Skip to main content
SpringerLink
Log in

Is too much neurohormonal blockade harmful?

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

A number of neurohormones and cytokines are activated in heart failure and their activity is related to the progression of heart failure. Inhibiting the deleterious effects of the activated sympathetic and the renin-angiotensin-aldosterone systems with -blockers, angiotensin-converting enzyme inhibitors, and aldosterone blockers has been remarkably successful in improving the survival of patients with heart failure. However, inhibition of the other neurohormones and cytokines has not provided the expected incremental benefit, and in some cases has been deleterious, suggesting a ceiling effect of further neurohormonal blockade. This article reviews some of these studies and analyzes the possible causes of these observations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Wilson JR, Schwartz JS, St. John Sutton M, et al.: Prognosis in severe heart failure and relation to hemodynamic measurements and ventricular ectopic activity. J Am Coll Cardiol 1983, 2:403–409.

    Article  PubMed  CAS  Google Scholar 

  2. Szlachcic J, Massie BM, Kramer BL, et al.: Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985, 55:1037–1042.

    Article  PubMed  CAS  Google Scholar 

  3. Cohn JN, Levine TB, Olivari MT, et al.: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984, 311:819–823.

    Article  PubMed  CAS  Google Scholar 

  4. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L: Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990, 82:1730–1736.

    PubMed  CAS  Google Scholar 

  5. Massie BM, Conway M: Survival of patients with congestive heart failure: past, present, and future prospects. Circulation 1987, 7:IV11-IV19.

    Google Scholar 

  6. Anand IS, Chugh SS: Mechanisms and management of renal dysfunction in heart failure. Curr Opin Cardiol 1997, 12:251–258.

    Article  PubMed  CAS  Google Scholar 

  7. Anand IS: Pathogenesis of salt and water retention in the syndrome of congestive heart failure. In Heart Failure; Scientific Principles and Clinical Practice. Edited by Poole-Wilson PA, Chatterjee K, Coates AJS, et al. London: Churchill Livingstone; 1996.

    Google Scholar 

  8. Anand IS, Florea VG: Alterations in ventricular structure: role of left ventricular remodeling. In Heart Failure: Companion to Braunwald's Heart Disease. Edited by Mann DL. Philadelphia: Saunders; 2002.

    Google Scholar 

  9. Mann D, Kent R, Parsons B, Cooper G: Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992, 85:790–804.

    PubMed  CAS  Google Scholar 

  10. Tan LB, Jalil JE, Pick R, et al.: Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991, 69:1185–1195.

    PubMed  CAS  Google Scholar 

  11. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002, 91:988–998. Excellent review of the roles of cytokines in the progression of HF and the lesions learned from the recent negative anticytokine trials.

    Article  PubMed  CAS  Google Scholar 

  12. Anand IS, Chandrashekhar Y: Neurohormonal responses in congestive heart failure: effect of ACE inhibitors in randomized controlled clinical trials. In Heart Hypertrophy and Failure. Edited by Dhalla NS, Singhal PK, Beamish RE. Boston: Kluwer Academic Publishers; 1996:487–501.

    Google Scholar 

  13. Anand IS, Fisher LD, Chiang YT, et al.: Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in Val-HeF. Circulation 2003, 107:1276–1281. Analysis of the Val-HeFT neurohormonal database showing that changes in BNP and norepinephrine over time in patients with moderate to severe HF are associated with corresponding changes in subsequent mortality and mortality.

    Google Scholar 

  14. 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, 316:1429–1435.

    Article  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. The MERIT-HF Investigators: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999, 353:2001–2007.

    Article  Google Scholar 

  17. Packer M, Coats AJ, Fowler MB, et al.: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001, 344:1651–1658.

    Article  PubMed  CAS  Google Scholar 

  18. 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, 341:709–717.

    Article  PubMed  CAS  Google Scholar 

  19. Cohn JN, Tognoni G: A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001, 345:1667–1675.

    Article  PubMed  CAS  Google Scholar 

  20. Packer M: The ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heat Failure) Study. Preliminary data presented at the51st annual American College of Cardiology meeting. Atlanta, GA; March 21, 2002.

  21. Packer M: Multicenter, double-blind, placebo-controlled study of long-term endothelin blockade with bosentan in congestive heart failure: results of the REACH-1 trial. Circulation 1998, 98(Suppl S):12.

    Google Scholar 

  22. 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, 106:920–926.

    Article  PubMed  CAS  Google Scholar 

  23. The CIBIS II Investigators: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999, 353:9–13.

    Article  Google Scholar 

  24. Bristow MR, Gilbert EM, Abraham WT, et al.: Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996, 94:2807–2816.

    PubMed  CAS  Google Scholar 

  25. Swedberg K, Bristow MR, Cohn JN, et al.: Effects of sustainedrelease moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation 2002, 105:1797–1803.

    Article  PubMed  CAS  Google Scholar 

  26. Cohn JN, Pfeffer MA, Rouleau J, et al.: Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003, 5:659–667. Results of the MOXCON study showing that the increase in mortality and hospitalization for HF seen in that trial was associated with a significant fall in plasma norepinephrine.

    Article  PubMed  CAS  Google Scholar 

  27. The BEST Investigators: A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001, 344:1659–1667.

    Article  Google Scholar 

  28. Bristow M, Krause-Steinrauf H, Abraham WT, et al.: Effect of Buchindolol adversely affected survival, and was disproportionately observed in the class IV subgroup of BEST. Circulation 2001, 104:II-755. Abstract of the BEST subgroup analysis showing that significant reduction in plasma norepinephrine in patients receiving the sympatholytic bblocker bucindolol was associated with an increase in mortality.

    Google Scholar 

  29. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al.: Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: a multicenter study. High Enalapril Dose Study Group. J Am Coll Cardiol 2000, 36:2090–2095.

    Article  PubMed  CAS  Google Scholar 

  30. Tang WH, Vagelos RH, Yee YG, et al.: Neurohormonal and clinical responses to high-versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002, 39:70–78. A study comparing the effect of low-versus high-dose enalapril in 75 patients with HF. Despite greater suppression of plasma ACE with high-dose enalapril, the levels of plasma aldosterone and angiotensin II were no different in the two groups, confirming the phenomenon of angiotensin II and aldosterone escape.

    Article  PubMed  CAS  Google Scholar 

  31. Kawamura M, Imanashi M, Matsushima Y, et al.: Circulating angiotensin II levels under repeated administration of lisinopril in normal subjects. Clin Exp Pharmacol Physiol 1992, 19:547–553.

    PubMed  CAS  Google Scholar 

  32. Jorde UP, Ennezat PV, 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.

    PubMed  CAS  Google Scholar 

  33. Pfeffer MA, Swedberg K, Granger CB, et al.: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003, 362:759–766.

    Article  PubMed  CAS  Google Scholar 

  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, 362:777–781.

    Article  PubMed  CAS  Google Scholar 

  35. 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, 362:772–776.

    Article  PubMed  CAS  Google Scholar 

  36. McMurray JJ, Ostergren J, Swedberg K, et al.: Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet 2003, 362:767–771.

    Article  PubMed  CAS  Google Scholar 

  37. 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, 349:1893–1906.

    Article  PubMed  CAS  Google Scholar 

  38. Anand IS, Glazer R, Chiang YT, et al.: A retrospective analysis of major determinants of heart failure mortality in patients receiving both ACE inhibitors and beta-blockers in Val-HeFT. J Card Fail 2003, 5:P304.

    Google Scholar 

  39. Yanagisawa M, Kurihara H, Kimura S, et al.: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988, 332:411–415.

    Article  PubMed  CAS  Google Scholar 

  40. Haynes WG, Webb DJ: Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994, 344:852–854.

    Article  PubMed  CAS  Google Scholar 

  41. Stewart DJ, Cernacek P, Costello KB, Rouleau JL: Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992, 85:510–517.

    PubMed  CAS  Google Scholar 

  42. McMurray JJ, Ray SG, Abdullah I, et al.: Plasma endothelin in chronic heart failure. Circulation 1992, 85:1374–1379.

    PubMed  CAS  Google Scholar 

  43. Omland T, Lie RT, Aakvaag A, et al.: Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994, 89:1573–1579.

    PubMed  CAS  Google Scholar 

  44. Fukuchi M, Giaid A: Expression of endothelin-1 and endothelinconverting enzyme-1 mRNAs and proteins in failing human hearts. J Cardiovasc Pharmacol 1998, 31(Suppl 1):S421-S423.

    Article  PubMed  CAS  Google Scholar 

  45. Sakai S, Miyauchi T, Kobayashi M, et al.: Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 1996, 384:353–355

    Article  PubMed  CAS  Google Scholar 

  46. Sutsch G, Kiowski W, Yan XW, et al.: Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998, 98:2262–2268.

    PubMed  CAS  Google Scholar 

  47. Luscher TF, Enseleit F, Pacher R, et al.: Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation 2002, 106:2666–2672.

    Article  PubMed  CAS  Google Scholar 

  48. Wada A, Tsutamoto T, Fukai D, et al.: Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure. J Am Coll Cardiol 1997, 30:1385–1392.

    Article  PubMed  CAS  Google Scholar 

  49. Anand IS, McMurray JJ, Cohn JN, et al.: Long-term effects of darusentan on LV remodeling and clinical outcomes — the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH). Lancet 2004, in press.

  50. Mann DL: Mechanisms and models in heart failure: a combinatorial approach. Circulation 1999, 100:999–1008.

    PubMed  CAS  Google Scholar 

  51. Aukrust P, Ueland T, Lien E, et al.: Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1999, 83:376–382.

    Article  PubMed  CAS  Google Scholar 

  52. Kapadia S, Torre-Amione G, Yokoyama T, Mann DL: Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro. Am J Physiol 1995, 268:H517-H525.

    PubMed  CAS  Google Scholar 

  53. Deswal A, Bozkurt B, Seta Y, et al.: Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999, 99:3224–3226.

    PubMed  CAS  Google Scholar 

  54. Bozkurt B, Torre-Amione G, Warren MS, et al.: Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001, 103:1044–1047.

    PubMed  CAS  Google Scholar 

  55. Wood S: RENEWAL trial: no improvement in CHF with etanercept. HeartWire News 2002. http://www.theheart.org

  56. Mann DL, Swedberg K, Packer M, et al.: Effects of cytokine antagonism with etanercept on morbidity and mortality in patients with chronic heart failure: results of the RENAISSANCE, RECOVERY, and RENEWAL trails. Paper presented at the6th annual meeting of the Heart Failure Society of America. Boca Raton, FL; September 25, 2002.

  57. Packer M, Chung E, Batra S, et al.: Randomized placebo-controlled dose-ranging trial of infliximab, a monoclonal antibody to tumor necrosis factor-alpha, in moderate to severe heart failure. Paper presented at the annual meeting of HFSA. September 25, 2002.

Download references

Author information

Authors and Affiliations

  1. VA Medical Center, One Veterans Drive, 111-C, 55417, Minneapolis, MN, USA

    Inder S. Anand MD

Authors
  1. Inder S. Anand MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anand, I.S. Is too much neurohormonal blockade harmful?. Curr Cardiol Rep 6, 169–175 (2004). https://doi.org/10.1007/s11886-004-0019-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-004-0019-6

Keywords

Search

Navigation