Abstract 14499: Beneficial Cardiac Effects of Endothelin Converting Enzyme Inhibition in Experimental Heart Failure
Introduction. Endothelin (ET) plasma concentrations are of predictive value in terms of clinical outcome and survival in heart failure (HF), and remain increased in humans with HF receiving optimal treatment. Antagonizing the effects of ET-1 via dual ETA-ETB or selective ETA receptor antagonists abrogates the deleterious effects of ET, i.e. vasoconstriction and adverse left ventricular (LV) remodeling in experimental HF. However, only dual ETA-ETB receptor blockade improves long-term survival in experimental HF, while in humans with CHF neither ETA nor dual ETA-ETB receptor antagonists improve, despite beneficial hemodynamic effects, long-term survival. Endothelin converting enzyme (ECE) inhibition might be a therapeutic alternative for ET receptor blockade, but whether ECE-inhibition exerts beneficial effects in HF is unknown. Thus, we sought the effects of ECE inhibition on LV function and structure in experimental HF.
Methods. In Wistar rats with HF (coronary artery ligation), LV hemodynamics and remodeling as well as LV tissue perfusion were assessed by cardiac catheterization (pressure-volume curves), echocardiography and MRI after treatment with the selective ECE inhibitor SM 1972 (10 mg/kg/day for 28 days starting 7 days after ligation) or placebo.
Results. In placebo treated animals, coronary artery ligation induced classical signs of HF, i.e. decreased LV end-systolic pressure (LVESP) and LVESP-volume relation and increased LV end-diastolic pressure (LVEDP) as well as LVEDP-volume relation, associated with increased LV diastolic diameter, reduced cardiac output (CO) and LV tissue perfusion. Compared to placebo treated HF animals, SM 1972 reduced LVESP (-5 %, p<.05), LVEDP (-51 %, p<.05) as well as LVEDP-volume relation (-28 %, p<.05) and increased LVESP-volume relation (+28 %, p<.05), while CO and LV tissue perfusion were increased (+20 and +20 % respectively, both p<.05). Moreover, SM 1972 reduced LV diastolic diameter (-9 %, p<.05) and LV collagen density (-28 %, p<.05) but not LV hypertrophy.
Conclusion. ECE inhibition reduces cardiac pre- and afterload, prevents LV remodeling and improves LV perfusion as well as function, demonstrating the potential interest of ECE inhibition for the treatment of CHF.
- © 2012 by American Heart Association, Inc.