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Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition

Virginie Mellin1, Arco Y Jeng, Christelle Monteil

  • 1INSERM U644, IFRMP no. 23, Rouen University Medical School, Rouen, France and Novarhis Institutes for BioMedical Research, East Hanover, New Jersey, USA.

Journal of Cardiovascular Pharmacology
|August 24, 2005
PubMed

Insights

Triple inhibition combining ACE, endothelin-converting enzyme, and neutral endopeptidase (ACE-ECE-NEP) improved heart failure hemodynamics and structure in rats more than dual inhibition. Further studies are needed to confirm effects on exercise tolerance and survival.

Area of Science:

  • Cardiology
  • Pharmacology
  • Experimental Medicine

Background:

  • Chronic heart failure (CHF) mortality remains high despite ACE inhibitor treatment due to persistent activation of other neurohumoral systems.
  • Endothelin and atrial natriuretic peptide pathways are implicated in CHF pathophysiology.
  • Dual endothelin-converting enzyme-neutral endopeptidase (ECE-NEP) inhibition shows promise in experimental CHF.

Purpose of the Study:

  • To compare the efficacy of triple inhibition (ACE-ECE-NEP) versus dual inhibition (ACE or ECE-NEP) in experimental CHF.
  • To evaluate the impact on left ventricular (LV) hemodynamics and cardiac remodeling in rats with CHF.

Main Methods:

  • Rats with CHF were treated with benazepril (ACE inhibitor) or CGS26303 (ECE-NEP inhibitor) alone or in combination for 28 days.
  • Hemodynamic and structural parameters of the left ventricle were assessed.

Main Results:

  • Triple ACE-ECE-NEP inhibition demonstrated a more significant reduction in blood pressure compared to ACE or ECE-NEP inhibition alone.
  • While all treatments increased cardiac output similarly, ACE-ECE-NEP inhibition led to greater reductions in LV diameter and end-diastolic pressure.
  • The most pronounced decrease in LV weight and myocardial collagen accumulation was observed with ACE-ECE-NEP inhibition.

Conclusions:

  • Triple ACE-ECE-NEP inhibition offers superior improvements in LV hemodynamics and cardiac structure in experimental CHF compared to dual ACE or ECE-NEP inhibition.
  • The clinical significance of these findings regarding exercise tolerance and survival in CHF patients requires further investigation.

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