Current Heart Failure Reports

, Volume 1, Issue 2, pp 57–64

Inhibition of RAAS—When is it too much?

  • Pablo Navarro
  • Robert Moskowitz
  • Thierry H. Le Jemtel
Article

Abstract

Deactivation of the renin-angiotensin-aldosterone system (RAAS) is clearly beneficial in patients with recent myocardial infarction and chronic heart failure. Most of the experience with deactivation of the RAAS has been collected in placebo-controlled randomized trials of angiotensinconverting enzyme inhibition (ACEI). The hypothesis that angiotensin receptor blockade may be a better approach to deactivate the RAAS has not survived the test of time. Despite the extensive experience with ACEI and aldosterone receptor blockade in patients with recent myocardial infarction and chronic heart failure, several issues remain unanswered. These are addressed in this review.

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References and Recommended Reading

  1. 1.
    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, 316:1429–1435.CrossRefGoogle Scholar
  2. 2.
    The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991, 325:293–302.CrossRefGoogle Scholar
  3. 3.
    The SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992, 327:685–691.CrossRefGoogle Scholar
  4. 4.
    Jong P, Yusuf S, Rousseau MF, Ahn SA, et al.: Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet 2003, 361:1843–1848.PubMedCrossRefGoogle Scholar
  5. 5.
    Pfeffer MA, Braunwald E, Moye LA, et al.: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992, 327:669–677.PubMedCrossRefGoogle Scholar
  6. 6.
    Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993, 342:821–828.Google Scholar
  7. 7.
    Arnold J, Yusuf S, Young J, et al.: Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 2003, 107:1284–1290.PubMedCrossRefGoogle Scholar
  8. 8.
    Jorde U, Ennezat P, Lisker J, et al.: Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000, 101:844–846.PubMedGoogle Scholar
  9. 9.
    Husain A, Li M, Graham R: Do studies with ACE N- and C-domain-selective inhibitors provide evidence for a non-ACE, non-chymase angiotensin II-forming pathway? Circ Res 2003, 93:91–93.PubMedCrossRefGoogle Scholar
  10. 10.
    Kokkonen J, Lindstedt K, Kovanen P: Role for chymase in heart failure: angiotensin II-dependent or-independent mechanisms? Circulation 2003, 107:2522–2524.PubMedCrossRefGoogle Scholar
  11. 11.
    Veldhuisen D, Genth-Zotz S, Brouwer J, et al.: High-versus low-dose ACE inhibition in chronic heart failure: a doubleblind, placebo-controlled study of imidapril. J Am Coll Cardiol 1998, 32:1811–1818.PubMedCrossRefGoogle Scholar
  12. 12.
    Clement D, De Buyzere M, Tomas M, et al.: Long-term effects of clinical outcome with low and high dose in the Captopril in Heart Insufficient Patients Study (CHIPS). Acta Cardiol 2000, 55:1–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. The NETWORK Investigators. Eur Heart J 1998, 19:481–489.Google Scholar
  14. 14.
    Packer M, Poole-Wilson PA, Armstrong PW, et al.: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS study group. Circulation 1999, 100:2312–2318. This is the largest (with the greatest duration) of the studies that examine the issue of ACE inhibitor dosing. ATLAS provides convincing evidence that high-dose ACE inhibition is associated with a reduction in morbidity yet no significant mortality benefit.PubMedGoogle Scholar
  15. 15.
    Nanas J, Alexopoulos G, Anastasiou-Nana M, et al.: Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. J Am Coll Cardiol 2000, 36:2090–2095.PubMedCrossRefGoogle Scholar
  16. 16.
    Kittleson M, Hurwitz S, Shah M, et al.: Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality. J Am Coll Cardiol 2003, 41:2029–2035.PubMedCrossRefGoogle Scholar
  17. 17.
    Pacher R, Stanek B, Berger R, et al.: Effects of two different enalapril dosages on clinical, haemodynamic and neurohormonal response of patients with severe congestive heart failure. Eur Heart J 1996, 17:1223–1232.PubMedGoogle Scholar
  18. 18.
    Berger R, Stanek B, Hulsmann M, et al.: Delayed effects of one-year treatment with low-dose as compared with highdose enalapril on morbidity and mortality of patients with severe heart failure. J Clin Bas Cardiol 1998, 1:19–24.Google Scholar
  19. 19.
    Pretorius M, Rosenbaum D, Vaughan D, et al.: Angiotensinconverting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation 2003, 107:579–585.PubMedCrossRefGoogle Scholar
  20. 20.
    McKelvie R, 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. Circulation 1999, 100:1056–1064.PubMedGoogle Scholar
  21. 21.
    Cohn J, Tognoni G: A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med 2001, 345:1667–1675.PubMedCrossRefGoogle Scholar
  22. 22.
    Wong M, Staszewsky L, Latini R, et al.: Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol 2002, 40:970–975.PubMedCrossRefGoogle Scholar
  23. 23.
    McMurrayJ, Ostergran J, Swedberg K, et al.: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting enzyme inhibitors: the CHARM-Added trial. Lancet 2003, 362:767–771. This recent study demonstrated a significant combined morbidity and mortality benefit with ACE inhibitor/ARB combination therapy in patients with relatively severe heart failure followed for more than 3 years.PubMedCrossRefGoogle Scholar
  24. 24.
    Pfeffer M, McMurray J, Velazquez E, et al.: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003, 349:1893–1906. This large, recent study found no significant advantages of combination therapy in patients with MI and heart failure, and provides further evidence of comparable effects of ACE inhibitor and ARB therapy. A post hoc analysis revealed a significant reduction in hospitalizations in the valsartan-and-captopril group compared with the captopril group.PubMedCrossRefGoogle Scholar
  25. 25.
    Jong P, Demers C, McKelvie R, et al.: Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Cardiol 2002, 39:463–470.PubMedCrossRefGoogle Scholar
  26. 26.
    Hamroff G, Katz S, Mancini D, et al.: Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation 1999, 99:990–992.PubMedGoogle Scholar
  27. 27.
    Pitt B, Poole-Wilson P, Segal R, et al.: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: a randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet 2000, 355:1582–1587.PubMedCrossRefGoogle Scholar
  28. 28.
    Berlowitz, Latif F, Hankins S, et al.: Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers. J Cardiovasc Pharmacol 2001, 37:692–696.PubMedCrossRefGoogle Scholar
  29. 29.
    Grady E, Sechi L, Griffin C, et al.: Expression of AT2 receptors in the developing rat fetus. J Clin Invest 1991, 88:921–933.PubMedCrossRefGoogle Scholar
  30. 30.
    Stoll M, Unger T: Angiotensin and its ATII receptor: new insights into an old system. Regul Pept 2001, 99:175–182.PubMedCrossRefGoogle Scholar
  31. 31.
    Malendowicz S, Ennezat P, Testa M, et al.: Angiotensin II receptor subtypes in the skeletal muscle vasculature of patients with severe congestive heart failure. Circulation 2000, 102:2210–2213.PubMedGoogle Scholar
  32. 32.
    Siragy H: The role of the AT2 receptor in hypertension. Am J Hypertens 2000, 13:62S-67S.PubMedCrossRefGoogle Scholar
  33. 33.
    Levy B: Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Circulation 2004, 109:8–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Abadir P, Carey R, Siragy H: Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice. Hypertension 2003, 42:600–604.PubMedCrossRefGoogle Scholar
  35. 35.
    Chen R, Iwai M, Wu L, et al.: Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. Hypertension 2003, 42:542–547.PubMedCrossRefGoogle Scholar
  36. 36.
    Kurisu S, Ozono R, Oshima T, et al.: Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. Hypertension 2003, 41:99–107.PubMedCrossRefGoogle Scholar
  37. 37.
    Scherrer-Crosbie M, Ullrich R, Bloch K, et al.: Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 2001, 104:1286.PubMedGoogle Scholar
  38. 38.
    Okubo S, Niimura F, Nishimura H, et al.: Angiotensin-independent mechanism of aldosterone synthesis during chronic extracellular fluid volume depletion. J Clin Invest 1997, 99:855–860.PubMedGoogle Scholar
  39. 39.
    Barr C, Lang C, Hanson J, et al.: Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995, 76:1259–1265.PubMedCrossRefGoogle Scholar
  40. 40.
    Jessup M: Aldosterone blockade and heart failure. N Engl J Med 2003, 348:1380–1382.PubMedCrossRefGoogle Scholar
  41. 41.
    Wang W: Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension 1994, 24:571–575.PubMedGoogle Scholar
  42. 42.
    Pitt B, Zannad F, Remme W, 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, 341:709–717. This landmark trial demonstrated that the addition of aldosterone blockade to background therapy in patients with severe congestive heart failure leads to a significant reduction in all-cause mortality and morbidity.PubMedCrossRefGoogle Scholar
  43. 43.
    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, 348:1309–1321. The recent EPHESUS trial extends the use of aldosterone blockade to patients with LV dysfunction and signs of heart failure after MI. Although significant, the magnitude of morbidity and mortality benefit was less than in RALES.PubMedCrossRefGoogle Scholar
  44. 44.
    Mariantonietta C, Zanolla L, Rossi A, et al.: Long-term, dosedependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2002, 40:304–310.CrossRefGoogle Scholar
  45. 45.
    Feola M, Menardi E, Ribichini F, et al.: Effects of the addition of a low dose of spironolactone on brain natriuretic peptide plasma level and cardiopulmonary function in patients with moderate congestive heart failure. Med Sci Monit 2003, 9:CR341-CR345.PubMedGoogle Scholar
  46. 46.
    Weir MR, Gray JM, Paster R, et al.: Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. Hypertension 1995, 26:124–130.PubMedGoogle Scholar
  47. 47.
    Exner D, Dries D, Domanski M, et al.: Lesser response to angiotensin-converting enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001, 344:1351–1357.PubMedCrossRefGoogle Scholar
  48. 48.
    Carson P, Ziesche S, Johnson G, et al.: Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999, 5:178–187.PubMedCrossRefGoogle Scholar
  49. 49.
    Dries D, Strong M, Cooper R, et al.: Efficacy of angiotensinconverting enzyme inhibition in reducing progression from asymptomatic left ventricular dysfunction to symptomatic heart failure in black and white patients. J Am Coll Cardiol 2002, 40:311–317.PubMedCrossRefGoogle Scholar
  50. 50.
    Shekelle P, Rich M, Morton S, et al.: Efficacy of angiotensinconverting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status. J Am Coll Cardiol 2003, 41:1529–1538. This meta-analysis provides evidence of ACE inhibitor benefit in several subgroups, except women with asymptomatic LV dysfunction. A pooled analysis revealed the same relative risk reduction with ACE inhibitor usage in black patients and white patients, although the reduction was not statistically significant in black patients.PubMedCrossRefGoogle Scholar
  51. 51.
    Agodoa L, Appel L, Bakris G, et al.: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis. JAMA 2001, 285:2719–2728.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Pablo Navarro
  • Robert Moskowitz
  • Thierry H. Le Jemtel
    • 1
  1. 1.Room G-46 Forchheimer BuildingAlbert Einstein College of MedicineBronxUSA

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