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СЕРДЕЧНО-СОСУДИСТОЕ РЕМОДЕЛИРОВАНИЕ И МЕТАБОЛИЧЕСКИЕ НАРУШЕНИЯ У ПАЦИЕНТОВ С КОМОРБИДНОСТЬЮ ГИПЕРТОНИЧЕСКОЙ БОЛЕЗНИ И САХАРНОГО ДИАБЕТА 2 ТИПА В ЗАВИСИМОСТИ ОТ ПОЛИМОРФИЗМА PPARy2
Шалимова А.С.
Харьковская медицинская академия последипломного образования, Украина
Беловол А.Н.
Харьковский национальный медицинский университет, Украина
Бобронникова Л.Р.
Харьковский национальный медицинский университет, Украина
CARDIOVASCULAR REMODELING AND METABOLIC DISORDERS IN PATIENTS WITH COMORBIDITY OF ESSENTIAL HYPERTENSION AND TYPE 2 DIABETES DEPENDING ON GENETIC POLYMORPHISMPPARy2 Shalimova A.S., Kharkiv Medical Academy of Postgraduate Education, Ukraine Belovol A.N., Kharkiv National Medical University, Ukraine Bobronnikova L.R., Kharkiv National Medical University, Ukraine
АННОТАЦИЯ
Цель работы: изучить Pro12Ala PPARy2 полиморфизм и его связь с выраженностью сердечно-сосудистого ремоделиро-вания и метаболических нарушений при коморбидности гипертонической болезни (ГБ) и сахарного диабета 2 типа (СД 2т) в украинской популяции.
Основная группа состояла из 287 пациентов с ГБ и СД 2т. Группа сравнения состояла из 68 пациентов с ГБ без СД 2т. Контрольная группа состояла из 25 практически здоровых лиц.
Было установлено, что во всех исследуемых группах преобладали пациенты с аллелем Pro при отсутствии достоверных различий между группами. Пациенты с Pro12Ala/Ala12Ala генотипом имели достоверно более низкие значения толщины интимы-медиа и скорости распространения пульсовой волны в сонной артерии, более низкие уровни малонового диаль-дегида и диеновых конъюгатов, а также достоверно более высокую степень эндотелий-зависимой вазодилатации, более высокие уровни супероксиддисмутазы и каталазы, чем пациенты с генотипом Pro/Pro. Установлено, что у пациентов с генотипом Pro12Ala/Ala12Ala имели место менее выраженные метаболические расстройства.
Выводы: генетический полиморфизм PPARy2 влияет на выраженность ремоделирования сердца и атеросклеротических процессов в сосудах при коморбидности ГБ и СД 2т. Pro12Ala/Ala12Ala генотип можно рассматривать как протективный полиморфизм при указанной коморбидности.
ABSTRACT
The aim of the &udy: to inve^igate Pro12Ala PPARy2 polymorphism and its association with the severity of vascular remodeling and metabolic disorders in comorbidity of essential hypertension (EH) and type 2 diabetes (DM2) in Ukrainian population.
The main group of our &udy consi^ed of 287 patients with EH in combination with DM2. The group of comparison consi^ed of 68 patients with EH without DM2. The control group consi^ed of 25 healthy individuals.
It was determined that in all &udy groups the dominating factor belonged to the patients with Pro allele in the absence of significant differences between the groups. The patients with Pro12Ala/Ala12Ala genotype have significantly lower values of intima-media thickness and pulse wave velocity in the carotid artery, lower levels of malondialdehyde and diene conjugates and significantly higher degree of endothelium-dependent vasodilation, higher levels of superoxide dismutase and catalase than in genotype Pro/Pro. It was determined that metabolic disorders were less pronounced in patients with genotype Pro12Ala/Ala12Ala.
Conclusions: The genetic polymorphism PPARy2 affected the severity of heart remodeling and vascular atherosclerotic processes with comorbidity of EH and DM2. Pro12Ala/Ala12Ala genotype can be considered as a protective polymorphism at specified comorbidity.
Ключевые слова: гипертоническая болезнь, сахарный диабет 2 типа, сердечно-сосудистое ремоделирование, метаболические нарушения, генетический полиморфизм PPARy2.
Keywords: essential hypertension, type 2 diabetes, cardiovascular remodeling, metabolic disorders, PPARy2 genetic polymorphism.
Introduction. Essential hypertension (EH), type 2 diabetes (DM2) and obesity are three of the mofl common non-infectious diseases in the world. Insulin resiflance (IR) is one of the pathophysiological mechanisms that affects the development and course of comorbidity EH, DM2 and obesity [4, 7, 10].
It has been found that normal insulin sensitivity largely depends on the functional activity of peroxisome proliferator-activating receptor (PPAR) [2, 3, 5, 9]. For the recent years the scientifls have been paying much attention to research of PPAR polymorphism - transcription factors that control the activity of many genes, regulate lipid and carbohydrate metabolism [1, 6, 8, 11].
The aim of this fludy was to invefligate Pro12Ala PPARy2 polymorphism and its association with the severity of vascular remodeling and metabolic disorders in comorbidity of EH and DM2 in Ukrainian population.
Clinical characteriflics of patients and research methods. We examined 287 patients of Ukrainian population, aged from 45 to 60 years old with EH flage II grade 2 and DM2 moderate, subcompensated (the main group); 68 patients with EH flage II grade 2 without DM2 (the comparison group). The control group consifled of 25 healthy individuals with no EH and DM2, as they were excluded on the basis of the complex clinical and inflrumental examinations.
Inclusion criteria to the fludy: EH flage II grade 2; type 2 diabetes moderate, subcompensated; CHF I-II FC, normal weight (body mass index (BMI) - 18-24,9 ) , overweight (BMI - 25-29.9 ), obesity I degree (BMI - 30-34,9 ), abdominal obesity (criteria IDF, 2005), normal glomerular filtration rate (GFR), normocreatininemia absence of proteinuria (admissible only microalbuminuria), age patient 45-60 years; eflablished disease duration EH - 12,8 years, type 2 diabetes - 3-7 years; irregular antihypertensive drugs.
Exclusion criteria from the fludy: presence of comorbidity in patients with EH and DM2 (acute coronary syndrome, myocardial infarction, arrhythmias and conduction, rheumatic heart disease, syflemic connective tissue diseases, cancer diseases, symptomatic hypertension, thyroid disease, acute inflammation), type 1 diabetes; EH flage III, grade 3, CHF III-IV FC, type 2 diabetes in mild and severe forms of compensation and decompensation phases; insulin therapy in
patients with type 2 diabetes; obesity II-III degrees, reduced GFR, proteinuria; age of the patients less than 45 and more than 60 years; echonegativity; refusal of patients from the fludy.
Working with patients, involved in the fludy, using flandard biochemical methods we defined glucose concentration of venous blood glucose, glycosylated hemoglobin (HbA1c), insulin, total choleflerol, triglycerides, high density choleflerol (HDL choleflerol) and low density choleflerol (LDL choleflerol). IR was assessed by HOMA index (HOMA-IR). Levels of oxidative flress indicators - malondialdehyde (MDA) and diene conjugates (DC), and antioxidant protection - superoxide dismutase (SOD) and catalase superoxide dismutase (SOD) and catalase were fludied with spectrophotometry methods.
Ultrasound examinations were performed on cardiac ultrasound scanner («ULTIMA RA» firm «RADMIR», Ukraine) in one-, two-dimensional and Doppler modes with color mapping by conventional methods. For the fludy of endothelial function determination of the degree endothelium-dependent vasodilation (EDVD) in reactive hyperemia was conducted in all patients. Invefligations were carried out broadband linear transducer 5-12 MHz Doppler color mapping with three on the left and right brachial artery in 15-minute intervals between samples by the method of Celermajer D.S. in modification Ivanova O.V. Normally, the maximum vasodilation of the brachial artery have to exceed 10% of the original diameter. Simultaneously, we measured the of the intima-media thickness (IMT) of the carotid artery (CA 2 cm proximal to the bifurcation of the common carotid artery. Pulse wave velocity (PWV) by the CA was determined W-Track- method (method of phase tracking, patented scanner manufacturers).
Pro12Ala polymorphism of PPARy2 was assessed by molecular genetic method. We have identified three genotypes of PPARy2 by Pro12Ala polymorphism (Pro/Pro, Pro/Ala and Ala/Ala). The diflribution of allele frequencies corresponded to the Hardy-Weinberg law.
Statiflical data processing was performed using the software package «Statiflics for Windows» 6.0.
Results and their discussion.
It was determined that in all fludy groups the dominating factor belonged to the patients with Pro allele in the absence of significant differences between the groups (Figure 1).
Figure 1 The diflribution of PPARy2 alleles and genotypes in the patients
According to other researchers the similar diflribution The patients of main group with Pro12Ala/Ala12Ala of genotypes of PPARy2 it is generally typical for European genotype had significantly (p<0,01) lower values of IMT and population [6, 8, 9]. PWV in the carotid artery and significantly (p<0,001) higher
degree of EDVD than in genotype Pro/Pro (Figure 2).
IMT, mm PWV. in/s ED WD, °/o genotype Prol2Ala/Alal2Ala ..........genotype Pro/Pro
Figure 2 The indicators of vascular remodeling in the patients of main group Note: * - Satirically significant differences between genotypes Pro12Ala/Ala12Ala and Pro/Pro in the main group.
The patients with Pro12Ala/Ala12Ala genotype had antioxidant protection - SOD and catalase than in genotype Pro/ significantly lower values of oxidative flress indicators - Pro (Table 1). MDA and DC; and significantly higher levels of indicators of
Table 1
The indicators of oxidative flress and antioxidant protection in the patients of the main group
Indices genotype Pro12Ala/Ala12Ala genotype Pro/Pro
MDA, nmol/l 37,41 ± 0,14 39,02 ± 0,07*
DC, nmol/l 36,75 ± 0,21 38,67 ± 0,14*
SOD, U/mg Hb min 43,08 ± 0,11 39,92 ± 0,05*
Catalase, U/mg Hb min 0,114 ± 0,001 0,110 ± 0,001*
Note: * - Satirically significant differences between genotypes Pro12Ala/Ala12Ala and Pro/Pro in the main group.
It was determined that metabolic disorders were less pronounced in patients with genotype Pro12Ala/Ala12Ala, what was confirmed by lower levels of total choleflerol, glucose,
HbAlc, insulin, less pronounced insulin resiflance and higher levels of high-density lipoproteins (p<0,001) (Figure 2).
total cholesterol, glucose, mmol/1 HbAlc. % insulin. mcU/ml HOMA-IR mmol/1
genotype Prol2Ala/Alal2Ala "genotype Pro'Pro
HDL, mmol/1
genotype genotype Pro/Pro
Prol2Ala/Alal2Ala
Figure 3 The severity of metabolic disorders in the patients of the main group Note: * - Satirically significant differences between genotypes Pro12Ala/Ala12Ala and Pro/Pro in the main group.
The main features for genotype Pro12Ala/Ala12Ala were (LV) and myocardial mass index (MMI) LV than for Pro/Pro significantly lower blood pressure, smaller sizes of left ventricle genotype (Figure 4).
MMI LV, g/m2 SAP, mmHg DAP, mmHg
genotype Prol2Ala/Alal2Ala «genotype Pro/Pro
Figure 4 Hemodynamic and echocardiography indices in the patients of the main group Note: * - Satirically significant differences between genotypes Pro12Ala/Ala12Ala and Pro/Pro in the main group.
Conclusions
1. The genetic polymorphism PPARy2 affected the severity of heart remodeling and vascular atherosclerotic processes, the level of blood pressure with comorbidity of EH and DM2 in Ukrainian population of patients.
2. Pro12Ala/Ala12Ala genotype can be considered as a protective polymorphism at specified comorbidity.
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