The long-term objective of this application is to identify the pathophysiologic mechanisms implicated in myocyte cell death and reactive cellular growth which underlie the onset, development and progression of pacing-induced dilated cardiomyopathy. Our principal working hypothesis is that mechanical forces generated by abnormalities in ventricular wall stress lead acutely to the formation of superoxide anion which activates the suicide program of myocytes, resulting in apoptotic myocyte cell death. Moreover, the loss in nitric (NO) from the coronary endothelium in the chronic stages of the myopathy is considered to play an important role in the temporal generation of myocyte cell death in the myocardium. Whether myocyte growth per se is coupled with the induction of myocyte cell death is a significant aspect of the proposed work. Specifically, acute ventricular dilation, associated with sudden elevations in diastolic wall stress, is proposed to be mediated by an architectural rearrangement of myocytes involving first scattered myocyte cell death and subsequently mural translocation of cells. In addition, the hypothesis is advanced that the synthesis of NO is impaired in the stressed ventricle and this defect alters the vasodilatatory capacity of the intramural branches of the coronary circulation resulting in focal ischemic myocyte necrosis. Also the possibility is raised that abnormalities in the generation of NO lead to enhanced oxygen consumption and increased aerobic metabolism of the mitochondrial compartment which, in turn, potentiates the formation of reactive oxygen species. This latter phenomenon, coupled with downregulation of genes possessing an antioxidant effect, may trigger programmed cell death. Importantly, it is anticipated that not only myocyte cellular hypertrophy but also myocyte cellular hyperplasia are involved in the restructuring of the wall with ventricular pacing. Since the protooncogene bcl-2 and one of its splicing forms, bcl-xL, protect from apoptosis, whereas the other splicing form, bcl-xs, and bax attenuate this beneficial influence, downregulation of bcl-2 and bcl-xL and/or upregulation of bcl-xs and bax may occur with this myopathy. Moreover, the surface molecule Fas may become overexpressed in enlarging myocytes exposed to excess mechanical loading and this may trigger programmed cell death. This phenomenon may be more apparent during cell proliferation because the formation of p53 protein is increased in this setting, and p53 enhances bax and depresses bcl-2 directly. Moreover, p53 may require immediate DNA repair for transcription and for DNA replication and failure to initiate this process may stimulate apoptosis. Therefore, alterations in myocardial loading with rapid ventricular pacing may lead to a change in protein-to-protein interactions among the members of the bcl-2 family in myocytes which, in combination with the generation of reactive oxygen species and the activation of genes involved in cell growth and cell death, may result in apoptosis. Ultimately, myocyte loss is expected to exceed the reactive growth processes of the cell, resulting in a progressive deterioration of function and end-stage cardiac failure.
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