SAGE Journals Online
Advertisement
Sign In to gain access to subscriptions and/or personal tools.

 

Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Advertisement

Sign In to gain access to subscriptions and/or personal tools.
Journal of Renin-Angiotensin-Aldosterone System
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Shah, N. C
Right arrow Articles by Struthers, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, N. C
Right arrow Articles by Struthers, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure

Nimit C Shah

Department of Medicine and Therapeutics, Level 7, Ninewells Hospital, Dundee, United Kingdom DD1 9SY, n.shah{at}dundee.ac.uk

Stuart Pringle

Department of Medicine and Therapeutics, Level 7, Ninewells Hospital, Dundee, United Kingdom DD1 9SY

Allan Struthers

Department of Medicine and Therapeutics, Level 7, Ninewells Hospital, Dundee, United Kingdom DD1 9SY

Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality1,2 and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure.

There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/ vascular function3,4 and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris.

Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.5

Key Words: Aldosterone blockade • Spironolactone • Angina • Renin-angiotensin-aldosterone system • ACE-inhibitors

References

  • Pitt B., Zannad F., Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.[Abstract/Free Full Text]
  • Pitt B., Remme W., Zannad F. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.[Abstract/Free Full Text]
  • Struthers AD Aldosterone blockade in heart failure. JRAAS 2004;5(Suppl 1):S23-S27.
  • Rocha R., Stier CT, Jr. Pathophysiological effects of aldosterone in cardiovascular tissues. Trends Endocrinol Metab 2001;12:308-14.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Rajagopalan S., Duquaine D., King S., Pitt B., Patel P. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 2002;105:2212-16.[Abstract/Free Full Text]
  • Guidelines S. Management of stable angina SIGN guidelines. In: Scottish Intercollegiate Guidelines Network; April 2001.
  • Struthers AD The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 2004; 6:539-45.[Abstract/Free Full Text]
  • Weber KT, Brilla CG Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849-65.[Abstract/Free Full Text]
  • Lopez-Sendon J., Swedberg K., McMurray J. et al. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease. The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 2004;25:1454-70.[Free Full Text]
  • Pfeffer MA, Pfeffer JM, Steinberg C., Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation 1985;72:406-12.[Abstract/Free Full Text]
  • Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.[Abstract]
  • Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302.[Abstract]
  • Garg R., Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450-6.[Abstract/Free Full Text]
  • GISSI-3 study protocol on the effects of lisinopril, of nitrates, and of their association in patients with acute myocardial infarction. GISSI-3-Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Am J Cardiol 1992;70:62C-69C.[Medline] [Order article via Infotrieve]
  • Foy SG, Crozier IG, Turner JG et al. Comparison of enalapril versus captopril on left ventricular function and survival three months after acute myocardial infarction (the "PRACTICAL" study). Am J Cardiol 1994;73:1180-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995;345:669-85.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Yusuf S., Sleight P., Pogue J., Bosch J., Davies R., Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53.[Abstract/Free Full Text]
  • Fox KM Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Braunwald E., Domanski MJ, Fowler SE et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68.[Abstract/Free Full Text]
  • Milan Gupta EMLaSV. Should patients with stable coronary artery disease be treated with ACE inhibitor therapy? Nat Clin Pract Cardiovasc Med 2005;2005:124-5.
  • Nomura M., Morohashi K., Kirita S. et al. Three forms of rat CYP11B genes: 11 beta-hydroxylase gene, aldosterone synthase gene, and a novel gene. J Biochem (Tokyo) 1993;113:144-52.[Abstract/Free Full Text]
  • Fardella CE, Miller WL Molecular biology of mineralocorticoid metabolism. Annu Rev Nutr 1996; 16:443-70.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Tremblay A., Waterman MR, Parker KL, Lehoux JG Regulation of rat adrenal messenger RNA and protein levels for cytochrome P-450s and adrenodoxin by dietary sodium depletion or potassium intake. J Biol Chem 1991;266:2245-51.[Abstract/Free Full Text]
  • Shibata H., Ogishima T., Mitani F. et al. Regulation of aldosterone synthase cytochrome P-450 in rat adrenals by angiotensin II and potassium. Endocrinology 1991;128: 2534-9.[Abstract/Free Full Text]
  • Biglieri EG, Arteaga E., Kater CE Effect of ACTH on aldosterone and other mineralocorticoid hormones. Ann N Y Acad Sci 1987;512:426-37.[CrossRef][Medline] [Order article via Infotrieve]
  • Aguilera G., Fujita K., Catt KJ Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin. Endocrinology 1981;108:522-8.[Abstract/Free Full Text]
  • Casey ML, MacDonald PC Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and metabolism. Endocr Rev 1982;3:396-403.[Abstract/Free Full Text]
  • Silvestre JS, Robert V., Heymes C. et al. Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J Biol Chem 1998;273:4883-91.[Abstract/Free Full Text]
  • Takeda Y., Miyamori I., Yoneda T. et al. Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin. J Clin Endocrinol Metab 1996;81:2797-800.[Abstract/Free Full Text]
  • Funder JW Aldosterone, mineralocorticoid receptors and vascular inflammation. Mol Cell Endocrinol 2004;217:263-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ikeda U., Kanbe T., Nakayama I., Kawahara Y., Yokoyama M., Shimada K. Aldosterone inhibits nitric oxide synthesis in rat vascular smooth muscle cells induced by interleukin-1 beta. Eur J Pharmacol 1995;290:69-73.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Farquharson CA, Struthers AD Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000;101:594-7.[Abstract/Free Full Text]
  • Keidar S., Kaplan M., Pavlotzky E. et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation 2004;109:2213-20.[Abstract/Free Full Text]
  • Bauersachs J., Heck M., Fraccarollo D. et al. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression. J Am Coll Cardiol 2002;39:351-8. oxide synthase expression. J Am Coll Cardiol 2002;39:351-8.[Abstract/Free Full Text]
  • Macdonald JE, Kennedy N., Struthers AD 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. Heart 2004;90:765-70.[Abstract/Free Full Text]
  • Taddei S., Mattei P., Virdis A., Sudano I., Ghiadoni L., Salvetti A. Effect of potassium on vasodilation to acetylcholine in essential hypertension. Hypertension 1994;23:485-90.[Abstract/Free Full Text]
  • Sugimoto T., Tobian L., Ganguli MC High potassium diets protect against dysfunction of endothelial cells in stroke-prone spontaneously hypertensive rats. Hypertension 1988;11(6 Pt 2):579-85.[Abstract/Free Full Text]
  • Rubanyi GM, Vanhoutte PM Potassium-induced release of endothelium-derived relaxing factor from canine femoral arteries. Circ Res 1988;62:1098-103.[Abstract/Free Full Text]
  • Edwards G., Dora KA, Gardener MJ, Garland CJ, Weston AH K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 1998;396:269-72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Farquharson CA, Struthers AD Increasing plasma potassium with amiloride shortens the QT interval and reduces ventricular extrasystoles but does not change endothelial function or heart rate variability in chronic heart failure. Heart 2002;88:475-80.[Abstract/Free Full Text]
  • MacFadyen RJ, Barr CS, Struthers AD Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 1997;35(1):30-4.[Abstract/Free Full Text]
  • Yee KM, Pringle SD, Struthers AD Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol 2001;37:1800-07.[Abstract/Free Full Text]
  • Farquharson CA, Struthers AD Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond) 2002;103:425-31.[Medline] [Order article via Infotrieve]
  • Garnier A., Bendall JK, Fuchs S. et al. Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice. Circulation 2004;110:1819-25.[Abstract/Free Full Text]
  • Struthers AD, MacDonald TM Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res 2004;61:663-70.[Abstract/Free Full Text]
  • Brilla CG, Matsubara LS, Weber KT Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993;25:563-75.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Robert V., Silvestre JS, Charlemagne D. et al. Biological determinants of aldosterone-induced cardiac fibrosis in rats. Hypertension 1995;26(6 Pt 1):971-8.[Abstract/Free Full Text]
  • Robert V., Van Thiem N., Cheav SL, Mouas C., Swynghedauw B., Delcayre C. Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension. Hypertension 1994;24(1):30-6.[Abstract/Free Full Text]
  • Young MJ, Moussa L., Dilley R., Funder JW Early inflammatory responses in experimental cardiac hypertrophy and fibrosis: effects of 11 beta-hydroxysteroid dehydrogenase inactivation. Endocrinology 2003;144:1121-5.[Abstract/Free Full Text]
  • Gerling IC, Sun Y., Ahokas RA et al. Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype. Am J Physiol Heart Circ Physiol 2003;285: H813-H821.[Abstract/Free Full Text]
  • Sun Y., Zhang J., Lu L., Chen SS, Quinn MT, Weber KT Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol 2002;161:1773-81.[Abstract/Free Full Text]
  • Rocha R., Rudolph AE, Frierdich GE et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002;283:H1802-10.[Abstract/Free Full Text]
  • Duprez DA, De Buyzere ML, Rietzschel ER et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 1998;19:1371-6.[Abstract/Free Full Text]
  • Rocha R., Chander PN, Khanna K., Zuckerman A., Stier CT, Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 1998;31(1 Pt 2):451-8.[Abstract/Free Full Text]
  • Brown NJ, Kim KS, Chen YQ et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab 2000;85:336-44.[Abstract/Free Full Text]
  • Ullian ME, Schelling JR, Linas SL Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses. Hypertension 1992;20(1):67-73.[Abstract/Free Full Text]
  • Sun Y., Ratajska A., Zhou G., Weber KT Angiotensin-converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J Lab Clin Med 1993;122:395-403.[Web of Science][Medline] [Order article via Infotrieve]
  • Rocha R., Stier CT, Jr., Kifor I. et al. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology 2000;141:3871-8.[Abstract/Free Full Text]
  • Klappacher G., Franzen P., Haab D. et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 1995;75:913-18.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Diez J., Laviades C., Mayor G., Gil MJ, Monreal I. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 1995;91:1450-6.[Abstract/Free Full Text]
  • Zannad F., Alla F., Dousset B., Perez A., Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000;102:2700-06.[Abstract/Free Full Text]
  • Korkmaz ME, Muderrisoglu H., Ulucam M., Ozin B. Effects of spironolactone on heart rate variability and left ventricular systolic function in severe ischemic heart failure. Am J Cardiol 2000;86:649-53.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Barr CS, Lang CC, Hanson J., Arnott M., Kennedy N., Struthers AD Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995;76:1259-65.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Wang W., McClain JM, Zucker IH Aldosterone response in man. Clin Sci (Lond) 1998;95:687-92. reduces baroreceptor discharge in the dog. Hypertension 1992;19:270-7.[Abstract/Free Full Text]
  • Yee KM, Struthers AD Aldosterone blunts the baroreflex response in man. Clin Sci (Lond) 1998;95.687-92. 66. Chowdhary S.,Townend JN Role of nitric oxide in the regulation of cardiovascular autonomic control. Clin Sci (Lond) 1999;97(1):5-17.[Medline] [Order article via Infotrieve]
  • Spieker LE, Corti R., Binggeli, Luscher TF, Noll G. Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans. J Am Coll Cardiol 2000;36:213-18.[Abstract/Free Full Text]
  • Nolan J., Batin PD, Andrews R. et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation 1998;98:1510-16.[Abstract/Free Full Text]
  • Bashir Y., Sneddon JF, Staunton HA et al. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol 1993;72:1156-62.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ascherio A., Rimm EB, Hernan MA et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation 1998;98:1198-204.[Abstract/Free Full Text]
  • MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? Heart 1999;82(1):57-61.[Abstract/Free Full Text]
  • McKelvie RS, Yusuf S., Pericak D. et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999;100:1056-64.[Abstract/Free Full Text]
  • Sato A., Saruta T. Aldosterone escape during angiotensinconverting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001;29(1):13-21.[Web of Science][Medline] [Order article via Infotrieve]
  • Davies JI, Band M., Morris A., Struthers AD Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia 2004;47:1687-94.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Dahlof B., Devereux RB, Kjeldsen SE et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033-41.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 7, No. 1, 20-30 (2006)
DOI: 10.3317/jraas.2006.002
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Shah, N. C
Right arrow Articles by Struthers, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shah, N. C
Right arrow Articles by Struthers, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Advertisement