Advertisement

Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure

  • Jasmine A. LuzumEmail author
  • Joseph D. English
  • Umair S. Ahmad
  • Jessie W. Sun
  • Benjamin D. Canan
  • Wolfgang Sadee
  • Joseph P. Kitzmiller
  • Philip F. Binkley
Original Article

Abstract

Two common genetic polymorphisms in the beta-1 adrenergic receptor (ADRB1 Ser49Gly [rs1801252] and Arg389Gly [rs1801253]) significantly affect receptor function in vitro. The objective of this study was to determine whether ADRB1 Ser49Gly and Arg389Gly are associated with recovery of left ventricular ejection fraction (LVEF) in patients with heart failure. Patients with heart failure and baseline LVEF ≤ 40% were genotyped (n = 98), and retrospective chart review assessed the primary outcome of LVEF recovery to ≥ 40%. Un/adjusted logistic regression models revealed that Ser49Gly, but not Arg389Gly, was significantly associated with LVEF recovery in a dominant genetic model. The adjusted odds ratio for Ser49 was 8.2 (95% CI = 2.1–32.9; p = 0.003), and it was the strongest predictor of LVEF recovery among multiple clinical variables. In conclusion, patients with heart failure and reduced ejection fraction that are homozygous for ADRB1 Ser49 were significantly more likely to experience LVEF recovery than Gly49 carriers.

Keywords

Beta-1 adrenergic receptor Genetics Polymorphism Beta-blocker Heart failure Left ventricular ejection fraction 

Abbreviations

ADRB1

Gene for the beta-1 adrenergic receptor

AHA

American Heart Association

ACC

American College of Cardiology

Arg

Arginine

BMI

Body mass index

CEPH

Centre d’Etude du Polymorphism Humain lymphoblastoid cell lines

CI

Confidence interval

FDA

United States Food and Drug Administration

Gly

Glycine

HF

Heart failure

HFpEF

Heart failure with preserved ejection fraction

HFrEF

Heart failure with reduced ejection fraction

LVEF

Left ventricular ejection fraction

NYHA

New York Heart Association

OR

Odds ratio

SBP

Systolic blood pressure

Ser

Serine

Notes

Compliance with Ethical Standards

Disclosures

None.

Human Subjects/Informed Consent Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Animal Studies

No animal studies were carried out by the authors for this article.

Clinical Relevance

These findings from a small study at a single site need to be replicated in a larger study of multiple sites to be clinically relevant. The potential clinical relevance is that a patient’s ADRB1 Ser49Gly (rs1801252) genotype may be a predictor of whether or not the patient with HFrEF will have recovery of their LVEF to ≥ 40%. This genotype was the strongest predictor of LVEF recovery, even compared to multiple clinical variables. Thus, if validated, HFrEF patients that are ADRB1 Gly49 carriers may need additional monitoring or therapies compared to Ser49 homozygotes.

Supplementary material

12265_2019_9866_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 17 kb)
12265_2019_9866_MOESM2_ESM.docx (18 kb)
ESM 2 (DOCX 18 kb)
12265_2019_9866_MOESM3_ESM.docx (15 kb)
ESM 3 (DOCX 14 kb)

References

  1. 1.
    Benjamin, E. J., Virani, S. S., Callaway, C. W., Chamberlain, A. M., Chang, A. R., Cheng, S., et al. (2018). Heart disease and stroke statistics—2018 update: a report from the American Heart Association (review-article). Circulation, 137(12), e67–e492.  https://doi.org/10.1161/CIR.0000000000000558.Google Scholar
  2. 2.
    Lupón, J., Díez-López, C., de Antonio, M., Domingo, M., Zamora, E., Moliner, P., et al. (2017). Recovered heart failure with reduced ejection fraction and outcomes: a prospective study. European Journal of Heart Failure, 19(12), 1615–1623.  https://doi.org/10.1002/ejhf.824.Google Scholar
  3. 3.
    Teeter, W. A., Thibodeau, J. T., Rao, K., Brickner, M. E., Toto, K. H., Nelson, L. L., et al. (2012). The natural history of new-onset heart failure with a severely depressed left ventricular ejection fraction: Implications for timing of implantable cardioverter-defibrillator implantation. American Heart Journal, 164(3), 358–364.  https://doi.org/10.1016/j.ahj.2012.06.009.Google Scholar
  4. 4.
    Merlo, M., Caiffa, T., Gobbo, M., Adamo, L., & Sinagra, G. (2018). Reverse remodeling in dilated cardiomyopathy: insights and future perspectives. International Journal of Cardiology: Heart & Vasculature, 18, 52–57.  https://doi.org/10.1016/j.ijcha.2018.02.005.Google Scholar
  5. 5.
    Mann, D., Kent, R., Parsons, B., & Cooper, G. (1992). Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation, 85(2), 790–804.  https://doi.org/10.1161/01.CIR.85.2.790.Google Scholar
  6. 6.
    MERIT-HF Study Group. (1999). Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF). The Lancet, 353(9169), 2001–2007.  https://doi.org/10.1016/S0140-6736(99)04440-2.Google Scholar
  7. 7.
    Hernandez, A. F., Hammill, B. G., O'Connor, C. M., Schulman, K. A., Curtis, L. H., & Fonarow, G. C. (2009). Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry. Journal of the American College of Cardiology, 53(2), 184.  https://doi.org/10.1016/j.jacc.2008.09.031.Google Scholar
  8. 8.
    Podlowski, S., Wenzel, K., Luther, H. P., Müller, J., Bramlage, P., Baumann, G., et al. (2000). β1-Adrenoceptor gene variations: a role in idiopathic dilated cardiomyopathy? Journal of Molecular Medicine, 78(2), 87–93.  https://doi.org/10.1007/s001090000080.Google Scholar
  9. 9.
    Rathz, D. A., Brown, K. M., Kramer, L. A., & Liggett, S. B. (2002). Amino acid 49 polymorphisms of the human [beta] 1-adrenergic receptor affect agonist-promoted trafficking. Journal of Cardiovascular Pharmacology, 39(2), 155–160.Google Scholar
  10. 10.
    Liggett, S. B., Mialet-Perez, J., Thaneemit-Chen, S., Weber, S. A., Greene, S. M., Hodne, D., et al. (2006). A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proceedings of the National Academy of Sciences, 103(30), 11288–11293.  https://doi.org/10.1073/pnas.0509937103.Google Scholar
  11. 11.
    Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Drazner, M. H., et al. (2013). 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. Journal of the American College of Cardiology, 62(16), e147–e239.  https://doi.org/10.1016/j.jacc.2013.05.019.Google Scholar
  12. 12.
    Binkley, P. F., Lesinski, A., Ferguson, J. P., Hatton, P. S., Yamokoski, L., Hardikar, S., et al. (2008). Recovery of normal ventricular function in patients with dilated cardiomyopathy: predictors of an increasingly prevalent clinical event. American Heart Journal, 155(1), 69–74.  https://doi.org/10.1016/j.ahj.2007.08.010.Google Scholar
  13. 13.
    Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, 16(3), 1215–1215.  https://doi.org/10.1093/nar/16.3.1215.Google Scholar
  14. 14.
    1000 Genomes Project, C. (2015). A global reference for human genetic variation (article). Nature, 526, 68.  https://doi.org/10.1038/nature15393.Google Scholar
  15. 15.
    Lanfear, D. E., Peterson, E. L., Zeld, N., Wells, K., Sabbah, H. N., & Williams, K. (2015). Beta blocker survival benefit in heart failure is associated with ADRB1 Ser49Gly genotype. Journal of Cardiac Failure, 21(8, Supplement), S50.  https://doi.org/10.1016/j.cardfail.2015.06.169.Google Scholar
  16. 16.
    Talameh, J., Garrand, A., Ghali, J., Oren, R. M., Dunlap, S., Bakel, A. V., et al. (2012). Beta-1 adrenergic receptor genotype Ser49Gly is associated with beta-blocker survival benefit in patients with heart failure. Journal of the American College of Cardiology, 59(13, Supplement), E861.  https://doi.org/10.1016/S0735-1097(12)60862-6.Google Scholar
  17. 17.
    Levin, M. C., Marullo, S., Muntaner, O., Andersson, B., & Magnusson, Y. (2002). The myocardium-protective Gly-49 variant of the β1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation. Journal of Biological Chemistry, 277(34), 30429–30435.  https://doi.org/10.1074/jbc.M200681200.Google Scholar
  18. 18.
    Terra, S. G., Hamilton, K. K., Pauly, D. F., Lee, C. R., Patterson, J. H., Adams, K. F., et al. (2005). Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenetics and Genomics, 15(4), 227.Google Scholar
  19. 19.
    de Groote, P., Helbecque, N., Lamblin, N., Hermant, X., Mc Fadden, E., Foucher-Hossein, C., et al. (2005). Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenetics and Genomics, 15(3), 137–142.  https://doi.org/10.1097/01213011-200503000-00001.Google Scholar
  20. 20.
    Nonen, S., Okamoto, H., Fujio, Y., Takemoto, Y., Yoshiyama, M., Hamaguchi, T., et al. (2008). Polymorphisms of norepinephrine transporter and adrenergic receptor α1D are associated with the response to β-blockers in dilated cardiomyopathy. The Pharmacogenomics Journal, 8(1), 78–84.  https://doi.org/10.1038/sj.tpj.6500450.Google Scholar
  21. 21.
    Chen, L., Meyers, D., Javorsky, G., Burstow, D., Lolekha, P., Lucas, M., et al. (2007). Arg389Gly-beta1-adrenergic receptors determine improvement in left ventricular systolic function in nonischemic cardiomyopathy patients with heart failure after chronic treatment with carvedilol. Pharmacogenetics and Genomics, 17(11), 941.  https://doi.org/10.1097/FPC.0b013e3282ef7354.Google Scholar
  22. 22.
    Perez, J. M., Rathz, D. A., Petrashevskaya, N. N., Hahn, H. S., Wagoner, L. E., Schwartz, A., et al. (2003). [Beta]1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nature Medicine, 9(10), 1300.  https://doi.org/10.1038/nm930.Google Scholar
  23. 23.
    Luo, M., Bi, Y., & Xu, Y. X. (2007). Effects of metoprolol on beta1 adrenergic receptor polymorphism and receptor density in urban Chinese patients with heart failure. Chinese Medical Journal, 120(19), 1720–1723.Google Scholar
  24. 24.
    Hu, H., Jui, H.-Y., Hu, F.-C., Chen, Y.-H., Lai, L.-P., & Lee, C.-M. (2007). Predictors of therapeutic response to beta-blockers in patients with heart failure in Taiwan. Journal of the Formosan Medical Association, 106(8), 641–648.  https://doi.org/10.1016/S0929-6646(08)60021-2.Google Scholar
  25. 25.
    Metra, M., Covolo, L., Pezzali, N., Zacà, V., Bugatti, S., Carlo, L., et al. (2010). Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovascular Drugs and Therapy, 24(1), 49–60.  https://doi.org/10.1007/s10557-010-6220-5.Google Scholar
  26. 26.
    Borjesson, M., Magnusson, Y., Hjalmarson, A., & Andersson, B. (2000). A novel polymorphism in the gene coding for the beta1-adrenergic receptor associated with survival in patients with heart failure. European Heart Journal, 21(22), 1853–1858.  https://doi.org/10.1053/euhj.1999.1994.Google Scholar
  27. 27.
    Magnusson, Y., Levin, M. C., Eggertsen, R., Nyström, E., Mobini, R., Schaufelberger, M., et al. (2005). Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy. Clinical Pharmacology and Therapeutics, 78(3), 221.  https://doi.org/10.1016/j.clpt.2005.06.004.Google Scholar
  28. 28.
    Cresci, S., Kelly, R. J., Cappola, T. P., Diwan, A., Dries, D., Kardia, S. L., et al. (2009). Clinical and genetic modifiers of long-term survival in heart failure. Journal of the American College of Cardiology, 54(5), 432–444.  https://doi.org/10.1016/j.jacc.2009.05.009.Google Scholar
  29. 29.
    Sehnert, A. J., Daniels, S. E., Elashoff, M., Wingrove, J. A., Burrow, C. R., Horne, B., et al. (2008). Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. Journal of the American College of Cardiology, 52(8), 644–651.  https://doi.org/10.1016/j.jacc.2008.05.022.Google Scholar
  30. 30.
    White, H. L., Boer, R. A., Maqbool, A., Greenwood, D., Veldhuisen, D. J., Cuthbert, R., et al. (2003). An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. European Journal of Heart Failure, 5(4), 463–468.  https://doi.org/10.1016/S1388-9842(03)00044-8.Google Scholar
  31. 31.
    The Beta-Blocker Evaluation of Survival Trial Investigators. (2001). A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. New England Journal of Medicine, 344(22), 1659–1667.  https://doi.org/10.1056/NEJM200105313442202.Google Scholar
  32. 32.
    Zou, C.-H., Zhang, J., Zhang, Y.-H., Wei, B.-Q., Wu, X.-F., Zhou, Q., et al. (2014). Frequency and predictors of normalization of left ventricular ejection fraction in recent-onset nonischemic cardiomyopathy. The American Journal of Cardiology, 113(10), 1705–1710.  https://doi.org/10.1016/j.amjcard.2014.02.028.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborUSA
  2. 2.Department of Biological Chemistry and PharmacologyOhio State University College of MedicineColumbusUSA
  3. 3.Heart and Vascular InstituteSumma Health SystemAkronUSA
  4. 4.Division of Cardiovascular Medicine, Department of Internal MedicineOhio State University College of MedicineColumbusUSA
  5. 5.Center for PharmacogenomicsOhio State University College of MedicineColumbusUSA
  6. 6.Department of Physiology and Cell BiologyOhio State University College of MedicineColumbusUSA

Personalised recommendations