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Role of the Renin-Angiotensin-Aldosterone System in Diastolic Heart Failure

Potential for Pharmacologic Intervention

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Abstract

Congestive heart failure (CHF) is a major public health problem that results in tremendous economic burden. Diastolic heart failure (DHF) forms an important subset with increasing incidence and prevalence. There are widely variable estimates of the prevalence, ranging from 13% to 74% of all CHF presentations, and this is predominantly a result of a lack of uniform criteria for establishing a diagnosis. New developments in management of DHF have lagged behind those for systolic heart failure (SHF), for which numerous new therapeutic and device strategies have been instituted. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both SHF as well as DHF. The beneficial role of ACE inhibitors as well as aldosterone antagonists in SHF has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for DHF. Thus far, in patients with primary DHF only the angiotensin receptor type 1 antagonist candesartan has been reported to decrease morbidity and probably mortality. Large, ongoing randomized trials including TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) and the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) are currently underway to establish the role of aldosterone antagonists in patients with DHF.

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References

  1. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994 Jul–Aug; 13(4): S107–12.

    PubMed  Google Scholar 

  2. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 1995 Dec; 26(7): 1565–74.

    Article  PubMed  CAS  Google Scholar 

  3. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 2004 Feb 4; 43(3): 317–27.

    Article  PubMed  Google Scholar 

  4. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005 Sep 20; 46(6): e1–82.

    Article  PubMed  Google Scholar 

  5. Yalcin F, Aksoy FG, Muderrisoglu H, et al. Treatment of hypertension with perindopril reduces plasma atrial natriuretic peptide levels, left ventricular mass, and improves echocardiographic parameters of diastolic function. Clin Cardiol 2000 Jun; 23(6): 437–41.

    Article  PubMed  CAS  Google Scholar 

  6. 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 Sep 6; 362(9386): 772–6.

    Article  PubMed  CAS  Google Scholar 

  7. 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 Apr 3; 348(14): 1309–21.

    Article  PubMed  CAS  Google Scholar 

  8. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996 Oct 15; 78 (8): 902–7.

  9. 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 Sep 7; 100(10): 1056–64.

    Article  PubMed  CAS  Google Scholar 

  10. Grossman W. Defining diastolic dysfunction. Circulation 2000 May 2; 101(17): 2020–1.

    Article  PubMed  CAS  Google Scholar 

  11. Zile MR. Diastolic heart failure: diagnosis, prognosis, treatment. Minerva Cardioangiol 2003 Apr; 51(2): 131–42.

    PubMed  CAS  Google Scholar 

  12. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation 2002 Mar 19; 105(11): 1387–93.

    Article  PubMed  Google Scholar 

  13. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation 2002 Mar 26; 105(12): 1503–8.

    Article  PubMed  Google Scholar 

  14. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000 May 2; 101(17): 2118–21.

    Article  PubMed  CAS  Google Scholar 

  15. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005 Jun; 26(11): 1115–40.

    Article  PubMed  Google Scholar 

  16. Weber KT. Angiotensin II and connective tissue: homeostasis and reciprocal regulation. Regul Pept 1999 Jun 30; 82(1–3): 1–17.

    Article  PubMed  CAS  Google Scholar 

  17. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993 Apr 26; 153(8): 937–42.

    Article  PubMed  CAS  Google Scholar 

  18. Zisman LS, Asano K, Dutcher DL, et al. Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation 1998 Oct 27; 98(17): 1735–41.

    Article  PubMed  CAS  Google Scholar 

  19. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000 Mar; 52(1): 11–34.

    PubMed  CAS  Google Scholar 

  20. Selye H. The general adaptation syndrome and the diseases of adaptation. Am J Med 1951 May; 10(5): 549–55.

    Article  PubMed  CAS  Google Scholar 

  21. Hall CE, Hall O. Hypertension and hypersalimentation: I. Aldosterone hypertension. Lab Invest 1965 Mar; 14: 285–94.

    PubMed  CAS  Google Scholar 

  22. Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001 Dec 6; 345(23): 1689–97.

    Article  PubMed  CAS  Google Scholar 

  23. Timmermans PB. Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics. Hypertens Res 1999 Jul; 22(2): 147–53.

    Article  PubMed  CAS  Google Scholar 

  24. Burlew BS, Weber KT. Cardiac fibrosis as a cause of diastolic dysfunction. Herz 2002 Mar; 27(2): 92–8.

    Article  PubMed  Google Scholar 

  25. Ramires FJ, Sun Y, Weber KT. Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. J Mol Cell Cardiol 1998 Mar; 30(3): 475–83.

    Article  PubMed  CAS  Google Scholar 

  26. Qin W, Rudolph AE, Bond BR, et al. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 2003 Jul 11; 93(1): 69–76.

    Article  PubMed  CAS  Google Scholar 

  27. Mottram PM, Haluska B, Leano R, et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004 Aug 3; 110(5): 558–65.

    Article  PubMed  CAS  Google Scholar 

  28. Laragh JH. Hormones and the pathogenesis of congestive heart failure: vasopressin, aldosterone, and angiotensin II: further evidence for renal-adrenal interaction from studies in hypertension and in cirrhosis. Circulation 1962 Jun; 25: 1015–23.

    Article  PubMed  CAS  Google Scholar 

  29. August JT, Nelson DH, Thorn GW. Response of normal subjects to large amounts of aldosterone. J Clin Invest 1958 Nov; 37(11): 1549–55.

    Article  PubMed  CAS  Google Scholar 

  30. Rovner DR, Conn JW, Knopf RF, et al. Nature of renal escape from the sodium-retaining effect of aldosterone in primary aldosteronism and in normal subjects. J Clin Endocrinol Metab 1965 Jan; 25: 53–64.

    Article  PubMed  CAS  Google Scholar 

  31. Zucker IH, Wang W, Brandie M, et al. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis 1995 May–Jun; 37(6): 397–414.

    Article  PubMed  CAS  Google Scholar 

  32. Barr CS, Lang CC, 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 Dec 15; 76(17): 1259–65.

    Article  PubMed  CAS  Google Scholar 

  33. 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 Feb 15; 101(6): 594–7.

    Article  PubMed  CAS  Google Scholar 

  34. Sakata Y, Masuyama T, Yamamoto K, et al. Renin angiotensin system-dependent hypertrophy as a contributor to heart failure in hypertensive rats: different characteristics from renin angiotensin system-independent hypertrophy. J Am Coll Cardiol 2001 Jan; 37(1): 293–9.

    Article  PubMed  CAS  Google Scholar 

  35. Yamamoto K, Masuyama T, Sakata Y, et al. Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc Res 2000 Aug; 47(2): 274–83.

    Article  PubMed  CAS  Google Scholar 

  36. Haber HL, Powers ER, Gimple LW, et al. Intracoronary angiotensin-converting enzyme inhibition improves diastolic function in patients with hypertensive left ventricular hypertrophy. Circulation 1994 Jun; 89(6): 2616–25.

    Article  PubMed  CAS  Google Scholar 

  37. Sato A, Hayashi M, Saruta T. Relative long-term effects of spironolactone in conjunction with an angiotensin-converting enzyme inhibitor on left ventricular mass and diastolic function in patients with essential hypertension. Hypertens Res 2002 Nov; 25(6): 837–42.

    Article  PubMed  CAS  Google Scholar 

  38. Grandi AM, Imperiale D, Santillo R, et al. Aldosterone antagonist improves diastolic function in essential hypertension. Hypertension 2002 Nov; 40(5): 647–52.

    Article  PubMed  CAS  Google Scholar 

  39. Roongsritong C, Sutthiwan P, Bradley J, et al. Spironolactone improves diastolic function in the elderly. Clin Cardiol 2005 Oct; 28(10): 484–7.

    Article  PubMed  Google Scholar 

  40. Diez J, Querejeta R, Lopez B, et al. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 2002 May 28; 105(21): 2512–7.

    Article  PubMed  CAS  Google Scholar 

  41. 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 Sep 6; 362(9386): 777–81.

    Article  PubMed  CAS  Google Scholar 

  42. Hayashida W, Donckier J, Van Mechelen H, et al. Diastolic properties in canine hypertensive left ventricular hypertrophy: effects of angiotensin converting enzyme inhibition and angiotensin II type-1 receptor blockade. Cardiovasc Res 1997 Jan; 33(1): 54–62.

    Article  PubMed  CAS  Google Scholar 

  43. Ohta T, Hasebe N, Tsuji S, et al. Effects of angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor blocker on cardiac dysfunction induced by isoproterenol in dogs. J Cardiovasc Pharmacol 2001 Oct; 38 Suppl. 1: S63–7.

    Article  PubMed  CAS  Google Scholar 

  44. Boateng SY, Naqvi RU, Koban MU, et al. Low-dose ramipril treatment improves relaxation and calcium cycling after established cardiac hypertrophy. Am J Physiol Heart Circ Physiol 2001 Mar; 280(3): H1029–38.

    PubMed  CAS  Google Scholar 

  45. Dietz R, Waas W, Susselbeck T, et al. Improvement of cardiac function by angiotensin converting enzyme inhibition: sites of action. Circulation 1993 May; 87(5 Suppl.): IV108–16.

    PubMed  CAS  Google Scholar 

  46. Anning PB, Grocott-Mason RM, Lewis MJ, et al. Enhancement of left ventricular relaxation in the isolated heart by an angiotensin-converting enzyme inhibitor. Circulation 1995 Nov 1; 92(9): 2660–5.

    Article  PubMed  CAS  Google Scholar 

  47. Fujii M, Wada A, Tsutamoto T, et al. Bradykinin improves left ventricular diastolic function under long-term angiotensin-converting enzyme inhibition in heart failure. Hypertension 2002 May; 39(5): 952–7.

    Article  PubMed  CAS  Google Scholar 

  48. Matsumoto T, Wada A, Tsutamoto T, et al. Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 2003 May 27; 107(20): 2555–8.

    Article  PubMed  Google Scholar 

  49. Anning PB, Grocott-Mason RM, Lewis MJ. Effects of sulphydryl- and non-sulphydryl-containing ACE inhibitors on left ventricular relaxation in the isolated guinea pig heart. Endothelium 1997; 5(4): 265–75.

    Article  PubMed  CAS  Google Scholar 

  50. Wachtell K, Bella JN, Rokkedal J, et al. Change in diastolic left ventricular filling after one year of antihypertensive treatment: the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Circulation 2002 Mar 5; 105(9): 1071–6.

    Article  PubMed  Google Scholar 

  51. Warner Jr JG, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999 May; 33(6): 1567–72.

    Article  PubMed  CAS  Google Scholar 

  52. Neves MF, Amiri F, Virdis A, et al. Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy. Can J Physiol Pharmacol 2005 Noc; 83(11): 999–1006.

    Article  PubMed  CAS  Google Scholar 

  53. Cicoira M, Zanolla L, Rossi A, et al. Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol 2002 Jul 17; 40(2): 304–10.

    Article  PubMed  CAS  Google Scholar 

  54. Oh JK, Hatle L, Tajik AJ, et al. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol 2006 Feb 7; 47(3): 500–6.

    Article  PubMed  Google Scholar 

  55. Wood JM, Maibaum J, Rahuel J, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003 Sep 5; 308(4): 698–705.

    Article  PubMed  CAS  Google Scholar 

  56. Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005 Mar 1; 111(8): 1012–8.

    Article  PubMed  CAS  Google Scholar 

  57. Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 2005 Sep; 46(3): 569–76.

    Article  PubMed  CAS  Google Scholar 

  58. Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998 Sep; 32(3): 387–92.

    Article  PubMed  CAS  Google Scholar 

  59. Carson PJ, Massie BM, McKelvie R, et al., for the I-PRESERE Invesigators. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. Card Fail 2005 Oct; 11(8): 576–85.

    Article  CAS  Google Scholar 

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Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Cardiology, Wayne State University, Veterans Affairs Medical Center, 11M, 4646 John R, Detroit, MI, 48201, USA

    Juan Bernal, Sridevi R. Pitta &  Deepak Thatai

  2. Department of Medicine, John D Dingell Veterans Hospital, Detroit, Michigan, USA

    Deepak Thatai

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  1. Juan Bernal
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  2. Sridevi R. Pitta
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Correspondence to Deepak Thatai.

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Bernal, J., Pitta, S.R. & Thatai, D. Role of the Renin-Angiotensin-Aldosterone System in Diastolic Heart Failure. Am J Cardiovasc Drugs 6, 373–381 (2006). https://doi.org/10.2165/00129784-200606060-00004

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