Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs

BACKGROUND: Observations in humans have raised the possibility that idiopathic dilated cardiomyopathy is characterized by myocyte cell loss and cell proliferation, which contribute to wall thinning and chamber dilation. Moreover, the mechanism of myocyte cell death in this patient population has been unclear. Because rapid ventricular pacing in dogs leads to a dilated myopathy that mimics the idiopathic form in man, this animal model was used to demonstrate whether myocyte nuclear mitotic division and programmed myocyte cell death occur in this setting. Additionally, the expression of proliferating cell nuclear antigen (PCNA) and Fas protein in myocytes was examined as a molecular indicator of the activation of the cell cycle and apoptotic cell death, respectively. EXPERIMENTAL DESIGN: Mongrel dogs were chronically instrumented for measurements of systemic hemodynamics and for left ventricular pacing. At sacrifice, myocardial samples were obtained for the estimation of the number of myocytes and interstitial cells showing mitosis and for the detection of DNA laddering. In addition, the number of myocyte nuclei exhibiting DNA strand breaks, as well as the frequency of myocytes labeled by PCNA and Fas protein, was determined. Finally, the distribution of nuclei in enzymatically dissociated myocytes was evaluated. RESULTS: Pacing-induced heart failure was characterized by DNA fragmentation and by 3700 myocytes per million cells undergoing apoptotic cell death. This phenomenon was accompanied by 11,000 cells per million expressing Fas protein. Concurrently, 22 and 17 myocytes and interstitial cells per million showed nuclear mitotic division, whereas no changes in the relative proportions of mononucleated and multinucleated myocytes were detected. Moreover, PCNA-labeled myocytes accounted for 40,000 cells per million. CONCLUSIONS: In conclusion, the induction of PCNA and Fas may be linked to the activation of myocyte proliferation and programmed cell death in the myocardium with rapid ventricular pacing, and these two cellular responses may play a key role in the development of the congestive dilated myopathy.