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Effects of Chronic Neutral Endopeptidase Inhibition on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs with Moderate Heart Failure

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Abstract

Background. The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure.

Methods. LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30–40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6).

Results. During the 3 months of follow-up, LV EF in control dogs decreased from 37 ± 1% to 28 ± 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 ± 3 vs. 84 ± 5 ml, P < 0.01); ESV: 45 ± 1 vs. 60 ± 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 ± 1% vs. 37 ± 2%), EDV (79± 5 vs. 78± 6 ml) and ESV (52 ± 3 vs. 49 ± 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control.

Conclusion. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.

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Authors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA

    Takayuki Mishima, Mitsuhiro Tanimura, George Suzuki, Anastassia Todor, Victor G. Sharov, Elaine J. Tanhehco, Sidney Goldstein & Hani N. Sabbah

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  1. Takayuki Mishima
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  2. Mitsuhiro Tanimura
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  3. George Suzuki
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  4. Anastassia Todor
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  5. Victor G. Sharov
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  6. Elaine J. Tanhehco
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  7. Sidney Goldstein
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  8. Hani N. Sabbah
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Mishima, T., Tanimura, M., Suzuki, G. et al. Effects of Chronic Neutral Endopeptidase Inhibition on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs with Moderate Heart Failure. Cardiovasc Drugs Ther 16, 209–214 (2002). https://doi.org/10.1023/A:1020644304771

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