BIOCHEMICAL BASIS OF HEART FUNCTION AND CONTRACTILE FAILURE

Although the hallmark of heart failure is a depression of cardiac pump function, no common biochemical defect has been identified that may explain the loss of myocardial contractility. Both energy production and energy utilization have been extensively investigated in clinical and experimental heart failure; however, abnormalities in these cellular processes are ruled out as a primary cause of decreased myocardial force development. For the past 25 years, much effort has been directed at studying the interaction of Ca2+ with various cellular components as well as identifying defects in myocardial Ca2+ metabolism in heart failure as a possible mechanism for cardiac dysfunction. It is now known that contraction of heart muscle is initiated by permeation of the heart cells by Ca2+ ions via voltage dependent Ca2+ channels and Na+-Ca2+ exchange in the sarcolemmal membrane. This Ca2+ signal is involved in Ca2+ release from the sarcoplasmic reticular Ca2+ stores in the myoplasm and ultimately the contractile machinery of the heart cell is activated. Muscle contraction is followed by a rapid sequestration of the cytoplasmic Ca2+ to the lumen of the sarcoplasmic reticulum as well as by transsarcolemmal Ca2+ efflux. Thus the concentration of free myoplasmic Ca2+ is reduced and this brings about the relaxation phase of the cardiac cycle. It can be seen that any defect in Ca2+-handling properties of sarcoplasmic reticular and/or sarcolemmal membrane may lead to abnormalities in the development of myocardial contractile force. Thus, in light of recent advances in studies of myocardial cell function in normal and failing myocardium, we have reviewed the current literature with emphasis on the involvement of cardiac sarcoplasmic reticulum and sarcolemmal membrane in cellular Ca2+ homeostasis. The role of mitochondria in handling Ca2+ and the interaction of Ca2+ with contractile proteins have also been discussed, providing an overall appreciation of biochemical abnormalities in heart dysfunction. Although varying degrees of defects in sarcolemmal Ca2+ channels, Na+-Ca2+ exchange, Ca2+ pump, adrenergic receptors and Na+-K+ ATPase have been identified in heart failure, some of these abnormalities are causative whereas others are adaptive in nature. It is apparent that the specific nature of defective cellular Ca2+ homeostasis may vary depending on the type and stage of heart failure.