CLINICAL STUDY: CONGESTIVE HEART FAILURE
Beneficial neurohormonal profile of spironolactone in severe congestive heart failure
Results from the RALES neurohormonal substudy
Michel F. Rousseau, MD, PhD, FACC*,*,
Olivier Gurné, MD, PhD*,
Daniel Duprez, MD, PhD, FACC ,
Walter Van Mieghem, MD, PhD ,
Annie Robert, PhD ,
Sylvie Ahn*,
Laurence Galanti, MD, PhD*,
Jean-Marie Ketelslegers, MD, PhD|| Belgian RALES Investigators
* Division of Cardiology, University of Louvain, Brussels, Belgium
School of Public Health, University of Louvain, Brussels, Belgium
|| Diabetes and Nutrition Unit, University of Louvain, Brussels, Belgium
Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota, USA
Hartcentrum Limburg, Genk, Belgium
Manuscript received April 23, 2002;
revised manuscript received May 28, 2002,
accepted July 15, 2002.
* Reprint requests and correspondence: Dr. Michel F. Rousseau, Division of Cardiology, University of Louvain, Avenue Hippocrate 10/2800, B-1200 Brussels, Belgium.
rousseau{at}card.ucl.ac.be
OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF).
BACKGROUND: In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified.
METHODS: The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months.
RESULTS: Compared with the placebo group, plasma levels of BNP (–23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (–19% at 3 months, p = 0.03; –16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001).
CONCLUSIONS: Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.
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Abbreviations and Acronyms
| | AII | | angiotensin II | | ACE | | angiotensin-converting enzyme | | BNP | | brain natriuretic peptide | | CHF | | congestive heart failure | | ET-1 | | endothelin-1 | | NE | | norepinephrine | | N-proANF | | N-terminal portion of pro-atrial natriuretic factor | | NYHA | | New York Heart Association | | RAAS | | renin-angiotensin-aldosterone system | | RALES | | Randomized ALdactone Evaluation Study |
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