Gasanov Yu. Ch.

Government Institution "L. T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine", Kharkiv, Ukraine

Influence of cytochrome Р450 2D6*4 gene polymorphism on efficacy of metoprolol succinate in patients with chronic heart failure and obesity. Psychosocial and clinical aspects

Chronic heart failure (CHF) is one of the main medical and social problems in the world. The sudden death frequency due to congestion CHF varies from 45 to 90 %. So, decreasing of mortality due to CHF is one of the main aims. Increased body weight plays an important role in CHF etiology. It triggers cardio-vascular system response, which manifests with the increased need in oxygen and nutrients and implements in increased pump function of heart and its structural and functional changes. Despite significant progress and efforts made my world cardiology in the field of CHF treatment, long-term prognosis in those patients is still unfavorable, and their life quality is unsatisfactory.

Clinical researches show that beta-blockers significantly decrease mortality risks in CHF patients (especially sudden death risks, for 41 to 56 %). That is accompanied by increasing of left ventricle ejection fraction, decreasing of CHF functional class, hospitalization frequency. According to MERIT-HF (1999), metoprolol succinate can significantly avert the progressing of CHF to its terminal stage in wide group of patients with CHF from 2^nd to 4^th functional classes and decrease mortality level due to CHF progression to 49 % which is the highest index among all existing beta blockers.

Nonetheless, increasing of CHF therapy efficacy including metoprolol succinate is still open field for research. The perspectives of future studies is considering the P450 2D6*4 isoenzyme gene of cytochrome system polymorphism in the metoprolol succinate pharmacokinetics.

Aim. Studying the influence of cytochrome Р450 CYP2D6*4 isoenzyme system genetic polymorphism on efficacy of metoprolol succinate in treatment of patients with chronic heart failure and obesity by estimating psychosocial factors (quality of life) and clinical state.

Materials and methods. The study has been performed during one year in Government Institution «L. T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine». We examined 89 persons with CHF of 2^nd–3^rd stages, NYHA functional class was 1–3, aged 32–87 (61 [56; 68]) years. There were 63 males and 26 females.

Selection criteria were age of 18 and more y. o., 2^nd-3^rd stage of CHF of ischemic or hypertensive genesis with sinus rhythm and progressing of left ventricle systolic dysfunction, which requires using of β-adrenoblockers (β-AB), absence of contraindications for them, inflammatory and neoplastic states which could affect results of the study. Exclusion criteria — refusal to participate or continue participating in study; presence or development of some states, which could affect the results.

According to BMI: normal weight were in 22 (24,7 %) patients (I group), excessive — 30 (33,7 %) patients (II group), 1 grade obesity — 22 (24,7 %) patients (III group), 2 grade obesity — 12 (13,5 %) patients (IV group), 3 grade obesity — 3 (3,4 %)persons (V group). Every group was comparable to etiology of CHF (frequency and severity of arterial hypertension, stable angina (stenocardia), diffuse and post-infarction cardiosclerosis). Clinical signs were marked according to scale of estimations of clinical symptoms (SECS). To estimate the exercise tolerance we used 6 minute walking test. To estimate psychosocial factors we used Minnesota Multiphasic Personality Inventory (MMPI).

To study allele polymorphism of CYP2D6 G1846A gene we used polymerase chain reaction (PCR) in real time using “Set of reagents for determination of polymorphism of CYP2D6 G1846A gene rs 3892097” (“SYNTOL”, Russian Federation) (cat. NP_468_100_CFX-96). Amplification and allele discrimination we performed using “CFX96 Touch™ Real-Time PCR Detection System” (BioRad Laboratories Pte.Ltd., Singapore).

Statistical analysis was performed with critical significance level 0,05. Prior estimation of distribution character by visual method and with Shapiro-Wilk W test showed difference from normal so we used non-parametric methods. While analyzing quantitative indices for central pattern and variability of signs in groups of patients, we calculated median (Me) and inter-quartile interval, showing lower quantile, 25 % (LQ) and upper one, 75 % (UQ). The result we expressed as Me [LQ; UQ].

Results and discussion. Survival index during observation period was 88 of 89 cases (98,9 %). We found a tendency (p<0,10) in association of unfavorable allele A of oligonucleotide polymorphism of isoenzyme gene of Р450 2D6*4 cytochrome system in heterozygote genotype GA and increased body weight. Its frequency was 14 of 37 (38 %) among patients with CHF and obesity, 15 of 52 (29 %) in patients with CHF and normal or excessive body weight; 5 of 21 (24 %) in healthy persons of control group.

Total frequency of clinically significant metoprolol succinate side effects (bradycardia, dizziness, weakness etc.) was 9 [6; 11] %, moreover statistically possible differences of side effects frequency in different groups weren’t found (j<2,0), but in persons with GA genotype we found a tendency to clinically worse results.

Thus, despite SECS characteristics showed in general essential improvements, GA genotype group that presented lower (4 [3; 6] points with initial 6,5 [5; 8]) comparing to GG genotype (3 [3; 5] and 7 [6; 8] respectively; p=0,05).

Total estimation of life quality according to Minnesota Multiphasic Personality Inventory had opposite dynamics depending on genotype. As in GG genotype we saw tendency to increasing to 48 [21,5; 61,5] comparing to initial 45 [31; 64] points, but in GA genotype group there was decreasing to 32 [16; 48] comparing to initial 54 [44; 64].

Our data need further research and addition. Prior is increasing of a contingent of patients, allowing us to increase statistical power of research and to reveal significant patterns, which for now are just tendencies.

Conclusions.

1. The metoprolol succinate efficacy in dynamics of treatment of CHF and obesity patients is influenced by oligonucleotide polymorphism of cytochrome system Р450 2D6*4 isoenzyme gene.

2. Unfavorable A allele of oligonucleotide polymorphism in heterozygote GA genotype is associated with the increased body weight.

3. In contingent with heterozygote GA genotype comparing to GG homozygote one, there was less positive dynamics of life quality parameters and clinical signs during metoprolol succinate treatment of patients with CHF and obesity.