Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure.
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.


CONCLUSIONS
Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.
Mishima
Takayuki
T
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, 2799 W. Grand Boulevard, Detroit, MI 48202, USA.
Tanimura
Mitsuhiro
M
Suzuki
George
G
Todor
Anastassia
A
Sharov
Victor G
VG
Tanhehco
Elaine J
EJ
Goldstein
Sidney
S
Sabbah
Hani N
HN
D000818:Animals; D002908:Chronic Disease; D017023:Coronary Angiography; D004285:Dogs; D006333:Heart Failure / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D015244:Thiorphan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
C049331:racecadotril; D015244:Thiorphan; D015260:Neprilysin