Programmed cell death in the progression of heart failure

A characteristic feature of heart failure is the progressive deterioration of left ventricular function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this haemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of cardiomyocytes and/or to ongoing degeneration and loss of viable cardiomyocytes. In this review we examine the concept of ongoing cardiac myocyte loss as a potential factor responsible for the progression of left ventricular dysfunction in heart failure. The discussion focuses on apoptosis or 'programmed cell death' as a potential mediator of cardiomyocyte loss. While available data support the existence of myocyte apoptosis in the failing heart, studies addressing possible physiological and molecular triggers of this process of cell death in the failing heart are lacking. As a part of the discussion, we construct a case in support of the concept that the failing myocardium is subject to regional hypoxia, an abnormality that can potentially trigger cardiomyocyte apoptosis. If loss of cardiomyocytes through apoptosis can be shown to be an important contributor to the progression of heart failure, and if the trigger of cardiomyocyte apoptosis in the failing heart can be identified, the foundation would be strengthened for the development of novel, target-specific therapeutic modalities aimed at preventing, or at the very least retarding, the process of progressive ventricular dysfunction and the transition toward intractable heart failure.