R J MacFadyen1, C S Barr, A D Struthers. 1. Department of Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, UK. macfadyen@clinpharm.dundee.ac.uk
Abstract
BACKGROUND: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. METHODS AND RESULTS: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50-100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability (n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00-09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. CONCLUSIONS: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.
RCT Entities:
BACKGROUND: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. METHODS AND RESULTS: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50-100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability (n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00-09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. CONCLUSIONS: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.