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J Am Coll Cardiol, 2002; 40:1596-1601
© 2002 by the American College of Cardiology Foundation
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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{dagger}, Walter Van Mieghem, MD, PhD{ddagger}, 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
{dagger} Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota, USA
{ddagger} 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.

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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