Cardiovascular Drugs and Therapy

, Volume 24, Issue 1, pp 49–60 | Cite as

Role of Beta-Adrenergic Receptor Gene Polymorphisms in the Long-Term Effects of Beta-Blockade with Carvedilol in Patients with Chronic Heart Failure

  • Marco Metra
  • Loredana Covolo
  • Natalia Pezzali
  • Valerio Zacà
  • Silvia Bugatti
  • Carlo Lombardi
  • Luca Bettari
  • Alessia Romeo
  • Umberto Gelatti
  • Raffaele Giubbini
  • Francesco Donato
  • Livio Dei Cas



Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration.

Methods and Results

We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) ≤ 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 ± 12.2% versus +7.1 ± 8.1% in the Gln27Gln homozygotes, and 8.3 ± 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered.


Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

Key words

Gene polymorphisms Beta-blockade Heart failure 



This paper was partially supported by funds from “Centro per lo studio del trattamento dello scompenso cardiaco” of the University of Brescia.

The Authors have no conflict of interest to disclose with respect to the present study.


  1. 1.
    Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 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): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235.CrossRefPubMedGoogle Scholar
  2. 2.
    Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;10:933–89.CrossRefPubMedGoogle Scholar
  3. 3.
    Lechat P, Escolano S, Golmard JL, Lardoux H, Witchitz S, Henneman JA, et al. Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation. 1997;96:2197–205.PubMedGoogle Scholar
  4. 4.
    Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, et al. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci U S A. 2006;103:11288–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Eichhorn EJ, Grayburn PA, Mayer SA, Sutton M, Appleton C, Plehn J, et al. Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST). Circulation. 2003;108:2336–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Metra M, Nodari S, Parrinello G, Giubbini R, Manca C, Dei Cas L. Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance. Am Heart J. 2003;145:292–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Seghatol FF, Shah DJ, Diluzio S, Bello D, Johnson MR, Cotts WG, et al. Relation between contractile reserve and improvement in left ventricular function with beta-blocker therapy in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2004;93:854–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Francis GS, Tang WH. Beta-blockers and reverse remodeling: what are the implications? Am Heart J. 2003;145:200–2.CrossRefPubMedGoogle Scholar
  9. 9.
    Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996;94:2807–16.PubMedGoogle Scholar
  10. 10.
    Konstam MA, Udelson JE, Anand IS, Cohn JN. Ventricular remodeling in heart failure: a credible surrogate endpoint. J Card Fail. 2003;9:350–3.CrossRefPubMedGoogle Scholar
  11. 11.
    de Groote P, Delour P, Mouquet F, Lamblin N, Dagorn J, Hennebert O, et al. The effects of beta-blockers in patients with stable chronic heart failure. Predictors of left ventricular ejection fraction improvement and impact on prognosis. Am Heart J. 2007;154:589–95.CrossRefPubMedGoogle Scholar
  12. 12.
    Bristow MR. Beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101:558–69.PubMedGoogle Scholar
  13. 13.
    Metra M, Nodari S, D’Aloia A, Bontempi L, Boldi E, Dei Cas L. A rationale for the use of beta-blockers as standard treatment for heart failure. Am Heart J. 2000;139:511–21.PubMedGoogle Scholar
  14. 14.
    Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol. 2003;43:381–411.CrossRefPubMedGoogle Scholar
  15. 15.
    Johnson JA, Terra SG. Beta-adrenergic receptor polymorphisms: cardiovascular disease associations and pharmacogenetics. Pharm Res. 2002;19:1779–87.CrossRefPubMedGoogle Scholar
  16. 16.
    Muthumala A, Drenos F, Elliott PM, Humphries SE. Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis. Eur J Heart Fail. 2008;10:3–13.CrossRefPubMedGoogle Scholar
  17. 17.
    Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human b1-adrenergic receptor. J Biol Chem. 1999;274:12670–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Mialet Perez J, Rathz DA, Petrashevskaya NN, Hahn HS, Wagoner LE, Schwartz A, et al. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med. 2003;9:1300–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Small KM, Wagoner L, Levin A, Kardia S, Liggett SB. Synergistic polymorphism of beta1- and α2C- adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002;347:1135–42.CrossRefPubMedGoogle Scholar
  20. 20.
    Covolo L, Gelatti U, Metra M, Nodari S, Piccichè A, Pezzali N, et al. Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study. Eur Heart J. 2004;25:1534–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Metra M, Zani C, Covolo L, Nodari S, Pezzali N, Gelatti U, et al. Role of beta1- and alpha2c-adrenergic receptor polymorphisms and their combination in heart failure: a case-control study. Eur J Heart Fail. 2006;8:131–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Brodde OE, Bruck H, Leineweber K. Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci. 2006;100:323–37.CrossRefPubMedGoogle Scholar
  23. 23.
    Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, et al. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med. 2001;345:1030–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Bruck H, Leineweber K, Büscher R, Ulrich A, Radke J, Insel PA, et al. The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics. 2003;13:59–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;24:1678–87.PubMedCrossRefGoogle Scholar
  27. 27.
    Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L. Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation. 2000;102:546–51.PubMedGoogle Scholar
  28. 28.
    Mann DL, McNamara DM. Pharmacogenomics and the failing heart are we waiting for godot? J Am Coll Cardiol. 2008;52:652–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Savva J, Maqbool A, White HL, Galloway SL, Yuldasheva NY, Ball SG, et al. Polymorphisms of adrenoceptors are not associated with an increased risk of adverse event in heart failure: a MERIT-HF substudy. J Card Fail. 2009;15:435–41.CrossRefPubMedGoogle Scholar
  30. 30.
    White HL, de Boer RA, Maqbool A, Greenwood D, van Veldhuisen DJ, Cuthbert R, et al. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail. 2003;5:463–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Shin J, Lobmeyer MT, Gong Y, Zineh I, Langaee TY, Yarandi H, et al. Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol. 2007;99:250–5.CrossRefPubMedGoogle Scholar
  32. 32.
    de Groote P, Lamblin N, Helbecque N, Mouquet F, Mc Fadden E, Hermant X, et al. The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail. 2005;7:966–73.CrossRefPubMedGoogle Scholar
  33. 33.
    Sehnert AJ, Daniels SE, Elashoff M, Wingrove JA, Burrow CR, Horne B, et al. Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll Cardiol. 2008;52:644–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, Thaneemit-Chen S, et al. An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure. Circ Heart Fail. 2010;3:21–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Terra SG, Hamilton KK, Pauly DF, Lee CR, Patterson JH, Adams KF, et al. Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics. 2005;15:227–34.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen L, Meyers D, Javorsky G, Burstow D, Lolekha P, Lucas M, et al. Arg389Gly-beta1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol. Pharmacogenet Genomics. 2007;17:941–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Lobmeyer MT, Gong Y, Terra SG, Beitelshees AL, Langaee TY, Pauly DF, et al. Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics. 2007;17:277–82.CrossRefPubMedGoogle Scholar
  38. 38.
    Kaye DM, Smirk B, Williams C, Jennings G, Esler M, Holst D. Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics. 2003;13:379–82.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marco Metra
    • 1
    • 4
  • Loredana Covolo
    • 2
  • Natalia Pezzali
    • 1
  • Valerio Zacà
    • 1
  • Silvia Bugatti
    • 1
  • Carlo Lombardi
    • 1
  • Luca Bettari
    • 1
  • Alessia Romeo
    • 1
  • Umberto Gelatti
    • 2
  • Raffaele Giubbini
    • 3
  • Francesco Donato
    • 2
  • Livio Dei Cas
    • 1
  1. 1.Institute of Cardiology, Department of Experimental and Applied MedicineUniversity of BresciaBresciaItaly
  2. 2.Institute of Hygiene, Epidemiology and Public Health, Department of Experimental and Applied MedicineUniversity of BresciaBresciaItaly
  3. 3.Institute of Nuclear MedicineUniversity of BresciaBresciaItaly
  4. 4.Cardiologia, c/o Spedali Civili, P.zza Spedali CiviliBresciaItaly

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