Gasanov Iu. Ch., Galchinskaya V. U., Petenyova L. L.

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

Hemodynamic aspect of influence of cytochrome Р450 2D6*4 gene polymorphism on efficacy of metoprolol succinate in patients with chronic heart failure and obesity

Despite progress in the field of chronic heart failure (CHF) treatment, long-term prognosis in those patients is still unfavorable, and their health-related quality of life is unsatisfactory. Clinical researches show that beta-adrenoblockers significantly decrease mortality risks in patients with CHF. That is accompanied with increased ejection fraction of left ventricle, decreasing of functional class of CHF and hospitalization frequency. 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 of influence of polymorphism of gene of isoenzyme of cytochrome Р450 CYP2D6*4 system on efficacy of metoprolol succinate in treatment of patients with chronic heart failure and obesity by estimating central hemodynamics indices.

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». Eighty-nine persons with CHF of 2^nd–3^rd stages, NYHA functional class was 1–3, aged 32–87 (61 [56; 68]) years have been examined. 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 was 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).

Central hemodynamics was studied using Doppler- and echocardiographic method (“Vivid 3”, General Electric, USA). We estimated end-diastolic volume of left ventricle (EDV LV), end-systolic volume of left ventricle (ESV LV), thickness of interventricular septum (IVST), left ventricle posterior wall thickness (LVPWT), left atrium diameter (LAD), right atrium diameter (RAD), early (E) and atrial (A) diastolic filling velocity, ejection fraction of left ventricle (LVEF), and left ventricle myocardium mass (LVMM).

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).

Metoprolol succinate was prescribed according standard scheme with dose titration every 2 weeks from 12,5 mg to 100–200 mg. According to the research design we had 2 control points (CP): CP1 — before prescribing metoprolol succinate, and CP2 — through 1 year of regular metoprolol succinate treatment in adequate dose. Except this BAB patients had ACE inhibitor, angiotensin II receptors blockers, aldosterone antagonists, and loop and thiazide diuretics as a CHF complex therapy. Groups were comparable with therapy.

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.

During treatment cardiac hemodynamic indices were in general improved (table 1). It is noteworthy that in GA genotype group changes of dynamics were less favorable or sometimes even had negative tendency.

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 cardiac hemodynamics during metoprolol succinate treatment of patients with CHF and obesity.

4. Perspective of our future researches is study of cytochrome P460 CYP2D6 isoenzyme gene polymorphism in the aspect of efficacy of using metoprolol succinate in treatment of patients with CHF and obesity. We have to observe as many cases as it’s possible to achieve proper statistical power of research to prove the protocols of metoprolol succinate using in patients with CHF and obesity considering cytochrome P450 CYP2D6*4 isoenzyme gene polymorphism.

Table 1

Echocardiography examination results of patients with CHF in one-year study of metoprolol succinate treatment including cytochrome Р450 2D6*4 isoenzyme gene polymorphism

Indices	I group, n=22		II group, n=30		III group, n=22		IV group, n=12		V group, n=3
	Genotype GG, n=15	Genotype GA, n=7	Genotype GG, n=22	Genotype GA, n=8	Genotype GG, n=16	Genotype GA, n=6	Genotype GG, n=6	Genotype GA, n=6	Genotype GG, n=1	Genotype GA, n=2
EDV LV (CP1), cm	6.2 [5.0; 6.8]	5.6 [5.0; 6.7]	5.8 [5.2; 6.4]	5.7 [5.3; 6.1]	5.3 [5.2; 6.2]	5.5 [5.2; 6.2]	6.1 [5.6; 6.6]	6.0 [5.0; 6.0]	5.8 [5.8; 5.8]	6.7 [6.0; 7.3]
EDV LV (CP2), cm	4.9 [4.9; 4.9]	–	5.7 [5.7; 6.1]	5.7 [5.7; 5.7]	5.7 [5.6; 6.3]	–	5.7 [4.8; 6.5]	6.5 [6.5; 6.5]^*	–	5.7 [5.7; 5.7]
ESV LV (CP1), cm	5.0 [3.9; 5.7]	4.4 [3.9; 5.5]	4.4 [4.0; 5.4]	4.3 [4.0; 4.7]	4.1 [4.0; 5.0]	4.6 [4.1; 5.3]	4.8 [4.4; 5.5]	4.8 [3.9; 5.0]	4.6 [4.6; 4.6]	5.5 [4.8; 6.2]
ESV LV (CP2), cm	3.6 [3.6; 3.6]	–	4.5 [4.4; 5.0]	4.4 [4.4; 4.4]	4.4 [4.1; 5.1]	–	4.6 [3.4; 5.0]	4.9 [4.9; 4.9]^*	–	4.1 [4.1; 4.1]
IVST (CP1), cm	1.2 [1.2; 1.4]	1.2 [1.0; 1.3]	1.2 [1.0; 1.3]	1.2 [1.2; 1.3]	1.2 [1.2; 1.3]	1.2 [1.2; 1.3]	1.2 [1.1; 1.3]	1.4 [1.2; 1.5]	1.3 [1.3; 1.3]	1.2 [1.1; 1.2]
IVST (CP2), cm	1.2 [1.2; 1.2]	–	1.2 [0.9; 1.2]	1.2 [1.2; 1.2]	1.3 [0.9; 1.5]	–	1.1 [1.1; 1.2]	1.6 [1.6; 1.6]^*	–	1.2 [1.2; 1.2]
LVPVT (CP1), cm	1.2 [1.1; 1.2]	1.2 [1.0; 1.3]	1.2 [1.0; 1.2]	1.2 [1.1; 1.3]	1.2 [1.2; 1.3]	1.2 [1.2; 1.3]	1.2 [1.2; 1.2]	1.3 [1.2; 1.5]	1.3 [1.3; 1.3]	1.2 [1.2; 1.2]
LVPVT (CP2), cm	1.2 [1.2; 1.2]	–	1.2 [0.9; 1.2]	1.2 [1.2; 1.2]	1.2 [1.2; 1.3]	–	1.2 [1.2; 1.2]	1.6 [1.6; 1.6]^*	–	1.2 [1.2; 1.2]
LAD (CP1), cm	4.6 [4.1; 4.9]	4.0; [3.7; 4.3]	4.3 [3.9; 4.8]	4.5 [4.3; 4.6]	4.3 [3.9; 4.4]	4.6 [4.0; 4.8]	4.5 [3.8; 5.0]	4.4 [3.7; 4.6]	4.2 [4.2; 4.2]	4.9 [4.6; 5.3]
LAD (CP2), cm	3.8 [3.8; 3.8]	–	4.3 [4.2; 4.4]	4.0 [4.0; 4.0]^*	4.3 [4.2; 4.4]	–	4.2 [3.8; 4.4]	4.4 [4.4; 4.4]^*	–	4.4 [4.4; 4.4]
RVD (CP1), cm	2.6 [2.6; 3.4]	2.8 [2.6; 3.0]	2.7 [2.6; 3.0]	2.8 [2.5; 3.0]	2.7 [2.6; 3.0]	3.0 [2.8; 3.3]	3.1 [2.6; 3.5]	2.8 [2.8; 3.0]	2.6 [2.6; 2.6]	3.5 [3.5; 3.5]
RVD (CP2), cm	2.6 [2.6; 2.6]	–	2.7 [2.6; 2.8]	3.0 [3.0; 3.0]^*	2.7 [2.6; 3.0]	–	2.6 [2.6; 3.0]	3.0 [3.0; 3.0]^*	–	3.5 [3.5; 3.5]
RAD (CP1), cm	3.8 [3.5; 4.8]	3.9 [3.6; 4.4]	3.8 [3.4; 4.4]	3.8 [3.5; 4.3]	3.8 [3.5; 4.1]	3.6 [3.3; 4.4]	4.3 [3.5; 4.8]	3.7 [3.4; 4.6]	3.8 [3.8; 3.8]	4.4 [4.4; 4.4]
RAD (CP2), cm	3.4 [3.4; 3.4]	–	3.8 [3.3; 3.8]	4.2 [4.2; 4.2]^*	3.8 [3.6; 4.0]	–	3.8 [3.3; 4.6]	4.6 [4.6; 4.6]^*	–	4.4 [4.4; 4.4]
LVEF (CP1), %	39 [36; 42]	41 [40; 43]	42 [36; 44]	42 [38; 45]	44 [40; 45]	43 [36; 44]	37 [35; 43]	43 [40; 44]	41 [41; 41]	35 [30; 40]
LVEF (CP2), %	51 [51; 51]	–	45 [45; 45]	45 [45; 45]	45 [38; 50]	–	44 [39; 55]	48 [48; 48]^*	–	53 [53; 53]
LVММ (CP1), g	183 [124; 217]	155 [113; 215]	157 [137; 227]	160 [138; 172]	142 [133; 182]	169 [144; 191]	186 [136; 228]	255 [193; 287]	170 [170; 170]	176 [176; 176]
LVММ (CP2), g	120 [120; 120]	–	161 [120; 172]	157 [157; 157]^*	152 [152; 205]	–	157 [115; 199]	282 [282; 282]^*	–	160 [160; 160]

Note. ^* — difference of index to GG genotype respectively is probable at р<0.05.