Cardiac remodeling and subcellular defects in heart failure due to myocardial infarction and aging.

Although several risk factors including hypertension, cardiac hypertrophy, coronary artery disease, and diabetes are known to result in heart failure, elderly subjects are more susceptible to myocardial infarction and more likely to develop heart failure. This article is intended to discuss that cardiac dysfunction in hearts failing due to myocardial infarction and aging is associated with cardiac remodeling and defects in the subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR), and myofibrils. Despite some differences in the pattern of heart failure due to myocardial infarction and aging with respect to their etiology and sequence of events, evidence has been presented to show that subcellular remodeling plays a critical role in the occurrence of intracellular Ca(2+)-overload and development of cardiac dysfunction in both types of failing heart. In particular, alterations in gene expression for SL and SR proteins induce Ca(2+)-handling abnormalities in cardiomyocytes, whereas those for myofibrillar proteins impair the interaction of Ca(2+) with myofibrils in hearts failing due to myocardial infarction and aging. In addition, different phosphorylation mechanisms, which regulate the activities of Ca(2+)-cycling proteins in SL and SR membranes as well as Ca(2+)-binding proteins in myofibrils, become defective in the failing heart. Accordingly, it is suggested that subcellular remodeling involving defects in Ca(2+)-handling and Ca(2+)-binding proteins as well as their regulatory mechanisms is intimately associated with cardiac remodeling and heart failure due to myocardial infarction and aging.

Alterations in sarcoplasmic reticulum and mitochondrial functions in diabetic cardiomyopathy.

Although diabetes due to insulin deficiency or insulin resistance is a major cause of heart disease, the pathogenesis of cardiac dysfunction during the development of diabetic cardiomyopathy is not fully understood. Varying degrees of defects in subcellular organelles, such as sarcolemma, mitochondria, sarcoplasmic reticulum, myofibrils and extracellular matrix have been observed in the diabetic heart. These subcellular abnormalities in chronic diabetes become evident with the occurrence of hormonal imbalance, metabolic defects, oxidative stress and intracellular Ca(2+) overload. During the initial stages of diabetes, hormonal imbalances, including elevated plasma levels of catecholamines and angiotensin II, as well as metabolic defects, appear to favour the development of oxidative stress; these changes lead to subcellular defects in the myocardium. Reductions in sarcoplasmic reticular Ca(2+) pump and Ca(2+) release channel function are associated with cardiac dysfunction, whereas alterations in sarcolemmal Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase activities contribute to intracellular Ca(2+) overload at late stages of diabetes. The continued accumulation of Ca(2+) in mitochondria produces Ca(2+) overload in these organelles, and this change induces impairment of energy production and depletion of energy stores as well as further promotion of oxidative stress in chronic diabetes. Generation of oxyradicals due to impaired electron transport results in the opening of mitochondrial pores, leakage of toxic proteins and myocardial cell damage in diabetes. These observations support the view that alterations in sarcoplasmic reticular and mitochondrial functions produce intracellular Ca(2+) overload and depletion of energy stores and, thus, play an important role in the development of cardiac dysfunction in diabetic cardiomyopathy.