EFFECTS OF ACE-INHIBITION ON CARDIOMYOCYTE APOPTOSIS IN DOGS WITH HEART-FAILURE

Cardiomyocyte apoptosis or programmed cell death has been shown to occ ur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term mon otherapy with an angiotensin-converting enzyme (ACE) inhibitor attenua tes cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30-40%) was produced in dogs by m ultiple sequential intracoronary microembolizations. Dogs were randomi zed to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragme ntation (nDNAf), a marker of apoptosis, was assessed in frozen LV sect ions using the immunohistochemical deoxynucleotidal transferase-mediat ed dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were al so stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (x40) were selected at ran dom, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyo cyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 +/- 0.13 vs. 2.65 +/- 0. 81, P < 0.029). This difference was due to a significantly lower incid ence of cardiomyocyte nDNAf events in LV regions bordering scarred tis sue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis i n dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.