Left ventricular unloading before reperfusion reduces endothelin-1 release and calcium overload in porcine myocardial infarction
ABSTRACT The aim of this study was to test the hypothesis that after an acute myocardial infarction, endothelin-1 release with subsequent calcium overload is a mediator of myocardial reperfusion injury, which can be inhibited, in part, by left ventricular unloading immediately before reperfusion. We recently have reported that left ventricular unloading before reperfusion reduces infarct size after acute myocardial infarction. However, the biologic mechanisms of infarct salvage in unloaded hearts subjected to ischemia/reperfusion remain undefined.
Twelve pigs were subjected to 1 hour of left anterior descending coronary artery occlusion followed by 4 hours of reperfusion. A left ventricular assist device was initiated 15 minutes before reperfusion and maintained during reperfusion (assist device group, n = 6). A control group (n = 6) was subjected to reperfusion alone. Infarct size, endothelin-1 plasma levels, intracellular calcium levels, and apoptosis were analyzed in both groups.
At reperfusion, left ventricular unloading significantly decreased left ventricular end-diastolic and end-systolic pressures. Infarct size, expressed as a percentage of zone at risk, was also significantly reduced by 54% in the group with the left ventricular assist device compared with controls. Support with a left ventricular assist device reduced endothelin-1 release from the heart at 15 minutes, 30 minutes, and 1 hour of reperfusion. Myocardial release of endothelin-1 was significantly correlated with infarct size at 15 minutes of reperfusion (r = 0.79; P = .008). Left ventricular unloading caused a significant reduction of calcium overload and of the percentage of apoptotic cells in the ischemic region.
Our findings suggest that endothelin-1 release and calcium overload are important mediators of reperfusion injury and that they can be significantly reduced by left ventricular unloading before coronary artery reperfusion during myocardial infarction.
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ABSTRACT: Purpose: In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca(2+)]i, and apoptosis. Methods: Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca(2+) and cell death were assessed with flow cytometry. Results: LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca(2+)]i increase and cell death for myocytes subjected to stimulated I/R. Conclusion: We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients.Cardiology 06/2013; 125(4):242-249. DOI:10.1159/000350655 · 2.04 Impact Factor
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ABSTRACT: Myocardial tissue engineering ambitions to regenerate, repair or replace damaged cardiac muscle by combining cellular and engineering technologies. Several issues must be addressed before this approach may one day find clinical applications for cardiac disorders such as congenital diseases or ventricular dysfunction following myocardial infarction for example. The chance of the myocardial tissue engineering approach is nevertheless real. Indeed, on the one hand, several clinical studies have recently confirmed the positive effect of stem cell therapy in patients with heart failure. On the other hand, research from several laboratories have demonstrated over the past decade that engineered muscle tissues can be created and successfully applied in models of myocardial injury. Engineering a functional myocardial graft faces with many challenges, and various approaches have been investigated. In the current chapter, we focus our review on hydrogel-based engineered tissues for myocardial application. The literature on injectable and implantable hydrogel constructs is discussed and an overview of our own experience is presented. We emphasize important aspects on development of hydrogel constructs in particular the mechanical and electrical conditioning of the construct as well as smart hydrogels.12/2010: pages 165-185;
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ABSTRACT: Oxygen Supply/Demand Approach to Reducing Infarct Size Great strides have been made in the treatment of acute myocardial infarction (MI). Improved outcomes and reduced mortality are largely the result of opening the occluded infarct artery as soon as possible and by keeping it open. Early reperfusion consistently reduces myocardial infarct size in both experimental animal models and in patients. Despite advances in stenting of the occluded coronary artery and shortening of the "door-to-balloon" time, 1 month mortality post infarction still hovers around 15% and post myocardial infarction heart failure remains problematic. Therefore, there is still a need to try to further reduce myocardial infarct size in 2013. Initial concepts focused on reducing myocardial infarct size by improving the imbalance between O2/nutrient supply and O2/nutrient demand of the heart (Table 1). Improving O2 supply by inducing early reperfusion with thrombolytic therapy, then angioplasty, and now stenting has been successful and dual antiplatelet therapy and possibly addition of anticoagulant therapy has further improved clinical outcomes, maintained vessel patency, and reduced stent thrombosis. Other techniques to improve O2/nutrient supply such as hyperoxemia and erythropoietin have shown benefit in some but not all studies. Antianginal agents that vasodilate the coronary arteries and may improve coronary flow such as nitrates and calcium blockers in general have failed to reduce myocardial infarct size in clinical trials.Circulation 06/2013; 128(4). DOI:10.1161/CIRCULATIONAHA.113.003976 · 14.95 Impact Factor