Apoptosis in the overloaded myocardium: potential stimuli and modifying signals

Distension-induced apoptosis of cardiomyocytes has been proposed as a mechanism for the progression from overload-induced cardiac hypertrophy to terminal heart failure with dilative remodeling, since extreme distension of myocardial preparations in vitro or of isolated myocytes in culture induces apoptosis. Furthermore, a very low number of apoptotic myocytes, disseminated in nonischemic myocardial areas of overloaded hearts, is demonstrable in experimental models and in explanted human myocardium. Hemodynamic unloading of terminally failing human hearts by ventricular assist devices reduces the amount of apoptotically cleaved DNA in myocardial extraxts and time-dependently renormalizes the myocardial expression of potentially proapoptotic signal molecules from the apoptotic machinery. While a cellular mechanism for distension-induced myocyte apoptosis in situ is not established, a tentative working hypothesis for the induction of apoptosis in overloaded, nonischemic myocardium postulates the combined actions of impaired mitochondrial function, exaggerated neuroendocrine activity, cytosolic calcium overload, and attenuated survival signals from cytoskeleton, from gpl30 containing receptors, and from IGF-1. However, it is not yet possible to derive a rate of myocyte loss from the reported figures of apoptotic myocyte nuclei in overloaded myocardium. Therefore, the causal role of demonstrable myocyte apoptosis in terminal hear failure is unknown.