Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment

Abstract

Objectives: To examine whether the favourable effects on endothelial function, vascular angiotensin converting enzyme (ACE) activity, cardiac remodelling, autonomic function, and QT intervals of spironolactone in combination with ACE inhibitor also occur in patients with New York Heart Association class I-II congestive heart failure (CHF) taking optimal treatment (including beta blockers).

Methods: Double blind, crossover study comparing 12.5-50 mg/24 hours spironolactone (three months) with placebo in 43 patients with class I-II CHF taking ACE inhibitors and beta blockers.

Results: Acetylcholine induced vasodilatation improved with spironolactone (p = 0.044). Vascular ACE activity fell (p = 0.006). QTc and QTd fell (mean (SD) QTc 473 (43.1) ms with placebo, 455 (35.4) ms with spironolactone, p = 0.002; QTd 84.5 (41.3) ms with placebo, 72.1 (32.3) ms with spironolactone, p = 0.037). beta-Type natriuretic peptide (BNP) and procollagen III N-terminal peptide (PIIINP) concentrations were also reduced by spironolactone (mean (SD) BNP 48.5 (29.6) pg/ml with placebo, 36.8 (28.5) pg/ml with spironolactone, p = 0.039; PIIINP 3.767 (1.157) microg/ml with placebo, 3.156 (1.123) microg/ml with spironolactone, p = 0.000).

Conclusions: Spironolactone improves vascular function (endothelial function, vascular ACE activity) and other markers of prognosis (BNP, collagen markers, and QT interval length) in asymptomatic or mild CHF when added to optimal treatment including beta blockade. This gives support to the hypothesis that the prognostic benefit seen in RALES (randomised aldactone evaluation study) and EPHESUS (eplerenone postacute myocardial infarction heart failure efficacy and survival study) may also occur in patients with milder CHF already taking standard optimal treatment.

Figure 1

Forearm blood flow ratio (FBFR) response to acetylcholine after spironolactone (S) or placebo (P). *p<0.05.

Figure 2

Forearm blood flow ratio (FBFR) response to angiotensin I after spironolactone (S) or placebo (P). **p<0.01.

Figure 3

Forearm blood flow ratio (FBFR) response to angiotensin II after spironolactone (S) or placebo (P). *p<0.05.

Figure 4

Forearm blood flow ratio (FBFR) response to N-monomethyl-l-arginine (L-NMMA) alone and co-infused with acetylcholine after spironolactone (S) or placebo (P).