MOLECULAR AND CELLULAR BIOLOGY OF HEART-FAILURE

In recent years, the striking development of molecular biology and mol ecular genetics has brought completely new insights into the understan ding of heart failure. Two aspects for which significant progress has been made in 1995 are discussed in this review: the genetic mechanisms of inherited cardiomyopathies and the molecular basis of heart failur e due to chronic hemodynamic overload. In familial hypertrophic cardio myopathy, a novel disease gene was found. It encodes myosin binding pr otein C, whose structure and function are poorly understood. Contracti le deficits associated with the myosin mutations were demonstrated, an d all this strengthened the hypothesis that hypertrophy is a compensat ory mechanism that occurs in presence of a sarcomeric defect. These st udies have important prognostic and clinical implications, but new and unexpected concerns have arisen, because a widespread difference in p henotype can be seen in patients harboring similar genotypes. In famil ial dilated cardiomyopathy, the main findings were the identification of four disease loci, but the genes are still unknown. With respect to the consequences of chronic hemodynamic overload on myocyte function and phenotype, recent data gave rise to lively discussions in the fiel ds of reexpression of fetal troponin T isoforms and of decreased funct ion and expression of the sarco(endo)plasmic reticulum Ca2+ ATPase in the failing human heart; at the moment it is difficult to draw definit ive conclusions. Interestingly, three new concepts emerged in the unde rstanding of the pathogenesis of heart failure: the increased contribu tion of the Na+-Ca2+ exchange, the possible recruitment of an inositol phosphate-sensitive calcium pool for myofibrillar activation, and the involvement of apoptotic myocyte and nonmyocyte cell death in myocard ial remodeling.