Influence of carriage of genetic variants CYP2D6 * 4 / CYP2D6 * 3 on maximum heart rate when using bisoprolol in patients with acute coronary syndrome
Authors: Shumkov VA , Zagorodnikova KA , Boldueva SA , Petrova VB 
Published: May 2021

Abstract

Funding Acknowledgements
Type of funding sources: None.

Introduction
Bisoprolol is one of the most effective and frequently prescribed beta-blockers. The widespread use of bisoprolol is due to its high efficiency in the treatment of patients with various cardiological pathologies: arterial hypertension, ischemic heart disease, chronic heart failure. Bisoprolol, like all members of the group of beta-adrenergic blockers, is effective in the treatment of patients with acute myocardial infarction, reducing the risk of complications such as rhythm disturbances and sudden cardiac death. In vitro studies indicate that bisoprolol is a substrate for two isoforms of cytochrome P450 - 3A4 and 2D6.

Purpose
The purpose of this work was to analyze the effect of CYP2D6 activity on the chronotropic effect of bisoprolol therapy in patients with acute coronary syndrome (ACS).

Materials and methods
The study included patients with ACS who was assigned bisoprolol according to clinical indications. All patients included in the study were Holter monitor on the 10th day of hospitalization - the minimum, mean, maximum heart rate during the day and the maximum heart rate were assessed at the time of exercise was evaluated against the background of the current therapy. All patients included in the study also underwent molecular genetic testing. The detection of polymorphic variants of СYP2D6 (*3/*4) gene was carried out by real-time PCR.

Results
A total of 93 patients, 58 males and 35 females were included in the study. The average age of patients is 63 years. In the studied population, CYP2D6 * 3 was not detected. The CYP2D6 * 4 mutation occurred with a frequency of 15%, which is comparable to previously published data on the Russian population. The distribution of alleles corresponded to the Hardy-Weinberg law (Chi square, p&gt; 0.05). In order to determine the effect of genetically determined CYP2D6 activity on the effectiveness of bisoprolol therapy in patients with ACS, we identified a group of patients - carriers of the allelic CYP2D6 * 4 variant in homozygous or heterozygous form (AA / AG) (group with a reduced metabolic rate), and a group with the CYP2D6 genotype GG (group with normal and increased metabolic rate). In the correlation analysis, carriage of CYP2D6 * 4 in heterozygous or homozygous form was associated with a lower maximum heart rate during exercise (r-0.21; p &lt;0.05). Maximum heart rate during exercise in carriers of CYP2D6 * 4 was 107 [105; 119], in the comparison group - 114 [108; 120]. The difference was significant with p &lt;0.05 (values are expressed as median [25%; 75%]).

Conclusion
In this study, for the first time, the role of the influence of allelic variants of the CYP2D6 gene on the achievement of maximum heart rate during exercise was revealed when using bisoprolol in patients with ACS. These data may have promising implications for maximizing the personalization of therapy for patients, including those with ACS.