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CLINICAL STUDY

Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure

^a Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA

Manuscript received December 13, 1999; revised manuscript received April 19, 2000, accepted June 19, 2000.

Reprint requests and correspondence: Dr. Hani N. Sabbah, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202
HSABBAH1{at}hfhs.org

OBJECTIVES

The purpose of this study was to determine if therapy with beta-blockade is associated with reduced cardiomyocyte apoptosis.

BACKGROUND

Chronic treatment with beta-adrenergic blocking agents has been shown to improve left ventricular (LV) ejection fraction and attenuate progressive LV remodeling in heart failure (HF). Cardiomyocyte apoptosis has also been shown to occur in the failing heart.

METHODS

Moderate HF was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to three months therapy with metoprolol (MET, 25 mg twice daily, n = 7) or to no therapy at all (n = 7). At the end of three months, dogs were sacrificed, and nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in LV tissue using the TUNEL assay. The number of cardiomyocytes with positive nDNAf labeling per 1,000 was quantified in LV regions bordering old infarcts and in regions remote from infarcts. Endonuclease activity and expression of the antiapoptotic protein Bcl-2 and the proapoptotic proteins Bax and caspase-3 were also evaluated in LV tissue.

RESULTS

The number of nDNAf events per 1,000 cardiomyocytes was lower in dogs treated with MET compared with untreated dogs with HF in the border regions (0.35 ± 0.07 vs. 5.32 ± 0.77, p < 0.001) as well as the remote regions (0.07 ± 0.05 vs. 0.39 ± 0.12, p < 0.05). Endonuclease activity was also significantly lower in MET-treated compared with untreated dogs (25 ± 3 vs. 37 ± 2 ng [³H]DNA rendered soluble/min/mg protein). Western blotting for Bcl-2, Bax and caspase-3 showed increased expression of Bcl-2, decreased expression of caspase-3 and no change in Bax in MET-treated compared with untreated dogs.

CONCLUSIONS

Chronic therapy with MET attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of ongoing cardiomyocyte loss through apoptosis may be one mechanism through which beta-blockers elicit their benefits in HF.

Abbreviations and Acronyms   CSQ = calsequestrin   HF = heart failure   LV = left ventricular   MET = metoprolol   nDNAf = nuclear DNA fragmentation   SDS = sodium dodecyl sulfate   TdT = terminal deoxynucleotidal transferase   TUNEL = TdT-mediated dUTP nick-end labeling

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