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


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.
Suzuki
George
G
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Detroit, Mich, USA.
Morita
Hideaki
H
Mishima
Takayuki
T
Sharov
Victor G
VG
Todor
Anastassia
A
Tanhehco
Elaine J
EJ
Rudolph
Amy E
AE
McMahon
Ellen G
EG
Goldstein
Sidney
S
Sabbah
Hani N
HN
D000284:Administration, Oral; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D000077545:Eplerenone; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects*
D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D013148:Spironolactone; D000077545:Eplerenone