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

PubMed Central

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

2013-01-01

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

Taxonomy of segmental myocardial systolic dysfunction

PubMed Central

McDiarmid, Adam K.; Pellicori, Pierpaolo; Cleland, John G.; Plein, Sven

2017-01-01

The terms used to describe different states of myocardial health and disease are poorly defined. Imprecision and inconsistency in nomenclature can lead to difficulty in interpreting and applying trial outcomes to clinical practice. In particular, the terms ‘viable’ and ‘hibernating’ are commonly applied interchangeably and incorrectly to myocardium that exhibits chronic contractile dysfunction in patients with ischaemic heart disease. The range of inherent differences amongst imaging modalities used to define myocardial health and disease add further challenges to consistent definitions. The results of several large trials have led to renewed discussion about the classification of dysfunctional myocardial segments. This article aims to describe the diverse myocardial pathologies that may affect the myocardium in ischaemic heart disease and cardiomyopathy, and how they may be assessed with non-invasive imaging techniques in order to provide a taxonomy of myocardial dysfunction. PMID:27147609

Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin II type 1 receptors

PubMed Central

Mączewski, M; Mączewska, J; Duda, M

2008-01-01

Background and purpose: Diet-induced hypercholesterolaemia exacerbates post-myocardial infarction (MI) ventricular remodelling and heart failure, but the mechanism of this phenomenon remains unknown. This study examined whether worsening of post-MI ventricular remodelling induced by dietary hypercholesterolaemia was related to upregulation of angiotensin II type 1 (AT1) receptor in the rat heart. Experimental approach: MI was induced surgically in rats fed normal or high cholesterol diet. Both groups of rats were then assigned to control, atorvastatin, losartan or atorvastatin+losartan-treated subgroups and followed for 8 weeks. Left ventricular (LV) function was assessed with echocardiography. In isolated hearts, LV pressures were measured with a latex balloon and a tip catheter. AT1-receptor density was assessed in LV membranes with radioligand-binding assays. Key results: High cholesterol diet exacerbated LV dilation and dysfunction in post-MI hearts. Atorvastatin or losartan prevented these hypercholesterolaemia-induced effects, whereas their combination was not more effective than each drug alone. AT1 receptors were upregulated 8 weeks after MI, this was further increased by hypercholesterolaemia and restored to baseline levels by atorvastatin. Conclusions and implications: Hypercholesterolaemia exacerbated LV remodelling and dysfunction in post-MI rat hearts and upregulated cardiac AT1 receptors. All these effects were effectively prevented by atorvastatin. Thus, the pleiotropic statin effects may include interference with the renin-angiotensin system through downregulation of AT1 receptors. PMID:18536757

Cardiac fibroblast GSK-3β regulates ventricular remodeling and dysfunction in ischemic heart

PubMed Central

Lal, Hind; Ahmad, Firdos; Zhou, Jibin; Yu, Justine E.; Vagnozzi, Ronald J.; Guo, Yuanjun; Yu, Daohai; Tsai, Emily J.; Woodgett, James; Gao, Erhe; Force, Thomas

2014-01-01

Background Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. Following MI, activated cardiac fibroblasts (CFs) deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate and new molecular targets are needed. Methods and Results Herein we report that GSK-3β is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using two fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in CFs leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a pro-fibrotic myofibroblast phenotype in isolated CFs, in post-MI hearts, and in MEFs deleted for GSK-3β. Mechanistically, GSK-3β inhibits pro-fibrotic TGF-β1-SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the suppression of SMAD-3 transcriptional activity. This pathway is central to the pathology since a small molecule inhibitor of SMAD-3 largely prevented fibrosis and limited LV remodeling. Conclusion These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of CFs in remodeling and ventricular dysfunction. PMID:24899689

Taxonomy of segmental myocardial systolic dysfunction.

PubMed

McDiarmid, Adam K; Pellicori, Pierpaolo; Cleland, John G; Plein, Sven

2017-04-01

The terms used to describe different states of myocardial health and disease are poorly defined. Imprecision and inconsistency in nomenclature can lead to difficulty in interpreting and applying trial outcomes to clinical practice. In particular, the terms 'viable' and 'hibernating' are commonly applied interchangeably and incorrectly to myocardium that exhibits chronic contractile dysfunction in patients with ischaemic heart disease. The range of inherent differences amongst imaging modalities used to define myocardial health and disease add further challenges to consistent definitions. The results of several large trials have led to renewed discussion about the classification of dysfunctional myocardial segments. This article aims to describe the diverse myocardial pathologies that may affect the myocardium in ischaemic heart disease and cardiomyopathy, and how they may be assessed with non-invasive imaging techniques in order to provide a taxonomy of myocardial dysfunction. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

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

Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension: Relative Contribution of Fibrosis and Myofibril Stiffness.

PubMed

Rain, Silvia; Andersen, Stine; Najafi, Aref; Gammelgaard Schultz, Jacob; da Silva Gonçalves Bós, Denielli; Handoko, M Louis; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; Andersen, Asger; van der Velden, Jolanda; Ottenheijm, Coen A C; de Man, Frances S

2016-07-01

The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness. © 2016 The Authors.

Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension

PubMed Central

Rain, Silvia; Andersen, Stine; Najafi, Aref; Gammelgaard Schultz, Jacob; da Silva Gonçalves Bós, Denielli; Handoko, M. Louis; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton; Andersen, Asger; van der Velden, Jolanda; Ottenheijm, Coen A.C.

2016-01-01

Background— The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction. Methods and Results— By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction. Conclusions— RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness. PMID:27370069

T1 mapping and survival in systemic light-chain amyloidosis

PubMed Central

Banypersad, Sanjay M.; Fontana, Marianna; Maestrini, Viviana; Sado, Daniel M.; Captur, Gabriella; Petrie, Aviva; Piechnik, Stefan K.; Whelan, Carol J.; Herrey, Anna S.; Gillmore, Julian D.; Lachmann, Helen J.; Wechalekar, Ashutosh D.; Hawkins, Philip N.; Moon, James C.

2015-01-01

Aims To assess the prognostic value of myocardial pre-contrast T1 and extracellular volume (ECV) in systemic amyloid light-chain (AL) amyloidosis using cardiovascular magnetic resonance (CMR) T1 mapping. Methods and results One hundred patients underwent CMR and T1 mapping pre- and post-contrast. Myocardial ECV was calculated at contrast equilibrium (ECVi) and 15 min post-bolus (ECVb). Fifty-four healthy volunteers served as controls. Patients were followed up for a median duration of 23 months and survival analyses were performed. Mean ECVi was raised in amyloid (0.44 ± 0.12) as was ECVb (mean 0.44 ± 0.12) compared with healthy volunteers (0.25 ± 0.02), P < 0.001. Native pre-contrast T1 was raised in amyloid (mean 1080 ± 87 ms vs. 954 ± 34 ms, P < 0.001). All three correlated with pre-test probability of cardiac involvement, cardiac biomarkers, and systolic and diastolic dysfunction. During follow-up, 25 deaths occurred. An ECVi of >0.45 carried a hazard ratio (HR) for death of 3.84 [95% confidence interval (CI): 1.53–9.61], P = 0.004 and pre-contrast T1 of >1044 ms = HR 5.39 (95% CI: 1.24–23.4), P = 0.02. Extracellular volume after primed infusion and ECVb performed similarly. Isolated post-contrast T1 was non-predictive. In Cox regression models, ECVi was independently predictive of mortality (HR = 4.41, 95% CI: 1.35–14.4) after adjusting for E:E′, ejection fraction, diastolic dysfunction grade, and NT-proBNP. Conclusion Myocardial ECV (bolus or infusion technique) and pre-contrast T1 are biomarkers for cardiac AL amyloid and they predict mortality in systemic amyloidosis. PMID:25411195

Time course of hydrogen peroxide-thioredoxin balance and its influence on the intracellular signalling in myocardial infarction.

PubMed

Schenkel, Paulo Cavalheiro; Tavares, Angela Maria Vicente; Fernandes, Rafael Oliveira; Diniz, Gabriela Placoná; Ludke, Ana Raquel Lehenbauer; Ribeiro, Maria Flavia Marques; Araujo, Alex Sander da Rosa; Barreto-Chaves, Maria Luiza; Belló-Klein, Adriane

2012-06-01

We investigated the myocardial thioredoxin-1 and hydrogen peroxide concentrations and their association with some prosurvival and pro-apoptotic proteins, during the transition from myocardial infarction (MI) to heart failure in rats. Male Wistar rats were divided into the following six groups: three sham-operated groups and three MI groups, each at at 2, 7 and 28 days postsurgery. Cardiac function was analysed by echocardiography; the concentration of H(2)O(2) and the ratio of reduced to oxidized glutathione were measured spectrophotometrically, while the myocardial immunocontent of thioredoxin-1, angiotensin II, angiotensin II type 1 and type 2 receptors, p-JNK/JNK, p-ERK/ERK, p-Akt/Akt, p-mTOR/mTOR and p-GSK3β/GSK3β was evaluated by Western blot. Our results show that thioredoxin-1 appears to make an important contribution to the reduced H(2)O(2) concentration. It was associated with lower JNK expression in the early period post-MI (2 days). However, thioredoxin-1 decreased, while renin-angiotensin system markers and levels of H(2)O(2) increased, over 28 days post-MI, in parallel with some signalling proteins involved in maladaptative cardiac remodelling and ventricular dysfunction. These findings provide insight into the time course profile of endogenous antioxidant adaptation to ischaemic injury, which may be useful for the design of therapeutical strategies targeting oxidative stress post-MI.

EXOGENOUS CYTOCHROME C RESTORES MYOCARDIAL CYTOCHROME OXIDASE ACTIVITY INTO THE LATE PHASE OF SEPSIS

PubMed Central

Piel, David A.; Deutschman, Clifford S.; Levy, Richard J.

2009-01-01

Mitochondrial dysfunction is thought to play a role in the pathogenesis of a variety of disease states, including sepsis. An acquired defect in oxidative phosphorylation potentially causes sepsis-induced organ dysfunction. Cytochrome oxidase (CcOX), the terminal oxidase of the respiratory chain, is competitively inhibited early in sepsis and progresses, becoming noncompetitive during the late phase. We have previously demonstrated that exogenous cytochrome c can overcome myocardial CcOX competitive inhibition and improve cardiac function during murine sepsis at the 24-h point. Here, we evaluate the effect of exogenous cytochrome c on CcOX activity and survival in mice at the later time points. Exogenous cytochrome c (800 μg) or saline was intravenously injected 24 h after cecal ligation and puncture (CLP) or sham operation. Steady-state mitochondrial cytochrome c levels and heme c content increased significantly 48 h post-CLP and remained elevated at 72 h in cytochrome c-injected mice compared with saline injection. Cecal ligation and puncture inhibited CcOX at 48 h in saline-injected mice. However, cytochrome c injection abrogated this inhibition and restored CcOX kinetic activity to sham values at 48 h. Survival after CLP to 96 h after cytochrome c injection approached 50% compared with only 15% after saline injection. Thus, a single injection of exogenous cytochrome c 24 h post-CLP repletes mitochondrial substrate levels for up to 72 h, restores myocardial COX activity, and significantly improves survival. PMID:18414235

Double valve replacement in a patient with implantable cardioverter defibrillator with severe left ventricular dysfunction.

PubMed

Manjunath, Girish; Rao, Prakash; Prakash, Nagendra; Shivaram, B K

2016-01-01

Recent data from landmark trials suggest that the indications for cardiac pacing and implantable cardioverter defibrillators (ICDs) are set to expand to include heart failure, sleep-disordered breathing, and possibly routine implantation in patients with myocardial infarction and poor ventricular function.[1] This will inevitably result in more patients with cardiac devices undergoing surgeries. Perioperative electromagnetic interference and their potential effects on ICDs pose considerable challenges to the anesthesiologists.[2] We present a case of a patient with automatic ICD with severe left ventricular dysfunction posted for double valve replacement.

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

PubMed Central

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

2013-01-01

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

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

PubMed Central

2003-01-01

Executive Summary Objective The objective of this health technology policy assessment was to determine the effectiveness safety and cost-effectiveness of using functional cardiac magnetic resonance imaging (MRI) for the assessment of myocardial viability and perfusion in patients with coronary artery disease and left ventricular dysfunction. Results Functional MRI has become increasingly investigated as a noninvasive method for assessing myocardial viability and perfusion. Most patients in the published literature have mild to moderate impaired LV function. It is possible that the severity of LV dysfunction may be an important factor that can alter the diagnostic accuracy of imaging techniques. There is some evidence of comparable or better performance of functional cardiac MRI for the assessment of myocardial viability and perfusion compared with other imaging techniques. However limitations to most of the studies included: Functional cardiac MRI studies that assess myocardial viability and perfusion have had small sample sizes. Some studies assessed myocardial viability/perfusion in patients who had already undergone revascularization, or excluded patients with a prior MI (Schwitter et al., 2001). Lack of explicit detail of patient recruitment. Patients with LVEF >35%. Interstudy variability in post MI imaging time(including acute or chronic MI), when patients with a prior MI were included. Poor interobserver agreement (kappa statistic) in the interpretation of the results. Traditionally, 0.80 is considered “good”. Cardiac MRI measurement of myocardial perfusion to as an adjunct tool to help diagnose CAD (prior to a definitive coronary angiography) has also been examined in some studies, with methodological limitations, yielding comparable results. Many studies examining myocardial viability and perfusion report on the accuracy of imaging methods with limited data on long-term patient outcome and management. Kim et al. (2000) revealed that the transmural 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 better select which patients [who have CAD and severe LV dysfunction (LVEF <35%)] may benefit from revascularization compared with an alternate noninvasive imaging technology. There is insufficient evidence whether functional cardiac MRI can better select which patients should proceed to invasive coronary angiography for the definitive diagnosis of CAD, compared with an alternate noninvasive imaging technology. There is a need for a large prospective (potentially multicentre) study with adequate follow-up time for patients with CAD and LV dysfunction (LVEF<35%) comparing MRI and PET. Since longer follow-up time may be associated with restenosis or graft occlusion, it has been suggested to have serial measurements after revascularization (Cowley et al., 1999). PMID:23074446

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

PubMed

Meybohm, Patrick; Kohlhaas, Madeline; Stoppe, Christian; Gruenewald, Matthias; Renner, Jochen; Bein, Berthold; Albrecht, Martin; Cremer, Jochen; Coburn, Mark; Schaelte, Gereon; Boening, Andreas; Niemann, Bernd; Sander, Michael; Roesner, Jan; Kletzin, Frank; Mutlak, Haitham; Westphal, Sabine; Laufenberg-Feldmann, Rita; Ferner, Marion; Brandes, Ivo F; Bauer, Martin; Stehr, Sebastian N; Kortgen, Andreas; Wittmann, Maria; Baumgarten, Georg; Meyer-Treschan, Tanja; Kienbaum, Peter; Heringlake, Matthias; Schoen, Julika; Treskatsch, Sascha; Smul, Thorsten; Wolwender, Ewa; Schilling, Thomas; Fuernau, Georg; Bogatsch, Holger; Brosteanu, Oana; Hasenclever, Dirk; Zacharowski, Kai

2018-03-26

Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats

PubMed Central

Wang, Li-li; Miller, Dori; Wanders, Desiree; Nanayakkara, Gayani; Amin, Rajesh; Judd, Robert; Morrison, Edward E; Zhong, Ju-ming

2016-01-01

Aim: Adiponectin has been reported to exert protective effects during pathological ventricular remodeling, but the role of adiponectin in volume overload-induced heart failure remains unclear. In this study we investigated the effect of adiponectin on cardiac myocyte contractile dysfunction following volume overload in rats. Methods: Volume overload was surgically induced in rats by infrarenal aorta-vena cava fistula. The rats were intravenously administered adenoviral adiponectin at 2-, 6- and 9-weeks following fistula. The protein expression of adiponectin, adiponectin receptors (AdipoR1/R2 and T-cadherin) and AMPK activity were measured using Western blot analyses. Isolated ventricular myocytes were prepared at 12 weeks post-fistula to examine the contractile performance of myocytes and intracellular Ca2+ transient. Results: A-V fistula resulted in significant reductions in serum and myocardial adiponectin levels, myocardial adiponectin receptor (AdipoR1/R2 and T-cadherin) levels, as well as myocardial AMPK activity. Consistent with these changes, the isolated myocytes exhibited significant depression in cell shortening and intracellular Ca2+ transient. Administration of adenoviral adiponectin significantly increased serum adiponectin levels and prevented myocyte contractile dysfunction in fistula rats. Furthermore, pretreatment of isolated myocytes with recombinant adiponectin (2.5 μg/mL) significantly improved their contractile performance in fistula rats, but had no effects in control or adenoviral adiponectin-administered rats. Conclusion: These results demonstrate a positive correlation between adiponectin downregulation and volume overload-induced ventricular remodeling. Adiponectin plays a protective role in volume overload-induced heart failure. PMID:26616727

IGF-1 Alleviates High Fat Diet-Induced Myocardial Contractile Dysfunction: Role of Insulin Signaling and Mitochondrial Function

PubMed Central

Zhang, Yingmei; Yuan, Ming; Bradley, Katherine M.; Dong, Feng; Anversa, Piero; Ren, Jun

2012-01-01

Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling. PMID:22275536

Predictors of transient left ventricular dysfunction following transcatheter patent ductus arteriosus closure in pediatric age.

PubMed

Agha, Hala Mounir; Hamza, Hala S; Kotby, Alyaa; Ganzoury, Mona E L; Soliman, Nanies

2017-10-01

To evaluate the left ventricular function before and after transcatheter percutaneous patent ductus arteriosus (PDA) closure, and to identify the predictors of myocardial dysfunction post-PDA closure if present. Transcatheter PDA closure; conventional, Doppler, and tissue Doppler imaging; and speckle tracking echocardiography. To determine the feasibility and reliability of tissue Doppler and myocardial deformation imaging for evaluating myocardial function in children undergoing transcatheter PDA closure. Forty-two children diagnosed with hemodynamically significant PDA underwent percutaneous PDA closure. Conventional, Doppler, and tissue Doppler imaging, and speckle-derived strain rate echocardiography were performed at preclosure and at 48 hours, 1 month, and 6 months postclosure. Tissue Doppler velocities of the lateral and septal mitral valve annuli were obtained. Global and regional longitudinal peak systolic strain values were determined using two-dimensional speckle tracking echocardiography. The median age of the patients was 2 years and body weight was 15 kg, with the mean PDA diameter of 3.11 ± 0.99 mm. M-mode measurements (left ventricular end diastolic diameter, left atrium diameter to aortic annulus ratio, ejection fraction, and shortening fraction) reduced significantly early after PDA closure ( p  < 0.001). After 1 month, left ventricular end diastolic diameter and left atrium diameter to aortic annulus ratio continued to decrease, while ejection fraction and fractional shortening improved significantly. All tissue Doppler velocities showed a significant decrease at 48 hours with significant prolongation of global myocardial function ( p  < 0.001) and then were normalized within 1 month postclosure. Similarly, global longitudinal strain significantly decreased at 48 hours postclosure ( p  < 0.001), which also recovered at 1 month follow-up. Preclosure global longitudinal strain showed a good correlation with the postclosure prolongation of the myocardial performance index. Transcatheter PDA closure causes a significant decrease in left ventricular performance early after PDA closure, which recovers completely within 1 month. Preclosure global longitudinal strain can be a predictor of postclosure myocardial dysfunction.

The inflammatory response in myocardial injury, repair and remodeling

PubMed Central

Frangogiannis, Nikolaos G.

2015-01-01

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of post-infarction remodeling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited remove dead cells and matrix debris by phagocytosis, while setting the stage for scar formation. Timely repression of the inflammatory response is critical for effective healing and followed by activation of infarct myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor-β family are critically involved in suppression of inflammation and activation of a pro-fibrotic program. Translation of these concepts in the clinic requires understanding of the pathophysiologic complexity and heterogeneity of post-infarction remodeling in human patients with myocardial infarction. Individuals with overactive and prolonged post-infarction inflammation might exhibit dilation and systolic dysfunction and benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with exaggerated fibrogenic reactions can develop diastolic heart failure and might require inhibition of the smad3 cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies. PMID:24663091

The GSK-3 family as therapeutic target for myocardial diseases

PubMed Central

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

2014-01-01

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

Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway.

PubMed

Martínez-Martínez, Ernesto; Buonafine, Mathieu; Boukhalfa, Ines; Ibarrola, Jaime; Fernández-Celis, Amaya; Kolkhof, Peter; Rossignol, Patrick; Girerd, Nicolas; Mulder, Paul; López-Andrés, Natalia; Ouvrard-Pascaud, Antoine; Jaisser, Frédéric

2017-12-01

Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase-associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10 -8 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10 -6 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved. © 2017 American Heart Association, Inc.

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism.

PubMed

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-11-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease.

Takotsubo-like Myocardial Dysfunction in a Patient with Botulism

PubMed Central

Tonomura, Shuichi; Kakehi, Yoshiaki; Sato, Masatoshi; Naito, Yuki; Shimizu, Hisao; Goto, Yasunobu; Takahashi, Nobuyuki

2017-01-01

Botulinum toxin A (BTXA) can disrupt the neuromuscular and autonomic functions. We herein report a case of autonomic system dysfunction that manifested as Takotsubo-like myocardial dysfunction in a patient with botulism. Takotsubo syndrome results in acute cardiac insufficiency, another fatal complication of botulism in addition to respiratory muscle paralysis, particularly in patients with cardiovascular disease. PMID:28924131

It's a trap! Clinical similarities and subtle ECG differences between takotsubo cardiomyopathy and myocardial infarction.

PubMed

Vivo, Rey P; Krim, Selim R; Hodgson, John

2008-11-01

We describe a 65-year-old woman with a history of hypertension and smoking who presented with an acute episode of chest pain precipitated by severe emotional stress. Her initial electrocardiogram done in the emergency room showed non-specific T wave changes in the lateral leads and her cardiac troponin levels were mildly elevated. Because of her clinical presentation, she was admitted with a presumptive diagnosis of acute myocardial infarction and managed with antiplatelet and anticoagulant therapy. Coronary angiogram did not reveal coronary artery disease and left ventriculography showed findings consistent with apical ballooning syndrome or takotsubo cardiomyopathy. Subsequent electrocardiograms displayed dramatic changes including T wave inversions, QT interval prolongation and U waves. The patient remained asymptomatic and recovered uneventfully. Three weeks post-discharge, an echocardiogram documented resolved left ventricular dysfunction. We describe the clinical features and highlight the electrocardiographic findings that may help differentiate takotsubo cardiomyopathy from myocardial infarction.

Evaluation of cerebral-cardiac syndrome using echocardiography in a canine model of acute traumatic brain injury.

PubMed

Qian, Rong; Yang, Weizhong; Wang, Xiumei; Xu, Zhen; Liu, Xiaodong; Sun, Bing

2015-01-01

Previous studies have confirmed that traumatic brain injury (TBI) can induce general adaptation syndrome (GAS), which subsequently results in myocardial dysfunction and damage in some patients with acute TBI; this condition is also termed as cerebral-cardiac syndrome. However, most clinicians ignore the detection and treatment of myocardial dysfunction, and instead concentrate only on the serious neural damage that is observed in acute TBI, which is one of the most important fatal factors. Therefore, clarification is urgently needed regarding the relationship between TBI and myocardial dysfunction. In the present study, we evaluated 18 canine models of acute TBI, by using real-time myocardial contrast echocardiography and strain rate imaging to accurately evaluate myocardial function and regional microcirculation, including the strain rate of the different myocardial segments, time-amplitude curves, mean ascending slope of the curve, and local myocardial blood flow. Our results suggest that acute TBI often results in cerebral-cardiac syndrome, which rapidly progresses to the serious stage within 3 days. This study is the first to provide comprehensive ultrasonic characteristics of cerebral-cardiac syndrome in an animal model of TBI.

Biventricular assist device for scombroid poisoning with refractory myocardial dysfunction: a bridge to recovery.

PubMed

Grinda, Jean-Michel; Bellenfant, Florence; Brivet, François Gilles; Carel, Yvan; Deloche, Alain

2004-09-01

We report the usefulness of biventricular mechanical circulatory support in a 36-yr-old woman with refractory myocardial dysfunction resulting from scombroid poisoning. Case report. Medical and surgical university care units. A previously healthy 36-yr-old woman with severe myocardial dysfunction unresponsive to epinephrine (1.3 microg/kg/min) and dobutamine (18 microg/kg/min) after the ingestion of cooked fresh tuna. Implantation at day 3 of a biventricular assist device consisting of two paracorporeal pneumatic pumps set at 70 beats/min to reach an output of 5.6 L/min during 8 days. The biventricular mechanical circulatory assist device allowed weaning of the inotropic drugs, maintenance of end-organ function, and support of the patient until myocardial recovery. The patient was successfully explanted 11 days after ingestion. Cardiac function had totally recovered, but a stroke was noted. At 3-yrs follow-up, there was no cardiac or neurologic sequela. This report describes severe myocardial dysfunction secondary to scombroid poisoning and demonstrates the usefulness of a mechanical circulatory assist device as a bridge to recovery.

Circulating Galectin-3 Levels Are Persistently Elevated After Heart Transplantation and Are Associated With Renal Dysfunction.

PubMed

Grupper, Avishay; Nativi-Nicolau, Jose; Maleszewski, Joseph J; Geske, Jennifer R; Kremers, Walter K; Edwards, Brooks S; Kushwaha, Sudhir S; Pereira, Naveen L

2016-11-01

This study evaluated changes in serum levels of galectin (Gal)-3 before and after heart transplantation (HTx) and assessed the role of pre-HTx Gal-3 as a biomarker for post-HTx outcomes. Gal-3 is a novel biomarker that reflects cardiac remodeling and fibrosis. Elevated serum Gal-3 levels are associated with poor prognosis in heart failure patients. Whether Gal-3 levels change following HTx and the significance of post-HTx outcomes are unknown. Serum Gal-3 levels were measured in 62 patients at 118 days (Interquartile Range [IQR]: 23 to 798 days) before and 365 days (IQR: 54 to 767 days) post HTx. Cardiac tissue taken during routine post-HTx endomyocardial biopsy was evaluated to assess the correlation between tissue Gal-3 staining and serum Gal-3 levels and with the presence of myocardial hypertrophy and fibrosis. Serum Gal-3 levels remained significantly elevated (>17.8 ng/ml) in 35 patients (56%) post HTx. There was a significant inverse correlation between Gal-3 levels and glomerular filtration rate measured before and after HTx (p > 0.005). There was no association between Gal-3 serum level and Gal-3 staining of myocardial tissue or with the presence of myocyte hypertrophy and interstitial fibrosis post HTx. Elevated pre-HTx Gal-3 levels were associated with reduced post-HTx exercise capacity, but this association was not significant after adjustment for age, body mass index, and glomerular filtration rate. This is the first study to demonstrate the fact that Gal-3 levels remain elevated in the majority of patients despite HTx and is associated with renal dysfunction. Our findings suggest Gal-3 is a systemic rather than cardiac-specific biomarker. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Both Selenium Deficiency and Modest Selenium Supplementation Lead to Myocardial Fibrosis in Mice via Effects on Redox-Methylation Balance

PubMed Central

Metes-Kosik, Nicole; Luptak, Ivan; DiBello, Patricia M.; Handy, Diane E.; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W.; Loscalzo, Joseph; Joseph, Jacob

2013-01-01

Scope Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. Methods and Results We examined the effects of selenium deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Conclusions Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. PMID:23097236

Post-infarct sleep disruption and its relation to cardiac remodeling in a rat model of myocardial infarction.

PubMed

Aghajani, Marjan; Faghihi, Mahdieh; Imani, Alireza; Vaez Mahdavi, Mohammad Reza; Shakoori, Abbas; Rastegar, Tayebeh; Parsa, Hoda; Mehrabi, Saman; Moradi, Fatemeh; Kazemi Moghaddam, Ehsan

2017-01-01

Sleep disruption after myocardial infarction (MI) by affecting ubiquitin-proteasome system (UPS) is thought to contribute to myocardial remodeling and progressive worsening of cardiac function. The aim of current study was to test the hypothesis about the increased risk of developing heart failure due to experience of sleep restriction (SR) after MI. Male Wistar rats (n = 40) were randomly assigned to four experimental groups: (1) Sham, (2) MI, (3) MI and SR (MI + SR) (4) Sham and SR (Sham + SR). MI was induced by permanent ligation of left anterior descending coronary artery. Twenty-four hours after surgery, animals were subjected to chronic SR paradigm. Blood sampling was performed at days 1, 8 and 21 after MI for determination of serum levels of creatine kinase-MB (CK-MB), corticosterone, malondialdehyde (MDA) and nitric oxide (NO). Finally, at 21 days after MI, echocardiographic parameters and expression of MuRF1, MaFBx, A20, eNOS, iNOS and NF-kB in the heart were evaluated. We used H&E staining to detect myocardial hypertrophy. We found out that post infarct SR increased corticosterone levels. Our results highlighted deteriorating effects of post-MI SR on NO production, oxidative stress, and echocardiographic indexes (p < 0.05). Moreover, its detrimental effects on myocardial damage were confirmed by overexpression of MuRF1, MaFBx, iNOS and NF-kB (p < 0.001) in left ventricle and downregulation of A20 and eNOS (p < 0.05). Furthermore, histological examination revealed that experience of SR after MI increased myocardial diameter as compared to Sham subjects (p < 0.05). Our data suggest that SR after MI leads to an enlargement of the heart within 21 days, marked by an increase in oxidative stress and NO production as well as an imbalance in UPS that ultimately results in cardiac dysfunction and heart failure.

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

PubMed Central

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

2014-01-01

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

Velocity vector imaging fails to quantify regional myocardial dysfunction in a mouse model of isoprenaline-induced cardiotoxicity.

PubMed

Täng, Margareta Scharin; Redfors, Bjorn; Shao, Yangzhen; Omerovic, Elmir

2012-08-01

Regional myocardial deformation patterns are important in a variety of cardiac diseases, including stress-induced cardiomyopathy. Velocity-vector-based imaging is a speckle-tracking echocardiography (STE)-based algorithm that has been shown to allow in-depth cardiac phenotyping in humans. Regional posterior wall myocardial dysfunction occurs during severe isoprenaline stress in mice. We have previously shown that regional posterior wall end-systolic transmural strain decreases after severe isoprenaline toxicity in mice. We hypothesize that STE can detect and further quantify these perturbations. Twenty-three mice underwent echocardiographic examination using the VEVO2100 system. Regional transmural radial strain and strain rate were calculated in both parasternal short-axis and parasternal long-axis cine loops using the VisualSonics VEVO 2100 velocity vector imaging (VVI) STE algorithm. Eight C57BL/6 mice underwent baseline echocardiographic examination using the VisualSonics VEVO 770 system, which can acquire >1,000 frames/s cine loops. In a parasternal short-axis cine loop, the heart was divided into six segments, and regional fractional wall thickening (FWT) was assessed manually. The same protocols were also performed 90 minutes post 400 mg/kg intraperitoneally isoprenaline. Regional myocardial FWT is uniform at baseline but increases significantly in anterolateral segments, whereas it decreases significantly in posterior segments (P < 0.05). A similar pattern is seen using the VVI algorithm although the variance is larger, and differences are smaller and fail to reach significance. VVI is less sensitive in detecting regional perturbations in myocardial function than manual tracing, possibly due to the low frame rate in the cine loops used. © 2012, Wiley Periodicals, Inc.

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

Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region.

PubMed

Datta, Kaberi; Basak, Trayambak; Varshney, Swati; Sengupta, Shantanu; Sarkar, Sagartirtha

2017-01-30

Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%-45% of patients developing heart failure, in a period of 5-25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling. Oxidative stress is the major driving force for cardiac damage during myocardial infarction. However, the impact of oxidative stress on the process of post MI remodeling in conducting the heart towards functional failure has not been well explored. In this study, a spatial and temporal approach was taken to elaborate the major proteins and cellular processes involved in post MI remodeling. Based on level/ intensity of ROS, spatially, infarct and noninfarct zones were chosen for analysis while on the temporal scale, early (30days) and late time points (120days) post MI were included in the study. This design enabled us to delineate the differential protein expression on a spectrum of maximum oxidative stress at infarct zone during MI to minimum oxidative stress at noninfarct zone during late time point post MI. The proteome profiles for each of the study groups when comparatively analysed gave a holistic idea about the dominant cellular processes involved in post MI remodeling such as cardiac metabolism, both for short term and long term remodeling as well as unique processes such as Desmin mediated cytoskeletal remodeling of the infarcted myocardium that are involved in the compromise of cardiac function. Copyright © 2016 Elsevier B.V. All rights reserved.

Cardiac macrophages promote diastolic dysfunction.

PubMed

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

2018-02-05

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

Assessment of diastolic function by tissue Doppler echocardiography: comparison with standard transmitral and pulmonary venous flow

NASA Technical Reports Server (NTRS)

Farias, C. A.; Rodriguez, L.; Garcia, M. J.; Sun, J. P.; Klein, A. L.; Thomas, J. D.

1999-01-01

The objective of this study was to determine the utility of Doppler tissue echocardiography in the evaluation of diastolic filling and in discriminating between normal subjects and those with various stages of diastolic dysfunction. We measured myocardial velocities in 51 patients with various stages of diastolic dysfunction and in 27 normal volunteers. The discriminating power of each of the standard Doppler indexes of left ventricular filling, pulmonary venous flow, and myocardial velocities was determined with the use of Spearman rank correlation and analysis of variance F statistics. Early diastolic myocardial velocity (E(m)) was higher in normal subjects (16.0 +/- 3.8 cm/s) than in patients with either delayed relaxation (n = 15, 7.5 +/- 2.2 cm/s), pseudonormal filling (n = 26, 7.6 +/- 2.3 cm/s), or restrictive filling (n = 10, 7.4 +/- 2.4 cm/s, P <.0001). E(m ) was the best single discriminator between control subjects and patients with diastolic dysfunction (P =.7, F = 64.5). Myocardial velocities assessed by Doppler tissue echocardiography are useful in differentiating patients with normal from those with abnormal diastolic function. Myocardial velocity remains reduced even in those stages of diastolic dysfunction characterized by increased preload compensation.

Estrogen receptor ERα plays a major role in ethanol-evoked myocardial oxidative stress and dysfunction in conscious female rats.

PubMed

Yao, Fanrong; Abdel-Rahman, Abdel A

2016-02-01

Our previous studies showed that ethanol elicited estrogen (E2)-dependent myocardial oxidative stress and dysfunction. In the present study we tested the hypothesis that E2 signaling via the estrogen receptor (ER), ERα, mediates this myocardial detrimental effect of alcohol. To achieve this goal, conscious female rats in proestrus phase (highest endogenous E2 level) received a selective ER antagonist (200 μg/kg; intra-venous [i.v.]) for ERα (MPP), ERβ (PHTPP) or GPER (G15) or saline 30 min before ethanol (1 g/kg; i.v.) or saline infusion. ERα blockade virtually abrogated ethanol-evoked myocardial dysfunction and hypotension, while ERβ blockade had little effect on the hypotensive response, but caused delayed attenuation of the ethanol-evoked reductions in left ventricular developed pressure and the rate of left ventricle pressure rise. GPER blockade caused delayed attenuation of all cardiovascular effects of ethanol. All three antagonists attenuated the ethanol-evoked increases in myocardial catalase and ALDH2 activities, Akt, ERK1/2, p38, eNOS, and nNOS phosphorylation, except for a lack of effect of PHTPP on p38. Finally, all three ER antagonists attenuated ethanol-evoked elevation in myocardial ROS, but this effect was most notable with ERα blockade. In conclusion, ERα plays a greater role in, and might serve as a molecular target for ameliorating, the E2-dependent myocardial oxidative stress and dysfunction caused by ethanol. Copyright © 2016 Elsevier Inc. All rights reserved.

Relationship of biomarkers of extracellular matrix with myocardial function in Type 2 diabetes mellitus.

PubMed

Liu, Ju-Hua; Chen, Yan; Zhen, Zhe; Ho, Lai-Ming; Tsang, Anita; Yuen, Michele; Lam, Karen; Tse, Hung-Fat; Yiu, Kai-Hang

2017-07-01

The study evaluated the relationship of extracellular matrix and renin angiotensin system with myocardial dysfunction in Type 2 diabetes mellitus. All patients underwent resting and exercise echocardiography, including conventional parameters, E/E' ratio, global longitudinal strain and diastolic function reserve index. Plasma matrix metalloproteinase-1, TIMP-1, amino-terminal propeptide of type I and type III procollagen and renin angiotensin system activity were measured. As patients with diastolic dysfunction had a higher plasma level of TIMP-1 and propeptide of type III procollagen than those with no diastolic dysfunction. After multivariate adjustment, TIMP-1 associated with E/E' (both at rest and stress) and diastolic function reserve index. TIMP-1 is independently associated with myocardial diastolic dysfunction in patients with Type 2 diabetes mellitus.

Transient ventricular dysfunction after an asphyxiation event: stress or hypoxia?

PubMed

Valletta, Mary E; Haque, Ikram; Al-Mousily, Faris; Udassi, Jai; Saidi, Arwa

2008-11-01

This report of a pediatric patient with acute upper airway obstruction causing asphyxiation emphasizes the need to maintain clinical suspicion for acquired myocardial dysfunction, despite the presumed role of noncardiogenic causes for pulmonary edema after an acute upper airway obstruction. Case report. A tertiary pediatric intensive care unit. A 10-year-old girl with no significant medical history who developed flash pulmonary edema and acute myocardial dysfunction after an acute upper airway obstruction. Serial echocardiograms, exercise stress test, and coronary angiography were performed. Serial pro-brain natriuretic peptide, troponins, and CK-MB levels were also followed. Troponin level normalized approximately 7 days after the acute event. CK-MB and pro-brain natriuretic peptide levels decreased but had not completely normalized by time of discharge. The patient was discharged home 10 days after the event on an anticipated 6-month course of metoprolol without any signs or symptoms of cardiac dysfunction. Myocardial dysfunction is rarely documented in children after an acute upper airway obstruction or an asphyxiation event. Pediatric intensivists and hospitalists should maintain a high degree of clinical suspicion and screen for possible myocardial dysfunction in the pediatric patient with an acute severe hypoxic event especially when accompanied by pulmonary edema. Prompt evaluation ensures appropriate support. Additionally, some role may exist for early adrenergic receptor blockade.

Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance.

PubMed

Metes-Kosik, Nicole; Luptak, Ivan; Dibello, Patricia M; Handy, Diane E; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W; Loscalzo, Joseph; Joseph, Jacob

2012-12-01

Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. We examined the effects of selenium-deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium-supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Employing Extracellular Volume Cardiovascular Magnetic Resonance Measures of Myocardial Fibrosis to Foster Novel Therapeutics.

PubMed

Schelbert, Erik B; Sabbah, Hani N; Butler, Javed; Gheorghiade, Mihai

2017-06-01

Quantifying myocardial fibrosis (MF) with myocardial extracellular volume measures acquired during cardiovascular magnetic resonance promises to transform clinical care by advancing pathophysiologic understanding and fostering novel therapeutics. Extracellular volume quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma. MF is a key domain of dysfunctional but viable myocardium among others (eg, microvascular dysfunction and cardiomyocyte/mitochondrial dysfunction). Although anatomically distinct, these domains may functionally interact. MF represents pathological remodeling in the heart associated with cardiac dysfunction and adverse outcomes likely mediated by interactions with the microvasculature and the cardiomyocyte. Reversal of MF improves key measures of cardiac dysfunction, so reversal of MF represents a likely mechanism for improved outcomes. Instead of characterizing the myocardium as homogenous tissue and using important yet still generic descriptors, such as thickness (hypertrophy) and function (diastolic or systolic), which lack mechanistic specificity, paradigms of cardiac disease have evolved to conceptualize myocardial disease and patient vulnerability based on the extent of disease involving its various compartments. Specifying myocardial compartmental involvement may then implicate cellular/molecular disease pathways for treatment and targeted pharmaceutical development and above all highlight the role of the cardiac-specific pathology in heart failure among myriad other changes in the heart and beyond. The cardiology community now requires phase 2 and 3 clinical trials to examine strategies for the regression/prevention of MF and eventually biomarkers to identify MF without reliance on cardiovascular magnetic resonance. It seems likely that efficacious antifibrotic therapy will improve outcomes, but definitive data are needed. © 2017 American Heart Association, Inc.

Pseudo-acute myocardial infarction due to transient apical ventricular dysfunction syndrome (Takotsubo syndrome).

PubMed

Maciel, Bruno Araújo; Cidrão, Alan Alves de Lima; Sousa, Italo Bruno Dos Santos; Ferreira, José Adailson da Silva; Messias Neto, Valdevino Pedro

2013-03-01

Takotsubo syndrome is characterized by predominantly medial-apical transient left ventricular dysfunction, which is typically triggered by physical or emotional stress. The present article reports the case of a 61-year-old female patient presenting with dizziness, excessive sweating, and sudden state of ill feeling following an episode involving intense emotional stress. The physical examination and electrocardiogram were normal upon admission, but the troponin I and creatine kinase-MB concentrations were increased. Acute myocardial infarction without ST segment elevation was suspected, and coronary angiography was immediately performed, which showed severe diffuse left ventricular hypokinesia, medial-apical systolic ballooning, and a lack of significant coronary injury. The patient was referred to the intensive care unit and was successfully treated with supportive therapy. As this case shows, Takotsubo syndrome might simulate the clinical manifestations of acute myocardial infarction, and coronary angiography is necessary to distinguish between both myocardial infarction and myocardial infarction in the acute stage. The present patient progressed with spontaneous resolution of the ventricular dysfunction without any sequelae.

Early detection of myocardial dysfunction using two-dimensional speckle tracking echocardiography in a young cat with hypertrophic cardiomyopathy

PubMed Central

Mochizuki, Yohei; Yoshimatsu, Hiroki; Niina, Ayaka; Teshima, Takahiro; Matsumoto, Hirotaka; Koyama, Hidekazu

2018-01-01

Case summary A 5-month-old intact female Scottish Fold cat was presented for cardiac evaluation. Careful auscultation detected a slight systolic murmur (Levine I/VI). The findings of electrocardiography, thoracic radiography, non-invasive blood pressure measurements and conventional echocardiographic studies were unremarkable. However, two-dimensional speckle tracking echocardiography revealed abnormalities in myocardial deformations, including decreased early-to-late diastolic strain rate ratios in longitudinal, radial and circumferential directions, and deteriorated segmental systolic longitudinal strain. At the follow-up examinations, the cat exhibited echocardiographic left ventricular hypertrophy and was diagnosed with hypertrophic cardiomyopathy using conventional echocardiography. Relevance and novel information This is the first report on the use of two-dimensional speckle tracking echocardiography for the early detection of myocardial dysfunction in a cat with hypertrophic cardiomyopathy; the myocardial dysfunction was detected before the development of hypertrophy. The findings from this case suggest that two-dimensional speckle tracking echocardiography can be useful for myocardial assessment when conventional echocardiographic and Doppler findings are ambiguous. PMID:29449957

Pseudo-acute myocardial infarction due to transient apical ventricular dysfunction syndrome (Takotsubo syndrome)

PubMed Central

Maciel, Bruno Araújo; Cidrão, Alan Alves de Lima; Sousa, Ítalo Bruno dos Santos; Ferreira, José Adailson da Silva; Messias Neto, Valdevino Pedro

2013-01-01

Takotsubo syndrome is characterized by predominantly medial-apical transient left ventricular dysfunction, which is typically triggered by physical or emotional stress. The present article reports the case of a 61-year-old female patient presenting with dizziness, excessive sweating, and sudden state of ill feeling following an episode involving intense emotional stress. The physical examination and electrocardiogram were normal upon admission, but the troponin I and creatine kinase-MB concentrations were increased. Acute myocardial infarction without ST segment elevation was suspected, and coronary angiography was immediately performed, which showed severe diffuse left ventricular hypokinesia, medial-apical systolic ballooning, and a lack of significant coronary injury. The patient was referred to the intensive care unit and was successfully treated with supportive therapy. As this case shows, Takotsubo syndrome might simulate the clinical manifestations of acute myocardial infarction, and coronary angiography is necessary to distinguish between both myocardial infarction and myocardial infarction in the acute stage. The present patient progressed with spontaneous resolution of the ventricular dysfunction without any sequelae. PMID:23887762

Losartan treatment attenuates tumor-induced myocardial dysfunction

PubMed Central

Stevens, Sarah CW; Velten, Markus; Youtz, Dane J.; Clark, Yvonne; Jing, Runfeng; Reiser, Peter J.; Bicer, Sabahattin; Devine, Raymond; McCarthy, Donna O.; Wold, Loren E.

2015-01-01

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT)1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Methods and Results: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8 weeks of age. Simultaneously, mice were administered Losartan (10 mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19 days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. Conclusions: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation. PMID:25988231

Losartan treatment attenuates tumor-induced myocardial dysfunction.

PubMed

Stevens, Sarah C W; Velten, Markus; Youtz, Dane J; Clark, Yvonne; Jing, Runfeng; Reiser, Peter J; Bicer, Sabahattin; Devine, Raymond D; McCarthy, Donna O; Wold, Loren E

2015-08-01

Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction.

PubMed

Lee, Heow Won; Ahmad, Monir; Wang, Hong-Wei; Leenen, Frans H H

2017-03-01

What is the central question of this study? Exercise training increases brain-derived neurotrophic factor (BDNF) in the hippocampus, which depends on a myokine, fibronectin type III domain-containing protein 5 (FNDC5). Whether exercise training after myocardial infarction induces parallel increases in FNDC5 and BDNF expression in skeletal muscle and the heart has not yet been studied. What is the main finding and its importance? Exercise training after myocardial infarction increases BDNF protein in skeletal muscle and the non-infarct area of the LV without changes in FNDC5 protein, suggesting that BDNF is not regulated by FNDC5 in skeletal muscle and heart. An increase in cardiac BDNF may contribute to the improvement of cardiac function by exercise training. Exercise training after myocardial infarction (MI) attenuates progressive left ventricular (LV) remodelling and dysfunction, but the peripheral stimuli induced by exercise that trigger these beneficial effects are still unclear. We investigated as possible mediators fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the skeletal muscle and heart. Male Wistar rats underwent either sham surgery or ligation of the left descending coronary artery, and surviving MI rats were allocated to either a sedentary (Sed-MI) or an exercise group (ExT-MI). Exercise training was done for 4 weeks on a motor-driven treadmill. At the end, LV function was evaluated, and FNDC5 and BDNF mRNA and protein were assessed in soleus muscle, quadriceps and non-, peri- and infarct areas of the LV. At 5 weeks post MI, FNDC5 mRNA was decreased in soleus muscle and all areas of the LV, but FNDC5 protein was increased in the soleus muscle and the infarct area. Mature BDNF (mBDNF) protein was decreased in the infarct area without a change in mRNA. Exercise training attenuated the decrease in ejection fraction and the increase in LV end-diastolic pressure post MI. Exercise training had no effect on FNDC5 mRNA and protein, but increased mBDNF protein in soleus muscle, quadriceps and the non-infarct area of the LV. The mBDNF protein in the non-infarct area correlated positively with ejection fraction and inversely with LV end-diastolic pressure. In conclusion, mBDNF is induced by exercise training in skeletal muscle and the non-infarct area of the LV, which may contribute to improvement of muscle dysfunction and cardiac function post MI. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Relation of Erectile Dysfunction to Subclinical Myocardial Injury.

PubMed

Omland, Torbjørn; Randby, Anna; Hrubos-Strøm, Harald; Røsjø, Helge; Einvik, Gunnar

2016-12-15

The circulating concentration of cardiac troponin I (cTnI) is an index of subclinical myocardial injury in several patient populations and in the general population. Erectile dysfunction is associated with greater risk for cardiovascular events, but the association with subclinical myocardial injury is not known. We aimed to test the hypothesis that the presence and severity of erectile dysfunction is associated with greater concentrations of cTnI in the general population. The presence and severity of erectile dysfunction was assessed by administering the International Index of Erectile Function 5 (IIEF-5) questionnaire to 260 men aged 30 to 65 years recruited from a population-based study. Concentrations of cTnI were determined by a high-sensitivity (hs) assay. Hs-cTnI levels were significantly higher in subjects with than in those without erectile dysfunction (median 2.9 vs 1.6 ng/l; p <0.001). Men with erectile dysfunction (i.e., IIEF-5 sum score <22) were also significantly older; had a higher systolic blood pressure, lower estimated glomerular filtration rate, higher augmentation index and N-terminal pro-B-type natriuretic peptide; and had a higher prevalence of hypertension, diabetes mellitus, and previous coronary artery disease than subjects without erectile dysfunction. These covariates were adjusted for in a multivariate linear regression model, yet the IIEF-5 sum score remained significantly negatively associated with the hs-cTnI concentration (standardized β -0.206; p <0.001). In conclusion, the presence and severity of erectile dysfunction is associated with circulating concentrations of hs-cTnI, indicating subclinical myocardial injury independently of cardiovascular risk factors, endothelial dysfunction and heart failure biomarkers. Copyright © 2016 Elsevier Inc. All rights reserved.

Estrogen modulation of the ethanol-evoked myocardial oxidative stress and dysfunction via DAPK3/Akt/ERK activation in male rats

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

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; Abdel-Rahman, Abdel A., E-mail: abdelrahmana@ecu.edu

Evidence suggests that male rats are protected against the hypotensive and myocardial depressant effects of ethanol compared with females. We investigated whether E{sub 2} modifies the myocardial and oxidative effects of ethanol in male rats. Conscious male rats received ethanol (0.5, 1 or 1.5 g/kg i.v.) 30-min after E{sub 2} (1 μg/kg i.v.) or its vehicle (saline), and hearts were collected at the conclusion of hemodynamic measurements for ex vivo molecular studies. Ethanol had no effect in vehicle-treated rats, but it caused dose-related reductions in LV developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of rise in LV pressure (dP/dt{sub max})more » and systolic (SBP) and diastolic (DBP) blood pressures in E{sub 2}-pretreated rats. These effects were associated with elevated (i) indices of reactive oxygen species (ROS), (ii) malondialdehyde (MDA) protein adducts, and (iii) phosphorylated death-associated protein kinase-3 (DAPK3), Akt, and extracellular signal-regulated kinases (ERK1/2). Enhanced myocardial anti-oxidant enzymes (heme oxygenase-1, catalase and aldehyde dehydrogenase 2) activities were also demonstrated. In conclusion, E{sub 2} promotes ethanol-evoked myocardial oxidative stress and dysfunction in male rats. The present findings highlight the risk of developing myocardial dysfunction in men who consume alcohol while receiving E{sub 2} for specific medical conditions. - Highlights: • Ethanol lowers blood pressure and causes LV dysfunction in E{sub 2}-treated rats. • E{sub 2}/ethanol aggravates cardiac oxidative state via of DAPK3/Akt/ERK activation. • E{sub 2}/ethanol causes a feedback increase in cardiac HO-1, catalase and ALDH2. • Alcohol might increase risk of myocardial dysfunction in men treated with E{sub 2}.« less

Effect of uridine derivatives on myocardial stunning during postischemic reperfusion of rat heart.

PubMed

Sapronov, N S; Eliseev, V V; Rodionova, O M

2000-10-01

Uridine and uridine-5'-monophosphate prevent myocardial stunning during postischemic reperfusion of isolated rat heart. Uridine-5'-diphosphate does not prevent postischemic myocardial dysfunction, while uridine-5'-triphosphate aggravates it.

Speckle tracking echocardiography in patients with septic shock: a case control study (SPECKSS).

PubMed

Ng, Pauline Yeung; Sin, Wai Ching; Ng, Andrew Kei-Yan; Chan, Wai Ming

2016-05-14

Sepsis-induced myocardial dysfunction is a well-recognized condition and confers worse outcomes in septic patients. Echocardiographic assessment by conventional parameters such as left ventricular ejection fraction (LVEF) is often affected by ongoing changes in preload and afterload conditions. Novel echocardiographic technologies such as speckle tracking echocardiography (STE) have evolved for direct assessment of the myocardial function. We investigate the measurement of myocardial strain by speckle tracking echocardiography for the diagnosis of sepsis-induced myocardial dysfunction. This is a case-control study at a university-affiliated medical intensive care unit. Consecutive adult medical patients admitted with a diagnosis of septic shock were included. Patients with other causes of myocardial dysfunction were excluded. They were compared to age-matched, gender-matched, and cardiovascular risk-factor-matched controls, who were admitted to hospital for sepsis but did not develop septic shock. Transthoracic echocardiography was performed on all patients within 24 hours of diagnosis, and a reassessment echocardiogram was performed in the study group of patients upon recovery. Patients with septic shock (n = 33) (study group) and 29 matched patients with sepsis but no septic shock (control group) were recruited. The mean sequential organ failure assessment (SOFA) score for the study and control groups were 10.2 and 1.6, respectively (P < 0.001). In patients with septic shock, the mean arterial pressure was lower (76 mmHg vs 82 mmHg, P = 0.032), and the heart rate was higher (99 bpm vs 86 bpm, P = 0.008). The cardiac output (5.9 L/min vs 5.5 L/min, P = 0.401) and systemic vascular resistance (1090 dynes•sec/cm(5) vs 1194 dynes•sec/cm(5), P = 0.303) were similar. The study group had a greater degree of myocardial dysfunction measured by global longitudinal strain (GLS) (-14.5 % vs -18.3 %, P <0.001), and the myocardial strain differed upon diagnosis and recovery (-14.5 % vs -16.0 %, P = 0.010). Conventional echocardiographic measurements such as LVEF (59 % in the study group vs 61 % in the control group, P = 0.169) did not differ between the two groups. Speckle tracking echocardiography can detect significant left ventricular impairment in patients with septic shock, which was not otherwise detectable by conventional echocardiography. The reversible nature of myocardial dysfunction in sepsis was also demonstrable. This echocardiographic technique is useful in the diagnosis and monitoring of sepsis-induced myocardial dysfunction.

Endothelial function is associated with myocardial diastolic function in women with systemic lupus erythematosus.

PubMed

Chin, Calvin W L; Chin, Chee-Yang; Ng, Marie X R; Le, Thu-Thao; Huang, Fei-Qiong; Fong, Kok-Yong; Thumboo, Julian; Tan, Ru-San

2014-09-01

Endothelial dysfunction is associated with traditional and systemic lupus erythematosus (SLE)-specific risk factors, and early data suggest reversibility of endothelial dysfunction with therapy. The clinical relevance of endothelial function assessment has been limited by the lack of studies, demonstrating its prognostic significance and impact on early myocardial function. Therefore, we aimed to determine the association between endothelial and myocardial diastolic function in SLE women. Women with SLE and no coronary artery disease were prospectively recruited and underwent radionuclide myocardial perfusion imaging (MPI) (Jetstream, Philips, the Netherlands) to exclude subclinical myocardial ischemia. Cardiac and vascular functions were assessed in all patients (Alpha 10, Aloka, Tokyo). Diastolic function was assessed using pulse wave early (E) and late mitral blood inflow and myocardial tissue Doppler (mean of medial and lateral annulus e') velocities. Endothelial function was measured using brachial artery flow-mediated vasodilatation (FMD%). Univariate and multivariate linear regressions were used to assess the association between FMD% and myocardial diastolic function, adjusting for potential confounders. Thirty-eight patients without detectable myocardial ischemia on MPI were studied (mean age 44 ± 10 years; mean disease duration 14 ± 6 years). About 61 % of patients had normal diastolic function (E/e' ≤ 8), and 5 % of patients had definite diastolic dysfunction with E/e' > 13 (mean 7.1 ± 2.9). FMD% was associated with E/e' (regression coefficient β = -0.35; 95 % CI -0.62 to -0.08; p = 0.01) independent of systolic blood pressure, age, and SLICC/ACR Damage Index.

Glutathione peroxidase deficiency exacerbates ischemia-reperfusion injury in male but not female myocardium: insights into antioxidant compensatory mechanisms.

PubMed

Lim, Chee Chew; Bryan, Nathan S; Jain, Mohit; Garcia-Saura, Maria F; Fernandez, Bernadette O; Sawyer, Douglas B; Handy, Diane E; Loscalzo, Joseph; Feelisch, Martin; Liao, Ronglih

2009-12-01

The female sex has been associated with increased resistance to acute myocardial ischemia-reperfusion (I/R) injury. While enhanced antioxidant capacity has been implicated in female cardioprotection, there is little evidence to support this assumption. Previous studies have shown an important role of cellular glutathione peroxidase (GPx1) in protection of the myocardium from I/R injury. Whether GPx1 is mechanistic in the protection of female myocardium, post-I/R, has not been examined. We utilized a murine model with homozygous deletion of GPx1 and examined its impact on postischemic myocardial recovery in male and female mice. Following I/R, male GPx1(-/-) hearts were more susceptible to contractile and diastolic dysfunction, and this was associated with increased protein carbonyls, a marker of oxidative stress. In contrast, GPx1 deficiency in female hearts did not exacerbate dysfunction or oxidative stress post-I/R. Both wild-type and GPx1(-/-) female hearts exhibited reduced creatine kinase leakage and a more favorable ascorbate redox status compared with males. Following I/R, female GPx1(-/-) hearts showed a comparable decrease in glutathione redox status as their male counterparts; however, they exhibited a greater decrease in nitrate-to-nitrite ratio, suggesting a higher consumption of nitrate in female GPx1(-/-) hearts. Our findings demonstrate that GPx1 is critical for cardioprotection during I/R in male, but not female, mice. The maintenance of cardioprotection in female mice lacking GPx1 post-I/R may be due to an improved ascorbate redox homeostasis and enhanced nitrate-to-nitrite conversion, which would predictably be accompanied by enhanced production of cardioprotective nitric oxide.

Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

PubMed

Guo, Rui; Ren, Jun

2010-01-18

Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH). ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined. Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF. Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

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

PubMed

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

2011-12-01

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

Left ventricular function abnormalities as a manifestation of silent myocardial ischemia.

PubMed

Lambert, C R; Conti, C R; Pepine, C J

1986-11-01

A large body of evidence exists indicating that left ventricular dysfunction is a common occurrence in patients with severe coronary artery disease and represents silent or asymptomatic myocardial ischemia. Such dysfunction probably occurs early in the time course of every ischemic episode in patients with coronary artery disease whether symptoms are eventually manifested or not. The pathophysiology of silent versus symptomatic left ventricular dysfunction due to ischemia appears to be identical. Silent ischemia-related left ventricular dysfunction can be documented during spontaneous or stress-induced perturbations in the myocardial oxygen supply/demand ratio. It also may be detected by nitroglycerin-induced improvement in ventricular function or by salutary changes in wall motion following revascularization. Silent left ventricular dysfunction is a very early occurrence during ischemia and precedes electrocardiographic abnormalities. In this light, its existence should always be kept in mind when dealing with patients with ischemic heart disease. It can be hypothesized that because silent ischemia appears to be identical to ischemia with symptoms in a pathophysiologic sense, prognosis and treatment in both cases should be the same.

Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines.

PubMed

Li, Longhu; Zhao, Dong; Jin, Zhe; Zhang, Jian; Paul, Christian; Wang, Yigang

2015-01-01

Treatment with short hairpin RNA (shRNA) interference therapy targeting phosphodiesterase 5a after myocardial infarction (MI) has been shown to mitigate post-MI heart failure. We investigated the mechanisms that underpin the beneficial effects of PDE5a inhibition through shRNA on post-MI heart failure. An adenoviral vector with an shRNA sequence inserted was adopted for the inhibition of phosphodiesterase 5a (Ad-shPDE5a) in vivo and in vitro. Myocardial infarction (MI) was induced in male C57BL/6J mice by left coronary artery ligation, and immediately after that, the Ad-shPDE5a was injected intramyocardially around the MI region and border areas. Four weeks post-MI, the Ad-shPDE5a-treated mice showed significant mitigation of the left ventricular (LV) dilatation and dysfunction compared to control mice. Infarction size and fibrosis were also significantly reduced in Ad-shPDE5a-treated mice. Additionally, Ad-shPDE5a treatment decreased the MI-induced inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β1, which was confirmed in vitro in Ad-shPDE5a transfected myofibroblasts cultured under oxygen glucose deprivation. Finally, Ad-shPDE5a treatment was found to activate the myocardial Akt signaling pathway in both in vivo and in vitro experiments. These findings indicate that PDE5a inhibition by Ad-shPDE5a via the Akt signal pathway could be of significant value in the design of future therapeutics for post-MI heart failure.

Xanthine Oxidase Inhibition with Febuxostat Attenuates Systolic Overload-induced Left Ventricular Hypertrophy and Dysfunction in Mice

PubMed Central

Xu, Xin; Hu, Xinli; Lu, Zhongbing; Zhang, Ping; Zhao, Lin; Wessale, Jerry L.; Bache, Robert J.; Chen, Yingjie

2008-01-01

The purine analog xanthine oxidase (XO) inhibitors (XOIs), allopurinol and oxypurinol, have been reported to protect against heart failure secondary to myocardial infarction or rapid ventricular pacing. Since these agents might influence other aspects of purine metabolism that could influence their effect, this study examined the effect of the non-purine XOI, febuxostat, on pressure overload-induced left ventricular (LV) hypertrophy and dysfunction. Transverse aortic constriction (TAC) in mice caused LV hypertrophy and dysfunction as well as increased myocardial nitrotyrosine at 8 days. TAC also caused increased phosphorylated Akt (p-AktSer473), p42/44 extracellular signal-regulated kinase (p-ErkThr202/Tyr204) and mammalian target of rapamycin (mTOR) (p-mTORSer2488). XO inhibition with febuxostat (5mg/kg/day by gavage for 8 days) beginning ~60 minutes after TAC attenuated the TAC-induced LV hypertrophy and dysfunction. Febuxostat blunted the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-ErkThr202/Tyr204 and p-mTORSer2488, with no effect on total Erk or total mTOR. Febuxostat had no effect on myocardial p-AktSer473 or total Akt. The results suggest that XO inhibition with febuxostat reduced oxidative stress in the pressure overloaded LV, thereby diminishing the activation of pathways that result in pathologic hypertrophy and contractile dysfunction. PMID:18995179

Myocardial Hypertrophy and Its Role in Heart Failure with Preserved Ejection Fraction

PubMed Central

Heinzel, Frank R.; Hohendanner, Felix; Jin, Ge; Sedej, Simon; Edelmann, Frank

2015-01-01

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load and cytokines associated with arterial hypertension, chronic kidney disease, diabetes and other co-morbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood but may include extracellular matrix changes, vascular dysfunction as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca2+ turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound co-morbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training on the other hand, in clinical trials improved exercise tolerance and diastolic function but did not reduce LVH. Thus, current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF. PMID:26183480

Cardiovascular and systemic effects of gastric dilatation and volvulus in dogs.

PubMed

Sharp, Claire R; Rozanski, Elizabeth A

2014-09-01

Gastric dilatation and volvulus (GDV) is a common emergency condition in large and giant breed dogs that is associated with high morbidity and mortality. Dogs with GDV classically fulfill the criteria for the systemic inflammatory response syndrome (SIRS) and can go on to develop multiple organ dysfunction syndrome (MODS). Previously reported organ dysfunctions in dogs with GDV include cardiovascular, respiratory, gastrointestinal, coagulation and renal dysfunction. Cardiovascular manifestations of GDV include shock, cardiac arrhythmias and myocardial dysfunction. Respiratory dysfunction is also multifactorial, with contributory factors including decreased respiratory excursion due to gastric dilatation, decreased pulmonary perfusion and aspiration pneumonia. Gastrointestinal dysfunction includes gastric necrosis and post-operative gastrointestinal upset such as regurgitation, vomiting, and ileus. Coagulation dysfunction is another common feature of MODS in dogs with GDV. Disseminated intravascular coagulation can occur, putting them at risk of complications associated with thrombosis in the early hypercoagulable state and hemorrhage in the subsequent hypocoagulable state. Acute kidney injury, acid-base and electrolyte disturbances are also reported in dogs with GDV. Understanding the potential for systemic effects of GDV allows the clinician to monitor patients astutely and detect such complications early, facilitating early intervention to maximize the chance of successful management. Copyright © 2014 Elsevier Inc. All rights reserved.

Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.

PubMed

Nolan, Jerry P; Neumar, Robert W; Adrie, Christophe; Aibiki, Mayuki; Berg, Robert A; Böttiger, Bernd W; Callaway, Clifton; Clark, Robert S B; Geocadin, Romergryko G; Jauch, Edward C; Kern, Karl B; Laurent, Ivan; Longstreth, W T; Merchant, Raina M; Morley, Peter; Morrison, Laurie J; Nadkarni, Vinay; Peberdy, Mary Ann; Rivers, Emanuel P; Rodriguez-Nunez, Antonio; Sellke, Frank W; Spaulding, Christian; Sunde, Kjetil; Hoek, Terry Vanden

2008-12-01

To review the epidemiology, pathophysiology, treatment and prognostication in relation to the post-cardiac arrest syndrome. Relevant articles were identified using PubMed, EMBASE and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Writing groups comprising international experts were assigned to each section. Drafts of the document were circulated to all authors for comment and amendment. The 4 key components of post-cardiac arrest syndrome were identified as (1) post-cardiac arrest brain injury, (2) post-cardiac arrest myocardial dysfunction, (3) systemic ischaemia/reperfusion response, and (4) persistent precipitating pathology. A growing body of knowledge suggests that the individual components of the post-cardiac arrest syndrome are potentially treatable.

Myocardial Ischemia Induces SDF-1α Release in Cardiac Surgery Patients.

PubMed

Kim, Bong-Sung; Jacobs, Denise; Emontzpohl, Christoph; Goetzenich, Andreas; Soppert, Josefin; Jarchow, Mareike; Schindler, Lisa; Averdunk, Luisa; Kraemer, Sandra; Marx, Gernot; Bernhagen, Jürgen; Pallua, Norbert; Schlemmer, Heinz-Peter; Simons, David; Stoppe, Christian

2016-06-01

In the present observational study, we measured serum levels of the chemokine stromal cell-derived factor-1α (SDF-1α) in 100 patients undergoing cardiac surgery with cardiopulmonary bypass at seven distinct time points including preoperative values, myocardial ischemia, reperfusion, and the postoperative course. Myocardial ischemia triggered a marked increase of SDF-1α serum levels whereas cardiac reperfusion had no significant influence. Perioperative SDF-1α serum levels were influenced by patients' characteristics (e.g., age, gender, aspirin intake). In an explorative analysis, we observed an inverse association between SDF-1α serum levels and the incidence of organ dysfunction. In conclusion, time of myocardial ischemia was identified as the key stimulus for a significant upregulation of SDF-1α, indicating its role as a marker of myocardial injury. The inverse association between SDF-1α levels and organ dysfunction association encourages further studies to evaluate its organoprotective properties in cardiac surgery patients.

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

PubMed

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

2016-09-01

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

Cardiocerebral protection by emulsified isoflurane during cardiopulmonary resuscitation.

PubMed

Zhang, Ya-Jie; Wu, Meng-Jun; Li, Yi; Yu, Hai

2015-01-01

Although improvement in cardiopulmonary resuscitation (CPR) performance and the increasing success at achieving return of spontaneous circulation (ROSC) have been possible in recent years, the survival and discharge rates of post-cardiac arrest (CA) patients remain disappointing. The high mortality rate is attributed to whole-body ischemia/reperfusion (I/R) induced multi-organ dysfunction that is well known as post-cardiac arrest syndrome. Post-cardiac arrest myocardial dysfunction and brain injury are the main clinical features of this complex pathophysiological process. Previous evidences have shown that volatile anesthetics, such as isoflurane, trigger a powerful and highly integrated cell survival response during I/R period in multiple organs, including heart and brain, which reduces I/R injury. This effect that called anesthetic-induced postconditioning can be shown when volatile anesthetics are administered after the onset of ischemia and at the time of reperfusion. Emulsified isoflurane (EIso) is a new anesthetic for intravenous administration, which is conveniently feasible outside operating room. Therefore, we hypothesize that EIso postconditioning could provide the cardiocerebral protection, and combined with therapeutic hypothermia as sedative agent could produce enhanced cardiocerebral protection, which can result in significant improvement of neurologically intact post-cardiac arrest survival. We consider that it would become a feasible, safe and efficient cardiocerebral protective intervention in the prevention and alleviation of post-cardiac arrest syndrome, which would also improve the outcomes after CA. Copyright © 2014 Elsevier Ltd. All rights reserved.

Coronary microvascular dysfunction equivalent to left main coronary artery disease.

PubMed

Panç, Cafer; Kocaağa, Mehmet; Erdoğan, Onur; Sarıkaya, Remzi; Umman, Sabahattin

2017-04-01

Coronary microvascular dysfunction, also known as cardiac syndrome X, is a clinical syndrome presenting with typical angina and evidence of myocardial ischemia in the absence of flow-limiting stenosis on coronary angiography. Of patients undergoing coronary angiography due to suspected myocardial ischemia, 50% are found to have normal or near-normal coronary arteries. Described in this case report is a patient who developed hypotension and ST segment depressions during treadmill exercise test. Left main coronary artery or multivessel disease was suspected. Coronary angiography was normal, but coronary flow reserve measurement revealed severe microvascular dysfunction.

Increase in mean platelet volume in patients with myocardial bridge.

PubMed

Bilen, Emine; Tanboga, Ibrahim Halil; Kurt, Mustafa; Kocak, Umran; Ayhan, Huseyin; Keles, Telat; Bozkurt, Engin

2013-01-01

Myocardial bridge is associated with atherosclerosis altered in shear stress and endothelial dysfunction. Mean platelet volume (MPV), a determinant of platelet activation, is shown to be related with atherosclerosis and endothelial dysfunction. In this study, we aimed to evaluate platelet function assessed by MPV in patients with myocardial bridge. Forty-two patients with myocardial bridge in the left anterior descending artery (LAD) and 43 age- and gender-matched healthy participants were included in the study. Myocardial bridging was defined as an intramyocardial systolic compression or milking of a segment of an epicardial coronary artery on angiography. For the entire study population, MPV was measured using an automatic blood counter. The study population consisted of 42 patients with myocardial bridge (52.7 ± 10.2, 76.2% male) and 43 age- and sex-matched healthy control participants (52.1 ± 10.4, 74.4% male). Compared to the control group, MPV value was significantly higher in patients with myocardial bridge (8.9 ± 1.24 vs 8.3 ± 0.78; P = .01). Further, there were no significant differences between groups regarding hemoglobin level, platelet count, fasting blood glucose, and creatinine levels. Our study findings indicated that myocardial bridge is associated with elevated MPV values. Our results might partly explain the increased cardiovascular events in patients with myocardial bridge.

Two-dimensional color tissue Doppler imaging detects myocardial dysfunction before occurrence of hypertrophy in a young Maine Coon cat.

PubMed

Chetboul, Valerie; Sampedrano, Carolina Carlos; Gouni, Vassiliki; Nicolle, Audrey P; Pouchelon, Jean-Louis

2006-01-01

A 20-month-old healthy male Maine Coon cat was referred for a cardiovascular evaluation. Physical examination and electrocardiogram were normal. The end-diastolic subaortic interventricular septal thickness (6 mm; reference range: < or = 6mm) and the mitral flow late diastolic velocity (0.89 m/s; reference range: 0.2-0.8m/s) were within the upper ranges. However, M-mode echocardiography did not reveal any sign of hypertrophic cardiomyopathy (HCM). Tissue Doppler imaging (TDI) identified a marked left ventricular free wall dysfunction characterized by decreased myocardial velocities in early diastole, increased myocardial velocities in late diastole and the presence of postsystolic contractions both at the base and the apex for the longitudinal motion. One year later, the diagnosis of HCM was confirmed by conventional echocardiography and the cat died suddenly 2 months later. This report demonstrates for the first time in spontaneous HCM the sensitivity of TDI for early diagnosis of myocardial dysfunction and suggests that TDI should form part of the screening techniques for early diagnosis of feline HCM.

Nucleolin mediated pro-angiogenic role of Hydroxysafflor Yellow A in ischaemic cardiac dysfunction: Post-transcriptional regulation of VEGF-A and MMP-9.

PubMed

Zou, Jiang; Wang, Nian; Liu, Manting; Bai, Yongping; Wang, Hao; Liu, Ke; Zhang, Huali; Xiao, Xianzhong; Wang, Kangkai

2018-05-01

Hydroxysafflor Yellow A (HSYA), a most representative ingredient of Carthamus tinctorius L., had long been used in treating ischaemic cardiovascular diseases in China and exhibited prominently anticoagulant and pro-angiogenic activities, but the underlying mechanisms remained largely unknown. This study aimed to further elucidate the pro-angiogenic effect and mechanism of HSYA on ischaemic cardiac dysfunction. A C57 mouse model of acute myocardial infarction (AMI) was firstly established, and 25 mg/kg HSYA was intraperitoneally injected immediately after operation and given once, respectively, each morning and evening for 2 weeks. It was found that HSYA significantly improved ischaemia-induced cardiac haemodynamics, enhanced the survival rate, alleviated the myocardial injury and increased the expressions of CD31, vascular endothelial growth factor-A (VEGF-A) and nucleolin in the ischaemic myocardium. In addition, HSYA promoted the migration and tube formation of human umbilical vein endothelial cells (HUVECs), enhanced the expressions of nucleolin, VEGF-A and matrix metalloproteinase-9 (MMP-9) in a dose- and time-dependent manner. However, down-regulation of nucleolin expression sharply abrogated the effect mentioned above of HSYA. Further protein-RNA coimmunoprecipitation and immunoprecipitation-RT-PCR assay showed that nucleolin binded to VEGF-A and MMP-9 mRNA and overexpression of nucleolin up-regulated the mRNA expressions of VEGF-A and MMP-9 in the HUVECs through enhancing the stability of VEGF-A and MMP-9 mRNA. Furthermore, HSYA increased the mRNA expressions of VEGF-A and MMP-9 in the extract of antinucleolin antibody-precipitated protein from the heart of AMI mice. Our data revealed that nucleolin mediated the pro-angiogenic effect of HSYA through post-transcriptional regulation of VEGF-A and MMP-9 expression, which contributed to the protective effect of HSYA on ischaemic cardiac dysfunction. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Adeno-associated Virus Serotype 9 – Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction

PubMed Central

Knezevic, Tijana; Myers, Valerie D.; Su, Feifei; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Gao, Erhe; Gao, Guofeng; Muniswamy, Madesh; Gupta, Manish K.; Gordon, Jennifer; Weiner, Kristen N.; Rabinowitz, Joseph; Ramsey, Frederick V.; Tilley, Douglas G.; Khalili, Kamel; Cheung, Joseph Y.; Feldman, Arthur M.

2016-01-01

Objectives The present study was undertaken to test the hypothesis that gene delivery of BCL2-Associated Athanogene 3 (BAG3) to the heart of mice with left ventricular dysfunction secondary to a myocardial infarction could enhance cardiac performance. Background BAG3 is a 575 amino acid protein that has pleotropic functions in the cell including pro-autophagy and anti-apoptosis. Mutations in BAG3 have been associated with both skeletal muscle dysfunction and familial dilated cardiomyopathy and BAG3 levels are diminished in non-familial heart failure. Methods Eight-week-old C57/BL6 mice underwent ligation of the left coronary artery (MI) or sham surgery (Sham). Eight weeks later, mice in both groups were randomly assigned to receive either a retro-orbital injection of rAAV9-BAG3 (MI-BAG3 or Sham-BAG3) or rAAV9-GFP (MI-GFP or Sham GFP). Mice were sacrificed at 3 weeks post-injection and myocytes were isolated from the left ventricle. Results MI-BAG3 mice demonstrated a significantly (p < 0.0001) higher left ventricular ejection fraction (LVEF) 9 days after rAAV9-BAG3 injection with further improvement in LVEF, fractional shortening and stroke volume at 3 weeks post-injection without changes in LV mass or LV volume. Injection of rAAV9-BAG3 had no effect on LVEF in Sham mice. The salutary benefits of rAAV9-BAG3 were also observed in myocytes isolated from MI hearts including improved cell shortening (p<0.05), increased systolic [Ca2+]i, increased [Ca2+]i transient amplitudes and increased maximal ICa amplitude. Implications The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure. PMID:28164169

Adeno-associated Virus Serotype 9 - Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction.

PubMed

Knezevic, Tijana; Myers, Valerie D; Su, Feifei; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Gao, Erhe; Gao, Guofeng; Muniswamy, Madesh; Gupta, Manish K; Gordon, Jennifer; Weiner, Kristen N; Rabinowitz, Joseph; Ramsey, Frederick V; Tilley, Douglas G; Khalili, Kamel; Cheung, Joseph Y; Feldman, Arthur M

2016-12-01

The present study was undertaken to test the hypothesis that gene delivery of BCL2-Associated Athanogene 3 (BAG3) to the heart of mice with left ventricular dysfunction secondary to a myocardial infarction could enhance cardiac performance. BAG3 is a 575 amino acid protein that has pleotropic functions in the cell including pro-autophagy and anti-apoptosis. Mutations in BAG3 have been associated with both skeletal muscle dysfunction and familial dilated cardiomyopathy and BAG3 levels are diminished in non-familial heart failure. Eight-week-old C57/BL6 mice underwent ligation of the left coronary artery (MI) or sham surgery (Sham). Eight weeks later, mice in both groups were randomly assigned to receive either a retro-orbital injection of rAAV9-BAG3 (MI-BAG3 or Sham-BAG3) or rAAV9-GFP (MI-GFP or Sham GFP). Mice were sacrificed at 3 weeks post-injection and myocytes were isolated from the left ventricle. MI-BAG3 mice demonstrated a significantly (p < 0.0001) higher left ventricular ejection fraction (LVEF) 9 days after rAAV9-BAG3 injection with further improvement in LVEF, fractional shortening and stroke volume at 3 weeks post-injection without changes in LV mass or LV volume. Injection of rAAV9-BAG3 had no effect on LVEF in Sham mice. The salutary benefits of rAAV9-BAG3 were also observed in myocytes isolated from MI hearts including improved cell shortening (p<0.05), increased systolic [Ca 2+ ] i , increased [Ca 2+ ] i transient amplitudes and increased maximal I Ca amplitude. The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.

Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

PubMed Central

Hiley, C Robin; Ford, William R

2003-01-01

Endocannabinoid production by platelets and macrophages is increased in circulatory shock. This may be protective of the cardiovascular system as blockade of CB1 cannabinoid receptors exacerbates endothelial dysfunction in haemorrhagic and endotoxin shock and reduces survival. Now evidence suggests that blockade of CB1 receptors starting 24 h after myocardial infarction in rats has a deleterious effect on cardiac performance, while use of a nonselective cannabinoid receptor agonist prevents hypotension and reduces endothelial dysfunction, although left ventricular end diastolic pressure is elevated. Cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction. PMID:12711614

Possible mechanism by which renal sympathetic denervation improves left ventricular remodelling after myocardial infarction.

PubMed

Zheng, Xiao-Xin; Li, Xiao-Yan; Lyu, Yong-Nan; He, Yi-Yu; Wan, Wei-Guo; Zhu, Hong-Ling; Jiang, Xue-Jun

2016-02-01

What is the central question of this study? The enzyme system that is responsible for extracellular matrix (ECM) turnover is the matrix metalloproteinases (MMPs), which can be blocked by the tissue inhibitors of MMPs (TIMPs). Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction left ventricular remodelling through attenuation of ECM via regulation of MMP activity and/or the MMP-TIMP complex remains unknown. What is the main finding and its importance? Renal sympathetic denervation has therapeutic effects on post-myocardial infarction left ventricular remodelling, probably by attenuating the ECM through regulation of the MMP9-TIMP1 complex in the transforming growth factor-β1 (a profibrotic cytokine that accelerates ECM remodelling after ischaemia) signalling pathway. Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction (post-MI) left ventricular (LV) remodelling by attenuation of the extracellular matrix via regulation of matrix metalloproteinase (MMP) activity and/or the MMP-tissue inhibitor of matrix metalloproteinase (TIMP) complex remains unknown. Sixty-five Sprague-Dawley rats were randomly divided into the following four groups: normal (N, n = 15), RSD (RSD, n = 15), myocardial infarction (MI, n = 15) and RSD 3 days after MI (MI3d+RSD, n = 20). The bilateral renal nerves were surgically denervated 3 days after MI had been induced by coronary artery ligation. Left ventricular function was assessed using echocardiography and a Millar catheter at 6 weeks post-MI. Plasma noradrenaline, angiotensin II and aldosterone, collagen volume fraction, transforming growth factor-β1 (TGF-β1), MMP2, MMP9 and TIMP1 in heart tissue were measured 6 weeks after MI. In rats with MI3d+RSD compared with MI rats, RSD improved systolic and diastolic function, resulting in an improvement in ejection fraction (P < 0.05), fractional shortening (P < 0.05) and LV internal dimension in systole (P < 0.05) and diastole (P < 0.05). Additionally, RSD treatment decreased left ventricular end-diastolic pressure (P < 0.05) and increased LV systolic pressure (P < 0.05) and maximal and minimal rate of LV pressure (both P < 0.05). Meanwhile, RSD reduced collagen content (P < 0.01). TIMP1 was upregulated (P < 0.05), whereas MMP2, MMP9 and TGF-β1 were downregulated in the LV of RSD-treated animals (P < 0.05). Renal sympathetic denervation has therapeutic effects on post-MI LV remodelling, probably owing to effects on the extracellular matrix by regulation of the MMP9-TIMP1 balance in the TGF-β1 signalling pathway. Renal sympathetic denervation may be considered as a non-pharmacological approach for the improvement of post-MI cardiac dysfunction. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Phaeochromocytoma in a 86-year-old patient presenting with reversible myocardial dysfunction.

PubMed

Szwench, Elżbieta; P Czkowska, Mariola; Marczewski, Krzysztof; Klisiewicz, Anna; Micha Owska, Ilona; Ciuba, Iwona; Januszewicz, Magdalena; Prejbisz, Aleksander; Hoffman, Piotr; Januszewicz, Andrzej

2011-12-01

BACKGROUND. Phaeochromocytomas and paragangliomas are rare, mostly benign catecholamine-producing tumours of chromaffin cells of the adrenal medulla or of extra-adrenal paraganglia. Phaeochromocytoma may occur at any age, the greatest frequency being in the fourth and fifth decades. Only on extremely rare occasions does the tumour develop in the very old patients. METHODS. We are describing an 86-year-old patient with phaeochromocytoma, presenting with reversible myocardial dysfunction. RESULTS. This very old patient with phaeochromocytoma had hypertension characterized by labile blood pressure values and increased daytime blood pressure variability. This patient exhibited reversible myocardial dysfunction suggestive for "catecholaminergic cardiomyopathy", as the complication of phaeochromocytoma. After surgical removal of the tumour, recovery of left ventricular function was documented by echocardiography showing normalization of systolic function and improvement of diastolic function. CONCLUSION. Phaeochromocytomas are rare forms of secondary hypertension, but should be considered in the differential diagnosis, regardless of age, even in very old patients.

Targeting inflammatory pathways in myocardial infarction

PubMed Central

Christia, Panagiota; Frangogiannis, Nikolaos G

2013-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies. PMID:23772948

Chagas' heart disease: gender differences in myocardial damage assessed by cardiovascular magnetic resonance.

PubMed

Assunção, Antonildes N; Jerosch-Herold, Michael; Melo, Rodrigo L; Mauricio, Alejandra V; Rocha, Liliane; Torreão, Jorge A; Fernandes, Fabio; Ianni, Barbara M; Mady, Charles; Ramires, José A F; Kalil-Filho, Roberto; Rochitte, Carlos E

2016-11-28

Since a male-related higher cardiovascular morbidity and mortality in patients with Chagas' heart disease has been reported, we aimed to investigate gender differences in myocardial damage assessed by cardiovascular magnetic resonance (CMR). Retrospectively, 62 seropositive Chagas' heart disease patients referred to CMR (1.5 T) and with low probability of having significant coronary artery disease were included in this analysis. Amongst both sexes, there was a strong negative correlation between LV ejection fraction and myocardial fibrosis (male r = 0.64, female r = 0.73, both P < 0.001), with males showing significantly greater myocardial fibrosis (P = 0.002) and lower LV ejection fraction (P < 0.001) than females. After adjustment for potential confounders, gender remained associated with myocardial dysfunction, and 53% of the effect was mediated by myocardial fibrosis (P for mediation = 0.004). Also, the transmural pattern was more prevalent among male patients (23.7 vs. 9.9%, P < 0.001) as well as the myocardial heterogeneity or gray zone (2.2 vs. 1.3 g, P = 0.003). We observed gender-related differences in myocardial damage assessed by CMR in patients with Chagas' heart disease. As myocardial fibrosis and myocardial dysfunction are associated to cardiovascular outcomes, our findings might help to understand the poorer prognosis observed in males in Chagas' disease.

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

PubMed

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

2004-12-01

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

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study.

PubMed

Olivier, A; Girerd, N; Michel, J B; Ketelslegers, J M; Fay, R; Vincent, J; Bramlage, P; Pitt, B; Zannad, F; Rossignol, P

2017-08-15

Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI. In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1month in 476 patients. When included in the same Cox regression model, baseline BNP (p=0.0003) and BigET-1 (p=0.026) as well as the relative changes (after 1month) from baseline in BNP (p=0.049) and BigET-1 (p=0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p=0.01 for the primary endpoint). Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies. In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Correlation between cardiac remodelling, function, and myocardial contractility in rat hearts 5 weeks after myocardial infarction.

PubMed

Gosselin, H; Qi, X; Rouleau, J L

1998-01-01

Early after infarction, ventricular dysfunction occurs as a result of loss of myocardial tissue. Although papillary muscle studies suggest that reduced myocardial contractility contributes to this ventricular dysfunction, in vivo studies indicate that at rest, cardiac output is normal or near normal, suggesting that contractility of the remaining viable myocardium of the ventricular wall is preserved. However, this has never been verified. To explore this further, 100 rats with various-sized myocardial infarctions had ventricular function assessed by Langendorff preparation or by isolated papillary muscle studies 5 weeks after infarction. Morphologic studies were also done. Rats with large infarctions (54%) had marked ventricular dilatation (dilatation index from 0.23 to 0.75, p < 0.01) and papillary muscle dysfunction (total tension from 6.7 to 3.2 g/mm2, p < 0.01) but only moderate left ventricular dysfunction (maximum developed tension from 206 to 151 mmHg (1 mmHg = 133.3 Pa), p < 0.01), a decrease less than one would expect with an infarct size of 54%. The contractility of the remaining viable myocardium of the ventricle was also moderately depressed (peak systolic midwall stress 91 to 60 mmHg, p < 0.01). Rats with moderate infarctions (32%) had less marked but still moderate ventricular dilatation (dilatation index 0.37, p < 0.001) and moderate papillary muscle dysfunction (total tension 4.2 g/mm2, p < 0.01). However, their decrease in ventricular function was only mild (maximum developed pressure 178 mmHg, p < 0.01) and less than one would expect with an infarct size of 32%. The remaining viable myocardium of the ventricular wall appeared to have normal contractility (peak systolic midwall stress = 86 mmHg, ns). We conclude that in this postinfarction model, in large myocardial infarctions, a loss of contractility of the remaining viable myocardium of the ventricular wall occurs as early as 5 weeks after infarction and that papillary muscle studies slightly overestimate the degree of ventricular dysfunction. In moderate infarctions, the remaining viable myocardium of the ventricular wall has preserved contractility while papillary muscle function is depressed. In this relatively early postinfarction phase, ventricular remodelling appears to help maintain left ventricular function in both moderate and large infarctions.

Cardioprotective Properties of Aerobic and Resistance Training Against Myocardial Infarction.

PubMed

Barboza, C A; Souza, G I H; Oliveira, J C M F; Silva, L M; Mostarda, C T; Dourado, P M M; Oyama, L M; Lira, F S; Irigoyen, M C; Rodrigues, B

2016-06-01

We evaluated the effects of aerobic and resistance exercise training on ventricular morphometry and function, physical capacity, autonomic function, as well as on ventricular inflammatory status in trained rats prior to myocardial infarction. Male Wistar rats were divided into the following groups: sedentary+Sham, sedentary+myocardial infarction, aerobic trained+myocardial infarction, and resistance trained+myocardial infarction. Sham and myocardial infarction were performed after training periods. In the days following the surgeries, evaluations were performed. Aerobic training prevents aerobic (to a greater extent) and resistance capacity impairments, ventricular dysfunction, baroreflex sensitivity and autonomic disorders (vagal tonus decrease and sympathetic tonus increase) triggered by myocardial infarction. Resistance training was able to prevent negative changes to aerobic and resistance capacity (to a greater extent) but not to ventricular dysfunction, and it prevented cardiovascular sympathetic increments. Additionally, both types of training reduced left ventricle inflammatory cytokine concentration. Our results suggest that aerobic and, for the first time, dynamic resistance training were able to reduce sympathetic tonus to the heart and vessels, as well as preventing the increase in pro-inflammatory cytokine concentrations in the left ventricle of trained groups. These data emphasizes the positive effects of aerobic and dynamic resistance training on the prevention of the negative changes triggered by myocardial infarction. © Georg Thieme Verlag KG Stuttgart · New York.

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

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

Watanabe, Tomoyuki; Saotome, Masao, E-mail: msaotome@hama-med.ac.jp; Nobuhara, Mamoru

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}),more » they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS failed to improve palmitate-induced insulin-resistance. • Mitochondrial dysfunction by lipid metabolites would induce insulin-resistance.« less

Splenic release of platelets contributes to increased circulating platelet size and inflammation after myocardial infarction.

PubMed

Gao, Xiao-Ming; Moore, Xiao-Lei; Liu, Yang; Wang, Xin-Yu; Han, Li-Ping; Su, Yidan; Tsai, Alan; Xu, Qi; Zhang, Ming; Lambert, Gavin W; Kiriazis, Helen; Gao, Wei; Dart, Anthony M; Du, Xiao-Jun

2016-07-01

Acute myocardial infarction (AMI) is characterized by a rapid increase in circulating platelet size but the mechanism for this is unclear. Large platelets are hyperactive and associated with adverse clinical outcomes. We determined mean platelet volume (MPV) and platelet-monocyte conjugation (PMC) using blood samples from patients, and blood and the spleen from mice with AMI. We further measured changes in platelet size, PMC, cardiac and splenic contents of platelets and leucocyte infiltration into the mouse heart. In AMI patients, circulating MPV and PMC increased at 1-3 h post-MI and MPV returned to reference levels within 24 h after admission. In mice with MI, increases in platelet size and PMC became evident within 12 h and were sustained up to 72 h. Splenic platelets are bigger than circulating platelets in normal or infarct mice. At 24 h post-MI, splenic platelet storage was halved whereas cardiac platelets increased by 4-fold. Splenectomy attenuated all changes observed in the blood, reduced leucocyte and platelet accumulation in the infarct myocardium, limited infarct size and alleviated cardiac dilatation and dysfunction. AMI-induced elevated circulating levels of adenosine diphosphate and catecholamines in both human and the mouse, which may trigger splenic platelet release. Pharmacological inhibition of angiotensin-converting enzyme, β1-adrenergic receptor or platelet P2Y12 receptor reduced platelet abundance in the murine infarct myocardium albeit having diverse effects on platelet size and PMC. In conclusion, AMI evokes release of splenic platelets, which contributes to the increase in platelet size and PMC and facilitates myocardial accumulation of platelets and leucocytes, thereby promoting post-infarct inflammation. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

PubMed

Li, Y Y; McTiernan, C F; Feldman, A M

2000-05-01

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

Sepsis-induced myocardial dysfunction and myocardial protection from ischemia/reperfusion injury.

PubMed

McDonough, Kathleen H; Virag, Jitka Ismail

2006-01-01

Sepsis, bacteremia and inflammation cause myocardial depression. The mechanism of the dysfunction is not clearly established partly because dysfunction can be elicited by many different mechanisms which can all manifest in disruption of myocardial mechanical function. In addition the models of sepsis and bacteremia and inflammation may vary drastically in the sequence of the coordinated immune response to the inflammatory or septic stimulus. Patterns of cytokine expression can vary as can other responses of the immune system. Patterns of neurohumoral activation in response to the stress of sepsis or bacteremia or inflammation can also vary in both magnitude of response and temporal sequence of response. Stress induced activation of the sympathetic nervous system and humoral responses to stress have a wide range of intensity that can be elicited. The fairly uniform response of the myocardium indicating cardiac dysfunction is surprisingly constant. Systolic performance, as measured by stroke volume or cardiac output and pressure work as estimated by ventricular pressure, are impaired when myocardial contraction is compromised. At times, diastolic function, assessed by ventricular relaxation and filling, is impaired. In addition to the dysfunction that occurs, there is a longer term response of the myocardium to sepsis, and this response is similar to that which is elicited in the heart by multiple brief ischemia/reperfusion episodes and by numerous pharmacological agents as well as heat stress and modified forms of lipopolysaccharide. The myocardium develops protection after an initial stress such that during a second stress, the myocardium does not exhibit as much damage as does a non-protected heart. Many agents can induce this protection which has been termed preconditioning. Both early preconditioning (protection that is measurable min to hours after the initial stimulus) and late preconditioning (protection that is measurable hours to days after the initial trigger or stimulus) are effective in protecting the heart from prolonged ischemia and reperfusion injury. Understanding the mechanisms of sepsis/bacteremia induced dysfunction and protection and if the dysfunction and protection are the products of the same intracellular pathways is important in protecting the heart from failing to perform adequately during severe sepsis and/or septic shock and for understanding the multitude of mechanism by which the myocardium maintains reserve capacity.

Myocardial dysfunction occurs prior to changes in ventricular geometry in mice with chronic kidney disease (CKD).

PubMed

Winterberg, Pamela D; Jiang, Rong; Maxwell, Josh T; Wang, Bo; Wagner, Mary B

2016-03-01

Uremic cardiomyopathy is responsible for high morbidity and mortality rates among patients with chronic kidney disease (CKD), but the underlying mechanisms contributing to this complex phenotype are incompletely understood. Myocardial deformation analyses (ventricular strain) of patients with mild CKD have recently been reported to predict adverse clinical outcome. We aimed to determine if early myocardial dysfunction in a mouse model of CKD could be detected using ventricular strain analyses. CKD was induced in 5-week-old male 129X1/SvJ mice through partial nephrectomy (5/6Nx) with age-matched mice undergoing bilateral sham surgeries serving as controls. Serial transthoracic echocardiography was performed over 16 weeks following induction of CKD. Invasive hemodynamic measurements were performed at 8 weeks. Gene expression and histology was performed on hearts at 8 and 16 weeks. CKD mice developed decreased longitudinal strain (-25 ± 4.2% vs. -29 ± 2.3%; P = 0.01) and diastolic dysfunction (E/A ratio 1.2 ± 0.15 vs. 1.9 ± 0.18; P < 0.001) compared to controls as early as 2 weeks following 5/6Nx. In contrast, ventricular hypertrophy was not apparent until 4 weeks. Hearts from CKD mice developed progressive fibrosis at 8 and 16 weeks with gene signatures suggestive of evolving heart failure with elevated expression of natriuretic peptides. Uremic cardiomyopathy in this model is characterized by early myocardial dysfunction which preceded observable changes in ventricular geometry. The model ultimately resulted in myocardial fibrosis and increased expression of natriuretic peptides suggestive of progressive heart failure. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-βl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

PubMed

Hong, Seul-Ki; Choo, Eun-Ho; Ihm, Sang-Hyun; Chang, Kiyuk; Seung, Ki-Bae

2017-11-01

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-βl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-β1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-β1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-β1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-β1-induced collagen production and TGF-β1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-β1 and Smad2/3 pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury

PubMed Central

Weinreuter, Martin; Kreusser, Michael M; Beckendorf, Jan; Schreiter, Friederike C; Leuschner, Florian; Lehmann, Lorenz H; Hofmann, Kai P; Rostosky, Julia S; Diemert, Nathalie; Xu, Chang; Volz, Hans Christian; Jungmann, Andreas; Nickel, Alexander; Sticht, Carsten; Gretz, Norbert; Maack, Christoph; Schneider, Michael D; Gröne, Hermann-Josef; Müller, Oliver J; Katus, Hugo A; Backs, Johannes

2014-01-01

CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes. PMID:25193973

Evaluation of mechanical dyssynchrony and myocardial perfusion using phase analysis of gated SPECT imaging in patients with left ventricular dysfunction

PubMed Central

Trimble, Mark A.; Borges-Neto, Salvador; Honeycutt, Emily F.; Shaw, Linda K.; Pagnanelli, Robert; Chen, Ji; Iskandrian, Ami E.; Garcia, Ernest V.; Velazquez, Eric J.

2010-01-01

Background Using phase analysis of gated single photon emission computed tomography (SPECT) imaging, we examined the relation between myocardial perfusion, degree of electrical dyssynchrony, and degree of SPECT-derived mechanical dyssynchrony in patients with left ventricular (LV) dysfunction. Methods and Results We retrospectively examined 125 patients with LV dysfunction and ejection fraction of 35% or lower. Fourier analysis converts regional myocardial counts into a continuous thickening function, allowing resolution of phase of onset of myocardial thickening. The SD of LV phase distribution (phase SD) and histogram bandwidth describe LV phase dispersion as a measure of dyssynchrony. Heart failure (HF) patients with perfusion abnormalities ities have higher degrees of dyssynchrony measured by median phase SD (45.5° vs 27.7°, P < .0001) and bandwidth (117.0° vs 73.0°, P = .0006). HF patients with prolonged QRS durations have higher degrees of dyssynchrony measured by median phase SD (54.1° vs 34.7°, P < .0001) and bandwidth (136.5° vs 99.0°, P = .0005). Mild to moderate correlations exist between QRS duration and phase analysis indices of phase SD (r = 0.50) and bandwidth (r = 0.40). Mechanical dyssynchrony (phase SD >43°) was 43.2%. Conclusions HF patients with perfusion abnormalities or prolonged QRS durations QRS durations have higher degrees of mechanical dyssynchrony. Gated SPECT myocardial perfusion imaging can quantify myocardial function, perfusion, and dyssynchrony and may help in evaluating patients for cardiac resynchronization therapy. PMID:18761269

Cardiomyocyte A Disintegrin And Metalloproteinase 17 (ADAM17) Is Essential in Post-Myocardial Infarction Repair by Regulating Angiogenesis.

PubMed

Fan, Dong; Takawale, Abhijit; Shen, Mengcheng; Wang, Wang; Wang, Xiuhua; Basu, Ratnadeep; Oudit, Gavin Y; Kassiri, Zamaneh

2015-09-01

A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme that mediates shedding of many membrane-bound molecules, thereby regulating multiple cellular responses. We investigated the role of cardiomyocyte ADAM17 in myocardial infarction (MI). Cardiomyocyte-specific ADAM17 knockdown mice (ADAM17(flox/flox)/α-MHC-Cre; f/f/Cre) and parallel controls (ADAM17(flox/flox); f/f) were subjected to MI by ligation of the left anterior descending artery. Post MI, f/f/Cre mice showed compromised survival, higher rates of cardiac rupture, more severe left ventricular dilation, and suppressed ejection fraction compared with parallel f/f-MI mice. Ex vivo ischemic injury (isolated hearts) resulted in comparable recovery in both genotypes. Myocardial vascular density (fluorescent-labeled lectin perfusion and CD31 immunofluorescence staining) was significantly lower in the infarct areas of f/f/Cre-MI compared with f/f-MI mice. Activation of vascular endothelial growth factor receptor 2 (VEGFR2), its mRNA, and total protein levels were reduced in infarcted myocardium in ADAM17 knockdown mice. Transcriptional regulation of VEGFR2 by ADAM17 was confirmed in cocultured cardiomyocyte-fibroblast as ischemia-induced VEGFR2 expression was blocked by ADAM17-siRNA. Meanwhile, ADAM17-siRNA did not alter VEGFA bioavailability in the conditioned media. ADAM17 knockdown mice (f/f/Cre-MI) exhibited reduced nuclear factor-κB activation (DNA binding) in the infarcted myocardium, which could underlie the suppressed VEGFR2 expression in these hearts. Post MI, inflammatory response was not altered by ADAM17 downregulation. This study highlights the key role of cardiomyocyte ADAM17 in post-MI recovery by regulating VEGFR2 transcription and angiogenesis, thereby limiting left ventricular dilation and dysfunction. Therefore, ADAM17 upregulation, within the physiological range, could provide protective effects in ischemic cardiomyopathy. © 2015 American Heart Association, Inc.

Heart involvement in cystic fibrosis: A specific cystic fibrosis-related myocardial changes?

PubMed

Labombarda, Fabien; Saloux, Eric; Brouard, Jacques; Bergot, Emmanuel; Milliez, Paul

2016-09-01

Cystic fibrosis is a complex multi-systemic chronic disease characterized by progressive organ dysfunction with development of fibrosis, possibly affecting the heart. Over the last four decades pathological, experimental, and clinical evidence points towards the existence of a specific myocardial involvement in cystic fibrosis. Multi-modality cardiac imaging, especially recent echocardiographic techniques, evidenced diastolic and/or systolic ventricular dysfunction in cystic fibrosis leading to the concept of a cystic fibrosis-related cardiomyopathy. Hypoxemia and inflammation are among the most important factors for heart involvement in cystic fibrosis. Cystic Fibrosis Transmembrane Regulator was found to be involved in the regulation of cardiomyocyte contraction and may also account for cystic fibrosis-related myocardial dysfunction. This review, mainly focused on echocardiographic studies, seeks to synthesize the existing literature for and against the existence of heart involvement in cystic fibrosis, its mechanisms and prognostic implications. Careful investigation of the heart function may be helpful for risk stratification and therapeutic decisions in patients with cystic fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Systems Biology and Biomechanical Model of Heart Failure

PubMed Central

Louridas, George E; Lourida, Katerina G

2012-01-01

Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. PMID:22935019

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

PubMed

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

2014-10-01

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

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

PubMed Central

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

2014-01-01

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

Protective effects of combination of quercetin and α-tocopherol on mitochondrial dysfunction and myocardial infarct size in isoproterenol-treated myocardial infarcted rats: biochemical, transmission electron microscopic, and macroscopic enzyme mapping evidences.

PubMed

Punithavathi, V R; Stanely Mainzen Prince, P

2010-01-01

Mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. We evaluated the combined protective effects of quercetin and α-tocopherol on mitochondrial damage and myocardial infarct size in isoproterenol-induced myocardia- infarcted rats. Rats were pretreated with quercetin (10 mg/kg) alone, α-tocopherol (10 mg/kg) alone, and combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) orally using an intragastric tube daily for 14 days. After pretreatment, rats were induced myocardial infarction by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Isoproterenol treatment caused significant increase in mitochondrial lipid peroxides with significant decrease in mitochondrial antioxidants. Significant decrease in the activities of isocitrate, succinate, malate, and α-ketoglutarate and NADH dehydrogenases and cytochrome-c-oxidase, significant increase in calcium, and significant decrease in adenosine triphosphate were observed in mitochondria of myocardial infarcted rats. Combined pretreatment with quercetin and α-tocopherol normalized all the biochemical parameters and preserved the integrity of heart tissue and restored normal mitochondrial function in myocardial-infarcted rats. Transmission electron microscopic findings on heart mitochondria and macroscopic enzyme mapping assay on the size of myocardial infarct also correlated with these biochemical parameters. The present study showed that combined pretreatment was highly effective than single pretreatment. Copyright 2010 Wiley Periodicals, Inc.

CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity.

PubMed

Cao, Li; Qin, Xing; Peterson, Matthew R; Haller, Samantha E; Wilson, Kayla A; Hu, Nan; Lin, Xin; Nair, Sreejayan; Ren, Jun; He, Guanglong

2016-03-01

Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction. C57BL/6 wild-type (WT) and CARD9(-/-) mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling. In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart. Copyright © 2016 Elsevier Ltd. All rights reserved.

NDUFA4L2 protects against ischaemia/reperfusion-induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I.

PubMed

Li, Jianhua; Bai, Caiyan; Guo, Junxia; Liang, Wanqian; Long, Jingning

2017-07-01

Myocardial ischaemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as mitochondrial dysfunction. The aims of the present study were to investigate whether NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) on myocardial ischaemia-reperfusion (I/R) injury and the underlying molecular mechanism. The hypoxia-reperfusion (H/R) model was established in vitro using H9c2 cells to simulate I/R injury. NDUFA4L2 and complex I expression levels were detected using RT-PCR and western blot. The apoptosis of H9c2 cells was evaluated by flow cytometry and the expression of Bax and Bcl-2 was detected by western blot. The mitochondrial function was assessed by ATP concentration, mPTP opening and cytochrome c (cyto C) expression. Our data indicated that NDUFA4L2 expression was significantly down-regulated in myocardial H/R injury. Overexpression of NDUFA4L2 led to a dramatic prevention of H/R-induced apoptosis accompanied by a decrease in the expression of Bax and an increase in the expression of Bcl-2. Meanwhile, augmentation of NDUFA4L2 dramatically prevented mitochondrial dysfunction caused by H/R as reflecting in the increased ATP concentration, delayed mPTP opening, as well as down-regulated cyto C expression. Moreover, complex I activation was heightened and negatively regulated by NDUFA4L2. Silencing complex I conspicuously attenuated cell apoptosis and mitochondrial dysfunction. Taken together, our findings demonstrated that NDUFA4L2 protects against H/R injury by preventing myocardium apoptosis and mitochondrial dysfunction via the complex I, and may be a potential therapeutic approach for attenuating myocardial I/R injury. © 2017 John Wiley & Sons Australia, Ltd.

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

PubMed

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

2016-07-01

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

Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis.

PubMed

Kim, Jin Sug; Kim, Weon; Park, Ji Yoon; Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyun; Moon, Ju-Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2017-01-01

Lipid lowering therapy is widely used for the prevention of cardiovascular complications after acute myocardial infarction (AMI). However, some studies show that this benefit is uncertain in patients with renal dysfunction, and the role of statins is based on the severity of renal dysfunction. In this study, we investigated the impact of statin therapy on major adverse cardiac events (MACEs) and all-cause mortality in patients with advanced renal dysfunction undergoing percutaneous coronary intervention (PCI) after AMI. This study was based on the Korea Acute Myocardial Infarction Registry database. We included 861 patients with advanced renal dysfunction from among 33,205 patients who underwent PCI after AMI between November 2005 and July 2012. Patients were divided into two groups: a statin group (n = 537) and a no-statin group (n = 324). We investigated the 12-month MACEs (cardiac death, myocardial infarction, repeated PCI or coronary artery bypass grafting) and all-cause mortality of each group. Subsequently, a propensity score-matched analysis was performed. In the total population studied, no significant differences were observed between the two groups with respect to the rate of recurrent MI, repeated PCI, coronary artery bypass grafting (CABG), or all-cause mortality. However, the cardiac death rate was significantly lower in the statin group (p = 0.009). Propensity score-matched analysis yielded 274 pairs demonstrating, results similar to those obtained from the total population. However, there was no significant difference in the cardiac death rate in the propensity score-matched population (p = 0.103). Cox-regression analysis revealed only left ventricular ejection fraction to be an independent predictor of 12-month MACEs (Hazard ratio [HR] of 0.979, 95% confidence interval [CI], 0962-0.996, p = 0.018). Statin therapy was not significantly associated with a reduction in the 12-month MACEs or all-cause mortality in patients with advanced renal dysfunction undergoing PCI after AMI.

Chronic Kidney Disease Exacerbates Myocardial Ischemia Reperfusion Injury: Role of Endoplasmic Reticulum Stress-Mediated Apoptosis.

PubMed

Guo, Junjie; Zhu, Jianbing; Ma, Leilei; Shi, Hongtao; Hu, Jiachang; Zhang, Shuning; Hou, Lei; Xu, Fengqiang; An, Yi; Yu, Haichu; Ge, Junbo

2018-06-01

Chronic kidney disease (CKD) is known to exacerbate myocardial ischemia reperfusion (IR) injury. However, the underlying mechanisms are still not well understood. Despite various strategies for cardioprotection, limited studies have been focused on the prevention of CKD-induced myocardial susceptibility to IR injury. Here, we hypothesized that excessive endoplasmic reticulum (ER) stress-mediated apoptosis involved in myocardial IR injury in CKD mice and pretreatment with chemical ER chaperone rendered the heart resistant to myocardial IR injury in the setting of CKD. CKD was induced by 5/6 subtotal nephrectomy (SN) in mice, whereas sham-operated mice served as control (Sham). CKD significantly aggravated the cardiac injury after IR in SN group than Sham group as reflected by more severe cardiac dysfunction, increased myocardial infarct size and the ratio of myocardial apoptosis. The expression of ER stress-mediated apoptotic proteins (Bcl-2 associated X protein (Bax), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12) was markedly upregulated after IR injury in SN group than Sham group, whereas the expression of anti-apoptotic protein, Bcl-2, was obviously downregulated. In addition, the chemical ER chaperone sodium 4-phenylbutyrate (4PBA) pretreatment ameliorated cardiac dysfunction and lessened the infarct size and myocardial apoptosis after IR injury in mice with CKD. Taken together, these findings demonstrated that excessive activation of ER stress-mediated apoptosis pathway involved in the CKD-induced myocardial susceptibility to IR injury, and chemical ER chaperone 4PBA alleviated myocardial IR injury in mice with CKD.

Levosimendan reduces myocardial damage and improves cardiodynamics in streptozotocin induced diabetic cardiomyopathy via SERCA2a/NCX1 pathway.

PubMed

Akhtar, Md Sayeed; Pillai, Krishna Kolappa; Hassan, Md Quamrul; Dhyani, Neha; Ismail, Md Vasim; Najmi, Abul Kalam

2016-05-15

Diabetic cardiomyopathy (DCM) is one of the most common causes of mortality. Its pathophysiology is not fully understood and involve number of factors including, cardiovascular and metabolic disorders. The present study was designed to study the pathogenesis of DCM and to explore the effects of levosimendan along with either ramipril or insulin in the long term management of DCM. Streptozotocin (STZ) was used to develop DCM in Wistar rats at the dose of 25mg/kg body weight for three consecutive days. Rats were randomly divided into 9 groups and treatments were started after 2weeks of STZ administration. Persistent hyperglycemia was observed in STZ treated rats, leading to significant contractile dysfunction as evidenced by decreased left ventricular pressure (LVP), +LV (dp/dt), -LV (dp/dt) as well as elevated Tau and LVEDP. Marked myocardial damage such as fibrosis, increased wall tension, depletion of contractile proteins were observed as evidenced by increased levels of TGF-β, BNP, cTroponin-I, as well as decreased expression of SERCA2a and NCX1 proteins in diabetic rats. The levosimendan alone and also in combination with either ramipril or insulin significantly normalized the myocardial dysfunctions developed during the course of persistent hyperglycemia. The study suggests that levosimendan treatment improves cardiac dysfunction significantly. Its combined use with ramipril proves better than with insulin in correcting myocardial performance as well as reduction in myocardial damage. Copyright © 2016 Elsevier Inc. All rights reserved.

Forgetting heart break: a fascinating case of transient left ventricular apical ballooning syndrome associated with dissociative amnesia.

PubMed

Toussi, Amir; Bryk, Jodie; Alam, Abdulkader

2014-01-01

Transient left ventricular apical ballooning syndrome (TLVABS), also known as takotsubo cardiomyopathy, is characterized by transient left ventricular dysfunction, electrocardiographic changes, and release of myocardial enzymes that mimic acute myocardial infarction in patients without angiographic evidence of coronary artery disease. Most patients are post-menopausal women and an emotional or physiologic stressor frequently precedes the presentation. Psychogenic or dissociative amnesia is a memory disorder characterized by sudden retrograde memory loss with inability to recall personal information said to occur for a period of time ranging from hours to years after a stressful event. Interestingly, the mechanism of both disorders has been linked to plasma elevation in catecholamines. Here we present the case of a 66-year-old female diagnosed with both TLVABS and dissociative amnesia following the sudden unexpected death of her sister. To our knowledge, this is surprisingly the first report of the co-occurrence of TLVABS and dissociative amnesia, two processes with a potential shared underlying etiology. © 2013.

Experimental Myocardial Infarction Upregulates Circulating Fibroblast Growth Factor-23.

PubMed

Andrukhova, Olena; Slavic, Svetlana; Odörfer, Kathrin I; Erben, Reinhold G

2015-10-01

Myocardial infarction (MI) is a major cause of death worldwide. Epidemiological studies have linked vitamin D deficiency to MI incidence. Because fibroblast growth factor-23 (FGF23) is a master regulator of vitamin D hormone production and has been shown to be associated with cardiac hypertrophy per se, we explored the hypothesis that FGF23 may be a previously unrecognized pathophysiological factor causally linked to progression of cardiac dysfunction post-MI. Here, we show that circulating intact Fgf23 was profoundly elevated, whereas serum vitamin D hormone levels were suppressed, after induction of experimental MI in rat and mouse models, independent of changes in serum soluble Klotho or serum parathyroid hormone. Both skeletal and cardiac expression of Fgf23 was increased after MI. Although the molecular link between the cardiac lesion and circulating Fgf23 concentrations remains to be identified, our study has uncovered a novel heart-bone-kidney axis that may have important clinical implications and may inaugurate the new field of cardio-osteology. © 2015 American Society for Bone and Mineral Research.

Tissue Doppler imaging for detection of radial and longitudinal myocardial dysfunction in a family of cats affected by dystrophin-deficient hypertrophic muscular dystrophy.

PubMed

Chetboul, Valérie; Blot, Stephane; Sampedrano, Carolina Carlos; Thibaud, Jean-Laurent; Granger, Nicolas; Tissier, Renaud; Bruneval, Patrick; Gaschen, Frederic; Gouni, Vassiliki; Nicolle, Audrey P; Pouchelon, Jean-Louis

2006-01-01

Diagnosis of feline hypertrophic cardiomyopathy currently is based on the presence of myocardial hypertrophy detected using conventional echocardiography. The accuracy of tissue Doppler imaging (TDI) for earlier detection of the disease has never been described. The objective of this sudy was to quantify left ventricular free wall (LVFW) velocities in cats with hypertrophic muscular dystrophy (HFMD) during preclinical cardiomyopathy using TDI. The study animals included 22 healthy controls and 7 cats belonging to a family of cats with HFMD (2 affected adult males, 2 heterozygous adult females, one 2.5-month-old affected male kitten, and 2 phenotypically normal female kittens from the same litter). All cats were examined via conventional echocardiography and 2-dimensional color TDI. No LVFW hypertrophy was detected in the 2 carriers or in the affected kitten when using conventional echocardiography and histologic examination, respectively. The LVFW also was normal for 1 affected male and at the upper limit of normal for the 2nd male. Conversely, LVFW dysfunction was detected in all affected and carrier cats with HFMD when using TDI. TDI consistently detects LVFW dysfunction in cats with HFMD despite the absence of myocardial hypertrophy. Therefore, TDI appears more sensitive than conventional echocardiography in detecting regional myocardial abnormalities.

Assessment of left ventricular functions and myocardial iron load with tissue Doppler and speckle tracking echocardiography and T2* MRI in patients with β-thalassemia major.

PubMed

Ari, Mehmet Emre; Ekici, Filiz; Çetin, İbrahim İlker; Tavil, Emine Betül; Yaralı, Neşe; Işık, Pamir; Hazırolan, Tuncay; Tunç, Bahattin

2017-03-01

The purpose of this study is to determine early myocardial dysfunction in β-thalassemia major (BTM) patients. Where the myocardial dysfunction cannot be detected by conventional echocardiography, it could be detected by tissue Doppler imaging (TDI) or speckle tracking echocardiography (STE). In this study, we analyzed 60 individuals, 30 of whom were BTM patients and the other 30 of whom were the control group. T2* magnetic resonance imaging (MRI) was used to measure cardiac iron deposition. The myocardial functions were evaluated by conventional echocardiography, TDI and STE. When basal lateral left ventricular and basal septal wall TDI values were compared between the patient group and control group, only isovolumic contraction time values were significantly longer in the patients. The global circumferential strain was significantly lower in the patients. When evaluated as segmental, longitudinal strain values of basal inferoseptum and circumferential strain values of anteroseptum, anterior, and inferolateral segments were significantly lower in the patients. In the patients, global longitudinal and circumferential strains in the group who had pathological T2* values were significantly lower than the group who did not. In addition, circumferential strain values in anteroseptum, anterolateral, inferior, and inferoseptum segments were significantly lower in the patients with T2* values<20 ms than those with T2* values≥20 ms. Although T2* MRI is the most sensitive test detecting myocardial iron load, TDI and STE can be used for screening myocardial dysfunction. The abnormal strain values, especially circumferential, may be detected as the first finding of abnormal iron load and related to T2* values. © 2017, Wiley Periodicals, Inc.

Females Are Protected From Iron-Overload Cardiomyopathy Independent of Iron Metabolism: Key Role of Oxidative Stress.

PubMed

Das, Subhash K; Patel, Vaibhav B; Basu, Ratnadeep; Wang, Wang; DesAulniers, Jessica; Kassiri, Zamaneh; Oudit, Gavin Y

2017-01-23

Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood. Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury. Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17β-estradiol therapy was protective in male iron-overloaded mice. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Myocardial Rupture in Acute Myocardial Infarction: Mechanistic Explanation Based on the Ventricular Myocardial Band Hypothesis.

PubMed

Vargas-Barron, Jesús; Antunez-Montes, Omar-Yassef; Roldán, Francisco-Javier; Aranda-Frausto, Alberto; González-Pacheco, Hector; Romero-Cardenas, Ángel; Zabalgoitia, Miguel

2015-01-01

Torrent-Guasp explains the structure of the ventricular myocardium by means of a helical muscular band. Our primary purpose was to demonstrate the utility of echocardiography in human and porcine hearts in identifying the segments of the myocardial band. The second purpose was to evaluate the relation of the topographic distribution of the myocardial band with some post-myocardial infarction ruptures. Five porcine and one human heart without cardiopathy were dissected and the ventricular myocardial segments were color-coded for illustration and reconstruction purposes. These segments were then correlated to the conventional echocardiographic images. Afterwards in three cases with post-myocardial infarction rupture, a correlation of the topographic location of the rupture with the distribution of the ventricular band was made. The human ventricular band does not show any differences from the porcine band, which confirms the similarities of the four segments; these segments could be identified by echocardiography. In three cases with myocardial rupture, a correlation of the intra-myocardial dissection with the distribution of the ventricular band was observed. Echocardiography is helpful in identifying the myocardial band segments as well as the correlation with the topographic distribution of some myocardial post-infarction ruptures.

Daily exercise prevents diastolic dysfunction and oxidative stress in a female mouse model of western diet induced obesity by maintaining cardiac heme oxygenase-1 levels.

PubMed

Bostick, Brian; Aroor, Annayya R; Habibi, Javad; Durante, William; Ma, Lixin; DeMarco, Vincent G; Garro, Mona; Hayden, Melvin R; Booth, Frank W; Sowers, James R

2017-01-01

Obesity is a global epidemic with profound cardiovascular disease (CVD) complications. Obese women are particularly vulnerable to CVD, suffering higher rates of CVD compared to non-obese females. Diastolic dysfunction is the earliest manifestation of CVD in obese women but remains poorly understood with no evidence-based therapies. We have shown early diastolic dysfunction in obesity is associated with oxidative stress and myocardial fibrosis. Recent evidence suggests exercise may increase levels of the antioxidant heme oxygenase-1 (HO-1). Accordingly, we hypothesized that diastolic dysfunction in female mice consuming a western diet (WD) could be prevented by daily volitional exercise with reductions in oxidative stress, myocardial fibrosis and maintenance of myocardial HO-1 levels. Four-week-old female C57BL/6J mice were fed a high-fat/high-fructose WD for 16weeks (N=8) alongside control diet fed mice (N=8). A separate cohort of WD fed females was allowed a running wheel for the entire study (N=7). Cardiac function was assessed at 20weeks by high-resolution cardiac magnetic resonance imaging (MRI). Functional assessment was followed by immunohistochemistry, transmission electron microscopy (TEM) and Western blotting to identify pathologic mechanisms and assess HO-1 protein levels. There was no significant body weight decrease in exercising mice, normalized body weight 14.3g/mm, compared to sedentary mice, normalized body weight 13.6g/mm (p=0.38). Total body fat was also unchanged in exercising, fat mass of 6.6g, compared to sedentary mice, fat mass 7.4g (p=0.55). Exercise prevented diastolic dysfunction with a significant reduction in left ventricular relaxation time to 23.8ms for exercising group compared to 33.0ms in sedentary group (p<0.01). Exercise markedly reduced oxidative stress and myocardial fibrosis with improved mitochondrial architecture. HO-1 protein levels were increased in the hearts of exercising mice compared to sedentary WD fed females. This study provides seminal evidence that exercise can prevent diastolic dysfunction in WD-induced obesity in females even without changes in body weight. Furthermore, the reduction in myocardial oxidative stress and fibrosis and improved HO-1 levels in exercising mice suggests a novel mechanism for the antioxidant effect of exercise. Copyright © 2016 Elsevier Inc. All rights reserved.

Intracoronary artery transplantation of cardiomyoblast-like cells from human adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction and survival in a swine model of chronic myocardial infarction

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

Okura, Hanayuki; Department of Somatic Stem Cell Therapy and Health Policy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047; Saga, Ayami

Highlights: Black-Right-Pointing-Pointer We administered human CLCs in a swine model of MI via intracoronary artery. Black-Right-Pointing-Pointer Histological studies demonstrated engraftment of hCLCs into the scarred myocardium. Black-Right-Pointing-Pointer Echocardiography showed rescue of cardiac function in the hCLCs transplanted swine. Black-Right-Pointing-Pointer Transplantation of hCLCs is an effective therapeutics for cardiac regeneration. -- Abstract: Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose tissue-derived multi-lineage progenitor cells improved left ventricular function and survival of rats with myocardial infarction. Here we examined the effect of intracoronary artery transplantation of human CLCs in a swine model of chronic heart failure. Twenty-four pigs underwent balloon-occlusion ofmore » the first diagonal branch followed by reperfusion, with a second balloon-occlusion of the left ascending coronary artery 1 week later followed by reperfusion. Four weeks after the second occlusion/reperfusion, 17 of the 18 surviving animals with severe chronic MI (ejection fraction <35% by echocardiography) were immunosuppressed then randomly assigned to receive either intracoronary artery transplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with heparin. Intracoronary artery transplantation was followed by the distribution of DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at post-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac function in the hCLCs transplanted group, but not in the control animals, indicating myocardial functional recovery by hCLCs intracoronary transplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted animals were still alive compared with only 1 of the 5 control (p = 0.0147). Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of human specific alpha-cardiac actin. Human alpha cardiac actin-positive cells also expressed cardiac nuclear factors; nkx2.5 and GATA-4. Our results suggest that intracoronary artery transplantation of hCLCs is a potentially effective therapeutic strategy for future cardiac tissue regeneration.« less

Evaluation of structural remodeling of the atria with OCT in a chronic rat model of myocardial infarction (Conference Presentation)

NASA Astrophysics Data System (ADS)

Eberle, Melissa M.; Thorn, Stephanie; Young, Lawerence; Pfau, Daniel; Madwed, Jeffrey; Small, Kersten; Kilmas, Michael; Choma, Michael A.; Sinusas, Albert J.

2017-02-01

Atrial fibrillation (AF) occurs following myocardial infarction (MI) and is associated with left ventricular dysfunction, which promotes the development of atrial remodeling and permanent atrial fibrosis. The purpose of this study was determining the effects of MI on left atrial (LA) remodeling with and without therapy with an angiotensin converting enzyme inhibition (ACEi) utilizing optical coherence tomography (OCT). As the composition of the myocardial tissue changes during LA remodeling the optical attenuation of the light will also change providing a metric to quantify the structural remodeling process. Lewis rats (240-275 g) underwent either surgical ligation of left coronary artery creating chronic MI, or SHAM surgery. 13 weeks post-surgery, ex vivo OCT imaging was performed of the LA appendage. Depth-resolved, attenuation coefficient volumes were calculated and the resulting atrial wall attenuation values were analyzed for four experimental groups: SHAM, SHAM with ACEi, MI no ACEi, and MI with ACEi. Quantification of tissue attenuation was performed and shown to significantly increase with MI in association with increases in collagen as verified with corresponding histological sectioning. Fractal analysis of the LA wall trabeculation patterns, 100 µm below the surface, was performed to quantify wall thickening associated with LA remodeling. A significant increase in fractal dimension was determined post MI compared to SHAM corresponding to a loss of the trabeculation pattern and wall thickening. The results from this study demonstrate OCT as an imaging technique capable of investigate LA remodeling with high resolution and label-free optical contrast processing.

Simultaneous assessment of myocardial perfusion and function during mental stress in patients with chronic coronary artery disease.

PubMed

Arrighi, James A; Burg, Matthew; Cohen, Ira S; Soufer, Robert

2003-01-01

Mental stress (MS) is an important provocateur of myocardial ischemia in many patients with chronic coronary artery disease. The majority of laboratory assessments of ischemia in response to MS have included measurements of either myocardial perfusion or function alone. We performed this study to determine the relationship between alterations in perfusion and ventricular function during MS. Methods and results Twenty-eight patients with reversible perfusion defects on exercise or pharmacologic stress myocardial perfusion imaging (MPI) underwent simultaneous technetium 99m sestamibi single photon emission computed tomography (SPECT) MPI and transthoracic echocardiography at rest and during MS according to a mental arithmetic protocol. In all cases the MS study was performed within 4 weeks of the initial exercise or pharmacologic MPI that demonstrated ischemia. SPECT studies were analyzed visually with the use of a 13-segment model and quantitatively by semiautomated circumferential profile analysis. Echocardiograms were graded on a segmental model for regional wall motion on a 4-point scale. Of 28 patients, 18 (64%) had perfusion defects and/or left ventricular dysfunction develop during MS: 9 (32%) had myocardial perfusion defects develop, 6 (21%) had regional or global left ventricular dysfunction develop, and 3 (11%) had both perfusion defects and left ventricular dysfunction develop. The overall concordance between perfusion and function criteria for ischemia during MS was only 46%. Among 9 patients with MS-induced left ventricular dysfunction, 5 had new regional wall motion abnormalities and 4 had a global decrement in function. In patients with MS-induced ischemia by SPECT, the number of reversible perfusion defects was similar during both MS and exercise/pharmacologic stress (2.8 +/- 2.0 vs 3.5 +/- 1.8, P =.41). Hemodynamic changes during MS were similar whether patients were divided on the basis of perfusion defects or left ventricular dysfunction during MS. These data indicate the feasibility of simultaneous assessment of perfusion and function responses during MS. Flow and function responses to MS are frequently not concordant. These data suggest that MS-induced changes in perfusion may represent a different phenomenon than MS-induced changes in left ventricular function (either globally or regionally).

Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction.

PubMed

Halade, Ganesh V; Kain, Vasundhara; Black, Laurence M; Prabhu, Sumanth D; Ingle, Kevin A

2016-10-18

Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO-fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11b low /F480 high and CD11b high /F480 high ) with increased pro-inflammatory (CD11bp + F4/80 + Ly6C hi ) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-α and IL-1β indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non-resolving microenvironment in aging.

Aging dysregulates D- and E-series resolvins to modulate cardiosplenic and cardiorenal network following myocardial infarction

PubMed Central

Halade, Ganesh V.; Kain, Vasundhara; Black, Laurence M.; Prabhu, Sumanth D.; Ingle, Kevin A.

2016-01-01

Post-myocardial infarction (MI), overactive inflammation is the hallmark of aging, however, the mechanism is unclear. We hypothesized that excess influx of omega 6 fatty acids may impair resolution, thus impacting the cardiosplenic and cardiorenal network post-MI. Young and aging mice were fed on standard lab chow (LC) and excess fatty acid (safflower oil; SO)-enriched diet for 2 months and were then subjected to MI surgery. Despite similar infarct areas and left ventricle (LV) dysfunction post-MI, splenic mass spectrometry data revealed higher levels of arachidonic acid (AA) derived pro-inflammatory metabolites in young-SO, but minimal formation of docosanoids, D- and E- series resolvins in SO-fed aged mice. The aged mice receiving excess intake of fatty acids exhibit; 1) decreased lipoxygenases (5-,12-, and 15) in the infarcted LV; 2) lower levels of 14HDHA, RvD1, RvD5, protectin D1, 7(S)maresin1, 8-,11-,18-HEPE and RvE3 with high levels of tetranor-12-HETEs; 3) dual population of macrophages (CD11blow/F480high and CD11bhigh/F480high) with increased pro-inflammatory (CD11b+F4/80+Ly6Chi) phenotype and; 4) increased kidney injury marker NGAL with increased expression of TNF-ɑ and IL-1β indicating MI-induced non-resolving response compared with LC-group. Thus, excess fatty acid intake magnifies the post-MI chemokine signaling and inflames the cardiosplenic and cardiorenal network towards a non-resolving microenvironment in aging. PMID:27777380

Aerobic exercise training rescues cardiac protein quality control and blunts endoplasmic reticulum stress in heart failure rats.

PubMed

Bozi, Luiz H M; Jannig, Paulo R; Rolim, Natale; Voltarelli, Vanessa A; Dourado, Paulo M M; Wisløff, Ulrik; Brum, Patricia C

2016-11-01

Cardiac endoplasmic reticulum (ER) stress through accumulation of misfolded proteins plays a pivotal role in cardiovascular diseases. In an attempt to reestablish ER homoeostasis, the unfolded protein response (UPR) is activated. However, if ER stress persists, sustained UPR activation leads to apoptosis. There is no available therapy for ER stress relief. Considering that aerobic exercise training (AET) attenuates oxidative stress, mitochondrial dysfunction and calcium imbalance, it may be a potential strategy to reestablish cardiac ER homoeostasis. We test the hypothesis that AET would attenuate impaired cardiac ER stress after myocardial infarction (MI). Wistar rats underwent to either MI or sham surgeries. Four weeks later, rats underwent to 8 weeks of moderate-intensity AET. Myocardial infarction rats displayed cardiac dysfunction and lung oedema, suggesting heart failure. Cardiac dysfunction in MI rats was paralleled by increased protein levels of UPR markers (GRP78, DERLIN-1 and CHOP), accumulation of misfolded and polyubiquitinated proteins, and reduced chymotrypsin-like proteasome activity. These results suggest an impaired cardiac protein quality control. Aerobic exercise training improved exercise capacity and cardiac function of MI animals. Interestingly, AET blunted MI-induced ER stress by reducing protein levels of UPR markers, and accumulation of both misfolded and polyubiquinated proteins, which was associated with restored proteasome activity. Taken together, our study provide evidence for AET attenuation of ER stress through the reestablishment of cardiac protein quality control, which contributes to better cardiac function in post-MI heart failure rats. These results reinforce the importance of AET as primary non-pharmacological therapy to cardiovascular disease. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Depressive disorder and gastrointestinal dysfunction after myocardial infarct are associated with abnormal tryptophan-5-hydroxytryptamine metabolism in rats

PubMed Central

Liu, Chunyan; Wang, Yangang

2017-01-01

In this study, we investigated the relationship between tryptophan-5-hydroxytryptamine metabolism, depressive disorder, and gastrointestinal dysfunction in rats after myocardial infarction. Our goal was to elucidate the physiopathologic bases of somatic/psychiatric depression symptoms after myocardial infarction. A myocardial infarction model was established by permanent occlusion of the left anterior descending coronary artery. Depression-like behavior was evaluated using the sucrose preference test, open field test, and forced swim test. Gastric retention and intestinal transit were detected using the carbon powder labeling method. Immunohistochemical staining was used to detect indoleamine 2,3-dioxygenase expression in the hippocampus and ileum. High-performance liquid chromatography with fluorescence and ultraviolet detection determined the levels of 5-hydroxytryptamine, its precursor tryptophan, and its metabolite 5-hydroxyindoleacetic acid in the hippocampus, distal ileum, and peripheral blood. All data were analyzed using one-way analyses of variance. Three weeks after arterial occlusion, rats in the model group began to exhibit depression-like symptoms. For example, the rate of sucrose consumption was reduced, the total and central distance traveled in the open field test were reduced, and immobility time was increased, while swimming, struggling and latency to immobility were decreased in the forced swim test. Moreover, the gastric retention rate and gastrointestinal transit rate were increased in the model group. Expression of indoleamine 2,3-dioxygenase was increased in the hippocampus and ileum, whereas 5-hydroxytryptamine metabolism was decreased, resulting in lower 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels in the hippocampus and higher levels in the ileum. Depressive disorder and gastrointestinal dysfunction after myocardial infarction involve abnormal tryptophan-5-hydroxytryptamine metabolism, which may explain the somatic, cognitive, and psychiatric symptoms of depression commonly observed after myocardial infarction. Peripheral 5-hydroxytryptamine is an important substance in the gut-brain axis, and its abnormal metabolism is a critical finding after myocardial infarct. PMID:28212441

Depressive disorder and gastrointestinal dysfunction after myocardial infarct are associated with abnormal tryptophan-5-hydroxytryptamine metabolism in rats.

PubMed

Lu, Xiaofang; Wang, Yuefen; Liu, Chunyan; Wang, Yangang

2017-01-01

In this study, we investigated the relationship between tryptophan-5-hydroxytryptamine metabolism, depressive disorder, and gastrointestinal dysfunction in rats after myocardial infarction. Our goal was to elucidate the physiopathologic bases of somatic/psychiatric depression symptoms after myocardial infarction. A myocardial infarction model was established by permanent occlusion of the left anterior descending coronary artery. Depression-like behavior was evaluated using the sucrose preference test, open field test, and forced swim test. Gastric retention and intestinal transit were detected using the carbon powder labeling method. Immunohistochemical staining was used to detect indoleamine 2,3-dioxygenase expression in the hippocampus and ileum. High-performance liquid chromatography with fluorescence and ultraviolet detection determined the levels of 5-hydroxytryptamine, its precursor tryptophan, and its metabolite 5-hydroxyindoleacetic acid in the hippocampus, distal ileum, and peripheral blood. All data were analyzed using one-way analyses of variance. Three weeks after arterial occlusion, rats in the model group began to exhibit depression-like symptoms. For example, the rate of sucrose consumption was reduced, the total and central distance traveled in the open field test were reduced, and immobility time was increased, while swimming, struggling and latency to immobility were decreased in the forced swim test. Moreover, the gastric retention rate and gastrointestinal transit rate were increased in the model group. Expression of indoleamine 2,3-dioxygenase was increased in the hippocampus and ileum, whereas 5-hydroxytryptamine metabolism was decreased, resulting in lower 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels in the hippocampus and higher levels in the ileum. Depressive disorder and gastrointestinal dysfunction after myocardial infarction involve abnormal tryptophan-5-hydroxytryptamine metabolism, which may explain the somatic, cognitive, and psychiatric symptoms of depression commonly observed after myocardial infarction. Peripheral 5-hydroxytryptamine is an important substance in the gut-brain axis, and its abnormal metabolism is a critical finding after myocardial infarct.

Selective Cerebro-Myocardial Perfusion in Complex Neonatal Aortic Arch Pathology: Midterm Results.

PubMed

Hoxha, Stiljan; Abbasciano, Riccardo Giuseppe; Sandrini, Camilla; Rossetti, Lucia; Menon, Tiziano; Barozzi, Luca; Linardi, Daniele; Rungatscher, Alessio; Faggian, Giuseppe; Luciani, Giovanni Battista

2018-04-01

Aortic arch repair in newborns and infants has traditionally been accomplished using a period of deep hypothermic circulatory arrest. To reduce neurologic and cardiac dysfunction related to circulatory arrest and myocardial ischemia during complex aortic arch surgery, an alternative and novel strategy for cerebro-myocardial protection was recently developed, where regional low-flow perfusion is combined with controlled and independent coronary perfusion. The aim of the present retrospective study was to assess short-term and mid-term results of selective and independent cerebro-myocardial perfusion in neonatal aortic arch surgery. From April 2008 to August 2015, 28 consecutive neonates underwent aortic arch surgery under cerebro-myocardial perfusion. There were 17 male and 11 female, with median age of 15 days (3-30 days) and median body weight of 3 kg (1.6-4.2 kg), 9 (32%) of whom with low body weight (<2.5 kg). The spectrum of pathologies treated was heterogeneous and included 13 neonates having single-stage biventricular repair (46%), 7 staged biventricular repair (25%), and 8 single-ventricle repair (29%). All operations were performed under moderate hypothermia and with a "beating heart and brain." Average cardiopulmonary bypass time was 131 ± 64 min (42-310 min). A period of cardiac arrest to complete intra-cardiac repair was required in nine patients (32%), and circulatory arrest in 1 to repair total anomalous pulmonary venous connection. Average time of splanchnic ischemia during cerebro-myocardial perfusion was 30 ± 11 min (15-69 min). Renal dysfunction, requiring a period of peritoneal dialysis was observed in 10 (36%) patients, while liver dysfunction was noted only in 3 (11%). There were three (11%) early and two late deaths during a median follow-up of 2.9 years (range 6 months-7.7 years), with an actuarial survival of 82% at 7 years. At latest follow-up, no patient showed signs of cardiac or neurologic dysfunction. The present experience shows that a strategy of selective and independent cerebro-myocardial perfusion is safe, versatile, and feasible in high-risk neonates with complex congenital arch pathology. Encouraging outcomes were noted in terms of cardiac and neurological function, with limited end-organ morbidity. © 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Mechanistic insights and characterization of sickle cell disease-associated cardiomyopathy.

PubMed

Desai, Ankit A; Patel, Amit R; Ahmad, Homaa; Groth, John V; Thiruvoipati, Thejasvi; Turner, Kristen; Yodwut, Chattanong; Czobor, Peter; Artz, Nicole; Machado, Roberto F; Garcia, Joe G N; Lang, Roberto M

2014-05-01

Cardiovascular disease is an important cause of morbidity and mortality in sickle cell disease (SCD). We sought to characterize sickle cell cardiomyopathy using multimodality noninvasive cardiovascular testing and identify potential causative mechanisms. Stable adults with SCD (n=38) and healthy controls (n=13) prospectively underwent same day multiparametric cardiovascular magnetic resonance (cine, T2* iron, vasodilator first pass myocardial perfusion, and late gadolinium enhancement imaging), transthoracic echocardiography, and applanation tonometry. Compared with controls, patients with SCD had severe dilation of the left ventricle (124±27 vs 79±12 mL/m(2)), right ventricle (127±28 vs 83±14 mL/m(2)), left atrium (65±16 vs 41±9 mL/m(2)), and right atrium (78±17 vs 56±17 mL/m(2); P<0.01 for all). Patients with SCD also had a 21% lower myocardial perfusion reserve index than control subjects (1.47±0.34 vs 1.87±0.37; P=0.034). A significant subset of patients with SCD (25%) had evidence of late gadolinium enhancement, whereas only 1 patient had evidence of myocardial iron overload. Diastolic dysfunction was present in 26% of patients with SCD compared with 8% in controls. Estimated filling pressures (E/e', 9.3±2.7 vs 7.3±2.0; P=0.0288) were higher in patients with SCD. Left ventricular dilation and the presence of late gadolinium enhancement were inversely correlated to hepatic T2* times (ie, hepatic iron overload because of frequent blood transfusions; P<0.05 for both), whereas diastolic dysfunction and increased filling pressures were correlated to aortic stiffness (augmentation pressure and index, P<0.05 for all). Sickle cell cardiomyopathy is characterized by 4-chamber dilation and in some patients myocardial fibrosis, abnormal perfusion reserve, diastolic dysfunction, and only rarely myocardial iron overload. Left ventricular dilation and myocardial fibrosis are associated with increased blood transfusion requirements, whereas left ventricular diastolic dysfunction is predominantly correlated with increased aortic stiffness. http://www.clinicaltrials.gov. Unique identifier: NCT01044901. © 2014 American Heart Association, Inc.

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

PubMed

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

2017-01-01

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

Curcumin ameliorates cardiac dysfunction induced by mechanical trauma.

PubMed

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

2017-11-05

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

Effects of intraaortic balloon augmentation in a porcine model of endotoxemic shock.

PubMed

Engoren, Milo; Habib, Robert H

2004-03-01

Patients with septic shock commonly have myocardial dysfunction associated with lactic acid production and troponin I release. The purpose of this study was to evaluate the effects on intraaortic balloon pump (IABP) support on myocardial dysfunction. Prospective, randomized controlled study. Animal research laboratory. Ten pigs had arterial, pulmonary arterial, and coronary catheters inserted. After receiving endotoxin infusion over 30 min, half the animals received IABP support. Coronary sinus lactic acid levels (P< 0.05 for both 90 min versus baseline and 60 min versus baseline) and arterial lactic acid levels (P < 0.05 for both 90 min versus baseline and 60 min versus baseline) increased with time but did not differ between IABP and sham groups. While overall there was no difference with time in myocardial lactic acid consumption or production (calculated as arterial lactic acid level minus coronary sinus lactic acid level), the IABP group showed net myocardial lactic acid consumption at 90 min, while the sham group showed myocardial lactic acid production. Three of five animals in each group showed troponin I release. The levels were similar and did not differ between groups. IABP had no benefits in this porcine model of endotoxemic shock.

3D cardiac wall thickening assessment for acute myocardial infarction

NASA Astrophysics Data System (ADS)

Khalid, A.; Chan, B. T.; Lim, E.; Liew, Y. M.

2017-06-01

Acute myocardial infarction (AMI) is the most severe form of coronary artery disease leading to localized myocardial injury and therefore irregularities in the cardiac wall contractility. Studies have found very limited differences in global indices (such as ejection fraction, myocardial mass and volume) between healthy subjects and AMI patients, and therefore suggested regional assessment. Regional index, specifically cardiac wall thickness (WT) and thickening is closely related to cardiac function and could reveal regional abnormality due to AMI. In this study, we developed a 3D wall thickening assessment method to identify regional wall contractility dysfunction due to localized myocardial injury from infarction. Wall thickness and thickening were assessed from 3D personalized cardiac models reconstructed from cine MRI images by fitting inscribed sphere between endocardial and epicardial wall. The thickening analysis was performed in 5 patients and 3 healthy subjects and the results were compared against the gold standard 2D late-gadolinium-enhanced (LGE) images for infarct localization. The notable finding of this study is the highly accurate estimation and visual representation of the infarct size and location in 3D. This study provides clinicians with an intuitive way to visually and qualitatively assess regional cardiac wall dysfunction due to infarction in AMI patients.

High Serum sTREM-1 Correlates With Myocardial Dysfunction and Predicts Prognosis in Septic Patients.

PubMed

Li, Zhenyu; Zhang, Enyuan; Hu, Yipeng; Liu, Yi; Chen, Bing

2016-06-01

This study aimed to evaluate the predictive and prognostic value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with myocardial dysfunction induced by severe sepsis and septic shock. A total of 84 patients with severe sepsis and septic shock were enrolled between May 2013 and December 2014.The patients were monitored by pulse indicator continuous cardiac output system and divided into myocardial depression group (cardiac function index [CFI] < 4.1/minute, n = 37) and nonmyocardial depression group (CFI ≥ 4.1/minute, n = 47 ). Additionally, the patients were divided into survival group (n = 40) and nonsurvival group (n = 44) based on 28-day mortality. Hemodynamic parameters and serum sTREM-1, B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) levels were collected on days 1, 3 and 5 after admission to intensive care unit. (1) The serum values of sTREM-1, BNP and cTnI in myocardial depression group were higher than those in nonmyocardial depression group (P < 0.01); and CFI, cardiac index, stroke volume, global ejection fraction and left ventricular contractility index (dpmax) in myocardial depression group were lower than those in nonmyocardial depression group on day 1 (P < 0.05); (2) serum sTREM-1 negatively correlated with left ventricular ejection fraction, CFI, cardiac index, global ejection fraction and dpmax, and it positively correlated with BNP and cTnI (P < 0.01); (3) the area under the receiver operating characteristics curve for sTREM-1 in the prediction of myocardial depression was 0.671 with a sensitivity of 83.8% and a specificity of 46.8% when cutoff point was 174.5ng/mL, the power of predicting septic depression for sTREM-1 was lower than that of BNP; logistic regression analysis showed that serum sTREM-1 was not an independent predictor of septic myocardial depression; the area under the receiver operating characteristics curve was 0.773 for sTREM-1 in predicting outcome with a sensitivity of 86.4% and a specificity of 80% when cutoff point was 182.3ng/mL, the power of predicting prognosis for sTREM-1 was superior to those of BNP and cTnI; (4) there was a decrease trend for sTREM-1 levels and an increasing trend for CFI in the survival group (P < 0.05). Myocardial dysfunction is common in patients with severe sepsis and septic shock and high serum levels of sTREM-1 correlates with myocardial dysfunction to some extent but is not an independent predictor, which more importantly showed prognostic value for septic shock outcome. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Cardiac hypertrophy limits infarct expansion after myocardial infarction in mice.

PubMed

Iismaa, Siiri E; Li, Ming; Kesteven, Scott; Wu, Jianxin; Chan, Andrea Y; Holman, Sara R; Calvert, John W; Haq, Ahtesham Ul; Nicks, Amy M; Naqvi, Nawazish; Husain, Ahsan; Feneley, Michael P; Graham, Robert M

2018-04-17

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in this transgenic model. Compared to non-transgenic littermates (NTLs), adult male dn-c-kit-Tg mice displayed CM hypertrophy and concentric left ventricular (LV) hypertrophy in the absence of an increase in workload. Stroke volume and cardiac output were preserved and LV wall stress was markedly lower than that in NTLs, leading to a more energy-efficient heart. In response to MI, infarct size in adult (16-week old) dn-c-kit-Tg hearts was similar to that of NTL after 24 h but was half that in NTL hearts 12 weeks post-MI. Cumulative CM cell cycle entry was only modestly increased in dn-c-kit-Tg hearts. However, dn-c-kit-Tg mice were more resistant to infarct expansion, adverse LV remodelling and contractile dysfunction, and suffered no early death from LV rupture, relative to NTL mice. Thus, pre-existing cardiac hypertrophy lowers wall stress in dn-c-kit-Tg hearts, limits infarct expansion and prevents death from myocardial rupture.

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

PubMed

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

2017-12-01

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

Implementing critical pathways and a multidisciplinary team approach to cardiovascular disease management.

PubMed

Peterson, Eric D; Albert, Nancy M; Amin, Alpesh; Patterson, J Herbert; Fonarow, Gregg C

2008-09-08

According to several medical registries, there is a need to improve the care of post-myocardial infarction (MI) patients, especially those with left ventricular dysfunction (LVD) and heart failure. This can potentially be achieved by implementing disease management programs, which include critical pathways, patient education, and multidisciplinary hospital teams. Currently, algorithms for critical pathways, including discharge processes, are lacking for post-MI LVD patients. Such schemes can increase the use of evidence-based medicines proved to reduce mortality. Educational programs are aimed at increasing patients' awareness of their condition, promoting medication compliance, and encouraging the adoption of healthy behaviors; such programs have been shown to be effective in improving outcomes of post-MI LVD patients. Reductions in all-cause hospitalizations and medical costs as well as improved survival rates have been observed when a multidisciplinary team (a nurse, a pharmacist, and a hospitalist) is engaged in patient care. In addition, the use of the "pay for performance" method, which can be advantageous for patients, physicians, and hospitals, may potentially improve the care of post-MI patients with LVD.

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

PubMed

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

2013-01-01

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

AT1 Receptor Modulator Attenuates the Hypercholesterolemia-Induced Impairment of the Myocardial Ischemic Post-Conditioning Benefits.

PubMed

Li, Yun-Wei; Li, Yan-Ming; Hon, Yan; Wan, Qi-Lin; He, Rui-Li; Wang, Zhi-Zhong; Zhao, Cui-Hua

2017-03-01

Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature's protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats. HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff's perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts. Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N 5 -(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS). Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC.

AT1 Receptor Modulator Attenuates the Hypercholesterolemia-Induced Impairment of the Myocardial Ischemic Post-Conditioning Benefits

PubMed Central

Li, Yun-Wei; Hon, Yan; Wan, Qi-Lin; He, Rui-Li; Wang, Zhi-Zhong; Zhao, Cui-Hua

2017-01-01

Background and Objectives Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature's protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats. Materials and Methods HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff's perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts. Results Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N5-(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS). Conclusion Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC. PMID:28382073

Cardiovascular magnetic resonance assessment of ventricular function and myocardial scarring before and early after repair of anomalous left coronary artery from the pulmonary artery

PubMed Central

2014-01-01

Background In patients with anomalous left coronary artery from the pulmonary artery (ALCAPA) left ventricular (LV) dilatation and dysfunction evolves due to diminished myocardial perfusion caused by coronary steal phenomenon. Using late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) imaging, myocardial scarring has been shown in ALCAPA patients late after repair, however the incidence of scarring before surgery and its impact on postoperative course after surgical repair remained unknown. Methods 8 ALCAPA-patients (mean age 10.0 ± 5.8 months) underwent CMR before and early after (mean 4.9 ± 2.5 months) coronary reimplantation procedures. CMR included functional analysis and LGE for detection of myocardial scars. Results LV dilatation (mean LVEDVI 171 ± 94 ml/m2) and dysfunction (mean LV-EF 22 ± 10 %) was present in all patients and improved significantly after surgery (mean LVEDV 68 ± 42 ml/m2, p = 0.02; mean LV-EF 58 ± 19 %, p < 0.001). Preoperative CMR revealed myocardial scarring in 2 of the 8 patients and did not predict postoperative course. At follow-up CMR, one LGE-positive patient showed delayed recovery of LV function while myocardial scarring was still present in both patients. In two patients new-onset transmural scarring was found, although functional recovery after operation was sufficient. One of them showed a stenosis of the left coronary artery and required resurgery. Conclusions Despite diminished myocardial perfusion and severely compromised LV function, myocardial scarring was preoperatively only infrequently present. Improvement of myocardial function was independent of new-onset scarring while the impact of preoperative scarring still needs to be defined. PMID:24387660

Regional myocardial extraction of a radioiodinated branched chain fatty acid during right ventricular pressure overload due to acute pulmonary hypertension

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

Hurford, W.; Lowenstein, E.; Zapol, W.

1985-05-01

To determine whether branched chain fatty acid extraction is reduced during right ventricular (RV) dysfunction due to acute pulmonary artery hypertension, studies were done in 6 anesthetized dogs. Regional branched chain fatty acid extraction was measured by comparing the myocardial uptake of I-125 labeled 15-(p-(iodophenyl))-3-methylpentadecanoic acid (I-PDA) to myocardial blood flow. Acute pulmonary hypertension was induced by incremental intravenous injection of 100 micron diameter glass beads into six pentobarbital anesthetized, mechanically ventilated dogs. Myocardial blood flow was measured by radiolabeled microspheres both under baseline conditions and during pulmonary hypertension. Mean RV pressure rose from 12 +- 2 (mean +- SEM)more » to 30 +-3mmHg resulting in a 225 +- 16% increase in RV stroke work. RV ejection fraction, as assessed by gated blood pool scans fell from 39 +- 2 to 18 +- 2%. Left ventricular (LV) pressures, stroke work and ejection fraction were unchanged. Myocardial blood flow increased 132 + 59% in the RV free wall and 67 +- 22% in the RV septum. LV blood flow was unchanged. Despite increased RV work and myocardial blood flow, no differences were noted in the branched chain fatty acid extraction ratios among LV or RV free walls or septum. The authors conclude that early RV dysfunction associated with pulmonary artery hypertension is not due to inadequate myocardial blood flow or branched chain fatty acid extraction.« less

β-Adrenergic receptors desensitization is not involved in exercise-induced cardiac fatigue: NADPH oxidase-induced oxidative stress as a new trigger.

PubMed

Vitiello, Damien; Boissière, Julien; Doucende, Grégory; Gayrard, Sandrine; Polge, Anne; Faure, Patrice; Goux, Aurélie; Tanguy, Stéphane; Obert, Philippe; Reboul, Cyril; Nottin, Stéphane

2011-11-01

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

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

PubMed

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

2018-01-01

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

Assessment of myocardial viability: comparison of echocardiography versus cardiac magnetic resonance imaging in the current era.

PubMed

Tomlinson, David R; Becher, Harald; Selvanayagam, Joseph B

2008-06-01

Detecting viable myocardium, whether hibernating or stunned, is of clinical significance in patients with coronary artery disease and left ventricular dysfunction. Echocardiographic assessments of myocardial thickening and endocardial excursion during dobutamine infusion provide a highly specific marker for myocardial viability, but with relatively less sensitivity. The additional modalities of myocardial contrast echocardiography and tissue Doppler have recently been proposed to provide further, quantitative measures of myocardial viability assessment. Cardiac magnetic resonance (CMR) has become popular for the assessment of myocardial viability as it can assess cardiac function, volumes, myocardial scar, and perfusion with high-spatial resolution. Both 'delayed enhancement' CMR and dobutamine stress CMR have important roles in the assessment of patients with ischaemic cardiomyopathy. This article reviews the recent advances in both echocardiography and CMR for the clinical assessment of myocardial viability. It attempts to provide a pragmatic approach toward the patient-specific assessment of this important clinical problem.

Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

PubMed Central

2011-01-01

Background Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC. Methods Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion. Results There was more myocardial apoptosis at 24 h vs 2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC. Conclusion PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC. PMID:21810244

Eplerenone : a pharmacoeconomic review of its use in patients with post-myocardial infarction heart failure.

PubMed

Croom, Katherine F; Plosker, Greg L

2005-01-01

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period. Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.

Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction.

PubMed

Blackburn, Nick J R; Vulesevic, Branka; McNeill, Brian; Cimenci, Cagla Eren; Ahmadi, Ali; Gonzalez-Gomez, Mayte; Ostojic, Aleksandra; Zhong, Zhiyuan; Brownlee, Michael; Beisswenger, Paul J; Milne, Ross W; Suuronen, Erik J

2017-09-01

Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG-AGEs) in MI using transgenic mice that over-express the MG-metabolizing enzyme glyoxalase-1 (GLO1). MI was induced in GLO1 mice and wild-type (WT) littermates. At 6 h post-MI, mass spectrometry revealed that MG-H1 (a principal MG-AGE) was increased in the hearts of WT mice, and immunohistochemistry demonstrated that this persisted for 4 weeks. GLO1 over-expression reduced MG-AGE levels at 6 h and 4 weeks, and GLO1 mice exhibited superior cardiac function at 4 weeks post-MI compared to WT mice. Immunohistochemistry revealed greater vascular density and reduced cardiomyocyte apoptosis in GLO1 vs. WT mice. The recruitment of c-kit + cells and their incorporation into the vasculature (c-kit + CD31 + cells) was higher in the infarcted myocardium of GLO1 mice. MG-AGEs appeared to accumulate in type I collagen surrounding arterioles, prompting investigation in vitro. In culture, the interaction of angiogenic bone marrow cells with MG-modified collagen resulted in reduced cell adhesion, increased susceptibility to apoptosis, fewer progenitor cells, and reduced angiogenic potential. This study reveals that MG-AGEs are produced post-MI and identifies a causative role for their accumulation in the cellular changes, adverse remodeling and functional loss of the heart after MI. MG may represent a novel target for preventing damage and improving function of the infarcted heart.

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.

Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs

PubMed Central

Zheng, Xiaoxin; Li, Xiaoyan; Lyu, Yongnan; He, Yiyu; Wan, Weiguo; Jiang, Xuejun

2016-01-01

Background The role of renal sympathetic denervation (RSD) in ameliorating post-myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown. Material/Methods MI and RSD were induced in Sprague–Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI. Results In the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end-diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end-diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats. Conclusions The potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21. PMID:27490896

Post-traumatic stress disorder symptoms in first-time myocardial infarction patients: roles of attachment and alexithymia.

PubMed

Gao, Wen; Zhao, Jing; Li, Yang; Cao, Feng-Lin

2015-11-01

To explore the roles of attachment and alexithymia in the severity of post-traumatic stress disorder symptoms and to specify the relationship between sub-dimensions of attachment, alexithymia and posttraumatic stress disorder symptoms in patients with first-time myocardial infarction in mainland China. Patients experiencing myocardial infarction have a risk of developing post-traumatic stress disorder symptoms. However, there have been few studies on the roles of attachment and alexithymia. A cross-sectional survey design. Ninety-seven patients participated in the assessment of post-traumatic stress disorder symptoms, attachment and alexithymia from June-December in 2012. To assess post-traumatic stress disorder symptoms and their correlates, we administered the Post-traumatic Stress Disorder Checklist-Civilian Version, the 20-item Toronto Alexithymia Scale and the Experiences in Close Relationships Scale 5-17 days after the remission of first myocardial infarction attack. Twenty-five (25·77%) patients met the criteria of posttraumatic stress disorder symptoms. Greater attachment anxiety and avoidance were associated with more severe posttraumatic stress disorder symptoms. Except for externally oriented thinking, all dimensions of alexithymia were significantly correlated with post-traumatic stress symptoms. In the regression model, attachment anxiety and difficulties identifying feelings were found to be predictive and the total regression equation explained 24·2% variance of posttraumatic stress disorder symptoms among myocardial infarction patients. First-time myocardial infarction patients were at risk of developing posttraumatic stress disorder symptoms. Attachment anxiety and difficulties identifying feelings were positively associated with posttraumatic stress disorder symptoms in the early stage of myocardial infarction rehabilitation. It is essential to evaluate the causal relationship between attachment, alexithymia and posttraumatic stress disorder symptoms in longitudinal studies. © 2015 John Wiley & Sons Ltd.

Systemic inflammation is associated with myocardial fibrosis, diastolic dysfunction, and cardiac hypertrophy in patients with hypertrophic cardiomyopathy

PubMed Central

Fang, Lu; Ellims, Andris H; Beale, Anna L; Taylor, Andrew J; Murphy, Andrew; Dart, Anthony M

2017-01-01

Background: Regional or diffuse fibrosis is an early feature of hypertrophic cardiomyopathy (HCM) and is related to poor prognosis. Previous studies have documented low-grade inflammation in HCM. The aim of this study was to examine the relationships between circulating inflammatory markers and myocardial fibrosis, systolic and diastolic dysfunction, and the degree of cardiac hypertrophy in HCM patients. Methods and results: Fifty HCM patients were recruited while 20 healthy subjects served as the control group. Seventeen inflammatory cytokines/chemokines were measured in plasma. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac phenotypes. Tumour necrosis factor (TNF)-α, interleukin (IL)-6 and serum amyloid P (SAP) were significantly increased in HCM patients compared to controls. IL-6, IL-4, and monocyte chemotactic protein (MCP)-1 were correlated with regional fibrosis while stromal cell-derived factor-1 and MCP-1 were correlated with diffuse fibrosis. Fractalkine and interferon-γ were associated with left ventricular wall thickness. The above associations remained significant in a linear regression model including age, gender, body mass index and family history. TNF-α, IL-6, SAP, MCP-1 and IL-10 were associated with parameters of diastolic dysfunction. White blood cells were also increased in HCM patients and correlated with diffuse fibrosis and diastolic dysfunction. However the associations between parameters of systemic inflammation and diastolic dysfunction were weakened in the linear regression analysis. Conclusions: Systemic inflammation is associated with parameters of the disease severity of HCM patients, particularly regional and diffuse fibrosis. Modifying inflammation may reduce myocardial fibrosis in HCM patients. PMID:29218105

Overexpression of Hsp20 Prevents Endotoxin-Induced Myocardial Dysfunction and Apoptosis via Inhibition of NF-κB Activation

PubMed Central

Wang, Xiaohong; Zingarelli, Basilia; Connor, Michael O’; Zhang, Pengyuan; Adeyemo, Adeola; Kranias, Evangelia G.; Wang, Yigang; Fan, Guo-Chang

2009-01-01

The occurrence of cardiovascular dysfunction in sepsis is associated with a significantly increased mortality rate of 70% to 90% compared with 20% in septic patients without cardiovascular impairment. Thus, rectification or blockade of myocardial depressant factors should partly ameliorate sepsis progression. Heat shock protein 20 (Hsp20) has been shown to enhance myocardial contractile function and protect against doxorubicin-induced cardiotoxicity. To investigate the possible role of Hsp20 in sepsis-mediated cardiac injury, we first examined the expression profiles of five major Hsps in response to lipopolysaccharide (LPS) challenge, and observed that only the expression of Hsp20 was downregulated in LPS-treated myocardium, suggesting that this decrease might be one of mechanisms contributing to LPS-induced cardiovascular defects. Further studies using loss-of-function and gain-of function approaches in adult rat cardiomyocytes verified that reduced Hsp20 levels were indeed correlated with the impaired contractile function. In fact, overexpression of Hsp20 significantly enhanced cardiomyocyte contractility upon LPS treatment. Moreover, after administration of LPS (25μg/g) in vivo, Hsp20 transgenic mice (10-fold overexpression) displayed: 1) an improvement in myocardial function; 2) reduced the degree of cardiac apoptosis; and 3) decreased NF-κB activity, accompanied with reduced myocardial cytokines IL-1β and TNF-α production, compared to the LPS-treated non-transgenic littermate controls. Thus, the increases in Hsp20 levels can protect against LPS-induced cardiac apoptosis and dysfunction, associated with inhibition of NF-κB activity, suggesting that Hsp20 may be a new therapeutic agent for the treatment of sepsis. PMID:19501592

Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with pressure-overload left ventricular hypertrophy

NASA Technical Reports Server (NTRS)

Koide, M.; Hamawaki, M.; Narishige, T.; Sato, H.; Nemoto, S.; DeFreyte, G.; Zile, M. R.; Cooper G, I. V.; Carabello, B. A.

2000-01-01

BACKGROUND: Because initially compensatory myocardial hypertrophy in response to pressure overloading may eventually decompensate to myocardial failure, mechanisms responsible for this transition have long been sought. One such mechanism established in vitro is densification of the cellular microtubule network, which imposes a viscous load that inhibits cardiocyte contraction. METHODS AND RESULTS: In the present study, we extended this in vitro finding to the in vivo level and tested the hypothesis that this cytoskeletal abnormality is important in the in vivo contractile dysfunction that occurs in experimental aortic stenosis in the adult dog. In 8 dogs in which gradual stenosis of the ascending aorta had caused severe left ventricular (LV) pressure overloading (gradient, 152+/-16 mm Hg) with contractile dysfunction, LV function was measured at baseline and 1 hour after the intravenous administration of colchicine. Cardiocytes obtained by biopsy before and after in vivo colchicine administration were examined in tandem. Microtubule depolymerization restored LV contractile function both in vivo and in vitro. CONCLUSIONS: These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload-induced cardiac hypertrophy.

Physiologic abnormalities of cardiac function in progressive systemic sclerosis with diffuse scleroderma

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

Follansbee, W.P.; Curtiss, E.I.; Medsger, T.A. Jr.

1984-01-19

To investigate cardiopulmonary function in progressive systemic sclerosis with diffuse scleroderma, we studied 26 patients with maximal exercise and redistribution thallium scans, rest and exercise radionuclide ventriculography, pulmonary-function testing, and chest roentgenography. Although only 6 patients had clinical evidence of cardiac involvement, 20 had abnormal thallium scans, including 10 with reversible exercise-induced defects and 18 with fixed defects (8 had both). Seven of the 10 patients who had exercise-induced defects and underwent cardiac catheterization had normal coronary angiograms. Mean resting left ventricular ejection fraction and mean resting right ventricular ejection fraction were lower in patients with post-exercise left ventricular thalliummore » defect scores above the median (59 +/- 13 per cent vs. 69 +/- 6 per cent, and 36 +/- 12 per cent vs. 47 +/- 7 per cent, respectively). The authors conclude that in progressive systemic sclerosis with diffuse scleroderma, abnormalities of myocardial perfusion are common and appear to be due to a disturbance of the myocardial microcirculation. Both right and left ventricular dysfunction appear to be related to this circulatory disturbance, suggesting ischemically mediated injury.« less

Pharmacological prevention of reperfusion injury in acute myocardial infarction. A potential role for adenosine as a therapeutic agent.

PubMed

Quintana, Miguel; Kahan, Thomas; Hjemdahl, Paul

2004-01-01

The concept of reperfusion injury, although first recognized from animal studies, is now recognized as a clinical phenomenon that may result in microvascular damage, no-reflow phenomenon, myocardial stunning, myocardial hibernation and ischemic preconditioning. The final consequence of this event is left ventricular (LV) systolic dysfunction leading to increased morbidity and mortality. The typical clinical case of reperfusion injury occurs in acute myocardial infarction (MI) with ST segment elevation in which an occlusion of a major epicardial coronary artery is followed by recanalization of the artery. This may occur either spontaneously or by means of thrombolysis and/or by primary percutaneous coronary intervention (PCI) with efficient platelet inhibition by aspirin (acetylsalicylic acid), clopidogrel and glycoprotein IIb/IIIa inhibitors. Although the pathophysiology of reperfusion injury is complex, the major role that neutrophils play in this process is well known. Neutrophils generate free radicals, degranulation products, arachidonic acid metabolites and platelet-activating factors that interact with endothelial cells, inducing endothelial injury and neutralization of nitrous oxide vasodilator capacity. Adenosine, through its multi-targeted pharmacological actions, is able to inhibit some of the above-mentioned detrimental effects. The net protective of adenosine in in vivo models of reperfusion injury is the reduction of the infarct size, the improvement of the regional myocardial blood flow and of the regional function of the ischemic area. Additionally, adenosine preserves the post-ischemic coronary flow reserve, coronary blood flow and the post-ischemic regional contractility. In small-scale studies in patients with acute MI, treatment with adenosine has been associated with smaller infarcts, less no-reflow phenomenon and improved LV function. During elective PCI adenosine reduced ST segment shifts, lactate production and ischemic symptoms. During the last years, three relatively large placebo-controlled clinical trials have been conducted: Acute Myocardial Infarction Study of Adenosine Trial (AMISTAD) I and II and Attenuation by Adenosine of Cardiac Complications (ATTACC). In the AMISTAD trials, the final infarct size was reduced and the LV systolic function was improved by adenosine treatment, mainly in patients with anterior MI localization. However, morbidity and mortality were not affected. In the ATTACC study, the LV systolic function was not affected by adenosine, however, trends towards improved survival were observed in patients with anterior MI localization. The possibility of obtaining a Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the infarct-related artery in up to 95% of patients with acute MI (increasing the occurrence of reperfusion injury) has turned back the interest towards the protection of myocardial cells from the impending ischemic and reperfusion injury in which adenosine alone or together with other cardio-protective agents may exert important clinical effects.

Long-Term Preservation of Left Ventricular Systolic Function in Patients With Refractory Angina Pectoris and Inducible Myocardial Ischemia on Optimal Medical Therapy.

PubMed

Slavich, Massimo; Maranta, Francesco; Fumero, Andrea; Godino, Cosmo; Giannini, Francesco; Oppizzi, Michele; Colombo, Antonio; Fragasso, Gabriele; Margonato, Alberto

2016-05-15

Refractory angina pectoris (RAP) represents a clinical condition characterized by frequent episodes of chest pain despite therapy optimization. According to myocardial stunning and myocardial hibernation definitions, RAP should represent the ideal condition for systolic dysfunction development. We aim to investigate the evolution of left ventricular (LV) function in patients with RAP. A retrospective study which encompasses 144 patients with RAP referred to our institution from 1999 to December 2014 was performed. Of them, 88 met the inclusion criteria, and LV function was assessed by echocardiography. All of them had persistent angina episodes on top of optimal medical therapy and evidence of significant inducible myocardial ischemia and no further revascularization options. Nitrates consumption rate, time of angina duration, and the number of angina attacks were evaluated. In the whole population, ejection fraction (EF) was 44% ± 2. EF was significantly lower in patients with previous myocardial infarction (41% ± 1.5 vs 51% ± 1.8, p <0.0001). The duration time and the number of angina attacks did not correlate with EF in the whole population and in patients without previous myocardial infarction. In patients with previous myocardial infarction, the number of anginal attacks did not correlate with EF, but EF appeared higher in patients with angina duration >5 years (<5 years EF 37% ± 1 [n = 26]; >5 years 44% ± 2 [n = 44]; p 0.02). Long-term LV function in patients with RAP is generally preserved. A previous history of myocardial infarction is the only determinant in the development of systolic dysfunction. In conclusion, frequent angina attacks and a long-term history of angina are not apparently associated to worse LV function. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats

PubMed Central

Patel, Snehal S.; Goyal, Ramesh K.

2011-01-01

Background: Normalization of hyperglycemia, hyperlipidemia, and oxidative stress is an important objective in preventing diabetes-induced cardiac dysfunction. Objective: This study was undertaken to examine the effects of gallic acid in myocardial dysfunctions associated with type-1 diabetes. Materials and Methods: Diabetes was induced by single intravenous injection of streptozotocin (STZ, 50 mg/kg i.v.). Gallic acid was administered daily at three different doses (100, 50, and 25 mg/kg p.o.) for 8 weeks at the end of which blood samples were collected and analyzed for various biochemical parameters. Results: Injection of STZ produced significant loss of body weight (BW), polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypertension, bradycardia, and myocardial functional alterations. Treatment with gallic acid significantly lowered fasting glucose, the AUCglucose level in a dose-dependent manner; however, the insulin level was not increased significantly at same the dose and prevented loss of BW, polyphagia, and polydypsia in diabetic rats. It also prevented STZ-induced hyperlipidemia, hypertension, bradycardia, structural alterations in cardiac tissue such as increase in force of contraction, left ventricular weight to body weight ratio, collagen content, protein content, serum lactate dehydrogenase, and creatinine kinase levels in a dose-dependent manner. Further, treatment also produced reduction in lipid peroxidation and increase in antioxidant parameters in heart of diabetic rats. Conclusion: The results of this study suggest that gallic acid to be beneficial for the treatment of myocardial damage associated with type-1 diabetes. PMID:22224046

Prognostic Value of the Thrombolysis in Myocardial Infarction Risk Score in ST-Elevation Myocardial Infarction Patients With Left Ventricular Dysfunction (from the EPHESUS Trial).

PubMed

Popovic, Batric; Girerd, Nicolas; Rossignol, Patrick; Agrinier, Nelly; Camenzind, Edoardo; Fay, Renaud; Pitt, Bertram; Zannad, Faiez

2016-11-15

The Thrombolysis in Myocardial Infarction (TIMI) risk score remains a robust prediction tool for short-term and midterm outcome in the patients with ST-elevation myocardial infarction (STEMI). However, the validity of this risk score in patients with STEMI with reduced left ventricular ejection fraction (LVEF) remains unclear. A total of 2,854 patients with STEMI with early coronary revascularization participating in the randomized EPHESUS (Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial were analyzed. TIMI risk score was calculated at baseline, and its predictive value was evaluated using C-indexes from Cox models. The increase in reclassification of other variables in addition to TIMI score was assessed using the net reclassification index. TIMI risk score had a poor predictive accuracy for all-cause mortality (C-index values at 30 days and 1 year ≤0.67) and recurrent myocardial infarction (MI; C-index values ≤0.60). Among TIMI score items, diabetes/hypertension/angina, heart rate >100 beats/min, and systolic blood pressure <100 mm Hg were inconsistently associated with survival, whereas none of the TIMI score items, aside from age, were significantly associated with MI recurrence. Using a constructed predictive model, lower LVEF, lower estimated glomerular filtration rate (eGFR), and previous MI were significantly associated with all-cause mortality. The predictive accuracy of this model, which included LVEF and eGFR, was fair for both 30-day and 1-year all-cause mortality (C-index values ranging from 0.71 to 0.75). In conclusion, TIMI risk score demonstrates poor discrimination in predicting mortality or recurrent MI in patients with STEMI with reduced LVEF. LVEF and eGFR are major factors that should not be ignored by predictive risk scores in this population. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-04-01

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

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial.

PubMed

Cerisano, Giampaolo; Buonamici, Piergiovanni; Gori, Anna Maria; Valenti, Renato; Sciagrà, Roberto; Giusti, Betti; Sereni, Alice; Raspanti, Silvia; Colonna, Paolo; Gensini, Gian Franco; Abbate, Rosanna; Schulz, Richard; Antoniucci, David

2015-10-15

The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Synergistic role of ADP and Ca2+ in diastolic myocardial stiffness

PubMed Central

Sequeira, Vasco; Najafi, Aref; McConnell, Mark; Fowler, Ewan D; Bollen, Ilse A E; Wüst, Rob C I; dos Remedios, Cris; Helmes, Michiel; White, Ed; Stienen, Ger J M; Tardiff, Jil; Kuster, Diederik W D; van der Velden, Jolanda

2015-01-01

Abstract Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+ handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathological levels of ADP and diastolic [Ca2+] revealed a 76 ± 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+ overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca2+, and thereby increase myocardial stiffness. Key points Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca2+] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. PMID:26096258

Rigor mortis at the myocardium investigated by post-mortem magnetic resonance imaging.

PubMed

Bonzon, Jérôme; Schön, Corinna A; Schwendener, Nicole; Zech, Wolf-Dieter; Kara, Levent; Persson, Anders; Jackowski, Christian

2015-12-01

Post-mortem cardiac MR exams present with different contraction appearances of the left ventricle in cardiac short axis images. It was hypothesized that the grade of post-mortem contraction may be related to the post-mortem interval (PMI) or cause of death and a phenomenon caused by internal rigor mortis that may give further insights in the circumstances of death. The cardiac contraction grade was investigated in 71 post-mortem cardiac MR exams (mean age at death 52 y, range 12-89 y; 48 males, 23 females). In cardiac short axis images the left ventricular lumen volume as well as the left ventricular myocardial volume were assessed by manual segmentation. The quotient of both (LVQ) represents the grade of myocardial contraction. LVQ was correlated to the PMI, sex, age, cardiac weight, body mass and height, cause of death and pericardial tamponade when present. In cardiac causes of death a separate correlation was investigated for acute myocardial infarction cases and arrhythmic deaths. LVQ values ranged from 1.99 (maximum dilatation) to 42.91 (maximum contraction) with a mean of 15.13. LVQ decreased slightly with increasing PMI, however without significant correlation. Pericardial tamponade positively correlated with higher LVQ values. Variables such as sex, age, body mass and height, cardiac weight and cause of death did not correlate with LVQ values. There was no difference in LVQ values for myocardial infarction without tamponade and arrhythmic deaths. Based on the observation in our investigated cases, the phenomenon of post-mortem myocardial contraction cannot be explained by the influence of the investigated variables, except for pericardial tamponade cases. Further research addressing post-mortem myocardial contraction has to focus on other, less obvious factors, which may influence the early post-mortem phase too. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Relation of cardiac troponin I and microvascular obstruction following ST-elevation myocardial infarction.

PubMed

Hallén, Jonas; Jensen, Jesper K; Buser, Peter; Jaffe, Allan S; Atar, Dan

2011-03-01

Presence of microvascular obstruction (MVO) following primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) confers higher risk of left-ventricular remodelling and dysfunction. Measurement of cardiac troponin I (cTnI) after STEMI reflects the extent of myocardial destruction. We aimed to explore whether cTnI values were associated with presence of MVO independently of infarct size in STEMI patients receiving pPCI. 175 patients with STEMI were included. cTnI was sampled at 24 and 48 h. MVO and infarct size was determined by delayed enhancement with cardiac magnetic resonance at five to seven days post index event. The presence of MVO following STEMI was associated with larger infarct size and higher values of cTnI at 24 and 48 h. For any given infarct size or cTnI value, there was a greater risk of MVO development in non-anterior infarctions. cTnI was strongly associated with MVO in both anterior and non-anterior infarctions (P < 0.01) after adjustment for covariates (including infarct size); and was reasonably effective in predicting MVO in individual patients (area-under-the-curve ≥0.81). Presence of MVO is reflected in levels of cTnI sampled at an early time-point following STEMI and this association persists after adjustment for infarct size.

Prevalence of scarred and dysfunctional myocardium in patients with heart failure of ischaemic origin: A cardiovascular magnetic resonance study

PubMed Central

2011-01-01

Background Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) can provide unique data on the transmural extent of scar/viability. We assessed the prevalence of dysfunctional myocardium, including partial thickness scar, which could contribute to left ventricular contractile dysfunction in patients with heart failure and ischaemic heart disease who denied angina symptoms. Methods We invited patients with ischaemic heart disease and a left ventricular ejection fraction < 50% by echocardiography to have LGE CMR. Myocardial contractility and transmural extent of scar were assessed using a 17-segment model. Results The median age of the 193 patients enrolled was 70 (interquartile range: 63-76) years and 167 (87%) were men. Of 3281 myocardial segments assessed, 1759 (54%) were dysfunctional, of which 581 (33%) showed no scar, 623 (35%) had scar affecting ≤50% of wall thickness and 555 (32%) had scar affecting > 50% of wall thickness. Of 1522 segments with normal contractile function, only 98 (6%) had evidence of scar on CMR. Overall, 182 (94%) patients had ≥1 and 107 (55%) patients had ≥5 segments with contractile dysfunction that had no scar or ≤50% transmural scar suggesting viability. Conclusions In this cohort of patients with left ventricular systolic dysfunction and ischaemic heart disease, about half of all segments had contractile dysfunction but only one third of these had > 50% of the wall thickness affected by scar, suggesting that most dysfunctional segments could improve in response to an appropriate intervention. PMID:21936915

Left ventricular diastolic dysfunction in type 2 diabetes patients: a novel 2D strain analysis based on cardiac magnetic resonance imaging.

PubMed

Chen, Qiang; Gan, Yan; Li, Zhi-Yong

2016-09-01

This study was to develop a strain analysis method to evaluate the left ventricular (LV) functions in type 2 diabetic patients with an asymptomatic LV diastolic dysfunction. Two groups (10 asymptomatic type 2 diabetic subjects and 10 control ones) were considered. All of the subjects had normal ejection fraction values but impaired diastolic functions assessed by the transmitral blood flow velocity. For each subject, based on cardiac MRI, global indexes including LV volume, LV myocardial mass, cardiac index (CI), and transmitral peak velocity, were measured, and regional indexes (i.e., LV deformation, strain and strain rate) were calculated through an image-registration technology. Most of the global indexes did not differentiate between the two groups, except for the CI, LV myocardial mass and transmitral peak velocity. While for the regional indexes, the global LV diastolic dysfunction of the diabetic indicated an increased strain (0.08 ± 0.044 vs. -0.031 ± 0.077, p = 0.001) and a reduced strain rate (1.834 ± 0.909 vs. 3.791 ± 2.394, p = 0.033) compared to the controls, moreover, the local LV diastolic dysfunction reflected by the strain and strain rate varied, and the degree of dysfunction gradually decreased from the basal level to the apical level. The results showed that the strain and strain rates are effective to capture the subtle alterations of the LV functions, and the proposed method can be used to estimate the LV myocardial function based on cardiac MRI.

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

PubMed

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

2016-10-28

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

Penehyclidine hydrochloride regulates mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provides cardioprotection in rats with myocardial ischemia-reperfusion injury.

PubMed

Feng, Min; Wang, Lirui; Chang, Siyuan; Yuan, Pu

2018-05-31

The potential mechanism of penehyclidine hydrochloride (PHC) against myocardial ischemia-reperfusion (I/R) injury has not been fully elucidated. The aim of the present study was to reveal whether mitochondrial dynamics, apoptosis, and MAPKs were involved in the cardioprotective effect of this drug on myocardial I/R injury. Ninety healthy adult male Wistar rats were separately pretreated with normal saline (0.9%); PHC; and signal pathway blockers of MAPKs, Drp1, and Bcl-2. Coronary artery ligation and subsequent reperfusion were performed to induce myocardial I/R injury. Echocardiography was performed. Myocardial enzymes and oxidative stress markers were detected. Myocardial cell apoptotic rates and infarct sizes were measured. Mitochondrial function was evaluated. Expression levels of MAPKs, mitochondria regulatory proteins (Drp1, Mfn1/2), and apoptosis-related proteins (Bcl-2, Bax) were determined. PHC pretreatment improved myocardial abnormalities (dysfunction, injury, infarct size, and apoptotic rate), mitochondrial abnormalities (dysfunction and fission), and excessive oxidative stress and inhibited the activities of p38MAPK and JNK signal pathways in rats with myocardial I/R injury (P < 0.05). Additionally, p38MAPK and JNK blockers (SB239063 and SP600125, respectively) had an effect on rats same as that of PHC. Although Drp1 blocker (Mdivi-1) showed a similar cardioprotective effect (P < 0.05), it did not affect the expression of MAPKs and apoptosis-related proteins (P > 0.05). In addition, Bcl-2 blocker (ABT-737) caused a high expression of Drp1 and a low expression of Mfn1/2 (P < 0.05). PHC regulated mitochondrial dynamics and apoptosis through p38MAPK and JNK signal pathways and provided cardioprotection in rats with myocardial I/R injury. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of a pure reduction in heart rate for the treatment of left ventricular dysfunction: clinical benefits of ivabradine in the BEAUTIFUL trial.

PubMed

Danchin, Nicolas

2009-01-01

Ivabradine is an I(f) current inhibitor, that has documented antianginal efficacy. The BEAUTIFUL trial tested ivabradine against placebo in a large population of 10,917 patients in sinus rhythm, with coronary artery disease and left ventricular dysfunction, defined as left ventricular ejection fraction < or =35%. Overall, there was no impact of ivabradine on the primary end-point of the trial (cardiovascular mortality, hospitalisation for myocardial infarction, new onset or worsening heart failure). In the placebo arm of the trial, baseline heart rate > or = 70 bpm was associated with an increased risk of cardiovascular mortality, myocardial infarction, heart failure and coronary revascularisation. In the subgroup of patients with a baseline heart rate > or =70 bpm, treatment with ivabradine resulted in a significant, 36% reduction in the risk of myocardial infarction and a 20% reduction in the need for coronary revascularisation. Ivabradine was well tolerated, with an increased rate of treatment discontinuation, mainly due to bradycardia, compared with placebo. Because of its safety and efficacy to control angina, ivabradine should be considered first-line antianginal treatment in coronary artery disease patients with left ventricular dysfunction and increased heart rate, already receiving beta-blocker therapy or in whom these medications are not tolerated.

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

PubMed

O'Farrell, Alice C; Evans, Rhys; Silvola, Johanna M U; Miller, Ian S; Conroy, Emer; Hector, Suzanne; Cary, Maurice; Murray, David W; Jarzabek, Monika A; Maratha, Ashwini; Alamanou, Marina; Udupi, Girish Mallya; Shiels, Liam; Pallaud, Celine; Saraste, Antti; Liljenbäck, Heidi; Jauhiainen, Matti; Oikonen, Vesa; Ducret, Axel; Cutler, Paul; McAuliffe, Fionnuala M; Rousseau, Jacques A; Lecomte, Roger; Gascon, Suzanne; Arany, Zoltan; Ky, Bonnie; Force, Thomas; Knuuti, Juhani; Gallagher, William M; Roivainen, Anne; Byrne, Annette T

2017-01-01

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

PubMed Central

Silvola, Johanna M. U.; Miller, Ian S.; Conroy, Emer; Hector, Suzanne; Cary, Maurice; Murray, David W.; Jarzabek, Monika A.; Maratha, Ashwini; Alamanou, Marina; Udupi, Girish Mallya; Shiels, Liam; Pallaud, Celine; Saraste, Antti; Liljenbäck, Heidi; Jauhiainen, Matti; Oikonen, Vesa; Ducret, Axel; Cutler, Paul; McAuliffe, Fionnuala M.; Rousseau, Jacques A.; Lecomte, Roger; Gascon, Suzanne; Arany, Zoltan; Ky, Bonnie; Force, Thomas; Knuuti, Juhani; Gallagher, William M.; Roivainen, Anne; Byrne, Annette T.

2017-01-01

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment. PMID:28129334

Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure.

PubMed

Shah, Sanjiv J; Aistrup, Gary L; Gupta, Deepak K; O'Toole, Matthew J; Nahhas, Amanda F; Schuster, Daniel; Chirayil, Nimi; Bassi, Nikhil; Ramakrishna, Satvik; Beussink, Lauren; Misener, Sol; Kane, Bonnie; Wang, David; Randolph, Blake; Ito, Aiko; Wu, Megan; Akintilo, Lisa; Mongkolrattanothai, Thitipong; Reddy, Mahendra; Kumar, Manvinder; Arora, Rishi; Ng, Jason; Wasserstrom, J Andrew

2014-01-01

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca(2+) cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats (n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca(2+) transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca(2+) cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca(2+) transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca(2+) cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

Association of Lifestyle-Related Comorbidities With Periodontitis

PubMed Central

Lee, Jae-Hong; Lee, Jung-Seok; Park, Jin-Young; Choi, Jung-Kyu; Kim, Dong-Wook; Kim, Young-Taek; Choi, Seong-Ho

2015-01-01

Abstract The aim of this study was to determine the association of periodontitis with lifestyle-related comorbidities (LCs) using data in the Korean National Health Insurance Cohort Database from 2002 to 2013. This was a retrospective study involving a large national cohort with patient samples (representing 2% of the total Korean population) stratified on the basis of sociodemographic information. Using this precisely extracted database, the correlations between LCs (cerebral infarction, angina pectoris, myocardial infarction, hypertension, diabetes mellitus, rheumatoid arthritis, erectile dysfunction, osteoporosis, and obesity) and periodontitis were investigated while adjusting for confounding bias. Univariate and multiple logistic regression analyses were used to evaluate differences in variable factors. Among a total of 1,025,340 samples, 321,103 (31.3%) cases were diagnosed with periodontitis. Statistically significant associations were found between all LCs except myocardial infarction and periodontitis (P < 0.005). Periodontitis is significantly and positively correlated with LCs (except for myocardial infarction) after adjusting for confounding bias. In particular, lifestyle-related diseases, erectile dysfunction, and osteoporosis seem to be intimately related to periodontitis. PMID:26376407

Effect of Levosimendan on Renal Outcome in Cardiac Surgery Patients With Chronic Kidney Disease and Perioperative Cardiovascular Dysfunction: A Substudy of a Multicenter Randomized Trial.

PubMed

Zangrillo, Alberto; Alvaro, Gabriele; Belletti, Alessandro; Pisano, Antonio; Brazzi, Luca; Calabrò, Maria G; Guarracino, Fabio; Bove, Tiziana; Grigoryev, Evgeny V; Monaco, Fabrizio; Boboshko, Vladimir A; Likhvantsev, Valery V; Scandroglio, Anna M; Paternoster, Gianluca; Lembo, Rosalba; Frassoni, Samuele; Comis, Marco; Pasyuga, Vadim V; Navalesi, Paolo; Lomivorotov, Vladimir V

2018-02-26

Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population. Post hoc analysis of a multicenter randomized trial. Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries. The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m 2 and perioperative myocardial dysfunction. Patients were assigned randomly to receive levosimendan (0.025-0.2 μg/kg/min) or placebo in addition to standard inotropic treatment. Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07). Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials. Copyright © 2018 Elsevier Inc. All rights reserved.

Integration of mechanical, structural and electrical imaging to understand response to cardiac resynchronization therapy.

PubMed

Silva, Etelvino; Bijnens, Bart; Berruezo, Antonio; Mont, Lluis; Doltra, Adelina; Andreu, David; Brugada, Josep; Sitges, Marta

2014-10-01

There is extensive controversy exists on whether cardiac resynchronization therapy corrects electrical or mechanical asynchrony. The aim of this study was to determine if there is a correlation between electrical and mechanical sequences and if myocardial scar has any relevant impact. Six patients with normal left ventricular function and 12 patients with left ventricular dysfunction and left bundle branch block, treated with cardiac resynchronization therapy, were studied. Real-time three-dimensional echocardiography and electroanatomical mapping were performed in all patients and, where applicable, before and after therapy. Magnetic resonance was performed for evaluation of myocardial scar. Images were postprocessed and mechanical and electrical activation sequences were defined and time differences between the first and last ventricular segment to be activated were determined. Response to therapy was defined as a reduction in left ventricular end-systolic volume ≥ 15% after 12 months of follow-up. Good correlation between electrical and mechanical timings was found in patients with normal left ventricular function (r(2) = 0.88; P = .005) but not in those with left ventricular dysfunction (r(2) = 0.02; P = not significant). After therapy, both timings and sequences were modified and improved, except in those with myocardial scar. Despite a close electromechanical relationship in normal left ventricular function, there is no significant correlation in patients with dysfunction. Although resynchronization therapy improves this correlation, the changes in electrical activation may not yield similar changes in left ventricular mechanics particularly depending on the underlying myocardial substrate. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Myocardial oedema as the sole marker of acute injury in Takotsubo cardiomyopathy: a cardiovascular magnetic resonance (CMR) study.

PubMed

Iacucci, Ilaria; Carbone, Iacopo; Cannavale, Giuseppe; Conti, Bettina; Iampieri, Ilaria; Rosati, Riccardo; Sardella, Gennaro; Frustaci, Andrea; Fedele, Francesco; Catalano, Carlo; Francone, Marco

2013-12-01

The main hallmark of Takotsubo cardiomyopathy (TT-CMP) is transient ischaemia, with completely reversible regional contractile dysfunction, which involves the mid-apical segments and shows no angiographic signs of coronary artery disease (CAD). The acute and reversible myocardial injury suggests that tissue oedema may be an important marker of disease. Seventeen patients with a clinical and angiographic diagnosis of TT-CMP underwent cardiovascular magnetic resonance (CMR) imaging in the acute phase and at follow-up after 4 months. A standard acquisition protocol including turbo spin echo (TSE) T2-weighted short-tau inversion-recovery (T2 STIR), steady-state free-precession cine (SSFP cine) and lateenhancement (LE) imaging after gadolinium benzyloxypropionic tetraacetic acid (Gd-BOPTA) administration was performed. All images were analysed, and data on oedema and LE were correlated with regional dysfunction and histological findings from endomyocardial biopsy (EMB) where available. In all patients, T2 STIR images showed a diffuse homogeneous hyperintensity that extended to all mid-apical segments and perfectly matched the area of regional dysfunction, reflecting tissue oedema. In the five patients who underwent EMB, histology confirmed the massive interstitial oedema associated with typical contraction-band necrosis. No cases of LE were observed. At follow-up, complete regression of oedema was observed in all cases, with significant recovery of regional and global left ventricular (LV) function (ejection fraction from 48.7% to 59.8%). Myocardial oedema on CMR is a characteristic feature of acute TT-CMP, which reflects acute inflammation and acute myocardial injury. It could therefore be used as a specific marker of disease severity.

CES1 Carriers in the PAPI Study

ClinicalTrials.gov

2018-04-10

Heart Diseases; Coronary Disease; Coronary Artery Disease; Cardiovascular Diseases; Myocardial Ischemia; Artery Occlusion; Aspirin Sensitivity; Clopidogrel, Poor Metabolism of; Platelet Dysfunction; Platelet Thrombus

Evaluation of Left Ventricle Function by Regional Fractional Area Change (RFAC) in a Mouse Model of Myocardial Infarction Secondary to Valsartan Treatment

PubMed Central

Castiglioni, Laura; Colazzo, Francesca; Fontana, Lucia; Colombo, Gualtiero I.; Piacentini, Luca; Bono, Elisa; Milano, Giuseppina; Paleari, Serena; Palermo, Annamaria; Guerrini, Uliano; Tremoli, Elena; Sironi, Luigi

2015-01-01

Aim Left ventricle (LV) regional fractional area change (RFAC) measured by cardiac magnetic resonance (CMR) allows the non-invasive localization and quantification of the degree of myocardial infarction (MI), and could be applied to assess the effectiveness of pharmacological or regenerative therapies. Here we investigate the ability of RFAC to identify regional dysfunction and discriminate the effect of pharmacological treatment with valsartan, a selective antagonist of angiotensin II type 1 receptor, in a model of MI. Methods and Results C57BL/6N mice, undergoing coronary artery ligation, were divided into two groups: untreated (MI) or treated with valsartan (MI+Val). Sham-operated mice were used as a control. Cardiac dimensions and function were assessed at baseline, 24 hours, 1 and 4 weeks post surgery by CMR and echocardiography. At sacrifice histology and whole-genome gene expression profiling were performed. RFAC was able to detect significant differences between treatment groups whereas the global ejection fraction was not. RFAC showed greater loss of regional contraction in remote non-infarcted myocardium in MI group than in MI+Val group. Consistently, in the same region MI+Val mice showed reduced myocyte hypertrophy, fibroblast proliferation, and fibrosis and modulation of target genes; in addition, left atrium volumes, appendage length and duct contraction were preserved. Conclusion In this study, RFAC effectively estimated the degree of systolic dysfunction and discriminated the regions preserved by pharmacological treatment. RFAC index is a promising tool to monitor changes in LV contraction and to assess the effectiveness of therapeutic regimens in clinical settings. PMID:26291973

Time course evaluation of myocardial perfusion after reperfusion therapy by 99mTc-tetrofosmin SPECT in patients with acute myocardial infarction.

PubMed

Tanaka, R; Nakamura, T

2001-09-01

Myocardial perfusion imaging with 99mTc-labeled agents immediately after reperfusion therapy can underestimate myocardial salvage. It is also conceivable that delayed imaging is useful for assessing the risk area. However, to our knowledge, very few studies have sequentially evaluated these image changes. We conducted 99mTc-tetrofosmin (TF) and 123I-beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) SPECT before and after reperfusion to treat acute myocardial infarction and quantified changes in TF myocardial accumulation and reverse redistribution. Seventeen patients with a first myocardial infarction underwent successful reperfusion. We examined SPECT images obtained at the onset (preimage), those acquired 30 min (early image) and 6 h (delayed image) after TF injection, and images acquired 1, 4, 7, and 20 d after reperfusion (post-1-d, post-4-d, post-7-d, and post-20-d image, respectively). We also examined BMIPP SPECT images after 7 +/- 1.8 d (BMIPP image). Polar maps were divided into 48 segments to calculate percentage uptake, and time course changes in segment numbers below 60% were observed as abnormal area. Moreover, cardiac function was analyzed by gated TF SPECT on 1 and 20 d after reperfusion. In reference to the abnormal area on the early images, the post-1-d image was significantly improved compared with the preimage (P < 0.01) as was the post-7-d image compared with the post-1-d and post-4-d images (P < 0.05, respectively). However, post-20-d and post-7-d images did not significantly differ. Therefore, the improvement in myocardial accumulation reached a plateau 7 d after reperfusion. On the other hand, the abnormal area on the delayed images was significantly greater (P < 0.01) compared with that on the early images from 4 to 20 d after reperfusion, as the value was essentially constant. The correlations of the abnormal area between the preimage and the post-7-d delayed image, the preimage and the BMIPP image, and the post-7-d delayed image and the BMIPP image were very close (r = 0.963, r = 0.981, and r = 0.975, respectively). Gated TF SPECT revealed that the left ventricular ejection fraction was not significantly different (P = not significant) between 1 and 20 d after reperfusion, but regional wall motion was significantly different after reperfusion (P < 0.05). These results suggest that the interval between reperfusion therapy and TF SPECT should be 7 d to evaluate the salvage effect and that TF delayed and BMIPP images are both useful in estimation of risk area.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction

PubMed Central

Zizola, Cynthia; Kennel, Peter J.; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi

2015-01-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. PMID:25713305

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

PubMed

Zizola, Cynthia; Kennel, Peter J; Akashi, Hirokazu; Ji, Ruiping; Castillero, Estibaliz; George, Isaac; Homma, Shunichi; Schulze, P Christian

2015-05-01

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. Copyright © 2015 the American Physiological Society.

Reducing myocardial infarct size: challenges and future opportunities

PubMed Central

Bulluck, Heerajnarain; Yellon, Derek M; Hausenloy, Derek J

2016-01-01

Despite prompt reperfusion by primary percutaneous coronary intervention (PPCI), the mortality and morbidity of patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) remain significant with 9% death and 10% heart failure at 1 year. In these patients, one important neglected therapeutic target is ‘myocardial reperfusion injury’, a term given to the cardiomyocyte death and microvascular dysfunction which occurs on reperfusing ischaemic myocardium. A number of cardioprotective therapies (both mechanical and pharmacological), which are known to target myocardial reperfusion injury, have been shown to reduce myocardial infarct (MI) size in small proof-of-concept clinical studies—however, being able to demonstrate improved clinical outcomes has been elusive. In this article, we review the challenges facing clinical cardioprotection research, and highlight future therapies for reducing MI size and preventing heart failure in patients presenting with STEMI at risk of myocardial reperfusion injury. PMID:26674987

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage

PubMed Central

Kumaran, Kandaswamy Senthil

2010-01-01

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat’s heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients. PMID:20376586

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage.

PubMed

Kumaran, Kandaswamy Senthil; Prince, Ponnian Stanely Mainzen

2010-11-01

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat's heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients.

Association of Exercise Training with Tobacco Smoking Prevents Fibrosis but has Adverse Impact on Myocardial Mechanics.

PubMed

Reis Junior, Dermeval; Antonio, Ednei Luiz; de Franco, Marcello Fabiano; de Oliveira, Helenita Antonia; Tucci, Paulo José Ferreira; Serra, Andrey Jorge

2016-12-01

There was no data for cardiac repercussion of exercise training associated with tobacco smoking. This issue is interesting because some smoking people can be enrolled in an exercise-training program. Thus, we evaluated swimming training effects on the function and structural myocardial in rats exposed to tobacco smoking. Male Wistar rats were assigned to one of four groups: C, untrained rats without exposure to tobacco smoking; E, exercised rats without exposure to tobacco smoking; CS, untrained rats exposed to tobacco smoking; ECS, exercised rats exposed to tobacco smoking. Rats swam five times a week twice daily (60min per session) for 8 weeks. Before each bout exercise, rats breathed smoke from 20 cigarettes for 60min. Twenty-four hours after the last day of the protocol, papillary muscles were isolated for in vitro analysis of myocardial mechanics. The myocardial mass and nuclear cardiomyocyte volume were used as hypertrophy markers, and collagen content was determined by picrosirius red staining. There was a well-pronounced myocardial hypertrophic effect for two interventions. The exercise blunted myocardial collagen increases induced by tobacco smoking. However, exercise and tobacco-smoking association was deleterious to myocardial performance. Thereby, in vitro experiments with papillary muscles contracting in isometric showed impairment myocardial inotropism in exercised rats exposed to tobacco smoking. This work presents novel findings on the role of exercise training on cardiac remodeling induced by tobacco smoking. Although exercise has mitigated tissue fibrosis, their association with tobacco smoking exacerbated hypertrophy and in vitro myocardial dysfunction. This is first study to show that the association of an aerobic exercise training with tobacco smoking intensifies the phenotype of pathological cardiac hypertrophy. Therefore, the combination of interventions resulted in exacerbated myocardial hypertrophy and contractility dysfunction. These findings have significant clinical implication because some smoking people can be enrolled in an exercise-training program. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

PubMed Central

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

2009-01-01

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

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

PubMed

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

2016-01-25

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

Carriers of the hypertrophic cardiomyopathy MYBPC3 mutation are characterized by reduced myocardial efficiency in the absence of hypertrophy and microvascular dysfunction.

PubMed

Timmer, Stefan A J; Germans, Tjeerd; Brouwer, Wessel P; Lubberink, Mark; van der Velden, Jolanda; Wilde, Arthur A M; Christiaans, Imke; Lammertsma, Adriaan A; Knaapen, Paul; van Rossum, Albert C

2011-12-01

Next to left ventricular (LV) hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by microvascular dysfunction and reduced myocardial external efficiency (MEE). Insights into the presence of these abnormalities as early markers of disease are of clinical importance in risk stratification, and development of therapeutic approaches. Therefore, the aim was to investigate myocardial perfusion and energetics in genotype-positive, phenotype-negative HCM subjects (carriers). Fifteen carriers of an MYBPC3 mutation underwent [(15)O]water positron emission tomography (PET) to assess myocardial blood flow (MBF). [(11)C]acetate PET was performed to obtain myocardial oxygen consumption (MVO(2)). By use of cardiovascular magnetic resonance imaging, LV volumes and mass were defined to calculate MEE, i.e. the ratio between external work and MVO(2). Eleven healthy, genotype-negative, family relatives underwent similar scanning protocols to serve as a control group. Left ventricular mass was comparable between carriers and controls (93 ± 25 vs. 99 ± 21 g, P= 0.85), as was MBF at rest (1.19 ± 0.34 vs. 1.18 ± 0.32 mL min(-1) g(-1), P= 0.92), and during hyperaemia (3.87 ± 0.75 vs. 3.96 ± 0.86 mL min(-1) g(-1), P= 0.77). Myocardial oxygen consumption averaged 0.137 ± 0.057 mL min(-1) g(-1) in carriers and was not significantly different from controls (0.125 ± 0.043 mL min(-1) g(-1), P= 0.29). Cardiac work, however, was slightly reduced in carriers (7398 ± 1384 vs. 9139 ± 2484 mmHg mL in controls, P= 0.08). As a consequence, MEE was significantly decreased in carriers (27 ± 10 vs. 36 ± 8% in controls, P= 0.02). Carriers display reduced myocardial work generation in relation to oxygen consumption, in the absence of hypertrophy and flow abnormalities. Hence, impaired myocardial energetics may constitute a primary component of HCM pathogenesis.

Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia.

PubMed

Tao, Yong-Kang; Zeng, Heng; Zhang, Guo-Qiang; Chen, Sean T; Xie, Xue-Jiao; He, Xiaochen; Wang, Shuo; Wen, Hongyan; Chen, Jian-Xiong

2017-06-01

Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development. This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI. Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2 + /Sca1 + and NG2 + /c-kit + progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b + macrophage infiltration into ischemic areas compared to that of WT mice. Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the pre-existing coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation. Copyright © 2016. Published by Elsevier B.V.

Punjabi Sikh patients' cardiac rehabilitation experiences following myocardial infarction: a qualitative analysis.

PubMed

Galdas, Paul M; Kang, H Bindy K

2010-11-01

To explore the cardiac rehabilitation experiences of Punjabi Sikh patients post myocardial infarction. Punjabi Sikh people are at significantly higher risk of mortality from myocardial infarction compared with those of European descent. Punjabi Sikh patients' participation in cardiac rehabilitation post myocardial infarction is therefore likely to yield considerable benefits. However, uptake of cardiac rehabilitation by South Asian people has been reported to be modest. Previous investigators have seldom provided insight into experiences of Punjabi Sikh patients post myocardial infarction and the steps that can be taken to improve the appropriateness of cardiac rehabilitation programmes for this at-risk patient group. Interpretive qualitative design. In-depth interviews, based on the McGill Illness Narrative Interview schedule, with 15 Punjabi Sikh patients post myocardial infarction attending a cardiac rehabilitation programme in British Columbia, Canada, were conducted; thematic analysis using grounded theory methods of coding and constant comparative analysis was employed. Four mutually exclusive themes emerged relating to the salient aspects of participants' cardiac rehabilitation experience: 'making sense of the diagnosis', 'practical dietary advice', 'ongoing interaction with peers and the multi-disciplinary team' and 'transport and attendance'. The themes identified point towards some of the ingredients necessary for providing culturally appropriate cardiac rehabilitation interventions for Punjabi Sikh patients following myocardial infarction. The findings highlight the importance of providing culturally relevant rehabilitation advice about diet and lifestyle changes and providing time for ongoing dialogue with support from health care professionals and peers. The findings from this study also illustrate the need to avoid generalisations about the impact religious beliefs may have on South Asian individuals' willingness to adhere to cardiac rehabilitation advice and make lifestyle adjustments. This study raises awareness of some of the salient features of experiences of Punjabi Sikh patients with post myocardial infarction that can help guide nurses to provide culturally appropriate cardiac rehabilitation and coronary health promotion. © 2010 Blackwell Publishing Ltd.

Multiple coronary stenting negatively affects myocardial recovery after coronary bypass grafting.

PubMed

Yajima, Shin; Yoshioka, Daisuke; Fukushima, Satsuki; Toda, Koichi; Miyagawa, Shigeru; Yoshikawa, Yasushi; Hata, Hiroki; Saito, Shunsuke; Domae, Keitaro; Sawa, Yoshiki

2018-05-14

We aimed to elucidate the relationship between the magnitude of myocardial recovery after coronary artery bypass grafting (CABG) and the prognosis and to explore the predictors of myocardial non-recovery. Eighty-one patients with a preoperative left ventricular ejection fraction (LVEF) ≤ 40% who underwent isolated CABG between 2002 and 2015 and had undergone echocardiographic follow-up (median follow-up, 3.1 years; interquartile range 1.2-6.0 years) were analyzed. The Recovery group comprised patients with LVEF improvement ≥ 10%, whereas the Non-recovery group comprised those with an LVEF improvement < 10%. Group differences in overall survival, freedom from major adverse cardiac events (MACEs), and readmission due to heart failure were evaluated. In addition, the risk factors for LVEF non-recovery were evaluated in a multivariate analysis. A total of 39 patients (48%) were in the Recovery group, whereas 42 patients (52%) were in the Non-recovery group. Although the survival and freedom from MACE rates were comparable, the rate of freedom from heart failure requiring hospitalization at 1, 5, and 8 years of follow-up was significantly lower in the Non-recovery group than in the Recovery group (p = 0.012). A history of percutaneous coronary intervention (PCI) was an exclusive independent risk factor for post-CABG myocardial non-recovery (odds ratio, 16.0; 95% confidence interval, 3.44-125). Furthermore, the number of coronary stents was negatively correlated with LVEF recovery (r = - 0.460, p = 0.024). Great consideration should be taken when performing CABG in patients with left ventricular dysfunction and a history of PCI, particularly in those with multiple coronary stents.

Serum Chloride and Sodium Interplay in Patients With Acute Myocardial Infarction and Heart Failure With Reduced Ejection Fraction: An Analysis From the High-Risk Myocardial Infarction Database Initiative.

PubMed

Ferreira, João Pedro; Girerd, Nicolas; Duarte, Kevin; Coiro, Stefano; McMurray, John J V; Dargie, Henry J; Pitt, Bertram; Dickstein, Kenneth; Testani, Jeffrey M; Zannad, Faiez; Rossignol, Patrick

2017-02-01

Serum chloride levels were recently found to be independently associated with mortality in heart failure (HF). We investigated the relationship between serum chloride and clinical outcomes in 7195 subjects with acute myocardial infarction complicated by reduced left ventricular function and HF. The studied outcomes were all-cause mortality, cardiovascular mortality, and hospitalization for HF. Both chloride and sodium had a nonlinear association with the studied outcomes (P<0.05 for linearity). Patients in the lowest chloride tertile (chloride ≤100) were older, had more comorbidities, and had lower sodium levels (P<0.05 for all). Serum chloride showed a significant interaction with sodium with regard to all studied outcomes (P for interaction <0.05 for all). The lowest chloride tertile (≤100 mmol/L) was associated with increased mortality rates in the context of lower sodium (≤138 mmol/L; adjusted hazard ratio [95% confidence interval] for all-cause mortality=1.42 (1.14-1.77); P=0.002), whereas in the context of higher sodium levels (>141 mmol/L), the association with mortality was lost. Spline-transformed chloride and its interaction with sodium did not add significant prognostic information on top of other well-established prognostic variables (P>0.05 for all outcomes). In post-myocardial infarction with systolic dysfunction and HF, low serum chloride was associated with mortality (but not hospitalization for HF) in the setting of lower sodium. Overall, chloride and its interaction with sodium did not add clinically relevant prognostic information on top of other well-established prognostic variables. Taken together, these data support an integrated and critical consideration of chloride and sodium interplay. © 2017 American Heart Association, Inc.

Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats

PubMed Central

Quinones, Quintin J.; Zhang, Zhiquan; Ma, Qing; Smith, Michael P.; Soderblom, Erik; Moseley, M. Arthur; Bain, James; Newgard, Christopher B.; Muehlbauer, Michael J.; Hirschey, Matthew; Drew, Kelly L.; Barnes, Brian M.; Podgoreanu, Mihai V.

2016-01-01

Background Hibernation is an adaptation to extreme environments known to provide organ protection against ischemia-reperfusion (I/R) injury. An unbiased systems approach was utilized to investigate hibernation-induced changes characteristic of the hibernator cardioprotective phenotype, by comparing the myocardial proteome of winter hibernating arctic ground squirrels (HIB AGS), summer active (SA) AGS, and rats subjected to I/R, and further correlating with targeted metabolic changes. Methods In a well-defined rodent model of I/R by deep hypothermic circulatory arrest followed by 3h or 24h of reperfusion or sham, myocardial protein abundance in AGS (HIB, SA) and rats (n=4-5/group) was quantified by label-free proteomics (n=4-5/group), and correlated with metabolic changes. Results Compared to rats, HIB AGS displayed markedly reduced plasma levels of Troponin I, myocardial apoptosis, and left ventricular contractile dysfunction. Of the 1,320 rat and 1,478 AGS proteins identified, 545 were differentially expressed between HIB AGS and rat hearts (47% upregulated, 53% downregulated). Gene ontology analysis revealed downregulation in HIB AGS hearts of most proteins involved in mitochondrial energy transduction, including electron transport chain complexes, acetyl CoA biosynthesis, Krebs cycle, glycolysis and ketogenesis. Conversely, fatty acid oxidation enzymes and Sirtuin-3 were upregulated in HIB AGS, with preserved peroxisome proliferator activated receptor-α activity and reduced tissue levels of acylcarnitines and ceramides following I/R. Conclusions Natural cardioprotective adaptations in hibernators involve extensive metabolic remodeling, featuring increased expression of fatty acid metabolic proteins and reduced levels of toxic lipid metabolites. Robust upregulation of Sirtuin-3 suggests that post-translational modifications may underlie organ protection in hibernating mammals. PMID:27187119

Is the epicardial left ventricular lead implantation an alternative approach to percutaneous attempt in patients with Steinert disease? A case report

PubMed Central

PAPA, ANDREA ANTONIO; RAGO, ANNA; PETILLO, ROBERTA; D’AMBROSIO, PAOLA; SCUTIFERO, MARIANNA; FEO, MARISA DE; MAIELLO, CIRO; PALLADINO, ALBERTO

2017-01-01

Steinert’s disease or Myotonic Dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder characterized by myotonia, muscle and facial weakness, cataracts, cognitive, endocrine and gastrointestinal involvement, and cardiac conduction abnormalities. Although mild myocardial dysfunction may be detected in this syndrome with age, overt myocardial dysfunction with heart failure is not frequent. Cardiac resynchronization therapy is an effective treatment to improve morbidity and reduce mortality in patients with DM1 showing intra-ventricular conduction delay and/or congestive heart failure. We report the case of a patient with Steinert disease showing an early onset ventricular dysfunction due to chronic right ventricular apical pacing, in which an epicardial left ventricular lead implantation was performed following the failure of the percutaneous attempt. As no relief in symptoms of heart failure, nor an improvement of left ventricular ejection fraction and reverse remodelling was observed six months later, the patient was addressed to the heart transplantation.

Right Ventricular Dysfunction Impairs Effort Tolerance Independent of Left Ventricular Function Among Patients Undergoing Exercise Stress Myocardial Perfusion Imaging.

PubMed

Kim, Jiwon; Di Franco, Antonino; Seoane, Tania; Srinivasan, Aparna; Kampaktsis, Polydoros N; Geevarghese, Alexi; Goldburg, Samantha R; Khan, Saadat A; Szulc, Massimiliano; Ratcliffe, Mark B; Levine, Robert A; Morgan, Ashley E; Maddula, Pooja; Rozenstrauch, Meenakshi; Shah, Tara; Devereux, Richard B; Weinsaft, Jonathan W

2016-11-01

Right ventricular (RV) and left ventricular (LV) function are closely linked due to a variety of factors, including common coronary blood supply. Altered LV perfusion holds the potential to affect the RV, but links between LV ischemia and RV performance, and independent impact of RV dysfunction on effort tolerance, are unknown. The population comprised 2051 patients who underwent exercise stress myocardial perfusion imaging and echo (5.5±7.9 days), among whom 6% had echo-evidenced RV dysfunction. Global summed stress scores were ≈3-fold higher among patients with RV dysfunction, attributable to increments in inducible and fixed LV perfusion defects (all P≤0.001). Regional inferior and lateral wall ischemia was greater among patients with RV dysfunction (both P<0.01), without difference in corresponding anterior defects (P=0.13). In multivariable analysis, inducible inferior and lateral wall perfusion defects increased the likelihood of RV dysfunction (both P<0.05) independent of LV function, fixed perfusion defects, and pulmonary artery pressure. Patients with RV dysfunction demonstrated lesser effort tolerance whether measured by exercise duration (6.7±2.8 versus 7.9±2.9 minutes; P<0.001) or peak treadmill stage (2.6±0.9 versus 3.1±1.0; P<0.001), paralleling results among patients with LV dysfunction (7.0±2.9 versus 8.0±2.9; P<0.001|2.7±1.0 versus 3.1±1.0; P<0.001 respectively). Exercise time decreased stepwise in relation to both RV and LV dysfunction (P<0.001) and was associated with each parameter independent of age or medication regimen. Among patients with known or suspected coronary artery disease, regional LV ischemia involving the inferior and lateral walls confers increased likelihood of RV dysfunction. RV dysfunction impairs exercise tolerance independent of LV dysfunction. © 2016 American Heart Association, Inc.

Acute Heart Failure Triggered by Coronary Spasm With Transient Left Ventricular Dysfunction.

PubMed

Adachi, Yusuke; Sakakura, Kenichi; Ibe, Tatsuro; Yoshida, Nanae; Wada, Hiroshi; Fujita, Hideo; Momomura, Shin-Ichi

2017-04-06

Coronary spasm is abnormal contraction of an epicardial coronary artery resulting in myocardial ischemia. Coronary spasm induces not only depressed myocardial contractility, but also incomplete myocardial relaxation, which leads to elevated ventricular filling pressure. We herein report the case of a 55-year-old woman who had repeated acute heart failure caused by coronary spasm. Acetylcholine provocation test with simultaneous right heart catheterization was useful for the diagnosis of elevated ventricular filling pressure as well as coronary artery spasm. We should add coronary spasm to a differential diagnosis for repeated acute heart failure.

Estrogen Receptors α and β Play Major Roles in Ethanol-Evoked Myocardial Oxidative Stress and Dysfunction in Conscious Ovariectomized Rats.

PubMed

Yao, Fanrong; Abdel-Rahman, Abdel A

2017-02-01

We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E 2 ), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ERα signaling in this phenomenon. However, a limitation of selective pharmacological loss-of-function approach is the potential contribution of the other 2 ERs to the observed effects because crosstalk exists between the 3 ERs. Here, we adopted a "regain"-of-function approach (using selective ER subtype agonists) to identify the ER subtype(s) required for unraveling the E 2 -dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats. OVX rats received a selective ERα (PPT), ERβ (DPN), or GPER (G1) agonist (10 μg/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemodynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies. EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, dP/dt max , and MAP after acute ERα (PPT) or ERβ (DPN) activation. These responses were associated with increases in the phosphorylation of ERK1/2 and eNOS, and in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the myocardium. GPER activation (G1) only unraveled a modest EtOH-evoked hypotension and elevation in myocardial ROS. PPT enhanced catalase, DPN reduced ALDH2, while G1 had no effect on the activity of either enzyme, and none of the agonists influenced alcohol dehydrogenase or CYP2E1 activities in the myocardium. Blood EtOH concentration (96.0 mg/dl) was significantly reduced following ERα (59.8 mg/dl) or ERβ (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats. ERα and ERβ play major roles in the E 2 -dependent myocardial dysfunction caused by EtOH by promoting combined accumulation of cardiotoxic (ROS and MDA) and cardiodepressant (NOS-derived NO) molecules in female myocardium. Copyright © 2016 by the Research Society on Alcoholism.

The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities

PubMed Central

Frangogiannis, Nikolaos G

2014-01-01

Extensive necrosis of ischemic cardiomyocytes in the infarcted myocardium activates the innate immune response triggering an intense inflammatory reaction. Release of danger signals from dying cells and damaged matrix activates the complement cascade and stimulates Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, resulting in activation of the Nuclear Factor (NF)-κB system and induction of chemokines, cytokines and adhesion molecules. Subsequent infiltration of the infarct with neutrophils and mononuclear cells serves to clear the wound from dead cells and matrix debris, while stimulating reparative pathways. In addition to its role in repair of the infarcted heart and formation of a scar, the immune system is also involved in adverse remodeling of the infarcted ventricle. Overactive immune responses and defects in suppression, containment and resolution of the post-infarction inflammatory reaction accentuate dilative remodeling in experimental models and may be associated with chamber dilation, systolic dysfunction and heart failure in patients surviving a myocardial infarction. Interventions targeting the inflammatory response to attenuate adverse remodeling may hold promise in patients with myocardial infarction that exhibit accentuated, prolonged, or dysregulated immune responses to the acute injury. PMID:24072174

Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

PubMed

Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

2015-01-01

Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials

PubMed Central

You, Zhigang; Huang, Lin; Cheng, Xiaoshu; Wu, Qinghua; Jiang, Xinghua; Wu, Yanqing

2016-01-01

Background and aim Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. Method Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. Results Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: −6.52 to −1.68; P=0.0009) and mechanical ventilation (h) support (95% CI −5.00 to −0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). Conclusion Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients. PMID:26766900

Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials.

PubMed

You, Zhigang; Huang, Lin; Cheng, Xiaoshu; Wu, Qinghua; Jiang, Xinghua; Wu, Yanqing

2016-01-01

Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: -6.52 to -1.68; P=0.0009) and mechanical ventilation (h) support (95% CI -5.00 to -0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients.

Should the patient with coronary artery disease use sildenafil?

PubMed

Cheitlin, Melvin D

2003-01-01

Since the etiology of erectile dysfunction is frequently related to endothelial dysfunction, a problem in common with much vascular disease, erectile dysfunction disproportionately affects patients with cardiovascular disease. With the development of phosphodiesterase 5 inhibitors, the first of which was sildenafil (Viagra), an effective oral medication became available. The question of safety of these drugs, especially in patients with latent or overt coronary artery disease, is of concern. Sildenafil relaxes smooth muscle and therefore lowers systolic and diastolic blood pressure slightly. With organic nitrates, the drop in blood pressure is potentiated, at times dangerously, thereby making it contraindicated to take nitrates within 24 hours of using sildenafil. In double-blind, placebo-controlled trials, there was no difference between sildenafil subjects and control patients in the incidence of myocardial infarction, cardiovascular, and total deaths. Coronary disease patients with stable angina, controlled on medications, were included in the trials. Therefore, sildenafil, as a drug, is safe in such patients. With a patient with coronary artery disease suddenly engaging in the physical exercise associated with sexual intercourse, there is the danger of increased risk of precipitating myocardial infarction or death. The cardiovascular metabolic cost of sexual activity is reviewed and appears to be approximately at the level of 3-5 metabolic equivalents of exercise. Sexual activity occurs within 2 hours of the onset of an acute myocardial infarction in <1.0% of patients. Although sexual intercourse is estimated to increase the risk of myocardial infarction by a factor of 2x, there is still only a very small increase in risk, a risk acceptable to patients who feel their quality of life will be markedly improved by their ability to engage in sexual activity.

A mathematical model for active contraction in healthy and failing myocytes and left ventricles.

PubMed

Cai, Li; Wang, Yongheng; Gao, Hao; Li, Yiqiang; Luo, Xiaoyu

2017-01-01

Cardiovascular disease is one of the leading causes of death worldwide, in particular myocardial dysfunction, which may lead to heart failure eventually. Understanding the electro-mechanics of the heart will help in developing more effective clinical treatments. In this paper, we present a multi-scale electro-mechanics model of the left ventricle (LV). The Holzapfel-Ogden constitutive law was used to describe the passive myocardial response in tissue level, a modified Grandi-Pasqualini-Bers model was adopted to model calcium dynamics in individual myocytes, and the active tension was described using the Niederer-Hunter-Smith myofilament model. We first studied the electro-mechanics coupling in a single myocyte in the healthy and diseased left ventricle, and then the single cell model was embedded in a dynamic LV model to investigate the compensation mechanism of LV pump function due to myocardial dysfunction caused by abnormality in cellular calcium dynamics. The multi-scale LV model was solved using an in-house developed hybrid immersed boundary method with finite element extension. The predictions of the healthy LV model agreed well with the clinical measurements and other studies, and likewise, the results in the failing states were also consistent with clinical observations. In particular, we found that a low level of intracellular Ca2+ transient in myocytes can result in LV pump function failure even with increased myocardial contractility, decreased systolic blood pressure, and increased diastolic filling pressure, even though they will increase LV stroke volume. Our work suggested that treatments targeted at increased contractility and lowering the systolic blood pressure alone are not sufficient in preventing LV pump dysfunction, restoring a balanced physiological Ca2+ handling mechanism is necessary.

Magnetic Resonance Characterization of Cardiac Adaptation and Myocardial Fibrosis in Pulmonary Hypertension Secondary to Systemic-To-Pulmonary Shunt.

PubMed

Pereda, Daniel; García-Lunar, Inés; Sierra, Federico; Sánchez-Quintana, Damián; Santiago, Evelyn; Ballesteros, Constanza; Encalada, Juan F; Sánchez-González, Javier; Fuster, Valentín; Ibáñez, Borja; García-Álvarez, Ana

2016-09-01

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are strong predictors of morbidity and mortality among patients with congenital heart disease. Early detection of RV involvement may be useful in the management of these patients. We aimed to assess progressive cardiac adaptation and quantify myocardial extracellular volume in an experimental porcine model of PH because of aorto-pulmonary shunt using cardiac magnetic resonance (CMR). To characterize serial cardiac adaptation, 12 pigs (aorto-pulmonary shunt [n=6] or sham operation [n=6]) were evaluated monthly with right heart catheterization, CMR, and computed tomography during 4 months, followed by pathology analysis. Extracellular volume by CMR in different myocardial regions was studied in 20 animals (aorto-pulmonary shunt [n=10] or sham operation [n=10]) 3 months after the intervention. All shunted animals developed PH. CMR evidenced progressive RV hypertrophy and dysfunction secondary to increased afterload and left ventricular dilatation secondary to volume overload. Shunt flow by CMR strongly correlated with PH severity, left ventricular end-diastolic pressure, and left ventricular dilatation. T1-mapping sequences demonstrated increased extracellular volume at the RV insertion points, the interventricular septum, and the left ventricular lateral wall, reproducing the pattern of fibrosis found on pathology. Extracellular volume at the RV insertion points strongly correlated with pulmonary hemodynamics and RV dysfunction. Prolonged systemic-to-pulmonary shunting in growing piglets induces PH with biventricular remodeling and myocardial fibrosis that can be detected and monitored using CMR. These results may be useful for the diagnosis and management of congenital heart disease patients with pulmonary overcirculation. © 2016 American Heart Association, Inc.

Myocardial Viability and Impact of Surgical Ventricular Reconstruction on Outcomes of Patients with Severe Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery: Results of the Surgical Treatment for Ischemic Heart Failure (STICH) Trial

PubMed Central

Holly, Thomas A.; Bonow, Robert O.; Arnold, J. Malcolm O.; Oh, Jae K.; Varadarajan, Padmini; Pohost, Gerald M.; Haddad, Haissam; Jones, Robert H.; Velazquez, Eric J.; Birkenfeld, Bozena; Asch, Federico M.; Malinowski, Marcin; Barretto, Rodrigo; Kalil, Renato A.K.; Berman, Daniel S.; Sun, Jie-Lena; Lee, Kerry L.; Panza, Julio A.

2014-01-01

Objective In the Surgical Treatment for Ischemic Heart Failure (STICH) trial, surgical ventricular reconstruction plus coronary artery bypass surgery was not associated with a reduction in the rate of death or cardiac hospitalization compared to bypass alone. We hypothesized that the absence of viable myocardium identifies patients with coronary artery disease and left ventricular dysfunction who have a greater benefit with coronary artery bypass graft surgery and surgical ventricular reconstruction compared to bypass alone. Methods Myocardial viability was assessed by single photon computed tomography in 267 of the 1,000 patients randomized to bypass or bypass plus surgical ventricular reconstruction in STICH. Myocardial viability was assessed on a per patient basis as well as regionally based on pre-specified criteria. Results At 3 years, there was no difference in mortality or the combined outcome of death or cardiac hospitalization between those with and those without viability, and there was no significant interaction between the type of surgery and global viability status with respect to mortality or death plus cardiac hospitalization. Furthermore, there was no difference in mortality or death plus cardiac hospitalization between those with and without anterior wall or apical scar, and no significant interaction between the presence of scar in these regions and the type of surgery with respect to mortality. Conclusion In patients with coronary artery disease and severe regional left ventricular dysfunction, assessment of myocardial viability does not identify patients who will derive a mortality benefit from adding surgical ventricular reconstruction to coronary artery bypass graft surgery. PMID:25152476

Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine

PubMed Central

Faller, Kiterie M E; Atzler, Dorothee; McAndrew, Debra J; Zervou, Sevasti; Whittington, Hannah J; Simon, Jillian N; Aksentijevic, Dunja; ten Hove, Michiel; Choe, Chi-un; Isbrandt, Dirk; Casadei, Barbara; Schneider, Jurgen E; Neubauer, Stefan; Lygate, Craig A

2018-01-01

Abstract Aims Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases. PMID:29236952

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

PubMed

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

2016-02-15

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

N-Acetylcysteine Restores Sevoflurane Postconditioning Cardioprotection against Myocardial Ischemia-Reperfusion Injury in Diabetic Rats.

PubMed

Lin, Jiefu; Wang, Tingting; Li, Yalan; Wang, Mengxia; Li, Haobo; Irwin, Michael G; Xia, Zhengyuan

2016-01-01

The effect of sevoflurane postconditioning (sevo-postC) cardioprotection is compromised in diabetes which is associated with increased oxidative stress. We hypothesized that antioxidant N-Acetylcysteine may enhance or restore sevo-postC cardioprotection in diabetes. Control or streptozotocin-induced Type 1 diabetic rats were either untreated or treated with N-Acetylcysteine for four weeks starting at five weeks after streptozotocin injection and were subjected to myocardial ischemia-reperfusion injury (IRI), in the absence or presence of sevo-postC. Diabetes showed reduction of cardiac STAT3 activation (p-STAT3) and adiponectin with concomitantly increase of FoxO1 and CD36, which associated with reduced sevo-postC cardioprotection. N-Acetylcysteine and sevo-postC synergistically reduced the infarct size in diabetic groups. N-Acetylcysteine remarkably increased cardiac p-STAT3 which was further enhanced by sevo-postC. N-Acetylcysteine but not sevo-postC decreased myocardial FoxO1 while sevo-postC but not N-Acetylcysteine significantly increased myocardiac adiponectin in diabetic rats. It is concluded that late stage diabetic rats displayed reduction of cardiac p-STAT3, adiponectin deficiency, and increase of FoxO1 and CD36 expression, which may be responsible for the loss of myocardial responsiveness to sevo-postC cardioprotection. N-Acetylcysteine restored Sevo-postC cardioprotection in diabetes possibly through enhancing cardiac p-STAT3 and adiponectin and reducing Fox1 and CD36.

Albumin, a marker for post-operative myocardial damage in cardiac surgery.

PubMed

van Beek, Dianne E C; van der Horst, Iwan C C; de Geus, A Fred; Mariani, Massimo A; Scheeren, Thomas W L

2018-06-06

Low serum albumin (SA) is a prognostic factor for poor outcome after cardiac surgery. The aim of this study was to estimate the association between pre-operative SA, early post-operative SA and postoperative myocardial injury. This single center cohort study included adult patients undergoing cardiac surgery during 4 consecutive years. Postoperative myocardial damage was defined by calculating the area under the curve (AUC) of troponin (Tn) values during the first 72 h after surgery and its association with SA analyzed using linear regression and with multivariable linear regression to account for patient related and procedural confounders. The association between SA and the secondary outcomes (peri-operative myocardial infarction [PMI], requiring ventilation >24 h, rhythm disturbances, 30-day mortality) was studied using (multivariable) log binomial regression analysis. In total 2757 patients were included. The mean pre-operative SA was 29 ± 13 g/l and the mean post-operative SA was 26 ± 6 g/l. Post-operative SA levels (on average 26 min after surgery) were inversely associated with postoperative myocardial damage in both univariable analysis (regression coefficient - 0.019, 95%CI -0.022/-0.015, p < 0.005) and after adjustment for patient related and surgical confounders (regression coefficient - 0.014 [95% CI -0.020/-0.008], p < 0.0005). Post-operative albumin levels were significantly correlated with the amount of postoperative myocardial damage in patients undergoing cardiac surgery independent of typical confounders. Copyright © 2018. Published by Elsevier Inc.

Fully automatic left ventricular myocardial strain estimation in 2D short-axis tagged magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Morais, Pedro; Queirós, Sandro; Heyde, Brecht; Engvall, Jan; 'hooge, Jan D.; Vilaça, João L.

2017-09-01

Cardiovascular diseases are among the leading causes of death and frequently result in local myocardial dysfunction. Among the numerous imaging modalities available to detect these dysfunctional regions, cardiac deformation imaging through tagged magnetic resonance imaging (t-MRI) has been an attractive approach. Nevertheless, fully automatic analysis of these data sets is still challenging. In this work, we present a fully automatic framework to estimate left ventricular myocardial deformation from t-MRI. This strategy performs automatic myocardial segmentation based on B-spline explicit active surfaces, which are initialized using an annular model. A non-rigid image-registration technique is then used to assess myocardial deformation. Three experiments were set up to validate the proposed framework using a clinical database of 75 patients. First, automatic segmentation accuracy was evaluated by comparing against manual delineations at one specific cardiac phase. The proposed solution showed an average perpendicular distance error of 2.35  ±  1.21 mm and 2.27  ±  1.02 mm for the endo- and epicardium, respectively. Second, starting from either manual or automatic segmentation, myocardial tracking was performed and the resulting strain curves were compared. It is shown that the automatic segmentation adds negligible differences during the strain-estimation stage, corroborating its accuracy. Finally, segmental strain was compared with scar tissue extent determined by delay-enhanced MRI. The results proved that both strain components were able to distinguish between normal and infarct regions. Overall, the proposed framework was shown to be accurate, robust, and attractive for clinical practice, as it overcomes several limitations of a manual analysis.

Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs.

PubMed

Shiroshita-Takeshita, Akiko; Sakabe, Masao; Haugan, Ketil; Hennan, James K; Nattel, Stanley

2007-01-23

Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction-enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia. Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (P=0.003) and increased AF duration (P=0.008), with AF lasting >3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (P=0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (P=0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemia-induced conduction slowing and AF duration increases. Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates.

Hypercholesterolemia and Myocardial function evaluated via Tissue Doppler Imaging

PubMed Central

2009-01-01

Objective To establish a link between hypercholesterolemia and myocardial dysfunction. Background Heart failure is a complex disease involving changes in systolic and diastolic function. Newer echocardiographic imaging modalities may be able to detect discreet changes in myocardial function associated with hypercholesterolemia. Therefore we sought to establish a link between hypercholesterolemia and myocardial dysfunction with tissue Doppler imaging (TDI). Methods Twenty-seven rabbits were studied: 7 were fed normal chow (group 1) and 20 a high cholesterol diet (10 with ezetimibe, 1 mg/kg/day; group 2 and 10 without, group 3). Echocardiographic images were obtained under general anesthesia. Serum cholesterol levels were obtained at baseline, 3 and 6 months and myocardial cholesterol levels measured following euthanasia. Results Doppler measurements, including E/A, E'/A' and S' were significantly lower in group 3 compared to both groups 1 and 2 but no significant differences were noted in chamber sizes or ejection fraction among the groups. Average serum cholesterol was higher in group 3 compared to groups 1 and 2 respectively (495 ± 305 mg/dl vs. 114 ± 95 mg/dl and 87 ± 37 mg/dl; p < 0.01). Myocardial cholesterol content was also higher in group 3 compared to group 2 (0.10 ± 0.04 vs. 0.06 mg/dl ± 0.02; p = 0.05). There was significant correlation between S', E'/A', E/E' and serum cholesterol (r2 = 0.17 p = 0.04, r2 = 0.37 p = 0.001 and r2 = 0.24 p = 0.01). Conclusion Cholesterol load in the serum and myocardium was significantly associated with decreased systolic and diastolic function by TDI. Moreover, lipid lowering was protective. PMID:19943937

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

[Renal dysfunction in patients with myocardial infarction concurrent with type 2 diabetes mellitus].

PubMed

Evseeva, M V; Karetnikova, V N; Barbarash, O L

2015-01-01

Carbohydrate metabolic disturbances are an independent risk factor for not only the development, but also poor course of cardiovascular diseases, particularly those concurrent with renal dysfunction (RD). This factor acquires particular relevance due to the fact that the incidence of type 2 diabetes mellitus significantly continues to rise worldwide. The review considers the main mechanisms and common components of the pathogenesis of RD, as well as the constituents forming its basis in the presence of carbohydrate metabolic disturbances. Moreover, it highlights the timely detection of RD, a search for new biomarkers of prognostic value for cardiovascular events, and the early diagnosis of RD. The review unveils the present view of optimal diagnostic and management tactics for patients with myocardial infarction concurrent with background diseases.

Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases

PubMed Central

Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito; Elliott, Katherine J.; Traynham, Christopher J.; Ibetti, Jessica; Eguchi, Satoru; Leosco, Dario; Ferrara, Nicola; Rengo, Giuseppe; Koch, Walter J.

2016-01-01

Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation by aldosterone leads to pathological myocardial signalling mediated by mitochondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic action. Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve cross-talk with the angiotensin II type-1 receptor (AT1R). Most importantly, we show that ventricular dysfunction caused by chronic hyper-aldosteronism in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 KO mice. However, aldosterone-induced cardiac hypertrophy is totally prevented in Grk5 KO mice. We also show human data consistent with MR activation status in heart failure influencing GRK2 levels. Therefore, our study uncovers GRKs as targets for ameliorating pathological cardiac effects associated with high-aldosterone levels. PMID:26932512

75 FR 54493 - Cardiovascular Devices; Reclassification of Certain Percutaneous Transluminal Coronary...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

... catheters when used for treatment of acute myocardial infarction (MI), treatment of in-stent restenosis (ISR) and/or post-deployment stent expansion. III. Device Description FDA identifies this generic type of... for the treatment of acute myocardial infarction; treatment of in-stent restenosis (ISR) and/or post...

Value of speckle tracking echocardiography for detection of clinically silent left ventricular dysfunction in patients with β-thalassemia.

PubMed

Parsaee, Mozhgan; Saedi, Sedigheh; Joghataei, Pegah; Azarkeivan, Azita; Alizadeh Sani, Zahra

2017-10-01

β-Thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia requiring chronic transfusion therapy. Cardiac involvement is the main cause of death in patients with thalassemia major. The narrow border is between overt myocardial dysfunction and clinically silent left ventricular (LV) dysfunction in patients with thalassemia. Therefore, we need novel parameters in different imaging techniques to discover cardiac involvement in an early and subtle stage. We explore to find a novel, straightforward and informative parameter in echocardiography as a noninvasive, economical and really routine in clinical practice. In this prospective study, 55 patients, who are known cases of β-thalassemia major, receiving long-term blood transfusions and undergoing iron chelation therapy were enrolled. Ferritin level, cardiac magnetic resonance (CMR) T2 * value, full conventional echocardiography and speckle tracking, LV regional circumferential and longitudinal strain values (%) and time-to-peak strain (ms) of 17 segments cardiac model in eyeball tomogram were measured. There was a significant reduction in global longitudinal strain (GLS) (-20.9% ± 1.9 vs. -22.2 ± 1.03) and also basal segments longitudinal strain compared to normal subjects group (-17.4% ± 2.7 vs. -19.6% ± 1.2). There was no significant difference in circumferential strain value between thalassemia patients and normal control group. Interestingly, there was no significant correlation between GLS and CMR T2 * values showing no association between cardiac iron load and longitudinal strain. Speckle tracking echocardiography could be used as a feasible method for evaluating subclinical myocardial dysfunction in patients with thalassemia major. Echocardiography, using GLS, could predict clinically silent myocardial dysfunction independent of CMR (T2 * value) and extension of iron deposition. Our study also puts forward other causes such as chronic tissue hypoxia resulting from chronic anemia as a root cause and initiating factor for subsequent injury by the iron deposition. Speckle tracking can recognize the cardiac involvement in really early stages.

[Anomalous origin of the left coronary artery from the pulmonary trunk with myocardial infarction and severe left ventricular dysfunction in infancy--assessment of myocardial damage using SPECT studies with 201TlCl and 123I-BMIPP].

PubMed

Miyamoto, T; Horigome, H; Sato, H; Yamada, M; Inai, K; Takeda, T; Ishikawa, N; Hoshino, H; Itai, Y

1996-02-01

A 4-month-old male infant with Bland-White-Garland (BWG) syndrome complicated myocardial infarction was reported. Signs included tachypnea, coughing, and failure to thrive. However, there was no sign of myocardial infarction. A chest radiograph revealed cardiomegaly (CTR = 65%) and electrocardiogram showed abnormal Q waves in I, aVL, V6 leads. Cardiac catheterization and angiography revealed marked dilatation of left ventricle (end-diastolic volume = 384 ml/m2) and extremely depressed ejection fraction (16%), confirming the diagnosis of BWG syndrome. A 201TlCl-myocardial SPECT demonstrated apical defect and hypoperfusion in the anterolateral, inferoposterior walls, whereas 123I-beta-methyl-p-iodophenylpentadecanoic-acid (123I-BMIPP) SPECT showed a wider defect area. SPECT studies with 201TlCl and 123I-BMIPP, are useful to assess myocardial viability more accurately in BWG syndrome.

Parametric techniques for characterizing myocardial tissue by magnetic resonance imaging (part 1): T1 mapping.

PubMed

Perea Palazón, R J; Ortiz Pérez, J T; Prat González, S; de Caralt Robira, T M; Cibeira López, M T; Solé Arqués, M

2016-01-01

The development of myocardial fibrosis is a common process in the appearance of ventricular dysfunction in many heart diseases. Magnetic resonance imaging makes it possible to accurately evaluate the structure and function of the heart, and its role in the macroscopic characterization of myocardial fibrosis by late enhancement techniques has been widely validated clinically. Recent studies have demonstrated that T1-mapping techniques can quantify diffuse myocardial fibrosis and the expansion of the myocardial extracellular space in absolute terms. However, further studies are necessary to validate the usefulness of this technique in the early detection of tissue remodeling at a time when implementing early treatment would improve a patient's prognosis. This article reviews the state of the art for T1 mapping of the myocardium, its clinical applications, and its limitations. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction

PubMed Central

Johnson, Megan S.; Ma, Lixin; Pulakat, Lakshmi; Mugerfeld, Irina; Hayden, Melvin R.; Garro, Mona; Knight, William; Britton, Steven L.; Koch, Lauren G.; Sowers, James R.

2012-01-01

The statistical association between endurance exercise capacity and cardiovascular disease suggests that impaired aerobic metabolism underlies the cardiovascular disease risk in men and women. To explore this connection, we applied divergent artificial selection in rats to develop low-capacity runner (LCR) and high-capacity runner (HCR) rats and found that disease risks segregated strongly with low running capacity. Here, we tested if inborn low aerobic capacity promotes differential sex-related cardiovascular effects. Compared with HCR males (HCR-M), LCR males (LCR-M) were overweight by 34% and had heavier retroperitoneal, epididymal, and omental fat pads; LCR females (LCR-F) were 20% heavier than HCR females (HCR-F), and their retroperitoneal, but not perireproductive or omental, fat pads were heavier as well. Unlike HCR-M, blood pressure was elevated in LCR-M, and this was accompanied by left ventricular (LV) hypertrophy. Like HCR-F, LCR-F exhibited normal blood pressure and LV weight as well as increased spontaneous cage activity compared with males. Despite normal blood pressures, LCR-F exhibited increased myocardial interstitial fibrosis and diastolic dysfunction, as indicated by increased LV stiffness, a decrease in the initial filling rate, and an increase in diastolic relaxation time. Although females exhibited increased arterial stiffness, ejection fraction was normal. Increased interstitial fibrosis and diastolic dysfunction in LCR-F was accompanied by the lowest protein levels of phosphorylated AMP-actived protein kinase [phospho-AMPK (Thr172)] and silent information regulator 1. Thus, the combination of risk factors, including female sex, intrinsic low aerobic capacity, and overweightness, promote myocardial stiffness/fibrosis sufficient to induce diastolic dysfunction in the absence of hypertension and LV hypertrophy. PMID:22345570

Association between left ventricular mechanics and diffuse myocardial fibrosis in patients with repaired Tetralogy of Fallot: a cross-sectional study.

PubMed

Haggerty, Christopher M; Suever, Jonathan D; Pulenthiran, Arichanah; Mejia-Spiegeler, Abba; Wehner, Gregory J; Jing, Linyuan; Charnigo, Richard J; Fornwalt, Brandon K; Fogel, Mark A

2017-12-11

Patients with repaired tetralogy of Fallot (TOF) have progressive, adverse biventricular remodeling, leading to abnormal contractile mechanics. Defining the mechanisms underlying this dysfunction, such as diffuse myocardial fibrosis, may provide insights into poor long-term outcomes. We hypothesized that left ventricular (LV) diffuse fibrosis is related to impaired LV mechanics. Patients with TOF were evaluated with cardiac magnetic resonance in which modified Look-Locker (MOLLI) T1-mapping and spiral cine Displacement encoding (DENSE) sequences were acquired at three LV short-axis positions. Linear mixed modeling was used to define the association between regional LV mechanics from DENSE based on regional T1-derived diffuse fibrosis measures, such as extracellular volume fraction (ECV). Forty patients (26 ± 11 years) were included. LV ECV was generally within normal range (0.24 ± 0.05). For LV mechanics, peak circumferential strains (-15 ± 3%) and dyssynchrony indices (16 ± 8 ms) were moderately impaired, while peak radial strains (29 ± 8%) were generally normal. After adjusting for patient age, sex, and regional LV differences, ECV was associated with log-adjusted LV dyssynchrony index (β = 0.67) and peak LV radial strain (β = -0.36), but not LV circumferential strain. Moreover, post-contrast T1 was associated with log-adjusted LV diastolic circumferential strain rate (β = 0.37). We observed several moderate associations between measures of fibrosis and impaired mechanics, particularly the LV dyssynchrony index and peak radial strain. Diffuse fibrosis may therefore be a causal factor in some ventricular dysfunction in TOF.

Prevention of Left Ventricular Thrombus Formation and Systemic Embolism After Anterior Myocardial Infarction: A Systematic Literature Review.

PubMed

Bastiany, Alexandra; Grenier, Marie-Eve; Matteau, Alexis; Mansour, Samer; Daneault, Benoit; Potter, Brian J

2017-10-01

Anterior myocardial infarction (MI) with apical dysfunction is associated with an increased risk of left ventricular thrombus (LVT) formation and systemic embolism (SE). However, the role for prophylactic anticoagulation in current practice is a matter of debate. We conducted a systematic review of peer-reviewed original articles in either English or French on the benefit of combining anticoagulation with standard therapy for the prevention of LVT/SE after MI by searching PubMed, Ovid/MedLine/Embase, the Cochrane Library, and Google Scholar. Of 7382 identified records, 14 were retained for analysis. Nine articles addressed anticoagulation for patients not treated with percutaneous coronary intervention (PCI). Another 5 included at least some patients treated with PCI. Only 1 study specifically addressed exclusively a primary PCI population. Some studies showed a benefit for combining anticoagulation with standard therapy in patients not treated with PCI, but results were inconsistent. No evidence of benefit was reported when PCI patients were included and 1 study reported a signal for net harm. There was important interstudy heterogeneity and methodological limitations. Studies were likely individually underpowered. The available studies of LVT/SE prevention after MI lacked statistical power and are heterogeneous in terms of treatments, revascularization methods, background medical therapy, and study design. We conclude that there is presently no compelling evidence for or against combining anticoagulation with standard therapy for post-MI patients with apical dysfunction after primary PCI, and inconsistent evidence supporting prophylaxis after thrombolysis. An appropriately powered randomized trial is required to answer this clinically relevant question. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction).

PubMed

Sanz-Ruiz, Ricardo; Casado Plasencia, Ana; Borlado, Luis R; Fernández-Santos, María Eugenia; Al-Daccak, Reem; Claus, Piet; Palacios, Itziar; Sádaba, Rafael; Charron, Dominique; Bogaert, Jan; Mulet, Miguel; Yotti, Raquel; Gilaberte, Immaculada; Bernad, Antonio; Bermejo, Javier; Janssens, Stefan; Fernández-Avilés, Franciso

2017-06-23

Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging-based efficacy end points. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439398. © 2017 American Heart Association, Inc.

Hypoxia-inducible factor 1-alpha release after intracoronary versus intramyocardial stem cell therapy in myocardial infarction.

PubMed

Gyöngyösi, Mariann; Hemetsberger, Rayyan; Posa, Aniko; Charwat, Silvia; Pavo, Noemi; Petnehazy, Ors; Petrasi, Zsolt; Pavo, Imre J; Hemetsberger, Hani; Benedek, Imre; Benedek, Teodora; Benedek, Istvan; Kovacs, Istvan; Kaun, Christoph; Maurer, Gerald

2010-04-01

We have investigated the effect of stem cell delivery on the release of hypoxia-inducible factor 1 alpha (HIF-1alpha) in peripheral circulation and myocardium in experimental myocardial ischemia. Closed-chest, reperfused myocardial infarction (MI) was created in domestic pigs. Porcine mesenchymal stem cells (MSCs) were cultured and delivered (9.8 +/- 1.2 x 10(6)) either percutaneously NOGA-guided transendocardially (Group IM) or intracoronary (Group IC) 22 +/- 4 days post-MI. Pigs without MSC delivery served as sham control (Group S). Plasma HIF-1alpha was measured at baseline, immediately post- and at follow-up (FUP; 2 h or 24 h) post-MSC delivery by ELISA kit. Myocardial HIF-1alpha expression of infarcted, normal myocardium, or border zone was determined by Western blot. Plasma level of HIF-1alpha increased immediately post-MI (from 278 +/- 127 to 631 +/- 375 pg/ml, p < 0.05). Cardiac delivery of MSCs elevated the plasma levels of HIF-1alpha significantly (p < 0.05) in groups IC and IM immediately post-MSC delivery, and returned to baseline level at FUP, without difference between the groups IC and IM. The myocardial tissue HIF-1alpha expression in the infarcted area was higher in Group IM than in Group IC or S (1,963 +/- 586 vs. 1,307 +/- 392 vs. 271 +/- 110 activity per square millimeter, respectively, p < 0.05), while the border zone contained similarly lower level of HIF-1alpha, but still significantly higher as compared with Group S. Trend towards increase in myocardial expression of HIF-1alpha was measured in Group IM at 24 h, in contrast to Group IC. In conclusion, both stem cell delivery modes increase the systemic and myocardial level of HIF-1alpha. Intramyocardial delivery of MSC seems to trigger the release of angiogenic HIF-1alpha more effectively than does intracoronary delivery.

Usefulness of Speckle-Tracking Imaging for Right Ventricular Assessment after Acute Myocardial Infarction: A Magnetic Resonance Imaging/Echocardiographic Comparison within the Relation between Aldosterone and Cardiac Remodeling after Myocardial Infarction Study.

PubMed

Lemarié, Jérémie; Huttin, Olivier; Girerd, Nicolas; Mandry, Damien; Juillière, Yves; Moulin, Frédéric; Lemoine, Simon; Beaumont, Marine; Marie, Pierre-Yves; Selton-Suty, Christine

2015-07-01

Right ventricular (RV) dysfunction after acute myocardial infarction (AMI) is frequent and associated with poor prognosis. The complex anatomy of the right ventricle makes its echocardiographic assessment challenging. Quantification of RV deformation by speckle-tracking echocardiography is a widely available and reproducible technique that readily provides an integrated analysis of all segments of the right ventricle. The aim of this study was to investigate the accuracy of conventional echocardiographic parameters and speckle-tracking echocardiographic strain parameters in assessing RV function after AMI, in comparison with cardiac magnetic resonance imaging (CMR). A total of 135 patients admitted for AMI (73 anterior, 62 inferior) were prospectively studied. Right ventricular function was assessed by echocardiography and CMR within 2 to 4 days of hospital admission. Right ventricular dysfunction was defined as CMR RV ejection fraction < 50%. Right ventricular global peak longitudinal systolic strain (GLPSS) was calculated by averaging the strain values of the septal, lateral, and inferior walls. Right ventricular dysfunction was documented in 20 patients. Right ventricular GLPSS was the best echographic correlate of CMR RV ejection fraction (r = -0.459, P < .0001) and possessed good diagnostic value for RV dysfunction (area under the receiver operating characteristic curve [AUROC], 0.724; 95% CI, 0.590-0.857), which was comparable with that of RV fractional area change (AUROC, 0.756; 95% CI, 0.647-0.866). In patients with inferior myocardial infarctions, the AUROCs for RV GLPSS (0.822) and inferolateral strain (0.877) were greater than that observed for RV fractional area change (0.760) Other conventional echocardiographic parameters performed poorly (all AUROCs < 0.700). After AMI, RV GLPSS is the best correlate of CMR RV ejection fraction. In patients with inferior AMIs, RV GLPSS displays even higher diagnostic value than conventional echocardiographic parameters. Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion

PubMed Central

Ibanez, Borja; Cimmino, Giovanni; Prat-González, Susanna; Vilahur, Gemma; Hutter, Randolph; García, Mario J.; Fuster, Valentin; Sanz, Javier; Badimon, Lina; Badimon, Juan J.

2013-01-01

Background Myocardial infarct size is a strong predictor of cardiovascular events. Intravenous metoprolol before coronary reperfusion has been shown to reduce infarct size; however, it is unknown whether oral metoprolol initiated early after reperfusion, as clinical guidelines recommend, is similarly cardioprotective. We compared the extent of myocardial salvage associated with intravenous pre-reperfusion-metoprolol administration in comparison with oral post-reperfusion-metoprolol or placebo. We also studied the effect on suspected markers of reperfusion injury. Methods Thirty Yorkshire-pigs underwent a reperfused myocardial infarction, being randomized to pre-reperfusion-metoprolol, post-reperfusion-metoprolol or placebo. Cardiac magnetic resonance imaging was performed in eighteen pigs at day 3 for the quantification of salvaged myocardium. The amounts of at-risk and infarcted myocardium were quantified using T2-weighted and post-contrast delayed enhancement imaging, respectively. Twelve animals were sacrificed after 24 h for reperfusion injury analysis. Results The pre-reperfusion-metoprolol group had significantly larger salvaged myocardium than the post-reperfusion-metoprolol or the placebo groups (31±4%, 13±6%, and 7±3% of myocardium at-risk respectively). Post-mortem analyses suggest lesser myocardial reperfusion injury in the pre-reperfusion-metoprolol in comparison with the other 2 groups (lower neutrophil infiltration, decreased myocardial apoptosis, and higher activation of the salvage-kinase phospho-Akt). Salvaged myocardium and reperfusion injury pair wise comparisons proved there were significant differences between the pre-reperfusion-metoprolol and the other 2 groups, but not among the latter two. Conclusions The intravenous administration of metoprolol before coronary reperfusion results in larger myocardial salvage than its oral administration initiated early after reperfusion. If confirmed in the clinical setting, the timing and route of β-blocker initiation could be revisited. PMID:19913314

Myocardial imaging with 99mTc-Tetrofosmin: Influence of post-stress acquisition time, regional radiotracer uptake, and wall motion abnormalities on the clinical result.

PubMed

Giorgetti, Assuero; Kusch, Annette; Casagranda, Mirta; Tagliavia, Irene D'Aragona; Marzullo, Paolo

2010-04-01

We previously demonstrated that early (15', T1) post-stress myocardial imaging with Tetrofosmin could be more accurate than standard acquisitions (45', T2) in identifying coronary artery disease. To clarify this phenomenon, 120 subjects (age 61 +/- 10 years) with both T1 and T2 scans were divided into Group 1 (53/120 pts) with more ischemia at T1 vs T2 imaging (T1-T2SDS > or = 3); Group 2 (67/120 pts) with similar results (T1-T2SDS < or = 2). Myocardial areas were categorized as control nonischemic, ischemic, and scarred on the basis of perfusion/contraction properties and coronary anatomy. In each area, regional myocardial count statistic and semiquantitative wall motion/thickening values were obtained. Analysis of T1 and T2 post-stress myocardial counts demonstrated a significant Tetrofosmin wash-out rate that was higher in Group 1 control nonischemic regions (15 +/- 8% vs 13.6 +/- 9.6%, P < .02), significantly lower in Group 1 ischemic regions (7 +/- 10% vs 12.2 +/- 9.5%, P < .0001), and comparable between scarred areas of the two groups (P = NS). Delta post-stress wall thickening (T1-T2) was lower in Group 1 ischemic regions (-4.5 +/- 9.15% vs -1.90 +/- 7.0%, P < .001) and comparable in both control nonischemic and scarred areas of the two groups (P = NS). The clinical result of Tetrofosmin gated-SPECT can be influenced by the post-stress acquisition time because of ischemic-induced regional wall thickening abnormalities and the existence of a differential radiotracer myocardial wash-out.

Acute Right Ventricular Dysfunction in Intensive Care Unit

PubMed Central

Domingo, Enric

2017-01-01

The role of the left ventricle in ICU patients with circulatory shock has long been considered. However, acute right ventricle (RV) dysfunction causes and aggravates many common critical diseases (acute respiratory distress syndrome, pulmonary embolism, acute myocardial infarction, and postoperative cardiac surgery). Several supportive therapies, including mechanical ventilation and fluid management, can make RV dysfunction worse, potentially exacerbating shock. We briefly review the epidemiology, pathophysiology, diagnosis, and recommendations to guide management of acute RV dysfunction in ICU patients. Our aim is to clarify the complex effects of mechanical ventilation, fluid therapy, vasoactive drug infusions, and other therapies to resuscitate the critical patient optimally. PMID:29201914

Coronary microvascular dysfunction in diabetes mellitus

PubMed Central

Selthofer-Relatic, Kristina; Drenjancevic, Ines; Bacun, Tatjana; Bosnjak, Ivica; Kibel, Dijana; Gros, Mario

2017-01-01

The significance, mechanisms and consequences of coronary microvascular dysfunction associated with diabetes mellitus are topics into which we have insufficient insight at this time. It is widely recognized that endothelial dysfunction that is caused by diabetes in various vascular beds contributes to a wide range of complications and exerts unfavorable effects on microcirculatory regulation. The coronary microcirculation is precisely regulated through a number of interconnected physiological processes with the purpose of matching local blood flow to myocardial metabolic demands. Dysregulation of this network might contribute to varying degrees of pathological consequences. This review discusses the most important findings regarding coronary microvascular dysfunction in diabetes from pre-clinical and clinical perspectives. PMID:28643578

The role of glycogen synthase kinase 3 beta in brain injury induced by myocardial ischemia/reperfusion injury in a rat model of diabetes mellitus.

PubMed

Zhao, Bo; Gao, Wen-Wei; Liu, Ya-Jing; Jiang, Meng; Liu, Lian; Yuan, Quan; Hou, Jia-Bao; Xia, Zhong-Yuan

2017-10-01

Myocardial ischemia/reperfusion injury can lead to severe brain injury. Glycogen synthase kinase 3 beta is known to be involved in myo-cardial ischemia/reperfusion injury and diabetes mellitus. However, the precise role of glycogen synthase kinase 3 beta in myocardial ischemia/reperfusion injury-induced brain injury is unclear. In this study, we observed the effects of glycogen synthase kinase 3 beta on brain injury induced by myocardial ischemia/reperfusion injury in diabetic rats. Rat models of diabetes mellitus were generated via intraperitoneal injection of streptozotocin. Models of myocardial ischemia/reperfusion injury were generated by occluding the anterior descending branch of the left coronary artery. Post-conditioning comprised three cycles of ischemia/reperfusion. Immunohistochemical staining and western blot assays demonstrated that after 48 hours of reperfusion, the structure of the brain was seriously damaged in the experimental rats compared with normal controls. Expression of Bax, interleukin-6, interleukin-8, terminal deoxynucleotidyl transferase dUTP nick end labeling, and cleaved caspase-3 in the brain was significantly increased, while expression of Bcl-2, interleukin-10, and phospho-glycogen synthase kinase 3 beta was decreased. Diabetes mellitus can aggravate inflammatory reactions and apoptosis. Ischemic post-conditioning with glycogen synthase kinase 3 beta inhibitor lithium chloride can effectively reverse these changes. Our results showed that myocardial ischemic post-conditioning attenuated myocardial ischemia/reperfusion injury-induced brain injury by activating glyco-gen synthase kinase 3 beta. According to these results, glycogen synthase kinase 3 beta appears to be an important factor in brain injury induced by myocardial ischemia/reperfusion injury.

Sepiapterin reduces postischemic injury in the rat heart.

PubMed

Tiefenbacher, Christiane P; Lee, Ching-Hua; Kapitza, Jolanthe; Dietz, Volker; Niroomand, Feraydoon

2003-10-01

A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5 x 10-min ligature of the left coronary artery, 5 x 20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H2-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.

Right ventricular myocardial infarction: presentation and acute outcomes.

PubMed

Chockalingam, Anand; Gnanavelu, G; Subramaniam, T; Dorairajan, Smrita; Chockalingam, V

2005-01-01

Acute inferior wall myocardial infarction can be complicated by right ventricular myocardial infarction (RVMI), and the excess mortality cannot be fully explained by mechanical reasons. The authors try to systematically assess the incidence, clinical presentation and early outcomes of right ventricular infarction in a tertiary-care setup. Their study was a prospective observational series of consecutive patients with RVMI. All patients with acute inferior myocardial infarction (n=135) were enlisted. RVMI was diagnosed by > or = 1 mm ST elevation in lead V(4R) in a right-sided electrocardiogram. Right ventricular (RV) infarction occurred in 37% (n=50) of patients with acute inferior infarctions. Patients with isolated inferior infarction served as controls (n=85). Echocardiography was performed within 24 hours of admission. From both groups, 66% qualified for thrombolysis. The incidence of hypotension-bradycardia and heart blocks requiring pacing support was much higher in right ventricular infarction (n=21) than in inferior infarction (n=13). Clinically manifest RV dysfunction (raised jugular venous pulse [JVP], hypotension, tricuspid regurgitation) and right ventricular dilation detected by echocardiography were seen in only 13 patients. The in-hospital mortality rate was significantly higher (n=8, 16%) in right ventricular infarction group than in inferior infarction group (n=3, 3.5%). Right ventricular infarction was seen in a third of inferior myocardial infarctions (IMIs), but hemodynamically evident right ventricular dysfunction occurred in only a tenth of acute IMIs. Nevertheless, the acute in-hospital mortality rate of patients with right ventricular infarction was much higher than in those with inferior infarction owing to arrhythmic and mechanical complications.

Common presentation of rare diseases: Left ventricular hypertrophy and diastolic dysfunction.

PubMed

Linhart, Ales; Cecchi, Franco

2018-04-15

Left ventricular hypertrophy may be a consequence of a hemodynamic overload or a manifestation of several diseases affecting different structural and functional proteins of cardiomyocytes. Among these, sarcomeric hypertrophic cardiomyopathy (HCM) represents the most frequent cause. In addition, several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases). The recognition of these rare causes of myocardial hypertrophy is important for family screening strategies, risk assessment, and treatment. Moreover, as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy. Diastolic dysfunction is a key feature of HCM and its phenocopies. Its assessment is complex and requires evaluation of several functional parameters and structural changes. Severe diastolic dysfunction carries a negative prognostic implication and its value in differential diagnosis is limited. Copyright © 2018 Elsevier B.V. All rights reserved.

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure.

PubMed

Barnes, Brian J; Howard, Patricia A

2005-01-01

To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

Coronary hemodynamic regulation by nitric oxide in experimental animals: recent advances.

PubMed

Toda, Noboru; Toda, Hiroshi

2011-09-30

Nitric oxide (NO) formed via endothelial NO synthase (eNOS) plays crucial roles in the regulation of coronary blood flow through vasodilatation and decreased vascular resistance and in the inhibition of platelet aggregation and adhesion, leading to the prevention of coronary circulatory failure, thrombosis, and atherosclerosis. NO restrains myocardial oxygen consumption, when coronary perfusion is restricted. Endothelial function is impaired by pathogenic factors including smoking, excess salt intake, obesity, aging, hypercholesterolemia, hyperglycemia, and hypertension. The mechanisms involved in endothelial dysfunction are reduced NOS expression and activity, decreased NO bioavailability, and increased production of oxygen radicals and endogenous NOS inhibitors. NADPH oxidase, xanthine oxidase, and NOS uncoupling are involved in increased superoxide generation. Plasma levels of asymmetric dimethylarginine, the endogenous NOS inhibitor, are increased by an impairment of enzymatic degradation by dimethylarginine dimethylaminohydrolase and alanine-glyoxylate aminotransferase 2. Impairment of coronary arteriolar dilatation induced by perivascular nitrergic nerve activation is involved in decreased coronary blood flow. NO derived from nNOS singly or in combination with eNOS protects against serious myocardial injury through ischemic insults. Ischemia-induced iNOS upregulation contributes to myocardial contractile dysfunction. Preventive and therapeutic measures, such as improvement of life-style and treatment with therapeutic agents, to eliminate pathogenic factors for endothelial dysfunction or nNOS-derived NO deprivation would be quite important for the prophylaxis and minimizing the development of coronary artery disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Myocardial mechanics, energetics, and hemodynamics during intraaortic balloon and transvalvular axial flow hemopump support with a bovine model of ischemic cardiac dysfunction.

PubMed

Marks, J D; Pantalos, G M; Long, J W; Kinoshita, M; Everett, S D; Olsen, D B

1999-01-01

Unlike the mechanisms of intraaortic balloon pump (IABP) support, the mechanisms by which transvalvular axial flow Hemopump (HP) support benefit dysfunctional myocardium are less clearly understood. To help elucidate these mechanisms, hemodynamic, metabolic, and mechanical indexes of left ventricular function were measured during conditions of control, ischemic dysfunction, IABP support, and HP support. A large animal (calf) model of left ventricular dysfunction was created with multiple coronary ligations. Peak intraventricular pressure increased with HP support and decreased with IABP support. Intramyocardial pressure (an indicator of intramyocardial stress), time rate of pressure change (an indicator of contractility), and left ventricular myocardial oxygen consumption decreased with IABP and HP support. Left ventricular work decreased with HP support and increased with IABP support. During HP support, indexes of wall stress, work, and contractility, all primary determinants of oxygen consumption, were reduced. During IABP support, indexes of wall stress and contractility were reduced and external work increased. These changes were attributed primarily to changes in ventricular preload, and geometry for HP support, and to a reduction in afterload for IABP support. These findings support the hypothesis that both HP and IABP support reduce intramyocardial stress development and the corresponding oxygen consumption, although via different mechanisms.

Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone

PubMed Central

Shimkunas, Rafael; Makwana, Om; Spaulding, Kimberly; Bazargan, Mona; Khazalpour, Michael; Takaba, Kiyoaki; Soleimani, Mehrdad; Myagmar, Bat-Erdene; Lovett, David H.; Simpson, Paul C.; Ratcliffe, Mark B.

2014-01-01

After myocardial infarction, a poorly contracting nonischemic border zone forms adjacent to the infarct. The cause of border zone dysfunction is unclear. The goal of this study was to determine the myofilament mechanisms involved in postinfarction border zone dysfunction. Two weeks after anteroapical infarction of sheep hearts, we studied in vitro isometric and isotonic contractions of demembranated myocardium from the infarct border zone and a zone remote from the infarct. Maximal force development (Fmax) of the border zone myocardium was reduced by 31 ± 2% versus the remote zone myocardium (n = 6/group, P < 0.0001). Decreased border zone Fmax was not due to a reduced content of contractile material, as assessed histologically, and from myosin content. Furthermore, decreased border zone Fmax did not involve altered cross-bridge kinetics, as assessed by muscle shortening velocity and force development kinetics. Decreased border zone Fmax was associated with decreased cross-bridge formation, as assessed from muscle stiffness in the absence of ATP where cross-bridge formation should be maximized (rigor stiffness was reduced 34 ± 6%, n = 5, P = 0.011 vs. the remote zone). Furthermore, the border zone myocardium had significantly reduced phosphorylation of myosin essential light chain (ELC; 41 ± 10%, n = 4, P < 0.05). However, for animals treated with doxycycline, an inhibitor of matrix metalloproteinases, rigor stiffness and ELC phosphorylation were not reduced in the border zone myocardium, suggesting that doxycycline had a protective effect. In conclusion, myofilament dysfunction contributes to postinfarction border zone dysfunction, myofilament dysfunction involves impaired cross-bridge formation and decreased ELC phosphorylation, and matrix metalloproteinase inhibition may be beneficial for limiting postinfarct border zone dysfunction. PMID:25128171

Cardiac Intensive Care Unit Management of Patients After Cardiac Arrest: Now the Real Work Begins.

PubMed

Randhawa, Varinder K; Grunau, Brian E; Debicki, Derek B; Zhou, Jian; Hegazy, Ahmed F; McPherson, Terry; Nagpal, A Dave

2018-02-01

Survival with a good quality of life after cardiac arrest continues to be abysmal. Coordinated resuscitative care does not end with the effective return of spontaneous circulation (ROSC)-in fact, quite the contrary is true. Along with identifying and appropriately treating the precipitating cause, various components of the post-cardiac arrest syndrome also require diligent observation and management, including post-cardiac arrest neurologic injury and myocardial dysfunction, systemic ischemia-reperfusion phenomenon with potential consequent multiorgan failure, and the various sequelae of critical illness. There is growing evidence that an early invasive approach to coronary reperfusion with percutaneous coronary intervention, together with active targeted temperature management and optimization of hemodynamic, ventilator, and metabolic parameters, may improve survival and neurologic outcomes in cardiac arrest survivors. Neuroprognostication is complex, as are survivorship issues and long-term rehabilitation. Our paramedics, emergency physicians, and resuscitation specialists are all to be congratulated for ever-increasing success with ROSC… but now the real work begins. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Polypyrrole-chitosan conductive biomaterial synchronizes cardiomyocyte contraction and improves myocardial electrical impulse propagation.

PubMed

Cui, Zhi; Ni, Nathan C; Wu, Jun; Du, Guo-Qing; He, Sheng; Yau, Terrence M; Weisel, Richard D; Sung, Hsing-Wen; Li, Ren-Ke

2018-01-01

Background: The post-myocardial infarction (MI) scar interrupts electrical impulse propagation and delays regional contraction, which contributes to ventricular dysfunction. We investigated the potential of an injectable conductive biomaterial to restore scar tissue conductivity and re-establish synchronous ventricular contraction. Methods: A conductive biomaterial was generated by conjugating conductive polypyrrole (PPY) onto chitosan (CHI) backbones. Trypan blue staining of neonatal rat cardiomyocytes (CMs) cultured on biomaterials was used to evaluate the biocompatibility of the conductive biomaterials. Ca 2+ imaging was used to visualize beating CMs. A cryoablation injury rat model was used to investigate the ability of PPY:CHI to improve cardiac electrical propagation in the injured heart in vivo . Electromyography was used to evaluate conductivity of scar tissue ex vivo . Results: Cell survival and morphology were similar between cells cultured on biomaterials-coated and uncoated-control dishes. PPY:CHI established synchronous contraction of two distinct clusters of spontaneously-beating CMs. Intramyocardial PPY:CHI injection into the cryoablation-induced injured region improved electrical impulse propagation across the scarred tissue and decreased the QRS interval, whereas saline- or CHI-injected hearts continued to have delayed propagation patterns and significantly reduced conduction velocity compared to healthy controls. Ex vivo evaluation found that scar tissue from PPY:CHI-treated rat hearts had higher signal amplitude compared to those from saline- or CHI-treated rat heart tissue. Conclusions: The PPY:CHI biomaterial is electrically conductive, biocompatible and injectable. It improved synchronous contraction between physically separated beating CM clusters in vitro . Intra-myocardial injection of PPY:CHI following cardiac injury improved electrical impulse propagation of scar tissue in vivo .

Correlation between right ventricular T1 mapping and right ventricular dysfunction in non-ischemic cardiomyopathy.

PubMed

Jellis, Christine L; Yingchoncharoen, Teerapat; Gai, Neville; Kusunose, Kenya; Popović, Zoran B; Flamm, Scott; Kwon, Deborah

2018-01-01

Right ventricular (RV) fibrosis is increasingly recognized as the underlying pathological substrate in a variety of clinical conditions. We sought to employ cardiac magnetic resonance (CMR) techniques of strain imaging and longitudinal relaxation time (T 1 ) mapping to better examine the relationship between RV function and structure. Our aim was to initially evaluate the feasibility of these techniques to evaluate the right ventricle. We then sought to explore the relationship between RV function and underlying fibrosis, along with examining the evolution of RV remodeling according to the amount of baseline fibrosis. Echocardiography was performed in 102 subjects with non-ischemic cardiomyopathy. Right ventricular parameters were assessed including: fractional area change (FAC) and longitudinal strain. The same cohort underwent CMR. Post-contrast T 1 mapping was performed as a marker of fibrosis with a Look-Locker technique using inversion recovery imaging. Mid-ventricular post-contrast T 1 values of the RV free wall, RV septum and lateral LV were calculated using prototype analysis software. Biventricular volumetric data including ejection fraction was measured by CMR using a cine short axis stack. CMR strain analysis was also performed to assess 2D RV longitudinal and radial strain. Simultaneous biochemical and anthropometric data were recorded. Subjects were followed over a median time of 29 months (IQR 20-37 months) with echocardiography to evaluate temporal change in RV FAC according to baseline post-contrast T 1 values. Longitudinal data analysis was performed to adjust for patient loss during follow-up. Subjects (62% men, 51 ± 15 years) had mild to moderately impaired global RV systolic function (RVEF = 39 ± 15%; RVEDV = 187 ± 69 ml; RVESV = 119 ± 68 ml) and moderate left ventricular dysfunction at baseline (LVEF 30 ± 17%). Good correlation was observed between mean LV and RV post-contrast T 1 values (r = 0.652, p < 0.001), with similar post-contrast T 1 values maintained in both the RV free wall and septum (r = 0.761, p < 0.001). CMR RVEF demonstrated a proportional correlation with echocardiographic measures of RV longitudinal function and CMR RV strain (longitudinal r = -0.449, p = 0.001; radial r = -0.549, p < 0.001). RVEF was related to RV post-contrast T 1 values, particularly in those with RV dysfunction (free wall T 1 r = 0.259 p = 0.027; septal T 1 r = 0.421 p < 0.001). RV strain was also related to RV post-contrast T 1 values (r = -0.417, p = 0.002). Linear regression analysis demonstrated strain and post-contrast T1 values to be independently associated with RVEF. Subjects with severe RV dysfunction (CMR RVEF <25%) demonstrated lower RV CMR strain (longitudinal p = 0.018; radial p < 0.001), RV T 1 values (free wall p = 0.013; septum <0.001) and RV longitudinal echocardiography parameters despite no difference in afterload. During follow-up, those with RV free wall post-contrast T 1 values ≥ 350 ms demonstrated ongoing improvement in FAC (Δ6%), whilst values <350 ms were associated with deterioration in RV function (ΔFAC = -5%) (p = 0.026). CMR provides a comprehensive method by which to evaluate right ventricular function. Post-contrast T 1 mapping and CMR strain imaging are technically feasible and provide incremental information regarding global RV function and structure. The proportional relationship between RV function and post-contrast T 1 values supports that myocardial fibrosis is a causative factor of RV dysfunction in NICM, irrespective of RV afterload. This same structural milieu also appears integral to the propensity for both positive and negative RV remodeling long-term, suggestive that this is also determined by the degree of underlying RV fibrosis.

Hypothyroidism-induced myocardial damage and heart failure: an overlooked entity.

PubMed

Shuvy, Mony; Shifman, Oshrat E Tayer; Nusair, Samir; Pappo, Orit; Lotan, Chaim

2009-01-01

Hypothyroid state may induce cardiac muscle impairment such as diastolic dysfunction and abnormal relaxation time. Advanced heart failure in hypothyroid patients has been described only in severe symptomatic cases, mostly during myxedematous coma. We describe an unusual case of asymptomatic patient with hypothyroidism who presented with severely reduced cardiac function with elevated cardiac enzymes reflecting significant myocardial injury. Comprehensive evaluation for heart failure was suggestive only for long-standing untreated hypothyroidism. Endomyocadial biopsy demonstrated unique histological findings of mucopolysaccharide accumulation attributed to hypothyroid state. Asymptomatic hypothyroidism may cause severe reduction in cardiac function accompanied with elevated cardiac enzymes. To our knowledge, this is the first description of human myocardial biopsy revealing mucopolysaccharide accumulation attributed to hypothyroid state.

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

PubMed

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

2015-11-01

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

Role of levosimendan in the management of subarachnoid hemorrhage.

PubMed

Varvarousi, Giolanda; Xanthos, Theodoros; Sarafidou, Pavlina; Katsioula, Ellisavet; Georgiadou, Marianthi; Eforakopoulou, Maria; Pavlou, Hlias

2016-02-01

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the leading causes of neurologic disability accounting for dismal long term survival rates. aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemodynamic instability which may critically hamper brain perfusion and oxygenation. In the setting of acute aSAH, administration of vasoactive drugs aims at stabilizing impaired hemodynamics. However, studies have shown that conventional treatment with vasoactive drugs that lead to Ca(+2) overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow. Levosimendan is a non-adrenergic inotropic Ca(+2) sensitizer with not only beneficial hemodynamic properties but also pleiotropic effects, contributing to its cardioprotective and neuroprotective role. Although there have been limited data available regarding the use of levosimendan in patients with aSAH, current evidence suggests that levosimendan may have a role in the setting of post-aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments and in intensive care units. The purpose of this review is to provide an overview of studies of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH. Copyright © 2015 Elsevier Inc. All rights reserved.

Characterizing cardiac dysfunction in fetuses with left congenital diaphragmatic hernia.

PubMed

Cruz-Lemini, Mónica; Valenzuela-Alcaraz, Brenda; Granados-Montiel, Julio; Martínez, Josep M; Crispi, Fátima; Gratacós, Eduard; Cruz-Martínez, Rogelio

2018-03-23

To evaluate cardiac function by conventional echocardiography and tissue Doppler imaging in fetuses with left congenital diaphragmatic hernia (CDH). Conventional echocardiography (myocardial performance index, ventricular filling velocities, and E/A ratios) and tissue Doppler imaging (annular myocardial peak velocities, E/E' and E'/A' ratios) in mitral, septal, and tricuspid annulus were evaluated in a cohort of 31 left-sided CDH fetuses and compared with 75 controls matched for gestational age 2:1. In comparison to controls, CDH fetuses had prolonged isovolumetric time periods (isovolumetric contraction time 35 ms vs 28 ms, P < .001), with higher myocardial performance index (0.49 vs 0.42, P < .001) and tricuspid E/A ratios (0.77 vs 0.72, P = .033). Longitudinal function assessed by tissue Doppler showed signs of impaired relaxation (mitral lateral A' 8.0 vs 10.1 cm/s, P < .001 and an increased mitral lateral E'/A' ratio 0.93 vs 0.78, P < .001) in the CDH fetuses as compared with controls, with preserved systolic function. Left CDH fetuses show echocardiographic signs of diastolic dysfunction, probably secondary to fetal heart compression, maintaining a preserved systolic function. © 2018 John Wiley & Sons, Ltd.

Nitroglycerin Use in Myocardial Infarction Patients: Risks and Benefits

PubMed Central

Ferreira, Julio C.B.; Mochly-Rosen, Daria

2012-01-01

Acute myocardial infarction and its sequelae are leading causes of morbidity and mortality worldwide. Nitroglycerin remains a first-line treatment for angina pectoris and acute myocardial infarction. Nitroglycerin achieves its benefit by giving rise to nitric oxide, which causes vasodilation and increases blood flow to the myocardium. However, continuous delivery of nitroglycerin results in tolerance, limiting the use of this drug. Nitroglycerin tolerance is due, at least in part, to inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme that converts nitroglycerin to the vasodilator, nitric oxide. We have recently found that, in addition to nitroglycerin’s effect on the vasculature, sustained treatment with nitroglycerin negatively affects cardiomyocyte viability following ischemia, thus resulting in increased infarct size in a myocardial infarction model in animals. Co-administration of Alda-1, an activator of ALDH2, with nitroglycerin improves metabolism of reactive aldehyde adducts and prevents the nitroglycerin-induced increase in cardiac dysfunction following myocardial infarction. In this review, we describe the molecular mechanisms associated with the benefits and risks of nitroglycerin administration in myocardial infarction. (167 of 200). PMID:22040938

Myocardial perfusion imaging study of CO(2)-induced panic attack.

PubMed

Soares-Filho, Gastão L F; Machado, Sergio; Arias-Carrión, Oscar; Santulli, Gaetano; Mesquita, Claudio T; Cosci, Fiammetta; Silva, Adriana C; Nardi, Antonio E

2014-01-15

Chest pain is often seen alongside with panic attacks. Moreover, panic disorder has been suggested as a risk factor for cardiovascular disease and even a trigger for acute coronary syndrome. Patients with coronary artery disease may have myocardial ischemia in response to mental stress, in which panic attack is a strong component, by an increase in coronary vasomotor tone or sympathetic hyperactivity setting off an increase in myocardial oxygen consumption. Indeed, coronary artery spasm was presumed to be present in cases of cardiac ischemia linked to panic disorder. These findings correlating panic disorder with coronary artery disease lead us to raise questions about the favorable prognosis of chest pain in panic attack. To investigate whether myocardial ischemia is the genesis of chest pain in panic attacks, we developed a myocardial perfusion study through research by myocardial scintigraphy in patients with panic attacks induced in the laboratory by inhalation of 35% carbon dioxide. In conclusion, from the data obtained, some hypotheses are discussed from the viewpoint of endothelial dysfunction and microvascular disease present in mental stress response. Copyright © 2014 Elsevier Inc. All rights reserved.

Myocardial scintigraphy with 201thallium in pediatric cardiology: A review of 52 cases

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

Bjoerkhem, G.E.; Evander, E.; White, T.

1990-01-01

We report our experience of myocardial scintigraphy with 201thallium (201Tl) in 52 children, aged 4 days to 18 years, in which 80 studies were made primarily to demonstrate or exclude impaired myocardial perfusion. For analysis, the patients were divided into the following eight groups: group I, coronary artery malformations (five patients); group II, Kawasaki's syndrome (six patients); group III, arterial switch operation (seven patients); group IV, dilated cardiomyopathy (18 patients); group V, hypertrophic cardiomyopathy (four patients); group VI, myocardial dysfunction after surgery for congenital heart disease (five patients); group VII, pulmonary atresia (three patients); and group VIII, miscellaneous (four patients).more » Myocardial scintigraphy was performed with a planar or tomographic technique at rest or after exercise (four patients). Isotope-uptake defects, indicating impaired myocardial perfusion, were present in 14 patients, including small infants. Defects were seen in all groups except those with hypertrophic cardiomyopathy and pulmonary atresia. The absence of such defects in several of the patients with Kawasaki's syndrome was particularly valuable as it made coronary angiography unnecessary. In the other groups of patients myocardial scintigraphy was a valuable adjunct to other investigations.« less

Detection and differentiation of early acute and following age stages of myocardial infarction with quantitative post-mortem cardiac 1.5T MR.

PubMed

Schwendener, Nicole; Jackowski, Christian; Persson, Anders; Warntjes, Marcel J; Schuster, Frederick; Riva, Fabiano; Zech, Wolf-Dieter

2017-01-01

Recently, quantitative MR sequences have started being used in post-mortem imaging. The goal of the present study was to evaluate if early acute and following age stages of myocardial infarction can be detected and discerned by quantitative 1.5T post-mortem cardiac magnetic resonance (PMCMR) based on quantitative T1, T2 and PD values. In 80 deceased individuals (25 female, 55 male), a cardiac MR quantification sequence was performed prior to cardiac dissection at autopsy in a prospective study. Focal myocardial signal alterations detected in synthetically generated MR images were MR quantified for their T1, T2 and PD values. The locations of signal alteration measurements in PMCMR were targeted at autopsy heart dissection and cardiac tissue specimens were taken for histologic examinations. Quantified signal alterations in PMCMR were correlated to their according histologic age stage of myocardial infarction. In PMCMR seventy-three focal myocardial signal alterations were detected in 49 of 80 investigated hearts. These signal alterations were diagnosed histologically as early acute (n=39), acute (n=14), subacute (n=10) and chronic (n=10) age stages of myocardial infarction. Statistical analysis revealed that based on their quantitative T1, T2 and PD values, a significant difference between all defined age groups of myocardial infarction can be determined. It can be concluded that quantitative 1.5T PMCMR quantification based on quantitative T1, T2 and PD values is feasible for characterization and differentiation of early acute and following age stages of myocardial infarction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Atrial electromechanical delay and diastolic dysfunction in primary Sjögren syndrome.

PubMed

Akyel, Ahmet; Tavil, Yusuf; Tufan, Abdurrahman; Yayla, Cagri; Kaya, Arif; Tezcan, Mehme Engin; Ozturk, Mehmet Akif; Boyaci, Bulent

2012-10-06

In this study we aimed to investigate myocardial function and atrial electromechanical properties by conventional and tissue doppler echocardiography in patients with primary Sjögren syndrome. Forty patients with Sjögren syndrome (SS) and 25 age- and sex-matched healthy volunteers were enrolled in the study. Using transthoracic echocardiography, myocardial performance index and atrial electromechanical properties were measured. Basal characteristics were similar between two groups. Myocardial performance index values were disturbed in patients with Sjögren syndrome (0.41 vs. 0.32, p < 0.01). There was significant intraatrial (16.4±6.4, 5.0±4.5, p < 0.01) and interatrial (30.6±10.1, 15.4±5.9, p < 0.01) electromechanical delay in this patient group. Myocardial function is disturbed and there is significant atrial electromechanical delay in patients with primary SS. This study is the first to show altered myocardial function and atrial electromechanical properties in primary SS.

Normal results of post-race thallium-201 myocardial perfusion imaging in marathon runners with elevated serum MB creatine kinase levels

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

Siegel, A.J.; Silverman, L.M.; Holman, B.L.

1985-10-01

Elevated cardiac enzyme values in asymptomatic marathon runners after competition can arise from skeletal muscle through exertional rhabdomyolysis, silent injury to the myocardium, or a combined tissue source. Peak post-race levels of the MB isoenzyme of creatine kinase are similar to values in patients with acute myocardial infarction. Previously reported normal results of infarct-avid myocardial scintigraphy with technetium 99m pyrophosphate in runners after competition suggest a non-cardiac source but cannot exclude silent injury to the myocardium. Therefore, thallium 201 myocardial perfusion imaging was performed in runners immediately after competition together with determination of sequential cardiac enzyme levels. Among 15 runnersmore » tested, the average peak in serum MB creatine kinase 24 hours after the race was 128 IU/liter with a cumulative MB creatine kinase release of 117 IU/liter; these values are comparable to those in patients with acute transmural myocardial infarction. Thallium 201 myocardial scintigraphic results were normal in five runners randomly selected from those who volunteered for determination of sequential blood levels. It is concluded that elevations of serum MB creatine kinase in marathon runners arise from a skeletal muscle source and that thallium 201 myocardial scintigraphy is useful to assess runners for myocardial injury when clinical questions arise.« less

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.

PubMed

Pfeffer, Marc A; McMurray, John J V; Velazquez, Eric J; Rouleau, Jean-Lucien; Køber, Lars; Maggioni, Aldo P; Solomon, Scott D; Swedberg, Karl; Van de Werf, Frans; White, Harvey; Leimberger, Jeffrey D; Henis, Marc; Edwards, Susan; Zelenkofske, Steven; Sellers, Mary Ann; Califf, Robert M

2003-11-13

Angiotensin-converting-enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients. Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival. Copyright 2003 Massachusetts Medical Society

Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction.

PubMed

Ribeiro Júnior, R F; Ronconi, K S; Jesus, I C G; Almeida, P W M; Forechi, L; Vassallo, D V; Guatimosim, S; Stefanon, I; Fernandes, A A

2018-01-15

Testosterone may affect myocardial contractility since its deficiency decreases the contraction and relaxation of the heart. Meanwhile, testosterone replacement therapy has raised concerns because it may worsen cardiac dysfunction and remodeling after myocardial infarction (MI). In this study, we evaluate cardiac contractility 60 days after MI in rats with suppressed testosterone. Male Wistar rats underwent bilateral orchidectomy one week before the ligation of the anterior descending left coronary artery. The animals were divided into orchidectomized (OCT); MI; orchidectomized + MI (OCT + MI); orchidectomized + MI + testosterone (OCT + MI + T) and control (Sham) groups. Eight weeks after MI, papillary muscle contractility was analyzed under increasing calcium (0.62, 1.25, 2.5 and 3.75 mM) and isoproterenol (10 -8 to 10 -2  M) concentrations. Ventricular myocytes were isolated for intracellular calcium measurements and assessment of Ca 2+ handling proteins. Contractility was preserved in the orchidectomized animals after myocardial infarction and was reduced when testosterone was replaced (Ca 2+ 3.75 mM: Sham: 608 ± 70 (n = 11); OCT: 590 ± 37 (n = 16); MI: 311 ± 33* (n = 9); OCT + MI: 594 ± 76 (n = 7); OCT + MI + T: 433 ± 38* (n=4), g/g *p < 0.05 vs Sham). Orchidectomy also increased the Ca 2+ transient amplitude of the ventricular myocytes and SERCA-2a protein expression levels. PLB phosphorylation levels at Thr 17 were not different in the orchidectomized animals compared to the Sham animals but were reduced after testosterone replacement. CAMKII phosphorylation and protein nitrosylation increased in the orchidectomized animals. Our results support the view that testosterone deficiency prevents MI contractility dysfunction by altering the key proteins involved in Ca 2+ handling. Copyright © 2017 Elsevier B.V. All rights reserved.

Elevation of serum N-terminal pro-brain natriuretic peptide after exercise is an index of myocardial damage or a cytoprotective reflection?

PubMed

Faviou, E; Zachari, A; Nounopoulos, C; Agrafiotis, E; Vourli, G; Dionyssiou-Asteriou, A

2008-03-01

Recent investigations have suggested the occurrence of transient cardiac dysfunction and reversible myocardial injury in healthy individuals after heavy exercise. Our purpose was to examine if the release of N-terminal pro-brain natriuretic peptide (NT-proBNP) after intense exercise in obviously healthy participants may have cytoprotective and growth-regulating effects or may result from myocardial dysfunction/damage with changes in cTnT as a marker for myocardial cell necrosis during exercise. In 43 highly-trained male athletes <35 years old, who were examined immediately after exercising as well as 2 days later, 21 age-matched male patients classified as stage-B according to ACC/AHA guidelines and 35 healthy age-matched males, we evaluated NT-proBNP and 3rd generation's cTnT by electrochemiluminescence immunoassay. All participants underwent a detailed cardiac protocol including echocardiography and electrocardiogram (ECG). In athletes, cTnT consistently remained <0.01 mg/L after exercising as well as after 2 days. NTproBNP immediately after exercising was 58.27+/-19.48 ng/L, without reaching pathological levels, decreasing 2 days later to 22.93+/-10.22 ng/L. Our patients maintained high levels of NTproBNP, as much as a six-fold increase with reference to the levels of our study's control group and with cTnT <0.01 mg/L. In the control group, cTnT and NTproBNP levels were statistically similar with those of the athletes 2 days after exercising. NT-proBNP as a biological marker can reliably discriminate pathological from physiological cardiac hypertrophy. A normal plasma concentration of NT-proBNP in consecutive routine check-up, before and after exercise, could minimize the possibility of cardiac dysfunction, whereas persistent elevated plasma concentrations warrant further cardiological evaluation.

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study.

PubMed

Le Page, Lydia M; Rider, Oliver J; Lewis, Andrew J; Ball, Vicky; Clarke, Kieran; Johansson, Edvin; Carr, Carolyn A; Heather, Lisa C; Tyler, Damian J

2015-08-01

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1-(13)C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 ± 0.7 vs. 8.4 ± 0.5 mmol/L), lower PDH flux (0.005 ± 0.001 vs. 0.017 ± 0.002 s(-1)), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E'] 12.2 ± 0.8 vs. 20 ± 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 ± 0.002 s(-1)), reversed diastolic dysfunction (E/E' 14 ± 1), and normalized blood glucose levels (7.5 ± 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Added clinical value of applying myocardial deformation imaging to assess right ventricular function.

PubMed

Sokalskis, Vladislavs; Peluso, Diletta; Jagodzinski, Annika; Sinning, Christoph

2017-06-01

Right heart dysfunction has been found to be a strong prognostic factor predicting adverse outcome in various cardiopulmonary diseases. Conventional echocardiographic measurements can be limited by geometrical assumptions and impaired reproducibility. Speckle tracking-derived strain provides a robust quantification of right ventricular function. It explicitly evaluates myocardial deformation, as opposed to tissue Doppler-derived strain, which is computed from tissue velocity gradients. Right ventricular longitudinal strain provides a sensitive tool for detecting right ventricular dysfunction, even at subclinical levels. Moreover, the longitudinal strain can be applied for prognostic stratification of patients with pulmonary hypertension, pulmonary embolism, and congestive heart failure. Speckle tracking-derived right atrial strain, right ventricular longitudinal strain-derived mechanical dyssynchrony, and three-dimensional echocardiography-derived strain are emerging imaging parameters and methods. Their application in research is paving the way for their clinical use. © 2017, Wiley Periodicals, Inc.

Severe Sepsis and Acute Myocardial Dysfunction in an Adolescent with Chlamydia Trachomatis Pelvic Inflammatory Disease: A Case Report.

PubMed

Morgan, Ashley M; Roden, R Claire; Matson, Steven C; Wallace, Grant M; Lange, Hannah L H; Bonny, Andrea E

2018-04-01

Although generally asymptomatic, severe Chlamydia trachomatis (C. trachomatis) infections have been documented. C. trachomatis has been associated with myocarditis as well as sepsis. A 19-year-old girl with type 1 diabetes mellitus developed sudden-onset mental status change and shock after resolution of diabetic ketoacidosis. Abdominal and pelvic imaging showed uterine and adnexal inflammation, and pelvic examination confirmed a diagnosis of pelvic inflammatory disease. The patient was intubated, required vasopressor support, and developed severe biventricular myocardial dysfunction. Infectious myocarditis workup was negative. Nucleic acid amplification testing from vaginal discharge was positive for C. trachomatis and Trichomonas vaginalis and negative for Neisseria gonorrhoeae. C. trachomatis should be considered in the workup of septic shock, particularly in populations at high risk for sexually transmitted infections. Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease

PubMed Central

Duncker, Dirk J.; Koller, Akos; Merkus, Daphne; Canty, John M.

2018-01-01

The major factors determining myocardial perfusion and oxygen delivery have been elucidated over the past several decades, and this knowledge has been incorporated into the management of patients with ischemic heart disease (IHD). The basic understanding of the fluid mechanical behavior of coronary stenoses has also been translated to the cardiac catheterization laboratory where measurements of coronary pressure distal to a stenosis and coronary flow are routinely obtained. However, the role of perturbations in coronary microvascular structure and function, due to myocardial hypertrophy or coronary microvascular dysfunction, in IHD is becoming increasingly recognized. Future studies should therefore be aimed at further improving our understanding of the integrated coronary microvascular mechanisms that control coronary blood flow, and of the underlying causes and mechanisms of coronary microvascular dysfunction. This knowledge will be essential to further improve the treatment of patients with IHD. PMID:25475073

Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major.

PubMed

Ehsan, Lubaina; Rashid, Mariam; Alvi, Najveen; Awais, Khadija; Nadeem, Omair; Asghar, Aleezay; Sajjad, Fatimah; Fatima, Malika; Qidwai, Asim; Hussain, Shabneez; Hasan, Erum; Brown, Nick; Altaf, Sadaf; Hasan, Babar; Kirmani, Salman

2018-06-12

Endocrinopathy due to iron overload is the most common morbidity whereas myocardial siderosis causing toxic cardiomyopathy is the leading cause of mortality among patients with transfusion dependent thalassemia major (TDTM). If detected early, this can be treated with aggressive chelation. T2* cardiac magnetic resonance imaging (CMR) guided chelation protocols are now the gold standard but have limited availability in low and middle-income countries. We hypothesized that markers of endocrine dysfunction would correlate with T2* CMR and can be used to predict the severity of myocardial siderosis and guide chelation therapy. We undertook a multicenter retrospective study of 280 patients with TDTM to assess the prevalence of endocrinopathies and the predictive value of a number of individual and composite markers of endocrinopathy with T2* CMR. The prevalence of hypogonadism, stunting, hypoparathyroidism, and hypothyroidism was 82%, 69%, 40%, and 30%, respectively. The sensitivity of hypogonadism and stunting predicting severe myocardial siderosis was 90% and 80%, respectively. We conclude that clinical markers of endocrine dysfunction, especially hypogonadism (positive likelihood ratio [LR+] = 1.4, 95% confidence interval [CI] = 1.0-1.9; positive predictive value [PPV] = 77%, 95% CI = 70-82; negative predictive value [NPV] = 57%, 95% CI = 34-77] and stunting (LR+ = 1.3, 95% CI = 1.1-1.6; PPV = 64%, 95% CI = 60-69; NPV = 55%, 95% CI = 45-64) in TDTM can predict severe myocardial siderosis and can potentially guide chelation therapy, especially where access to T2* CMR is limited. © 2018 Wiley Periodicals, Inc.

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

PubMed

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

2015-01-06

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

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

PubMed Central

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

2015-01-01

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

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

PubMed

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

2016-11-01

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

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

PubMed Central

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

2013-01-01

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

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction *

PubMed Central

Sakamuri, Siva S. V. P.; Siddesha, Jalahalli M.; Saifudeen, Zubaida; Ma, Lixin; Siebenlist, Ulrich; Gardner, Jason D.; Chandrasekar, Bysani

2016-01-01

TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IκB kinase (IKK)/NF-κB, JNK/AP-1, and c/EBPβ and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg). Echocardiography, magnetic resonance imaging, and pressure-volume conductance catheterization revealed impaired cardiac function in 2-month-old male transgenic (Tg) mice as evidenced by decreased ejection fraction, stroke volume, cardiac output, and peak ejection rate. Moreover, the male Tg mice spontaneously developed myocardial hypertrophy (increased heart/body weight ratio, cardiomyocyte cross-sectional area, GATA4 induction, and fetal gene re-expression). Furthermore, TRAF3IP2 overexpression resulted in the activation of IKK/NF-κB, JNK/AP-1, c/EBPβ, and p38 MAPK and induction of proinflammatory cytokines, chemokines, and extracellular matrix proteins in the heart. Although myocardial hypertrophy decreased with age, cardiac fibrosis (increased number of myofibroblasts and enhanced expression and deposition of fibrillar collagens) increased progressively. Despite these adverse changes, TRAF3IP2 overexpression did not result in cell death at any time period. Interestingly, despite increased mRNA expression, TRAF3IP2 protein levels and activation of its downstream signaling intermediates remained unchanged in the hearts of female Tg mice. The female Tg mice also failed to develop myocardial hypertrophy. In summary, these results demonstrate that overexpression of TRAF3IP2 in male mice is sufficient to induce myocardial hypertrophy, cardiac fibrosis, and contractile dysfunction. PMID:27466370

Impaired left ventricular diastolic function is related to the formation of left ventricular apical thrombus in patients with acute anterior myocardial infarction.

PubMed

Choi, Ung Lim; Park, Jae-Hyeong; Sun, Byung Joo; Oh, Jin Kyung; Seong, Seok Woo; Lee, Jae-Hwan; Choi, Si Wan; Jeong, Jin-Ok; Kwon, In Sun; Seong, In-Whan

2018-05-01

Left ventricular (LV) apical thrombus is a clinically important complication which can cause systemic embolization in patients with anterior acute myocardial infarction (AMI). Systolic dysfunction has been a risk factor for developing LV apical thrombus in AMI patients. However, the role of diastolic dysfunction in the development of LV apical thrombus in these patients is still unknown. We performed this study to evaluate whether diastolic dysfunction can influence the development of LV apical thrombus in anterior AMI patients. We retrospectively analyzed all consecutive anterior AMI patients with available echocardiographic images within 1 month from January 2005 to April 2016. After gathering clinical characteristics from their medical records, systolic and diastolic functions were analyzed from digitally stored echocardiographic images. We included a total of 1045 patients (748 males, mean age 64 ± 12 years) with anterior AMI, and 494 (47%) were diagnosed as STEMI. The incidence of LV apical thrombus was 3.3% (34/1045). The LV apical thrombus group had larger LV diastolic dimension, larger LV diastolic and systolic volumes, and lower LVEF than the no LV thrombus group. The LV apical thrombus group showed higher mitral E velocity over mitral annular E' velocity ratio, an indicator of LV end-diastolic pressure (P < 0.001). In the LV apical thrombus group, the incidence of grade 2 diastolic dysfunction (32 vs 12%, P = 0.001) and grade 3 diastolic dysfunction (26 vs 2%, P < 0.001) were significantly higher than in the no LV apical thrombus group. The presence of more than grade 2 diastolic dysfunction, LVEF and presence of LV apical aneurysm were statistically significant factors associated with LV apical thrombus after the multivariate analysis. In conclusion, along with LV systolic dysfunction and LV apical aneurysm, LV diastolic dysfunction was also related with the presence of LV apical thrombus in patients with anterior AMI.

Relationship of myocardial hibernation, scar, and angiographic collateral flow in ischemic cardiomyopathy with coronary chronic total occlusion.

PubMed

Wang, Li; Lu, Min-Jie; Feng, Lei; Wang, Juan; Fang, Wei; He, Zuo-Xiang; Dou, Ke-Fei; Zhao, Shi-Hua; Yang, Min-Fu

2018-03-07

The relationship between myocardial viability and angiographic collateral flow is not fully elucidated in ischemic cardiomyopathy (ICM) with coronary artery chronic total occlusion (CTO). We aimed to clarify the relationship between myocardial hibernation, myocardial scar, and angiographic collateral flow in these patients. Seventy-one consecutive ICM patients with 122 CTOs and 652 dysfunctional segments within CTO territories were retrospectively analyzed. Myocardial hibernation (perfusion-metabolism mismatch) and the extent of 18 F-fluorodeoxyglucose (FDG) abnormalities were assessed using 99m Tc-sestamibi and 18 F-FDG imaging. Myocardial scar was evaluated by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) imaging. Collateral flow observed on coronary angiography was assessed using Rentrop classification. In these patients, neither the extent nor frequency of myocardial hibernation or scar was related to the status of collateral flow. Moreover, the matching rate in determining myocardial viability was poor between any 2 imaging indices. The extent of 18 F-FDG abnormalities was linearly related to the extent of LGE rather than myocardial hibernation. Of note, nearly one-third (30.4%) of segments with transmural scar still had hibernating tissue. Hibernation and non-transmural scar had higher sensitivity (63.0% and 66.7%) than collateral flow (37.0%) in predicting global functional improvement. Angiographic collateral cannot accurately predict myocardial viability, and has lower sensitivity in prediction of functional improvement in CTO territories in ICM patients. Hence, assessment of myocardial viability with non-invasive imaging modalities is of importance. Moreover, due to the lack of correlation between myocardial hibernation and scar, these two indices are complementary but not interchangeable.

Troxerutin Preconditioning and Ischemic Postconditioning Modulate Inflammatory Response after Myocardial Ischemia/Reperfusion Injury in Rat Model.

PubMed

Badalzadeh, Reza; Baradaran, Behzad; Alihemmati, Alireza; Yousefi, Bahman; Abbaszadeh, Azam

2017-02-01

Protective effects of ischemic postconditioning in myocardial ischemia/reperfusion (I/R) injury have been ever demonstrated, but the exact mechanisms remain unclear. Because of their multiplex activities, using natural pharmaceuticals seems to be clinically interesting. The aim of present study was to investigate the effects of troxerutin preconditioning and ischemic postconditioning on inflammatory responses after myocardial I/R injury in a rat model. Twenty-four Wistar rats were divided into four groups as the control, troxerutin receiving (TXR), postconditioning receiving (PostC), and combined therapy (TXR + PostC). Rats' isolated hearts underwent 30-min LAD regional ischemia followed by 45-min reperfusion. Troxerutin was orally administered for a month before I/R. Ischemic PostC was applied by alternative three cycles of 30-s R/I at the onset of reperfusion. The coronary effluent and ischemic left ventricular samples were used to determine the activities of creatine kinase (CK), intercellular adhesion molecule-1 (ICAM-1), interlukin-1beta (IL-1β), tumor-necrosis factor (TNF-α), and also histopathological studies. Pretreatment of rats with troxerutin significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels and ICAM-1 activity after I/R insult compared to those of control I/R hearts (P < 0.05). Application of PostC showed similar impacts on those parameters. In fact, anti-inflammatory mechanisms of both treatments were associated with their protective effects against myocardial damages causing from I/R injury. Pretreatment with troxerutin as well as postconditioning can induce cardioprotection through prevention of the cell-cell interaction and release of inflammatory mediators, minimizing I/R pathological changes in myocardial cells. These two treatments may share same mechanisms in their actions since they showed no significant additive effects.

Sequential evaluation of coronary flow patterns after primary angioplasty in acute anterior ST-elevation myocardial infarction predicts recovery of left ventricular systolic function.

PubMed

Sharif, Dawod; Sharif-Rasslan, Amal; Makhoul, Nabeel; Shefer, Arie; Hassan, Amin; Rosenschein, Uri

2014-05-01

Function of the microcirculation after primary percutaneous coronary intervention (PCI) is dynamic and contributes to unpredictability of recovery of left ventricular (LV) systolic function. This study was conducted to evaluate sequential Doppler velocity parameters of the left anterior descending coronary artery (LAD) in predicting recovery of global and regional LV systolic function. Thirty-five consecutive patients, 24 males, age 59 ± 12 years, with acute anterior ST-elevation myocardial infarction (STEMI) who had primary PCI were studied. Thrombolysis in myocardial infarction (TIMI) and myocardial blush grades were evaluated. Transthoracic echocardiographic (TTE) studies, evaluation of left ventricular ejection fraction (LVEF), LAD territory wall-motion score index (WMSI), and sampling of LAD Doppler velocities up to 6 hours post-PCI, 48 hours postprocedure, and predischarge were performed. Thrombolysis in myocardial infarction grade before PCI averaged 0.86 ± 1.19 and post-PCI 2.89 ± 0.32, P < 0.05. Myocardial blush grade before PCI was 0.41 ± 0.98 and after PCI 2.22 ± 0.93, P < 0.05. Diastolic velocity deceleration time (DDT) in the LAD early after PCI was less than 600 ms in 16 subjects. Immediately after PCI, in subjects with DDT > 600 ms, LVEF was 38.5 ± 6% and predischarge 49.2 ± 8.7%, P = 9.77 × 10−5 and LAD-WMSI decreased from 2 ± 0.38 to 1.4 ± 0.48, P = 0.000163. In subjects with DDT < 600 ms LAD-WMSI did not change significantly. Early and minimal LAD-DDT correlated with improvement in LV systolic function, r = 0.6, whereas post-PCI blush grade had lower correlation with LVEF, r = 0.39. Global and regional LV systolic function after PCI in acute anterior MI can be predicted by LAD-DDT better than by post-PCI myocardial blush.

Detrimental effects of acute hyperglycaemia on the rat heart.

PubMed

Mapanga, R F; Joseph, D; Symington, B; Garson, K-L; Kimar, C; Kelly-Laubscher, R; Essop, M Faadiel

2014-03-01

Hyperglycaemia is an important risk factor for acute myocardial infarction. It can lead to increased induction of non-oxidative glucose pathways (NOGPs) - polyol and hexosamine biosynthetic pathways, advanced glycation end products and protein kinase C - that may contribute to cardiovascular diseases onset. However, the precise underlying mechanisms remain poorly understood. Here we hypothesized that acute hyperglycaemia increases myocardial oxidative stress and NOGP activation resulting in cardiac dysfunction during ischaemia-reperfusion and that inhibition of, and/or shunting flux away from NOGPs [by benfotiamine (BFT) treatment], leads to cardioprotection. We employed several experimental systems: (i) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mm glucose vs. controls (11 mm glucose) ± global ischaemia and reperfusion ± BFT (first 20 min of reperfusion); (ii) Infarct size determination as per the ischaemic protocol, but with regional ischaemia and reperfusion ± BFT treatment; in separate experiments, NOGP inhibitors were also employed for (i) and (ii); and (iii) In vivo coronary ligations performed on streptozotocin-treated rats ± BFT treatment (early reperfusion). Acute hyperglycaemia generated myocardial oxidative stress, NOGP activation and apoptosis, but caused no impairment of cardiac function during pre-ischaemia, thereby priming hearts for later damage. Following ischaemia-reperfusion (under hyperglycaemic conditions), such effects were exacerbated together with cardiac contractile dysfunction. Moreover, inhibition of respective NOGPs and shunting away by BFT treatment (in part) improved cardiac function during ischaemia-reperfusion. Coordinate NOGP activation in response to acute hyperglycaemia results in contractile dysfunction during ischaemia-reperfusion, allowing for the development of novel cardioprotective agents. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Calcineurin Regulates Myocardial Function during Acute Endotoxemia

PubMed Central

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

2006-01-01

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

Myocardial Viability: From Proof of Concept to Clinical Practice

PubMed Central

Tan, Timothy C.; Hsu, Chijen; Denniss, Alan Robert

2016-01-01

Ischaemic left ventricular (LV) dysfunction can arise from myocardial stunning, hibernation, or necrosis. Imaging modalities have become front-line methods in the assessment of viable myocardial tissue, with the aim to stratify patients into optimal treatment pathways. Initial studies, although favorable, lacked sufficient power and sample size to provide conclusive outcomes of viability assessment. Recent trials, including the STICH and HEART studies, have failed to confer prognostic benefits of revascularisation therapy over standard medical management in ischaemic cardiomyopathy. In lieu of these recent findings, assessment of myocardial viability therefore should not be the sole factor for therapy choice. Optimization of medical therapy is paramount, and physicians should feel comfortable in deferring coronary revascularisation in patients with coronary artery disease with reduced LV systolic function. Newer trials are currently underway and will hopefully provide a more complete understanding of the pathos and management of ischaemic cardiomyopathy. PMID:27313943

Dobutamine stress magnetic resonance imaging suffices for the demonstration of myocardial ischaemia and viability.

PubMed

Lamers, F P L; van Dijkman, P R M; Kuijpers, Th J A; van Herpen, G

2003-02-01

We report three patients in whom dobutamine stress magnetic imaging (DS-MRI) was essential in assessing myocardial ischaemia. Two patients were referred to the cardiologist because of chest pain. Patient A had typical exertional angina and a normal resting electrocardiogram (ECG). Patient B had typical exercise-induced angina and had recently experienced an attack of severe chest pain at rest for 15 minutes. The ECG showed a complete left bundle branch block (LBBB). Patient C was referred for heart failure of unknown origin. There were no symptoms of chest pain during rest or exercise. Echocardiography in this patient demonstrated global left ventricular (LV) dilatation, systolic dysfunction and a small dyskinetic segment in the inferior wall. In all these patients exercise stress testing had failed to demonstrate myocardial ischaemia. Patients A and C produced normal findings whereas in patient B the abnormal repolarisation due to pre-existent LBBB precluded a diagnosis of ischaemia. Breath-hold DS-MRI was performed to study LV wall motion and wall thickening at rest through increasing doses of dobutamine. A test was considered positive for myocardial ischaemia if wall motion abnormalities developed at high-dose levels of the drug (20 μg/kg/min or more with a maximum of 40 μg/kg/min) in previously normal vascular territories or worsened in a segment that was normal at baseline. Recovery of wall thickening in a previously hypokinetic or akinetic segment at a low dose of dobutamine (5-10 μg/kg/min) was taken as proof of viability. Patients A and B developed hypokinesia progressing into akinesia at high-dose dobutamine in the anteroseptal area of the LV indicative of ischaemia. These findings were corroborated by coronary angiography demonstrating severe coronary artery disease which led to coronary artery bypass grafting (CABG) in patient A and balloon angioplasty in patient B. In patient C global recovery of LV contractions during low-dose dobutamine was followed by hypokinesia in the inferoseptal area during high-dose dobutamine. This biphasic response indicates myocardial viability as well as ischaemia. CABG was carried out because of multiple stenoses in the left coronary artery. Post-operatively LV function normalised. DS-MRI is a valuable method for detecting myocardial ischaemia and viability in patients with suspected coronary artery, and can be applied in every hospital with MRI equipment at its disposal.

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

PubMed Central

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

2010-01-01

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

Prevalence of arterial stiffness and the risk of myocardial diastolic dysfunction in women.

PubMed

Seeland, Ute; Brecht, Anna; Nauman, Ahmad T; Oertelt-Prigione, Sabine; Ruecke, Mirjam; Knebel, Fabian; Stangl, Verena; Regitz-Zagrosek, Vera

2016-10-01

The present study determines the prevalence of vascular dysfunction and arterial stiffness (ASt) in a female urban population by measuring the brachial augmentation index (AIx) and aortic pulse wave velocity (PWV). The study tests the hypothesis that the measurement of AIx and PWV is useful in addition to that of traditional cardiovascular risk factors when assessing the risk for left ventricular diastolic dysfunction (LVDD). This cross-sectional study recruited 965 women aged 25-75 years from 12 districts of Berlin. The ASt indices, brachial AIx, aortic PWV and the central blood pressure were measured by an oscillometric method. A randomly selected subgroup (n=343) was examined by echocardiography. Trans-mitral inflow E/A ratio and diastolic mitral annulus velocity (é) were assessed. Questionnaires, medical history and blood sampling were used for the evaluation of individual risk factors. Normal vascular function was found in 55% of the women included. The prevalence of women with pathological AIx only (AIx ⩾ -10%, PWV normal) was 21.5%, whereas 17.9% were affected by increased AIx and PWV (AIx ⩾ -10%, PWV ⩾9.7 m/s), and 6% with only pathological PWV values. The prevalence of LVDD was 31.7%. LVDD was significantly associated with pathological PWV ⩾ 9.7 m/s [OR: 1.27, 95%CI: 1.02-1.57], age [OR: 4.17, 95%CI: 2.87-6.07] and a waist circumference >80 cm [OR: 3.61, 95%CI: 1.85-7.04] in multiple regression analysis. The high prevalence of markers for vascular dysfunction and ASt in a general female population and their importance as a mediator of diastolic dysfunction should encourage implementation of aortic PWV measurement to improve cardiovascular-risk assessment in particular to identify subclinical myocardial diastolic dysfunction. © 2016 The Author(s).

Diastolic dysfunction in the critically ill patient.

PubMed

Suárez, J C; López, P; Mancebo, J; Zapata, L

2016-11-01

Left ventricular diastolic dysfunction is a common finding in critically ill patients. It is characterized by a progressive deterioration of the relaxation and the compliance of the left ventricle. Two-dimensional and Doppler echocardiography is a cornerstone in its diagnosis. Acute pulmonary edema associated with hypertensive crisis is the most frequent presentation of diastolic dysfunction critically ill patients. Myocardial ischemia, sepsis and weaning failure from mechanical ventilation also may be associated with diastolic dysfunction. The treatment is based on the reduction of pulmonary congestion and left ventricular filling pressures. Some studies have found a prognostic role of diastolic dysfunction in some diseases such as sepsis. The present review aims to analyze thoroughly the echocardiographic diagnosis and the most frequent scenarios in critically ill patients in whom diastolic dysfunction plays a key role. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

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

PubMed Central

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

2014-01-01

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

The Predictive Role of Serum Triglyceride to High-Density Lipoprotein Cholesterol Ratio According to Renal Function in Patients with Acute Myocardial Infarction.

PubMed

Kim, Jin Sug; Kim, Weon; Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyoon; Moon, Joo Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2016-01-01

A high serum triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported as an independent predictor for cardiovascular events in the general population. However, the prognostic value of this ratio in patients with renal dysfunction is unclear. We examined the association of the TG/HDL-C ratio with major adverse cardiovascular events (MACEs) according to renal function in patients with acute myocardial infarction (AMI). This study was based on the Korea Acute Myocardial Infarction Registry database. Of 13,897 patients who were diagnosed with AMI, the study population included the 7,016 patients with available TG/HDL-C ratio data. Patients were stratified into three groups according to their estimated glomerular filtration rate (eGFR), and the TG/HDL-C ratio was categorized into tertiles. We investigated 12-month MACEs, which included cardiac death, myocardial infarction, and repeated percutaneous coronary intervention or coronary artery bypass grafting. During the 12-month follow up period, 593 patients experienced MACEs. There was a significant association between the TG/HDL-C ratio and MACEs (p<0.001) in the entire study cohort. Having a TG/HDL-C ratio value in the highest tertile of TG/HDL-C ratio was an independent factor associated with increased risk of MACEs (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.26-1.93; p<0.001). Then we performed subgroup analyses according to renal function. In patients with normal renal function (eGFR ≥ 90 ml/min/1.73m2) and mild renal dysfunction (eGFR ≥ 60 to < 90ml/min/1.73m2), a higher TG/HDL-C ratio was significantly associated with increased risk of MACEs (HR, 1.64; 95% CI, 1.04-2.60; p = 0.035; and HR, 1.56; 95% CI, 1.14-2.12; p = 0.005, respectively). However, in patients with moderate renal dysfunction (eGFR < 60 ml/min/1.73m2), TG/HDL-C ratio lost its predictive value on the risk of MACEs (HR, 1.23; 95% CI, 0.82-1.83; p = 0.317). In patients with AMI, TG/HDL-C ratio is a useful independent predictor of 12-month MACEs. However, this ratio does not have predictive power in patients with moderate renal dysfunction.

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction.

PubMed

Li, Longhu; Haider, Husnain Kh; Wang, Linlin; Lu, Gang; Ashraf, Muhammad

2012-05-15

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.

Angiotensin-converting enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: an overview of long-term randomized controlled trials.

PubMed

Danchin, Nicolas; Cucherat, Michel; Thuillez, Christian; Durand, Eric; Kadri, Zena; Steg, Philippe G

2006-04-10

Results of randomized trials of angiotensin-converting enzyme inhibitors in patients with coronary artery disease (CAD) and preserved left ventricular function are conflicting. We undertook this study to determine whether long-term prescription of angiotensin-converting enzyme inhibitors decreases major cardiovascular events and mortality in patients who have CAD and no evidence of left ventricular systolic dysfunction. We searched MEDLINE, EMBASE, and IPA databases, the Cochrane Controlled Trials Register (1990-2004), and reports from scientific meetings (2003-2004), and we reviewed secondary sources. Search terms included angiotensin-converting enzyme inhibitors, coronary artery disease, randomi(s)zed controlled trials, clinical trials, and myocardial infarction. Eligible studies included randomized controlled trials in patients who had CAD and no heart failure or left ventricular dysfunction, with follow-up omicronf 2 years or longer. Of 1146 publications screened, 7 met our selection criteria and included a total of 33 960 patients followed up for a mean of 4.4 years. Five trials included only patients with documented CAD. One trial included patients with documented CAD (80%) or patients who had diabetes mellitus and 1 or more additional risk factors, and another trial included patients who had CAD, a history of transient ischemic attack, or intermittent claudication. Treatment with angiotensin-converting enzyme inhibitors decreased overall mortality (odds ratio, 0.86; 95% confidence interval, 0.79-0.93), cardiovascular mortality (odds ratio, 0.81; 95% confidence interval, 0.73-0.90), myocardial infarction (odds ratio, 0.82; 95% confidence interval, 0.75-0.89), and stroke (odds ratio, 0.77; 95% confidence interval, 0.66-0.88). Other end points, including resuscitation after cardiac arrest, myocardial revascularization, and hospitalization because of heart failure, were also reduced. Angiotensin-converting enzyme inhibitors reduce total mortality and major cardiovascular end points in patients who have CAD and no left ventricular systolic dysfunction or heart failure.

Tissue angiotensin-converting enzyme inhibitors for the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure: a pooled meta-analysis of randomized placebo-controlled clinical trials.

PubMed

Saha, S A; Molnar, J; Arora, R R

2008-01-01

The aim of this study was to determine the role of tissue angiotensin-converting enzyme (ACE) inhibitors in the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure in randomized placebo-controlled clinical trials using pooled meta-analysis techniques. Randomized placebo-controlled clinical trials of at least 12 months duration in patients with diabetes mellitus without left ventricular systolic dysfunction or heart failure who had experienced a prior cardiovascular event or were at high cardiovascular risk were selected. A total of 10 328 patients (43 517 patient-years) from four selected trials were used for meta-analysis. Relative risk estimations were made using data pooled from the selected trials and statistical significance was determined using the Chi-squared test (two-sided alpha error <0.05). The number of patients needed to treat was also calculated. Tissue ACE inhibitors significantly reduced the risk of cardiovascular mortality by 14.9% (p = 0.022), myocardial infarction by 20.8% (p = 0.002) and the need for invasive coronary revascularization by 14% (p = 0.015) when compared to placebo. The risk of all-cause mortality also tended to be lower among patients randomized to tissue ACE inhibitors, whereas the risks of stroke and hospitalization for heart failure were not significantly affected. Treating about 65 patients with tissue ACE inhibitors for about 4.2 years would prevent one myocardial infarction, whereas treating about 85 patients would prevent one cardiovascular death. Pooled meta-analysis of randomized placebo-controlled trials suggests that tissue ACE inhibitors modestly reduce the risk of myocardial infarction and cardiovascular death and tend to reduce overall mortality in diabetic patients without left ventricular systolic dysfunction or heart failure.

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

PubMed Central

Li, Longhu; Haider, Husnain Kh.; Wang, Linlin; Lu, Gang

2012-01-01

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction. PMID:22447941

Establishment of a canine model of acute pulmonary embolism with definite right ventricular dysfunction through introduced autologous blood clots.

PubMed

Zhao, Lin-Bo; Jia, Zhen-Yu; Lu, Guang-Dong; Zhu, Yin-Su; Jing, Lei; Shi, Hai-Bin

2015-04-01

To establish a canine model of acute pulmonary embolism (PE) with right ventricular (RV) dysfunction using autologous blood clots and evaluate by echocardiography and contrast-enhanced Computed Tomography (CT). Autologous blood clots formed in vitro were introduced sequentially into the pulmonary arteries of eight healthy mixed-breed dogs while monitoring pulmonary and systemic hemodynamic function. Blood clots were injected until the mean pulmonary artery pressure (MPAP) reached two-three times the baseline pressure, which was maintained up to 1 hour. The RV function was assessed by echocardiography and ECG-gated dual-source contrast CT. All animals survived the imaging procedure. The post-injection pulmonary angiograms showed extensive PE, and MPAP increased from 16.50±2.45 mmHg to 43.13±4.91 mmHg (P<0.001). On echocardiography, the RV fractional area change decreased from 42.06±3.36 to 27.96±3.54 (P<0.001), and the RV myocardial performance increased from 0.20±0.05 to 0.63±0.16 (P<0.001). On CT, the RV end-systolic volume increased from 11.11±1.81 ml to 24.71±4.60 ml (P<0.001), RV end-diastolic volume from 20.73±2.83 ml to 34.63±5.76 ml (P<0.001), and the four-chamber RV/left ventricular diameter ratio from 0.38±0.07 to 0.81±0.14 (P<0.001). Acute PE with RV dysfunction was established in a large animal model through controlled injection of autologous blood clots, which may be useful for developing and evaluating new therapeutic approaches for acute PE with RV dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Fractional flow reserve of non-culprit vessel post-myocardial infarction: is it reliable?

PubMed

Leite, Luís; Moura Ferreira, Joana; Silva Marques, João; Jorge, Elisabete; Matos, Vítor; Guardado, Jorge; Calisto, João; Pego, Mariano

2015-10-14

Multi-vessel disease is frequent in patients presenting with myocardial infarction and have an important prognostic impact. The decision to proceed to revascularization in non-culprit vessels can be postponed until ischemia is proven in non-invasive stress tests. On the other hand, there is an increasing evidence to support the role of fractional flow reserve (FFR) in acute coronary syndrome setting. We report a case in which a FFR-guided strategy for non-culprit vessels, 3 weeks after an ST-segment elevation myocardial infarction, was followed by a short-term sub-occlusion of the evaluated vessel. The timing of the coronary microcirculation recovery post-myocardial infarction, avoiding a possible false negative FFR, and the diagnostic gaps between ischemia and plaque vulnerability are under discussion. An FFR-guided strategy in this setting should be interpreted with caution.

Posttraumatic stress disorder after myocardial infarction and coronary artery bypass grafting.

PubMed

Singh, Amitoj; Agrawal, Sahil; Gargya, Sanchita; Saluja, Sabir; Kumar, Akshat; Kumar, Abhishek; Kalra, Kartik; Thind, Munveer; Saluja, Sajeev; Stone, Lauren E; Ali, Farhan; Duarte-Chavez, Rodrigo; Marchionni, Christine; Sholevar, Farhad; Shirani, Jamshid; Nanda, Sudip

2017-01-01

Post traumatic stress disorder is a psychiatric disease that is usually precipitated by life threatening stressors. Myocardial infarction, especially in the young can count as one such event. The development of post traumatic stress after a coronary event not only adversely effects psychiatric health, but leads to increased cardiovascular morbidity and mortality. There is increasing evidence that like major depression, post traumatic stress disorder is also a strong coronary risk factor. Early diagnosis and treatment of this disease in patients with acute manifestations of coronary artery disease can improve patient outcomes.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

PubMed

Kontonika, Marianthi; Barka, Eleonora; Roumpi, Maria; La Rocca, Vassilios; Lekkas, Panagiotis; Daskalopoulos, Evangelos P; Vilaeti, Agapi D; Baltogiannis, Giannis G; Vlahos, Antonios P; Agathopoulos, Simeon; Kolettis, Theofilos M

2017-02-01

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials.

PubMed

Ezekowitz, Justin A; McAlister, Finlay A

2009-02-01

Aldosterone blockade has been used to treat acute myocardial infarction (MI) and chronic heart failure. The aim of this study is to summarize the evidence on the efficacy of spironolactone (SP), eplerenone (EP), or canrenoate (CAN) in patients with left ventricular dysfunction. A search of multiple electronic databases until June 2008 was supplemented by hand searches of reference lists of included studies and review articles, meeting abstracts, FDA reports, and contact with study authors and drug manufacturers. Studies were eligible for inclusion if they included patients with left ventricular systolic or diastolic dysfunction, treatment with SP, EP, or CAN vs. control, and reported clinical outcomes. Nineteen randomized controlled trials (four in acute MI and 15 in heart failure, n = 10 807 patients) were included -- 14 of SP, three of EP, and three of CAN. Analysis was performed using relative risks (RRs) with 95% confidence intervals (CIs) and a random effects model with statistical heterogeneity assessed by I(2). Aldosterone blockade reduced all-cause mortality by 20% (RR 0.80, 95% CI 0.74-0.87). All-cause mortality was reduced in both heart failure (RR = 0.75, 95% CI 0.67-0.84) and post-MI (RR 0.85, 95% CI 0.76-0.95) patients. Only nine trials reported hospitalizations, and the RR reduction was 23% (RR 0.77, 95% CI 0.68-0.87), although 98% of the outcomes came from two trials. Ejection fraction (EF) improved in the seven heart failure trials, which assessed this outcome (weighted mean difference 3.1%, 95% CI 1.6-4.5). We demonstrated a 20% reduction in all-cause mortality with the use of aldosterone blockade in a clinically heterogeneous group of clinical trial participants with heart failure and post-MI. In addition, we found a 3.1% improvement in EF. Further study in those with less severe symptoms or preserved systolic function is warranted.

Pre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats.

PubMed

Knapp, Jürgen; Bergmann, Greta; Bruckner, Thomas; Russ, Nicolai; Böttiger, Bernd W; Popp, Erik

2013-10-01

Post-resuscitation myocardial dysfunction is an important cause of death in the intensive care unit after initially successful cardiopulmonary resuscitation (CPR) of pre-hospital cardiac arrest (CA) patients. Volatile anaesthetics reduce ischaemic-reperfusion injury in regional ischaemia in beating hearts. This effect, called anaesthetic-induced pre- or postconditioning, can be shown when the volatile anaesthetic is given either before regional ischaemia or in the reperfusion phase. However, up to now, little data exist for volatile anaesthetics after global ischaemia due to CA. Therefore, the goal of this study was to clarify whether Sevoflurane improves post-resuscitation myocardial dysfunction after CA in rats. Following institutional approval by the Governmental Animal Care Committee, 144 male Wistar rats (341±19g) were randomized either to a control group or to one of the 9 interventional groups receiving 0.25 MAC, 0.5 MAC or 1 MAC of Sevoflurane for 5min either before resuscitation (SBR), during resuscitation (SDR) or after resuscitation (SAR). After 6min of electrically induced ventricular fibrillation CPR was performed. Before CA (baseline) as well as 1h and 24h after restoration of spontaneous circulation (ROSC), continuous measurement of ejection fraction (EF), and preload adjusted maximum power (PAMP) as primary outcome parameters and end systolic pressure (ESP), end diastolic volume (EDV) and maximal slope of systolic pressure increment (dP/dtmax) as secondary outcome parameters was performed using a conductance catheter. EF was improved in all Sevoflurane treated groups 1h after ROSC in comparison to control, except for the 0.25 MAC SDR and 0.25 MAC SAR group (0.25 MAC SBR: 38±8, p=0.02; 0.5 MAC SBR: 39±7, p=0.04; 1 MAC SBR: 40±6, p=0.007; 0.5 MAC SDR: 38±7, p=0.02; 1 MAC SDR: 40±6, p=0.006; 0.5 MAC SAR: 39±6, p=0.01; 1 MAC SAR: 39±6, p=0.002, vs. 30±7%). Twenty-four hours after ROSC, EF was higher than control in all interventional groups (p<0.05 for all groups). EF recovered to baseline values 24h after ROSC in all SBR and SAR groups. PAMP was improved in comparison to control (4.6±3.0mW/μl(2)) 24h after ROSC in 0.5 MAC SBR (9.4±6.9mW/μl(2), p=0.04), 1 MAC SBR (8.9±4.4mW/μl(2), p=0.04), 1 MAC SDR (8.0±5.7mW/μl(2), p=0.04), and 1 MAC SAR (7.3±3.5mW/μl(2), p=0.04). ESP, EDV, and dP/dtmax was not different from control 1h as well as 24h after ROSC with the exception of 1 MAC SDR with a reduced ESP 1h after ROSC (89±16 vs. 103±22mmHg, p=0.04). Sevoflurane treatment did not affect survival rate. This animal study of CA and resuscitation provides the hypothesis that pharmacological pre- or postconditioning with the volatile anaesthetic Sevoflurane - administered before CA, during resuscitation or after ROSC - results in an improved myocardial inotropy 24h after ROSC. Sevoflurane treatment seems to improve EF even in the early phase of reperfusion 1h after ROSC. Therefore further targeted studies on the optimal dose and time point of administration of Sevoflurane in cardiopulmonary resuscitation seem to be worthwhile (Institutional protocol number: 35-9185.81/G-24/08). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

McConnell's sign in intra-operative acute right ventricle ischaemia: An under-recognized aetiology.

PubMed

Longo, S A; Echegaray, A; Acosta, C M; Rinaldi, L I; Cabrera Schulmeyer, M C; Olavide Goya, I

2016-11-01

Transoesophageal echocardiography (TEE) has become a fundamental tool in modern cardiothoracic anaesthesia. It has an indisputable role in coronary valve surgery and revascularisations with severe impairment of ventricle function. It helps in making diagnoses that can optimise the surgical strategy and to minimal invasively dynamically monitor volaemia and cardiac function during the post-operative period, detecting complications unobservable by other methods. The McConnell sign, visualised using TEE as an akinesis of the right ventricular free wall, with a normal apex motility and enlargement of the right cavities, is characteristic of right ventricular (RV) dysfunction. This sign has a 77% sensitivity and 94% specificity for the diagnosis of acute pulmonary embolism (APE). The case is presented of a 53-year-old man scheduled for aortic valve and ascending aorta replacement surgery, with a history of severe valve aortic stenosis, aortic root and arch aneurysm, and with normal coronary arteries. Post-cardiopulmonary bypass (CBP), the patient presented with haemodynamic instability, with the TEE showing a typical image of the McConnell sign, with no pulmonary hypertension. This enabled making an early diagnosis of acute RV ischaemia, that led to a change in the surgical plan, the performing of coronary revascularisation surgery. As a result, the McConnell sign, which describes the characteristics of RV dysfunction, led to making a differential diagnosis between APE, RV infarction and acute myocardial ischaemia. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Bioelectronic block of paravertebral sympathetic nerves mitigates post-myocardial infarction ventricular arrhythmias.

PubMed

Chui, Ray W; Buckley, Una; Rajendran, Pradeep S; Vrabec, Tina; Shivkumar, Kalyanam; Ardell, Jeffrey L

2017-11-01

Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT). To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI). In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs. Chronic MI was induced by microsphere embolization of the left anterior descending coronary artery. At termination, in anesthetized animals and following thoracotomy, an epicardial sock array was placed over both ventricles and a quadripolar carousel electrode positioned underlying the right T1-T2 paravertebral chain. In acute animals, the efficacy of CBDC carousel (CBDCC) block was assessed by evaluating cardiac function during T2 paravertebral ganglion stimulation with and without CBDCC. In chronic MI animals, VT inducibility was assessed by extrasystolic (S1-S2) stimulations at baseline and under >66% CBDCC blockade of T2-evoked sympathoexcitation. CBDCC demonstrated a current-dependent and reversible block without impacting basal cardiac function. VT was induced at baseline in all chronic MI animals. One animal died after baseline induction. Of the 6 remaining animals, only 1 was reinducible with simultaneous CBDCC application (P < .002 from baseline). The ventricular effective refractory period (VERP) was prolonged with CBDCC (323 ± 26 ms) compared to baseline (271 ± 32 ms) (P < .05). Axonal block of the T1-T2 paravertebral chain with CBDCC reduced VT in a chronic MI model. CBDCC prolonged VERP, without altering baseline cardiac function, resulting in improved electrical stability. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury.

PubMed

Zoladz, Phillip R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah L; Fry, Megan E; Johnson, Brandon L; Rorabaugh, Boyd R

2016-01-01

Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner.

Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality

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

Xia, Congying; Dong, Ruolan; Chen, Chen

Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (αMHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejectionmore » fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. αMHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPARγ-coactivator-1α (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling. - Highlights: • ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction. • ACOT1 can regulate PPARa/PGC1a signaling pathway. • We first generate the transgenic mice with cardiomyocyte specific expression of ACOT1.« less

One-Month Diesel Exhaust Inhalation Produces Hypertensive Gene Expression Phenotype in Healthy Rats

EPA Science Inventory

Exposure to diesel exhaust (DE) is linked to vasoconstriction, endothelial 26 dysfunction, and myocardial ischemia in compromised individuals. We hypothesized that DE 27 inhalation would cause greater inflammation, hematological alterations, and cardiac molecular 28 impairment ...

Detection and monitoring of cardiotoxicity-what does modern cardiology offer?

PubMed

Jurcut, Ruxandra; Wildiers, Hans; Ganame, Javier; D'hooge, Jan; Paridaens, Robert; Voigt, Jens-Uwe

2008-05-01

With new anticancer therapies, many patients can have a long life expectancy. Treatment-related comorbidities become an issue for cancer survivors. Cardiac toxicity remains an important side effect of anticancer therapies. Myocardial dysfunction can become apparent early or long after end of therapy and may be irreversible. Detection of cardiac injury is crucial since it may facilitate early therapeutic measures. Traditionally, chemotherapy-induced cardiotoxicity has been detected by measuring changes in left ventricular ejection fraction. This parameter is, however, insensitive to subtle changes in myocardial function as they occur in early cardiotoxicity. This review will discuss conventional and modern cardiologic approaches of assessing myocardial function. It will focus on Doppler myocardial imaging, a method which allows to sensitively measure myocardial function parameters like myocardial velocity, deformation (strain), or deformation rate (strain rate) and which has been shown to reliably detect early abnormalities in both regional and global myocardial function in an early stage. Other newer echocardiographic function estimators are based on automated border detection algorithms and ultrasonic integrated backscatter analysis. A further technique to be discussed is dobutamine stress echocardiography. The use of new biomarkers like B-type natriuretic peptide and troponin and less often used imaging techniques like magnetic resonance imaging and computed tomography will also be mentioned.

TU-G-BRA-08: BEST IN PHYSICS (JOINT IMAGING-THERAPY): Hybrid PET-MRI Imaging of Acute Radiation Induced Cardiac Toxicity

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

El-Sherif, O; Xhaferllari, I; Gaede, S

Purpose: To identify the presence of low-dose radiation induced cardiac toxicity in a canine model using hybrid positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: Research ethics board approval was obtained for a longitudinal imaging study of 5 canines after cardiac irradiation. Animals were imaged at baseline, 1 week post cardiac irradiation, and 1 month post cardiac irradiation using a hybrid PET- MRI system (Biograph mMR, Siemens Healthcare). The imaging protocol was designed to assess acute changes in myocardial perfusion and inflammation. Myocardial perfusion imaging was performed using N13-ammonia tracer followed by a dynamic PET acquisition scan. Amore » compartmental tracer kinetic model was used for absolute perfusion quantification. Myocardial inflammation imaging was performed using F18-fluorodeoxyglucose (FDG) tracer. The standard uptake value (SUV) over a region encompassing the whole heart was used to compare FDG scans. All animals received a simulation CT scan (GE Medical Systems) for radiation treatment planning. Radiation treatment plans were created using the Pinncale3 treatment planning system (Philips Radiation Oncology Systems) and designed to resemble the typical cardiac exposure during left-sided breast cancer radiotherapy. Cardiac irradiations were performed in a single fraction using a TrueBeam linear accelerator (Varian Medical Systems). Results: The delivered dose (mean ± standard deviation) to heart was 1.8±0.2 Gy. Reductions in myocardial stress perfusion relative to baseline were observed in 2 of the 5 animals 1 month post radiation. A global inflammatory response 1 month post radiation was observed in 4 of the 5 animals. The calculated SUV at 1 month post radiation was significantly higher (p=0.05) than the baseline SUV. Conclusion: Low doses of cardiac irradiation (< 2 Gy) may lead to myocardial perfusion defects and a global inflammatory response that can be detectable as early as 1 month post irradiation using hybrid PET-MRI imaging techniques.« less

Long-term administration of tolvaptan increases myocardial remodeling and mortality via exacerbation of congestion in mice heart failure model after myocardial infarction.

PubMed

Eguchi, Akiyo; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Naito, Yoshiro; Mano, Toshiaki; Masuyama, Tohru; Hirotani, Shinichi

2016-10-15

In contrast to loop diuretics, tolvaptan does not cause neurohormonal activation in several animal heart failure models. However, it remains unknown whether chronic vasopressin type 2 receptor blockade exerts beneficial effects on mortality in murine heart failure after myocardial infarction (MI). In an experimental heart failure model, we tested the hypothesis that tolvaptan reduces myocardial remodeling and mortality. MI was induced in 9-week-old male C57Bl6/J by the left coronary artery ligation. In study 1, animals were randomly assigned to treatment with placebo or tolvaptan starting 14days post-MI. In study 2, animals were randomized to tolvaptan or furosemide+tolvaptan starting 14days post-MI. Interestingly, results showed lower survival rate in tolvaptan group compared to placebo. Tolvaptan group had higher serum osmolality, heavier body weight, more severe myocardial remodeling, and lung congestion at day 28 of drug administration compared to placebo. In study 2, addition of furosemide significantly reduced mortality rate seen with tolvaptan, and presented with decreased osmolality, myocardial remodeling, and lung congestion compared to tolvaptan-treated mice. Increase in proximal tubular expression of aquaporin 1, Angiotensin II, and vasopressin seen with tolvaptan treatments were normalized to basal levels, similar to levels in placebo-treated mice. Contrary to our hypothesis, tolvaptan was associated with increased mortality in murine heart failure after MI. This increase in lung congestion, myocardial remodeling, could be prevented by co-administration of furosemide, which resulted in normalized serum osmolality, neurohormonal activation, and renal aquaporin 1 expression, and hence decreased mortality post-MI. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats.

PubMed

Wu, Jianjiang; Yang, Long; Xie, Peng; Yu, Jin; Yu, Tian; Wang, Haiying; Maimaitili, Yiliyaer; Wang, Jiang; Ma, Haiping; Yang, Yining; Zheng, Hong

2017-01-01

Previous studies from our group have demonstrated that sevoflurane post-conditioning (SPC) protects against myocardial ischemia reperfusion injury via elevating the intranuclear expression of hypoxia inducible factor-1 alpha (HIF-1α). However, diabetic SPC is associated with decreased myocardial protection and disruption of the HIF-1 signaling pathway. Previous studies have demonstrated that cobalt chloride (CoCl 2 ) can upregulate HIF-1α expression under diabetic conditions, but whether myocardial protection by SPC can be restored afterward remains unclear. We established a rat model of type 2 diabetes and a Langendorff isolated heart model of ischemia-reperfusion injury. Prior to reperfusion, 2.4% sevoflurane was used as a post-conditioning treatment. The diabetic rats were treated with CoCl 2 24 h before the experiment. At the end of reperfusion, tests were performed to assess myocardial function, infarct size, mitochondrial morphology, nitric oxide (NO), Mitochondrial reactive oxygen species (ROS), mitochondrial respiratory function and enzyme activity, HIF-1α, vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS) protein levels. In addition, myocardial protection by SPC was monitored after the blood glucose levels were lowered by insulin. The diabetic state was associated with deficient SPC protection and decreased HIF-1α expression. After treating the diabetic rats with CoCl 2 , SPC significantly upregulated the expression of HIF-1α, VEGF and eNOS, which markedly improved cardiac function, NO, mitochondrial respiratory function, and enzyme activity and decreased the infarction areas and ROS. In addition, these effects were not influenced by blood glucose levels. This study proved that CoCl 2 activates the HIF-1α signaling pathway, which restores SPC-dependent myocardial protection under diabetic conditions, and the protective effects of SPC were independent of blood glucose levels.

Non-ischemic diabetic cardiomyopathy may initially exhibit a transient subclinical phase of hyperdynamic myocardial performance.

PubMed

Hensel, Kai O

2016-09-01

Cardiovascular complications are the key cause for mortality in diabetes mellitus. Besides ischemia-related cardiac malfunction there is growing evidence for non-ischemic diabetes-associated heart failure in both type 1 and type 2 diabetes mellitus. The underlying pathophysiology of non-ischemic diabetic cardiomyopathy (NIDC) is poorly understood and data on myocardial mechanics in early stages of the disease are rare. However, several studies in both human and experimental animal settings have reported prima facie unexplained features indicating myocardial hyperdynamics early in the course of the disease. The new hypothesis is that - other than previously thought - NIDC may be non-linear and initially feature an asymptomatic subclinical phase of myocardial hypercontractility that precedes the long-term development of diabetes-associated cardiac dysfunction and ultimately heart failure. Diabetes-induced metabolic imbalances may lead to a paradoxic inotropic increase and inefficient myocardial mechanics that finally result in a gradual deterioration of myocardial performance. In conclusion, diabetic patients should be screened regularly and early in the course of the disease utilizing ultra-sensitive myocardial deformation imaging in order to identify patients at risk for diabetes-associated heart failure. Moreover, hyperdynamic myocardial deformation might help distinguish non-ischemic from ischemic diabetic cardiomyopathy. Further studies are needed to illuminate the underlying pathophysiological mechanisms, the exact spatiotemporal evolvement of diabetic cardiomyopathy and its long-term relation to clinical outcome parameters. Copyright © 2016 Elsevier Ltd. All rights reserved.

Feasibility of Extracorporeal Shock Wave Myocardial Revascularization Therapy for Post-Acute Myocardial Infarction Patients and Refractory Angina Pectoris Patients.

PubMed

Myojo, Masahiro; Ando, Jiro; Uehara, Masae; Daimon, Masao; Watanabe, Masafumi; Komuro, Issei

2017-04-06

Extracorporeal shockwave myocardial revascularization (ESMR) is one of the new treatment options for refractory angina pectoris (RAP), and some studies have indicated its effectiveness. A single-arm prospective trial to assess the feasibility of ESMR using Cardiospec for patients with post-acute myocardial infarction (AMI) and RAP was designed and performed. The patients were treated with 9 sessions of ESMR to the ischemic areas for 9 weeks. The feasibility measures included echocardiography; cardiac magnetic resonance imaging; troponin T, creatine kinase-MB (CK-MB), and brain natriuretic peptide testing; and a Seattle Angina Questionnaire (SAQ) survey. Three post-AMI patients and 3 RAP patients were enrolled. The post-AMI patients had already undergone revascularization with percutaneous coronary intervention (PCI) in the acute phase. In two patients, adverse events requiring admission occurred: one a lumbar disc hernia in a post-AMI patient and the other congestive heart failure resulting in death in an RAP patient. No apparent elevations in CK-MB and troponin T levels during the trial were observed. Echocardiography revealed no remarkable changes of ejection fraction; however, septal E/E' tended to decrease after treatments (11.6 ± 4.8 versus 9.2 ± 2.8, P = 0.08). Concerning the available SAQ scores for two RAP patients, one patient reported improvements in angina frequency and treatment satisfaction and the other reported improvements in physical limitations and angina stability. In this feasibility study, ESMR seems to be a safe treatment for both post-AMI patients and RAP patients. The efficacy of ESMR for post-AMI patients remains to be evaluated with additional studies.

Sevoflurane postconditioning protects the myocardium against ischemia/reperfusion injury via activation of the JAK2–STAT3 pathway

PubMed Central

Wu, Jianjiang; Yu, Jin; Xie, Peng; Maimaitili, Yiliyaer; Wang, Jiang; Yang, Long; Ma, Haiping; Zhang, Xing; Yang, Yining

2017-01-01

Background Sevoflurane postconditioning (S-post) has similar cardioprotective effects as ischemic preconditioning. However, the underlying mechanism of S-post has not been fully elucidated. Janus kinase signaling transduction/transcription activator (JAK2–STAT3) plays an important role in cardioprotection. The purpose of this study was to determine whether the cardioprotective effects of S-post are associated with activation of the JAK2–STAT3 signal pathway. Methods An adult male Sprague–Dawley (SD) rat model of myocardial ischemia/reperfusion (I/R) injury was established using the Langendorff isolated heart perfusion apparatus. At the beginning of reperfusion, 2.4% sevoflurane alone or in combination with AG490 (a JAK2 selective inhibitor) was used as a postconditioning treatment. The cardiac function indicators, myocardial infarct size, lactic dehydrogenase (LDH) release, mitochondrial ultrastructure, mitochondrial reactive oxygen species (ROS) generation rates, ATP content, protein expression of p-JAK, p-STAT3, Bcl-2 and Bax were measured. Results Compared with the I/R group, S-post significantly increased the expression of p-JAK, p-STAT3 and Bcl-2 and reduced the protein expression of Bax, which markedly decreased the myocardial infarction areas, improved the cardiac function indicators and the mitochondrial ultrastructure, decreased the mitochondrial ROS and increased the ATP content. However, the cardioprotective effects of S-post were abolished by treatment with a JAK2 selective inhibitor (p < 0.05). Conclusion This study demonstrates that the cardioprotective effects of S-post are associated with the activation of JAK2–STAT3. The mechanism may be related to an increased expression of p-JAK2 and p-STAT3 after S-post, which reduced mitochondrial ROS generation and increased mitochondrial ATP content, thereby reducing apoptosis and myocardial infarct size. PMID:28392989

Mitochondrial dysfunction in myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy.

PubMed

Sleeper, Meg M; Rosato, Bradley P; Bansal, Seema; Avadhani, Narayan G

2012-11-01

To compare mitochondrial complex I and complex IV activity in myocardial mitochondria of clinically normal dogs, clinically normal dogs exposed to inhalation anesthesia, and dogs affected with dilated cardiomyopathy. Myocardial samples obtained from 21 euthanized dogs (6 clinically normal [control] dogs, 5 clinically normal dogs subjected to inhalation anesthesia with isoflurane prior to euthanasia, 5 dogs with juvenile-onset dilated cardiomyopathy, and 5 dogs with adult-onset dilated cardiomyopathy). Activity of mitochondrial complex I and complex IV was assayed spectrophotometrically in isolated mitochondria from left ventricular tissue obtained from the 4 groups of dogs. Activity of complex I and complex IV was significantly decreased in anesthetized dogs, compared with activities in the control dogs and dogs with juvenile-onset or adult-onset dilated cardiomyopathy. Inhalation anesthesia disrupted the electron transport chain in the dogs, which potentially led to an outburst of reactive oxygen species that caused mitochondrial dysfunction. Inhalation anesthesia depressed mitochondrial function in dogs, similar to results reported in other species. This effect is important to consider when anesthetizing animals with myocardial disease and suggested that antioxidant treatments may be beneficial in some animals. Additionally, this effect should be considered when designing studies in which mitochondrial enzyme activity will be measured. Additional studies that include a larger number of animals are warranted.

Cpg-ODN, a TLR9 Agonist, Aggravates Myocardial Ischemia/Reperfusion Injury by Activation of TLR9-P38 MAPK Signaling.

PubMed

Xie, Liang; He, Songqing; Kong, Na; Zhu, Ying; Tang, Yi; Li, Jianhua; Liu, Zhengbing; Liu, Jing; Gong, Jianbin

2018-06-19

Toll-like receptors (TLRs) have been implicated in myocardial ischemia/ reperfusion (I/R) injury. We examined the effect of CpG-oligodeoxynucleotide (ODN) on myocardial I/R injury. Male Sprague-Dawley rats were treated with either CpG-ODN or control ODN 1 h prior to myocardial ischemia (30 min) followed by reperfusion. Rats treated with phosphate-buffered saline (PBS) served as I/R controls (n = 8/group). Infarct size was determined by 2,3,5-triphenyltetrazolium chloride and Evans blue straining. Cardiac function was examined by echocardiography before and up to 14 days after myocardial I/R. CpG-ODN administration significantly increased infarct size and reduced cardiac function and survival rate after myocardial I/R, compared to the PBS-treated I/R group. Control-ODN did not alter I/R-induced myocardial infarct size, cardiac dysfunction, and survival rate. Additionally, CpG-ODN promoted I/R-induced myocardial apoptosis and cleaved caspase-3 levels in the myocardium. CpG-ODN increased TLR9 activation and p38 phosphorylation in the myocardium. In vitro data also suggested that CpG-ODN treatment induced TLR9 activation and p38 phosphorylation. Importantly, p38 mitogen-activated protein kinase (MAPK) inhibition abolished CpG-ODN-induced cardiac injury. CpG-ODN, the TLR9 ligand, accelerates myocardial I/R injury. The mechanisms involve activation of the TLR9-p38 MAPK signaling pathway. © 2018 The Author(s). Published by S. Karger AG, Basel.

Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction.

PubMed

Lax, Antonio; Sanchez-Mas, Jesus; Asensio-Lopez, Maria C; Fernandez-Del Palacio, Maria J; Caballero, Luis; Garrido, Iris P; Pastor-Perez, Francisco J; Januzzi, James L; Pascual-Figal, Domingo A

2015-01-01

This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined. In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. MRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction.

PubMed

Cappetta, Donato; Esposito, Grazia; Coppini, Raffaele; Piegari, Elena; Russo, Rosa; Ciuffreda, Loreta Pia; Rivellino, Alessia; Santini, Lorenzo; Rafaniello, Concetta; Scavone, Cristina; Rossi, Francesco; Berrino, Liberato; Urbanek, Konrad; De Angelis, Antonella

2017-11-01

Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg -1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg -1 , daily) for the following 4 weeks. While diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. Ranolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc. © 2017 The British Pharmacological Society.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

PubMed Central

Shimauchi, Tsukasa; Numaga-Tomita, Takuro; Ito, Tomoya; Nishimura, Akiyuki; Matsukane, Ryosuke; Oda, Sayaka; Hoka, Sumio; Ide, Tomomi; Koitabashi, Norimichi; Uchida, Koji; Sumimoto, Hideki; Mori, Yasuo

2017-01-01

Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress–mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load–induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy. PMID:28768915

Energy Drinks and Myocardial Ischemia: A Review of Case Reports.

PubMed

Lippi, Giuseppe; Cervellin, Gianfranco; Sanchis-Gomar, Fabian

2016-07-01

The use and abuse of energy drinks (EDs) is constantly increasing worldwide. We performed a systematic search in Medline, Scopus and Web of Science to identify evidence about the potential link between these beverages and myocardial ischemia. Overall, 8 case reports could be detected, all of which described a realistic association between large intake of EDs and episodes of myocardial ischemia. Interestingly, no additional triggers of myocardial ischemia other than energy drinks could be identified in the vast majority of cases. Some plausible explanations can be brought in support of this association. Most of the biological effects of EDs are seemingly mediated by a positive inotropic effect on cardiac function, which entails increase in heart rate, cardiac output and contractility, stroke volume and arterial blood pressure. Additional biological abnormalities reported after EDs intake include increased platelet aggregation, endothelial dysfunction, hyperglycemia as well as an increase in total cholesterol, triglycerides and low-density lipoprotein cholesterol. Although a causal relationship between large consumption of EDs and myocardial ischemia cannot be definitely established so far, concerns about the cardiovascular risk of excessive consumption of these beverages are seemingly justified.

Myocardial viability assessment with dynamic low-dose iodine-123-iodophenylpentadecanoic acid metabolic imaging: comparison with myocardial biopsy and reinjection SPECT thallium after myocardial infarction.

PubMed

Murray, G L; Schad, N C; Magill, H L; Vander Zwaag, R

1994-04-01

Aggressive cardiac revascularization requires recognition of stunned and hibernating myocardium, and cost considerations may well govern the technique used. Dynamic low-dose (1 mCi) [123I]iodophenylpentadecanoic acid (IPPA) metabolic imaging is a potential alternative to PET using either 18FDG or 15O-water. Resting IPPA images were obtained from patients with severe ischemic cardiomyopathy, and transmural myocardial biopsies were obtained during coronary bypass surgery to confirm viability. Thirty-nine of 43 (91%) biopsies confirmed the results of the IPPA images with a sensitivity for viability of 33/36 (92%) and a specificity of 6/7 (86%). Postoperatively, wall motion improved in 80% of IPPA-viable, dysfunctional segments. Furthermore, when compared to reinjection thallium (SPECT-TI) scans after myocardial infarction, IPPA-SPECT-TI concordance occurred in 27/35 (77%) (K = 0.536, p = 0.0003). Similar to PET, IPPA demonstrated more viability than SPECT-TI, 26/35 (74%) versus 18/35 (51%) (p = 0.047). Metabolic IPPA cardiac viability imaging is a safe, inexpensive technique that may be a useful alternative to PET.

Soluble Components of Ultraflne Particulate Matter Stimulate Endothelial H202 Production

EPA Science Inventory

A growing body of evidence shows a strong association between particulate matter (PM) exposure and adverse cardiovascular health effects such as atherosclerosis and myocardial ischemia. The mechanisms by which PM causes cardiovascular dysfunction is unknown, but there is increasi...

A Case of Post Myocardial Infarction Papillary Muscle Rupture.

PubMed

Anuwatworn, Amornpol; Milnes, Christopher; Kumar, Vishesh; Raizada, Amol; Nykamp, Verlyn; Stys, Adam

2016-06-01

Papillary muscle rupture is a rare, life-threatening post myocardial infarction mechanical complication. Without surgical intervention, prognosis is very poor. Clinicians need to recognize this complication early, as prompt therapy is crucial. We present a case of inferior ST elevation myocardial infarction complicated by posteromedial papillary muscle rupture resulting in severe acute mitral regurgitation (flail anterior mitral leaflet), acute pulmonary edema and cardiogenic shock. In our patient, a new mitral regurgitation murmur suggested this mechanical complication. Complete disruption of papillary muscle was visualized by transesophageal echocardiography. This case illustrates the importance of good physical examination for early diagnosis of papillary muscle rupture, so that life-saving treatment can be administered without delay.

Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target.

PubMed

Kagaya, Yutaka; Asaumi, Yasuhide; Wang, Wanting; Takeda, Morihiko; Nakano, Makoto; Satoh, Kimio; Fukumoto, Yoshihiro; Shimokawa, Hiroaki

2012-06-01

Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.

Cardiac Expression of Human Type 2 Iodothyronine Deiodinase Increases Glucose Metabolism and Protects Against Doxorubicin-induced Cardiac Dysfunction in Male Mice

PubMed Central

Hong, Eun-Gyoung; Kim, Brian W.; Young Jung, Dae; Hun Kim, Jong; Yu, Tim; Seixas Da Silva, Wagner; Friedline, Randall H.; Bianco, Suzy D.; Seslar, Stephen P.; Wakimoto, Hiroko; Berul, Charles I.; Russell, Kerry S.; Won Lee, Ki; Larsen, P. Reed; Bianco, Antonio C.

2013-01-01

Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction. PMID:23861374

Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

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

Montaigne, David; Marechal, Xavier; Baccouch, Riadh

2010-05-01

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solutionmore » containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.« less

Assessment of subclinical right ventricular systolic dysfunction in coal miners using myocardial isovolumic acceleration.

PubMed

Ozcan Abacıoglu, Ozge; Kaplan, Mehmet; Abacıoglu, Serkan; Quisi, Ala

2017-09-01

Several studies have been conducted regarding the effects of coal mining on the respiratory system. However, there is a lack of data concerning potential effects of coal mining on the cardiovascular system. In this study, we aimed to evaluate the potential subclinical right and left ventricular dysfunction in coal miners. This single-center, prospective study included a total of 102 patients. Patient and control groups consisted of 54 coal miners and 48 healthy men, respectively. All patients underwent 12-lead electrocardiography, transthoracic echocardiography, and pulmonary function test. As compared to control group, coal miners had significantly higher right ventricular myocardial performance index (RVMPI) (0.41 ± 0.03 vs 0.37 ± 0.02, P < .001), lower right ventricular fractional area change (RVFAC) (33.55% ± 6.70% vs 37.04 ± 9.26 P < .05), lower tricuspid annular plane systolic excursion (TAPSE) (1.54 ± 0.17 vs 1.73 ± 0.25, P < .001), lower myocardial isovolumic acceleration (IVA) (2.13 ± 0.16 vs 2.56 ± 0.36 P < .001) and decreased aortic distensibility (AD) (4.14 ± 2.18 vs 6.63 ± 3.91 P < .001). All of the echocardiographic parameters were positively correlated with exposure time to coal mine dust, except IVA. Echocardiographic parameters of both right and left ventricular dysfunction, including RVMPI, RVFAC, TAPSE, IVA, and AD, are impaired in coal miners. © 2017 The Authors Echocardiography Published by Wiley Periodicals, Inc.

Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts.

PubMed

Guo, Rui; Hu, Nan; Kandadi, Machender R; Ren, Jun

2012-04-01

Chronic drinking leads to myocardial contractile dysfunction where ethanol metabolism plays an essential role. Acetaldehyde, the main ethanol metabolite, mediates alcohol-induced cell injury although the underlying mechanism is still elusive. This study was designed to examine the mechanism involved in accelerated ethanol metabolism-induced cardiac defect with a focus on autophagy. Wild-type FVB and cardiac-specific overexpression of alcohol dehydrogenase mice were placed on a 4% nutrition-balanced alcohol diet for 8 weeks. Myocardial histology, immunohistochemistry, autophagy markers and signal molecules were examined. Expression of micro RNA miR-30a, a potential target of Beclin 1, was evaluated by real-time PCR. Chronic alcohol intake led to cardiac acetaldehyde accumulation, hypertrophy and overt autophagosome accumulation (LC3-II and Atg7), the effect of which was accentuated by ADH. Signaling molecules governing autophagy initiation including class III PtdIns3K, phosphorylation of mTOR and p70S6K were enhanced and dampened, respectively, following alcohol intake. These alcohol-induced signaling responses were augmented by ADH. ADH accentuated or unmasked alcohol-induced downregulation of Bcl-2, Bcl-xL and MiR-30a. Interestingly, ADH aggravated alcohol-induced p62 accumulation. Autophagy inhibition using 3-MA abolished alcohol-induced cardiomyocyte contractile anomalies. Moreover, acetaldehyde led to cardiomyocyte contractile dysfunction and autophagy induction, which was ablated by 3-MA. Ethanol or acetaldehyde increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by 3-MA but unaffected by lysosomal inhibition using bafilomycin A(1), E64D and pepstatin A. In summary, these data suggested that facilitated acetaldehyde production via ADH following alcohol intake triggered cardiac autophagosome formation along with impaired lysosomal degradation, en route to myocardial defect.

Chinese patent medicine Xin-Ke-Shu inhibits Ca2+ overload and dysfunction of fatty acid β-oxidation in rats with myocardial infarction induced by LAD ligation.

PubMed

Yang, Yong; Jia, Hongmei; Yu, Meng; Zhou, Chao; Sun, Lili; Zhao, Yang; Zhang, Hongwu; Zou, Zhongmei

2018-03-15

Myocardial infarction (MI) occurs during a sustained insufficient blood supply to the heart, eventually leading to myocardial necrosis. Xin-Ke-Shu tablet (XKS) is a prescription herbal compound and a patented medicine extensively used in the clinical treatment of coronary heart disease (CHD). To understand the molecular mechanism of the XKS action against MI in detail, it is necessary to investigate the altered metabolome and related pathways coincident with clinical features. In this study, tissue-targeted metabonomics based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) were developed to explore the metabolic changes associated with XKS treatment in the heart tissue of rats with MI induced by a left anterior descending coronary artery ligation (LAD). The metabolic disorder induced by LAD was alleviated after low-dose XKS (LD) and intermediate-dose XKS (MD) treatment. XKS modulated six perturbed metabolic pathways. Among them, inhibition of Ca 2+ overload and dysfunction of fatty acid β-oxidation-related metabolic pathways likely underlie the therapeutic effects of XKS against MI. In agreement with its observed effect on metabolite perturbation, XKS reversed the over-expression of the four key proteins, long-chain acyl-CoA synthetase 1 (ACSL1), carnitine palmitoyl transferase-1 (CPT1B), calcium/calmodulin-dependent kinase II (CaMKII), and phospholipase A2IIA (PLA2IIA). Both metabolite and protein changes suggested that XKS exerts its therapeutic effect on metabolic perturbations in LAD-induced MI mainly by inhibiting the Ca 2+ overload and fatty acid β-oxidation dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2010-01-01

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

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

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

Lin, Lin; Zhang, Ming; Yan, Rui

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

Diastolic dysfunction in hypertension.

PubMed

Nazário Leão, R; Marques da Silva, P

Hypertension and coronary heart disease, often coexisting, are the most common risk factors for heart failure. The progression of hypertensive heart disease involves myocardial fibrosis and alterations in the left ventricular geometry that precede the functional change, initially asymptomatic. The left ventricular diastolic dysfunction is part of this continuum being defined by the presence of left ventricular diastolic dysfunction without signs or symptoms of heart failure or poor left ventricular systolic function. It is highly prevalent in hypertensive patients and is associated with increased cardiovascular morbidity and mortality. Despite its growing importance in clinical practice it remains poorly understood. This review aims to present the epidemiological fundamentals and the latest developments in the pathophysiology, diagnosis and treatment of left ventricular diastolic dysfunction. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Association between left ventricular perfusion defects and myocardial deformation indexes in heart transplantation recipients.

PubMed

D'Andrea, Antonello; De Rimini, Maria Luisa; America, Raffaella; Cirillo, Chiara; Riegler, Lucia; Limongelli, Giuseppe; D'Alto, Michele; Salerno, Gemma; Maiello, Ciro; Muto, Pietro; Russo, Maria Giovanna; Calabrò, Raffaele; Bossone, Eduardo; Pacileo, Giuseppe

2017-10-01

The aim of the study was to analyze possible correlations between strain echocardiography (STE) and PET myocardial perfusion in a population of heart transplantation (HTx) recipients showing preserved left ventricular (LV) ejection fraction. By STE, LV global longitudinal strain (LV GLS) was lower in HTx. PET showed no transient or chronic ischemia in 83 of 115 HTx (73%). Fixed perfusion defects were observed in 17% of HTx and reversible ischemia in 10%. Significant coronary stenosis was observed only in 10 cases. GLS was independently associated with age at HTx and fixed perfusion defects (HR 0.41; P<.001). Such relationships underline STE ability to early identify HTx pts with subclinical myocardial dysfunction during long-term follow-up. © 2017, Wiley Periodicals, Inc.

[The role of physical training in patients after myocardial infarction].

PubMed

Lazović, Milica; Devecerski, Gordana; Lazović, Marko; Zivković, Vesna

2006-01-01

Physical training is an optimal method of rehabilitation of cardiovascular patients, especially in patients with myocardial infarction. The aim of this study was to evaluate the effects of physical training in patients with myocardial infarction during the post-hospital phase and prolonged rehabilitation by determining the test exercise parameters. This prospective clinical study included 230 patients after myocardial infarction. Group A (180 patients) participated in organized forms of exercise (post-hospital rehabilitation and prolonged rehabilitation at home) for 48 +/- 6.4 months, while the control group was without physical training. The first clinical examination and the exercise test were performed in group A after post-hospital rehabilitation and after 191 +/- 16.4 days in the control group. In all patients the last control was performed 48 +/- 6.4 months after myocardial infarction. After the first control, the mean physical workload in group A was significantly higher compared with the control group (p < 0.05). After a 48 month follow-up period the physical workload was significantly higher in group A (p < 0.01), while in the control group a significant increase of workload was not observed (p > 0.05). Comparing the duration of exercise testing, significant differences were found after the first and last control (p < 0.05; p < 0.01, respectively). The double product was significantly higher in group A than in the control group after the first and last control (p < 0.05; p < 0.01, respectively). Prolonged physical training is beneficial for patients after myocardial infarction, because it improves cardiovascular functions and physical work capacity, improves angina threshold and the patient's general health.

Transient severe left ventricular dysfunction following percutaneous patent ductus arteriosus closure in an adult with bicuspid aortic valve: A case report

PubMed Central

HWANG, HUI-JEONG; YOON, KYUNG LIM; SOHN, IL SUK

2016-01-01

The present study reported the case of a 60-year-old female with patent ductus arteriosus (PDA) and a bicuspid aortic valve, who presented with transient severe left ventricular (LV) dysfunction following percutaneous closure of PDA, as identified by speckle tracking analysis. Transient LV dysfunction following PDA closure has previously been reported; however, severe LV dysfunction is rare. In the present case, the combination of a large PDA size, large amount of shunting, LV remodeling and bicuspid aortic valve may have induced serious deterioration of LV function following PDA closure. Furthermore, speckle-tracking echocardiography may be useful in the estimation of functional alterations in the myocardium of the LV following PDA closure. The observations detailed in the present study may improve the understanding of the pathophysiology and myocardial patterns of transient left ventricular dysfunction following PDA closure in adult humans. PMID:26998021

Transient severe left ventricular dysfunction following percutaneous patent ductus arteriosus closure in an adult with bicuspid aortic valve: A case report.

PubMed

Hwang, Hui-Jeong; Yoon, Kyung Lim; Sohn, Il Suk

2016-03-01

The present study reported the case of a 60-year-old female with patent ductus arteriosus (PDA) and a bicuspid aortic valve, who presented with transient severe left ventricular (LV) dysfunction following percutaneous closure of PDA, as identified by speckle tracking analysis. Transient LV dysfunction following PDA closure has previously been reported; however, severe LV dysfunction is rare. In the present case, the combination of a large PDA size, large amount of shunting, LV remodeling and bicuspid aortic valve may have induced serious deterioration of LV function following PDA closure. Furthermore, speckle-tracking echocardiography may be useful in the estimation of functional alterations in the myocardium of the LV following PDA closure. The observations detailed in the present study may improve the understanding of the pathophysiology and myocardial patterns of transient left ventricular dysfunction following PDA closure in adult humans.

Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair.

PubMed

Packard, René R Sevag; Baek, Kyung In; Beebe, Tyler; Jen, Nelson; Ding, Yichen; Shi, Feng; Fei, Peng; Kang, Bong Jin; Chen, Po-Heng; Gau, Jonathan; Chen, Michael; Tang, Jonathan Y; Shih, Yu-Huan; Ding, Yonghe; Li, Debiao; Xu, Xiaolei; Hsiai, Tzung K

2017-08-17

This study sought to develop an automated segmentation approach based on histogram analysis of raw axial images acquired by light-sheet fluorescent imaging (LSFI) to establish rapid reconstruction of the 3-D zebrafish cardiac architecture in response to doxorubicin-induced injury and repair. Input images underwent a 4-step automated image segmentation process consisting of stationary noise removal, histogram equalization, adaptive thresholding, and image fusion followed by 3-D reconstruction. We applied this method to 3-month old zebrafish injected intraperitoneally with doxorubicin followed by LSFI at 3, 30, and 60 days post-injection. We observed an initial decrease in myocardial and endocardial cavity volumes at day 3, followed by ventricular remodeling at day 30, and recovery at day 60 (P < 0.05, n = 7-19). Doxorubicin-injected fish developed ventricular diastolic dysfunction and worsening global cardiac function evidenced by elevated E/A ratios and myocardial performance indexes quantified by pulsed-wave Doppler ultrasound at day 30, followed by normalization at day 60 (P < 0.05, n = 9-20). Treatment with the γ-secretase inhibitor, DAPT, to inhibit cleavage and release of Notch Intracellular Domain (NICD) blocked cardiac architectural regeneration and restoration of ventricular function at day 60 (P < 0.05, n = 6-14). Our approach provides a high-throughput model with translational implications for drug discovery and genetic modifiers of chemotherapy-induced cardiomyopathy.

Regenerative Medicine at Early Echelons: Changing Medical Care & Outcomes

DTIC Science & Technology

2010-04-01

HFM-182 combat lifesaver. First aid includes tourniquet application, fracture stabilization with splints , and application of sterile dressings to...dysfunction and remodeling after myocardial infarction. Stem Cells. 2008; 26:1646-1655. PMID: 18420834. [72] Shin D.M., Zuba-Surma E.K., Wu W

Electrical cardioversion

PubMed Central

Sucu, Murat; Davutoglu, Vedat; Ozer, Orhan

2009-01-01

External electrical cardioversion was first performed in the 1950s. Urgent or elective cardioversions have specific advantages, such as termination of atrial and ventricular tachycardia and recovery of sinus rhythm. Electrical cardioversion is life-saving when applied in urgent circumstances. The succcess rate is increased by accurate tachycardia diagnosis, careful patient selection, adequate electrode (paddles) application, determination of the optimal energy and anesthesia levels, prevention of embolic events and arrythmia recurrence and airway conservation while minimizing possible complications. Potential complications include ventricular fibrillation due to general anesthesia or lack of synchronization between the direct current (DC) shock and the QRS complex, thromboembolus due to insufficient anticoagulant therapy, non-sustained VT, atrial arrhythmia, heart block, bradycardia, transient left bundle branch block, myocardial necrosis, myocardial dysfunction, transient hypotension, pulmonary edema and skin burn. Electrical cardioversion performed in patients with a pacemaker or an incompatible cardioverter defibrillator may lead to dysfunction, namely acute or chronic changes in the pacing or sensitivity threshold. Although this procedure appears fairly simple, serious consequences might occur if inappropriately performed. PMID:19448376

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

PubMed

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

2014-04-01

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

Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits

PubMed Central

Zhang, Wen-zhong; Li, Rong; Liu, Song; Ning, Xian-feng; Cai, Shang-lang

2016-01-01

We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI-PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI-PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia-reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C. PMID:28097153

The effects of scenario-based communication training on nurses' communication competence and self-efficacy and myocardial infarction knowledge.

PubMed

Hsu, Li-Ling; Huang, Ya-Hsuan; Hsieh, Suh-Ing

2014-06-01

The aim of the study was to determine the effects of a simulated communication training course on nurses' communication competence, self-efficacy, communication performance, myocardial infarction knowledge, and general satisfaction with their learning experience. A randomized controlled trial was conducted with a pre-test and two post-tests. The experimental group underwent simulated communication training course and the control group received a case-based communication training course. The experimental group made more significant improvement in competence and self-efficacy in communication from pre-test to the second post-test than the control group. Although both groups' satisfaction with their learning experience significantly increased from the first post-test to the second post-test, the experimental group was found to be more satisfied with their learning experience than the control group. No significant differences in communication performance and myocardial infarction knowledge between the two groups were identified. Scenario-based communication training can be more fully incorporated into in-service education for nurses to boost their competence and self-efficacy in communication and enhance their communication performance in myocardial infarction patient care. Introduction of real-life communication scenarios through multimedia in communication education could make learners more motivated to practice communication, hence leading to improved communication capacity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Treatment of Angina Pectoris Associated with Coronary Microvascular Dysfunction.

PubMed

Ong, Peter; Athanasiadis, Anastasios; Sechtem, Udo

2016-08-01

Treatment of angina pectoris associated with coronary microvascular dysfunction is challenging as the underlying mechanisms are often diverse and overlapping. Patients with type 1 coronary microvascular dysfunction (i.e. absence of epicardial coronary artery disease and myocardial disease) should receive strict control of their cardiovascular risk factors and thus receive statins and ACE-inhibitors in most cases. Antianginal medication consists of ß-blockers and/or calcium channel blockers. Second line drugs are ranolazine and nicorandil with limited evidence. Despite individually titrated combinations of these drugs up to 30 % of patients have refractory angina. Rho-kinase inhibitors and endothelin-receptor antagonists represent potential drugs that may prove useful in these patients in the future.

Regional Pericarditis Status Post Cardiac Ablation: A Case Report

PubMed Central

Orme, Joseph; Eddin, Moneer; Loli, Akil

2014-01-01

Context: Regional pericarditis is elusive and difficult to diagnosis. Healthcare providers should be familiar with post-cardiac ablation complications as this procedure is now widespread and frequently performed. The management of regional pericarditis differs greatly from that of acute myocardial infarction. Case report: A 52 year-old male underwent atrial fibrillation ablation and developed severe mid-sternal chest pain the following day with electrocardiographic findings suggestive of acute myocardial infarction, and underwent coronary angiography, a left ventriculogram, and 2D transthoracic echocardiogram, all of which were unremarkable without evidence of obstructive coronary disease, wall motion abnormalities, or pericardial effusions. Ultimately, the patient was diagnosed with regional pericarditis. After diagnosis, the patient's presenting symptoms resolved with treatment including nonsteroidal anti-inflammatory agents and colchicine. Conclusion: This is the first reported case study of regional pericarditis status post cardiac ablation. Electrocardiographic findings were classic for an acute myocardial infarction; however, coronary angiography and left ventriculogram demonstrated no acute coronary occlusion or ventricular wall motion abnormalities. Healthcare professionals must remember that the electrocardiographic findings in pericarditis are not always classic and that pericarditis can occur status post cardiac ablation. PMID:25317395

Regional pericarditis status post cardiac ablation: a case report.

PubMed

Orme, Joseph; Eddin, Moneer; Loli, Akil

2014-09-01

Regional pericarditis is elusive and difficult to diagnosis. Healthcare providers should be familiar with post-cardiac ablation complications as this procedure is now widespread and frequently performed. The management of regional pericarditis differs greatly from that of acute myocardial infarction. A 52 year-old male underwent atrial fibrillation ablation and developed severe mid-sternal chest pain the following day with electrocardiographic findings suggestive of acute myocardial infarction, and underwent coronary angiography, a left ventriculogram, and 2D transthoracic echocardiogram, all of which were unremarkable without evidence of obstructive coronary disease, wall motion abnormalities, or pericardial effusions. Ultimately, the patient was diagnosed with regional pericarditis. After diagnosis, the patient's presenting symptoms resolved with treatment including nonsteroidal anti-inflammatory agents and colchicine. This is the first reported case study of regional pericarditis status post cardiac ablation. Electrocardiographic findings were classic for an acute myocardial infarction; however, coronary angiography and left ventriculogram demonstrated no acute coronary occlusion or ventricular wall motion abnormalities. Healthcare professionals must remember that the electrocardiographic findings in pericarditis are not always classic and that pericarditis can occur status post cardiac ablation.

Beneficial effects of intracoronary nicorandil on microvascular dysfunction after primary percutaneous coronary intervention: demonstration of its superiority to nitroglycerin in a cross-over study.

PubMed

Ito, Noritoshi; Nanto, Shinsuke; Doi, Yasuji; Kurozumi, Yuma; Natsukawa, Tomoaki; Shibata, Hiroyuki; Morita, Masaya; Kawata, Atsushi; Tsuruoka, Ayumu; Sawano, Hirotaka; Okada, Ken-ichiro; Sakata, Yasuhiko; Kai, Tatsuro; Hayashi, Toru

2013-08-01

In patients undergoing primary percutaneous coronary intervention (PCI) for the treatment of ST-segment elevation myocardial infarction (STEMI), coronary microvascular dysfunction is associated with poor prognosis. Coronary microvascular resistance is predominantly regulated by ATP-sensitive potassium (KATP) channels. The aim of this study was to clarify whether nicorandil, a hybrid KATP channel opener and nitric oxide donor, may be a good candidate for improving microvascular dysfunction even when administered after primary PCI. We compared the beneficial effects of nicorandil and nitroglycerin on microvascular function in 60 consecutive patients with STEMI. After primary PCI, all patients received single intracoronary administrations of nitroglycerin (250 μg) and nicorandil (2 mg) in a randomized order; 30 received nicorandil first, while the other 30 received nitroglycerin first. Microvascular dysfunction was evaluated with the index of microcirculatory resistance (IMR), defined as the distal coronary pressure multiplied by the hyperemic mean transit time. As a first administration, nicorandil decreased IMR significantly more than did nitroglycerin (median [interquartile ranges]: 10.8[5.2-20.7] U vs. 2.1[1.0-6.0] U, p=0.0002).As a second administration, nicorandil further decreased IMR, while nitroglycerin did not (median [interquartile ranges]: 6.0[1.3-12.7] U vs. -1.4[-2.6 to 1.3] U, p<0.0001). The IMR after the second administration was significantly associated with myocardial blush grade, angiographic TIMI frame count after the procedure, and peak creatine kinase level. Intracoronary nicorandil reduced microvascular dysfunction after primary PCI more effectively than did nitroglycerin in patients with STEMI, probably via its KATP channel-opening effect.

Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.

PubMed

Zhang, Donghui; Li, Yifei; Heims-Waldron, Danielle; Bezzerides, Vassilios; Guatimosim, Silvia; Guo, Yuxuan; Gu, Fei; Zhou, Pingzhu; Lin, Zhiqiang; Ma, Qing; Liu, Jianming; Wang, Da-Zhi; Pu, William T

2018-01-05

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction. © 2017 American Heart Association, Inc.

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

PubMed

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

2014-03-01

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

Mitochondrial Bioenergetics and Dysfunction in Failing Heart.

PubMed

Sheeran, Freya L; Pepe, Salvatore

2017-01-01

Energy insufficiency has been recognized as a key feature of systolic heart failure. Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse. Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure. Diminished REDOX capacity with lower total glutathione and coenzyme Q 10 levels are also a feature of chronic left ventricular failure. Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications. In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins. Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure.

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA)

PubMed Central

Porter, John B.; Piga, Antonio; Lai, Yongrong; El-Beshlawy, Amal; Belhoul, Khawla M.; Elalfy, Mohsen; Yesilipek, Akif; Kilinç, Yurdanur; Lawniczek, Tomasz; Habr, Dany; Weisskopf, Marianne; Zhang, Yiyun; Aydinok, Yesim

2014-01-01

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938. PMID:24385534

Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction.

PubMed

Carberry, Jaclyn; Carrick, David; Haig, Caroline; Rauhalammi, Samuli M; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C; Eteiba, Hany; Hood, Stuart; Watkins, Stuart; Lindsay, Mitchell; Davie, Andrew; Mahrous, Ahmed; Ford, Ian; Sattar, Naveed; Welsh, Paul; Radjenovic, Aleksandra; Oldroyd, Keith G; Berry, Colin

2016-08-01

The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10-2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850. © 2016 The Authors.

Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction

PubMed Central

Carberry, Jaclyn; Carrick, David; Haig, Caroline; Rauhalammi, Samuli M.; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C.; Eteiba, Hany; Hood, Stuart; Watkins, Stuart; Lindsay, Mitchell; Davie, Andrew; Mahrous, Ahmed; Ford, Ian; Sattar, Naveed; Welsh, Paul; Radjenovic, Aleksandra; Oldroyd, Keith G.

2016-01-01

The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10–2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850. PMID:27354423

Inhibitors of soluble epoxide hydrolase minimize ischemia-reperfusion-induced cardiac damage in normal, hypertensive, and diabetic rats.

PubMed

Islam, Oliul; Patil, Prashanth; Goswami, Sumanta K; Razdan, Rema; Inamdar, Mohammed N; Rizwan, Mohammed; Mathew, Jubin; Inceoglu, Bora; Stephen Lee, Kin S; Hwang, Sung H; Hammock, Bruce D

2017-06-01

We designed a study to evaluate the cardioprotective effect of two soluble epoxide hydrolase (sEH) inhibitors, 1-(1-propanoylpiperidin-4-yl)-3-(4-trifluoromethoxy)phenyl)urea (TPPU) and trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB), in ischemia-reperfusion (IR) model. Cardioprotective effects of the sEH inhibitors were evaluated against IR-induced myocardial damage in hearts from normal, hypertensive, and diabetic rats using Langendorff's apparatus. In addition, the effect of sEH inhibitors on endothelial function was evaluated in vitro and ex vivo using isolated rat thoracic aorta. Ischemia-reperfusion (IR) increased the myocardial damage in hearts from normal rats. IR-induced myocardial damage was augmented in hearts isolated from hypertensive and diabetic rats. Myocardial damage as evident from increase in the activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in heart perfusate was associated with significant decrease in the heart rate and developed tension, and increase in the resting tension in isolated heart. Both sEH inhibitors protected the heart in normal, hypertensive, and diabetic rats subjected to IR injury. The sEH inhibitor t-TUCB relaxed phenylephrine precontracted aorta from normal rats. Relaxant effect of acetylcholine (ACh) was reduced in aortas from diabetic and hypertensive rats compared to normal rats. Pretreatment of sEH inhibitors to diabetic and hypertensive rats increased relaxant effect of ACh on aortas isolated from these rats. Prophylactic treatment with sEH inhibitors decreased myocardial damage due to IR, hypertension and diabetes, and decreased endothelial dysfunction created by diabetes and hypertension. Therefore, inhibitors of sEH are useful probes to study cardiovascular pathology, and inhibition of the sEH is a potential approach in the management of IR-induced cardiac damage and endothelial dysfunction-related cardiovascular disorders. © 2017 John Wiley & Sons Ltd.

Improved recovery of regional left ventricular function after PCI of chronic total occlusion in STEMI patients: a cardiovascular magnetic resonance study of the randomized controlled EXPLORE trial.

PubMed

Elias, Joëlle; van Dongen, Ivo M; Hoebers, Loes P; Ouweneel, Dagmar M; Claessen, Bimmer E P M; Råmunddal, Truls; Laanmets, Peep; Eriksen, Erlend; van der Schaaf, René J; Ioanes, Dan; Nijveldt, Robin; Tijssen, Jan G; Hirsch, Alexander; Henriques, José P S

2017-07-19

The Evaluating Xience and left ventricular function in PCI on occlusiOns afteR STEMI (EXPLORE) trial did not show a significant benefit of percutaneous coronary intervention (PCI) of the concurrent chronic total occlusion (CTO) in ST-segment elevation myocardial infarction (STEMI) patients on global left ventricular (LV) systolic function. However a possible treatment effect will be most pronounced in the CTO territory. Therefore, we aimed to study the effect of CTO PCI compared to no-CTO PCI on the recovery of regional LV function, particularly in the CTO territory. Using cardiovascular magnetic resonance (CMR) we studied 180 of the 302 EXPLORE patients with serial CMR (baseline and 4 months follow-up). Segmental wall thickening (SWT) was quantified on cine images by an independent core laboratory. Dysfunctional segments were defined as SWT < 45%. Dysfunctional segments were further analyzed by viability (transmural extent of infarction (TEI) ≤50%.). All outcomes were stratified for randomization treatment. In the dysfunctional segments in the CTO territory recovery of SWT was better after CTO PCI compared to no-CTO PCI (ΔSWT 17 ± 27% vs 11 ± 23%, p = 0.03). This recovery was most pronounced in the dysfunctional but viable segments(TEI < 50%) (ΔSWT 17 ± 27% vs 11 ± 22%, p = 0.02). Furthermore in the CTO territory, recovery of SWT was significantly better in the dysfunctional segments in patients with Rentrop grade 2-3 collaterals compared to grade 0-1 collaterals to the CTO (16 ± 26% versus 11 ± 24%, p = 0.04). CTO PCI compared with no-CTO PCI is associated with a greater recovery of regional systolic function in the CTO territory, especially in the dysfunctional but viable segments. Further research is needed to evaluate the use of CMR in selecting post-STEMI patients for CTO PCI and the effect of regional LV function recovery on clinical outcome. Trialregister.nl NTR1108 , Date registered NTR: 30-okt-2007.

Increased intracranial pressure elicits hypertension, increased sympathetic activity, electrocardiographic abnormalities and myocardial damage in rats.

PubMed

Shanlin, R J; Sole, M J; Rahimifar, M; Tator, C H; Factor, S M

1988-09-01

Intracranial pressure was increased in 59 rats by inflating a subdural balloon to a total mass volume of 0.3 ml. The increase in intracranial pressure ranged from 75 to greater than 500 mm Hg. With few exceptions, mean arterial pressure increased to as high as 227 mm Hg during the increase in intracranial pressure. Significant increases in plasma catecholamines, major electrocardiographic changes and a considerably shortened survival time were observed only in the rats that demonstrated an increase in mean arterial pressure greater than 50 mm Hg. A perfusion study with liquid silicone rubber (Microfil) revealed dilated irregular myocardial vessels with areas of focal constriction consistent with microvascular spasm. Histologic examination of the myocardium revealed widespread patches of contraction band necrosis and occasional contraction bands in the smooth muscle media of large coronary arteries. These observations suggest that myocardial damage after suddenly increased intracranial pressure resulted both from exposure to toxic levels of catecholamines and from myocardial reperfusion. Extension of these studies to humans suggests that a detailed assessment of myocardial function should be performed in victims of severe brain injury. Myocardial dysfunction may be a major determinant of the patient's prognosis or may render the heart unsuitable for transplantation.

The Predictive Role of Serum Triglyceride to High-Density Lipoprotein Cholesterol Ratio According to Renal Function in Patients with Acute Myocardial Infarction

PubMed Central

Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyoon; Moon, Joo Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2016-01-01

Objective A high serum triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported as an independent predictor for cardiovascular events in the general population. However, the prognostic value of this ratio in patients with renal dysfunction is unclear. We examined the association of the TG/HDL-C ratio with major adverse cardiovascular events (MACEs) according to renal function in patients with acute myocardial infarction (AMI). Method This study was based on the Korea Acute Myocardial Infarction Registry database. Of 13,897 patients who were diagnosed with AMI, the study population included the 7,016 patients with available TG/HDL-C ratio data. Patients were stratified into three groups according to their estimated glomerular filtration rate (eGFR), and the TG/HDL-C ratio was categorized into tertiles. We investigated 12-month MACEs, which included cardiac death, myocardial infarction, and repeated percutaneous coronary intervention or coronary artery bypass grafting. Results During the 12-month follow up period, 593 patients experienced MACEs. There was a significant association between the TG/HDL-C ratio and MACEs (p<0.001) in the entire study cohort. Having a TG/HDL-C ratio value in the highest tertile of TG/HDL-C ratio was an independent factor associated with increased risk of MACEs (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.26–1.93; p<0.001). Then we performed subgroup analyses according to renal function. In patients with normal renal function (eGFR ≥ 90 ml/min/1.73m2) and mild renal dysfunction (eGFR ≥ 60 to < 90ml/min/1.73m2), a higher TG/HDL-C ratio was significantly associated with increased risk of MACEs (HR, 1.64; 95% CI, 1.04–2.60; p = 0.035; and HR, 1.56; 95% CI, 1.14–2.12; p = 0.005, respectively). However, in patients with moderate renal dysfunction (eGFR < 60 ml/min/1.73m2), TG/HDL-C ratio lost its predictive value on the risk of MACEs (HR, 1.23; 95% CI, 0.82–1.83; p = 0.317). Conclusions In patients with AMI, TG/HDL-C ratio is a useful independent predictor of 12-month MACEs. However, this ratio does not have predictive power in patients with moderate renal dysfunction. PMID:27788233

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

Hu Shunying; Chen Yundai; Li Libing

Purpose: Irradiation to the heart may lead to late cardiovascular complications. The purpose of this study was to investigate whether adenovirus-mediated delivery of the human hepatocyte growth factor gene could reduce post-irradiation damage of the rat heart and improve heart function. Methods and Materials: Twenty rats received single-dose irradiation of 20 Gy gamma ray locally to the heart and were randomized into two groups. Two weeks after irradiation, these two groups of rats received Ad-HGF or mock adenovirus vector intramyocardial injection, respectively. Another 10 rats served as sham-irradiated controls. At post-irradiation Day 120, myocardial perfusion was tested by myocardial contrastmore » echocardiography with contrast agent injected intravenously. At post-irradiation Day 180, cardiac function was assessed using the Langendorff technique with an isolated working heart model, after which heart samples were collected for histological evaluation. Results: Myocardial blood flow was significantly improved in HGF-treated animals as measured by myocardial contrast echocardiography at post-irradiation Day 120 . At post-irradiation Day 180, cardiac function was significantly improved in the HGF group compared with mock vector group, as measured by left ventricular peak systolic pressure (58.80 +- 9.01 vs. 41.94 +- 6.65 mm Hg, p < 0.05), the maximum dP/dt (5634 +- 1303 vs. 1667 +- 304 mm Hg/s, p < 0.01), and the minimum dP/dt (3477 +- 1084 vs. 1566 +- 499 mm Hg/s, p < 0.05). Picrosirius red staining analysis also revealed a significant reduction of fibrosis in the HGF group. Conclusion: Based on the study findings, hepatocyte growth factor gene transfer can attenuate radiation-induced cardiac injury and can preserve cardiac function.« less

Cardiovascular protection and antioxidant activity of the extracts from the mycelia of Cordyceps sinensis act partially via adenosine receptors.

PubMed

Yan, Xiao-Feng; Zhang, Zhong-Miao; Yao, Hong-Yi; Guan, Yan; Zhu, Jian-Ping; Zhang, Lin-Hui; Jia, Yong-Liang; Wang, Ru-Wei

2013-11-01

Mycelia of cultured Cordyceps sinensis (CS) is one of the most common substitutes for natural CS and was approved for arrhythmia in China. However, the role of CS in ameliorating injury during ischemia-reperfusion (I/R) is still unclear. We examined effects of extracts from CS on I/R and investigated the possible mechanisms. Post-ischemic coronary perfusion pressure, ventricular function, and coronary flow were measured using the Langendorff mouse heart model. Oxidative stress of cardiac homogenates was performed using an ELISA. Our results indicate that CS affords cardioprotection possibly through enhanced adenosine receptor activation. Cardioprotection was demonstrated by reduced post-ischemic diastolic dysfunction and improved recovery of pressure development and coronary flow. Treatment with CS largely abrogates oxidative stress and damage in glucose- or pyruvate-perfused hearts. Importantly, observed reductions in oxidative stress [glutathione disulfide (GSSG)]/[GSSG + glutathione] and [malondialdehyde (MDA)]/[superoxide dismutase + MDA] ratios as well as the resultant damage upon CS treatment correlate with functional markers of post-ischemic myocardial outcome. These effects of CS were partially blocked by 8-ρ-sulfophenyltheophylline, an adenosine receptor antagonist. Our results demonstrate a suppressive role of CS in ischemic contracture. Meanwhile, the results also suggest pre-ischemic adenosine receptor activation may be involved in reducing contracture in hearts pretreated with CS. Copyright © 2012 John Wiley & Sons, Ltd.

Functional CT assessment of extravascular contrast distribution volume and myocardial perfusion in acute myocardial infarction.

PubMed

So, Aaron; Wisenberg, Gerald; Teefy, Patrick; Yadegari, Andrew; Bagur, Rodrigo; Hadway, Jennifer; Morrison, Laura; MacDonald, Anna; Gaskin, Dave; Butler, John; Biernaski, Heather; Skanes, Stephanie; Park, Stella DohYeoun; Islam, Ali; Hsieh, Jiang; Lee, Ting-Yim

2018-04-26

In a pig model of acute myocardial infarction (AMI), we validated a functional computed tomography (CT) technique for concomitant assessment of myocardial edema and ischemia through extravscualar contrast distribution volume (ECDV) and myocardial perfusion (MP) measurements from a single dynamic imaging session using a single contrast bolus injection. In seven pigs, balloon catheter was used to occlude the distal left anterior descending artery for one hour followed by reperfusion. CT and cardiac magnetic resonance (CMR) imaging studies were acquired on 3 days and 12 ± 3 day post ischemic insult. In each CT study, 0.7 ml/kg of iodinated contrast was intravenously injected at 3-4 ml/s before dynamic contrast-enhanced (DCE) cardiac images were acquired with breath-hold using a 64-row CT scanner. DCE cardiac images were analyzed with a model-based deconvolution to generate ECDV and MP maps. ECDV as an imaging marker of edema was validated against CMR T2 weighted imaging in normal and infarcted myocardium delineated from ex-vivo histological staining. ECDV in infarcted myocardium was significantly higher (p < 0.05) than that in normal myocardium on both days post AMI and was in agreement with the findings of CMR T2 weighted imaging. MP was significantly lower (p < 0.05) in the infarcted region compared to normal on both days post AMI. This imaging technique can rapidly and simultaneously assess myocardial edema and ischemia through ECDV and MP measurements, and may be useful for delineation of salvageable tissue within at-risk myocardium to guide reperfusion therapy. Copyright © 2017. Published by Elsevier B.V.

The role of advanced echocardiography and cardiovascular magnetic resonance in the assessment of myocardial function in Marfan syndrome-An update.

PubMed

Kiotsekoglou, Anatoli; Moggridge, James C; Child, Anne H; Rask, Peter

2017-05-01

Cardiovascular assessment of patients with Marfan syndrome has normally focused on the aortic root and vascular manifestations of the disease due to the high risk of aortic dissection. Although primary myocardial impairment has long been suspected in these patients, the evidence has been controversial. Advanced echocardiography and cardiovascular magnetic resonance imaging have proven to be effective, accurate, and more sensitive in the detection of subtle cardiac dysfunction. The application of these techniques to Marfan syndrome over the last 10 years has made significant progress in demonstrating the presence of primary myocardial impairment in these patients, but further work is still required to obtain confirmatory molecular, pathophysiological, and prognostic clinical data. Phenotypic expression of the disease has prognostic value, also suggesting potential effective medical therapy. © 2017, Wiley Periodicals, Inc.

Cardiovascular dysfunction in symptomatic primary hyperparathyroidism and its reversal after curative parathyroidectomy: results of a prospective case control study.

PubMed

Agarwal, Gaurav; Nanda, Gitika; Kapoor, Aditya; Singh, Kul Ranjan; Chand, Gyan; Mishra, Anjali; Agarwal, Amit; Verma, Ashok K; Mishra, Saroj K; Syal, Sanjeev K

2013-12-01

Cardiovascular mortality in primary hyperparathyroidism (PHPT) is attributed to myocardial and endothelial dysfunction. In this prospective, case-control study we assessed cardiovascular dysfunction in patients with symptomatic PHPT and its reversal after successful parathyroidectomy. Fifty-six patients with symptomatic PHPT underwent two-dimensional echocardiography, tissue Doppler (diastolic function assessment), serum N-terminal pro-brain natriuretic peptide (s-NTproBNP, a myocardial damage marker), and endothelial- and smooth muscle-dependent vasodilatory response (vascular dysfunction) studies before, 3, and 6 months after parathyroidectomy; 25 age-matched controls were studied similarly. Patients had greater left ventricular mass (192 ± 70 vs. 149 ± 44 g; P = .006), interventricular septal thickness (10.8 ± 2.5 vs. 9.0 ± 1.6 mm; P = .001), posterior wall thickness (9.9 ± 2.0 vs. 8.6 ± 2.2 mm; P = .004), and diastolic dysfunction (lower E/A trans-mitral flow velocity ratio [1.0 ± 0.4 vs. 1.3 ± 0.4; P = .01). Patients had greater s-NTproBNP (4,625 ± 1,130 vs. 58 ± 49 pg/mL; P = .002) and lower endothelial-mediated vasodilation (9.3 ± 8.6 vs. 11.7 ± 6.3%; P = .03) and smooth muscle-mediated vasodilation (20.1 ± 17.9 vs. 23.8 ± 11.2%; P = .01). Improvements in left ventricular mass, systolic and diastolic function, and smooth muscle-mediated vasodilation were noted from 3 to 6 months after parathyroidectomy. Endothelial-mediated vasodilation did not improve significantly. S-NTproBNP levels mirrored echocardiographic changes with a substantial, sustained decrease. Results were similar in hypertensive and normotensive patients. Symptomatic PHPT patients have substantial cardiac and vascular dysfunction, which improve by 6 months after parathyroidectomy. Objective cardiovascular evaluation may improve outcomes in symptomatic PHPT patients. Copyright © 2013 Mosby, Inc. All rights reserved.

Dobutamine stress magnetic resonance imaging suffices for the demonstration of myocardial ischaemia and viability

PubMed Central

Lamers, F.P.L.; van Dijkman, P.R.M.; Kuijpers, Th.J.A.; van Herpen, G.

2003-01-01

We report three patients in whom dobutamine stress magnetic imaging (DS-MRI) was essential in assessing myocardial ischaemia. Two patients were referred to the cardiologist because of chest pain. Patient A had typical exertional angina and a normal resting electrocardiogram (ECG). Patient B had typical exercise-induced angina and had recently experienced an attack of severe chest pain at rest for 15 minutes. The ECG showed a complete left bundle branch block (LBBB). Patient C was referred for heart failure of unknown origin. There were no symptoms of chest pain during rest or exercise. Echocardiography in this patient demonstrated global left ventricular (LV) dilatation, systolic dysfunction and a small dyskinetic segment in the inferior wall. In all these patients exercise stress testing had failed to demonstrate myocardial ischaemia. Patients A and C produced normal findings whereas in patient B the abnormal repolarisation due to pre-existent LBBB precluded a diagnosis of ischaemia. Breath-hold DS-MRI was performed to study LV wall motion and wall thickening at rest through increasing doses of dobutamine. A test was considered positive for myocardial ischaemia if wall motion abnormalities developed at high-dose levels of the drug (20 μg/kg/min or more with a maximum of 40 μg/kg/min) in previously normal vascular territories or worsened in a segment that was normal at baseline. Recovery of wall thickening in a previously hypokinetic or akinetic segment at a low dose of dobutamine (5-10 μg/kg/min) was taken as proof of viability. Patients A and B developed hypokinesia progressing into akinesia at high-dose dobutamine in the anteroseptal area of the LV indicative of ischaemia. These findings were corroborated by coronary angiography demonstrating severe coronary artery disease which led to coronary artery bypass grafting (CABG) in patient A and balloon angioplasty in patient B. In patient C global recovery of LV contractions during low-dose dobutamine was followed by hypokinesia in the inferoseptal area during high-dose dobutamine. This biphasic response indicates myocardial viability as well as ischaemia. CABG was carried out because of multiple stenoses in the left coronary artery. Post-operatively LV function normalised. DS-MRI is a valuable method for detecting myocardial ischaemia and viability in patients with suspected coronary artery, and can be applied in every hospital with MRI equipment at its disposal. ImagesFigure 1Figure 2 PMID:25696185

Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.

PubMed

Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi

2016-09-01

The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

PubMed Central

Iliodromitis, Efstathios K; Lazou, Antigone; Görbe, Anikó; Giricz, Zoltán; Schulz, Rainer

2017-01-01

Hypercholesterolaemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS‐cGMP, reperfusion injury salvage kinase, peroxynitrite‐MMP2 signalling pathways, modulation of ATP‐sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non‐ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted. Linked Articles This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc PMID:28060997

Continuous cardiac troponin I release in Fabry disease.

PubMed

Feustel, Andreas; Hahn, Andreas; Schneider, Christian; Sieweke, Nicole; Franzen, Wolfgang; Gündüz, Dursun; Rolfs, Arndt; Tanislav, Christian

2014-01-01

Fabry disease (FD) is a rare lysosomal storage disorder also affecting the heart. The aims of this study were to determine the frequency of cardiac troponin I (cTNI) elevation, a sensitive parameter reflecting myocardial damage, in a smaller cohort of FD-patients, and to analyze whether persistent cTNI can be a suitable biomarker to assess cardiac dysfunction in FD. cTNI values were determined at least twice per year in 14 FD-patients (6 males and 8 females) regularly followed-up in our centre. The data were related to other parameters of heart function including cardiac magnetic resonance imaging (cMRI). Three patients (21%) without specific vascular risk factors other than FD had persistent cTNI-elevations (range 0.05-0.71 ng/ml, normal: <0.01). cMRI disclosed late gadolinium enhancement (LGE) in all three individuals with cTNI values ≥0.01, while none of the 11 patients with cTNI <0.01 showed a pathological enhancement (p<0.01). Two subjects with increased cTNI-values underwent coronary angiography, excluding relevant stenoses. A myocardial biopsy performed in one during this procedure demonstrated substantial accumulation of globotriaosylceramide (Gb3) in cardiomyocytes. Continuous cTNI elevation seems to occur in a substantial proportion of patients with FD. The high accordance with LGE, reflecting cardiac dysfunction, suggests that cTNI-elevation can be a useful laboratory parameter for assessing myocardial damage in FD.

Doppler-derived myocardial performance index in patients with impaired left ventricular relaxation and preserved systolic function.

PubMed

Fernandes, José Maria G; Rivera, Ivan Romero; de Oliveira Romão, Benício; Mendonça, Maria Alayde; Vasconcelos, Miriam Lira Castro; Carvalho, Antônio Carlos; Campos, Orlando; De Paola, Angelo Amato V; Moisés, Valdir A

2009-09-01

The Doppler-derived myocardial performance index (MPI) has been used in the evaluation of left ventricular (LV) function in several diseases. In patients with isolated diastolic dysfunction, the diagnostic utility of this index remains unclear. The aim of this study was to determine the diagnostic utility of MPI in patients with systemic hypertension, impaired LV relaxation, and normal ejection fraction. Thirty hypertensive patients with impaired LV relaxation were compared to 30 control subjects. MPI and its components, isovolumetric relaxation time (IRT), isovolumetric contraction time (ICT), and the ejection time (ET), were measured from LV outflow and mitral inflow Doppler velocity profiles. MPI was higher in patients than in control subjects (0.45 +/- 0.13 vs 0.37 +/- 0.07 P < 0.0029). The increase in MPI was due to the prolongation of IRT without significant change of ICT and ET. MPI cutoff value of > or =0.40 identified impaired LV relaxation with a sensitivity of 63% and specificity of 70% while an IRT >94 ms had a sensitivity of 67% and specificity of 80%. Multivariate analysis identified relative wall thickness, mitral early filling wave velocity (E), and systolic myocardial velocity (Sm) as independent predictors of MPI in patients with hypertension. MPI was increase in patients with hypertension, diastolic dysfunction, and normal ejection fraction but was not superior to IRT to detect impaired LV relaxation.

Asymptomatic cardiovascular manifestations in diabetes mellitus: left ventricular diastolic dysfunction and silent myocardial ischemia.

PubMed

Seferović-Mitrović, Jelena P; Lalić, Nebojsa M; Vujisić-Tesić, Bosiljka; Lalić, Katarina; Jotić, Aleksandra; Ristić, Arsen D; Giga, Vojislav; Tesić, Milorad; Milić, Natasa; Lukić, Ljiljana; Milicić, Tanja; Singh, Sandra; Seferović, Petar M

2011-01-01

Several cardiovascular manifestations in patients with diabetes may be asymptomatic. Left ventricular diastolic dysfunction (LVDD) is considered to be the earliest metabolic myocardial lesion in these patients, and can be diagnosed with tissue Doppler echocardiography. Silent myocardial ischemia (SMI) is a characteristic and frequently described form of ischemic heart disease in patients with diabetes. Objective The aim of the study was to assess the prevalence of LVDD and SMI in patients with type 2 diabetes, as well as to compare demographic, clinical, and metabolic data among defined groups (patients with LVDD, patients with SMI and patients with type 2 diabetes, without LVDD and SMI). We investigated 104 type 2 diabetic patients (mean age 55.4 +/- 9.1 years, 64.4% males) with normal blood pressure, prehypertension and arterial hypertension stage I. Study design included basic laboratory assessment and cardiological workup (transthoracic echocardiography and tissue Doppler, as well as the exercise stress echocardiography). LVDD was diagnosed in twelve patients (11.5%), while SMI was revealed in six patients (5.8%). Less patients with LVDD were using metformin, in comparison to other two groups (chi2 =12.152; p=0.002). Values of HDL cholesterol (F=4.515; p=0.013) and apolipoprotein A1 (F=5.128; p= 0.008) were significantly higher in patients with LVDD. The study confirmed asymptomatic cardiovascular complications in 17.3% patients with type 2 diabetes.

High-Sensitivity C-Reactive Protein Is a Predictor of Coronary Microvascular Dysfunction in Patients with Ischemic Heart Disease.

PubMed

Tong, David C; Whitbourn, Robert; MacIsaac, Andrew; Wilson, Andrew; Burns, Andrew; Palmer, Sonny; Layland, Jamie

2017-01-01

Inflammation and microvascular dysfunction (MVD) are independently associated with adverse cardiovascular outcomes in patients with ischemic heart disease. This study aimed to assess the relationship between inflammation, MVD, and myocardial injury. Coronary microvascular function was assessed in 74 patients undergoing percutaneous coronary intervention (PCI) using the index of microvascular resistance (IMR) by a pressure-temperature sensor-tipped wire. Serum high-sensitivity C-reactive protein (hsCRP) level was quantified by rate turbidimetry. Severe MVD was defined as IMR ≥ 30. Pearson correlation was computed to assess the relationships between hsCRP, troponin, and IMR of culprit vessel. Predictors of severe MVD were assessed by regression analysis. Acute coronary syndromes (ACSs) represented 49% of the total cohort. Study cohort was divided into low C-reactive protein (CRP) (hsCRP < 3 mg/L) and high CRP (hsCRP ≥ 3 mg/L) groups. There was higher representation of smokers (78 vs. 52%), diabetics (39 vs. 18%), and ACS (61 vs. 33%), as well as higher body mass index (29.4 ± 4.6 vs. 27.2 ± 4.1) in the high CRP group. Pre-PCI and post-PCI IMR were significantly elevated in the high CRP group compared to the low CRP group (pre-PCI IMR: 29.0 ± 13.9 vs. 17.4 ± 11.1, p  < 0.0001; post-PCI IMR: 23.0 ± 16.8 vs. 15.5 ± 8.4, p  = 0.02). Peak troponin levels were significantly raised in the high CRP group (9.96 ± 17.19 vs. 1.17 ± 3.00 μg/L, p  = 0.002). There was a strong positive correlation between hsCRP and pre-PCI IMR ( r  = 0.85, p  < 0.0001). Pre- and post-PCI IMR levels were correlated with peak troponin level ( r  = 0.45, p  < 0.0001; r  = 0.33, p  = 0.005, respectively). Predictors of severe MVD include male gender (OR 3.0), diabetes (OR 3.7), smoking history (OR 4.0), ACS presentation (OR 8.5), and hsCRP ≥ 3 mg/L (OR 5.6). hsCRP is a significant predictor of MVD while MVD is associated with myocardial injury, supporting the central role of inflammation and MVD in the pathophysiology and complications of coronary artery disease. Australian New Zealand Clinical Trials Registry (ACTRN): 12617000648325. Universal Trial Number (UTN): U1111-1196-2246.

Cobalt Chloride Upregulates Impaired HIF-1α Expression to Restore Sevoflurane Post-conditioning-Dependent Myocardial Protection in Diabetic Rats

PubMed Central

Wu, Jianjiang; Yang, Long; Xie, Peng; Yu, Jin; Yu, Tian; Wang, Haiying; Maimaitili, Yiliyaer; Wang, Jiang; Ma, Haiping; Yang, Yining; Zheng, Hong

2017-01-01

Previous studies from our group have demonstrated that sevoflurane post-conditioning (SPC) protects against myocardial ischemia reperfusion injury via elevating the intranuclear expression of hypoxia inducible factor-1 alpha (HIF-1α). However, diabetic SPC is associated with decreased myocardial protection and disruption of the HIF-1 signaling pathway. Previous studies have demonstrated that cobalt chloride (CoCl2) can upregulate HIF-1α expression under diabetic conditions, but whether myocardial protection by SPC can be restored afterward remains unclear. We established a rat model of type 2 diabetes and a Langendorff isolated heart model of ischemia-reperfusion injury. Prior to reperfusion, 2.4% sevoflurane was used as a post-conditioning treatment. The diabetic rats were treated with CoCl2 24 h before the experiment. At the end of reperfusion, tests were performed to assess myocardial function, infarct size, mitochondrial morphology, nitric oxide (NO), Mitochondrial reactive oxygen species (ROS), mitochondrial respiratory function and enzyme activity, HIF-1α, vascular endothelial growth factor (VEGF) and endothelial NO synthase (eNOS) protein levels. In addition, myocardial protection by SPC was monitored after the blood glucose levels were lowered by insulin. The diabetic state was associated with deficient SPC protection and decreased HIF-1α expression. After treating the diabetic rats with CoCl2, SPC significantly upregulated the expression of HIF-1α, VEGF and eNOS, which markedly improved cardiac function, NO, mitochondrial respiratory function, and enzyme activity and decreased the infarction areas and ROS. In addition, these effects were not influenced by blood glucose levels. This study proved that CoCl2activates the HIF-1α signaling pathway, which restores SPC-dependent myocardial protection under diabetic conditions, and the protective effects of SPC were independent of blood glucose levels. PMID:28659817

Do implantable cardioverter defibrillators improve survival in patients with severe left ventricular systolic dysfunction after coronary artery bypass graft surgery?

PubMed

Fazal, Iftikhar A; Bates, Matthew G D; Matthews, Iain G; Turley, Andrew J

2011-06-01

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether implantable cardioverter defibrillators (ICD) improve survival in patients with severe left ventricular systolic dysfunction (LVSD) after coronary artery bypass graft (CABG) surgery. ICDs are designed to terminate potentially fatal cardiac tachyarrhythmias. A right ventricular lead is mandatory for detection, pacing and defibrillation capabilities. Dual chamber ICDs have an additional right atrial lead and are used for patients with conventional atrioventricular pacing indications. More sophisticated, biventricular devices exist to provide cardiac resynchronisation therapy (CRT) in addition to defibrillation (CRT-D). ICDs have been extensively investigated in patients with LVSD post myocardial infarction and in patients with non-ischaemic cardiomyopathy for both secondary prevention (history of ventricular arrhythmias) and primary prevention (deemed high risk for ventricular arrhythmias). This best evidence topic aims to review the evidence and its applicability to patients post CABG. Nine hundred and sixteen papers were identified using the search method outlined. Eight randomised controlled trials, two meta-analyses, and one non-randomised trial, in addition to international guidelines presented the best evidence to answer the clinical question. The current evidence base and guidelines suggest that ICDs should be considered for all patients with LVSD [ejection fraction (EF) ≤30-40%] receiving optimal pharmacological management, who are ≥40 days post MI [four weeks for National Institute for Health and Clinical Excellence (NICE)] and in New York Heart Association (NYHA) class I-III. UK NICE guidelines require in addition; non-sustained ventricular tachycardia (NSVT) on a Holter monitor and inducible ventricular tachycardia at electrophysiological study for EF between 30 and 35%; or a QRS >120 ms if EF <30%. The North American guidelines recommend EF <30% as a threshold for those with NYHA class I symptoms. The evidence is applicable to patients post CABG, provided all the other criteria are met. European Society of Cardiology (ESC) guidelines recommend waiting at least three months (consensus opinion) after revascularisation prior to assessment for an ICD, to allow time for potential recovery of ventricular function.

Extracellular Superoxide Dismutase Deficiency Exacerbates Pressure Overload–Induced Left Ventricular Hypertrophy and Dysfunction

PubMed Central

Lu, Zhongbing; Xu, Xin; Hu, Xinli; Zhu, Guangshuo; Zhang, Ping; van Deel, Elza D.; French, Joel P.; Fassett, John T.; Oury, Tim D.; Bache, Robert J.; Chen, Yingjie

2008-01-01

Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)–induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload. PMID:17998475

Is 2D speckle tracking echocardiography useful for detecting and monitoring myocardial dysfunction in adult m.3243A>G carriers? - a retrospective pilot study.

PubMed

Koene, S; Timmermans, J; Weijers, G; de Laat, P; de Korte, C L; Smeitink, J A M; Janssen, M C H; Kapusta, L

2017-03-01

Cardiomyopathy is a common complication of mitochondrial disorders, associated with increased mortality. Two dimensional speckle tracking echocardiography (2DSTE) can be used to quantify myocardial deformation. Here, we aimed to determine the usefulness of 2DSTE in detecting and monitoring subtle changes in myocardial dysfunction in carriers of the 3243A>G mutation in mitochondrial DNA. In this retrospective pilot study, 30 symptomatic and asymptomatic carriers of the mitochondrial 3243A>G mutation of whom two subsequent echocardiograms were available were included. We measured longitudinal, circumferential and radial strain using 2DSTE. Results were compared to published reference values. Speckle tracking was feasible in 90 % of the patients for longitudinal strain. Circumferential and radial strain showed low face validity (low number of images with sufficient quality; suboptimal tracking) and were therefore rejected for further analysis. Global longitudinal strain showed good face validity, and was abnormal in 56-70 % (depending on reference values used) of the carriers (n = 27). Reproducibility was good (mean difference of 0.83 for inter- and 0.40 for intra-rater reproducibility; ICC 0.78 and 0.89, respectively). The difference between the first and the second measurement exceeded the measurement variance in 39 % of the cases (n = 23; feasibility of follow-up 77 %). Even in data collected as part of clinical care, two-dimensional strain echocardiography seems a feasible method to detect and monitor subtle changes in longitudinal myocardial deformation in adult carriers of the mitochondrial 3243A>G mutation. Based on our data and the reported accuracy of global longitudinal strain in other studies, we suggest the use of global longitudinal strain in a prospective follow-up or intervention study.

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

PubMed Central

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

2018-01-01

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

[Myocardial viability: update in nuclear cardiology].

PubMed

Vallejo, Enrique

2007-01-01

Evaluation of myocardial viability with the aid of radionuclides, is a technique that offers reliable, reproducible information, with an attractive cost-benefit relationship, in the study of the myocardial viability, integrating cardiac molecular, metabolic, and functional aspects. Nowadays, coronary risk stratification in post-myocardial infarction patients pretends to locate them as low-, intermediate, and high risk-subjects that can suffer cardiovascular complications in the very near future. Low-risk patients are characterized by a cardiac-related mortality below 1%, whereas high-risk mortality is greater than 3%. Because of clinical complications following a myocardial infarction are observed during the first month of evolution, clinical guidelines suggest to evaluate the cardiovascular risk before hospital discharge.

Role of ivabradine in management of stable angina in patients with different clinical profiles

PubMed Central

Kaski, Juan Carlos; Gloekler, Steffen; Ferrari, Roberto; Fox, Kim; Lévy, Bernard I; Komajda, Michel; Vardas, Panos; Camici, Paolo G

2018-01-01

In chronic stable angina, elevated heart rate contributes to the development of symptoms and signs of myocardial ischaemia by increasing myocardial oxygen demand and reducing diastolic perfusion time. Accordingly, heart rate reduction is a well-known strategy for improving both symptoms of myocardial ischaemia and quality of life (QOL). The heart rate-reducing agent ivabradine, a direct and selective inhibitor of the I f current, decreases myocardial oxygen consumption while increasing diastolic time, without affecting myocardial contractility or coronary vasomotor tone. Ivabradine is indicated for treatment of stable angina and chronic heart failure (HF). This review examines available evidence regarding the efficacy and safety of ivabradine in stable angina, when used as monotherapy or in combination with beta-blockers, in particular angina subgroups and in patients with stable angina with left ventricular systolic dysfunction (LVSD) or HF. Trials involving more than 45 000 patients receiving treatment with ivabradine have shown that this agent has antianginal and anti-ischaemic effects, regardless of age, sex, severity of angina, revascularisation status or comorbidities. This heart rate-lowering agent might also improve prognosis, reduce hospitalisation rates and improve QOL in angina patients with chronic HF and LVSD. PMID:29632676

Rehabilitation of Patients Following Myocardial Infarction.

ERIC Educational Resources Information Center

Blumenthal, James A.; Emery, Charles F.

1988-01-01

Examines three behavioral strategies in cardiac rehabilitation (CR) for formal treatment for physical and psychosocial sequelae of myocardial infarction (MI): exercise therapy, Type A modification, and nonspecific psychological therapies. Concludes CR improves the quality of life among post-MI patients, but does not prolong life or significantly…

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

PubMed

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

2014-01-01

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

Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi.

PubMed

Santos, Fabiane M; Mazzeti, Ana L; Caldas, Sérgio; Gonçalves, Karolina R; Lima, Wanderson G; Torres, Rosália M; Bahia, Maria Terezinha

2016-09-01

Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and the relevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the present study, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzi strain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiac muscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. The effect of the treatment on reducing the parasite load was monitored by blood PCR and blood culture assays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function was evaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatment in reducing the parasite burden was demonstrated by a marked decrease in positive blood culture and PCR assay results until 30days post-treatment. At this time, the PCR and blood culture assays yielded negative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However, a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the blood culture assays at follow-up. The parasite load reduction induced by treatment was compatible with the lower degree of tissue damage among animals euthanized in the first month after treatment and with the increased cardiac damage after this period, reaching levels similar to those in untreated animals at the one-year follow-up. The two infected groups also presented similar, significantly smaller values for early tissue septal velocity (E' SIV) than the non-infected dogs did at this later time. Moreover, in the treated animals, an increase in the E/E' septal tissue filling pressure ratio was observed when compared with basal values as well as with values in non-infected dogs. These findings strongly suggest that the temporary reduction in the parasite load that was induced by benznidazole treatment was not able to prevent myocardial lesions and diastolic dysfunction for long after treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Sevoflurane post-conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phopshorylated NHE1 levels.

PubMed

Cao, Jianfang; Xie, Hong; Sun, Ying; Zhu, Jiang; Ying, Ming; Qiao, Shigang; Shao, Qin; Wu, Haorong; Wang, Chen

2015-12-01

The protective effects of sevoflurane post-conditioning against myocardial ischemia/reperfusion (I/R) injury (MIRI) have been previously reported. However, the mechanisms responsible for these protective effects remain elusive. In this study, in order to investigate the molecular mechanisms responsible for the protective effects of sevoflurane post-conditioning on isolated rat hearts subjected to MIRI, Sprague-Dawley rat hearts were randomly divided into the following 6 groups: i) the sham-operated control; ii) 2.5% sevoflurane; iii) ischemia/reperfusion (I/R); iv) 2.5% sevoflurane post-conditioning plus I/R; v) 2.5% sevoflurane post-conditioning + NG-nitro-L-arginine methyl ester (L-NAME) plus I/R; and vi) L-NAME plus I/R. The infarct size was measured using 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Additionally, the myocardial nitric oxide (NO), NO synthase (NOS) and nicotinamide adenine dinucleotide (NAD+) levels were determined. Autophagosomes and apoptosomes in the myocardium were detected by transmission electron microscopy. The levels of Bcl-2, cleaved caspase-3, Beclin-1, microtubule-associated protein light chain 3 (LC3)‑I/II, Na+/H+ exchanger 1 (NHE1) and phosphorylated NHE1 protein were measured by western blot analysis. NHE1 mRNA levels were measured by reverse transcription-quantitative polymerase chain reaction. Compared with the I/R group, 15 min of exposure to 2.5% sevoflurane during early reperfusion significantly decreased the myocardial infarct size, the autophagic vacuole numbers, the NHE1 mRNA and protein expression of cleaved caspase-3, Beclin-1 and LC3-I/II. Post-conditioning with 2.5% sevoflurane also increased the NO and NOS levels and Bcl-2 protein expression (p<0.05 or p<0.01). Notably, the cardioprotective effects of sevoflurane were partly abolished by the NOS inhibitor, L-NAME. The findings of the present study suggest that sevoflurane post-conditioning protects the myocardium against I/R injury and reduces the myocardial infarct size. The underlying protective mechanisms are associated with the inhibition of mitochondrial permeability transition pore opening, and with the attenuation of cardiomyoctye apoptosis and excessive autophagy. These effects are mediated through an increase in NOS and a decrease in phopshorylated NHE1 levels.

Right Ventricular Dysfunction in Chronic Lung Disease

PubMed Central

Kolb, Todd M.; Hassoun, Paul M.

2012-01-01

Right ventricular dysfunction arises in chronic lung disease when chronic hypoxemia and disruption of pulmonary vascular beds contribute to increase ventricular afterload, and is generally defined by hypertrophy with preserved myocardial contractility and cardiac output. Although the exact prevalence is unknown, right ventricular hypertrophy appears to be a common complication of chronic lung disease, and more frequently complicates advanced lung disease. Right ventricular failure is rare, except during acute exacerbations of chronic lung disease or when multiple co-morbidities are present. Treatment is targeted at correcting hypoxia and improving pulmonary gas exchange and mechanics. There are presently no convincing data to support the use of pulmonary hypertension-specific therapies in patients with right ventricular dysfunction secondary to chronic lung disease. PMID:22548815

Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

PubMed Central

Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

2012-01-01

Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy.

PubMed

Dassanayaka, Sujith; Brainard, Robert E; Watson, Lewis J; Long, Bethany W; Brittian, Kenneth R; DeMartino, Angelica M; Aird, Allison L; Gumpert, Anna M; Audam, Timothy N; Kilfoil, Peter J; Muthusamy, Senthilkumar; Hamid, Tariq; Prabhu, Sumanth D; Jones, Steven P

2017-05-01

The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure. Protein O-GlcNAcylation levels were increased in myocardial tissue from heart failure patients compared with normal patients. To test the role of OGT in the heart, we subjected cardiomyocyte-specific, inducibly deficient Ogt (i-cmOgt -/- ) mice and Ogt competent littermate wild-type (WT) mice to transverse aortic constriction. Deletion of cardiomyocyte Ogt significantly decreased O-GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic and fibrotic signaling were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i-cmOgt -/- cardiomyocytes from surgically naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation were elevated in Ogt-deficient cardiomyocytes. Although no significant differences in cardiac dysfunction were apparent after recombination, it is possible that such changes in dedifferentiation markers could reflect a larger phenotypic shift within the Ogt-deficient cardiomyocytes. We conclude that cardiomyocyte Ogt is not required for cardiomyocyte hypertrophy in vivo; however, loss of Ogt may exert subtle phenotypic differences in cardiomyocytes that sensitize the heart to pressure overload-induced ventricular dysfunction.

Effects of aluminum oxide (Al2O3) nanoparticles on ECG, myocardial inflammatory cytokines, redox state, and connexin 43 and lipid profile in rats: possible cardioprotective effect of gallic acid.

PubMed

El-Hussainy, El-Hussainy M A; Hussein, Abdelaziz M; Abdel-Aziz, Azza; El-Mehasseb, Ibrahim

2016-08-01

The objectives of present study were to examine the effects of aluminum oxide (Al2O3) nanoparticles on myocardial functions, electrical activities, morphology, inflammation, redox state, and myocardial expression of connexin 43 (Cx43) and the effect of gallic acid (GA) on these effects in a rat animal model. Forty male albino rats were divided into 4 equal groups: the control (normal) group; the Al2O3 group, rats received Al2O3 (30 mg·kg(-1), i.p.) daily for 14 days; the nano-alumina group, rats received nano-alumina (30 mg·kg(-1), i.p.) daily for 14 days; and the nano-alumina + GA group, rats received GA (100 mg·kg(-1) orally once daily) for 14 days before nano-alumina administration. The results showed disturbed ECG variables and significant increases in serum levels of LDH, creatine phosphokinase (CPK), CK-MB, triglycerides (TGs), cholesterol and LDL, nitric oxide (NO), and TNF-α and myocardial concentrations of NO, TNF-α, and malondialdehyde (MDA), with significant decreases in serum HDL and myocardial GSH, SOD, catalase (CAT), and Cx43 expression in the nano-alumina group. Pretreatment with GA improved significantly all parameters except serum and myocardial NO. We concluded that chronic administration of Al2O3 NPs caused myocardial dysfunctions, and pretreatment with GA ameliorates myocardial injury induced by nano-alumina, probably through its hypolipidaemic, anti-inflammatory, and antioxidant effects and upregulation of Cx43 in heart.

Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63-Integrin β1 Interaction.

PubMed

Takawale, Abhijit; Zhang, Pu; Patel, Vaibhav B; Wang, Xiuhua; Oudit, Gavin; Kassiri, Zamaneh

2017-06-01

Myocardial fibrosis is excess accumulation of the extracellular matrix fibrillar collagens. Fibrosis is a key feature of various cardiomyopathies and compromises cardiac systolic and diastolic performance. TIMP1 (tissue inhibitor of metalloproteinase-1) is consistently upregulated in myocardial fibrosis and is used as a marker of fibrosis. However, it remains to be determined whether TIMP1 promotes tissue fibrosis by inhibiting extracellular matrix degradation by matrix metalloproteinases or via an matrix metalloproteinase-independent pathway. We examined the function of TIMP1 in myocardial fibrosis using Timp1 -deficient mice and 2 in vivo models of myocardial fibrosis (angiotensin II infusion and cardiac pressure overload), in vitro analysis of adult cardiac fibroblasts, and fibrotic myocardium from patients with dilated cardiomyopathy (DCM). Timp1 deficiency significantly reduced myocardial fibrosis in both in vivo models of cardiomyopathy. We identified a novel mechanism for TIMP1 action whereby, independent from its matrix metalloproteinase-inhibitory function, it mediates an association between CD63 (cell surface receptor for TIMP1) and integrin β1 on cardiac fibroblasts, initiates activation and nuclear translocation of Smad2/3 and β-catenin, leading to de novo collagen synthesis. This mechanism was consistently observed in vivo, in cultured cardiac fibroblasts, and in human fibrotic myocardium. In addition, after long-term pressure overload, Timp1 deficiency persistently reduced myocardial fibrosis and ameliorated diastolic dysfunction. This study defines a novel matrix metalloproteinase-independent function of TIMP1 in promoting myocardial fibrosis. As such targeting TIMP1 could prove to be a valuable approach in developing antifibrosis therapies. © 2017 American Heart Association, Inc.

Differential loss of natural killer cell activity in patients with acute myocardial infarction and stable angina pectoris.

PubMed

Yan, Wenwen; Zhou, Lin; Wen, Siwan; Duan, Qianglin; Huang, Feifei; Tang, Yu; Liu, Xiaohong; Chai, Yongyan; Wang, Lemin

2015-01-01

To evaluate the activity of natural killer cells through their inhibitory and activating receptors and quantity in peripheral blood mononuclear cells extracted from patients with acute myocardial infarction, stable angina pectoris and the controls. 100 patients with myocardial infarction, 100 with stable angina, and 20 healthy volunteers were recruited into the study. 20 randomly chosen people per group were examined for the whole human genome microarray analysis to detect the gene expressions of all 40 inhibitory and activating natural killer cell receptors. Flow cytometry analysis was applied to all 200 patients to measure the quantity of natural killer cells. In myocardial infarction group, the mRNA expressions of six inhibitory receptors KIR2DL2, KIR3DL3, CD94, NKG2A, KLRB1, KLRG1, and eight activating receptors KIR2DS3, KIR2DS5, NKp30, NTB-A, CRACC, CD2, CD7 and CD96 were significantly down-regulated (P<0.05) compared with both angina patients and the controls. There was no statistical difference in receptor expressions between angina patients and control group. The quantity of natural killer cells was significantly decreased in both infarction and angina patients compared with normal range (P<0.001). The significant mRNAs down-regulation of several receptors in myocardial infarction group and reduction in the quantity of natural killer cells in both myocardial infarction and angina patients showed a quantitative loss and dysfunction of natural killer cells in myocardial infarction patients.

In vivo assessment of regional mechanics post-myocardial infarction: A focus on the road ahead.

PubMed

Romito, Eva; Shazly, Tarek; Spinale, Francis G

2017-10-01

Cardiovascular disease, particularly the occurrence of myocardial infarction (MI), remains a leading cause of morbidity and mortality (Go et al., Circulation 127: e6-e245, 2013; Go et al. Circulation 129: e28-e292, 2014). There is growing recognition that a key factor for post-MI outcomes is adverse remodeling and changes in the regional structure, composition, and mechanical properties of the MI region itself. However, in vivo assessment of regional mechanics post-MI can be confounded by the species, temporal aspects of MI healing, as well as size, location, and extent of infarction across myocardial wall. Moreover, MI regional mechanics have been assessed over varying phases of the cardiac cycle, and thus, uniform conclusions regarding the material properties of the MI region can be difficult. This review assesses past studies that have performed in vivo measures of MI mechanics and attempts to provide coalescence on key points from these studies, as well as offer potential recommendations for unifying approaches in terms of regional post-MI mechanics. A uniform approach to biophysical measures of import will allow comparisons across studies, as well as provide a basis for potential therapeutic markers.

Targeted ultrasound contrast imaging of matrix metalloproteinase-2 in ischemia-reperfusion rat model: ex vivo and in vivo studies.

PubMed

Su, Haili; Du, Yongfeng; Qian, Yunqiu; Zong, Yujin; Li, Jun; Zhuang, Ran; He, Jianguo; Wei, Zhangrui; Zhang, Jun; Zhou, Xiaodong

2011-04-01

We hypothesized that post-myocardial ischemia-reperfusion (I/R) remodeling associated matrix metalloproteinase-2 (MMP(2)) activation could be detected by using novel MMP(2) targeted ultrasound imaging. We study the combination of MMP(2)-targeted microbubbles (TMB(2)) and control microbubbles with myocardium in 1 week post-I/R rats. In in vitro studies, TMB(2) significantly bound within the risk area (RA) of 1-week post-I/R myocardial sections while rare binding was observed in the control area (CA). In in vivo studies, increased focal retention of TMB(2) was observed within the RA, with the higher myocardial video intensity (RA 42.85 ± 20.12 dB versus CA 25.85 ± 13.40 dB, p < 0.01). However, there was no difference of control microbubble retention in both CA and RA. A targeted ultrasound contrast imaging approach that employs novel TMB(2) has the potential to provide a less-invasive, higher-resolution technique for in vivo localization of MMP(2) activation and tracking of MMP-mediated post-I/R remodeling.

Neonatal Lipopolysaccharide Exposure Gender-Dependently Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Male Rats.

PubMed

Zhang, Peng; Lv, Juanxiu; Li, Yong; Zhang, Lubo; Xiao, Daliao

2017-01-01

Background: Adverse stress exposure during the early neonatal period has been shown to cause aberrant development, resulting in an increased risk of adult disease. We tested the hypothesis that neonatal exposure to lipopolysaccharide (LPS) does not alter heart function at rest condition but causes heart dysfunction under stress stimulation later in life. Methods: Saline control or LPS were administered to neonatal rats via intraperitoneal injection. Experiments were conducted in 6 week-old male and female rats. Isolated hearts were perfused in a Langendorff preparation. Results: Neonatal LPS exposure exhibited no effects on the body weight of the developing rats, but induced decreases in the left ventricle (LV) to the body weight ratio in male rats. Neonatal LPS exposure showed no effects on the baseline heart function determined by in vivo and ex vivo experiments, but caused decreases in the post-ischemic recovery of the LV function in male but not female rats. Neonatal LPS-mediated LV dysfunction was associated with an increase in myocardial infarct size and the LDH release in the male rats. Conclusion: The present study provides novel evidence that neonatal immune challenges could induce gender-dependent long-term effects on cardiac development and heart function, which reinforces the notion that adverse stress exposure during the early neonatal period can aggravate heart functions and the development of a heart ischemia-sensitive phenotype later in life.

Acute impairment of regional myocardial glucose uptake in the apical ballooning (takotsubo) syndrome.

PubMed

Bybee, Kevin A; Murphy, Joseph; Prasad, Abhiram; Wright, R Scott; Lerman, Amir; Rihal, Charanjit S; Chareonthaitawee, Panithaya

2006-01-01

Apical ballooning syndrome (ABS) is a poorly understood clinical entity characterized by acute, transient systolic dysfunction of the left ventricular (LV) apex in the absence of epicardial coronary artery disease and commonly associated with acute emotional stress. We report abnormal regional myocardial perfusion and glucose uptake in 4 consecutive ABS patients studied using positron emission tomography with 13N-ammonia and 18F-fluorodeoxyglucose within 72 hours of presentation with ABS. All patients were postmenopausal females, 3 of whom had a major recent life stress event. Coronary angiography revealed no or minimal obstructive epicardial coronary artery disease. All patients exhibited reduced glucose uptake in the mid-LV and apical myocardial segments, which was out of proportion to perfusion abnormalities in half of the cases. In all 4 patients, affected regions subsequently recovered regional LV systolic function within 6 weeks.

Stem Cells for Cardiac Regeneration by Cell Therapy and Myocardial Tissue Engineering

NASA Astrophysics Data System (ADS)

Wu, Jun; Zeng, Faquan; Weisel, Richard D.; Li, Ren-Ke

Congestive heart failure, which often occurs progressively following a myocardial infarction, is characterized by impaired myocardial perfusion, ventricular dilatation, and cardiac dysfunction. Novel treatments are required to reverse these effects - especially in older patients whose endogenous regenerative responses to currently available therapies are limited by age. This review explores the current state of research for two related approaches to cardiac regeneration: cell therapy and tissue engineering. First, to evaluate cell therapy, we review the effectiveness of various cell types for their ability to limit ventricular dilatation and promote functional recovery following implantation into a damaged heart. Next, to assess tissue engineering, we discuss the characteristics of several biomaterials for their potential to physically support the infarcted myocardium and promote implanted cell survival following cardiac injury. Finally, looking ahead, we present recent findings suggesting that hybrid constructs combining a biomaterial with stem and supporting cells may be the most effective approaches to cardiac regeneration.

The role of myocardial viability in contemporary cardiac practice.

PubMed

Jamiel, Abdelrahman; Ebid, Mohamad; Ahmed, Amjad M; Ahmed, Dalia; Al-Mallah, Mouaz H

2017-07-01

Ischemic heart disease (IHD) remains the single most common cause of death worldwide. Ischemic cardiomyopathy is a major sequel of coronary artery disease. The economic health burden of IHD is substantial. In patients with old myocardial infarction (OMI), the extent of viable myocardium (VM) directly affects the short- and long-term outcome. There is a considerable collection of observational data showing substantial improvement in patients with significant left ventricular dysfunction when the need for revascularization is guided by preoperative assessment of viability and hibernation. However, a major challenge for present cardiovascular imaging is to identify better ways to assess viable but inadequately perfused myocardium and thus optimize selection of patients for coronary revascularization. Several non-invasive techniques have been developed to detect signs of viability. Hence, our aim is to provide the reader a state-of-the art review for the assessment of myocardial viability.

Incretin-related drug therapy in heart failure.

PubMed

Vest, Amanda R

2015-02-01

The new pharmacological classes of GLP-1 agonists and DPP-4 inhibitors are now widely used in diabetes and have been postulated as beneficial in heart failure. These proposed benefits arise from the inter-related pathophysiologies of diabetes and heart failure (diabetes increases the risk of heart failure, and heart failure can induce insulin resistance) and also in light of the dysfunctional myocardial energetics seen in heart failure. The normal heart utilizes predominantly fatty acids for energy production, but there is some evidence to suggest that increased myocardial glucose uptake may be beneficial for the failing heart. Thus, GLP-1 agonists, which stimulate glucose-dependent insulin release and enhance myocardial glucose uptake, have become a focus of investigation in both animal models and humans with heart failure. Limited pilot data for GLP-1 agonists shows potential improvements in systolic function, hemodynamics, and quality of life, forming the basis for current phase II trials.

Discrete microstructural cues for the attenuation of fibrosis following myocardial infarction.

PubMed

Pinney, James R; Du, Kim T; Ayala, Perla; Fang, Qizhi; Sievers, Richard E; Chew, Patrick; Delrosario, Lawrence; Lee, Randall J; Desai, Tejal A

2014-10-01

Chronic fibrosis caused by acute myocardial infarction (MI) leads to increased morbidity and mortality due to cardiac dysfunction. We have developed a therapeutic materials strategy that aims to mitigate myocardial fibrosis by utilizing injectable polymeric microstructures to mechanically alter the microenvironment. Polymeric microstructures were fabricated using photolithographic techniques and studied in a three-dimensional culture model of the fibrotic environment and by direct injection into the infarct zone of adult rats. Here, we show dose-dependent down-regulation of expression of genes associated with the mechanical fibrotic response in the presence of microstructures. Injection of this microstructured material into the infarct zone decreased levels of collagen and TGF-β, increased elastin deposition and vascularization in the infarcted region, and improved functional outcomes after six weeks. Our results demonstrate the efficacy of these discrete anti-fibrotic microstructures and suggest a potential therapeutic materials approach for combatting pathologic fibrosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

A case of reversible dilated cardiomyopathy after alpha-interferon therapy in a patient with renal cell carcinoma.

PubMed

Kuwata, Akiko; Ohashi, Masuo; Sugiyama, Masaya; Ueda, Ryuzo; Dohi, Yasuaki

2002-12-01

A 47-year-old man with renal cell carcinoma underwent nephrectomy, and postoperative chemotherapy was performed with recombinant alpha-interferon. Five years later, he experienced dyspnea during physical exertion. An echocardiogram revealed dilatation and systolic dysfunction of the left ventricle, and thallium-201 myocardial scintigraphy showed diffuse heterogeneous perfusion. We diagnosed congestive heart failure because of cardiomyopathy induced by alpha-interferon therapy. Withdrawal of interferon therapy and the combination of an angiotensin-converting enzyme inhibitor, diuretics, and digitalis improved left ventricular systolic function. Furthermore, myocardial scintigraphy using [123I] beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) or [123 I]metaiodobenzylguanidine (123I-MIBG) revealed normal perfusion after the improvement of congestive heart failure. This is a rare case of interferon-induced cardiomyopathy that resulted in normal myocardial images in 123I-BMIPP and 123I-MIBG scintigrams after withdrawal of interferon therapy.

Fisetin Confers Cardioprotection against Myocardial Ischemia Reperfusion Injury by Suppressing Mitochondrial Oxidative Stress and Mitochondrial Dysfunction and Inhibiting Glycogen Synthase Kinase 3β Activity.

PubMed

Shanmugam, Karthi; Ravindran, Sriram; Kurian, Gino A; Rajesh, Mohanraj

2018-01-01

Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Timely reperfusion is considered an optimal treatment for AMI. Paradoxically, the procedure of reperfusion can itself cause myocardial tissue injury. Therefore, a strategy to minimize the reperfusion-induced myocardial tissue injury is vital for salvaging the healthy myocardium. Herein, we investigated the cardioprotective effects of fisetin, a natural flavonoid, against ischemia/reperfusion (I/R) injury (IRI) using a Langendorff isolated heart perfusion system. I/R produced significant myocardial tissue injury, which was characterized by elevated levels of lactate dehydrogenase and creatine kinase in the perfusate and decreased indices of hemodynamic parameters. Furthermore, I/R resulted in elevated oxidative stress, uncoupling of the mitochondrial electron transport chain, increased mitochondrial swelling, a decrease of the mitochondrial membrane potential, and induction of apoptosis. Moreover, IRI was associated with a loss of the mitochondrial structure and decreased mitochondrial biogenesis. However, when the animals were pretreated with fisetin, it significantly attenuated the I/R-induced myocardial tissue injury, blunted the oxidative stress, and restored the structure and function of mitochondria. Mechanistically, the fisetin effects were found to be mediated via inhibition of glycogen synthase kinase 3 β (GSK3 β ), which was confirmed by a biochemical assay and molecular docking studies.

Diabetes-induced changes in specific lipid molecular species in rat myocardium.

PubMed Central

Han, X; Abendschein, D R; Kelley, J G; Gross, R W

2000-01-01

Intrinsic cardiac dysfunction during the diabetic state has been causally linked to changes in myocardial lipid metabolism. However, the precise alterations in the molecular species of myocardial polar and non-polar lipids during the diabetic state and their responses to insulin have not been investigated. Herein we demonstrate four specific alterations in rat myocardial lipid molecular species after induction of the diabetic state by streptozotocin treatment: (i) a massive remodelling of triacylglycerol molecular species including a >5-fold increase in tripalmitin mass and a 60% decrease in polyunsaturated triacylglycerol molecular species mass (i.e. triacylglycerols containing at least one acyl residue with more than two double bonds); (ii) a 46% increase in myocardial phosphatidylinositol mass; (iii) a 44% increase in myocardial plasmenylethanolamine mass and (iv) a 22% decrease in 1-stearoyl-2-arachidonoyl phosphatidylethanolamine content. Each of the changes in phospholipid classes, subclasses and individual molecular species were prevented by insulin treatment after induction of the diabetic state. In sharp contrast, the alterations in triacylglycerol molecular species were not preventable by peripheral insulin treatment after induction of the diabetic state. These results segregate diabetes-induced alterations in myocardial lipid metabolism into changes that can be remedied or not by routine peripheral insulin treatment and suggest that peripheral insulin therapy alone may not be sufficient to correct all of the metabolic alterations present in diabetic myocardium. PMID:11062060

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

Kajimoto, Masaki; O'Kelly-Priddy, Colleen M.; Ledee, Dolena R.

Extracorporeal membrane oxygenation (ECMO) supports infants and children with severe cardiopulmonary compromise. Nutritional support for these children includes provision of medium- and long-chain fatty acids (FAs). However, ECMO induces a stress response, which could limit the capacity for FA oxidation. Metabolic impairment could induce new or exacerbate existing myocardial dysfunction. Using a clinically relevant piglet model, we tested the hypothesis that ECMO maintains the myocardial capacity for FA oxidation and preserves myocardial energy state. Provision of 13-Carbon labeled medium-chain FA (octanoate), longchain free FAs (LCFAs), and lactate into systemic circulation showed that ECMO promoted relative increases in myocardial LCFA oxidationmore » while inhibiting lactate oxidation. Loading of these labeled substrates at high dose into the left coronary artery demonstrated metabolic flexibility as the heart preferentially oxidized octanoate. ECMO preserved this octanoate metabolic response, but also promoted LCFA oxidation and inhibited lactate utilization. Rapid upregulation of pyruvate dehydrogenase kinase-4 (PDK4) protein appeared to participate in this metabolic shift during ECMO. ECMO also increased relative flux from lactate to alanine further supporting the role for pyruvate dehydrogenase inhibition by PDK4. High dose substrate loading during ECMO also elevated the myocardial energy state indexed by phosphocreatine to ATP ratio. ECMO promotes LCFA oxidation in immature hearts, while maintaining myocardial energy state. These data support the appropriateness of FA provision during ECMO support for the immature heart.« less

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

PubMed

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

2017-11-14

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

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

PubMed Central

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

2017-01-01

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

Myocardial strain estimation from CT: towards computer-aided diagnosis on infarction identification

NASA Astrophysics Data System (ADS)

Wong, Ken C. L.; Tee, Michael; Chen, Marcus; Bluemke, David A.; Summers, Ronald M.; Yao, Jianhua

2015-03-01

Regional myocardial strains have the potential for early quantification and detection of cardiac dysfunctions. Although image modalities such as tagged and strain-encoded MRI can provide motion information of the myocardium, they are uncommon in clinical routine. In contrary, cardiac CT images are usually available, but they only provide motion information at salient features such as the cardiac boundaries. To estimate myocardial strains from a CT image sequence, we adopted a cardiac biomechanical model with hyperelastic material properties to relate the motion on the cardiac boundaries to the myocardial deformation. The frame-to-frame displacements of the cardiac boundaries are obtained using B-spline deformable image registration based on mutual information, which are enforced as boundary conditions to the biomechanical model. The system equation is solved by the finite element method to provide the dense displacement field of the myocardium, and the regional values of the three principal strains and the six strains in cylindrical coordinates are computed in terms of the American Heart Association nomenclature. To study the potential of the estimated regional strains on identifying myocardial infarction, experiments were performed on cardiac CT image sequences of ten canines with artificially induced myocardial infarctions. The leave-one-subject-out cross validations show that, by using the optimal strain magnitude thresholds computed from ROC curves, the radial strain and the first principal strain have the best performance.

Cardioprotective effects of red wine and vodka in a model of endothelial dysfunction

PubMed Central

Lassaletta, Antonio D; Chu, Louis M; Elmadhun, Nassrene Y; Burgess, Thomas A; Feng, Jun; Robich, Michael P; Sellke, Frank W

2012-01-01

Background Moderate alcohol consumption is largely believed to be cardioprotective, while red wine is hypothesized to offer benefit in part due to the pro-angiogenic and antioxidant properties of polyphenols. We investigated the cardiovascular effects of both red wine and vodka in a swine model of endothelial dysfunction. Methods Twenty-seven male Yorkshire swine fed a high-fat/cholesterol diet were divided into three groups and received either no alcohol (Control), red wine, or vodka. After seven weeks, myocardial perfusion was measured, and ventricular tissue was analyzed for microvascular reactivity, and immunohistochemical studies. Results There were no differences in myocardial perfusion, in arteriolar or capillary density, or in VEGF expression among groups. Total protein oxidation as well as expression of superoxide dismutase-1 and -2 (SOD1, SOD2) and NADPH-oxidase (NOX2) was decreased in both treatment groups compared to controls. Endothelium-dependent microvessel relaxation, however, was significantly improved only in the red wine-supplemented group. Conclusions Supplementation with both red wine and vodka decreased oxidative stress by several measures, implicating the effects of ethanol in reducing oxidative stress in the myocardium. However, it was only in the red wine-supplemented group that an improvement in microvessel function was observed. This suggests that a component of red wine, independent of ethanol, possibly a polyphenol such as resveratrol, may confer cardioprotection by normalizing endothelial dysfunction induced by an atherogenic diet. PMID:22748601

Predictive factor of secondary tricuspid regurgitation after aortic valve replacement for aortic stenosis: the importance of myocardial hypertrophy and diastolic dysfunction.

PubMed

Igarashi, Takashi; Tanji, Masahiro; Takahashi, Koki; Ishida, Keiichi; Sasaki, Satomi; Yokoyama, Hitoshi

2017-05-01

The aim of this study is to determine the predictors of secondary tricuspid regurgitation after aortic valve replacement for aortic stenosis. Seventy-one patients, who underwent aortic valve replacement for aortic stenosis at our institute from January 2006 to July 2011, were divided into two groups: an STR group, which included 15 patients with moderate or greater than moderate secondary tricuspid regurgitation at a follow-up visit and a control group. Echocardiography was performed before surgery, at discharge, and at a late follow-up visit (mean follow-up 36 ± 19 months, range 0-77). Preoperatively, the number of women (p < .01), body surface area (p < .001), and relative wall thickness (0.60 ± 0.15 vs 0.71 ± 0.13, p = .022) showed significant differences between the two groups. At a follow-up visit, moderate or severe mitral regurgitation (p = .0001) and severe diastolic dysfunction (p = .003) showed significant differences between the two groups. In the Cox regression analysis, moderate or severe mitral regurgitation at follow-up (p = .038, hazard ratio 4.394, 95% CI 1.085-17.791) was the only independent predictor of secondary tricuspid regurgitation. This study suggested that preoperative concentric myocardial hypertrophy and diastolic dysfunction were associated with development of the secondary tricuspid regurgitation at late follow-up.

Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure

NASA Technical Reports Server (NTRS)

Komamura, K.; Shannon, R. P.; Pasipoularides, A.; Ihara, T.; Lader, A. S.; Patrick, T. A.; Bishop, S. P.; Vatner, S. F.

1992-01-01

We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.

Cardiovascular Abnormalities in Carbon Monoxide Poisoning.

PubMed

Garg, Jalaj; Krishnamoorthy, Parasuram; Palaniswamy, Chandrasekar; Khera, Sahil; Ahmad, Hasan; Jain, Diwakar; Aronow, Wilbert S; Frishman, William H

Acute carbon monoxide (CO) poisoning is the most common cause of poisoning and poisoning-related death in the United States. It manifests as broad spectrum of symptoms ranging from mild headache, nausea, and fatigue to dizziness, syncope, coma, seizures resulting in cardiovascular collapse, respiratory failure, and death. Cardiovascular complications of CO poisoning has been well reported and include myocardial stunning, left ventricular dysfunction, pulmonary edema, and arrhythmias. Acute myocardial ischemia has also been reported from increased thrombogenicity due to CO poisoning. Myocardial toxicity from CO exposure is associated with increased short-term and long-term mortality. Carboxyhemoglobin (COHb) levels do not correlate well with the clinical severity of CO poisoning. Supplemental oxygen remains the cornerstone of therapy for CO poisoning. Hyperbaric oxygen therapy increases CO elimination and has been used with wide variability in patients with evidence of neurological and myocardial injury from CO poisoning, but its benefit in limiting or reversing cardiac injury is unknown. We present a comprehensive review of literature on cardiovascular manifestations of CO poisoning and propose a diagnostic algorithm for managing patients with CO poisoning.

The Psycho-cardiac Coupling, Myocardial Remodeling, and Neuroendocrine Factor Levels: The Psychosomatics of Major Depressive Disorder.

PubMed

Syeda, Javeria N; Rutkofsky, Ian H; Muhammad, Adnan S; Balla Abdalla, Tarig H; Saghir, Zahid

2018-04-11

The association of major depressive disorder (MDD) with myocardial infarction (MI) and vice versa is not unknown. Depression, along with many other systemic factors like atherosclerosis, obesity, diabetes and vascular dysfunction, contributes to the development of adverse cardiac events in the future and, has always been a topic of interest in the fields of cardiology and psychosomatics. We wrote this review article to elaborate this relationship in detail. This article suggests that the individuals with type D personality who already had cardiovascular disease had undergone more serious myocardial damage. In addition, we elucidated the effects of depression on sympathetic activity and remodeling of myocardium after MI. The alterations in the neuroendocrine factors, which included the changes in levels of Serotonin (5-HT), Norepinephrine and Corticosterone, also geared towards the changes associated with depression-induced myocardial injury. However, we need more studies in the near future to further dig into this association process. Therefore, we recommend more research to explore the relationship of psychological factors and adverse cardiac outcomes.

[Structural and functional changes of myocardium in Chernobyl disaster clean-up workers with atrial fibrillation].

PubMed

Khomaziuk, I M; Habulavichene, Zh M; Khomaziuk, V A

2011-01-01

Particularities and clinical importance of the structural and functional changes of myocardium were estimated in Chernobyl disaster clean-up workers with atrial fibrillation (AF). We examined 122 men with AF, which was associated with ischemic heart disease and arterial hypertension. Paroxysmal AF was diagnosed in 42 patients, 80 patients had permanent AE Control group comprised 80 men without AF. Echocardiography and Doppler studies were performed using ultrasound scanner Aloka SSD-630 (Japan). Significant structural and functional changes of the heart were revealed already in paroxysmal AF and became more pronounced in permanent AF. Increased left atrial size, its ratio to left ventricular end diastolic diameter, diastolic dysfunction were important echocardiographic predictors of AF. Heart walls thickening was accompanied by disorders of myocardial relaxation, increase in myocardial mass led to ischemia, and together they promoted overload, dysfunction of atrium and development of AF. Obligatory echocardiographic examination of the Chernobyl disaster clean-up workers with ischemic heart disease and arterial hypertension is necessary for predicting AF early, ordering adequate therapy in proper time and improving prognosis.

Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy.

PubMed

Jneid, Hani; Moukarbel, George V; Dawson, Bart; Hajjar, Roger J; Francis, Gary S

2007-12-01

Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.

Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

PubMed Central

Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal; Givvimani, Srikanth; Metreveli, Naira; Lominadze, David

2010-01-01

Myocardial infarction (MI) results in significant metabolic derangement, causing accumulation of metabolic by product, such as homocysteine (Hcy). Hcy is a nonprotein amino acid generated during nucleic acid methylation and demethylation of methionine. Folic acid (FA) decreases Hcy levels by remethylating the Hcy to methionine, by 5-methylene tetrahydrofolate reductase (5-MTHFR). Although clinical trials were inconclusive regarding the role of Hcy in MI, in animal models, the levels of 5-MTHFR were decreased, and FA mitigated the MI injury. We hypothesized that FA mitigated MI-induced injury, in part, by mitigating cardiac remodeling during chronic heart failure. Thus, MI was induced in 12-wk-old male C57BL/J mice by ligating the left anterior descending artery, and FA (0.03 g/l in drinking water) was administered for 4 wk after the surgery. Cardiac function was assessed by echocardiography and by a Millar pressure-volume catheter. The levels of Hcy-metabolizing enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 5-MTHFR, were estimated by Western blot analyses. The results suggest that FA administered post-MI significantly improved cardiac ejection fraction and induced tissue inhibitor of metalloproteinase, CBS, CSE, and 5-MTHFR. We showed that FA supplementation resulted in significant improvement of myocardial function after MI. The study eluted the importance of homocysteine (Hcy) metabolism and FA supplementation in cardiovascular disease. PMID:20802128

Glycosylated Chromogranin A: Potential Role in the Pathogenesis of Heart Failure.

PubMed

Ottesen, Anett H; Christensen, Geir; Omland, Torbjørn; Røsjø, Helge

2017-12-01

Endocrine and paracrine factors influence the cardiovascular system and the heart by a number of different mechanisms. The chromogranin-secretogranin (granin) proteins seem to represent a new family of proteins that exerts both direct and indirect effects on cardiac and vascular functions. The granin proteins are produced in multiple tissues, including cardiac cells, and circulating granin protein concentrations provide incremental prognostic information to established risk indices in patients with myocardial dysfunction. In this review, we provide recent data for the granin proteins in relation with cardiovascular disease, and with a special focus on chromogranin A and heart failure. Chromogranin A is the most studied member of the granin protein family, and shorter, functionally active peptide fragments of chromogranin A exert protective effects on myocardial cell death, ischemia-reperfusion injury, and cardiomyocyte Ca 2+ handling. Granin peptides have also been found to induce angiogenesis and vasculogenesis. Protein glycosylation is an important post-translational regulatory mechanism, and we recently found chromogranin A molecules to be hyperglycosylated in the failing myocardium. Chromogranin A hyperglycosylation impaired processing of full-length chromogranin A molecules into physiologically active chromogranin A peptides, and patients with acute heart failure and low rate of chromogranin A processing had increased mortality compared to other acute heart failure patients. Other studies have also demonstrated that circulating granin protein concentrations increase in parallel with heart failure disease stage. The granin protein family seems to influence heart failure pathophysiology, and chromogranin A hyperglycosylation could directly be implicated in heart failure disease progression.

A web-based tool to predict acute kidney injury in patients with ST-elevation myocardial infarction: Development, internal validation and comparison.

PubMed

Zambetti, Benjamin R; Thomas, Fridtjof; Hwang, Inyong; Brown, Allen C; Chumpia, Mason; Ellis, Robert T; Naik, Darshan; Khouzam, Rami N; Ibebuogu, Uzoma N; Reed, Guy L

2017-01-01

In ST-elevation myocardial infarction (STEMI), acute kidney injury (AKI) may increase subsequent morbidity and mortality. Still, it remains difficult to predict AKI risk in these patients. We sought to 1) determine the frequency and clinical outcomes of AKI and, 2) develop, validate and compare a web-based tool for predicting AKI. In a racially diverse series of 1144 consecutive STEMI patients, Stage 1 or greater AKI occurred in 12.9% and was severe (Stage 2-3) in 2.9%. AKI was associated with increased mortality (5.7-fold, unadjusted) and hospital stay (2.5-fold). AKI was associated with systolic dysfunction, increased left ventricular end-diastolic pressures, hypotension and intra-aortic balloon counterpulsation. A computational algorithm (UT-AKI) was derived and internally validated. It showed higher sensitivity and improved overall prediction for AKI (area under the curve 0.76) vs. other published indices. Higher UT-AKI scores were associated with more severe AKI, longer hospital stay and greater hospital mortality. In a large, racially diverse cohort of STEMI patients, Stage 1 or greater AKI was relatively common and was associated with significant morbidity and mortality. A web-accessible, internally validated tool was developed with improved overall value for predicting AKI. By identifying patients at increased risk, this tool may help physicians tailor post-procedural diagnostic and therapeutic strategies after STEMI to reduce AKI and its associated morbidity and mortality.

Illness perceptions of fatigue and the association with sense of coherence and stress in patients one year after myocardial infarction.

PubMed

Alsén, Pia; Eriksson, Monica

2016-02-01

To explore the associations between illness perceptions of fatigue, sense of coherence and stress in patients one year after myocardial infarction. Post-myocardial infarction fatigue is a stressful symptom that is difficult to cope with. Patients' illness perceptions of fatigue guide professionals in predicting how individuals will respond emotionally and cognitively to symptoms. Individuals' sense of coherence can be seen as a coping resource in managing stressors. A cross-sectional study design was used. One year post-myocardial infarction, a total of 74 patients still experiencing fatigue completed four questionnaires: the Multidimensional Fatigue Scale Inventory-20, the Brief Illness Perception Questionnaire, the Sense of Coherence scale (sense of coherence-13) and a single-item measure of stress symptoms. Descriptive statistics, correlations and stepwise regression analysis were carried out. Strong negative associations were found between illness perceptions of fatigue, sense of coherence and stress. Sense of coherence has an impact on illness perceptions of fatigue. Of the dimensions of sense of coherence, comprehensibility seemed to play the greatest role in explaining illness perceptions of fatigue one year after myocardial infarction. To strengthen patients' coping resources, health-care professionals should create opportunities for patients to gain individual-level knowledge that allows them to distinguish between common fatigue symptoms and warning signs for myocardial infarction. There is a need to improve strategies for coping with fatigue. It is also essential to identify patients with fatigue after myocardial infarction, as they need explanations for their symptoms and extra support. © 2016 John Wiley & Sons Ltd.

Naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering

PubMed Central

Singelyn, Jennifer M.; DeQuach, Jessica A.; Seif-Naraghi, Sonya B.; Littlefield, Robert B.; Schup-Magoffin, Pamela J.; Christman, Karen L.

2009-01-01

Myocardial tissue lacks the ability to significantly regenerate itself following a myocardial infarction, thus tissue engineering strategies are required for repair. Several injectable materials have been examined for cardiac tissue engineering; however, none have been designed specifically to mimic the myocardium. The goal of this study was to investigate the in vitro properties and in vivo potential of an injectable myocardial matrix designed to mimic the natural myocardial extracellular environment. Porcine myocardial tissue was decellularized and processed to form a myocardial matrix with the ability to gel in vitro at 37°C and in vivo upon injection into rat myocardium. The resulting myocardial matrix maintained a complex composition, including glycosaminoglycan content, and was able to self-assemble to form a nanofibrous structure. Endothelial cells and smooth muscle cells were shown to migrate towards the myocardial matrix both in vitro and in vivo, with a significant increase in arteriole formation at 11 days post-injection. The matrix was also successfully pushed through a clinically used catheter, demonstrating its potential for minimally invasive therapy. Thus, we have demonstrated the initial feasibility and potential of a naturally derived myocardial matrix as an injectable scaffold for cardiac tissue engineering. PMID:19608268

Role of myocardial collagen degradation and fibrosis in right ventricle dysfunction in transposition of the great arteries after atrial switch.

PubMed

Ladouceur, Magalie; Baron, Stephanie; Nivet-Antoine, Valérie; Maruani, Gérard; Soulat, Gilles; Pereira, Helena; Blanchard, Anne; Boutouyrie, Pierre; Paul, Jean Louis; Mousseaux, Elie

2018-05-01

Heart failure is a serious event in patients with transposition of the great arteries (D-TGA) after atrial redirection surgery. We aimed to determine the association between myocardial fibrosis and systolic and diastolic systemic right ventricle (sRV) dysfunction. Diastolic and systolic function of sRV was prospectively assessed using echocardiography and cardiac magnetic resonance imaging (CMR) in 48 patients with atrially switched D-TGA and 26 healthy subjects. Diastolic function of the subaortic ventricle was assessed by echocardiography Doppler and DTI. In CMR, ejection fraction of sRV and wall stress defined as the product of the systolic blood pressure and volume/mass ratio were assessed. Fibrosis extent within sRV myocardium was evaluated using gadolinium-enhanced magnetic resonance and serum collagen turnover biomarkers. Late gadolinium enhancement (LGE) was found in 35% of D-TGA patients, and the collagen degradation biomarker pro-MMP1:TIMP1 ratio was significantly increased in D-TGA patients compared to healthy subjects (1.0 × 10 -2 vs. 2.5 × 10 -2 , p = 0.04). Increase in sRV wall stress was significantly associated with LGE (p = 0.01) and pro-MMP1:TIMP1 ratio (r = 0.77, p < 0.01). After adjustment for age, sex, BMI, blood pressure and cardiac treatment, pro-MMP1:TIMP1 ratio was the strongest determinant of sRVEF (R 2  = 0.85, p < 0.01). Pro-MMP1:TIMP1 ratio was also significantly correlated with the early diastolic filling parameter E/E' (r = 0.53, p = 0.02), but this was not anymore the case after adjustment. Diastolic and systolic sRV dysfunction is related to myocardial collagen degradation and fibrosis. Research in medical therapies that reduce systemic sRV afterload and limit collagen degradation is warranted in this setting. Copyright © 2018 Elsevier B.V. All rights reserved.

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis

PubMed Central

Matyas, Csaba; Varga, Zoltan V.; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T.; Nan, Mintong; Hasko, Gyorgy; Gao, Bin

2016-01-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. PMID:27106042

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis.

PubMed

Matyas, Csaba; Varga, Zoltan V; Mukhopadhyay, Partha; Paloczi, Janos; Lajtos, Tamas; Erdelyi, Katalin; Nemeth, Balazs T; Nan, Mintong; Hasko, Gyorgy; Gao, Bin; Pacher, Pal

2016-06-01

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. Copyright © 2016 the American Physiological Society.

Gender Differences in Left Ventricular Function Following Percutaneous Coronary Intervention for First Anterior Wall ST-Segment Elevation Myocardial Infarction.

PubMed

Weissler-Snir, Adaya; Kornowski, Ran; Sagie, Alexander; Vaknin-Assa, Hana; Perl, Leor; Porter, Avital; Lev, Eli; Assali, Abid

2014-11-15

Little is known regarding gender differences in left ventricular (LV) function after anterior wall ST-segment elevation myocardial infarction (STEMI), despite it being a major determinant of patients' morbidity and mortality. We therefore sought to investigate the impact of gender on LV function after primary percutaneous coronary intervention (PCI) for first anterior wall STEMI. Seven hundred eighty-nine consecutive patients (625 men) with first anterior STEMI were included in the analysis. All patients underwent an echocardiographic study within 48 hours of PCI. Women were older and more likely to have diabetes, hypertension, chronic renal failure, and a higher Killip score. Women had prolonged ischemic time, which was driven by prolonged symptom-to-presentation time (2.75 [interquartile range 1.5 to 4] vs 2 [interquartile range 1 to 3.5] hours, p = 0.005). A higher percentage of women had moderate or worse LV dysfunction (LV ejection fraction <40%; 61.6% vs 48%, p = 0.002). In a univariable analysis female gender was associated with moderate or worse LV function (p = 0.002). However, after accounting for variable baseline risk profiles between the 2 groups using multivariable and propensity score techniques, ischemic time >3.5 hours, leukocytosis, and pre-PCI Thrombolysis In Myocardial Infarction flow grade <2 were independent predictors of moderate or worse LV dysfunction, whereas female gender was not. Data on LV function recovery at 6 months, which were available for 45% of female and male patients with moderate or worse LV dysfunction early after PCI, showed no significant gender related difference in LV function recovery. In conclusion, women undergoing PCI for the first event of anterior STEMI demonstrate worse LV function than that of men, which might be partially attributed to delay in presentation. Hence greater efforts should be devoted to increasing women's awareness of cardiac symptoms during the prehospital course of STEMI. Copyright © 2014 Elsevier Inc. All rights reserved.

Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

PubMed Central

da Silva, Jaqueline S; Gabriel-Costa, Daniele; Sudo, Roberto T; Wang, Hao; Groban, Leanne; Ferraz, Emanuele B; Nascimento, José Hamilton M; Fraga, Carlos Alberto M; Barreiro, Eliezer J; Zapata-Sudo, Gisele

2017-01-01

Background This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). Methods Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg−1.d−1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg−1.d−1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg−1.d−1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg−1.d−1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. Conclusion In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound’s potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension. PMID:28293100

Myocardial ischemia/reperfusion upregulates the transcription of the Neuregulin1 receptor ErbB3, but only postconditioning preserves protein translation: Role in oxidative stress.

PubMed

Morano, Michela; Angotti, Carmelina; Tullio, Francesca; Gambarotta, Giovanna; Penna, Claudia; Pagliaro, Pasquale; Geuna, Stefano

2017-04-15

Neuregulin1 (Nrg1) and its receptors ErbB are crucial for heart development and for adult heart structural maintenance and function and Nrg1 has been proposed for heart failure treatment. Infarct size is the major determinant of heart failure and the mechanism of action and the role of each ErbB receptor remain obscure, especially in the post-ischemic myocardium. We hypothesized that Nrg1 and ErbB are affected at transcriptional level early after ischemia/reperfusion (I/R) injury, and that the protective postconditioning procedure (PostC, brief cycles of ischemia/reperfusion carried out after a sustained ischemia) can influence this pathway. The Langendorff's heart was used as an ex-vivo model to mimic an I/R injury in the whole rat heart; after 30min of ischemia and 2h of reperfusion, with or without PostC, Nrg1 and ErbB expression were analysed by quantitative real-time PCR and Western blot. While no changes occur for ErbB2, ErbB4 and Nrg1, an increase of ErbB3 expression occurs after I/R injury, with and without PostC. However, I/R reduces ErbB3 protein, whereas PostC preserves it. An in vitro analysis with H9c2 cells exposed to redox-stress indicated that the transient over-expression of ErbB3 alone is able to increase cell survival (MTT assay), limiting mitochondrial dysfunction (JC-1 probe) and apoptotic signals (Bax/Bcl-2 ratio). This study suggests ErbB3 as a protective factor against death pathways activated by redox stress and supports an involvement of this receptor in the pro-survival responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Perioperative Assessment of Myocardial Deformation

PubMed Central

Duncan, Andra E.; Alfirevic, Andrej; Sessler, Daniel I.; Popovic, Zoran B.; Thomas, James D.

2014-01-01

Evaluation of left ventricular performance improves risk assessment and guides anesthetic decisions. However, the most common echocardiographic measure of myocardial function, the left ventricular ejection fraction (LVEF), has important limitations. LVEF is limited by subjective interpretation which reduces accuracy and reproducibility, and LVEF assesses global function without characterizing regional myocardial abnormalities. An alternative objective echocardiographic measure of myocardial function is thus needed. Myocardial deformation analysis, which performs quantitative assessment of global and regional myocardial function, may be useful for perioperative care of surgical patients. Myocardial deformation analysis evaluates left ventricular mechanics by quantifying strain and strain rate. Strain describes percent change in myocardial length in the longitudinal (from base to apex) and circumferential (encircling the short-axis of the ventricle) direction and change in thickness in the radial direction. Segmental strain describes regional myocardial function. Strain is a negative number when the ventricle shortens longitudinally or circumferentially and is positive with radial thickening. Reference values for normal longitudinal strain from a recent meta-analysis using transthoracic echocardiography are (mean ± SD) −19.7 ± 0.4%, while radial and circumferential strain are 47.3 ± 1.9 and −23.3 ± 0.7%, respectively. The speed of myocardial deformation is also important and is characterized by strain rate. Longitudinal systolic strain rate in healthy subjects averages −1.10 ± 0.16 sec−1. Assessment of myocardial deformation requires consideration of both strain (change in deformation), which correlates with LVEF, and strain rate (speed of deformation), which correlates with rate of rise of left ventricular pressure (dP/dt). Myocardial deformation analysis also evaluates ventricular relaxation, twist, and untwist, providing new and noninvasive methods to assess components of myocardial systolic and diastolic function. Myocardial deformation analysis is based on either Doppler or a non-Doppler technique, called speckle-tracking echocardiography. Myocardial deformation analysis provides quantitative measures of global and regional myocardial function for use in the perioperative care of the surgical patient. For example, coronary graft occlusion after coronary artery bypass grafting is detected by an acute reduction in strain in the affected coronary artery territory. In addition, assessment of left ventricular mechanics detects underlying myocardial pathology before abnormalities become apparent on conventional echocardiography. Certainly, patients with aortic regurgitation demonstrate reduced longitudinal strain before reduction in LVEF occurs, which allows detection of subclinical left ventricular dysfunction and predicts increased risk for heart failure and impaired myocardial function after surgical repair. In this review we describe the principles, techniques, and clinical application of myocardial deformation analysis. PMID:24557101

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Gender differences in physical activity following acute myocardial infarction in adults: A prospective, observational study.

PubMed

Minges, Karl E; Strait, Kelly M; Owen, Neville; Dunstan, David W; Camhi, Sarah M; Lichtman, Judith; Geda, Mary; Dreyer, Rachel P; Bueno, Héctor; Beltrame, John F; Curtis, Jeptha P; Krumholz, Harlan M

2017-01-01

Aims Despite the benefits of regular physical activity participation following acute myocardial infarction, little is known about gender differences in physical activity among patients after acute myocardial infarction. We described, by gender, physical activity trajectories pre- and post-acute myocardial infarction, and determined whether gender was independently associated with physical activity. Methods and results The Variation in Recovery: Role of Gender on Outcomes of Young AMI patients (VIRGO) study, conducted at 103 US, 24 Spanish, and three Australian hospitals, was designed, in part, to evaluate gender differences in lifestyle behaviors following acute myocardial infarction. We used baseline, one-month, and 12-month data collected from patients aged 18-55 years ( n = 3572). Patients were assigned to American Heart Association-defined levels of physical activity. A generalized estimating equation model was used to account for repeated measures within the same individual over time. Men were more active (≥150 min/wk moderate or ≥75 min/wk vigorous activity) than women at baseline (42% vs 34%), one month (45% vs 34%), and 12 months (48% vs 36%) (all p < 0.0001). Men engaged in a significantly longer duration of activity at each time point. When controlling for all other factors, women had 1.37 times the odds of being less active than men from pre-acute myocardial infarction to 12-months post-acute myocardial infarction (95% confidence interval: 1.21-1.55). Non-white race, non-active workplaces, smoking, diabetes, hypertension, and obesity were also associated independently with being less active over time (all p < 0.05). Conclusions Although activity increased modestly over time, women recovering from acute myocardial infarction were less likely to meet physical activity recommendations than were men. By identifying factors associated with low levels of activity during acute myocardial infarction recovery, targeted interventions can be introduced prior to hospital discharge.

Static cardiomyoplasty with synthetic elastic net suppresses ventricular dilatation and dysfunction after myocardial infarction in the rat: a chronic study.

PubMed

Kato, Nobusuke; Kawaguchi, Akira T; Kishida, Akio; Yamaoka, Tetsuji

2013-07-01

Although static cardiomyoplasty prevents the left ventricle (LV) from dilatation, it may interfere with diastolic relaxation, or cause restriction. We developed a synthetic net with dual elasticity and tested its effect late after myocardial infarction in the rat. LV pressure-volume relationships (PVR) were successively analyzed before, after intravenous volume load, and 10 minutes after occlusion of the left anterior descending artery. Rats were then randomized into groups receiving synthetic net wrapping around the heart (NET+, n = 8) and only partially behind LV (NET-, n = 9), and they underwent the same PVR studies 6 weeks later. End-diastolic and end-systolic PVR were defined, and LV size and function were compared under standardized loading conditions. Although there was no difference in Day 0, increase in LV end-diastolic and end-systolic volumes were significantly attenuated in NET+ rats 6 weeks later when there was a significant correlation between LV volumes by PVR estimation and actual measurements, with significant differences in both measures between the groups: NET+ < NET-. The presence or absence of net did not show restrictive hemodynamics under acute volume load. Static cardiomyoplasty using a synthetic elastic net significantly attenuated LV dilatation and dysfunction without restriction late after myocardial infarction in the rat. © 2013, Copyright the Authors. Artificial Organs © 2013, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

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

PubMed

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

2013-10-15

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

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy.

PubMed

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-10-09

Insulin-like growth factor-1 (IGF-1), transforming growth factor beta (TGFbeta) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFbeta and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFbeta, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies.

Cardiac insulin-like growth factor-1 and cyclins gene expression in canine models of ischemic or overpacing cardiomyopathy

PubMed Central

Mahmoudabady, Maryam; Mathieu, Myrielle; Touihri, Karim; Hadad, Ielham; Da Costa, Agnes Mendes; Naeije, Robert; Mc Entee, Kathleen

2009-01-01

Background Insulin-like growth factor-1 (IGF-1), transforming growth factor β (TGFβ) and cyclins are thought to play a role in myocardial hypertrophic response to insults. We investigated these signaling pathways in canine models of ischemic or overpacing-induced cardiomyopathy. Methods Echocardiographic recordings and myocardial sampling for measurements of gene expressions of IGF-1, its receptor (IGF-1R), TGFβ and of cyclins A, B, D1, D2, D3 and E, were obtained in 8 dogs with a healed myocardial infarction, 8 dogs after 7 weeks of overpacing and in 7 healthy control dogs. Results Ischemic cardiomyopathy was characterized by moderate left ventricular systolic dysfunction and eccentric hypertrophy, with increased expressions of IGF-1, IGF-1R and cyclins B, D1, D3 and E. Tachycardiomyopathy was characterized by severe left ventricular systolic dysfunction and dilation with no identifiable hypertrophic response. In the latter model, only IGF-1 was overexpressed while IGF-1R, cyclins B, D1, D3 and E stayed unchanged as compared to controls. The expressions of TGFβ, cyclins A and D2 were comparable in the 3 groups. The expression of IGF-1R was correlated with the thickness of the interventricular septum, in systole and diastole, and to cyclins B, D1, D3 and E expression. Conclusion These results agree with the notion that IGF-1/IGF-1R and cyclins are involved in the hypertrophic response observed in cardiomyopathies. PMID:19818143

Continuous Cardiac Troponin I Release in Fabry Disease

PubMed Central

Schneider, Christian; Sieweke, Nicole; Franzen, Wolfgang; Gündüz, Dursun; Rolfs, Arndt

2014-01-01

Background Fabry disease (FD) is a rare lysosomal storage disorder also affecting the heart. The aims of this study were to determine the frequency of cardiac troponin I (cTNI) elevation, a sensitive parameter reflecting myocardial damage, in a smaller cohort of FD-patients, and to analyze whether persistent cTNI can be a suitable biomarker to assess cardiac dysfunction in FD. Methods cTNI values were determined at least twice per year in 14 FD-patients (6 males and 8 females) regularly followed-up in our centre. The data were related to other parameters of heart function including cardiac magnetic resonance imaging (cMRI). Results Three patients (21%) without specific vascular risk factors other than FD had persistent cTNI-elevations (range 0.05–0.71 ng/ml, normal: <0.01). cMRI disclosed late gadolinium enhancement (LGE) in all three individuals with cTNI values ≥0.01, while none of the 11 patients with cTNI <0.01 showed a pathological enhancement (p<0.01). Two subjects with increased cTNI-values underwent coronary angiography, excluding relevant stenoses. A myocardial biopsy performed in one during this procedure demonstrated substantial accumulation of globotriaosylceramide (Gb3) in cardiomyocytes. Conclusion Continuous cTNI elevation seems to occur in a substantial proportion of patients with FD. The high accordance with LGE, reflecting cardiac dysfunction, suggests that cTNI-elevation can be a useful laboratory parameter for assessing myocardial damage in FD. PMID:24626231

HIF-1α signaling activation by post-ischemia treatment with astragaloside IV attenuates myocardial ischemia-reperfusion injury.

PubMed

Si, Jingwen; Wang, Ning; Wang, Huan; Xie, Juan; Yang, Jian; Yi, Hui; Shi, Zixuan; Ma, Jing; Wang, Wen; Yang, Lifang; Yu, Shiqiang; Li, Junchang

2014-01-01

In this study, we evaluated the effect of astragaloside IV (Ast IV) post-ischemia treatment on myocardial ischemia-reperfusion (IR) injury (IRI). We also examined whether hypoxia inducible factor-1α (HIF-1α) and its downstream gene-inducible nitric oxide (NO) synthase (iNOS) play roles in the cardioprotective effect of Ast IV. Cultured cardiomyocytes and perfused isolated rat hearts were exposed to Ast IV during reperfusion in the presence or absence of the HIF-1α inhibitor 2-methoxyestradiol (2-MeOE2). The post-ischemia treatment with Ast IV protected cardiomyocytes from the apoptosis and death induced by simulated IRI (SIRI). Additionally, in cardiomyocytes, 2-MeOE2 and HIF-1α siRNA treatment each not only abolished the anti-apoptotic effect of post-ischemia treatment with Ast IV but also reversed the upregulation of HIF-1α and iNOS expression. Furthermore, after treatment with Ast IV, post-ischemic cardiac functional recovery and lactate dehydrogenase (LDH) release in the coronary flow (CF) were improved, and the myocardial infarct size was decreased. Moreover, the number of apoptotic cells was reduced, and the upregulation of the anti-apoptotic protein Bcl2 and downregulation of the pro-apoptotic protein Caspase3 were reversed. 2-MeOE2 reversed these effects of Ast IV on IR-injured hearts. These results suggest that post-ischemia treatment with Ast IV can attenuate IRI by upregulating HIF-1α expression, which transmits a survival signal to the myocardium.

Lisinopril. A review of its pharmacology and clinical efficacy in the early management of acute myocardial infarction.

PubMed

Goa, K L; Balfour, J A; Zuanetti, G

1996-10-01

Following establishment of its efficacy in hypertension and congestive heart failure, the ACE inhibitor lisinopril has now been shown to reduce mortality and cardiovascular morbidity in patients with myocardial infarction when administered as early treatment. The ability of lisinopril to attenuate the detrimental effects of left ventricular remodelling is a key mechanism; however, additional cardioprotective and vasculoprotective actions are postulated to play a role in mediating the early benefit. The GISSI-3 trial in > 19 000 patients has demonstrated that, when given orally within 24 hours of symptom onset and continued for 6 weeks, lisinopril (with or without nitrates) produces measurable survival benefits within 1 to 2 days of starting treatment. Compared with no lisinopril treatment, reductions of 11% in risk of mortality and 7.7% in a combined end-point (death plus severe left ventricular dysfunction) were evident at 6 weeks. Advantages were apparent in all types of patients. Thus, those at high risk-women, the elderly, patients with diabetes mellitus and those with anterior infarct and/or Killip class > 1 -also benefited. These gains in combined end-point events persisted in the longer term, despite treatment withdrawal after 6 weeks in most patients. At 6 months, the incidence rate for the combined end-point remained lower than with control (a 6.2% reduction). The GISSI-3 results concur with those from recent large investigations (ISIS-4, CCS-1, SMILE) of other ACE inhibitors as early management in myocardial infarction. However, the results of the CONSENSUS II trial (using intravenous enalaprilat then oral enalapril) were unfavourable in some patients. These findings, together with the development of persistent hypotension and, to a lesser extent, renal dysfunction among patients in the GISSI-3 trial, have prompted considerable debate over optimum treatment strategies. Present opinion generally holds that therapy with lisinopril or other ACE inhibitors shown to be beneficial may be started within 24 hours in haemodynamically stable patients with no other contraindications; current labelling in the US and other countries reflects this position. There is virtually unanimous agreement that such therapy is indicated in high-risk patients, particularly those with left ventricular dysfunction. The choice of ACE inhibitor appears less important than the decision to treat; it seems likely that these benefits are a class effect. Lisinopril has a tolerability profile resembling that of other ACE inhibitors, can be given once daily and may be less costly than other members of its class. However, present cost analyses are flawed and this latter points remains to be proven in formal cost-effectiveness analyses. In conclusion, early treatment with lisinopril (within 24 hours of symptom onset) for 6 weeks improves survival and reduces cardiovascular morbidity in patients with myocardial infarction, and confers ongoing benefit after drug withdrawal. While patients with symptoms of left ventricular dysfunction are prime candidates for treatment, all those who are haemodynamically stable with no other contraindications are also eligible to receive therapy. Lisinopril and other ACE inhibitors shown to be beneficial should therefore be considered an integral part of the early management of myocardial infarction in suitable patients.

Role of antioxidants in redox regulation of diabetic cardiovascular complications.

PubMed

Turan, Belma

2010-12-01

Cardiovascular dysfunction is leading cause for the mortality of diabetic individuals, in part due to a specific cardiomyopathy, and due to altered endothelial dependent/independent vascular reactivity. Cardiovascular complications result from multiple parameters including glucotoxicity, lipotoxicity, fibrosis and mitochondrial uncoupling. Oxidative stress arises from an imbalance between the production of reactive oxygen and nitrogen species (ROS and RNS) and the capability of biological system to readily detoxify reactive intermediates. Several studies have reported beneficial effects of a therapy with antioxidant agents, including trace elements and other antioxidants, against the cardiovascular system dysfunction due to the diabetes. Antioxidants act through different mechanisms to prevent oxidant-induced cell damages acting either directly or indirectly. They can reduce the generation of ROS, scavenge ROS, or interfere with ROS-induced alterations. Modulating mitochondrial activity is an important possibility to control ROS production. Hence, the use of PPARα agonist to reduce fatty acid oxidation and of trace elements such as selenium as antioxidant and other antioxidants such as vitamins E and C, contribute to the prevention of diabetes-induced cardiovascular dysfunction. The paradigm that, inhibiting the overproduction of superoxides and peroxides would prevent cardiac dysfunction in diabetes has been difficult to verify using conventional antioxidants like vitamins E and C. That led to use of catalytic antioxidants such as SOD/CAT mimetics. Hence, well-tuned, balanced and responsive antioxidant defence systems are vital for proper prevention against diabetic damage. Myocardial cell death is observed in the hearts of diabetic patients and animal models; however, its importance in the development of diabetic cardiomyopathy is not completely understood. This review aims to summarize our present knowledge on various strategies to control oxidative stress and antagonize cardiovascular dysfunction during diabetes. In here, we consider aspects of redox signaling in the cardiovascular system, focusing on the molecular basis of redox sensing by proteins and the array of post-translational oxidative modifications that can occur. In addition, we discuss studies identify redox-sensitive cardiac proteins, as well as those assessing redox signalling in cardiovascular disease.

Differential expression of myocardial heat shock proteins in rats acutely exposed to fluoride.

PubMed

Panneerselvam, Lakshmikanthan; Raghunath, Azhwar; Perumal, Ekambaram

2017-09-01

Acute fluoride (F - ) toxicity is known to cause severe cardiac complications and leads to sudden heart failure. Previously, we reported that increased myocardial oxidative damage, apoptosis, altered cytoskeleton and AMPK signaling proteins associated with energy deprivation in acute F - induced cardiac dysfunction. The present study was aimed to decipher the status of myocardial heat shock proteins (Hsps-Hsp27, Hsp32, Hsp40, Hsp60, Hsp70, Hsp90) and heat shock transcription factor 1 (Hsf1) in acute F - -intoxicated rats. In order to study the expression of myocardial Hsps, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F - for 24 h. The expression levels of myocardial Hsps were determined using RT-PCR, western blotting, and immunohistochemical studies. Acute F - -intoxicated rats showed elevated levels of both the transcripts and protein expression of Hsf1, Hsp27, Hsp32, Hsp60, and Hsp70 when compared to control. In addition, the expression levels of Hsp40 and Hsp90 were significantly declined in a dose-dependent fashion in F - -treated animals. Our result suggests that differential expression of Hsps in the rat myocardium could serve as a balance between pro-survival and death signal during acute F - -induced heart failure.

Mangiferin protect myocardial insults through modulation of MAPK/TGF-β pathways.

PubMed

Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N; Ojha, Shreesh; Kumari, Santosh; Bhatia, Jagriti; Arya, Dharamvir Singh

2016-04-05

Mangiferin, a xanthone glycoside isolated from leaves of Mangifera indica (Anacardiaceae) is known to modulate many biological targets in inflammation and oxidative stress. The present study was designed to investigate whether mangiferin exerts protection against myocardial ischemia-reperfusion (IR) injury and possible role of Mitogen Activated Protein Kinase (MAPKs) and Transforming Growth Factor-β (TGF-β) pathways in its cardioprotection. Male albino Wistar rats were treated with mangiferin (40 mg/kg, i.p.) for 15 days. At the end of the treatment protocol, rats were subjected to IR injury consisting of 45 min ischemia followed by 1h reperfusion. IR-control rats caused significant cardiac dysfunction, increased serum cardiac injury markers, lipid peroxidation and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats revealed myocardial necrosis, edema and infiltration of inflammatory cells. However, pretreatment with mangiferin significantly restored myocardial oxidant-antioxidant status, maintained membrane integrity, and attenuated the levels of proinflammatory cytokines, pro-apoptotic proteins and TGF-β. Furthermore, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. These results suggest that mangiferin protects against myocardial IR injury by modulating MAPK mediated inflammation and apoptosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.

PubMed

da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho

2015-10-01

The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.

Overexpression of Cx43 in cells of the myocardial scar: Correction of post-infarct arrhythmias through heterotypic cell-cell coupling.

PubMed

Roell, Wilhelm; Klein, Alexandra M; Breitbach, Martin; Becker, Torsten S; Parikh, Ashish; Lee, Jane; Zimmermann, Katrin; Reining, Shaun; Gabris, Beth; Ottersbach, Annika; Doran, Robert; Engelbrecht, Britta; Schiffer, Miriam; Kimura, Kenichi; Freitag, Patricia; Carls, Esther; Geisen, Caroline; Duerr, Georg D; Sasse, Philipp; Welz, Armin; Pfeifer, Alexander; Salama, Guy; Kotlikoff, Michael; Fleischmann, Bernd K

2018-05-08

Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). Biological correction of the conduction inhomogeneity that underlies re-entry could be a major advance in infarction therapy. As minimal increases in conduction of infarcted tissue markedly influence VT susceptibility, we reasoned that enhanced propagation of the electrical signal between non-excitable cells within a resolving infarct might comprise a simple means to decrease post-infarction arrhythmia risk. We therefore tested lentivirus-mediated delivery of the gap-junction protein Connexin 43 (Cx43) into acute myocardial lesions. Cx43 was expressed in (myo)fibroblasts and CD45 + cells within the scar and provided prominent and long lasting arrhythmia protection in vivo. Optical mapping of Cx43 injected hearts revealed enhanced conduction velocity within the scar, indicating Cx43-mediated electrical coupling between myocytes and (myo)fibroblasts. Thus, Cx43 gene therapy, by direct in vivo transduction of non-cardiomyocytes, comprises a simple and clinically applicable biological therapy that markedly reduces post-infarction VT.

Prognostic Value of Real Time Myocardial Contrast Echocardiography after Percutaneous Coronary Intervention.

PubMed

Yang, Lixia; Xia, Chunmei; Mu, Yuming; Guan, Lina; Wang, Chunmei; Tang, Qi; Verocai, Flavia Gomes; Fonseca, Lea Mirian Barbosa da; Shih, Ming Chi

2016-03-01

Real time myocardial contrast echocardiography (RTMCE) is a cost-effective and simple method to quantify coronary flow reserve (CFR). We aimed to determine the value of RTMCE to predict cardiac events after percutaneous coronary intervention (PCI). We have studied myocardial blood volume (A), velocity (β), flow indexes (MBF, A × β), and vasodilator reserve (stress-to-rest ratios) in 36 patients with acute coronary syndrome (ACS) who underwent PCI. CFR (MBF at stress/MBF at rest) was calculated for each patient. Perfusion scores were used for visual interpretation by MCE and correlation with TIMI flow grade. In qualitative RTMCE assessment, post-PCI visual perfusion scores were higher than pre-PCI (Z = -7.26, P < 0.01). Among 271 arteries with TIMI flow grade 3 post-PCI, 72 (36%) did not reach visual perfusion score 1. The β- and A × β-reserve of the abnormal segments supplied by obstructed arteries increased after PCI comparing to pre-PCI values (P < 0.01). Patients with adverse cardiac events had significantly lower β- and lower A × β-reserve than patients without adverse cardiac events. In the former group, the CFR was ≥ 1.5 both pre- and post-PCI. CFR estimation by RTMCE can quantify myocardial perfusion in patients with ACS who underwent PCI. The parameters β-reserve and CFR combined might predict cardiac events on the follow-up. © 2015, Wiley Periodicals, Inc.

Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes

PubMed Central

Li, Jianmin; Zhu, Huaqing; Shen, E; Wan, Li; Arnold, J. Malcolm O.; Peng, Tianqing

2010-01-01

OBJECTIVE Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes. RESEARCH DESIGN AND METHODS Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose. RESULTS In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase. CONCLUSIONS Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy. PMID:20522592

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

PubMed

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

2015-01-19

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

Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury

PubMed Central

Abarbanell, Aaron M.; Wang, Yue; Herrmann, Jeremy L.; Weil, Brent R.; Poynter, Jeffrey A.; Manukyan, Mariuxi C.

2010-01-01

Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC-mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production. PMID:20173040

Fractal analysis of the ischemic transition region in chronic ischemic heart disease using magnetic resonance imaging.

PubMed

Michallek, Florian; Dewey, Marc

2017-04-01

To introduce a novel hypothesis and method to characterise pathomechanisms underlying myocardial ischemia in chronic ischemic heart disease by local fractal analysis (FA) of the ischemic myocardial transition region in perfusion imaging. Vascular mechanisms to compensate ischemia are regulated at various vascular scales with their superimposed perfusion pattern being hypothetically self-similar. Dedicated FA software ("FraktalWandler") has been developed. Fractal dimensions during first-pass (FD first-pass ) and recirculation (FD recirculation ) are hypothesised to indicate the predominating pathomechanism and ischemic severity, respectively. Twenty-six patients with evidence of myocardial ischemia in 108 ischemic myocardial segments on magnetic resonance imaging (MRI) were analysed. The 40th and 60th percentiles of FD first-pass were used for pathomechanical classification, assigning lesions with FD first-pass  ≤ 2.335 to predominating coronary microvascular dysfunction (CMD) and ≥2.387 to predominating coronary artery disease (CAD). Optimal classification point in ROC analysis was FD first-pass  = 2.358. FD recirculation correlated moderately with per cent diameter stenosis in invasive coronary angiography in lesions classified CAD (r = 0.472, p = 0.001) but not CMD (r = 0.082, p = 0.600). The ischemic transition region may provide information on pathomechanical composition and severity of myocardial ischemia. FA of this region is feasible and may improve diagnosis compared to traditional noninvasive myocardial perfusion analysis. • A novel hypothesis and method is introduced to pathophysiologically characterise myocardial ischemia. • The ischemic transition region appears a meaningful diagnostic target in perfusion imaging. • Fractal analysis may characterise pathomechanical composition and severity of myocardial ischemia.

Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?

PubMed

Giatti, Silvia; Diviccaro, Silvia; Panzica, Giancarlo; Melcangi, Roberto Cosimo

2018-04-19

Sexual dysfunction is a clinical condition due to different causes including the iatrogenic origin. For instance, it is well known that sexual dysfunction may occur in patients treated with antidepressants like selective serotonin reuptake inhibitors (SSRI). A similar side effect has been also reported during treatment with finasteride, an inhibitor of the enzyme 5alpha-reductase, for androgenetic alopecia. Interestingly, sexual dysfunction persists in both cases after drug discontinuation. These conditions have been named post-SSRI sexual dysfunction (PSSD) and post-finasteride syndrome (PFS). In particular, feeling of a lack of connection between the brain and penis, loss of libido and sex drive, difficulty in achieving an erection and genital paresthesia have been reported by patients of both conditions. It is interesting to note that the incidence of these diseases is probably so far underestimated and their etiopathogenesis is not sufficiently explored. To this aim, the present review will report the state of art of these two different pathologies and discuss, on the basis of the role exerted by three different neuromodulators such as dopamine, serotonin and neuroactive steroids, whether the persistent sexual dysfunction observed could be determined by common mechanisms.

Effect of color coding and subtraction on the accuracy of contrast echocardiography

NASA Technical Reports Server (NTRS)

Pasquet, A.; Greenberg, N.; Brunken, R.; Thomas, J. D.; Marwick, T. H.

1999-01-01

BACKGROUND: Contrast echocardiography may be used to assess myocardial perfusion. However, gray scale assessment of myocardial contrast echocardiography (MCE) is difficult because of variations in regional backscatter intensity, difficulties in distinguishing varying shades of gray, and artifacts or attenuation. We sought to determine whether the assessment of rest myocardial perfusion by MCE could be improved with subtraction and color coding. METHODS AND RESULTS: MCE was performed in 31 patients with previous myocardial infarction with a 2nd generation agent (NC100100, Nycomed AS), using harmonic triggered or continuous imaging and gain settings were kept constant throughout the study. Digitized images were post processed by subtraction of baseline from contrast data and colorized to reflect the intensity of myocardial contrast. Gray scale MCE alone, MCE images combined with baseline and subtracted colorized images were scored independently using a 16 segment model. The presence and severity of myocardial contrast abnormalities were compared with perfusion defined by rest MIBI-SPECT. Segments that were not visualized by continuous (17%) or triggered imaging (14%) after color processing were excluded from further analysis. The specificity of gray scale MCE alone (56%) or MCE combined with baseline 2D (47%) was significantly enhanced by subtraction and color coding (76%, p<0.001) of triggered images. The accuracy of the gray scale approaches (respectively 52% and 47%) was increased to 70% (p<0.001). Similarly, for continuous images, the specificity of gray scale MCE with and without baseline comparison was 23% and 42% respectively, compared with 60% after post processing (p<0.001). The accuracy of colorized images (59%) was also significantly greater than gray scale MCE (43% and 29%, p<0.001). The sensitivity of MCE for both acquisitions was not altered by subtraction. CONCLUSION: Post-processing with subtraction and color coding significantly improves the accuracy and specificity of MCE for detection of perfusion defects.

Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial β-adrenergic system and does not compromise cardiac function.

PubMed

Vileigas, Danielle F; de Deus, Adriana F; da Silva, Danielle C T; de Tomasi, Loreta C; de Campos, Dijon H S; Adorni, Caroline S; de Oliveira, Scarlet M; Sant'Ana, Paula G; Okoshi, Katashi; Padovani, Carlos R; Cicogna, Antonio C

2016-09-01

Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial β-adrenergic (βA) system. The purpose of this study was to evaluate the cardiac function and βA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high-fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of β1- and β2-adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high-fat diet-induced obesity was not effective in triggering cardiac dysfunction and impair the beta-adrenergic signaling. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Electrotonic remodeling following myocardial infarction in dogs susceptible and resistant to sudden cardiac death.

PubMed

Del Rio, Carlos L; McConnell, Patrick I; Kukielka, Monica; Dzwonczyk, Roger; Clymer, Bradley D; Howie, Michael B; Billman, George E

2008-02-01

Passive electrical remodeling following myocardial infarction (MI) is well established. These changes can alter electrotonic loading and trigger the remodeling of repolarization currents, a potential mechanism for ventricular fibrillation (VF). However, little is known about the role of passive electrical markers as tools to identify VF susceptibility post-MI. This study investigated electrotonic remodeling in the post-MI ventricle, as measured by myocardial electrical impedance (MEI), in animals prone to and resistant to VF. MI was induced in dogs by a two-stage left anterior descending (LAD) coronary artery ligation. Before infarction, MEI electrodes were placed in remote (left circumflex, LCX) and infarcted (LAD) myocardium. MEI was measured in awake animals 1, 2, 7, and 21 days post-MI. Subsequently, VF susceptibility was tested by a 2-min LCX occlusion during exercise; 12 animals developed VF (susceptible, S) and 12 did not (resistant, R). The healing infarct had lower MEI than the normal myocardium. This difference was stable by day 2 post-MI (287 +/- 32 Omega vs. 425 +/- 62 Omega, P < 0.05). Significant differences were observed between resistant and susceptible animals 7 days post-MI; susceptible dogs had a wider electrotonic gradient between remote and infarcted myocardium (R: 89 +/- 60 Omega vs. S: 180 +/- 37 Omega). This difference increased over time in susceptible animals (252 +/- 53 Omega at 21 days) due to post-MI impedance changes on the remote myocardium. These data suggest that early electrotonic changes post-MI could be used to assess later arrhythmia susceptibility. In addition, passive-electrical changes could be a mechanism driving active-electrical remodeling post-MI, thereby facilitating the induction of arrhythmias.

Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure).

PubMed

AbouEzzeddine, Omar F; Haines, Phillip; Stevens, Susanna; Nativi-Nicolau, Jose; Felker, G Michael; Borlaug, Barry A; Chen, Horng H; Tracy, Russell P; Braunwald, Eugene; Redfield, Margaret M

2015-03-01

This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

[Psychological stress and sudden death].

PubMed

Pignalberi, Carlo; Ricci, Renato; Santini, Massimo

2002-10-01

Recent studies provide relevant evidence that psychological stress significantly influences the pathogenesis of sudden cardiac death. Psychological stress expresses a situation of imbalance, derived from a real or perceived disparity between environmental demands and the individual's ability to cope with these demands. A situation of psychological stress may include different components: personality factors and character traits, anxiety and depression, social isolation and acute or chronic adverse life events. In particular, it has been documented that a sudden extremely hard event, such as an earthquake or a war strike, can significantly increase the incidence of sudden death. Nevertheless, each one of these factors, if not present, can balance a partially unfavorable situation; this overview suggests a multifactorial situation where almost all elements are present and in which the relative influence of each one varies according to the individual examined. Sudden death occurs when a transient disruption (such as acute myocardial ischemia, platelet activation or neuroendocrine variations), occurring in a patient with a diseased myocardium (such as one with a post-necrotic scar or hypertrophy), triggers a malignant arrhythmia. Psychological stress acts at both levels: by means of a "chronic" action it contributes to create the myocardial background, while by means of an acute action it can create the transient trigger precipitating sudden death. In the chronic action two possible mechanisms can be detected: the first is a direct interaction, which contributes to cause a hypertension status or to exacerbate coronary atherosclerosis consequent to endothelial dysfunction; the second one acts through adverse health behaviors, such as a poor diet, alcohol consumption or smoking. In case of acute psychological stress, the mechanisms involved are mainly the ability to trigger myocardial ischemia, to promote arrhythmogenesis, to stimulate platelet function, and to increase blood viscosity. Finally, some individuals have a sympathetic nervous system hyper-responsitivity, manifesting as exaggerated heart rate and blood pressure responses which result in accelerated atherosclerosis.

Relation of Stature to Outcomes in Korean Patients Undergoing Primary Percutaneous Coronary Intervention for Acute ST-Elevation Myocardial Infarction (from the INTERSTELLAR Registry).

PubMed

Moon, Jeonggeun; Suh, Jon; Oh, Pyung Chun; Lee, Kyounghoon; Park, Hyun Woo; Jang, Ho-Jun; Kim, Tae-Hoon; Park, Sang-Don; Kwon, Sung Woo; Kang, Woong Chol

2016-07-15

Although epidemiologic studies have shown the impact of height on occurrence and/or prognosis of cardiovascular diseases, the underlying mechanism is unclear. In addition, the relation in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) remains unknown. We sought to assess the influence of height on outcomes of patients with acute STEMI undergoing primary PCI and to provide a pathophysiological explanation. All 1,490 patients with STEMI undergoing primary PCI were analyzed. Major adverse cardiac and cerebrovascular events (MACCE) were defined as all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned hospitalization for heart failure (HF). Patients were divided into (1) MACCE (+) versus MACCE (-) and (2) first- to third-tertile groups according to height. MACCE (+) group was shorter than MACCE (-) group (164 ± 8 vs 166 ± 8 cm, p = 0.012). Prognostic impact of short stature was significant in older (≥70 years) male patients even after adjusting for co-morbidities (hazard ratio 0.951, 95% confidence interval 0.912 to 0.991, p = 0.017). The first-tertile group showed the worst MACCE-free survival (p = 0.035), and most cases of MACCE were HF (n, 17 [3%] vs 6 [1%] vs 2 [0%], p = 0.004). On post-PCI echocardiography, left atrial volume and early diastolic mitral velocity to early diastolic mitral annulus velocity ratio showed an inverse relation with height (p <0.001 for all) despite similar left ventricular ejection fraction. In conclusion, short stature is associated with occurrence of HF after primary PCI for STEMI, and its influence is prominent in aged male patients presumably for its correlation with diastolic dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Duration of Untreated Cardiac Arrest and Clinical Relevance of Animal Experiments: The Relationship Between the "No-Flow" Duration and the Severity of Post-Cardiac Arrest Syndrome in a Porcine Model.

PubMed

Babini, Giovanni; Grassi, Luigi; Russo, Ilaria; Novelli, Deborah; Boccardo, Antonio; Luciani, Anita; Fumagalli, Francesca; Staszewsky, Lidia; Fiordaliso, Fabio; De Maglie, Marcella; Salio, Monica; Zani, Davide D; Letizia, Teresa; Masson, Serge; Luini, Mario V; Pravettoni, Davide; Scanziani, Eugenio; Latini, Roberto; Ristagno, Giuseppe

2018-02-01

The study investigated the effect of untreated cardiac arrest (CA), that is, "no-flow" time, on postresuscitation myocardial and neurological injury, and survival in a pig model to identify an optimal duration that adequately reflects the most frequent clinical scenario. An established model of myocardial infarction followed by CA and cardiopulmonary resuscitation was used. Twenty-two pigs were subjected to three no-flow durations: short (8-10 min), intermediate (12-13 min), and long (14-15 min). Left ventricular ejection fraction (LVEF) was assessed together with thermodilution cardiac output (CO) and high sensitivity cardiac troponin T (hs-cTnT). Neurological impairment was evaluated by neurological scores, serum neuron specific enolase (NSE), and histopathology. More than 60% of animals survived when the duration of CA was ≤13 min, compared to only 20% for a duration ≥14 min. Neuronal degeneration and neurological scores showed a trend toward a worse recovery for longer no-flow durations. No animals achieved a good neurological recovery for a no-flow ≥14 min, in comparison to a 56% for a duration ≤13 min (P = 0.043). Serum NSE levels significantly correlated with the no-flow duration (r = 0.892). Longer durations of CA were characterized by lower LVEF and CO compared to shorter durations (P < 0.05). The longer was the no-flow time, the higher was the number of defibrillations delivered (P = 0.043). The defibrillations delivered significantly correlated with LVEF and plasma hs-cTnT. Longer no-flow durations caused greater postresuscitation myocardial and neurological dysfunction and reduced survival. An untreated CA of 12-13 min may be an optimal choice for a clinically relevant model.

AMPKα2 regulates expression of estrogen-related receptor alpha, a metabolic transcription factor related to heart failure development

PubMed Central

Hu, Xinli; Xu, Xin; Lu, Zhongbing; Zhang, Ping; Fassett, John; Zhang, Ying; Xin, Yi; Hall, Jennifer L.; Viollet, Benoit; Bache, Robert J.; Huang, Yimin; Chen, Yingjie

2011-01-01

The normal expression of myocardial mitochondrial enzymes is essential to maintain the cardiac energy reserve and facilitate responses to stress, but the molecular mechanisms to maintain myocardial mitochondrial enzyme expression have been elusive. Here we report that congestive heart failure is associated with a significant decrease of myocardial Estrogen-Related Receptor alpha (ERRα), but not PPAR gamma coactivator-1 alpha (PGC1α), in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRα expression that was significantly correlated to the degree of LV dysfunction, pulmonary congestion and decreases of a group of myocardial energy metabolism related genes. We found that the metabolic sensor AMP activated protein kinase (AMPK) regulates ERRα expression in vivo and in vitro. AMPKα2 KO decreased myocardial ERRα (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial PGC1α expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKα significantly induced ERRα mRNA, protein and promoter activity. Conversely, selective gene silencing of AMPKα2 repressed ERRα and its target gene levels, indicating that AMPKα2 is involved in the regulation of ERRα expression. In addition, over-expression of ERRα in AMPKα2 KO neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism related genes. These data support an important role for AMPKα2 in regulating the expression of myocardial ERRα and its downstream mitochondrial enzymes. PMID:21825219

Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats

PubMed Central

Cai, Zhaobin; Shi, Tingting; Zhuang, Rangxiao; Fang, Hongying; Jiang, Xiaojie; Shao, Yidan; Zhou, Hongping

2018-01-01

With the development of science and technology, and development of artery bypass, methods such as cardiopulmonary cerebral resuscitation have been practiced in recent years. Despite this, some methods fail to promote or recover the function of tissues and organs, and in some cases, may aggravate dysfunction and structural damage to tissues. The latter is typical of ischemia-reperfusion (IR) injury. Lipid peroxidation mediated by free radicals is an important process of myocardial IR injury. Myocardial IR has been demonstrated to induce the formation of large numbers of free radicals in rats, which promotes the peroxidation of lipids within unsaturated fatty acids in the myocardial cell membrane. Markers of lipid peroxidation include malondialdehyde, superoxide dismutase and lactic dehydrogenase. Recent studies have demonstrated that N-acetylcysteine (NAC) is able to dilate blood vessels, prevent oxidative damage, improve immunity, inhibit apoptosis and the inflammatory response and promote glutathione synthesis in cells. NAC also improves the systolic function of myocardial cells and cardiac function, prevents myocardial apoptosis, protects ventricular remodeling and vascular remodeling, reduces opiomelanocortin levels in the serum and increases the content of nitric oxide in the serum, thus improving vascular endothelial function. Therefore, NAC has potent pharmacological activity; however, the relatively fast metabolism of NAC, along with its large clinical dose and low bioavailability, limit its applications. The present study combined NAC with medicinal activated carbons, and prepared N-acetylcysteine activated carbon sustained-release microcapsules (ACNACs) to overcome the limitations of NAC. It was demonstrated that ACNACs exerted greater effective protective effects than NAC alone on myocardial IR injury in rats. PMID:29434769

Mitochondrial JNK activation triggers autophagy and apoptosis and aggravates myocardial injury following ischemia/reperfusion.

PubMed

Xu, Jie; Qin, Xinghua; Cai, Xiaoqing; Yang, Lu; Xing, Yuan; Li, Jun; Zhang, Lihua; Tang, Ying; Liu, Jiankang; Zhang, Xing; Gao, Feng

2015-02-01

c-Jun N-terminal kinase (JNK) is a stress-activated mitogen-activated protein kinase that plays a central role in initiating apoptosis in disease conditions. Recent studies have shown that mitochondrial JNK signaling is partly responsible for ischemic myocardial dysfunction; however, the underlying mechanism remains unclear. Here we report for the first time that activation of mitochondrial JNK, rather than JNK localization on mitochondria, induces autophagy and apoptosis and aggravates myocardial ischemia/reperfusion injury. Myocardial ischemia/reperfusion induced a dominant increase of mitochondrial JNK phosphorylation, while JNK mitochondrial localization was reduced. Treatment with Tat-SabKIM1, a retro-inverso peptide which blocks JNK interaction with mitochondria, decreased mitochondrial JNK activation without affecting JNK mitochondrial localization following reperfusion. Tat-SabKIM1 treatment reduced Bcl2-regulated autophagy, cytochrome c-mediated apoptosis and myocardial infarct size. Notably, selective inhibition of mitochondrial JNK activation using Tat-SabKIM1 produced a similar infarct size-reducing effect as inhibiting universal JNK activation with JNK inhibitor SP600125. Moreover, insulin-treated animals exhibited significantly dampened mitochondrial JNK activation accompanied by reduced infarct size and diminished autophagy and apoptosis following reperfusion. Taken together, these findings demonstrate that mitochondrial JNK activation, rather than JNK mitochondrial localization, induces autophagy and apoptosis and exacerbates myocardial ischemia/reperfusion injury. Insulin selectively inhibits mitochondrial JNK activation, contributing to insulin cardioprotection against myocardial ischemic/reperfusion injury. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

Low-dose adenosine stress echocardiography: detection of myocardial viability.

PubMed

Djordjevic-Dikic, Ana; Ostojic, Miodrag; Beleslin, Branko; Nedeljkovic, Ivana; Stepanovic, Jelena; Stojkovic, Sinisa; Petrasinovic, Zorica; Nedeljkovic, Milan; Saponjski, Jovica; Giga, Vojislav

2003-06-03

The aim of this study was to evaluate the diagnostic potential of low-dose adenosine stress echocardiography in detection of myocardial viability. Vasodilation through low dose dipyridamole infusion may recruit contractile reserve by increasing coronary flow or by increasing levels of endogenous adenosine. Forty-three patients with resting dyssynergy, due to previous myocardial infarction, underwent low-dose adenosine (80, 100, 110 mcg/kg/min in 3 minutes intervals) echocardiography test. Gold standard for myocardial viability was improvement in systolic thickening of dyssinergic segments of >or= 1 grade at follow-up. Coronary angiography was done in 41 pts. Twenty-seven patients were revascularized and 16 were medically treated. Echocardiographic follow up data (12 +/- 2 months) were available in 24 revascularized patients. Wall motion score index improved from rest 1.55 +/- 0.30 to 1.33 +/- 0.26 at low-dose adenosine (p < 0.001). Of the 257 segments with baseline dyssynergy, adenosine echocardiography identified 122 segments as positive for viability, and 135 as necrotic since no improvement of systolic thickening was observed. Follow-up wall motion score index was 1.31 +/- 0.30 (p < 0.001 vs. rest). The sensitivity of adenosine echo test for identification of viable segments was 87%, while specificity was 95%, and diagnostic accuracy 90%. Positive and negative predictive values were 97% and 80%, respectively. Low-dose adenosine stress echocardiography test has high diagnostic potential for detection of myocardial viability in the group of patients with left ventricle dysfunction due to previous myocardial infarction. Low dose adenosine stress echocardiography may be adequate alternative to low-dose dobutamine test for evaluation of myocardial viability.

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

PubMed Central

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

2012-01-01

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

[The theory of cardiac lesions from blunt chest injury].

PubMed

Tumanov, E V; Sokolova, Z Iu

2010-01-01

The main theories of myocardial lesions associated with a blunt chest injury proposed starting from the XIXth century till the present time are considered based on the overview of the literature data. It is shown that the theory of selective mechanical activation of ATP-dependent K+ channels is most promising for further investigations into the mechanisms of myocardial dysfunction resulting from blunt chest injuries. The authors emphasize the absence of the universally accepted theory explaining the mechanism behind traumatic cardiac troubles and its fatal outcome despite numerous studies of cardiac lesions in patients with a blunt chest injury. It dictates the necessity of further research, both clinical and experimental, for a deeper insight into the problem.

Multiple cardiac complications after adjuvant therapy for breast cancer: the importance of echocardiography. A case report and review of the literature.

PubMed

Gurghean, Adriana Luminita; Savulescu-Fiedler, Ilinca; Mihailescu, Anca

2017-01-31

Cardiovascular complications induced by adjuvant cancer therapies may become symptomatic after many years, being responsible for increased morbidity and mortality in long-term survivors. We report a case of a 54-year old female admitted for severe heart failure induced by myocardial and valvular damage after postoperative adjuvant therapy for left breast cancer 6 years ago. Her recent history revealed nonST elevation myocardial infarction in the absence of significant cardiovascular risk factors. Transthoracic echocardiography, tissue Doppler imaging and speckle-tracking imaging revealed severe biventricular systolic dysfunction, severe mitral and tricuspid regurgitation and severe pulmonary hypertension.

Quantitation of stress echocardiography by tissue Doppler and strain rate imaging: a dream come true?

PubMed

Galderisi, Maurizio; Mele, Donato; Marino, Paolo Nicola

2005-01-01

Tissue Doppler (TD) is an ultrasound tool providing a quantitative agreement of left ventricular regional myocardial function in different modalities. Spectral pulsed wave (PW) TD, performed online during the examination, measures instantaneous myocardial velocities. By means of color TD, velocity images are digitally stored for subsequent off-line analysis and mean myocardial velocities are measured. An implementation of color TD includes strain rate imaging (SRI), based on post-processing conversion of regional velocities in local myocardial deformation rate (strain rate) and percent deformation (strain). These three modalities have been applied to stress echocardiography for quantitative evaluation of regional left ventricular function and detection of ischemia and viability. They present advantages and limitations. PWTD does not permit the simultaneous assessment of multiple walls and therefore is not compatible with clinical stress echocardiography while it could be used in a laboratory setting. Color TD provides a spatial map of velocity throughout the myocardium but its results are strongly affected by the frame rate. Both color TD and PWTD are also influenced by overall cardiac motion and tethering from adjacent segments and require reference velocity values for interpretation of regional left ventricular function. High frame rate (i.e. > 150 ms) post-processing-derived SRI can potentially overcome these limitations, since measurements of myocardial deformation have not any significant apex-to-base gradient. Preliminary studies have shown encouraging results about the ability of SRI to detect ischemia and viability, in terms of both strain rate changes and/or evidence of post-systolic thickening. SRI is, however, Doppler-dependent and time-consuming. Further technical refinements are needed to improve its application and introduce new ultrasound modalities to overcome the limitations of the Doppler-derived deformation analysis.

Identification of Temporal and Region-Specific Myocardial Gene Expression Patterns in Response to Infarction in Swine

PubMed Central

Nonell, Lara; Puigdecanet, Eulàlia; Astier, Laura; Solé, Francesc; Bayes-Genis, Antoni

2013-01-01

Molecular mechanisms associated with pathophysiological changes in ventricular remodelling due to myocardial infarction (MI) remain poorly understood. We analyzed changes in gene expression by microarray technology in porcine myocardial tissue at 1, 4, and 6 weeks post-MI. MI was induced by coronary artery ligation in 9 female pigs (30–40 kg). Animals were randomly sacrificed at 1, 4, or 6 weeks post-MI (n = 3 per group) and 3 healthy animals were also included as control group. Total RNA from myocardial samples was hybridized to GeneChip® Porcine Genome Arrays. Functional analysis was obtained with the Ingenuity Pathway Analysis (IPA) online tool. Validation of microarray data was performed by quantitative real-time PCR (qRT-PCR). More than 8,000 different probe sets showed altered expression in the remodelling myocardium at 1, 4, or 6 weeks post-MI. Ninety-seven percent of altered transcripts were detected in the infarct core and 255 probe sets were differentially expressed in the remote myocardium. Functional analysis revealed 28 genes de-regulated in the remote myocardial region in at least one of the three temporal analyzed stages, including genes associated with heart failure (HF), systemic sclerosis and coronary artery disease. In the infarct core tissue, eight major time-dependent gene expression patterns were recognized among 4,221 probe sets commonly altered over time. Altered gene expression of ACVR2B, BID, BMP2, BMPR1A, LMNA, NFKBIA, SMAD1, TGFB3, TNFRSF1A, and TP53 were further validated. The clustering of similar expression patterns for gene products with related function revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes at different stages after MI. PMID:23372767

Modulation of Myocardial Mitochondrial Mechanisms during Severe Polymicrobial Sepsis in the Rat

PubMed Central

Chopra, Mani; Golden, Honey B.; Mullapudi, Srinivas; Dowhan, William; Dostal, David E.; Sharma, Avadhesh C.

2011-01-01

Background We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoKATP channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Methodology/Principal Findings Male Sprague-Dawley rats (350–400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (−40%) and at 6 hr post-sepsis (−20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. Conclusion The data suggest that Bax activation is an upstream event that may precede the opening of the mitoKATP channels in sepsis. We concluded that mitoKATP channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction. PMID:21712982

Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.

PubMed

Chopra, Mani; Golden, Honey B; Mullapudi, Srinivas; Dowhan, William; Dostal, David E; Sharma, Avadhesh C

2011-01-01

We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.

Predictive value of myocardial perfusion single-photon emission computed tomography and the impact of renal function on cardiac death.

PubMed

Hakeem, Abdul; Bhatti, Sabha; Dillie, Kathryn Sullivan; Cook, Jeffrey R; Samad, Zainab; Roth-Cline, Michelle D; Chang, Su Min

2008-12-09

Patients with chronic kidney disease (CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT (MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated. We followed up 1652 consecutive patients who underwent stress MPS (32% exercise, 95% gated) for cardiac death for a mean of 2.15+/-0.8 years. MPS defects were defined with a summed stress score (normal summed stress score <4, abnormal summed stress score>or=4). Ischemia was defined as a summed stress score >or=4 plus a summed difference score >or=2, and scar was defined as a summed difference score <2 plus a summed stress score >or=4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD (estimated glomerular filtration rate <60 mL . min(-1) . 1.73 m(-2)) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS (2.7% versus 0.8%, P=0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects (hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD (hazard ratio 1.96, 95% CI 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction (global chi(2) 207.5 versus 169.3, P<0.0001). MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan.

CaMKII determines mitochondrial stress responses in heart

PubMed Central

Joiner, Mei-ling A.; Koval, Olha M.; Jingdong, Li; He, B. Julie; Allamargot, Chantal; Gao, Zhan; Luczak, Elizabeth D.; Hall, Duane D.; Fink, Brian D.; Chen, Biyi; Yang, Jinying; Moore, Steven A.; Scholz, Thomas D.; Strack, Stefan; Mohler, Peter J.; Sivitz, William I.; Song, Long-Sheng; Anderson, Mark E.

2012-01-01

Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress. PMID:23051746

Myocardial Oxidative Stress in Infants Undergoing Cardiac Surgery.

PubMed

Sznycer-Taub, Nathaniel; Mackie, Stewart; Peng, Yun-Wen; Donohue, Janet; Yu, Sunkyung; Aiyagari, Ranjit; Charpie, John

2016-04-01

Cardiac surgery for congenital heart disease often necessitates a period of myocardial ischemia during cardiopulmonary bypass and cardioplegic arrest, followed by reperfusion after aortic cross-clamp removal. In experimental models, myocardial ischemia-reperfusion is associated with significant oxidative stress and ventricular dysfunction. A prospective observational study was conducted in infants (<1 year) who underwent elective surgical repair of a ventricular septal defect (VSD) or tetralogy of Fallot (TOF). Blood samples were drawn following anesthetic induction (baseline) and directly from the coronary sinus at 1, 3, 5, and 10 min following aortic cross-clamp removal. Samples were analyzed for oxidant stress using assays for thiobarbituric acid-reactive substances, protein carbonyl, 8-isoprostane, and total antioxidant capacity. For each subject, raw assay data were normalized to individual baseline samples and expressed as fold-change from baseline. Results were compared using a one-sample t test with Bonferroni correction for multiple comparisons. Sixteen patients (ten with TOF and six with VSD) were enrolled in the study, and there were no major postoperative complications observed. For the entire cohort, there was an immediate, rapid increase in myocardial oxidative stress that was sustained for 10 min following aortic cross-clamp removal in all biomarker assays (all P < 0.01), except total antioxidant capacity. Infant cardiac surgery is associated with a rapid, robust, and time-dependent increase in myocardial oxidant stress as measured from the coronary sinus in vivo. Future studies with larger enrollment are necessary to assess any association between myocardial oxidative stress and early postoperative outcomes.

The Impact of Timing and Graft Dysfunction on Survival and Cardiac Allograft Vasculopathy in Antibody Mediated Rejection

PubMed Central

Clerkin, Kevin J.; Restaino, Susan W.; Zorn, Emmanuel; Vasilescu, Elena R.; Marboe, Charles C.; Mancini, Donna M.

2017-01-01

Background Antibody mediated rejection (AMR) has been associated with increased mortality and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction while recent reports have demonstrated an association with increased mortality. We sought to investigate the timing of AMR and its association with graft dysfunction, mortality, and CAV. Methods This retrospective cohort study identified all adult heart transplant recipients at Columbia University Medical Center from 2004–2013 (689 patients). There were 68 primary cases of AMR, which were stratified by early (<1 year post-OHT) or late (>1-year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. Results From January 1, 2004 through October 1, 2015 43 patients had early AMR (median 23 days post-OHT) and 25 had late AMR (median 1084 days post-OHT). Graft dysfunction was less common with early compared with late AMR (25.6% vs. 56%, p=0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1-year 80% vs. 93%, 5-year 51% vs. 73%, p<0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30-day 79%, 1-year 64%, and 5-year 36%, p<0.006). The association remained irrespective of age, sex, DSA, LVAD use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de-novo CAV (50% at 1 year, HR 5.42, p=0.009), while all other groups were all similar to the general transplant population. Conclusion Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR there is an early and sustained increased risk of mortality and rapid development of de-novo CAV despite aggressive treatment. PMID:27423693

Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling.

PubMed

Tourki, Bochra; Halade, Ganesh

2017-10-01

In response to myocardial infarction (MI), time-dependent leukocyte infiltration is critical to program the acute inflammatory response. Post-MI leukocyte density, residence time in the infarcted area, and exit from the infarcted injury predict resolving or nonresolving inflammation. Overactive or unresolved inflammation is the primary determinant in heart failure pathology post-MI. Here, our review describes supporting evidence that the acute inflammatory response also guides the generation of healing and regenerative mediators after cardiac damage. Time-dependent leukocyte density and diversity and the magnitude of myocardial injury is responsible for the resolving and nonresolving pathway in myocardial healing. Post MI, the diversity of leukocytes, such as neutrophils, macrophages, and lymphocytes, has been explored that regulate the clearance of deceased cardiomyocytes by using the classic and reparative pathways. Among the innovative factors and intermediates that have been recognized as essential in acute the self-healing and clearance mechanism, we highlight specialized proresolving mediators as the emerging factor for post-MI reparative mechanisms-translational leukocyte modifiers, such as aging, the source of leukocytes, and the milieu around the leukocytes. In the clinical setting, it is possible that leukocyte diversity is more prominent as a result of risk factors, such as obesity, diabetes, and hypertension. Pharmacologic agents are critical modifiers of leukocyte diversity in healing mechanisms that may impair or stimulate the clearance mechanism. Future research is needed, with a focused approach to understand the molecular targets, cellular effectors, and receptors. A clear understanding of resolving and nonresolving inflammation in myocardial healing will help to develop novel targets with major emphasis on the resolution of inflammation in heart failure pathology.-Tourki, B., Halade, G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. © FASEB.

MG53 participates in ischaemic postconditioning through the RISK signalling pathway

PubMed Central

Zhang, Yan; Lv, Fengxiang; Jin, Li; Peng, Wei; Song, Ruisheng; Ma, Jianjie; Cao, Chun-Mei; Xiao, Rui-Ping

2011-01-01

Aims Recent studies show that ischaemic postconditioning (PostC), similar to the well-established ischaemic preconditioning (IPC), confers cardioprotection against ischaemia/reperfusion (IR) injury, and both IPC and PostC can activate the reperfusion injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) pathway. PostC is clinically more attractive because of its therapeutic application at the predictable onset of reperfusion. Our previous studies have demonstrated that MG53 is a primary component of the IPC machinery. Here, we investigated the potential role of MG53 in PostC-mediated myocardial protection and explored the underlying mechanism. Methods and results Using Langendorff perfusion, we investigated IR injury in wild-type (wt) and MG53-deficient (mg53−/−) mouse hearts with or without PostC. IR-induced myocardial damage was markedly exacerbated in mg53−/− hearts compared with wt controls. PostC protected wt hearts against IR-induced myocardial infarction, myocyte necrosis, and apoptosis, but failed to protect mg53−/− hearts. The loss of PostC protection in mg53−/− hearts was attributed to selectively impaired PostC-activated RISK signalling. Mechanistically, MG53 is required for the interaction between caveolin 3 (CaV3) and the p85 subunit of phosphoinositide 3-kinase (p85-PI3K) and PostC-mediated activation of the RISK pathway. Importantly, a structure–function study revealed that the MG53 tripartite motif (TRIM) domain (aa1–284) physically interacted with CaV3 but not p85-PI3K, whereas the MG53 SPRY domain (aa285–477) interacted with p85-PI3K but not CaV3, indicating that MG53 binds to CaV3 and p85 at its N- and C-terminus, respectively. Conclusions We conclude that MG53 participates in PostC-mediated cardioprotection largely through tethering CaV3 and PI3K and subsequent activation of the RISK pathway. PMID:21285295

Tako-tsubo-like syndrome, a case report.

PubMed

Patanè, Salvatore; Marte, Filippo

2008-02-29

Tako-tsubo-like (Japanese word for octopus-catcher) left ventricular dysfunction is an enigmatic cardiomyopathy. Typically, the patients have a history of recent stressful incidents immediately preceding onset of mild to moderate chest pain, have ST-segment elevation in leads V3 through V6, ECG changes that typically demonstrate diffuse T-wave inversions and abnormal QS-wave development, discrete wall motion abnormalities involving the lower anterior wall and apex on echocardiography or left ventriculography, and limited myocardial enzyme release without evidence for hemodynamically significant coronary arterial stenoses by angiography. We describe a case of a Tako-tsubo-like left ventricular dysfunction in a 72-year-old female Italian woman.

Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.

PubMed

Chandra, Mini; Escalante-Alcalde, Diana; Bhuiyan, Md Shenuarin; Orr, Anthony Wayne; Kevil, Christopher; Morris, Andrew J; Nam, Hyung; Dominic, Paari; McCarthy, Kevin J; Miriyala, Sumitra; Panchatcharam, Manikandan

2018-04-01

Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of Incretin-Based Therapies on Neuro-Cardiovascular Dynamic Changes Induced by High Fat Diet in Rats.

PubMed

Marques-Neto, Silvio Rodrigues; Castiglione, Raquel Carvalho; Pontes, Aiza; Oliveira, Dahienne Ferreira; Ferraz, Emanuelle Baptista; Nascimento, José Hamilton Matheus; Bouskela, Eliete

2016-01-01

Obesity promotes cardiac and cerebral microcirculatory dysfunction that could be improved by incretin-based therapies. However, the effects of this class of compounds on neuro-cardiovascular system damage induced by high fat diet remain unclear. The aim of this study was to investigate the effects of incretin-based therapies on neuro-cardiovascular dysfunction induced by high fat diet in Wistar rats. We have evaluated fasting glucose levels and insulin resistance, heart rate variability quantified on time and frequency domains, cerebral microcirculation by intravital microscopy, mean arterial blood pressure, ventricular function and mitochondrial swelling. High fat diet worsened biometric and metabolic parameters and promoted deleterious effects on autonomic, myocardial and haemodynamic parameters, decreased capillary diameters and increased functional capillary density in the brain. Biometric and metabolic parameters were better improved by glucagon like peptide-1 (GLP-1) compared with dipeptdyl peptidase-4 (DPP-4) inhibitor. On the other hand, both GLP-1 agonist and DPP-4 inhibitor reversed the deleterious effects of high fat diet on autonomic, myocardial, haemodynamic and cerebral microvascular parameters. GLP-1 agonist and DPP-4 inhibitor therapy also increased mitochondrial permeability transition pore resistance in brain and heart tissues of rats subjected to high fat diet. Incretin-based therapies improve deleterious cardiovascular effects induced by high fat diet and may have important contributions on the interplay between neuro-cardiovascular dynamic controls through mitochondrial dysfunction associated to metabolic disorders.

Future Perspectives for Management of Stage A Heart Failure.

PubMed

Tanaka, Hidekazu

2018-05-07

Patients with Stage A heart failure (HF) show no HF symptoms but have related comorbid diseases with a high risk of progressing to HF. Screening for comorbid diseases warrants closer attention because of the growing interest in addressing Stage A HF as the best means of preventing eventual progression to overt HF such as Stages C and D. The identification of individuals of Stage A HF is potentially useful for the implementation of HF-prevention strategies; however, not all Stage A HF patients develop left ventricular (LV) structural heart disease or symptomatic HF, which lead to advanced HF stages. Therefore, Stage A HF requires management with the long-term goal of avoiding HF development; likewise, Stage B HF patients are ideal targets for HF prevention. Although the early detection of subclinical LV dysfunction is, thus, essential for delaying the progression to HF, the assessment of subclinical LV dysfunction can be challenging. Global longitudinal strain (GLS) as assessed by speckle-tracking echocardiography has recently been reported to be a sensitive marker of early subtle LV myocardial abnormalities, helpful for the prediction of the outcomes for various cardiac diseases, and superior to conventional echocardiographic indices. GLS reflects LV longitudinal myocardial systolic function, and can be assessed usually by means of two-dimensional speckle-tracking. This article reviews the importance of the assessment of subclinical LV dysfunction in Stage A HF patients by means of GLS, and its current potential to prevent progression to later stage HF.

Quantification of coronary flow reserve in patients with ischaemic and non-ischaemic cardiomyopathy and its association with clinical outcomes.

PubMed

Majmudar, Maulik D; Murthy, Venkatesh L; Shah, Ravi V; Kolli, Swathy; Mousavi, Negareh; Foster, Courtney R; Hainer, Jon; Blankstein, Ron; Dorbala, Sharmila; Sitek, Arkadiusz; Stevenson, Lynne W; Mehra, Mandeep R; Di Carli, Marcelo F

2015-08-01

Patients with left ventricular systolic dysfunction frequently show abnormal coronary vascular function, even in the absence of overt coronary artery disease. Moreover, the severity of vascular dysfunction might be related to the aetiology of cardiomyopathy.We sought to determine the incremental value of assessing coronary vascular dysfunction among patients with ischaemic (ICM) and non-ischaemic (NICM) cardiomyopathy at risk for adverse cardiovascular outcomes. Coronary flow reserve (CFR, stress/rest myocardial blood flow) was quantified in 510 consecutive patients with rest left ventricular ejection fraction (LVEF) ≤45% referred for rest/stress myocardial perfusion PET imaging. The primary end point was a composite of major adverse cardiovascular events (MACE) including cardiac death, heart failure hospitalization, late revascularization, and aborted sudden cardiac death.Median follow-up was 8.2 months. Cox proportional hazards model was used to adjust for clinical variables. The annualized MACE rate was 26.3%. Patients in the lowest two tertiles of CFR (CFR ≤ 1.65) experienced higher MACE rates than those in the highest tertile (32.6 vs. 15.5% per year, respectively, P = 0.004), irrespective of aetiology of cardiomyopathy. Impaired coronary vascular function, as assessed by reduced CFR by PET imaging, is common in patients with both ischaemic and non-ischaemic cardiomyopathy and is associated with MACE. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase and nuclear factor-κB signaling pathways.

PubMed

Wang, Lixin; Ma, Hao; Xue, Yan; Shi, Haiyan; Ma, Teng; Cui, Xiaozheng

2018-02-01

Myocardial ischemia-reperfusion injury is one of the most common cardiovascular diseases, and can lead to serious damage and dysfunction of the myocardial tissue. Previous studies have demonstrated that berberine exhibits ameliorative effects on cardiovascular disease. The present study further investigated the efficacy and potential mechanism underlying the effects of berberine on ischemia-reperfusion injury in a mouse model. Inflammatory markers were measured in the serum and levels of inflammatory proteins in myocardial cells were investigated after treatment with berberine. In addition, the apoptosis of myocardial cells was investigated after berberine treatment. Apoptosis-associated gene expression levels and apoptotic signaling pathways were analyzed in myocardial cells after treatment with berberine. The phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) and nuclear factor (NF)-κB signaling pathways were also analyzed in myocardial cells after treatment with berberine. Histological analysis was used to analyze the potential benefits of berberine in ischemia-reperfusion injury. The present study identified that inflammatory responses and inflammatory factors were decreased in the myocardial cells of the mouse model of ischemia-reperfusion injury. Mechanism analysis demonstrated that berberine inhibited apoptotic protease-activating factor 1, caspase-3 and caspase-9 expression in myocardial cells. The expression of Bcl2-associated agonist of cell death, Bcl-2-like protein 1 and cellular tumor antigen p53 was upregulated. Expression of NF-κB p65, inhibitor of NF-κB kinase subunit β (IKK-β), NF-κB inhibitor α (IκBα), and NF-κB activity, were inhibited in myocardial cells in the mouse model of ischemia-reperfusion injury. In conclusion, the results of the present study indicate that berberine inhibits inflammatory responses through the NF-κB signaling pathway and suppresses the apoptosis of myocardial cells via the PI3K/AKT signaling pathway in a mouse model of ischemia-reperfusion injury. These results suggest that berberine is a potential drug for the treatment of patients with ischemia-reperfusion injury.

Berberine inhibits the ischemia-reperfusion injury induced inflammatory response and apoptosis of myocardial cells through the phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase and nuclear factor-κB signaling pathways

PubMed Central

Wang, Lixin; Ma, Hao; Xue, Yan; Shi, Haiyan; Ma, Teng; Cui, Xiaozheng

2018-01-01

Myocardial ischemia-reperfusion injury is one of the most common cardiovascular diseases, and can lead to serious damage and dysfunction of the myocardial tissue. Previous studies have demonstrated that berberine exhibits ameliorative effects on cardiovascular disease. The present study further investigated the efficacy and potential mechanism underlying the effects of berberine on ischemia-reperfusion injury in a mouse model. Inflammatory markers were measured in the serum and levels of inflammatory proteins in myocardial cells were investigated after treatment with berberine. In addition, the apoptosis of myocardial cells was investigated after berberine treatment. Apoptosis-associated gene expression levels and apoptotic signaling pathways were analyzed in myocardial cells after treatment with berberine. The phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) and nuclear factor (NF)-κB signaling pathways were also analyzed in myocardial cells after treatment with berberine. Histological analysis was used to analyze the potential benefits of berberine in ischemia-reperfusion injury. The present study identified that inflammatory responses and inflammatory factors were decreased in the myocardial cells of the mouse model of ischemia-reperfusion injury. Mechanism analysis demonstrated that berberine inhibited apoptotic protease-activating factor 1, caspase-3 and caspase-9 expression in myocardial cells. The expression of Bcl2-associated agonist of cell death, Bcl-2-like protein 1 and cellular tumor antigen p53 was upregulated. Expression of NF-κB p65, inhibitor of NF-κB kinase subunit β (IKK-β), NF-κB inhibitor α (IκBα), and NF-κB activity, were inhibited in myocardial cells in the mouse model of ischemia-reperfusion injury. In conclusion, the results of the present study indicate that berberine inhibits inflammatory responses through the NF-κB signaling pathway and suppresses the apoptosis of myocardial cells via the PI3K/AKT signaling pathway in a mouse model of ischemia-reperfusion injury. These results suggest that berberine is a potential drug for the treatment of patients with ischemia-reperfusion injury. PMID:29403554

Methanolic seed extract of Vitis vinifera ameliorates oxidative stress, inflammation and ATPase dysfunction in infarcted and non-infarcted heart of streptozotocin-nicotinamide induced male diabetic rats.

PubMed

Giribabu, Nelli; Roslan, Josef; Rekha, Somesula Swapna; Salleh, Naguib

2016-11-01

We hypothesized that consumption of Vitis vinifera seed by diabetics could help to ameliorate myocardial damage. Therefore, in this study, we investigated effects of V. vinifera seed methanolic extract (VVSME) on parameters related to myocardial damage in diabetes with or without myocardial infarction (MI). Streptozotocin-nicotinamide induced diabetic rats received oral VVSME for 28days. MI was induced by intraperitoneal injection of isoproterenol on last two days. Prior to sacrifice, blood was collected and fasting blood glucose (FBG), glycated hemoglobin (HbA1c), lipid profile and insulin levels were measured. Levels of serum cardiac injury marker (troponin-I and CK-MB) were determined and histopathological changes in the heart were observed following harvesting. Levels of oxidative stress (LPO, SOD, CAT, GPx and RAGE), inflammation (NF-κB, TNF-α, IL-1β and IL-6) and cardiac ATPases (Na(+)/K(+)-ATPase and Ca(2+)-ATPase) were determined in heart homogenates. LC-MS was used to identify constituents in the extracts. Consumption of VVSME by diabetic rats with or without MI improved the metabolic profiles while decreased the cardiac injury marker levels with lesser myocardial damage observed. Additionally, VVSME consumption reduced the levels of LPO, RAGE, TNF-α, Iκκβ, NF-κβ, IL-1β and IL-6 while increased the levels of SOD, CAT, GPx, Na(+)/K(+)-ATPase and Ca(2+)-ATPase in the infarcted and non-infarcted heart of diabetic rats (p<0.05). LC-MS analysis revealed 17 major compounds in VVSME which might be responsible for the observed effects. Consumption of VVSME by diabetics helps to ameliorate damage to the infarcted and non-infarcted myocardium by decreasing oxidative stress, inflammation and cardiac ATPases dysfunctions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Oestradiol supplement minimises coronary occlusion-induced myocardial infarction and ventricular dysfunction in oophorectomised female rats.

PubMed

Zheng, Xiao-Pu; Ma, Ai-Qun; Dong, An-Ping; Wang, Shun; Jiang, Wen-Hui; Wang, Ting-Zhong; Fan, Fen-Ling; Ling, Shanhong

2011-09-15

Endogenous oestrogen deficiency after menopause is associated with high risk of acute cardiac events and the protection of exogenous oestrogen supplements remains uncertain. This study investigates whether oestrogen therapy protects the heart from ischemic injury in oophorectomised rats. Sexually mature female Sprague-Dawley rats (6 for each group) with bilateral oophorectomy underwent selective ligation (occlusion) of left coronary artery for 4 weeks. 17β-oestradiol (E2) supplements (10 μg, i.m., every other day) were started before (preventive-therapeutic supplement) or after coronary occlusion (therapeutic supplement). In oophorectomised rats plasma levels of E2 declined from 1301 ± 80 to 196 ± 48 pmol/L (p<0.01) and cardiac expression of oestrogen receptors (ER) decreased by ∼60%. E2 supplements recovered the ER expression. Selective ligation of left coronary led myocardial infarction in the left ventricle, with an increase in plasma cardiac troponin I (cTn-I), decrease in systolic blood pressure (SBP), and reduction of left ventricular pressures. Preventive-therapeutic but not therapeutic E2 supplement reduced cTn-I levels (from 21.9 ± 2.0 to 6.0 ± 0.3 ng/mL, p<0.01), minimised infarction (from 37.0 ± 1.2% to 18.1 ± 2.3%, p<0.05), increased SBP (from 82 ± 4.2 to 97 ± 4.4mm Hg, p<0.05), and improved left ventricular end pressures in the oophorectomised rats following coronary occlusion. Postmenopausal (ooporectomised) oestrogen supplement commenced before establishment of myocardial ischemia minimises myocardial infarction and ventricular dysfunction following the coronary artery occlusion. Cellular and molecular mechanisms underlying the cardiac protection of oestrogen therapy remain unclear, in which activation of cardiac ER expression and increasing in circulating CD90(+) stem cells may be involved. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

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

2017-08-01

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

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

PubMed

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

2018-04-13

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

The bizzare phenomenon of smokers' paradox in the immediate outcome post acute myocardial infarction: an insight into the Malaysian National Cardiovascular Database-Acute Coronary Syndrome (NCVD-ACS) registry year 2006-2013.

PubMed

Venkatason, Padmaa; Salleh, Norsabihin Mohd; Zubairi, Yong; Hafidz, Imran; Ahmad, Wan Azman Wan; Han, Sim Kui; Zuhdi, Ahmad Syadi Mahmood

2016-01-01

'Smoker's paradox' is a controversial phenomenon of an unexpected favourable outcome of smokers post acute myocardial infarction. There are conflicting evidences from the literature so far. We investigate for the existence of this phenomenon in our post acute myocardial infarction patients. We analysed 12,442 active smokers and 10,666 never-smokers diagnosed with STEMI and NSTEMI from the Malaysian National Cardiovascular Database-Acute Coronary Syndrome (NCVD-ACS) year 2006-2013 from 18 hospitals across Malaysia. Comparisons in the baseline characteristics, clinical presentation, in-hospital treatment and short term clinical outcome were made between the two groups. To compare the clinical outcome, an extensive multivariate adjustment was made to estimate the allcause mortality risk ratios for both groups. The active smokers were younger (smokers 53.7 years vs non-smokers 62.3 years P < 0.001) and had lower cardiovascular risk burden and other co-morbidities. STEMI is more common in smokers and intravenous thrombolysis was the main reperfusion therapy in both groups. Smokers had a higher rate of in-hsopital coronary revascularisation in NSTEMI group (21.6 % smokers vs 16.7 % non-smokers P < 0.001) but similar to non-smokers in the STEMI group. Multivariate adjusted mortality risk ratios showed significantly lower mortality risks of smokers at both in-hospital (RR 0.510 [95 % CI 0.442-0.613]) and 30-day post discharge (RR 0.534 [95 % CI 0.437-0.621]). Smoking seems to be associated with a favourable outcome post myocardial infarction. The phenomenon of 'smoker's paradox' is in fact a reality in our patients population. The definitive explanation for this unexpected protective effect of smoking remains unclear.

Early changes in myocardial repolarization and coronary perfusion after cardiopulmonary bypass surgery for ASD repair in children.

PubMed

Aburawi, Elhadi H; Souid, Abdul-Kader; Liuba, Petru; Zoubeidi, Taoufik; Pesonen, Erkki

2013-09-10

In adults, impaired myocardial repolarization and increased risk of arrhythmia are known consequences of open heart surgery. Little is known, however, about post-operative consequences of cardiopulmonary bypass surgery in children. The aim of this study was to assess ventricular repolarization and coronary perfusion after bypass surgery for atrial septal defect (ASD) repair in children. Twelve patients with ASD were assessed one day before and 5-6 days after ASD repair. Myocardial repolarization (corrected QT interval, QTc, QT dispersion, QTd, and PQ interval) was determined on 12-lead electrocardiograms. Coronary flow in proximal left anterior descending artery (peak flow velocity in diastole, PFVd) was assessed by transthoracic Doppler echocardiography. Ten of the 12 (83%) children had normal myocardial repolarization before and after surgery. After surgery, QTc increased 1-9% in 5 (42%) patients, decreased 2-11% in 5 (42%) patients and did not change in 2 (16%) patients. Post-op QTc positively correlated with bypass time (R=0.686, p=0.014) and changes in PFVd (R=0.741, p=0.006). After surgery, QTd increased 33-67% in 4 (33%) patients, decreased 25-50% in 6 patients (50%) and did not change in 2 (16%) patients. After surgery, PQ interval increased 5-30% in 4 (33%) patients, decreased 4-29% in 6 (50%) patients and did not change in 1 (8%) patient. Post-op PQ positively correlated with bypass time (R=0.636, p=0.027). As previously reported, PFVd significantly increased after surgery (p<0.001). Changes in QTc, PQ and PFVd are common in young children undergoing surgery for ASD repair. Post-op QTc significantly correlates with bypass time, suggesting prolonged cardiopulmonary bypass may impair ventricular repolarization. Post-op QTc significantly correlates with PFVd changes, suggesting increased coronary flow may also impair ventricular repolarization. The clinical significance and reversibility of these alternations require further investigations.

Study design for the "effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion" (METOCARD-CNIC): a randomized, controlled parallel-group, observer-blinded clinical trial of early pre-reperfusion metoprolol administration in ST-segment elevation myocardial infarction.

PubMed

Ibanez, Borja; Fuster, Valentin; Macaya, Carlos; Sánchez-Brunete, Vicente; Pizarro, Gonzalo; López-Romero, Pedro; Mateos, Alonso; Jiménez-Borreguero, Jesús; Fernández-Ortiz, Antonio; Sanz, Ginés; Fernández-Friera, Leticia; Corral, Ervigio; Barreiro, Maria-Victoria; Ruiz-Mateos, Borja; Goicolea, Javier; Hernández-Antolín, Rosana; Acebal, Carlos; García-Rubira, Juan Carlos; Albarrán, Agustín; Zamorano, José Luis; Casado, Isabel; Valenciano, Juan; Fernández-Vázquez, Felipe; de la Torre, José María; Pérez de Prado, Armando; Iglesias-Vázquez, José Antonio; Martínez-Tenorio, Pedro; Iñiguez, Andrés

2012-10-01

Infarct size predicts post-infarction mortality. Oral β-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early intravenous (IV) β-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)-based experimental studies, the β(1)-blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion β-blocker initiation in STEMI. The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with β-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI. Copyright © 2012 Mosby, Inc. All rights reserved.

Peri-operative kidney injury and long-term chronic kidney disease following orthotopic heart transplantation in children.

PubMed

Hoskote, Aparna; Burch, Michael

2015-06-01

Significant advances in cardiac intensive care including extracorporeal life support have enabled children with complex congenital heart disease and end-stage heart failure to be supported while awaiting transplantation. With an increasing number of survivors after heart transplantation in children, the complications from long-term immunosuppression, including renal insufficiency, are becoming more apparent. Severe renal dysfunction after heart transplant is defined by a serum creatinine level >2.5 mg/dL (221 μmol/L), and/or need for dialysis or renal transplant. The degree of renal dysfunction is variable and is progressive over time. About 3-10 % of heart transplant recipients will go on to develop severe renal dysfunction within the first 10 years post-transplantation. Multiple risk factors for chronic kidney disease post-transplant have been identified, which include pre-transplant worsening renal function, recipient demographics and morbidity, peri-transplant haemodynamics and long-term exposure to calcineurin inhibitors. Renal insufficiency increases the risk of post-transplant morbidity and mortality. Hence, screening for renal dysfunction pre-, peri- and post-transplantation is important. Early and timely detection of renal insufficiency may help minimize renal insults, and allow prompt implementation of renoprotective strategies. Close monitoring and pre-emptive management of renal dysfunction is an integral aspect of peri-transplant and subsequent post-transplant long-term care.

Long term effects of cocaine on the heart assessed by cardiovascular magnetic resonance at 3T

PubMed Central

2014-01-01

Background Cocaine is an addictive, sympathomimetic drug with potentially lethal effects. The prevalence and features of cocaine cardiotoxicity are not well known. We aimed to assess these effects using a comprehensive cardiovascular magnetic resonance (CMR) protocol in a large group of asymptomatic cocaine users. Methods Consecutive (n = 94, 81 males, 36.6 ±7 years), non-selected, cocaine abusers were recruited and had a medical history, examination, ECG, blood test and CMR. The CMR study included measurement of left and right ventricular (LV, RV) dimensions and ejection fraction (EF), sequences for detection of myocardial oedema and late gadolinium enhancement (LGE). Images were compared to a cohort of healthy controls. Results Years of regular cocaine use were 13.9 ± 9. When compared to the age-matched healthy cohort, the cocaine abusers had increased LV end-systolic volume, LV mass index and RV end-systolic volume, with decreased LVEF and RVEF. No subject had myocardial oedema, but 30% had myocardial LGE indicating myocardial damage. Conclusions CMR detected cardiovascular disease in 71% of this cohort of consecutive asymptomatic cocaine abusers and mean duration of abuse was related to probability of LV systolic dysfunction. PMID:24758161

Use of wave intensity analysis of carotid arteries in identifying and monitoring left ventricular systolic function dynamics in rabbits.

PubMed

Zhang, Hui; Zheng, Rongqin; Qian, Xiaoxian; Zhang, Chengxi; Hao, Baoshun; Huang, Zeping; Wu, Tao

2014-03-01

Wave intensity analysis (WIA) of the carotid artery was conducted to determine the changes that occur in left ventricular systolic function after administration of doxorubicin in rabbits. Each randomly selected rabbit was subject to routine ultrasound, WIA of the carotid artery, cardiac catheterization and pathologic examination every week and was followed for 16 wk. The first positive peak (WI1) of the carotid artery revealed that left ventricular systolic dysfunction occurred earlier than conventional indexes of heart function. WI1 was highly, positively correlated with the maximum rate of rise in left ventricular pressure in cardiac catheterization (r = 0.94, p < 0.01) and moderately negatively correlated with the apoptosis index of myocardial cells, an indicator of myocardial damage (r = -0.69, p < 0.01). Ultrasound WIA of the carotid artery sensitively reflects early myocardial damage and cardiac function, and the result is highly consistent with cardiac catheterization findings and the apoptosis index of myocardial cells. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

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.

Urine and serum microRNA-1 as novel biomarkers for myocardial injury in open-heart surgeries with cardiopulmonary bypass.

PubMed

Zhou, Xian; Mao, Anqiong; Wang, Xiaobin; Duan, Xiaoxia; Yao, Yi; Zhang, Chunxiang

2013-01-01

MicroRNA-1 (miR-1) is a cardio-specific/enriched microRNA. Our recent studies have revealed that serum and urine miR-1 could be a novel sensitive biomarker for acute myocardial infarction. Open-heart surgeries with cardiopulmonary bypass (CPB) are often accompanied with surgery injury and CPB-associated injury on the hearts. However, the association of miR-1 and these intra-operative and post-operative cardiac injures is unknown. The objective of this study was to test the hypothesis that urine and serum miR-1 might be a novel biomarker for myocardial injuries in open-heart surgeries with CPB. Serum and urine miR-1 levels in 20 patients with elective mitral valve surgery were measured at pre-surgery, pre-CPB, 60 min post-CBP, and 24h post-CBP. Serum cardiac troponin-I (cTnI) was used as a positive control biomarker for cardiac injury. Compared with these in pre-operative and pre-CPB groups, the levels of miR-1 in serum and urine from patients after open-heart surgeries and CPB were significant increased at all observed time points. A similar pattern of serum cTnI levels and their strong positive correlation with miR-1 levels were identified in these patients. The results suggest that serum and urine miR-1 may be a novel sensitive biomarker for myocardial injury in open-heart surgeries with CPB.

CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling.

PubMed

DeLeon-Pennell, Kristine Y; Tian, Yuan; Zhang, Bai; Cates, Courtney A; Iyer, Rugmani Padmanabhan; Cannon, Presley; Shah, Punit; Aiyetan, Paul; Halade, Ganesh V; Ma, Yonggang; Flynn, Elizabeth; Zhang, Zhen; Jin, Yu-Fang; Zhang, Hui; Lindsey, Merry L

2016-02-01

After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling. Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression. Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis. © 2015 American Heart Association, Inc.

Reduced Admissions for Acute Myocardial Infarction Associated with a Public Smoking Ban: Matched Controlled Study

ERIC Educational Resources Information Center

Seo, Dong-Chul; Torabi, Mohammad R.

2007-01-01

There has been no research linking implementation of a public smoking ban and reduced incidence of acute myocardial infarction (AMI) among nonsmoking patients. An ex post facto matched control group study was conducted to determine whether there was a change in hospital admissions for AMI among nonsmoking patients after a public smoking ban was…

Proteomic analysis of cardiac metabolic enzymes in asphyxiated newborn piglets.

PubMed

Fert-Bober, Justyna; Sawicki, Grzegorz; Lopaschuk, Gary D; Cheung, Po-Yin

2008-11-01

Hypoxia/reoxygenation (H/R) creates an energetic deficiency in the heart, which may contribute to myocardial dysfunction. We hypothesized that H/R-induced impairment of cardioenergetic enzymes occurs in asphyxiated newborn animals. After hypoxia for 2 h (10-15% oxygen), newborn piglets were resuscitated with 100% oxygen for 1 h, followed by 21% oxygen for 3 h. Sham-operated control piglets had no H/R. Hemodynamic parameters in the piglets were continuously measured. At the end of experiment, hearts were isolated for proteomic analysis. In asphyxiated hearts, the level of isocitrate dehydrogenase and malate dehydrogenase was reduced compared to controls. Inverse correlations between the level of myocardial malate dehydrogenase and cardiac function were observed in the control, but not the H/R hearts. We conclude that reoxygenation of asphyxiated newborn piglets reduces the level of myocardial isocitrate dehydrogenase and malate dehydrogenase. While the cause is not clear, it may be related to the impaired tricarboxylic acid cycle pathway and energy production in the heart.

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

PubMed

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

2017-12-15

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

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

PubMed

Westerdahl, Daniel E; Chang, David H; Hamilton, Michele A; Nakamura, Mamoo; Henry, Timothy D

2016-09-01

Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

Mechanical Dyssynchrony Precedes QRS Widening in ATP‐Sensitive K+ Channel–Deficient Dilated Cardiomyopathy

PubMed Central

Yamada, Satsuki; Arrell, D. Kent; Kane, Garvan C.; Nelson, Timothy J.; Perez‐Terzic, Carmen M.; Behfar, Atta; Purushothaman, Saranya; Prinzen, Frits W.; Auricchio, Angelo; Terzic, Andre

2013-01-01

Background Contractile discordance exacerbates cardiac dysfunction, aggravating heart failure outcome. Dissecting the genesis of mechanical dyssynchrony would enable an early diagnosis before advanced disease. Methods and Results High‐resolution speckle‐tracking echocardiography was applied in a knockout murine surrogate of adult‐onset human cardiomyopathy caused by mutations in cardioprotective ATP‐sensitive K+ (KATP) channels. Preceding the established criteria of cardiac dyssynchrony, multiparametric speckle‐based strain resolved nascent erosion of dysfunctional regions within cardiomyopathic ventricles of the KATP channel–null mutant exposed to hemodynamic stress. Not observed in wild‐type counterparts, intraventricular disparity in wall motion, validated by the degree, direction, and delay of myocardial speckle patterns, unmasked the disease substrate from asymptomatic to overt heart failure. Mechanical dyssynchrony preceded widening of the QRS complex and exercise intolerance and progressed into global myocardial discoordination and decompensated cardiac pump function, precipitating a low output syndrome. Conclusions The present study, with the use of high‐resolution imaging, prospectively resolved the origin and extent of intraventricular motion disparity in a KATP channel–knockout model of dilated cardiomyopathy. Mechanical dyssynchrony established as an early marker of cardiomyopathic disease offers novel insight into the pathodynamics of dyssynchronous heart failure. PMID:24308936

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.

Atrial fibrillation: effects beyond the atrium?

PubMed

Wijesurendra, Rohan S; Casadei, Barbara

2015-03-01

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

The heartbreak of depression: 'Psycho-cardiac' coupling in myocardial infarction.

PubMed

Headrick, John P; Peart, Jason N; Budiono, Boris P; Shum, David H K; Neumann, David L; Stapelberg, Nicolas J C

2017-05-01

Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort. Copyright © 2017 Elsevier Ltd. All rights reserved.

Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain.

PubMed

Chung, Charles S; Mitov, Mihail I; Callahan, Leigh Ann; Campbell, Kenneth S

2014-06-15

Diastolic dysfunction is a clinically significant problem for patients with diabetes and often reflects increased ventricular stiffness. Attached cross-bridges contribute to myocardial stiffness and produce short-range forces, but it is not yet known whether these forces are altered in diabetes. In this study, we tested the hypothesis that cross-bridge-based short-range forces are increased in the streptozotocin (STZ) induced rat model of type 1 diabetes. Chemically permeabilized myocardial preparations were obtained from 12week old rats that had been injected with STZ or vehicle 4weeks earlier, and activated in solutions with pCa (=-log10[Ca(2+)]) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were ∼67% greater in the samples from the diabetic rats than in the control preparations. This change was mostly due to an increased elastic limit (the length change at the peak short-range force) as opposed to increased passive muscle stiffness. The STZ-induced increase in short-ranges forces is thus unlikely to reflect changes to titin and/or collagen filaments. Gel electrophoresis showed that STZ increased the relative expression of β myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if β myosin molecules remain bound between the filaments for longer durations than α molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

Early Treatment With Zofenopril and Ramipril in Combination With Acetyl Salicylic Acid in Patients With Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction: Results of a 5-Year Follow-up of Patients of the SMILE-4 Study.

PubMed

Borghi, Claudio; Omboni, Stefano; Novo, Salvatore; Vinereanu, Dragos; Ambrosio, Giuseppe; Ambrosioni, Ettore

2017-05-01

The SMILE-4 study showed that in patients with left ventricular dysfunction (LVD) after acute myocardial infarction, early treatment with zofenopril plus acetyl salicylic acid is associated with an improved 1-year survival, free from death or hospitalization for cardiovascular (CV) causes, as compared to ramipril plus acetyl salicylic acid. We now report CV outcomes during a 5-year follow-up of the patients of the SMILE-4 study. Three hundred eighty-six of the 518 patients completing the study (51.2%) could be tracked after the study end and 265 could be included in the analysis. During the 5.5 (±2.1) years of follow-up, the primary endpoint occurred in 27.8% of patients originally randomized and treated with zofenopril and in 43.8% of patients treated with ramipril [odds ratio (OR) and 95% confidence interval, 0.65 (0.43-0.98), P = 0.041]. Such a result was achieved through a significantly larger reduction in CV hospitalization under zofenopril [OR: 0.61 (0.37-0.99), P = 0.047], whereas reduction in mortality rate with zofenopril did not achieve statistical significance versus ramipril [OR: 0.75 (0.36-1.59), P = 0.459]. These results were in line with those achieved during the initial 1-year follow-up. Benefits of early treatment of patients with LVD after acute myocardial infarction with zofenopril are sustained over many years as compared to ramipril.

Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI)

PubMed Central

Yu, Xichun; Tesiram, Yasvir A; Towner, Rheal A; Abbott, Andrew; Patterson, Eugene; Huang, Shijun; Garrett, Marion W; Chandrasekaran, Suresh; Matsuzaki, Satoshi; Szweda, Luke I; Gordon, Brian E; Kem, David C

2007-01-01

Background Diabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes. Methods Diabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls. Results After 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction. Conclusion Our study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy. PMID:17309798

Evaluation of the metabolism of high energy phosphates in patients with Chagas' disease.

PubMed

Leme, Ana Maria Betim Paes; Salemi, Vera Maria Cury; Parga, José Rodrigues; Ianni, Bárbara Maria; Mady, Charles; Weiss, Robert G; Kalil-Filho, Roberto

2010-08-01

Abnormalities in myocardial metabolism have been observed in patients with heart failure of different etiologies. Magnetic resonance spectroscopy (MRS) with phosphorus-31 is a noninvasive technique that allows detection of myocardial metabolic changes. To determine the resting metabolism of high-energy phosphates in patients with Chagas' disease (CD) by MRS with phosphorus-31. We studied 39 patients with CD, 23 with preserved ventricular function (PF Group) and 16 with ventricular dysfunction (VD Group), assessed by Doppler echocardiography. MRS of the anterosseptal region was performed in 39 patients and 8 normal subjects (C Group) through a Phillips 1.5 Tesla device, obtaining the phosphocreatine/beta-adenosine triphosphate myocardial ratio (PCr/β-ATP). The levels of cardiac PCr/β-ATP were reduced in VD Group in relation to PF Group, and the latter presented reduced levels compared to C Group (VD Group: 0.89 ± 0.31 vs PF Group: 1.47 ± 0.34 vs C Group: 1.88 ± 0.08, p < 0.001). A correlation was found between left ventricular ejection fraction and PCr/β-ATP in 39 patients (r = 0.64, p < 0.001). Patients under functional class I (n = 22) presented PCr/β-ATP of 1.45 ± 0.35, and those in functional classes II and III (n = 17), PCr/β-ATP of 0.94 ± 0.36 (p < 0.001). The 31-phosphorus MRS was able to detect non-invasively changes in the rest energy metabolism of patients with Chagas' disease, with and without systolic dysfunction. These changes were related to the severity of heart impairment.

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

PubMed

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

2016-01-08

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

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

PubMed Central

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

2016-01-01

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

Assessment of left ventricular myocardial deformation by cardiac MRI strain imaging reveals myocardial dysfunction in patients with primary cardiac tumors.

PubMed

Chen, Jing; Yang, Zhi-Gang; Xu, Hua-Yan; Shi, Ke; Guo, Ying-Kun

2018-02-15

To assess left ventricular myocardial deformation in patients with primary cardiac tumors. MRI was retrospectively performed in 61 patients, including 31 patients with primary cardiac tumors and 30 matched normal controls. Left ventricular strain and function parameters were then assessed by MRI-tissue tracking. Differences between the tumor group and controls, left and right heart tumor groups, left ventricular wall tumor and non-left ventricular wall tumor groups, and tumors with and without LV enlargement groups were assessed. Finally, the correlations among tumor diameter, myocardial strain, and LV function were analyzed. Left ventricular myocardial strain was milder for tumor group than for normal group. Peak circumferential strain (PCS) and its diastolic strain rate, longitudinal strains (PLS) and its diastolic strain rates, and peak radial systolic and diastolic velocities of the right heart tumor group were lower than those of the left heart tumor group (all p<0.050), but the peak radial systolic strain rate of the former was higher than that of the latter (p=0.017). The corresponding strains were lower in the left ventricular wall tumor groups than in the non-left ventricular wall tumor group (p<0.050). Peak radial systolic velocities were generally higher for tumors with LV enlargement than for tumors without LV enlargement (p<0.050). Peak radial strain, PCS, and PLS showed important correlations with the left ventricular ejection fraction (all p<0.050). MRI-tissue tracking is capable of quantitatively assessing left ventricular myocardial strain to reveal sub-clinical abnormalities of myocardial contractile function. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of PET quantification in cardiovascular imaging.

PubMed

Slomka, Piotr; Berman, Daniel S; Alexanderson, Erick; Germano, Guido

2014-08-01

Positron Emission Tomography (PET) has several clinical and research applications in cardiovascular imaging. Myocardial perfusion imaging with PET allows accurate global and regional measurements of myocardial perfusion, myocardial blood flow and function at stress and rest in one exam. Simultaneous assessment of function and perfusion by PET with quantitative software is currently the routine practice. Combination of ejection fraction reserve with perfusion information may improve the identification of severe disease. The myocardial viability can be estimated by quantitative comparison of fluorodeoxyglucose ( 18 FDG) and rest perfusion imaging. The myocardial blood flow and coronary flow reserve measurements are becoming routinely included in the clinical assessment due to enhanced dynamic imaging capabilities of the latest PET/CT scanners. Absolute flow measurements allow evaluation of the coronary microvascular dysfunction and provide additional prognostic and diagnostic information for coronary disease. Standard quantitative approaches to compute myocardial blood flow from kinetic PET data in automated and rapid fashion have been developed for 13 N-ammonia, 15 O-water and 82 Rb radiotracers. The agreement between software methods available for such analysis is excellent. Relative quantification of 82 Rb PET myocardial perfusion, based on comparisons to normal databases, demonstrates high performance for the detection of obstructive coronary disease. New tracers, such as 18 F-flurpiridaz may allow further improvements in the disease detection. Computerized analysis of perfusion at stress and rest reduces the variability of the assessment as compared to visual analysis. PET quantification can be enhanced by precise coregistration with CT angiography. In emerging clinical applications, the potential to identify vulnerable plaques by quantification of atherosclerotic plaque uptake of 18 FDG and 18 F-sodium fluoride tracers in carotids, aorta and coronary arteries has been demonstrated.

Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity.

PubMed

Bakkehaug, Jens Petter; Kildal, Anders Benjamin; Engstad, Erik Torgersen; Boardman, Neoma; Næsheim, Torvind; Rønning, Leif; Aasum, Ellen; Larsen, Terje Steinar; Myrmel, Truls; How, Ole-Jakob

2015-07-01

Omecamtiv mecarbil (OM) is a novel inotropic agent that prolongs systolic ejection time and increases ejection fraction through myosin ATPase activation. We hypothesized that a potentially favorable energetic effect of unloading the left ventricle, and thus reduction of wall stress, could be counteracted by the prolonged contraction time and ATP-consumption. Postischemic left ventricular dysfunction was created by repetitive left coronary occlusions in 7 pigs (7 healthy pigs also included). In both groups, systolic ejection time and ejection fraction increased after OM (0.75 mg/kg loading for 10 minutes, followed by 0.5 mg/kg/min continuous infusion). Cardiac efficiency was assessed by relating myocardial oxygen consumption to the cardiac work indices, stroke work, and pressure-volume area. To circumvent potential neurohumoral reflexes, cardiac efficiency was additionally assessed in ex vivo mouse hearts and isolated myocardial mitochondria. OM impaired cardiac efficiency; there was a 31% and 23% increase in unloaded myocardial oxygen consumption in healthy and postischemic pigs, respectively. Also, the oxygen cost of the contractile function was increased by 63% and 46% in healthy and postischemic pigs, respectively. The increased unloaded myocardial oxygen consumption was confirmed in OM-treated mouse hearts and explained by an increased basal metabolic rate. Adding the myosin ATPase inhibitor, 2,3-butanedione monoxide abolished all surplus myocardial oxygen consumption in the OM-treated hearts. Omecamtiv mecarbil, in a clinically relevant model, led to a significant myocardial oxygen wastage related to both the contractile and noncontractile function. This was mediated by that OM induces a continuous activation in resting myosin ATPase. © 2015 American Heart Association, Inc.

Low-dose adenosine stress echocardiography: Detection of myocardial viability

PubMed Central

Djordjevic-Dikic, Ana; Ostojic, Miodrag; Beleslin, Branko; Nedeljkovic, Ivana; Stepanovic, Jelena; Stojkovic, Sinisa; Petrasinovic, Zorica; Nedeljkovic, Milan; Saponjski, Jovica; Giga, Vojislav

2003-01-01

Objective The aim of this study was to evaluate the diagnostic potential of low-dose adenosine stress echocardiography in detection of myocardial viability. Background Vasodilation through low dose dipyridamole infusion may recruit contractile reserve by increasing coronary flow or by increasing levels of endogenous adenosine. Methods Forty-three patients with resting dyssynergy, due to previous myocardial infarction, underwent low-dose adenosine (80, 100, 110 mcg/kg/min in 3 minutes intervals) echocardiography test. Gold standard for myocardial viability was improvement in systolic thickening of dyssinergic segments of ≥ 1 grade at follow-up. Coronary angiography was done in 41 pts. Twenty-seven patients were revascularized and 16 were medically treated. Echocardiographic follow up data (12 ± 2 months) were available in 24 revascularized patients. Results Wall motion score index improved from rest 1.55 ± 0.30 to 1.33 ± 0.26 at low-dose adenosine (p < 0.001). Of the 257 segments with baseline dyssynergy, adenosine echocardiography identified 122 segments as positive for viability, and 135 as necrotic since no improvement of systolic thickening was observed. Follow-up wall motion score index was 1.31 ± 0.30 (p < 0.001 vs. rest). The sensitivity of adenosine echo test for identification of viable segments was 87%, while specificity was 95%, and diagnostic accuracy 90%. Positive and negative predictive values were 97% and 80%, respectively. Conclusion Low-dose adenosine stress echocardiography test has high diagnostic potential for detection of myocardial viability in the group of patients with left ventricle dysfunction due to previous myocardial infarction. Low dose adenosine stress echocardiography may be adequate alternative to low-dose dobutamine test for evaluation of myocardial viability. PMID:12812523

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

PubMed

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

2016-04-01

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

Obesity Resistance Promotes Mild Contractile Dysfunction Associated with Intracellular Ca2+ Handling

PubMed Central

de Sá, Felipe Gonçalves dos Santos; Lima-Leopoldo, Ana Paula; Jacobsen, Bruno Barcellos; Ferron, Artur Junio Togneri; Estevam, Wagner Muller; Campos, Dijon Henrique Salomé; Castardeli, Edson; da Cunha, Márcia Regina Holanda; Cicogna, Antonio Carlos; Leopoldo, André Soares

2015-01-01

Background Diet-induced obesity is frequently used to demonstrate cardiac dysfunction. However, some rats, like humans, are susceptible to developing an obesity phenotype, whereas others are resistant to that. Objective To evaluate the association between obesity resistance and cardiac function, and the impact of obesity resistance on calcium handling. Methods Thirty-day-old male Wistar rats were distributed into two groups, each with 54 animals: control (C; standard diet) and obese (four palatable high-fat diets) for 15 weeks. After the experimental protocol, rats consuming the high-fat diets were classified according to the adiposity index and subdivided into obesity-prone (OP) and obesity-resistant (OR). Nutritional profile, comorbidities, and cardiac remodeling were evaluated. Cardiac function was assessed by papillary muscle evaluation at baseline and after inotropic maneuvers. Results The high-fat diets promoted increase in body fat and adiposity index in OP rats compared with C and OR rats. Glucose, lipid, and blood pressure profiles remained unchanged in OR rats. In addition, the total heart weight and the weight of the left and right ventricles in OR rats were lower than those in OP rats, but similar to those in C rats. Baseline cardiac muscle data were similar in all rats, but myocardial responsiveness to a post-rest contraction stimulus was compromised in OP and OR rats compared with C rats. Conclusion Obesity resistance promoted specific changes in the contraction phase without changes in the relaxation phase. This mild abnormality may be related to intracellular Ca2+ handling. PMID:26761369

Prognostic value of a low post-exercise ankle brachial index as assessed by primary care physicians.

PubMed

Diehm, Curt; Darius, Harald; Pittrow, David; Schwertfeger, Markus; Tepohl, Gerhart; Haberl, Roman L; Allenberg, Jens Rainer; Burghaus, Ina; Trampisch, Hans Joachim

2011-02-01

We aimed to investigate whether the post-exercise ankle brachial index (ABI) performed by primary care physicians offers useful information for the prediction of death or cardiovascular events, beyond the traditional resting ABI. An additional focus was on patients with intermittent claudication and normal resting ABI. Using data from the 5-year follow-up of 6468 elderly patients in the primary care setting in Germany (getABI study) we used multivariate Cox regression models adjusted for age, gender and conventional risk factors to determine the association of resting ABI and/or post-exercise ABI and all-cause mortality/morbidity. Mean post-exercise ABI in the total cohort was 0.977 and resting ABI was 1.034. For post-exercise ABI, a threshold value of 0.825 had nearly the same sensitivity (28.6%) and specificity (85.7%) as the conventionally used resting ABI with a cut-off value of 0.9 to predict death. Compared to patients with normal post-exercise ABI, a low post-exercise ABI was associated with an almost identical risk increase for mortality (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.30-1.86) as a low resting ABI (HR 1.65; CI 1.39-1.97) and/or myocardial infarction/stroke. Slight differences were observed for coronary/carotid revascularisation and peripheral revascularisation/amputation. In combined models it could not be shown that post-exercise ABI yielded relevant additional information for the prognosis of mortality and/or myocardial infarction/stroke, not even in the subgroup analysis of patients with intermittent claudication and normal resting ABI. It could not be shown that the post-exercise ABI is a useful tool for the prognosis of mortality and/or myocardial infarction/stroke beyond the resting ABI. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Impaired in vivo mitochondrial Krebs cycle activity after myocardial infarction assessed using hyperpolarized magnetic resonance spectroscopy.

PubMed

Dodd, Michael S; Atherton, Helen J; Carr, Carolyn A; Stuckey, Daniel J; West, James A; Griffin, Julian L; Radda, George K; Clarke, Kieran; Heather, Lisa C; Tyler, Damian J

2014-11-01

Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Using hyperpolarized carbon-13 ((13)C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased (13)C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. © 2014 American Heart Association, Inc.

Impaired In Vivo Mitochondrial Krebs Cycle Activity After Myocardial Infarction Assessed Using Hyperpolarized Magnetic Resonance Spectroscopy

PubMed Central

Carr, Carolyn A.; Stuckey, Daniel J.; West, James A.; Griffin, Julian L.; Radda, George K.; Clarke, Kieran; Heather, Lisa C.; Tyler, Damian J.

2015-01-01

Background Myocardial infarction (MI) is one of the leading causes of heart failure. An increasing body of evidence links alterations in cardiac metabolism and mitochondrial function with the progression of heart disease. The aim of this work was to, therefore, follow the in vivo mitochondrial metabolic alterations caused by MI, thereby allowing a greater understanding of the interplay between metabolic and functional abnormalities. Methods and Results Using hyperpolarized carbon-13 (13C)-magnetic resonance spectroscopy, in vivo alterations in mitochondrial metabolism were assessed for 22 weeks after surgically induced MI with reperfusion in female Wister rats. One week after MI, there were no detectable alterations in in vivo cardiac mitochondrial metabolism over the range of ejection fractions observed (from 28% to 84%). At 6 weeks after MI, in vivo mitochondrial Krebs cycle activity was impaired, with decreased 13C-label flux into citrate, glutamate, and acetylcarnitine, which correlated with the degree of cardiac dysfunction. These changes were independent of alterations in pyruvate dehydrogenase flux. By 22 weeks, alterations were also seen in pyruvate dehydrogenase flux, which decreased at lower ejection fractions. These results were confirmed using in vitro analysis of enzyme activities and metabolomic profiles of key intermediates. Conclusions The in vivo decrease in Krebs cycle activity in the 6-week post-MI heart may represent an early maladaptive phase in the metabolic alterations after MI in which reductions in Krebs cycle activity precede a reduction in pyruvate dehydrogenase flux. Changes in mitochondrial metabolism in heart disease are progressive and proportional to the degree of cardiac impairment. PMID:25201905

Stromal Vascular Fraction Transplantation as an Alternative Therapy for Ischemic Heart Failure: Anti-inflammatory Role

PubMed Central

2011-01-01

Background The aims of this study were: (1) to show the feasibility of using adipose-derived stromal vascular fraction (SVF) as an alternative to bone marrow mono nuclear cell (BM-MNC) for cell transplantation into chronic ischemic myocardium; and (2) to explore underlying mechanisms with focus on anti-inflammation role of engrafted SVF and BM-MNC post chronic myocardial infarction (MI) against left ventricular (LV) remodelling and cardiac dysfunction. Methods Four weeks after left anterior descending coronary artery ligation, 32 Male Lewis rats with moderate MI were divided into 3 groups. SVF group (n = 12) had SVF cell transplantation (6 × 106 cells). BM-MNC group (n = 12) received BM-MNCs (6 × 106) and the control (n = 10) had culture medium. At 4 weeks, after the final echocardiography, histological sections were stained with Styrus red and immunohistochemical staining was performed for α-smooth muscle actin, von Willebrand factor, CD3, CD8 and CD20. Results At 4 weeks, in SVF and BM-MNC groups, LV diastolic dimension and LV systolic dimension were smaller and fractional shortening was increased in echocardiography, compared to control group. Histology revealed highest vascular density, CD3+ and CD20+ cells in SVF transplanted group. SVF transplantation decreased myocardial mRNA expression of inflammatory cytokines TNF-α, IL-6, MMP-1, TIMP-1 and inhibited collagen deposition. Conclusions Transplantation of adipose derived SVF cells might be a useful therapeutic option for angiogenesis in chronic ischemic heart disease. Anti-inflammation role for SVF and BM transplantation might partly benefit for the cardioprotective effect for chronic ischemic myocardium. PMID:21453457

Serial assessment of the index of microcirculatory resistance during primary percutaneous coronary intervention comparing manual aspiration catheter thrombectomy with balloon angioplasty (IMPACT study): a randomised controlled pilot study.

PubMed

Hoole, Stephen P; Jaworski, Catherine; Brown, Adam J; McCormick, Liam M; Agrawal, Bobby; Clarke, Sarah C; West, Nick E J

2015-01-01

Utilising a novel study design, we evaluated serial measurements of the index of microcirculatory resistance (IMR) in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) to assess the impact of device therapy on microvascular function, and determine what proportion of microvascular injury is related to the PPCI procedure, and what is an inevitable consequence of STEMI. 41 patients undergoing PPCI for STEMI were randomised to balloon angioplasty (BA, n=20) or manual thrombectomy (MT, n=21) prior to stenting. Serial IMR measurements, corrected for collaterals, were recorded at baseline and at each stage of the procedure. Microvascular obstruction (MVO) and infarct size at 24 h and 3 months were measured by troponin and cardiac MRI (CMR). IMR did not change significantly following PPCI, but patients with lower IMR values (<32, n=30) at baseline had a significant increase in IMR following PPCI (baseline: 21.2±7.9 vs post-stent: 33.0±23.7, p=0.01) attributable to prestent IRA instrumentation (baseline: 21.7±8.0 vs post-BA or MT: 36.9±25.9, p=0.006). Post-stent IMR correlated with early MVO on CMR (p=0.01). There was no significant difference in post-stent IMR, presence of early MVO or final infarct size between patients with BA and patients treated with MT. Patients with STEMI and less microcirculatory dysfunction may be susceptible to acute iatrogenic microcirculatory injury from prestent coronary devices. MT did not appear to be superior to BA in maintaining microcirculatory integrity when the guide wire partially restores IRA flow during PPCI. ISRCTN31767278.

Encapsulated Glucagon-Like Peptide-1-Producing Mesenchymal Stem Cells Have a Beneficial Effect on Failing Pig Hearts

PubMed Central

Wright, Elizabeth J.; Farrell, Kelly A.; Malik, Nadim; Kassem, Moustapha; Lewis, Andrew L.; Wallrapp, Christine

2012-01-01

Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with cardioprotective properties but a short half-life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups were cell-free beads and beads containing unmodified MSCs (bead-MSC), n = 4–5 per group. Echocardiography confirmed left ventricular (LV) dysfunction at time of delivery in all groups. Four weeks after intervention, only the bead-GLP-1 MSC group demonstrated LV function improvement toward baseline and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more vessels per mm2 were noted in the infarct of the bead-GLP-1 MSC group. No differences were observed in myocyte cross-sectional area between groups. Post-MI delivery of GLP-1 encapsulated genetically modified MSCs provided a prolonged supply of GLP-1 and paracrine stem cell factors, which improved LV function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodeling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would be beneficial for recovery following MI. PMID:23197668

Role of (123)I-Iobenguane Myocardial Scintigraphy in Predicting Short-term Left Ventricular Functional Recovery: An Interesting Image.

PubMed

Feola, Mauro; Chauvie, Stephane; Biggi, Alberto; Testa, Marzia

2015-01-01

(123)I-iobenguane myocardial scintigraphy (MIBG) has been shown to be a predictor of sudden cardiac mortality in patients with heart failure. One patient with recent anterior myocardial infarction (MI) treated with coronary angioplasty and having left ventricular ejection fraction (LVEF) of 30% underwent early MIBG myocardial scintigraphy/tetrofosmin single-photon emission computed tomography (SPECT) in order to help evaluate his eligibility for implantable cardioverter defibrillator (ICD). The late heart/mediastinum (H/M) ratio was calculated to be 1.32% and the washout rate was 1%. At 40-day follow-up after angioplasty, LVEF proved to be 32%, New York Heart Association (NYHA) class was still II-III, and an ICD was placed in order to reduce mortality from ventricular arrhythmias. MIBG myocardial scintigraphy might be a promising method for evaluating left ventricular recovery in post-MI patients.