INCREASED CARDIOMYOCYTE APOPTOSIS DURING THE TRANSITION TO HEART-FAILURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

The transition from compensated hypertrophy to failure in spontaneousl y hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca2+-activated myofibrillar force. We hypothesized that the re duction in myocyte mass and associated functional loss may be due to i ncreased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matche d Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had bee n treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quan tified in cross sections of myocardium by the terminal deoxynucleotidy ltransferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labelin g technique. To identify the type of the cells undergoing apoptosis, s ections were also stained for cu-sarcomeric actin. Apoptotic cells wer e significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3 .98 cells/100,000 nuclei in SHR-NF; P < 0.05 and vs. 2.21 +/- 1.4 cell s/100,000 nuclei in WKY; P < 0.01). Captopril treatment of SHR-F reduc ed the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P < 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl- 2 protein expressed by hearts among the three groups. WAF-1 mRNA level s were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apopto tic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that a ccompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhib itor captopril, which ameliorates heart failure in this model, is asso ciated with a reduction in the exaggerated apoptosis that accompanies heart failure.