Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure

Circulation. 2002 Dec 3;106(23):2967-72. doi: 10.1161/01.cir.0000039104.56479.42.

Abstract

Background: In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF.

Methods and results: HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis.

Conclusions: Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Chronic Disease
  • Disease Models, Animal
  • Disease Progression
  • Dogs
  • Echocardiography
  • Enzyme Activation / drug effects
  • Eplerenone
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism
  • Heart / drug effects
  • Heart Failure / complications
  • Heart Failure / drug therapy*
  • Heart Failure / pathology
  • Hemodynamics / drug effects
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Myocardium / metabolism
  • Myocardium / pathology
  • RNA, Messenger / metabolism
  • Spironolactone / analogs & derivatives*
  • Spironolactone / therapeutic use*
  • Stroke Volume / drug effects
  • Treatment Outcome
  • Ventricular Dysfunction, Left / complications
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / prevention & control
  • Ventricular Remodeling / drug effects*

Substances

  • Mineralocorticoid Receptor Antagonists
  • RNA, Messenger
  • Fibroblast Growth Factor 2
  • Spironolactone
  • Eplerenone