Association of β1- and β2-Adrenergic Receptor Gene Polymorphisms with the Effectiveness of Bisoprolol and Carvedilol in Patients with Heart Failure of Ischemic Etiology

DOI: https://doi.org/10.30702/ujcvs/24.32(03)/KK048-2837
Keywords: postinfarction cardiosclerosis, mutation, atrial fibrillation, heart rate, left ventricular ejection fraction

Abstract

The aim. To study the relationship between β1-, β2-adrenergic receptor (β-AR) gene polymorphisms and the effectiveness of bisoprolol and carvedilol in patients with heart failure (HF) and coronary heart disease.

Materials and methods. We examined 201 patients with HF on the background of post-infarction cardiosclerosis. Control group included 43 healthy individuals of comparable age and sex. Genotyping was carried out for 3 polymorphisms (rs1801253 and rs1801252 of the β1-AR gene; rs1042714 of the β2-AR gene). The patients were divided into 2 groups: the first group included 104 (51.7%) patients who took bisoprolol during the year of observation; 97 (48.3%) patients of the second group were treated with carvedilol. Statistical analysis was performed using Statistica 10.0 and SNPStats programs.

Results. In patients with HF, the mutant C-allele (rs1801253 polymorphism) of the β1-AR gene was associated with a decrease in the probability of heart rate reduction >15 min-1 against the background of the use of β-blocker during the year (odds ratio [OR] = 0.42 [0.16-0.98], p = 0.041, recessive inheritance model; OR = 0.62 [0.40-0.97], p = 0.038; log-additive inheritance model). The probability of positive dynamics of the left ventricular ejection fraction (LVEF) increased in carriers of the wild A-allele of the rs1801252 (Ser49Gly) polymorphism of the β1-AR gene (OR = 4.86 [2.35-10.08], p < 0.0001, codominant model; OR = 5.18 [2.51-10.68], p < 0.0001, dominant model; OR = 4.68 [2.26-9.68], p < 0.0001, over-dominant model; OR = 5.05 [2.48-10.28], p < 0.0001, log-additive inheritance model). The probability of an increase in LVEF within a year increased with treatment with carvedilol in homozygous mutant G/G rs1042714 polymorphism (Gln27Glu) of the β2-AR gene in patients with HF (OR = 6.09 [1.16-31.88], p = 0.038, dominant inheritance model).

Conclusions. Patients with HF of ischemic etiology, carriers of the mutant C-allele of rs1801253 polymorphism of the β1-adrenoceptor gene, are worse responders to the use of β-blockers compared to patients with the wild G-allele (a lower proportion of patients with a decrease in heart rate >15 min-1: 6.8% vs. 14.5%, respectively; OR = 0.42 [0.16-0.98], p = 0.041). The frequency of an increase in the value of the LVEF >10% was higher compared to patients with the mutant G-allele (39.3% vs. 11.1%, respectively; OR = 4.86 [2.35-10.08], p < 0.0001) against the background of application of β-blockers. The use of carvedilol was more appropriate in homozygous carriers of the mutant G-allele of the rs1042714 polymorphism (Gln27Glu) of the β2-AR gene compared to bisoprolol (a greater proportion of patients with an increase in the LVEF: 17.6% vs. 9.1%, respectively; OR = 6.09 [1.16-31.88], p = 0.038). No probable associations of rs1801253 and rs1801252 polymorphisms of the β1-AR gene with the pharmacodynamics of bisoprolol and carvedilol in patients with HF of ischemic etiology were found.

References

  1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al.; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. https://doi.org/10.1093/eurheartj/ehab368
  2. Paolillo S, Dell’Aversana S, Esposito I, Poccia A, Perrone Filardi P. The use of β-blockers in patients with heart failure and comorbidities: Doubts, certainties and unsolved issues. Eur J Intern Med. 2021;88:9-14. https://doi.org/10.1016/j.ejim.2021.03.035
  3. Luzum JA, Campos-Staffico AM, Li J, She R, Gui H, Peterson EL, et al. Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction. Genes (Basel). 2023;14(11):2019. https://doi.org/10.3390/genes14112019
  4. dbSNP Short Genetic Variations: 1801252 frequency. Available from: https://www.ncbi.nlm.nih.gov/snp/rs1801252#frequency_tab [cited September 21, 2022].
  5. Matuskova L, Czippelova B, Turianikova Z, Svec D, Kolkova Z, Lasabova Z, et al. Beta-Adrenergic Receptors Gene Polymorphisms are Associated With Cardiac Contractility and Blood Pressure Variability. Physiol Res. 2021;70(S3):S327-S337. https://doi.org/10.33549/physiolres.934837
  6. Levin MG, Tsao NL, Singhal P, Liu C, Vy HMT, Paranjpe I, et al. Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure. Nat Commun. 2022;13(1):6914. https://doi.org/10.1038/s41467-022-34216-6
  7. Metaxa S, Missouris C, Mavrogianni D, Miliou A, Oikonomou E, Toli E, et al. Polymorphism Gln27Glu of β2 Adrenergic Receptors in Patients with Ischaemic Cardiomyopathy. Curr Vasc Pharmacol. 2018;16(6):618-623. https://doi.org/10.2174/1570161115666170919180959
  8. dbSNP Short Genetic Variations: rs1042714 frequency. Available from: https://www.ncbi.nlm.nih.gov/snp/rs1042714#frequency_tab [cited September 21, 2022].
  9. Graffelman J, Weir BS. The transitivity of the Hardy-Weinberg law. Forensic Sci Int Genet. 2022;58:102680. https://doi.org/10.1016/j.fsigen.2022.102680
  10. Wikstrand J, Wedel H, Castagno D, McMurray JJ. The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. J Intern Med. 2014;275(2):134-143. https://doi.org/10.1111/joim.12141
  11. Bristow MR, Mann DL. Cardiac Adrenergic Activation in Heart Failure With Preserved Ejection Fraction: A Role for β-Blockade? JACC Basic Transl Sci. 2022;7(2):128-130. https://doi.org/10.1016/j.jacbts.2022.01.003
  12. Greene SJ, Vaduganathan M, Wilcox JE, Harinstein ME, Maggioni AP, Subacius H, et al.; EVEREST Trial Investigators. The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial. JACC Heart Fail. 2013;1(6):488-496. https://doi.org/10.1016/j.jchf.2013.08.005
  13. Duarte JD, Cavallari LH. Pharmacogenetics to guide cardiovascular drug therapy. Nat Rev Cardiol. 2021;18(9):649-665. https://doi.org/10.1038/s41569-021-00549-w
  14. Paldino A, Dal Ferro M, Stolfo D, Gandin I, Medo K, Graw S, et al. Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies. J Am Coll Cardiol. 2022;80(21):1981-1994. https://doi.org/10.1016/j.jacc.2022.08.804
  15. Lee HY, Chung WJ, Jeon HK, Seo HS, Choi DJ, Jeon ES, et al. Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study. Korean J Intern Med. 2016;31(2):277-287. https://doi.org/10.3904/kjim.2015.043
  16. Fiuzat M, Neely ML, Starr AZ, Kraus WE, Felker GM, Donahue M, et al. Association between adrenergic receptor genotypes and beta-blocker dose in heart failure patients: analysis from the HF-ACTION DNA substudy. Eur J Heart Fail. 2013;15(3):258-266. https://doi.org/10.1093/eurjhf/hfs175
  17. Rau T, Düngen HD, Edelmann F, Waagstein F, Lainščak M, Dimković S, et al. Impact of the β1-Adrenoceptor Arg389Gly Polymorphism on Heart-Rate Responses to Bisoprolol and Carvedilol in Heart-Failure Patients. Clin Pharmacol Ther. 2012;92(1):21-28. https://doi.org/10.1038/clpt.2012.18
  18. Albuquerque FN, Brandão AA, Silva DA, Rocha RM, Bittencourt MI, Sales ALF, et al. Ser49Gly Beta1-Adrenergic Receptor Genetic Polymorphism as a Death Predictor in Brazilian Patients with Heart Failure. Arq Bras Cardiol. 2020;114(4):616-624. https://doi.org/10.36660/abc.20190187
  19. Luzum JA, English JD, Ahmad US, Sun JW, Canan BD, Sadee W, et al. Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure. J Cardiovasc Transl Res. 2019;12(4):280-289. https://doi.org/10.1007/s12265-019-09866-5
  20. Bruck H, Leineweber K, Park J, Weber M, Heusch G, Philipp T, et al. Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo. Clin Pharmacol Ther. 2005;78(3):232-238. https://doi.org/10.1016/j.clpt.2005.06.002
  21. Castaño-Amores C, Antúnez-Rodríguez A, Pozo-Agundo A, García-Rodríguez S, Martínez-González LJ, Dávila-Fajardo CL. Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome. Biomed Pharmacother. 2023;169:115869. ht t ps://doi.org/10.1016/j.biopha.2023.115869
Published
2024-09-27
How to Cite
1.
Kulaiets NM, Kulaiets VM. Association of β1- and β2-Adrenergic Receptor Gene Polymorphisms with the Effectiveness of Bisoprolol and Carvedilol in Patients with Heart Failure of Ischemic Etiology. ujcvs [Internet]. 2024Sep.27 [cited 2024Dec.21];32(3):28-7. Available from: https://cvs.org.ua/index.php/ujcvs/article/view/667
Issue
Ukrainian Journal of Cardiovascular Surgery Vol 32 No 3 2024
Section
ISCHEMIC HEART DISEASE