Role of aldosterone receptor antagonist eplerenone in aortic stenosis
Article Outline
Stewert et al1 have done a study showing that use of epleronone in patients with moderate-severe aortic stenosis (AS) did not slow onset of left ventricle (LV) systolic or diastolic dysfunction, decrease LV mass, or reduce progression of valve stenosis. I have a few concerns.
Experimental studies have demonstrated increased expression of hypertrophic markers (NPPA, NPPB, and ACTA1) in cardiac myocytes by phosphorylation of protein kinase D and collagen expression (COL1A1, COL1A2, and COL3A1) and transforming growth factor-beta1 in cardiac fibroblasts by up-regulation of phosphoinositide 3-kinase-p100delta with aldosterone.2 Aldosterone antagonist spironolactone reversed interstitial fibrosis, attenuated myocyte disarray, and improved diastolic function in cardiac troponin T-Q92 by inhibition of protein kinase D and phosphoinositide 3-kinase-p110delta.2, 3
To the contrary when these studies were performed on humans, they showed negative effects. Cardiac and/or plasma aldosterone levels measured in organ donors and hypertrophic cardiomyopathy (HCM) patients were similar. The effect of aldosterone synthase (CYP11B2) C-344T polymorphism on LV mass index and interventricular septum thickness was determined in 79 genetically independent HCM subjects, suggesting that the association between the CYP11B2 C-344T polymorphism and hypertrophy in HCM was most likely related to T allele–related increases in circulating aldosterone. Hence, this study questioned the need for further studies in determining the benefit of aldosterone blockade in such patients with left ventricular outflow tract obstruction.4
The Randomized Aldactone Evaluation Study (RALES) showed a 30% reduction in mortality in patients with stages III and IV heart failure using spironolactone, and epleronone used in the Eplerone Heart Failure Efficacy and Survival Study (EPHESUS) trial demonstrated decreased cardiovascular mortality in patients with post–myocardial infarction.5, 6 Therefore, there is only a minimal benefit of using epleronone in asymptomatic patients. There is no evidence to show that drugs improve the life expectancy in patients with severe AS without surgery; hence, use in symptomatic patients may not be beneficial.7 3-Hydroxy-3-methylglutaryl coenzyme A inhibitors have shown some evidence in slowing the progression of AS.8
References
- A randomized trial of the aldosterone-receptor antagonist eplerenone in asymptomatic moderate-severe aortic stenosis. Am Heart J. 2008;156:348–355
- Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation. 2004;109:1284–1291
- . Combined effects of low-dose spironolactone and captopril therapy in a rat model of genetic hypertrophic cardiomyopathy. J Cardiovasc Pharmacol. 2006;48:265–273
- Cardiac aldosterone in subjects with hypertrophic cardiomyopathy. J Renin Angiotensin Aldosterone Syst. 2006;7:225–230
- The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717
- Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–1321
- . Degenerative aortic stenosis. BMJ. 2008;336:550–555
- Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol. 2007;49:554–561
PII: S0002-8703(08)00914-9
doi:10.1016/j.ahj.2008.10.022
© 2009 Mosby, Inc. All rights reserved.
Refers to article:
- A randomized trial of the aldosterone-receptor antagonist eplerenone in asymptomatic moderate-severe aortic stenosis , 05 June 2008
