CARDIOVASCULAR MEDICINE

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

J E Macdonald¹, N Kennedy², A D Struthers¹

¹ Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK
² Department of Medical Physics, Ninewells Hospital and Medical School

Correspondence to:
Correspondence to:
Professor Allan D Struthers
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee DD19SY, UK; a.d.struthers{at}dundee.ac.uk

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 ß 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 ß 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). ß-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) µg/ml with placebo, 3.156 (1.123) µg/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 ß 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.

Abbreviations: ACE, angiotensin converting enzyme; BNP, ß-type natriuretic peptide; EPHESUS, eplerenone postacute myocardial infarction heart failure efficacy and survival study; FBFR, forearm blood flow ratio; HAD, hospital anxiety and depression; L-NMMA, N-monomethyl-L-arginine; MLWHF, Minnesota living with heart failure; NYHA, New York Heart Association; PIIINP, procollagen III N-terminal peptide; QTc, corrected QT interval; QTd, QT dispersion; QTdc, corrected QT dispersion; RALES, randomised aldactone evaluation study; SDNN, standard deviation of all NN intervals; ValHeFt, valsartan heart failure trial

Keywords: heart failure; spironolactone; endothelial function; ß-type natriuretic peptide; aldosterone; angiotensin converting enzyme

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Parthasarathy, H. K., Pieske, B., Weisskopf, M., Andrews, C. D., Brunel, P., Struthers, A. D., MacDonald, T. M. (2009). A randomized, double-blind, placebo-controlled study to determine the effects of valsartan on exercise time in patients with symptomatic heart failure with preserved ejection fraction. Eur J Heart Fail 11: 980-989 [Abstract] [Full Text]  
• Waanders, F., Rienstra, H., Boer, M. W., Zandvoort, A., Rozing, J., Navis, G., van Goor, H., Hillebrands, J.-L. (2009). Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats. Am. J. Physiol. Renal Physiol. 296: F1072-F1079 [Abstract] [Full Text]  
• Rosenberg, J., Schou, M., Gustafsson, F., Badskjaer, J., Hildebrandt, P. (2009). Prognostic threshold levels of NT-proBNP testing in primary care. Eur Heart J 30: 66-73 [Abstract] [Full Text]  
• Caprio, M., Newfell, B. G., la Sala, A., Baur, W., Fabbri, A., Rosano, G., Mendelsohn, M. E., Jaffe, I. Z. (2008). Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion. Circ. Res. 102: 1359-1367 [Abstract] [Full Text]  
• Connell, J. M. C., MacKenzie, S. M., Freel, E. M., Fraser, R., Davies, E. (2008). A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function. Endocr. Rev. 29: 133-154 [Abstract] [Full Text]  
• Savoia, C., Touyz, R. M., Amiri, F., Schiffrin, E. L. (2008). Selective Mineralocorticoid Receptor Blocker Eplerenone Reduces Resistance Artery Stiffness in Hypertensive Patients. Hypertension 51: 432-439 [Abstract] [Full Text]  
• Sartorio, C. L., Fraccarollo, D., Galuppo, P., Leutke, M., Ertl, G., Stefanon, I., Bauersachs, J. (2007). Mineralocorticoid Receptor Blockade Improves Vasomotor Dysfunction and Vascular Oxidative Stress Early After Myocardial Infarction. Hypertension 50: 919-925 [Abstract] [Full Text]  
• Berry, C., Murphy, N., De Vito, G., Galloway, S., Seed, A., Fisher, C., Sattar, N., Vallance, P., Hillis, W. S., McMurray, J. (2007). Effects of aldosterone receptor blockade in patients with mild-moderate heart failure taking a beta-blocker. Eur J Heart Fail 9: 429-434 [Abstract] [Full Text]  
• Pitt, B., Gheorghiade, M., Zannad, F., Anderson, J. L., van Veldhuisen, D. J., Parkhomenko, A., Corbalan, R., Klug, E. Q., Mukherjee, R., Solomon, H., On behalf of the EPHESUS Investigators, (2006). Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <=30%. Eur J Heart Fail 8: 295-301 [Abstract] [Full Text]  
• McKie, P. M., Rodeheffer, R. J., Cataliotti, A., Martin, F. L., Urban, L. H., Mahoney, D. W., Jacobsen, S. J., Redfield, M. M., Burnett, J. C. Jr (2006). Amino-Terminal Pro-B-Type Natriuretic Peptide and B-Type Natriuretic Peptide: Biomarkers for Mortality in a Large Community-Based Cohort Free of Heart Failure. Hypertension 47: 874-880 [Abstract] [Full Text]  
• Covic, A., Gusbeth-Tatomir, P., Goldsmith, D. J. A. (2006). Is it time for spironolactone therapy in dialysis patients?. Nephrol Dial Transplant 21: 854-858 [Full Text]  
• Shah, N. C, Pringle, S., Struthers, A. (2006). Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure. Journal of Renin-Angiotensin-Aldosterone System 7: 20-30 [Abstract]  
• Marcy, T. R., Ripley, T. L. (2006). Aldosterone antagonists in the treatment of heart failure. Am J Health Syst Pharm 63: 49-58 [Abstract] [Full Text]  
• Connell, J. M C, Davies, E. (2005). The new biology of aldosterone. J Endocrinol 186: 1-20 [Abstract] [Full Text]  
• Struthers, A D (2005). Pathophysiology of heart failure following myocardial infarction. Heart 91: ii14-ii16 [Abstract] [Full Text]  
• Francis, G. S., Tang, W.H. W. (2005). Should we consider aldosterone as the primary screening target for preventing cardiovascular events?. J Am Coll Cardiol 45: 1249-1250 [Full Text]