Role of Intracellular Ca2+-overload in Cardiac Dysfunction in Heart Disease

Abstract

Various heart diseases such as genetically-determined heart failure, acute myocardial infarction, ischemia-reperfusion injury and catecholamine-induced cardiomyopathies are associated with cardiac dysfunction, cellular damage, subcellular derangements and metabolic alterations. Since increase in myocardial Ca2+ is accompanied by these abnormalities, it is generally held that intracellular Ca2+-overload plays an important role in the pathogenesis of cardiac dysfunction as well as cellular and metabolic defects in different cardiovascular diseases. This view is supported by observations in hearts subjected to Ca2+-paradox, where reperfusion of Ca2+-free perfused hearts with Ca2+-containing medium was found to produce a marked increase in myocardial Ca2+-content, cellular damage and cardiac contracture. The intracellular Ca2+-overload in the heart has also been shown to produce mitochondrial Ca2+-overload, depress ATP production, release different toxic substances and induce cardiomyocyte apoptosis. By virtue of its ability to depress cardiac gene expression and increase proteolysis of sarcolemma (SL) sarcoplasmic reticulum (SR) and myofibrils (MF), the intracellular Ca2+-overload has been reported to reduce SL, SR and MF protein content and activities. Such remodeling of subcellular organelles is associated with dramatic alterations in Ca2+ -handling by SL and SR membranes as well as interaction of Ca2+ with MF for the impairment of cardiac function. Thus, it is evident that mitochondrial Ca2+-overload, and subcellular remodeling for Ca2+-handling defects are responsible for the occurrence of cardiac dysfunction, metabolic derangements and cellular damage during the development of heart disease.