Modulation of the Renin-Angiotensin-Aldosterone System in Heart Failure

Coronary Heart Disease (JA Farmer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Coronary Heart Disease


The renin-angiotensin-aldosterone system (RAAS) is well-established and continues to be pursued as a therapeutic target in the treatment of heart failure, predominantly due to the success of agents that block RAAS in clinical trials of systolic heart failure. The optimal treatment of heart failure patients with preserved ejection fraction (HFpEF), however, remains unclear. Early trials of direct renin inhibitors have suggested that these agents may play a role in HFpEF, but recent clinical trial results have not been encouraging. Preliminary trials of angiotensin-receptor/neprilysin inhibitors look promising. Whether results with these or other drugs will alter current recommendations remains to be seen. In this review, we assess the current understanding of the role of RAAS modulation in heart failure.


Novel therapy Treatment Drugs Renin-angiotensin-aldosterone blockers Chronic heart failure Reduced/preserved ejection fraction 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.••
    McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803–69. Latest European guidelines for Heart Failure Management incorporating levels of evidence. PubMedCrossRefGoogle Scholar
  2. 2.••
    Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Latest North American guidelines for Heart Failure Management incorporating levels of evidence. Google Scholar
  3. 3.
    McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med. 2010;362(3):228–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Bueno H, Ross JS, Wang Y, et al. Trends in length of stay and short-term outcomes among medicare patients hospitalized for heart failure, 1993-2006. Jama. 2010;303(21):2141–7.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation. 2012;126(1):65–75.PubMedCrossRefGoogle Scholar
  6. 6.•
    Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32(6):670–9. A useful review of the pathophysiology and difference between HFpEF and HFrEF. PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–33.CrossRefGoogle Scholar
  8. 8.
    The SOLVD. Investigators. 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(5):293–302.CrossRefGoogle Scholar
  9. 9.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative north scandinavian enalapril survival study (CONSENSUS). N Engl J Med. 1987;316(23):1429–35.CrossRefGoogle Scholar
  10. 10.
    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(10):669–77.PubMedCrossRefGoogle Scholar
  11. 11.•
    Koitabashi N, Kass DA. Reverse remodeling in heart failure–mechanisms and therapeutic opportunities. Nat Rev Cardiol. 2012;9(3):147–57. Concise review of mechanisms underpinning potential therapeutics advances. CrossRefGoogle Scholar
  12. 12.
    Konstam MA, Rousseau MF, Kronenberg MW, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD investigators. Circulation. 1992;86(2):431–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Goussev A, Sharov VG, Shimoyama H, et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol. 1998;275(2 Pt 2):H626–31.PubMedGoogle Scholar
  14. 14.
    McMurray JJ, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation. 2004;110(20):3281–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–906.PubMedCrossRefGoogle Scholar
  16. 16.
    Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the losartan heart failure survival study ELITE II. Lancet. 2000;355(9215):1582–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-alternative trial. Lancet. 2003;362(9386):772–6.PubMedCrossRefGoogle Scholar
  18. 18.
    McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-added trial. Lancet. 2003;362(9386):767–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–75.PubMedCrossRefGoogle Scholar
  20. 20.
    Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.PubMedCrossRefGoogle Scholar
  21. 21.
    Kuenzli A, Bucher HC, Anand I, et al. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS One. 2010;5(4):e9946.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Bulletin. NP. Dual renin-angiotensin aldosterone system blockade in diabetic nephropathy and increased adverse events. 2012; Accessed 4th September 2013
  23. 23.
    Zannad F. Angiotensin-converting enzyme inhibitor and spironolactone combination therapy. New objectives in congestive heart failure treatment. Am J Cardiol. 1993;71(3):34A–9A.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann N Y Acad Sci. 2002;970:89–100.PubMedCrossRefGoogle Scholar
  26. 26.
    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(17):1259–65.PubMedCrossRefGoogle Scholar
  27. 27.
    The RALES. Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (]). Am J Cardiol. 1996;78(8):902–7.CrossRefGoogle Scholar
  28. 28.
    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(14):1309–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351(6):543–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Wei L, Struthers AD, Fahey T, Watson AD, Macdonald TM. Spironolactone use and renal toxicity: population based longitudinal analysis. BMJ. 2010;340:c1768.PubMedCrossRefGoogle Scholar
  32. 32.
    Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R. Serum potassium and clinical outcomes in the eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS). Circulation. 2008;118(16):1643–50.PubMedCrossRefGoogle Scholar
  33. 33.
    Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27(19):2338–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet. 2003;362(9386):777–81.PubMedCrossRefGoogle Scholar
  35. 35.
    Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Lund LH, Benson L, Dahlstrom U, Edner M. Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. Jama. 2012;308(20):2108–17.PubMedCrossRefGoogle Scholar
  37. 37.
    Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the aldo-dhf randomized controlled trial. Jama. 2013;309(8):781–91.PubMedCrossRefGoogle Scholar
  38. 38.
    Nguyen G. Renin, (pro)renin and receptor: an update. Clin Sci (Lond). 2011;120(5):169–78.CrossRefGoogle Scholar
  39. 39.
    Moilanen AM, Rysa J, Serpi R, et al. (Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function. PLoS One. 2012;7(7):e41404.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47(8):515–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Seed A, Gardner R, McMurray J, et al. Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail. 2007;9(11):1120–7.PubMedCrossRefGoogle Scholar
  42. 42.
    van Esch JH, Moltzer E, van Veghel R, et al. Beneficial cardiac effects of the renin inhibitor aliskiren in spontaneously hypertensive rats. J Hypertens. 2010;28(10):2145–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Gradman AH, Kad R. Renin inhibition in hypertension. J Am Coll Cardiol. 2008;51(5):519–28.PubMedCrossRefGoogle Scholar
  44. 44.
    Pitt B, Latini R, Maggioni AP, et al. Neurohumoral effects of aliskiren in patients with symptomatic heart failure receiving a mineralocorticoid receptor antagonist: the aliskiren observation of heart failure treatment study. Eur J Heart Fail. 2011;13(7):755–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Solomon SD, Shin SH, Shah A, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J. 2011;32(10):1227–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Novartis. Novartis announces termination of ALTITUDE study with Rasilez®/ Tekturna® in high-risk patients with diabetes and renal impairment. 2011; Accessed 1 June 2013
  47. 47.
    Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Gheorghiade M, Böhm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the astronaut randomized trial. Jama. 2013;309(11):1125–35.PubMedCrossRefGoogle Scholar
  49. 49.
    Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013;11(38):21.Google Scholar
  50. 50.
  51. 51.
    Krum H, Massie B, Abraham WT, et al. Direct renin inhibition in addition to or as an alternative to angiotensin converting enzyme inhibition in patients with chronic systolic heart failure: rationale and design of the aliskiren trial to minimize OutcomeS in patients with HEart failuRE (ATMOSPHERE) study. Eur J Heart Fail. 2011;13(1):107–14.PubMedCrossRefGoogle Scholar
  52. 52.•
    McMurray JJ, Abraham WT, Dickstein K, Kober L, Massie BM, Krum H. Aliskiren, ALTITUDE, and the implications for ATMOSPHERE. Eur J Heart Fail. 2012;14(4):341–3. Interesting article by key opinion leaders indicating the present state of play with Aliskiren. PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Bevan EG, Connell JM, Doyle J, et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens. 1992;10(7):607–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Lang CC, Motwani J, Coutie WJ, Struthers AD. Influence of candoxatril on plasma brain natriuretic peptide in heart failure. Lancet. 1991;338(8761):255.PubMedCrossRefGoogle Scholar
  55. 55.
    McDowell G, Coutie W, Shaw C, Buchanan KD, Struthers AD, Nicholls DP. The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides. Br J Clin Pharmacol. 1997;43(3):329–32.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Kentsch M, Otter W, Drummer C, Notges A, Gerzer R, Muller-Esch G. Neutral endopeptidase 24.11 Inhibition may not exhibit beneficial haemodynamic effects in patients with congestive heart failure. Eur J Clin Pharmacol. 1996;51(3–4):269–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Corti R, Burnett Jr JC, Rouleau JL, Ruschitzka F, Luscher TF. Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? Circulation. 2001;104(15):1856–62.PubMedCrossRefGoogle Scholar
  58. 58.
    Rouleau JL, Pfeffer MA, Stewart DJ, et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet. 2000;356(9230):615–20.PubMedCrossRefGoogle Scholar
  59. 59.
    Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE). Circulation. 2002;106(8):920–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the omapatrilat cardiovascular treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11.PubMedCrossRefGoogle Scholar
  61. 61.
    Fryer RM, Segreti J, Banfor PN, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol. 2008;153(5):947–55.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010;50(4):401–14.PubMedCrossRefGoogle Scholar
  63. 63.
    Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255–66.PubMedCrossRefGoogle Scholar
  64. 64.
    Kobalava ZPE, Averkov O. First experience with concomitant AT1 and neprilysin (NEP 24.11) Inhibition with LCZ696 in patients with chronic heart failure. Circulation. 2010;122, A19378.Google Scholar
  65. 65.
    Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95.PubMedCrossRefGoogle Scholar
  66. 66.
    Mearns BM, Phase II. PARAMOUNT trial of LCZ696. Nat Rev Cardiol. 2012;9(11):612.PubMedCrossRefGoogle Scholar
  67. 67.
    Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007;157(5):545–59.PubMedCrossRefGoogle Scholar
  68. 68.
    Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant. 2013;28(1):36–43.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Cardiovascular & Diabetes Medicine, Medical Research InstituteUniversity of DundeeDundeeUK
  2. 2.Division of Cardiovascular & Diabetes MedicineMailbox 2, Ninewells Hospital and Medical SchoolDundeeUK

Personalised recommendations