Cellular and molecular pathways to myocardial necrosis and replacement fibrosis

Abstract

Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signaltransducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca 2+ overloading and subsequent induction of oxidative stress, Correspondence to: Karl T. Weber, KTWeber@uthsc.edu. NIH Public Access Author ManuscriptHeart Fail Rev. Author manuscript; available in PMC 2012 January 1. Published in final edited form as:Heart Fail Rev. 2011 January ; 16(1): 23-34. doi:10.1007/s10741-010-9169-3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca 2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn 2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn 2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca 2+ -Zn 2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.

Pathological assessment of end-stage heart failure in explanted hearts in correlation with hemodynamics in patients undergoing orthotopic heart transplantation

“…Previous studies [21,22] reported that diabetic cardiomyopathy, detected in 1 of our 18 NICMP cases (6%), is a distinct CMP characterized by CMC dysfunction as a direct result from diabetes mellitus, even in the absence of epicardial coronary artery disease, hypertension, and significant valvular disease. According to previously published works [19,23,24], our findings confirm that, in HF, two different types of fibrotic accumulation can occur in the myocardium:…”

Differences in left ventricular cardiomyocyte loss induced by chronic intermittent hypoxia between spontaneously hypertensive and Wistar–Kyoto rats

“…In contrast, apoptotic cells are rapidly phagocytosed before secondary necrosis occurs, thus causing a minimal inflammatory response [41]. Furthermore, the extensive nature of this microscopic scarring suggests that cardiomyocyte necrosis is widespread and that the loss of these contractile elements, combined with fibrous tissue deposition in the form of stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump [42]. In contrast, the apoptotic bodies are removed either by neighbouring cells or phagocytes with minimal structural tissue disruption [43].…”

Roles of SIRT3 in heart failure: from bench to bedside

“…Nearly all types of HF are accompanied by increased cell death, attributed to stresses from circulating neurohormones, inflammation, oxidative stress, or toxins (Konstantinidis et al, 2012;Richter and Kostin, 2015). This leads to the release of growth factors which can result in the formation of fibrosis (Gandhi et al, 2011). In conjunction with cell death, remodeling of the extracellular matrix is also observed.…”