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EXPERIMENTAL STUDIES

Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure

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

Manuscript received April 22, 1999; revised manuscript received August 6, 1999, accepted October 5, 1999.

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

OBJECTIVES

In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF.

BACKGROUND

Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF).

METHODS

Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7).

RESULTS

In untreated dogs, EF decreased from 35 ± 1% before initiating therapy to 29 ± 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 ± 3 vs. 84 ± 8 ml, p = 0.08; ESV: 46 ± 2 vs. 60 ± 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 ± 2% before initiating therapy to 39 ± 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 ± 3 vs. 71 ± 4 ml, p = 0.05; ESV: 48 ± 2 vs. 43 ± 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis.

CONCLUSIONS

In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF.

Abbreviations and Acronyms   EDV = end-diastolic volume   EF = ejection fraction   ESV = end-systolic volume   ET = endothelin   ETA = endothelin-1 type A receptor   ETB = endothelin-1 type B receptor   ET-1 = endothelin-1   HF = heart failure   LV = left ventricular

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