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

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.

• Authors: George Suzuki, Hideaki Morita, Takayuki Mishima, Victor G Sharov, Anastassia Todor, Elaine J Tanhehco, Amy E Rudolph, Ellen G McMahon, Sidney Goldstein, Hani N Sabbah
• Journal: Circulation (Circulation) Vol. 106 Issue 23 Pg. 2967-72 (Dec 03 2002) ISSN: 1524-4539 [Electronic] United States
• PMID: 12460880 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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