)/KDR(+)/CD117(+), CD34(+)/KDR(+)/CD133(+), and CD34(+)/KDR(+)/CD31(+) cells in blood; (iii) promoted the proliferative capacity of these CPC subsets, and (iv) elevated plasma nitrite/nitrate, stromal cell-derived factor-1 (SDF-1), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor-A (VEGF-A) concentrations. Despite the lack of changes in Q(H) and the number or proliferative capacity of CD34(+)/KDR(+)/CD117(+) or CD34(+)/KDR(+)/CD31(+) cells, the NT regimen elevated both Q(M) and plasma nitrite/nitrate levels and suppressed the shedding of endothelial cells (CD34(-)/KDR(+)/phosphatidylserine(+) cells). The HT regimen improves cardiac and muscular hemodynamic adaptations, possibly by promoting the mobilization/function of CPCs and the production of angiogenic factors. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

GPER mediates the effects of 17β-estradiol in cardiac mitochondrial biogenesis and function.

PubMed

Sbert-Roig, Miquel; Bauzá-Thorbrügge, Marco; Galmés-Pascual, Bel M; Capllonch-Amer, Gabriela; García-Palmer, Francisco J; Lladó, Isabel; Proenza, Ana M; Gianotti, Magdalena

2016-01-15

Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17β-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects. In H9c2 cardiomyocytes we observed that G-protein coupled estrogen receptor (GPER) agonist mimicked the effects of E2 in enhancing mitochondrial function and biogenesis, whereas GPER inhibitor neutralized them. These data suggest that E2 enhances mitochondrial function and decreases oxidative stress in cardiac muscle, thus it could be responsible for the sexual dimorphism observed in mitochondrial biogenesis and function in this tissue. These effects seem to be mediated through GPER stimulation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Simulation-guided cardiac auscultation improves medical students' clinical skills: the Pavia pilot experience.

PubMed

Perlini, Stefano; Salinaro, Francesco; Santalucia, Paola; Musca, Francesco

2014-03-01

Clinical evaluation is the cornerstone of any cardiac diagnosis, although excessive over-specialisation often leads students to disregard the value of clinical skills, and to overemphasize the approach to instrumental cardiac diagnosis. Time restraints, low availability of "typical" cardiac patients on whom to perform effective bedside teaching, patients' respect and the underscoring of the value of clinical skills all lead to a progressive decay in teaching. Simulation-guided cardiac auscultation may improve clinical training in medical students and residents. Harvey(©) is a mannequin encompassing more than 50 cardiac diagnoses that was designed and developed at the University of Miami (Florida, USA). One of the advantages of Harvey(©) simulation resides in the possibility of listening, comparing and discussing "real" murmurs. To objectively assess its teaching performance, the capability to identify five different cardiac diagnoses (atrial septal defect, normal young subject, mitral stenosis with tricuspid regurgitation, chronic mitral regurgitation, and pericarditis) out of more than 50 diagnostic possibilities was assessed in 523 III-year medical students (i.e. at the very beginning of their clinical experience), in 92 VI-year students, and in 42 residents before and after a formal 10-h teaching session with Harvey(©). None of them had previously experienced simulation-based cardiac auscultation in addition to formal lecturing (all three groups) and bedside teaching (VI-year students and residents). In order to assess the "persistence" of the acquired knowledge over time, the test was repeated after 3 years in 85 students, who did not repeat the formal 10-h teaching session with Harvey(©) after the III year. As expected, the overall response was poor in the "beginners" who correctly identified 11.0 % of the administered cardiac murmurs. After simulation-guided training, the ability to recognise the correct cardiac diagnoses was much better (72.0 %; p < 0

Effect of granulocyte colony stimulating EPC on cardiac function and myocardial energy expenditure in patients with heart failure after myocardial infarction.

PubMed

Zhao, Zilin; Luo, Jianchun; Ma, Lixian; Luo, Xia; Huang, Liangyan

2015-01-01

To study the changes of cardiac function and myocardial energy expenditure following treatment with granulocyte colony stimulating factor (G-CSF) in patients with heart failure after myocardial infarction. Thirty-eight patients with heart failure after myocardial infarction were randomized into G-CSF treatment group and control group. All the patients received conventional treatment (medication and interventional therapy), and the patients in treatment group were given additional G-CSF (600 μg/day) for 7 consecutive days. The plasma level of brain-type natriuretic peptide (BNP) and the number of endothelial progenitor cells (EPC) in the peripheral blood were detected before and at 7 days and 4 months after the treatment. The cardiac functions (LVEF, FS, LVIDs, PWTs, EDV, SV, ET) was evaluated by ultrasonic imaging before and at 2 weeks and 4 months after the treatment. The MEE and circumferential end-systolic wall stress (cESS) were calculated by correlation formula. The number of EPC was significantly higher in the treatment group than in the control group after the treatment especially at 7 days (P<0.01). In both groups, BNP level was lowered significantly after the treatment to recover the normal level (P<0.01). The cardiac functions and myocardial energy expenditure were improved in all the patients at 2 weeks and 4 months after the treatment, and the improvement was more obvious in the treatment group (P<0.05), especially in terms of the MEE and cESS was significantly lowered in the treatment group than in the control group after the treatment at 2 weeks (P<0.01), the LVEF and FS was significantly increased in the treatment group than in the control group after the treatment at 4 months (P<0.01). EPC mobilization by G-CSF can effectively improve the cardiac functions, lessen ventricular remodeling and reduce myocardial energy expenditure in patients with heart failure after myocardial infarction.

c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction

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

Ledee, Dolena; Smith, Lincoln; Bruce, Margaret

Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (TAC; n=7/group). A separate group underwent sham surgery (Sham, n=5). After two weeks, function was measured in isolated workingmore » hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (predominately glucose) contribution. The changes in free fatty acid and unlabeled fractional contributions were abrogated by Myc inactivation during TAC (MycKO-TAC). Additionally, protein posttranslational modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. Lastly, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy.« less

c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction

DOE PAGES

Ledee, Dolena; Smith, Lincoln; Bruce, Margaret; ...

2015-08-12

Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (TAC; n=7/group). A separate group underwent sham surgery (Sham, n=5). After two weeks, function was measured in isolated workingmore » hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (predominately glucose) contribution. The changes in free fatty acid and unlabeled fractional contributions were abrogated by Myc inactivation during TAC (MycKO-TAC). Additionally, protein posttranslational modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. Lastly, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy.« less

Skeletal myoblasts for heart regeneration and repair: state of the art and perspectives on the mechanisms for functional cardiac benefits.

PubMed

Formigli, L; Zecchi-Orlandini, S; Meacci, E; Bani, D

2010-01-01

Until recently, skeletal myoblasts (SkMBs) have been the most widely used cells in basic research and clinical trials of cell based therapy for cardiac repair and regeneration. Although SkMB engraftment into the post-infarcted heart has been consistently found to improve cardiac contractile function, the underlying therapeutic mechanisms remain still a matter of controversy and debate. This is basically because SkMBs do not attain a cardiac-like phenotype once homed into the diseased heart nor they form a contractile tissue functionally coupled with the surrounding viable myocardium. This issue of concern has generated the idea that the cardiotropic action of SkMBs may depend on the release of paracrine factors. However, the paracrine hypothesis still remains ill-defined, particularly concerning the identification of the whole spectrum of cell-derived soluble factors and details on their cardiac effects. In this context, the possibility to genetically engineering SkMBs to potentate their paracrine attitudes appears particularly attractive and is actually raising great expectation. Aim of the present review is not to cover all the aspects of cell-based therapy with SkMBs, as this has been the object of previous exhaustive reviews in this field. Rather, we focused on novel aspects underlying the interactions between SkMBs and the host cardiac tissues which may be relevant for directing the future basic and applied research on SkMB transplantation for post ischemic cardiac dysfunction.

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

PubMed Central

Ramos, Fresnida J.; Chen, Steven C.; Garelick, Michael G.; Dai, Dao-Fu; Liao, Chen-Yu; Schreiber, Katherine H.; MacKay, Vivian L.; An, Elroy H.; Strong, Randy; Ladiges, Warren C.; Rabinovitch, Peter S.; Kaeberlein, Matt; Kennedy, Brian K.

2013-01-01

Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna–/– mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna–/– mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. PMID:22837538

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.

PubMed

Shettigar, Vikram; Zhang, Bo; Little, Sean C; Salhi, Hussam E; Hansen, Brian J; Li, Ning; Zhang, Jianchao; Roof, Steve R; Ho, Hsiang-Ting; Brunello, Lucia; Lerch, Jessica K; Weisleder, Noah; Fedorov, Vadim V; Accornero, Federica; Rafael-Fortney, Jill A; Gyorke, Sandor; Janssen, Paul M L; Biesiadecki, Brandon J; Ziolo, Mark T; Davis, Jonathan P

2016-02-24

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.

Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease

PubMed Central

Shettigar, Vikram; Zhang, Bo; Little, Sean C.; Salhi, Hussam E.; Hansen, Brian J.; Li, Ning; Zhang, Jianchao; Roof, Steve R.; Ho, Hsiang-Ting; Brunello, Lucia; Lerch, Jessica K.; Weisleder, Noah; Fedorov, Vadim V.; Accornero, Federica; Rafael-Fortney, Jill A.; Gyorke, Sandor; Janssen, Paul M. L.; Biesiadecki, Brandon J.; Ziolo, Mark T.; Davis, Jonathan P.

2016-01-01

Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca2+ signal. Promisingly, our smartly formulated Ca2+-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease. PMID:26908229

American Heart Association Response to the 2015 Institute of Medicine Report on Strategies to Improve Cardiac Arrest Survival.

PubMed

Neumar, Robert W; Eigel, Brian; Callaway, Clifton W; Estes, N A Mark; Jollis, James G; Kleinman, Monica E; Morrison, Laurie J; Peberdy, Mary Ann; Rabinstein, Alejandro; Rea, Thomas D; Sendelbach, Sue

2015-09-15

The American Heart Association (AHA) commends the recently released Institute of Medicine (IOM) report, Strategies to Improve Cardiac Arrest Survival: A Time to Act (2015). The AHA recognizes the unique opportunity created by the report to meaningfully advance the objectives of improving outcomes for sudden cardiac arrest. For decades, the AHA has focused on the goal of reducing morbidity and mortality from cardiovascular disease though robust support of basic, translational, clinical, and population research. The AHA also has developed a rigorous process using the best available evidence to develop scientific, advisory, and guideline documents. These core activities of development and dissemination of scientific evidence have served as the foundation for a broad range of advocacy initiatives and programs that serve as a foundation for advancing the AHA and IOM goal of improving cardiac arrest outcomes. In response to the call to action in the IOM report, the AHA is announcing 4 new commitments to increase cardiac arrest survival: (1) The AHA will provide up to $5 million in funding over 5 years to incentivize resuscitation data interoperability; (2) the AHA will actively pursue philanthropic support for local and regional implementation opportunities to increase cardiac arrest survival by improving out-of-hospital and in-hospital systems of care; (3) the AHA will actively pursue philanthropic support to launch an AHA resuscitation research network; and (4) the AHA will cosponsor a National Cardiac Arrest Summit to facilitate the creation of a national cardiac arrest collaborative that will unify the field and identify common goals to improve survival. In addition to the AHA's historic and ongoing commitment to improving cardiac arrest care and outcomes, these new initiatives are responsive to each of the IOM recommendations and demonstrate the AHA's leadership in the field. However, successful implementation of the IOM recommendations will require a timely

Transgenic Analysis of the Role of FKBP12.6 in Cardiac Function and Intracellular Calcium Release

PubMed Central

Liu, Ying; Chen, Hanying; Ji, Guangju; Li, Baiyan; Mohler, Peter J.; Zhu, Zhiming; Yong, Weidong; Chen, Zhuang; Xu, Xuehong

2011-01-01

Abstract FK506 binding protein12.6 (FKBP12.6) binds to the Ca2+ release channel ryanodine receptor (RyR2) in cardiomyocytes and stabilizes RyR2 to prevent premature sarcoplasmic reticulum Ca2+ release. Previously, two different mouse strains deficient in FKBP12.6 were reported to have different abnormal cardiac phenotypes. The first mutant strain displayed sex-dependent cardiac hypertrophy, while the second displayed exercise-induced cardiac arrhythmia and sudden death. In this study, we tested whether FKBP12.6-deficient mice that display hypertrophic hearts can develop exercise-induced cardiac sudden death and whether the hypertrophic heart is a direct consequence of abnormal calcium handling in mutant cardiomyocytes. Our data show that FKBP12.6-deficient mice with cardiac hypertrophy do not display exercise-induced arrhythmia and/or sudden cardiac death. To investigate the role of FKBP12.6 overexpression for cardiac function and cardiomyocyte calcium release, we generated a transgenic mouse line with cardiac specific overexpression of FKBP12.6 using α-myosin heavy chain (αMHC) promoter. MHC-FKBP12.6 mice displayed normal cardiac development and function. We demonstrated that MHC-FKBP12.6 mice are able to rescue abnormal cardiac hypertrophy and abnormal calcium release in FKBP12.6-deficient mice. PMID:22087651

Cardiac surgery productivity and throughput improvements.

PubMed

Lehtonen, Juha-Matti; Kujala, Jaakko; Kouri, Juhani; Hippeläinen, Mikko

2007-01-01

The high variability in cardiac surgery length--is one of the main challenges for staff managing productivity. This study aims to evaluate the impact of six interventions on open-heart surgery operating theatre productivity. A discrete operating theatre event simulation model with empirical operation time input data from 2603 patients is used to evaluate the effect that these process interventions have on the surgery output and overtime work. A linear regression model was used to get operation time forecasts for surgery scheduling while it also could be used to explain operation time. A forecasting model based on the linear regression of variables available before the surgery explains 46 per cent operating time variance. The main factors influencing operation length were type of operation, redoing the operation and the head surgeon. Reduction of changeover time between surgeries by inducing anaesthesia outside an operating theatre and by reducing slack time at the end of day after a second surgery have the strongest effects on surgery output and productivity. A more accurate operation time forecast did not have any effect on output, although improved operation time forecast did decrease overtime work. A reduction in the operation time itself is not studied in this article. However, the forecasting model can also be applied to discover which factors are most significant in explaining variation in the length of open-heart surgery. The challenge in scheduling two open-heart surgeries in one day can be partly resolved by increasing the length of the day, decreasing the time between two surgeries or by improving patient scheduling procedures so that two short surgeries can be paired. A linear regression model is created in the paper to increase the accuracy of operation time forecasting and to identify factors that have the most influence on operation time. A simulation model is used to analyse the impact of improved surgical length forecasting and five selected process

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.

Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment.

PubMed

Lyra-Leite, Davi M; Andres, Allen M; Petersen, Andrew P; Ariyasinghe, Nethika R; Cho, Nathan; Lee, Jezell A; Gottlieb, Roberta A; McCain, Megan L

2017-10-01

Mitochondria in cardiac myocytes are critical for generating ATP to meet the high metabolic demands associated with sarcomere shortening. Distinct remodeling of mitochondrial structure and function occur in cardiac myocytes in both developmental and pathological settings. However, the factors that underlie these changes are poorly understood. Because remodeling of tissue architecture and extracellular matrix (ECM) elasticity are also hallmarks of ventricular development and disease, we hypothesize that these environmental factors regulate mitochondrial function in cardiac myocytes. To test this, we developed a new procedure to transfer tunable polydimethylsiloxane disks microcontact-printed with fibronectin into cell culture microplates. We cultured Sprague-Dawley neonatal rat ventricular myocytes within the wells, which consistently formed tissues following the printed fibronectin, and measured oxygen consumption rate using a Seahorse extracellular flux analyzer. Our data indicate that parameters associated with baseline metabolism are predominantly regulated by ECM elasticity, whereas the ability of tissues to adapt to metabolic stress is regulated by both ECM elasticity and tissue alignment. Furthermore, bioenergetic health index, which reflects both the positive and negative aspects of oxygen consumption, was highest in aligned tissues on the most rigid substrate, suggesting that overall mitochondrial function is regulated by both ECM elasticity and tissue alignment. Our results demonstrate that mitochondrial function is regulated by both ECM elasticity and myofibril architecture in cardiac myocytes. This provides novel insight into how extracellular cues impact mitochondrial function in the context of cardiac development and disease. NEW & NOTEWORTHY A new methodology has been developed to measure O 2 consumption rates in engineered cardiac tissues with independent control over tissue alignment and matrix elasticity. This led to the findings that matrix

Cardiac structure and function in the obese: a cardiovascular magnetic resonance imaging study.

PubMed

Danias, Peter G; Tritos, Nicholas A; Stuber, Matthias; Kissinger, Kraig V; Salton, Carol J; Manning, Warren J

2003-07-01

Obesity is a major health problem in the Western world. Among obese subjects cardiac pathology is common, but conventional noninvasive imaging modalities are often suboptimal for detailed evaluation of cardiac structure and function. We investigated whether cardiovascular magnetic resonance imaging (CMR) can better characterize possible cardiac abnormalities associated with obesity, in the absence of other confounding comorbidities. In this prospective cross-sectional study, CMR was used to quantify left and right ventricular volumes, ejection fraction, mass, cardiac output, and apical left ventricular rotation in 25 clinically healthy obese men and 25 age-matched lean controls. Obese subjects had higher left ventricular mass (203 +/- 38 g vs. 163 +/- 22 g, p < 0.001), end-diastolic volume (176 +/- 29 mL vs. 156 +/- 25 mL, p < 0.05), and cardiac output (8.2 +/- 1.2 L/min vs. 6.4 +/- 1.3 L/min, p < 0.001). The obese also had increased right ventricular mass (105 +/- 25 g vs. 87 +/- 18 g, p < 0.005) and end-diastolic volume (179 +/- 36 mL vs. 155 +/- 28 mL, p < 0.05). When indexed for height, differences in left and right ventricular mass, and left ventricular end-diastolic volume remained significant. Apical left ventricular rotation and rotational velocity patterns were also different between obese and lean subjects. Obesity is independently associated with remodeling of the heart. Cardiovascular magnetic resonance imaging identifies subtle cardiac abnormalities and may be the preferred imaging technique to evaluate cardiac structure and function in the obese.

In vivo imaging of cardiac development and function in zebrafish using light sheet microscopy.

PubMed

Weber, Michael; Huisken, Jan

2015-01-01

Detailed studies of heart development and function are crucial for our understanding of cardiac failures and pave the way for better diagnostics and treatment. However, the constant motion and close incorporation into the cardiovascular system prevent in vivo studies of the living, unperturbed heart. The complementary strengths of the zebrafish model and light sheet microscopy provide a useful platform to fill this gap. High-resolution images of the embryonic vertebrate heart are now recorded from within the living animal: deep inside the unperturbed heart we can follow cardiac contractions and measure action potentials and calcium transients. Three-dimensional reconstructions of the entire beating heart with cellular resolution give new insights into its ever-changing morphology and facilitate studies into how individual cells form the complex cardiac network. In addition, cardiac dynamics and robustness are now examined with targeted optical manipulation. Overall, the combination of zebrafish and light sheet microscopy represents a promising addition for cardiac research and opens the door to a better understanding of heart function and development.

Functional 3-D cardiac co-culture model using bioactive chitosan nanofiber scaffolds.

PubMed

Hussain, Ali; Collins, George; Yip, Derek; Cho, Cheul H

2013-02-01

The in vitro generation of a three-dimensional (3-D) myocardial tissue-like construct employing cells, biomaterials, and biomolecules is a promising strategy in cardiac tissue regeneration, drug testing, and tissue engineering applications. Despite significant progress in this field, current cardiac tissue models are not yet able to stably maintain functional characteristics of cardiomyocytes for long-term culture and therapeutic purposes. The objective of this study was to fabricate bioactive 3-D chitosan nanofiber scaffolds using an electrospinning technique and exploring its potential for long-term cardiac function in the 3-D co-culture model. Chitosan is a natural polysaccharide biomaterial that is biocompatible, biodegradable, non-toxic, and cost effective. Electrospun chitosan was utilized to provide structural scaffolding characterized by scale and architectural resemblance to the extracellular matrix (ECM) in vivo. The chitosan fibers were coated with fibronectin via adsorption in order to enhance cellular adhesion to the fibers and migration into the interfibrous milieu. Ventricular cardiomyocytes were harvested from neonatal rats and studied in various culture conditions (i.e., mono- and co-cultures) for their viability and function. Cellular morphology and functionality were examined using immunofluorescent staining for alpha-sarcomeric actin (SM-actin) and gap junction protein, Connexin-43 (Cx43). Scanning electron microscopy (SEM) and light microscopy were used to investigate cellular morphology, spatial organization, and contractions. Calcium indicator was used to monitor calcium ion flux of beating cardiomyocytes. The results demonstrate that the chitosan nanofibers retained their cylindrical morphology in long-term cell cultures and exhibited good cellular attachment and spreading in the presence of adhesion molecule, fibronectin. Cardiomyocyte mono-cultures resulted in loss of cardiomyocyte polarity and islands of non-coherent contractions. However

Recombinant human deoxyribonuclease improves atelectasis in mechanically ventilated children with cardiac disease.

PubMed

Prodhan, Parthak; Greenberg, B; Bhutta, Adnan T; Hyde, Carrie; Vankatesan, Ajay; Imamura, Michiaki; Jaquiss, Robert Db; Dyamenahalli, Umesh

2009-01-01

To investigate whether a mucolytic agent, recombinant human deoxyribonuclease (rhDNase), improves atelectasis in children with cardiac illness requiring mechanical ventilation. A retrospective cohort study on consecutive patients receiving short-term (< or =14 days) rhDNase therapy for atelectasis in the cardiac intensive care unit from January 2005 through February 2007 was carried out. Data relating to patient characteristics, gas exchange, ventilatory parameters, and chest radiographs were collected and analyzed. The effectiveness of rhDNase therapy in the presence of neutrophils and/or bacteria in the pre-rhDNase therapy tracheal aspirates was also investigated. rhDNase was effective in significantly improving established atelectasis without any major changes in gas exchange and ventilatory parameters. Therapeutic effect of rhDNase is most effective in ameliorating atelectasis in the lungs within 10 doses. rhDNase was more effective in improving chest radiographic atelectasis score in patients who had > moderate amounts of polymophonuclear neutrophils (P value = 0.0008), or bacteria (P value = 0.007) or both (P value = 0.004) present in their pre-rhDNase therapy trachea aspirate. No adverse effects were seen with rhDNase administration in the study cohort. rhDNase can be safely and effectively used to improve atelectasis in mechanically ventilated children with cardiac disease especially in the presence of bacteria and/or moderate amounts of polymophonuclear neutrophils in the pre-rhDNase therapy tracheal aspirate.

Recombinant Human Deoxyribonuclease Improves Atelectasis in Mechanically Ventilated Children with Cardiac Disease

PubMed Central

Prodhan, P; Greenberg, B; Bhutta, AT; Hyde, C; Vankatesan, A; Imamura, M; Jaquiss, RDB; Dyamenahalli, U

2010-01-01

Objective To investigate if a mucolytic agent, recombinant human deoxyribonuclease (rhDNase), improves atelectasis in children with cardiac illness requiring mechanical ventilation. Design A retrospective cohort study on consecutive patients receiving short-term (≤ 14 days) rhDNase therapy for atelectasis in the cardiac intensive care unit from January 2005 through February 2007 was carried out. Data relating to patient characteristics, gas exchange, ventilatory parameters and chest radiographs was collected and analyzed. The effectiveness of rhDNase therapy in the presence of neutrophils and/ or bacteria in the pre-rhDNase therapy tracheal aspirates was also investigated. Results rhDNase was effective in significantly improving established atelectasis without any major changes in gas exchange and ventilatory parameters. Therapeutic effect of rhDNase is most effective in ameliorating atelectasis in the lungs within 10 doses. rhDNase was more effective in improving chest radiographic atelectasis score in patients who had > moderate amounts PMN (p value= 0.0008), or bacteria (p value=0.007) or both (p value =0.004) present in their pre-rhDNase therapy trachea aspirate. No adverse effects were seen with rhDNase administration in the study cohort. Conclusions rhDNase can be safely and effectively used to improve atelectasis in mechanically ventilated children with cardiac disease especially in the presence of bacteria and/ or moderate amounts of PMN in the pre-rhDNase therapy tracheal aspirate. PMID:19489944

Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy.

PubMed

Ludke, Ana; Wu, Jun; Nazari, Mansoreh; Hatta, Kota; Shao, Zhengbo; Li, Shu-Hong; Song, Huifang; Ni, Nathan C; Weisel, Richard D; Li, Ren-Ke

2015-07-01

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Three good reasons for heart surgeons to understand cardiac metabolism.

PubMed

Doenst, Torsten; Bugger, Heiko; Schwarzer, Michael; Faerber, Gloria; Borger, Michael A; Mohr, Friedrich W

2008-05-01

It is the principal goal of cardiac surgeons to improve or reinstate contractile function with, through or after a surgical procedure on the heart. Uninterrupted contractile function of the heart is irrevocably linked to the uninterrupted supply of energy in the form of ATP. Thus, it would appear natural that clinicians interested in myocardial contractile function are interested in the way the heart generates ATP, i.e. the processes generally referred to as energy metabolism. Yet, it may appear that the relevance of energy metabolism in cardiac surgery is limited to the area of cardioplegia, which is a declining research interest. It is the goal of this review to change this trend and to illustrate the role and the therapeutic potential of metabolism and metabolic interventions for management. We present three compelling reasons why cardiac metabolism is of direct, practical interest to the cardiac surgeon and why a better understanding of energy metabolism might indeed result in improved surgical outcomes: (1) To understand cardioplegic arrest, ischemia and reperfusion, one needs a working knowledge of metabolism; (2) hyperglycemia is an underestimated and modifiable risk factor; (3) acute metabolic interventions can be effective in patients undergoing cardiac surgery.

Hypoxia signaling controls postnatal changes in cardiac mitochondrial morphology and function

PubMed Central

Neary, Marianne T.; Ng, Keat-Eng; Ludtmann, Marthe H.R.; Hall, Andrew R.; Piotrowska, Izabela; Ong, Sang-Bing; Hausenloy, Derek J.; Mohun, Timothy J.; Abramov, Andrey Y.; Breckenridge, Ross A.

2014-01-01

Fetal cardiomyocyte adaptation to low levels of oxygen in utero is incompletely understood, and is of interest as hypoxia tolerance is lost after birth, leading to vulnerability of adult cardiomyocytes. It is known that cardiac mitochondrial morphology, number and function change significantly following birth, although the underlying molecular mechanisms and physiological stimuli are undefined. Here we show that the decrease in cardiomyocyte HIF-signaling in cardiomyocytes immediately after birth acts as a physiological switch driving mitochondrial fusion and increased postnatal mitochondrial biogenesis. We also investigated mechanisms of ATP generation in embryonic cardiac mitochondria. We found that embryonic cardiac cardiomyocytes rely on both glycolysis and the tricarboxylic acid cycle to generate ATP, and that the balance between these two metabolic pathways in the heart is controlled around birth by the reduction in HIF signaling. We therefore propose that the increase in ambient oxygen encountered by the neonate at birth acts as a key physiological stimulus to cardiac mitochondrial adaptation. PMID:24984146

Mechanisms of epoxyeicosatrienoic acids to improve cardiac remodeling in chronic renal failure disease.

PubMed

Zhang, Kun; Wang, Ju; Zhang, Huanji; Chen, Jie; Zuo, Zhiyi; Wang, Jingfeng; Huang, Hui

2013-02-15

Both clinical and basic science studies have demonstrated that cardiac remodeling in patients with chronic renal failure (CRF) is very common. It is a key feature during the course of heart failure and an important risk factor for subsequent cardiac mortality. Traditional drugs or therapies rarely have effects on cardiac regression of CRF and cardiovascular events are still the first cause of death. Epoxyeicosatrienoic acids (EETs) are the products of arachidonic acids metabolized by cytochrome P450 epoxygenases. It has been found that EETs have important biological effects including anti-hypertension and anti-inflammation. Recent data suggest that EETs are involved in regulating cardiomyocyte injury, renal dysfunction, chronic kidney disease (CKD)-related risk factors and signaling pathways, all of which play key roles in cardiac remodeling induced by CRF. This review analyzes the literature to identify the possible mechanisms for EETs to improve cardiac remodeling induced by CRF and indicates the therapeutic potential of EETs in it. Copyright © 2012 Elsevier B.V. All rights reserved.

Computational approaches to understand cardiac electrophysiology and arrhythmias

PubMed Central

Roberts, Byron N.; Yang, Pei-Chi; Behrens, Steven B.; Moreno, Jonathan D.

2012-01-01

Cardiac rhythms arise from electrical activity generated by precisely timed opening and closing of ion channels in individual cardiac myocytes. These impulses spread throughout the cardiac muscle to manifest as electrical waves in the whole heart. Regularity of electrical waves is critically important since they signal the heart muscle to contract, driving the primary function of the heart to act as a pump and deliver blood to the brain and vital organs. When electrical activity goes awry during a cardiac arrhythmia, the pump does not function, the brain does not receive oxygenated blood, and death ensues. For more than 50 years, mathematically based models of cardiac electrical activity have been used to improve understanding of basic mechanisms of normal and abnormal cardiac electrical function. Computer-based modeling approaches to understand cardiac activity are uniquely helpful because they allow for distillation of complex emergent behaviors into the key contributing components underlying them. Here we review the latest advances and novel concepts in the field as they relate to understanding the complex interplay between electrical, mechanical, structural, and genetic mechanisms during arrhythmia development at the level of ion channels, cells, and tissues. We also discuss the latest computational approaches to guiding arrhythmia therapy. PMID:22886409

Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease

PubMed Central

Angelini, Aude; Pi, Xinchun; Xie, Liang

2017-01-01

The heart must consume a significant amount of energy to sustain its contractile activity. Although the fuel demands are huge, the stock remains very low. Thus, in order to supply its daily needs, the heart must have amazing adaptive abilities, which are dependent on dioxygen availability. However, in myriad cardiovascular diseases, “fuel” depletion and hypoxia are common features, leading cardiomyocytes to favor low-dioxygen-consuming glycolysis rather than oxidation of fatty acids. This metabolic switch makes it challenging to distinguish causes from consequences in cardiac pathologies. Finally, despite the progress achieved in the past few decades, medical treatments have not improved substantially, either. In such a situation, it seems clear that much remains to be learned about cardiac diseases. Therefore, in this review, we will discuss how reconciling dioxygen availability and cardiac metabolic adaptations may contribute to develop full and innovative strategies from bench to bedside. PMID:29311974

An exploratory investigation of echocardiographic parameters and the effects of posture on cardiac structure and function in the Livingstone's fruit bat (Pteropus livingstonii).

PubMed

Drane, Aimee L; Shave, Robert; Routh, Andrew; Barbon, Alberto

2018-01-01

There is growing evidence that dilated cardiomyopathy may be a major cause of death in captive Livingstone's fruit bats (Pteropus livingstonii). Therefore, the primary aim of this prospective, exploratory study was to examine whether a systematic cardiac ultrasound protocol is feasible in this critically endangered species and to report basic measures of cardiac structure and function from a cohort of apparently healthy bats. A secondary aim was to test the effect posture (dorsal recumbency vs. roosting) has upon cardiac function in this species. Transthoracic echocardiograms, including 2D, Doppler, and tissue Doppler measures of cardiac structure and function were completed as part of routine health examinations for bats at a single center (n = 19). Bats were then grouped by age and disease status and the mean and range data reported for each group. In healthy adult bats, with the exception of a reduction in heart rate (P ≤ 0.05), right atrial systolic area (P ≤ 0.05), and right ventricular velocity during atrial contraction, there were no significant changes in cardiac structure or function in response to the roosting position. However, in the bats presenting with dilated cardiomyopathy the current data suggest that left ventricular ejection fraction is improved while roosting. Further work is required to confirm our initial findings, generate diagnostic reference intervals, and explore the causes of dilated cardiomyopathy in this species. © 2017 American College of Veterinary Radiology.

Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.

PubMed

Piao, Lin; Fang, Yong-Hu; Kubler, Manfred M; Donnino, Michael W; Sharp, Willard W

2017-01-01

Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown. We hypothesized that therapeutic hypothermia (TH) following CA is associated with the inhibition of PDK activity and increased PDH activity. We further hypothesized that an inhibitor of PDK activity, dichloroacetate (DCA), would improve PDH activity and post-CA outcomes. Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 12-minute KCl-induced CA followed by cardiopulmonary resuscitation. Compared to normothermic (37°C) CA controls, administering TH (30°C) improved overall survival (72-hour survival rate: 62.5% vs. 28.6%, P<0.001), post-resuscitation myocardial function (ejection fraction: 50.9±3.1% vs. 27.2±2.0%, P<0.001; aorta systolic pressure: 132.7±7.3 vs. 72.3±3.0 mmHg, P<0.001), and neurological scores at 72-hour post CA (9.5±1.3 vs. 5.4±1.3, P<0.05). In both heart and brain, CA increased lactate concentrations (1.9-fold and 3.1-fold increase, respectively, P<0.01), decreased PDH enzyme activity (24% and 50% reduction, respectively, P<0.01), and increased PDK protein expressions (1.2-fold and 1.9-fold, respectively, P<0.01). In contrast, post-CA treatment with TH normalized lactate concentrations (P<0.01 and P<0.05) and PDK expressions (P<0.001 and P<0.05), while increasing PDH activity (P<0.01 and P<0.01) in both the heart and brain. Additionally, treatment with DCA (0.2 mg/g body weight) 30 min prior to CA improved both myocardial hemodynamics 2 hours post-CA (aortic systolic pressure: 123±3 vs. 96±4 mmHg, P<0.001) and 72-hour survival rates (50

Hibiscus sabdariffa (Roselle) Polyphenol-rich Extract Averts Cardiac Functional and Structural Abnormalities in Type 1 Diabetic Rats.

PubMed

Mohammed Yusof, Nur Liyana; Zainalabidin, Satirah; Mohd Fauzi, Norsyahida; Budin, Siti Balkis

2018-05-04

Diabetes mellitus is often associated with cardiac functional and structural alteration, an initial event leading to cardiovascular complications. Hibiscus sabdariffa or roselle has been widely proven as an antioxidant and recently has incited research interest for its potential in treating cardiovascular disease. Therefore, this study aimed to determine the cardioprotective effects of H. sabdariffa (roselle) polyphenol-rich extract (HPE) in type-1 induced diabetic rats. Twenty-four male Sprague-Dawley rats were randomized into four groups (n=6/group): non-diabetic (NDM), diabetic alone (DM), diabetic supplemented with HPE (DM+HPE) and metformin (DM+MET). Type-1 diabetes was induced with streptozotocin (55 mg/kg/i.p). Rats were forced-fed HPE (100 mg/kg) and metformin (150 mg/kg) daily for eight weeks. Results showed that HPE supplementation improved hyperglycemia and dyslipidemia significantly (p<0.05) in DM+HPE compared to DM group. HPE supplementation attenuated cardiac oxidative damage in DM group, indicated by low malondialdehyde and advanced oxidation protein product. As for the antioxidant status, HPE significantly (p<0.05) increased glutathione level, as well as catalase and superoxide dismutase 1 and 2 activities. These findings correlate with cardiac function, whereby HPE supplementation improved left ventricle developed pressure, coronary flow, cardiac contractility and relaxation rate significantly (p<0.05). Histological analysis showed a marked decrease in cardiomyocyte hypertrophy and fibrosis in DM+HPE compared to DM group. Ultrastructural changes and impairment of mitochondria induced by diabetes were minimized by HPE supplementation. Collectively, these findings suggest that HPE is a potential cardioprotective agent in a diabetic setting through its hypoglycemic, anti-hyperlipidemia and antioxidant properties.

Hypothyroidism and its rapid correction alter cardiac remodeling.

PubMed

Hajje, Georges; Saliba, Youakim; Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

PubMed Central

Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro

PubMed Central

Tolmachov, Oleg; Ma, Yu-Ling; Themis, Michael; Patel, Pravina; Spohr, Hilmar; MacLeod, Kenneth T; Ullrich, Nina D; Kienast, Yvonne; Coutelle, Charles; Peters, Nicholas S

2006-01-01

Background Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. Methods To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin® and the polycation transduction enhancer Transfectam®. The EGFP-positive transduced cells were then enriched by flow cytometry. Results More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro.

PubMed

Tolmachov, Oleg; Ma, Yu-Ling; Themis, Michael; Patel, Pravina; Spohr, Hilmar; Macleod, Kenneth T; Ullrich, Nina D; Kienast, Yvonne; Coutelle, Charles; Peters, Nicholas S

2006-06-06

Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin and the polycation transduction enhancer Transfectam. The EGFP-positive transduced cells were then enriched by flow cytometry. More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than in the co-cultures of non

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

Innovative web-based multimedia curriculum improves cardiac examination competency of residents.

PubMed

Criley, Jasminka M; Keiner, Jennifer; Boker, John R; Criley, Stuart R; Warde, Carole M

2008-03-01

Proper diagnosis of cardiac disorders is a core competency of internists. Yet numerous studies have documented that the cardiac examination (CE) skills of physicians have declined compared with those of previous generations of physicians, attributed variously to inadequate exposure to cardiac patients and lack of skilled bedside teaching. With growing concerns about ensuring patient safety and quality of care, public and professional organizations are calling for a renewed emphasis on the teaching and evaluation of clinical skills in residency training. The objective of the study was to determine whether Web training improves CE competency, whether residents retain what they learn, and whether a Web-based curriculum plus clinical training is better than clinical training alone. Journal of Hospital Medicine 2008;3:124-133. (c) 2008 Society of Hospital Medicine. This was a controlled intervention study. The intervention group (34 internal and family medicine interns) participated in self-directed use of a Web-based tutorial and three 1-hour teaching sessions taught by a hospitalist. Twenty-five interns from the prior year served as controls. We assessed overall CE competency and 4 subcategories of CE competency: knowledge, audio skills, visual skills, and audio-visual integration. The over mean score of the intervention group significantly improved, from 54 to 66 (P = .002). This improvement was retained (63.5, P = .05). When compared with end-of-year controls, the intervention group had significantly higher end-of-year CE scores (57 vs. 63.5, P = .05), knowledge (P = .04), and audio skills (P = .01). At the end of the academic year, all improvements were retained (P improvement in CE competence and was better than clinical training alone. (c) 2008 Society of Hospital Medicine.

Effect of prolonged space flight on cardiac function and dimensions

NASA Technical Reports Server (NTRS)

Henry, W. L.; Epstein, S. E.; Griffith, J. M.; Goldstein, R. E.; Redwood, D. R.

1974-01-01

Echocardiographic studies were performed preflight 5 days before launch and on recovery day and 1, 2, 4, 11, 31 and 68 days postflight. From these echocardiograms measurements were made. From these primary measurements, left ventricular end-diastolic volume, end-systolic volume, stroke volume, and mass were derived using the accepted assumptions. Findings in the Scientist Pilot and Pilot resemble those seen in trained distance runners. Wall thickness measurements were normal in all three crewmembers preflight. Postflight basal studies were unchanged in the Commander on recovery day through 68 days postflight in both the Scientist Pilot and Pilot, however, the left ventricular end-diastolic volume, stroke volume, and mass were decreased slightly. Left ventricular function curves were constructed for the Commander and Pilot by plotting stroke volume versus end-diastolic volume. In both astronauts, preflight and postflight data fell on the same straight line demonstrating that no deterioration in cardiac function had occurred. These data indicate that the cardiovascular system adapts well to prolonged weightlessness and suggest that alterations in cardiac dimensions and function are unlikely to limit man's future in space.

Favorable Changes in Cardiac Geometry and Function Following Gastric Bypass Surgery

PubMed Central

Owan, Theophilus; Avelar, Erick; Morley, Kimberly; Jiji, Ronny; Hall, Nathaniel; Krezowski, Joseph; Gallagher, James; Williams, Zachary; Preece, Kevin; Gundersen, Nancy; Strong, Michael B.; Pendleton, Robert C.; Segerson, Nathan; Cloward, Tom V.; Walker, James M.; Farney, Robert J.; Gress, Richard E.; Adams, Ted D.; Hunt, Steven C.; Litwin, Sheldon E.

2013-01-01

Objectives The objective of this study was to test the hypothesis that gastric bypass surgery (GBS) would favorably impact cardiac remodeling and function. Background GBS is increasingly used to treat severe obesity, but there are limited outcome data. Methods We prospectively studied 423 severely obese patients undergoing GBS and a reference group of severely obese subjects that did not have surgery (n = 733). Results At a 2-year follow up, GBS subjects had a large reduction in body mass index compared with the reference group (−15.4 ± 7.2 kg/m2 vs. −0.03 ± 4.0 kg/m2; p < 0.0001), as well as significant reductions in waist circumference, systolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, and insulin resistance. High-density lipoprotein cholesterol increased. The GBS group had reductions in left ventricular (LV) mass index and right ventricular (RV) cavity area. Left atrial volume did not change in GBS but increased in reference subjects. In conjunction with reduced chamber sizes, GBS subjects also had increased LV midwall fractional shortening and RV fractional area change. In multivariable analysis, age, change in body mass index, severity of nocturnal hypoxemia, E/E', and sex were independently associated with LV mass index, whereas surgical status, change in waist circumference, and change in insulin resistance were not. Conclusions Marked weight loss in patients undergoing GBS was associated with reverse cardiac remodeling and improved LV and RV function. These data support the use of bariatric surgery to prevent cardiovascular complications in severe obesity. PMID:21292133

Coronary Microvascular Dysfunction is Related to Abnormalities in Myocardial Structure and Function in Cardiac Amyloidosis

PubMed Central

Dorbala, Sharmila; Vangala, Divya; Bruyere, John; Quarta, Christina; Kruger, Jenna; Padera, Robert; Foster, Courtney; Hanley, Michael; Di Carli, Marcelo F.; Falk, Rodney

2014-01-01

Objectives We sought to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. Background Effort angina is common in subjects with cardiac amyloidosis even in the absence of epicardial coronary artery disease (CAD). Methods Thirty one subjects were prospectively enrolled in this study including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2D echocardiography. Global LV myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF / rest MBF) adjusting for rest rate pressure product. Results Compared to the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 vs. 0.88 ± 0.23 ml/g/min, P = 0.004), stress MBF (0.85 ± 0.29 vs. 1.85 ± 0.45 vs. ml/min/g, P < 0.0001), CFR (1.19 ± 0.38 vs. 2.23 ± 0.88, P < 0.0001), and higher minimal coronary vascular resistance (111 ± 40 vs. 70 ± 19 mm Hg/mL/g/min, P = 0.004). Of note, almost all amyloid subjects (> 95%) demonstrated significantly reduced peak stress MBF (< 1.3 mL/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased LV mass and age were the only independent predictors of impaired coronary vasodilator function. Conclusions Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis. PMID:25023822

Inactivation of INK4a and ARF induces myocardial proliferation and improves cardiac repair following ischemia‑reperfusion.

PubMed

An, Songtao; Chen, Yan; Gao, Chuanyu; Qin, Bingyu; Du, Xianhui; Meng, Fanmin; Qi, Yanyan

2015-10-01

The growth of the heart during mammalian embryonic development is primarily dependent on an increase in the number of cardiomyocytes (CM). However, shortly following birth, CMs cease proliferating and further growth of the myocardium is achieved via hypertrophic expansion of the existing CM population. The cyclin-dependent kinase inhibitor 2A (Cdkn2a) locus encodes overlapping genes for two tumor suppressor proteins, p16INK4a and p19 alternative reading frame (ARF). To determine whether decreased Cdkn2a gene expression results in improved cardiac regeneration in vitro and in vivo following cardiac injury, the proliferation of CMs isolated from Cdkn2a knockout (KO) and wild‑type (WT) mice in vitro and in vivo were evaluated following generation of ischemia reperfusion (IR) injury. The KO mice demonstrated enhanced CM proliferation not only in vitro, but also in vivo. Furthermore, heart function was improved and scar size was decreased in the KO mice compared with that of the WT mice. The results also indicated that microRNA (miR)‑1 and miR‑195 expression levels associated with cell proliferation were reduced following IR injury in KO mice compared with those of WT mice. These results suggested that the inactivation of INK4a and ARF stimulated CM proliferation and promoted cardiac repair.

Effects of glutamine treatment on myocardial damage and cardiac function in rats after severe burn injury.

PubMed

Yan, Hong; Zhang, Yong; Lv, Shang-jun; Wang, Lin; Liang, Guang-ping; Wan, Qian-xue; Peng, Xi

2012-01-01

Treatment with glutamine has been shown to reduce myocardial damage associated with ischemia/reperfusion injury. However, the cardioprotective effect of glutamine specifically after burn injury remains unclear. The present study explores the ability of glutamine to protect against myocardial damage in rats that have been severely burned. Seventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B) and a glutamine-treated group (G). Groups B and G were subjected to full thickness burns comprising 30% of total body surface area. Group G was administered 1.5 g/ (kg•d) glutamine and group B was given the same dose of alanine via intragastric administration for 3 days. Levels of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and blood lactic acid were measured, as well as myocardial ATP and glutathione (GSH) contents. Cardiac function indices and histopathological changes were analyzed at 12, 24, 48 and 72 post-burn hours. In both burned groups, levels of serum CK, LDH, AST and blood lactic acid increased significantly, while myocardial ATP and GSH contents decreased. Compared with group B, CK, LDH, and AST levels were lower and blood lactic acid, myocardial ATP and GSH levels were higher in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage were significantly reduced in group G compared to B. Taken together, these results show that glutamine supplementation protects myocardial structure and function after burn injury by improving energy metabolism and by promoted the synthesis of ATP and GSH in cardiac myocytes.

Effects of glutamine treatment on myocardial damage and cardiac function in rats after severe burn injury

PubMed Central

Yan, Hong; Zhang, Yong; Lv, Shang-jun; Wang, Lin; Liang, Guang-ping; Wan, Qian-xue; Peng, Xi

2012-01-01

Treatment with glutamine has been shown to reduce myocardial damage associated with ischemia/reperfusion injury. However, the cardioprotective effect of glutamine specifically after burn injury remains unclear. The present study explores the ability of glutamine to protect against myocardial damage in rats that have been severely burned. Seventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B) and a glutamine-treated group (G). Groups B and G were subjected to full thickness burns comprising 30% of total body surface area. Group G was administered 1.5 g/ (kg•d) glutamine and group B was given the same dose of alanine via intragastric administration for 3 days. Levels of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and blood lactic acid were measured, as well as myocardial ATP and glutathione (GSH) contents. Cardiac function indices and histopathological changes were analyzed at 12, 24, 48 and 72 post-burn hours. In both burned groups, levels of serum CK, LDH, AST and blood lactic acid increased significantly, while myocardial ATP and GSH contents decreased. Compared with group B, CK, LDH, and AST levels were lower and blood lactic acid, myocardial ATP and GSH levels were higher in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage were significantly reduced in group G compared to B. Taken together, these results show that glutamine supplementation protects myocardial structure and function after burn injury by improving energy metabolism and by promotedthe synthesis of ATP and GSH in cardiac myocytes. PMID:22977661

Intravital imaging of cardiac function at the single-cell level.

PubMed

Aguirre, Aaron D; Vinegoni, Claudio; Sebas, Matt; Weissleder, Ralph

2014-08-05

Knowledge of cardiomyocyte biology is limited by the lack of methods to interrogate single-cell physiology in vivo. Here we show that contracting myocytes can indeed be imaged with optical microscopy at high temporal and spatial resolution in the beating murine heart, allowing visualization of individual sarcomeres and measurement of the single cardiomyocyte contractile cycle. Collectively, this has been enabled by efficient tissue stabilization, a prospective real-time cardiac gating approach, an image processing algorithm for motion-artifact-free imaging throughout the cardiac cycle, and a fluorescent membrane staining protocol. Quantification of cardiomyocyte contractile function in vivo opens many possibilities for investigating myocardial disease and therapeutic intervention at the cellular level.

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.

Improvement of cardiac CT reconstruction using local motion vector fields.

PubMed

Schirra, Carsten Oliver; Bontus, Claas; van Stevendaal, Udo; Dössel, Olaf; Grass, Michael

2009-03-01

The motion of the heart is a major challenge for cardiac imaging using CT. A novel approach to decrease motion blur and to improve the signal to noise ratio is motion compensated reconstruction which takes motion vector fields into account in order to correct motion. The presented work deals with the determination of local motion vector fields from high contrast objects and their utilization within motion compensated filtered back projection reconstruction. Image registration is applied during the quiescent cardiac phases. Temporal interpolation in parameter space is used in order to estimate motion during strong motion phases. The resulting motion vector fields are during image reconstruction. The method is assessed using a software phantom and several clinical cases for calcium scoring. As a criterion for reconstruction quality, calcium volume scores were derived from both, gated cardiac reconstruction and motion compensated reconstruction throughout the cardiac phases using low pitch helical cone beam CT acquisitions. The presented technique is a robust method to determine and utilize local motion vector fields. Motion compensated reconstruction using the derived motion vector fields leads to superior image quality compared to gated reconstruction. As a result, the gating window can be enlarged significantly, resulting in increased SNR, while reliable Hounsfield units are achieved due to the reduced level of motion artefacts. The enlargement of the gating window can be translated into reduced dose requirements.

Extracorporeal shockwave myocardial revascularization improves clinical symptoms and left ventricular function in patients with refractory angina.

PubMed

Zuozienė, Gitana; Laucevičius, Aleksandras; Leibowitz, David

2012-01-01

Medical therapy for refractory angina is limited and the prognosis is poor. Experimental data suggest that the use of extracorporeal shockwave myocardial revascularization (ESMR) can contribute to angiogenesis and improve symptoms of angina and left ventricular (LV) function. The objective of this study was to examine the effects of ESMR on clinical symptoms as well as LV function as assessed by cardiac MRI in patients with refractory angina. Patients with Canadian Cardiovascular Society (CCS) class III-IV angina despite medical therapy and ischemia documented on thallium or echo-dobutamine were eligible for the study. ESMR therapy was applied with a commercially available cardiac shockwave generator system under echocardiographic guidance. LV function was assessed before and 6 months after therapy by cardiac MRI. Twenty patients (four women, 16 men; mean age 64 years, range 45-83) were included in the study. The CCS class after treatment improved in all patients (16 patients angina pectoris CCS from III to II and four patients from IV to III). The use of sublingual nitroglycerin was significantly reduced as well. There was a significant improvement in LV ejection fraction as assessed by blinded MRI following therapy in the overall population (51 vs. 59%, P<0.05). This study demonstrates the potential efficacy of ESMR for the treatment of refractory angina pectoris. The patients showed both a significant clinical response as well as improved LV ejection fraction on serial MRI imaging. Larger studies are needed to adequately define the clinical utility of this novel therapy.

Trastuzumab Alters the Expression of Genes Essential for Cardiac Function and Induces Ultrastructural Changes of Cardiomyocytes in Mice

PubMed Central

ElZarrad, M. Khair; Mukhopadhyay, Partha; Mohan, Nishant; Hao, Enkui; Dokmanovic, Milos; Hirsch, Dianne S.; Shen, Yi; Pacher, Pal; Wu, Wen Jin

2013-01-01

Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity. PMID:24255707

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

PubMed Central

Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Chen, Ming-Huei; Leening, Maarten J.G.; Völker, Uwe; Großmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Dörthe; Lyytikäinen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco M, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kähönen, Mika; investigators, KNHI; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Lindgren, Cecilia M.; Loley, Christina; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Müller, Christian; Müller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Sharp, Andrew S.P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Töglhofer, Anna M.; Uitterlinden, André G.; Völzke, Henry; Ziegler, Andreas; Münzel, Thomas; März, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W.V.; Melander, Olle; Lehtimäki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Dörr, Marcus

2017-01-01

BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING. For detailed information per study, see Acknowledgments. PMID:28394258

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

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

PubMed Central

McDermott-Roe, Chris; Ye, Junmei; Ahmed, Rizwan; Sun, Xi-Ming; Serafín, Anna; Ware, James; Bottolo, Leonardo; Muckett, Phil; Cañas, Xavier; Zhang, Jisheng; Rowe, Glenn C.; Buchan, Rachel; Lu, Han; Braithwaite, Adam; Mancini, Massimiliano; Hauton, David; Martí, Ramon; García-Arumí, Elena; Hubner, Norbert; Jacob, Howard; Serikawa, Tadao; Zidek, Vaclav; Papousek, Frantisek; Kolar, Frantisek; Cardona, Maria; Ruiz-Meana, Marisol; García-Dorado, David; Comella, Joan X; Felkin, Leanne E; Barton, Paul JR; Arany, Zoltan; Pravenec, Michal; Petretto, Enrico; Sanchis, Daniel; Cook, Stuart A.

2011-01-01

Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation3 and the regulatory mechanisms for blood pressure (BP)-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems-genetics approaches in the rat6,7 now provide a powerful complementary tool to GWAS and we applied integrative genomics to dissect a highly replicated, BP-independent LVM locus on rat chromosome 3p. We identified endonuclease G (Endog), previously implicated in apoptosis8 but not hypertrophy, as the gene at the locus and demonstrated loss-of-function mutation in Endog associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly inferred ENDOG in fundamental mitochondrial processes unrelated to apoptosis. We showed direct regulation of ENDOG by ERRα and PGC1α, master regulators of mitochondrial and cardiac function9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, Endog deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated reactive oxygen species (ROS), which was associated with enlarged and steatotic cardiomyocytes. Our studies establish further the link between mitochondrial dysfunction, ROS and heart disease and demonstrate a new role for Endog in maladaptive cardiac hypertrophy. PMID:21979051

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function

PubMed Central

Pinkham, Maximilian I.; Loftus, Michael T.; Amirapu, Satya; Guild, Sarah-Jane; Quill, Gina; Woodward, William R.; Habecker, Beth A.

2017-01-01

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart. PMID:28052866

Nanowired three-dimensional cardiac patches

NASA Astrophysics Data System (ADS)

Dvir, Tal; Timko, Brian P.; Brigham, Mark D.; Naik, Shreesh R.; Karajanagi, Sandeep S.; Levy, Oren; Jin, Hongwei; Parker, Kevin K.; Langer, Robert; Kohane, Daniel S.

2011-11-01

Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds. These biomaterials, which are usually made of either biological polymers such as alginate or synthetic polymers such as poly(lactic acid) (PLA), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit. Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches.

2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy

PubMed Central

Cheng, Yuanhua; Hogarth, Kaley A.; O'Sullivan, M. Lynne; Regnier, Michael

2015-01-01

Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca2+ sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM. PMID:26497964

2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy.

PubMed

Cheng, Yuanhua; Hogarth, Kaley A; O'Sullivan, M Lynne; Regnier, Michael; Pyle, W Glen

2016-01-01

Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca(2+) sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM. Copyright © 2016 the American Physiological Society.

Cardiac function is preserved following 4 weeks of voluntary wheel running in a rodent model of chronic kidney disease.

PubMed

Kuczmarski, James M; Martens, Christopher R; Kim, Jahyun; Lennon-Edwards, Shannon L; Edwards, David G

2014-09-01

The purpose of this investigation was to determine the effect of 4 wk of voluntary wheel running on cardiac performance in the 5/6 ablation-infarction (AI) rat model of chronic kidney disease (CKD). We hypothesized that voluntary wheel running would be effective in preserving cardiac function in AI. Male Sprague-Dawley rats were divided into three study groups: 1) sham, sedentary nondiseased control; 2) AI-SED, sedentary AI; and 3) AI-WR, wheel-running AI. Animals were maintained over a total period of 8 wk following AI and sham surgery. The 8-wk period included 4 wk of disease development followed by a 4-wk voluntary wheel-running intervention/sedentary control period. Cardiac performance was assessed using an isolated working heart preparation. Left ventricular (LV) tissue was used for biochemical tissue analysis. In addition, soleus muscle citrate synthase activity was measured. AI-WR rats performed a low volume of exercise, running an average of 13 ± 2 km, which resulted in citrate synthase activity not different from that in sham animals. Isolated AI-SED hearts demonstrated impaired cardiac performance at baseline and in response to preload/afterload manipulations. Conversely, cardiac function was preserved in AI-WR vs. sham hearts. LV nitrite + nitrate and expression of LV nitric oxide (NO) synthase isoforms 2 and 3 in AI-WR were not different from those of sham rats. In addition, LV H2O2 in AI-WR was similar to that of sham and associated with increased expression of LV superoxide-dismutase-2 and glutathione peroxidase-1/2. The findings of the current study suggest that a low-volume exercise intervention is sufficient to maintain cardiac performance in rats with CKD, potentially through a mechanism related to improved redox homeostasis and increased NO. Copyright © 2014 the American Physiological Society.

Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice.

PubMed

Bish, Lawrence T; Yarchoan, Mark; Sleeper, Meg M; Gazzara, Jeffrey A; Morine, Kevin J; Acosta, Pedro; Barton, Elisabeth R; Sweeney, H Lee

2011-01-01

Duchenne muscular dystrophy (DMD) is a degenerative disorder affecting skeletal and cardiac muscle for which there is no effective therapy. Angiotension receptor blockade (ARB) has excellent therapeutic potential in DMD based on recent data demonstrating attenuation of skeletal muscle disease progression during 6-9 months of therapy in the mdx mouse model of DMD. Since cardiac-related death is major cause of mortality in DMD, it is important to evaluate the effect of any novel treatment on the heart. Therefore, we evaluated the long-term impact of ARB on both the skeletal muscle and cardiac phenotype of the mdx mouse. Mdx mice received either losartan (0.6 g/L) (n = 8) or standard drinking water (n = 9) for two years, after which echocardiography was performed to assess cardiac function. Skeletal muscle weight, morphology, and function were assessed. Fibrosis was evaluated in the diaphragm and heart by Trichrome stain and by determination of tissue hydroxyproline content. By the study endpoint, 88% of treated mice were alive compared to only 44% of untreated (p = 0.05). No difference in skeletal muscle morphology, function, or fibrosis was noted in losartan-treated animals. Cardiac function was significantly preserved with losartan treatment, with a trend towards reduction in cardiac fibrosis. We saw no impact on the skeletal muscle disease progression, suggesting that other pathways that trigger fibrosis dominate over angiotensin II in skeletal muscle long term, unlike the situation in the heart. Our study suggests that ARB may be an important prophylactic treatment for DMD-associated cardiomyopathy, but will not impact skeletal muscle disease.

Inhibition of Oct 3/4 mitigates the cardiac progenitor-derived myocardial repair in infarcted myocardium.

PubMed

Zhao, Yu Tina; Du, Jianfeng; Chen, Youfang; Tang, Yaoliang; Qin, Gangjian; Lv, Guorong; Zhuang, Shougang; Zhao, Ting C

2015-12-24

Recent evidence has demonstrated that cardiac progenitor cells play an essential role in the induction of angiomyogenesis in infarcted myocardium. We and others have shown that engraftment of c-kit(+) cardiac stem cells (CSCs) into infarcted hearts led to myocardium regeneration and neovascularization, which was associated with an improvement of ventricular function. The purpose of this study is aimed at investigating the functional role of transcription factor (TF) Oct3/4 in facilitating CSCs to promote myocardium regeneration and preserve cardiac performance in the post-MI heart. c-kit(+) CSCs were isolated from adult hearts and re-introduced into the infarcted myocardium in which the mouse MI model was created by permanent ligation of the left anterior descending artery (LAD). The Oct3/4 of CSCs was inhibited by transfection of Oct3/4 siRNA, and transfection of CSCs with control siRNA serves as control groups. Myocardial functions were evaluated by echocardiographic measurement. Histological analysis was employed to assess newly formed cardiogenesis, neovascularization, and cell proliferations. Terminal deoxynucleotidyltransferase (TdT) nick-end labeling (TUNEL) was carried out to assess apoptotic cardiomyocytes. Real time polymerase chain reaction and Western blot were carried out to evaluate the level of Oct 3/4 in CSCs. Two weeks after engraftment, CSCs increased ventricular functional recovery as shown by a serial echocardiographic measurement, which is concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Suppression of Oct 3/4 of CSCs abrogated functional improvements and mitigated the hypertrophic response and cardiac remodeling. Transplantation of c-kit(+) CSCs into MI hearts promoted cardiac regeneration and neovascularization, which were abolished with the knockdown of Oct3/4. Additionally, suppression of Oct3/4 abrogated myocyte proliferation in the CSC-engrafted myocardium. Our results indicate

Genome-Wide Screens for In Vivo Tinman Binding Sites Identify Cardiac Enhancers with Diverse Functional Architectures

PubMed Central

Jin, Hong; Stojnic, Robert; Adryan, Boris; Ozdemir, Anil; Stathopoulos, Angelike; Frasch, Manfred

2013-01-01

The NK homeodomain factor Tinman is a crucial regulator of early mesoderm patterning and, together with the GATA factor Pannier and the Dorsocross T-box factors, serves as one of the key cardiogenic factors during specification and differentiation of heart cells. Although the basic framework of regulatory interactions driving heart development has been worked out, only about a dozen genes involved in heart development have been designated as direct Tinman target genes to date, and detailed information about the functional architectures of their cardiac enhancers is lacking. We have used immunoprecipitation of chromatin (ChIP) from embryos at two different stages of early cardiogenesis to obtain a global overview of the sequences bound by Tinman in vivo and their linked genes. Our data from the analysis of ∼50 sequences with high Tinman occupancy show that the majority of such sequences act as enhancers in various mesodermal tissues in which Tinman is active. All of the dorsal mesodermal and cardiac enhancers, but not some of the others, require tinman function. The cardiac enhancers feature diverse arrangements of binding motifs for Tinman, Pannier, and Dorsocross. By employing these cardiac and non-cardiac enhancers in machine learning approaches, we identify a novel motif, termed CEE, as a classifier for cardiac enhancers. In vivo assays for the requirement of the binding motifs of Tinman, Pannier, and Dorsocross, as well as the CEE motifs in a set of cardiac enhancers, show that the Tinman sites are essential in all but one of the tested enhancers; although on occasion they can be functionally redundant with Dorsocross sites. The enhancers differ widely with respect to their requirement for Pannier, Dorsocross, and CEE sites, which we ascribe to their different position in the regulatory circuitry, their distinct temporal and spatial activities during cardiogenesis, and functional redundancies among different factor binding sites. PMID:23326246

Exercise and type 2 diabetes mellitus: changes in tissue-specific fat distribution and cardiac function.

PubMed

Jonker, Jacqueline T; de Mol, Pieter; de Vries, Suzanna T; Widya, Ralph L; Hammer, Sebastiaan; van Schinkel, Linda D; van der Meer, Rutger W; Gans, Rijk O B; Webb, Andrew G; Kan, Hermien E; de Koning, Eelco J P; Bilo, Henk J G; Lamb, Hildo J

2013-11-01

To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus. Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years ± 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two-tailed paired t tests were used for statistical analysis. Exercise reduced visceral abdominal fat volume from 348 mL ± 57 to 219 mL ± 33 (P < .01), and subcutaneous abdominal fat volume remained unchanged (P = .9). Exercise decreased hepatic TG content from 6.8% ± 2.3 to 4.6% ± 1.6 (P < .01) and paracardial fat volume from 4.6 mL ± 0.9 to 3.7 mL ± 0.8 (P = .02). Exercise did not change epicardial fat volume (P = .9), myocardial TG content (P = .9), intramyocellular lipid content (P = .3), or cardiac function (P = .5). A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study. RSNA, 2013

Specific beta1-adrenergic receptor silencing with small interfering RNA lowers high blood pressure and improves cardiac function in myocardial ischemia.

PubMed

Arnold, Anne-Sophie; Tang, Yao Liang; Qian, Keping; Shen, Leping; Valencia, Valery; Phillips, Michael Ian; Zhang, Yuan Clare

2007-01-01

Beta-blockers are widely used and effective for treating hypertension, acute myocardial infarction (MI) and heart failure, but they present side-effects mainly due to antagonism of beta2-adrenergic receptor (AR). Currently available beta-blockers are at best selective but not specific for beta1 or beta2-AR. To specifically inhibit the expression of the beta1-AR, we developed a small interfering RNA (siRNA) targeted to beta1-AR. Three different sequences of beta1 siRNA were delivered into C6-2B cells with 90% efficiency. One of the three sequences reduced the level of beta1-AR mRNA by 70%. The siRNA was highly specific for beta1-AR inhibition with no overlap with beta2-AR. To test this in vivo, systemic injection of beta1 siRNA complexed with liposomes resulted in efficient delivery into the heart, lung, kidney and liver, and effectively reduced beta1-AR expression in the heart without altering beta2-AR. beta1 siRNA significantly lowered blood pressure of spontaneously hypertensive rats (SHR) for at least 12 days and reduced cardiac hypertrophy following a single injection. Pretreatment with beta1 siRNA 3 days before induction of MI in Wistar rats significantly improved cardiac function, as demonstrated by dP/dt and electrocardiogram following the MI. The protective mechanism involved reduction of cardiomyocyte apoptosis in the beta1 siRNA-treated hearts. The present study demonstrates the possibility of using siRNA for treating cardiovascular diseases and may represent a novel beta-blocker specific for beta1-AR.

Mitochondrial oxidative stress and cardiac ageing.

PubMed

Martín-Fernández, Beatriz; Gredilla, Ricardo

According with different international organizations, cardiovascular diseases are becoming the first cause of death in western countries. Although exposure to different risk factors, particularly those related to lifestyle, contribute to the etiopathogenesis of cardiac disorders, the increase in average lifespan and aging are considered major determinants of cardiac diseases events. Mitochondria and oxidative stress have been pointed out as relevant factors both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy and diabetic cardiomyopathy. During aging, cellular processes related with mitochondrial function, such as bioenergetics, apoptosis and inflammation are altered leading to cardiac dysfunction. Increasing our knowledge about the mitochondrial mechanisms related with the aging process, will provide new strategies in order to improve this process, particularly the cardiovascular ones. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection.

PubMed

Testai, Lara; Barrese, Vincenzo; Soldovieri, Maria Virginia; Ambrosino, Paolo; Martelli, Alma; Vinciguerra, Iolanda; Miceli, Francesco; Greenwood, Iain Andrew; Curtis, Michael John; Breschi, Maria Cristina; Sisalli, Maria Josè; Scorziello, Antonella; Canduela, Miren Josune; Grandes, Pedro; Calderone, Vincenzo; Taglialatela, Maurizio

2016-05-01

Plasmalemmal Kv7.1 (KCNQ1) channels are critical players in cardiac excitability; however, little is known on the functional role of additional Kv7 family members (Kv7.2-5) in cardiac cells. In this work, the expression, function, cellular and subcellular localization, and potential cardioprotective role against anoxic-ischaemic cardiac injury of Kv7.4 channels have been investigated. Expression of Kv7.1 and Kv7.4 transcripts was found in rat heart tissue by quantitative polymerase chain reaction. Western blots detected Kv7.4 subunits in mitochondria from Kv7.4-transfected cells, H9c2 cardiomyoblasts, freshly isolated adult cardiomyocytes, and whole hearts. Immunofluorescence experiments revealed that Kv7.4 subunits co-localized with mitochondrial markers in cardiac cells, with ∼ 30-40% of cardiac mitochondria being labelled by Kv7.4 antibodies, a result also confirmed by immunogold electron microscopy experiments. In isolated cardiac (but not liver) mitochondria, retigabine (1-30 µM) and flupirtine (30 µM), two selective Kv7 activators, increased Tl(+) influx, depolarized the membrane potential, and inhibited calcium uptake; all these effects were antagonized by the Kv7 blocker XE991. In intact H9c2 cells, reducing Kv7.4 expression by RNA interference blunted retigabine-induced mitochondrial membrane depolarization; in these cells, retigabine decreased mitochondrial Ca(2+) levels and increased radical oxygen species production, both effects prevented by XE991. Finally, retigabine reduced cellular damage in H9c2 cells exposed to anoxia/re-oxygenation and largely prevented the functional and morphological changes triggered by global ischaemia/reperfusion (I/R) in Langendorff-perfused rat hearts. Kv7.4 channels are present and functional in cardiac mitochondria; their activation exerts a significant cardioprotective role, making them potential therapeutic targets against I/R-induced cardiac injury. Published on behalf of the European Society of Cardiology. All

Improving cardiac surgical care: a work systems approach.

PubMed

Wiegmann, Douglas A; Eggman, Ashley A; Elbardissi, Andrew W; Parker, Sarah Henrickson; Sundt, Thoralf M

2010-09-01

Over the past 50 years, significant improvements in cardiac surgical care have been achieved. Nevertheless, surgical errors that significantly impact patient safety continue to occur. In order to further improve surgical outcomes, patient safety programs must focus on rectifying work system factors in the operating room (OR) that negatively impact the delivery of reliable surgical care. The goal of this paper is to provide an integrative review of specific work system factors in the OR that may directly impact surgical care processes, as well as the subsequent recommendations that have been put forth to improve surgical outcomes and patient safety. The important role that surgeons can play in facilitating work system changes in the OR is also discussed. The paper concludes with a discussion of the challenges involved in assessing the impact that interventions have on improving surgical care. Opportunities for future research are also highlighted throughout the paper. 2010 Elsevier Ltd. All rights reserved.

Electrophysiological Modeling of Cardiac Ventricular Function: From Cell to Organ

PubMed Central

Winslow, R. L.; Scollan, D. F.; Holmes, A.; Yung, C. K.; Zhang, J.; Jafri, M. S.

2005-01-01

Three topics of importance to modeling the integrative function of the heart are reviewed. The first is modeling of the ventricular myocyte. Emphasis is placed on excitation-contraction coupling and intracellular Ca2+ handling, and the interpretation of experimental data regarding interval-force relationships. Second, data on use of diffusion tensor magnetic resonance (DTMR) imaging for measuring the anatomical structure of the cardiac ventricles are presented. A method for the semi-automated reconstruction of the ventricles using a combination of gradient recalled acquisition in the steady state (GRASS) and DTMR images is described. Third, we describe how these anatomically and biophysically based models of the cardiac ventricles can be implemented on parallel computers. PMID:11701509

Sokolow-Lyon voltage is suitable for monitoring improvement in cardiac function and prognosis of patients with idiopathic dilated cardiomyopathy.

PubMed

Fukaya, Kenji; Takeshita, Kyosuke; Okumura, Takahiro; Hiraiwa, Hiroaki; Aoki, Soichiro; Ichii, Takeo; Sugiura, Yuki; Kitagawa, Katsuhide; Kondo, Toru; Watanabe, Naoki; Kano, Naoaki; Furusawa, Kenji; Sawamura, Akinori; Morimoto, Ryota; Bando, Yasuko; Murohara, Toyoaki

2017-09-01

The clinical significance of electrocardiogram in the assessment of patients with idiopathic dilated cardiomyopathy (IDCM) is currently unknown. The aim of this study was to determine the feasibility of recording serial changes in Sokolow-Lyon voltage (∆%QRS-voltage) in one year to estimate left ventricular reverse remodeling (LVRR) and predict a prognosis of IDCM patients under tailored medical therapy. Sixty-eight consecutive patients with mild symptoms (52.1 ± 13 years old; 69% men; NYHA I/II/III/IV; 33/29/6/0) underwent electrocardiography and echocardiography at baseline and 12 month follow-up (follow-up period: 3.9 years). LVRR was observed in 30 patients (44.1%). The ∆%QRS-voltage was significantly lower in the LVRR group (LVRR; -26.9%, non-LVRR: -9.2%, p < .001). Univariate analysis showed that ∆%QRS-voltage correlated with ∆%LV end-diastolic diameter (r = .634, p < .001), and with ∆%LV ejection fraction and ∆%LV mass index (r = -.412, p < .001; r = .429, p < .001 respectively). Using receiver operating characteristic curve analysis for the estimation of LVRR, ∆%QRS of -14.7% showed optimal sensitivity (63.2%) and specificity (83.3%) (AUC = 0.775, p < .001). The composite endpoints of cardiac death (n = 0), hospitalization for advanced heart failure (n = 11) and fatal arrhythmia (n = 2) were observed in 13 patients during the follow-up period. Kaplan-Meier analysis showed significantly higher event-free rate in patients of the low ∆%QRS-voltage group (<-14.7%) (83%) than those of the high group (66%, p = .022). The present study showed that decrease in Sokolow-Lyon voltage is associated with improvement in cardiac function and favorable prognosis in IDCM patients on medical therapy, suggesting that this index is a feasible marker for response to treatment of IDCM. © 2017 Wiley Periodicals, Inc.

Update on the slow delayed rectifier potassium current (I(Ks)): role in modulating cardiac function.

PubMed

Liu, Zhenzhen; Du, Lupei; Li, Minyong

2012-01-01

The slow delayed rectifier current (I(Ks)) is the slow component of cardiac delayed rectifier current and is critical for the late phase repolarization of cardiac action potential. This current is also an important target for Sympathetic Nervous System (SNS) to regulate the cardiac electivity to accommodate to heart rate alterations in response to exercise or emotional stress and can be up-regulated by β- adrenergic or other signal molecules. I(Ks) channel is originated by the co-assembly of pore-forming KCNQ1 α-subunit and accessory KCNE1 β-subunit. Mutations in any subunit can bring about severe long QT syndrome (LQT-1, LQT-5) as characterized by deliquium, seizures and sudden death. This review summarizes the normal physiological functions and molecular basis of I(Ks) channels, as well as illustrates up-to-date development on its blockers and activators. Therefore, the current extensive survey should generate fundamental understanding of the role of I(Ks) channel in modulating cardiac function and donate some instructions to the progression of I(Ks) blockers and activators as potential antiarrhythmic agents or pharmacological tools to determine the physiological and pathological function of I(Ks).

Cardiac function in children with premature ventricular contractions: the effect of omega-3 polyunsaturated fatty acid supplementation.

PubMed

Oner, Taliha; Ozdemir, Rahmi; Doksöz, Onder; Genc, Dildar B; Guven, Baris; Demirpence, Savas; Yilmazer, Murat M; Yozgat, Yilmaz; Mese, Timur; Tavli, Vedide

2018-07-01

Premature ventricular contractions are accepted as benign in structurally normal hearts. However, reversible cardiomyopathy can sometimes develop. Omega-3 polyunsaturated fatty acids have anti-arrhythmic properties in animals and humans.AimWe evaluated left ventricular function in children with premature ventricular contractions with normal cardiac anatomy and assessed the impact of omega-3 fatty acid supplementation on left ventricular function in a prospective trial. A total of 25 patients with premature ventricular contraction, with more than 2% premature ventricular contractions on 24-hour Holter electrocardiography, and 30 healthy patients were included into study. All patients underwent electrocardiography, left ventricular M-mode echocardiography, and myocardial performance index testing. Patients with premature ventricular contraction were given omega-3 fatty acids at a dose of 1 g/day for 3 months, and control echocardiography and 24-hour Holter electrocardiography were performed. Neither placebo nor omega-3 fatty acids were given to the control group. Compared with the values of the control group, the patients with premature ventricular contraction had significantly lower fractional shortening. The myocardial performance index decreased markedly in the patient groups. The mean heart rate and mean premature ventricular contraction percentage of Group 2 significantly decreased in comparison with their baseline values after the omega-3 supplementation. In conclusion, premature ventricular contractions can lead to systolic cardiac dysfunction in children. Omega-3 supplementation may improve cardiac function in children with premature ventricular contractions. This is the first study conducted in children to investigate the possible role of omega-3 fatty acid supplementation on treatment of premature ventricular contractions.

Implementation study of an analog spiking neural network for assisting cardiac delay prediction in a cardiac resynchronization therapy device.

PubMed

Sun, Qing; Schwartz, François; Michel, Jacques; Herve, Yannick; Dalmolin, Renzo

2011-06-01

In this paper, we aim at developing an analog spiking neural network (SNN) for reinforcing the performance of conventional cardiac resynchronization therapy (CRT) devices (also called biventricular pacemakers). Targeting an alternative analog solution in 0.13- μm CMOS technology, this paper proposes an approach to improve cardiac delay predictions in every cardiac period in order to assist the CRT device to provide real-time optimal heartbeats. The primary analog SNN architecture is proposed and its implementation is studied to fulfill the requirement of very low energy consumption. By using the Hebbian learning and reinforcement learning algorithms, the intended adaptive CRT device works with different functional modes. The simulations of both learning algorithms have been carried out, and they were shown to demonstrate the global functionalities. To improve the realism of the system, we introduce various heart behavior models (with constant/variable heart rates) that allow pathologic simulations with/without noise on the signals of the input sensors. The simulations of the global system (pacemaker models coupled with heart models) have been investigated and used to validate the analog spiking neural network implementation.

LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice.

PubMed

Suematsu, Yasunori; Miura, Shin-Ichiro; Goto, Masaki; Matsuo, Yoshino; Arimura, Tadaaki; Kuwano, Takashi; Imaizumi, Satoshi; Iwata, Atsushi; Yahiro, Eiji; Saku, Keijiro

2016-04-01

Angiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice. Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-β (TGF-β) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group. The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-β. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696. © 2016 The Authors European Journal of Heart Failure © 2016 European Society of Cardiology.

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

PubMed

Shah, A S; Khoury, P R; Dolan, L M; Ippisch, H M; Urbina, E M; Daniels, S R; Kimball, T R

2011-04-01

We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

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

MicroRNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart.

PubMed

Dakhlallah, Duaa; Zhang, Jianying; Yu, Lianbo; Marsh, Clay B; Angelos, Mark G; Khan, Mahmood

2015-03-01

: Cardiovascular disease is the number 1 cause of morbidity and mortality in the United States. The most common manifestation of cardiovascular disease is myocardial infarction (MI), which can ultimately lead to congestive heart failure. Cell therapy (cardiomyoplasty) is a new potential therapeutic treatment alternative for the damaged heart. Recent preclinical and clinical studies have shown that mesenchymal stem cells (MSCs) are a promising cell type for cardiomyoplasty applications. However, a major limitation is the poor survival rate of transplanted stem cells in the infarcted heart. miR-133a is an abundantly expressed microRNA (miRNA) in the cardiac muscle and is downregulated in patients with MI. We hypothesized that reprogramming MSCs using miRNA mimics (double-stranded oligonucleotides) will improve survival of stem cells in the damaged heart. MSCs were transfected with miR-133a mimic and antagomirs, and the levels of miR-133a were measured by quantitative real-time polymerase chain reaction. Rat hearts were subjected to MI and MSCs transfected with miR-133a mimic or antagomir were implanted in the ischemic hearts. Four weeks after MI, cardiac function, cardiac fibrosis, miR-133a levels, and apoptosis-related genes (Apaf-1, Caspase-9, and Caspase-3) were measured in the heart. We found that transfecting MSCs with miR-133a mimic improves survival of MSCs as determined by the MTT assay. Similarly, transplantation of miR-133a mimic transfected MSCs in rat hearts subjected to MI led to a significant increase in cell engraftment, cardiac function, and decreased fibrosis when compared with MSCs only or MI groups. At the molecular level, quantitative real-time polymerase chain reaction data demonstrated a significant decrease in expression of the proapoptotic genes; Apaf-1, caspase-9, and caspase-3 in the miR-133a mimic transplanted group. Furthermore, luciferase reporter assay confirmed that miR-133a is a direct target for Apaf-1. Overall, bioengineering of stem

Soy Protein Alleviates Hypertension and Fish Oil Improves Diastolic Heart Function in the Han:SPRD-Cy Rat Model of Cystic Kidney Disease.

PubMed

Ibrahim, Naser H M; Thandapilly, Sijo J; Jia, Yong; Netticadan, Thomas; Aukema, Harold

2016-05-01

Abnormalities in cardiac structure and function are very common among people with chronic kidney disease, in whom cardiovascular disease is the major cause of death. Dietary soy protein and fish oil reduce kidney disease progression in the Han:SPRD-Cy model of cystic renal disease. However, the effects of these dietary interventions in preventing alterations in cardiac structure and function due to kidney disease (reno-cardiac syndrome) in a cystic kidney disease model are not known. Therefore, weanling Han:SPRD-Cy diseased (Cy/+) and normal (+/+) rats were given diets containing either casein or soy protein, and either soy or fish oil in a three-way design for 8 weeks. Diseased rats had larger hearts, augmented left ventricular mass, and higher systolic and mean arterial blood pressure compared to the normal rats. Assessment of cardiac function using two-dimensional guided M-mode and pulse-wave Doppler echocardiography revealed that isovolumic relaxation time was prolonged in the diseased compared to normal rats, reflecting a diastolic heart dysfunction, and fish oil prevented this elevation. Soy protein resulted in a small improvement in systolic and mean arterial pressure but did not improve diastolic heart function, while fish oil prevented diastolic heart dysfunction in this model of cystic kidney disease.

Dual function of the UNC-45b chaperone with myosin and GATA4 in cardiac development

PubMed Central

Chen, Daisi; Li, Shumin; Singh, Ram; Spinette, Sarah; Sedlmeier, Reinhard; Epstein, Henry F.

2012-01-01

Summary Cardiac development requires interplay between the regulation of gene expression and the assembly of functional sarcomeric proteins. We report that UNC-45b recessive loss-of-function mutations in C3H and C57BL/6 inbred mouse strains cause arrest of cardiac morphogenesis at the formation of right heart structures and failure of contractile function. Wild-type C3H and C57BL/6 embryos at the same stage, E9.5, form actively contracting right and left atria and ventricles. The known interactions of UNC-45b as a molecular chaperone are consistent with diminished accumulation of the sarcomeric myosins, but not their mRNAs, and the resulting decreased contraction of homozygous mutant embryonic hearts. The novel finding that GATA4 accumulation is similarly decreased at the protein but not mRNA levels is also consistent with the function of UNC-45b as a chaperone. The mRNAs of known downstream targets of GATA4 during secondary cardiac field development, the cardiogenic factors Hand1, Hand2 and Nkx-2.5, are also decreased, consistent with the reduced GATA4 protein accumulation. Direct binding studies show that the UNC-45b chaperone forms physical complexes with both the alpha and beta cardiac myosins and the cardiogenic transcription factor GATA4. Co-expression of UNC-45b with GATA4 led to enhanced transcription from GATA promoters in naïve cells. These novel results suggest that the heart-specific UNC-45b isoform functions as a molecular chaperone mediating contractile function of the sarcomere and gene expression in cardiac development. PMID:22553207

Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection

PubMed Central

See Hoe, Louise E.; Schilling, Jan M.; Tarbit, Emiri; Kiessling, Can J.; Busija, Anna R.; Niesman, Ingrid R.; Du Toit, Eugene; Ashton, Kevin J.; Roth, David M.; Headrick, John P.; Patel, Hemal H.

2014-01-01

Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02–1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10–30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression. PMID:25063791

Self-reported physical activity and lung function two months after cardiac surgery--a prospective cohort study.

PubMed

Jonsson, Marcus; Urell, Charlotte; Emtner, Margareta; Westerdahl, Elisabeth

2014-03-28

Physical activity has well-established positive health-related effects. Sedentary behaviour has been associated with postoperative complications and mortality after cardiac surgery. Patients undergoing cardiac surgery often suffer from impaired lung function postoperatively. The association between physical activity and lung function in cardiac surgery patients has not previously been reported. Patients undergoing cardiac surgery were followed up two months postoperatively. Physical activity was assessed on a four-category scale (sedentary, moderate activity, moderate regular exercise, and regular activity and exercise), modified from the Swedish National Institute of Public Health's national survey. Formal lung function testing was performed preoperatively and two months postoperatively. The sample included 283 patients (82% male). Two months after surgery, the level of physical activity had increased (p < 0.001) in the whole sample. Patients who remained active or increased their level of physical activity had significantly better recovery of lung function than patients who remained sedentary or had decreased their level of activity postoperatively in terms of vital capacity (94 ± 11% of preoperative value vs. 91 ± 9%; p = 0.03), inspiratory capacity (94 ± 14% vs. 88 ± 19%; p = 0.008), and total lung capacity (96 ± 11% vs. 90 ± 11%; p = 0.01). An increased level of physical activity, compared to preoperative level, was reported as early as two months after surgery. Our data shows that there could be a significant association between physical activity and recovery of lung function after cardiac surgery. The relationship between objectively measured physical activity and postoperative pulmonary recovery needs to be further examined to verify these results.

Bystander capability to activate speaker function for continuous dispatcher assisted CPR in case of suspected cardiac arrest.

PubMed

Steensberg, Alvilda T; Eriksen, Mette M; Andersen, Lars B; Hendriksen, Ole M; Larsen, Heinrich D; Laier, Gunnar H; Thougaard, Thomas

2017-06-01

The European Resuscitation Council Guidelines 2015 recommend bystanders to activate their mobile phone speaker function, if possible, in case of suspected cardiac arrest. This is to facilitate continuous dialogue with the dispatcher including (if required) cardiopulmonary resuscitation instructions. The aim of this study was to measure the bystander capability to activate speaker function in case of suspected cardiac arrest. In 87days, a systematic prospective registration of bystander capability to activate the speaker function, when cardiac arrest was suspected, was performed. For those asked, "can you activate your mobile phone's speaker function", audio recordings were examined and categorized into groups according to the bystanders capability to activate speaker function on their own initiative, without instructions, or with instructions from the emergency medical dispatcher. Time delay was measured, in seconds, for the bystanders without pre-activated speaker function. 42.0% (58) was able to activate the speaker function without instructions, 2.9% (4) with instructions, 18.1% (25) on own initiative and 37.0% (51) were unable to activate the speaker function. The median time to activate speaker function was 19s and 8s, with and without instructions, respectively. Dispatcher assisted cardiopulmonary resuscitation with activated speaker function, in cases of suspected cardiac arrest, allows for continuous dialogue between the emergency medical dispatcher and the bystander. In this study, we found a 63.0% success rate of activating the speaker function in such situations. Copyright © 2017 Elsevier B.V. All rights reserved.

Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening.

PubMed

Lu, Hong Fang; Leong, Meng Fatt; Lim, Tze Chiun; Chua, Ying Ping; Lim, Jia Kai; Du, Chan; Wan, Andrew C A

2017-05-11

Cardiotoxicity is one of the major reasons for clinical drug attrition. In vitro tissue models that can provide efficient and accurate drug toxicity screening are highly desired for preclinical drug development and personalized therapy. Here, we report the fabrication and characterization of a human cardiac tissue model for high throughput drug toxicity studies. Cardiac tissues were fabricated via cellular self-assembly of human transgene-free induced pluripotent stem cells-derived cardiomyocytes in pre-fabricated polydimethylsiloxane molds. The formed tissue constructs expressed cardiomyocyte-specific proteins, exhibited robust production of extracellular matrix components such as laminin, collagen and fibronectin, aligned sarcomeric organization, and stable spontaneous contractions for up to 2 months. Functional characterization revealed that the cardiac cells cultured in 3D tissues exhibited higher contraction speed and rate, and displayed a significantly different drug response compared to cells cultured in age-matched 2D monolayer. A panel of clinically relevant compounds including antibiotic, antidiabetic and anticancer drugs were tested in this study. Compared to conventional viability assays, our functional contractility-based assays were more sensitive in predicting drug-induced cardiotoxic effects, demonstrating good concordance with clinical observations. Thus, our 3D cardiac tissue model shows great potential to be used for early safety evaluation in drug development and drug efficiency testing for personalized therapy.

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.

Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function.

PubMed

Fritah, Asmaà; Steel, Jennifer H; Nichol, Donna; Parker, Nadeene; Williams, Sharron; Price, Anthony; Strauss, Leena; Ryder, Timothy A; Mobberley, Margaret A; Poutanen, Matti; Parker, Malcolm; White, Roger

2010-06-01

Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate networks of genes involved in cellular processes, including metabolism. An important role for RIP140 in metabolic control has been identified in RIP140 null mice, whose phenotypes include derepression of genes involved in energy mobilization or catabolism in adipocytes and a switch to more oxidative fibres in skeletal muscle. We hypothesized that ubiquitous expression of RIP140 would suppress metabolic processes, leading to defects in development or cellular function. The primary effect of exogenous expression of RIP140 mRNA (real-time PCR) and protein (western blotting) in transgenic mice is impaired postnatal heart function. There was rapid onset of cardiac hypertrophy and ventricular fibrosis, detected microscopically, in male RIP140 transgenic mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 exogenous expression in the heart leads to decreased mitochondria state III and state IV membrane potential and oxygen consumption. Quantitative PCR showed more than 50% reduced expression of genes involved in mitochondrial activity and fatty acid metabolism, including mitochondrial transcription factor A, cytochrome oxidase VIIa, cytochrome XII, CD36, medium-chain acyl dehydrogenase, and fatty acid transport protein, many of which are known targets for nuclear receptors, including peroxisome proliferator-activated receptors PPARalpha and PPARdelta and oestrogen-related receptors ERRalpha and ERRgamma. This study demonstrates that RIP140 is an important cofactor in postnatal cardiac function and that inhibition of the action of RIP140 may provide a model system to investigate specific interventions designed to prevent or delay the onset of cardiac disease.

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.

Exercise Prevents Cardiac Injury and Improves Mitochondrial Biogenesis in Advanced Diabetic Cardiomyopathy with PGC-1α and Akt Activation.

PubMed

Wang, Hui; Bei, Yihua; Lu, Yan; Sun, Wei; Liu, Qi; Wang, Yalong; Cao, Yujie; Chen, Ping; Xiao, Junjie; Kong, Xiangqing

2015-01-01

Diabetic cardiomyopathy (DCM) represents the major cause of morbidity and mortality among diabetics. Exercise has been reported to be effective to protect the heart from cardiac injury during the development of DCM. However, the potential cardioprotective effect of exercise in advanced DCM remains unclear. Seven-week old male C57BL/6 wild-type or db/db mice were either subjected to a running exercise program for 15 weeks or kept sedentary. Cardiac function, myocardial apoptosis and fibrosis, and mitochondrial biogenesis were examined for evaluation of cardiac injury. A reduction in ejection fraction and fractional shortening in db/db mice was significantly reversed by exercise training. DCM induced remarkable cardiomyocyte apoptosis and increased ratio of Bax/Bcl-2 at the protein level. Meanwhile, DCM caused slightly myocardial fibrosis with elevated mRNA levels of collagen I and collagen III. Also, DCM resulted in a reduction of mitochondrial DNA (mtDNA) replication and transcription, together with reduced mtDNA content and impaired mitochondrial ultrastructure. All of these changes could be abolished by exercise training. Furthermore, DCM-associated inhibition of PGC-1α and Akt signaling was significantly activated by exercise, indicating that exercise-induced activation of PGC-1α and Akt signaling might be responsible for mediating cardioprotective effect of exercise in DCM. Exercise preserves cardiac function, prevents myocardial apoptosis and fibrosis, and improves mitochondrial biogenesis in the late stage of DCM. Exercise-induced activation of PGC-1α and Akt signaling might be promising therapeutic targets for advanced DCM. © 2015 S. Karger AG, Basel.