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, nϭ7) or no therapy at all (control, nϭ7). 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 (62Ϯ4 versus 68Ϯ4 mL, PϽ0.001, and 38Ϯ3 versus 47Ϯ3 mL, PϽ0.001, respectively), and EF decreased significantly (38Ϯ1% versus 31Ϯ2%, PϽ0.001). 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.

Effects of Aldosterone on the Vasculature

“…Aldosterone also increased and MR blockade reduced vascular inflammation and metalloproteinase-2 and -9 activation, suggesting that aldosterone may play a role in plaque rupture. 67 These effects are Figure 2. Mechanisms of genomic (longterm) and nongenomic (rapid) aldosterone (Aldo) effects.…”

Sympathetic drive stimulating diastolic dysfunction?

“…18 Reduced MIBG uptake into presynaptic sympathetic nerve terminals, as measured by a reduced MIBG heart-to-mediastinum ratio, reflects reduced beta AR density in heart failure patients. It also is strongly correlated with heart failure progression and cardiac death in heart failure patients with left ventricular dysfunction.…”

Effects of Eplerenone and Salt Intake on Left Ventricular Remodeling after Myocardial Infarction in Rats

“…It has been reported that aldosterone synthesis in local cardiac tissues and its effects are related with the process of left ventricular remodeling (26). Aldosterone blockers have been reported to suppress cardiac hypertrophy and cardiac fibrosis (27,28). Takeda et al reported that a high-salt intake accelerates the expression of the aldosterone synthase gene, CYP11B2 mRNA, in the cardiac tissues while also increasing cardiac aldosterone synthesis locally, which may affect cardiac hypertrophy independently of the RAAS in blood (29).…”