APOPTOSIS IN THE FAILING HUMAN HEART

Background Loss of myocytes is an important mechanism in the developme nt of cardiac failure of either ischemic or nonischemic origin. Howeve r, whether programmed cell death (apoptosis) is implicated in the term inal stages of heart failure is not known. We therefore studied the ma gnitude of myocyte apoptosis in patients with intractable congestive h eart failure. Methods Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hea rts of 3 patients who died soon after myocardial infarction. Samples f rom 11 normal hearts were used as controls. Apoptosis was evaluated hi stochemically, biochemically, and by a combination of histochemical an alysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. Results H eart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin conden sation and fragmentation by confocal microscopy. Ail these findings re flect apoptosis of myocytes. The percentage of myocytes labeled with B CL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, w hereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. Conclus ions Programmed death of myocytes occurs in the decompensated human he art in spite of the enhanced expression of BCL2 this phenomenon may co ntribute to the progression of cardiac dysfunction. (C) 1997, Massachu setts Medical Society.