Diabetes mellitus — metabolic preconditioning in protecting the heart from ischemic damage?

The negative impact of diabetes mellitus (DM) on the cardiovascular system has been confirmed by numerous clinical studies. However, there are experimental studies that show an increase in the resistance of the heart to ischemic and reperfusion damage in animals with DM. This phenomenon is characterized by a smaller size of the infarct zone, better preservation of the contractile function of the myocardium, and a lower incidence of ischemic and reperfusion arrhythmias. It is assumed that at a certain stage in the development of DM, a “metabolic window” is formed, in which metabolic alterations at the cellular level trigger adaptive mechanisms that increase the viability of cardiomyocytes. Published data confirm that the magnitude of the protective effect induced by DM is comparable to, and in some cases even exceeds, the effect of the preconditioning phenomenon. It is recognized that the mechanisms that protect the heart from ischemic and reperfusion damage against the background of DM are universal and are associated with the modulation of the antioxidant system, apoptosis factors, pro-inflammatory cytokines, and signaling systems that ensure cell survival. The one of the main pathogenic factor in DM is hyperglycemia, but under stress it plays the role of an adaptive mechanism aimed at meeting the increased energy demand in pathological conditions. Probably, at a certain stage of DM, hyperglycemia becomes a trigger for the development of protective effects and activates not only signaling pathways, but also the restructuring of energy metabolism, which makes it possible to maintain ATP production at a sufficient level to maintain the vital activity of heart cells under ischemia/reperfusion conditions. It is possible that an increased level of glucose, accompanied by the activation of insulin-independent mechanisms of its entry into cells, as well as the availability of this energy substrate, will contribute to a better restoration of energy production in heart cells after a infarction, which, in turn, will significantly reduce the degree of myocardial damage and will help preserve the contractile function of the heart. Identification of the conditions and mechanisms of the cardioprotective phenomenon induced by DM will make it possible to simulate the metabolic state in which the protection of cardiomyocytes from damaging factors is realized

GENE CYP2C19 POLYMORPHISM G681A INFLUENCE ON THE EFFICACY OF CLOPIDOGREL IN ENDOVASCULAR TREATMENT OF ISCHEMIC HEART DISEASE COMORBID WITH TYPE 2 DIABETES

Aim. To research on the influence of polymorphism G681A gene CYP2C19 on efficacy of clopidogrel for planned endovascular treatment in stable CHD with second type diabetes.Material and methods. Totally 242 patients included, with chronic CHD, underwent planned angioplastics and stenting of coronary arteries. Of those 79 had 2nd type DM. All patients received double antiplatelet therapy, including acetylsalicylic acid and clopidogrel. For efficacy evaluation, we performed the test of induced platelet aggregation with ADP in 2,5 and 5,0 mcM concentrations after total dose of clopidogrel 300 mg. Genotyping was done with allele-specific polymerase chain reaction with commercial panel “SNP-express” (SPC “LITECH”, Moscow).Results. In our selection, the carriers of allele A differed from homozygous GG with an increased grade of platelet aggregation in ADP stimulation, concentrations 2,5 mcM and 5,0 mcM. While selecting subgroups according to diabetes existence, the mention association was found in non-diabetic group, but not in comorbidity group (CHD and DM). In GG genotype, patients having 2 type DM showed the grade of induced platelet aggregation higher than in carriers of the same genotype without DM. At the same time, allele A carriers without DM did not differ from comorbidity selection in sense of ADP induced response of platelets.Conclusion. So, A allele carriage of G681A polymorphism of gene CYP2C19 is a risk factor for lower clopidogrel efficacy. Diabetes of second type also negatively influences the sensitivity to clopidogrel, but only in GG homozygous

Association of ACE gene polymorphisms with cardiovascular events in patients after elective percutaneous coronary interventions

Aim. To reveal the association of the INS/DEL polymorphism of the angiotensinconverting enzyme (ACE) gene with acute and long-term complications of elective percutaneous coronary interventions (PCI).Material and methods. This prospective study included 286 patients with chronic coronary artery disease who underwent elective endovascular myocardial revascularization in accordance with current guidelines. The ACE gene INS/DEL (I/D) polymorphism was determined in patients using polymerase chain reaction. Acute periprocedural complications were recorded. Acute myocardial injury (AMI) was detected in 30,4% of patients. Type 4a acute myocardial infarction developed in 3,1% of patients. A significant decrease in the glomerular filtration rate by more than 30% due to periprocedural acute kidney injury (AKI) was diagnosed in 6,5% of patients. Outcomes of elective PCIs were assessed after 4 years via telephone interviews. Cardiovascular and any-cause mortality was 3,6% and 5,1%, respectively. Acute coronary syndrome during the follow-up period developed in 15,2%, while cerebrovascular accident — in 5,4% of patients. Any-stent thrombosis was detected in 10%, and restenosis ≥30% — in 21,8% of patients. Statistical analysis was carried out using the STATISTICA 10. The odds ratio (OR) was calculated with a 95% confidence interval.Results. Analysis of the association of ACE gene I/D polymorphism with acute and long-term complications of the PCI revealed that the presence of I allele is associated with the risk of periprocedural AKI (p=0,017; OR, 2,627 (1,161- 5,947)), as well as long-term cardiovascular events, vascular complications such as acute coronary syndrome (p=0,045; OR, 1,610 (1,007-2,573)) and stent thrombosis (p=0,01; OR, 2,073 (1,178-3,650)). The presence of genotype II further increases the risk of AKI (p=0,029; OR, 5,138 (1,022-25,824)), any acute clinical complications of PCI (p=0,041; OR, 1,996 (1,024-3,980)), and stent thrombosis (p=0,018, OR, 3,498 (1,178-10,392)).Conclusion. In patients with chronic coronary artery disease, the carriage of allele I and genotype II of the ACE gene I/D polymorphism is associated with the risk of acute clinical complications of elective PCI, periprocedural AKI, as well as the risk of stent thrombosis and acute coronary syndrome within 4-year follow-up period after PCI

Сопряженность экспрессии кальций-транспортирующих белков саркоплазматического ретикулума с их полиморфными вариантами генов и структурно-функциональным состоянием сердца пациентов с фибрилляцией предсердий

Aim. To investigate the relationship between the expression of Ca2+ handling proteins of the sarcoplasmic reticulum, polymorphic variants of their genes, and structural and functional parameters of the heart in patients with atrial fibrillation (AF).Materials and methods. The study included patients with AF. The patients underwent radiofrequency ablation, during which a myocardial biopsy was taken. The patients underwent echocardiography (EchoCG) before surgery. Polymorphic variants rs1860561 of the ATP2A2 gene and rs6684209 and rs7521023 of the CASQ2 gene were determined in the patients by real-time polymerase chain reaction (PCR), and the level of expression of SERCA2a and CASQ2 proteins in the myocardium was detected by immunoblotting.Results. Carriers of the GG genotype at rs1860561 of the ATP2A2 gene and CC genotype at rs6684209 of the CASQ2 gene were characterized by significantly higher expression of the corresponding proteins. Using cluster analysis, we identified groups of patients by the level of SERCA2a and CASQ2 expression: group 1 – patients with low protein content; group 2 – patients with high protein content. According to clinical and anamnestic parameters, the patients in the selected groups were homogeneous. In patients with high SERCA2a levels, the end systolic and diastolic volumes of the left ventricle (LV) were significantly higher than those in patients with low levels of this protein. The rates of early (peak E) and late left ventricular diastolic filling (peak A) were significantly lower in the group with high SERCA2a expression. A comparative analysis of EchoCG data of patients distributed by the level of CASQ2 expression in the myocardium did not reveal significant differences between the groups.Conclusion. The polymorphic variant rs1860561 of the ATP2A2 gene and rs6684209 of the CASQ2 gene can modulate the level of SERCA2a and CASQ2 expression. SERCA2a expression is associated with the functional and structural parameters of the heart in patients with AF.Цель. Исследовать взаимосвязь между экспрессией Са2+-транспортирующих белков саркоплазматического ретикулума, полиморфными вариантами их генов и структурно-функциональным состоянием сердца пациентов с фибрилляцией предсердий (ФП).Материалы и методы. В исследование включили пациентов с ФП. Больным проведена радиочастотная аблация, во время которой была взята биопсия миокарда. Пациентам проводили эхокардиографию (ЭхоКГ) до оперативного вмешательства. У больных определены полиморфные варианты rs1860561 гена ATP2A2 и rs6684209, rs7521023 гена CASQ2 методом полимеразной цепной реакции в режиме реального времени и уровень экспрессии белков SERCA2a и CASQ2 в миокарде методом иммуноблоттинга.Результаты. Для носителей генотипов GG rs1860561 гена ATP2A2 и CC rs6684209 гена CASQ2 характерны значимо более высокие экспрессии соответствующих белков. С помощью кластерного анализа были выявлены группы пациентов по уровню экспрессии SERCА2a и CASQ2: 1 – пациенты с низким содержанием белков; 2 – с высоким содержанием белков. По клинико-анамнестическим показателям пациенты отобранных групп оказались практически однородны. У пациентов с высоким уровнем SERCА2a величины конечного систолического и диастолического объемов левого желудочка (ЛЖ) были значимо больше, чем таковые у больных с низким уровнем этого белка. Скорости раннего (пик Е) и позднего диастолического наполнения (пик А) ЛЖ были статистически значимо ниже в группе с высоким уровнем экспрессии SERCА2a. Сравнительный анализ данных ЭхоКГ пациентов, распределенных по уровню экспрессии CASQ2 в миокарде, не выявил значимых различий между группами.Заключение. Генотипы rs1860561 гена ATP2A2 и rs6684209 гена CASQ2 могут модулировать уровень экспрессии SERCA2a и CASQ2. Экспрессия SERCA2a сопряжена с функционально-структурными показателями сердца пациентов с ФП.

Association of polymorphic variants of ADRB1 gene with contractile myocardial dysfunction and erythrocyte adrenoreactivity in patients with rhythm disorders

Aim. To study the association of the rs1801252 (A145G, Ser49Gly) and rs1801253 polymorphic variants (G1165C, Gly389Arg) of the p1-adrenoreceptor ADRB1 gene with the clinical manifestations of chronic heart failure (CHF) and the adrenoreactivity of their erythrocyte membranes in patients with cardiac arrhythmias.Material and methods. The study included 47 patients with atrial fibrillation and I-III FC CHF. A standard clinical examination of patients was performed, including a six-minute walk test and an echocardiographic study. The rs1801252 (A145G, Ser49Gly), rs 1801253 (G1165C, Gly389Arg) polymorphic variants of the p1-adrenoceptor ADRB1 gene and p-adrenoreactivity of erythrocyte membranes were determined.Results. A statistically significant inverse correlation of p-adrenoreactivity of erythrocyte membranes with the left ventricular ejection fraction (r=-0,336, p=0,021) and a direct correlation with the end-systolic volume (r=0,320, p=0,039) were defined. Depending on the FC of CHF, there was a pronounced tendency (p=0,058) of p-adrenoreactivity increasing. In patients with I FC — 25,88 (12,07; 46,37) relative units, II FC — 30,54 (14,50; 43,36) relative units, III FC — 3774 (33,67; 41,81) relative units. Diastolic dysfunction in patients was combined with a decrease in the adrenoreactivity of the organism. The median of p-adrenoreactivity of erythrocyte membranes in the group of patients with diastolic dysfunction was significantly (p=0,021) higher (33,04 (16,30; 4729) relative units) than in the group without diastolic dysfunction (15,91 (11,10; 26,47) relative units). In the studied sample, there were no statistically significant differences in the frequency of diastolic dysfunction in carriers of different genotypes of the rs1801252 and rs1801253 polymorphic variants of the ADRB1 gene (p=1,0 and p=0,058, respectively). An association (p=0,042) of a carrier of the homozygous 145AA rs1801252 genotype with high p-adrenoreactivity of erythrocyte membranes (32,5 (14,6; 473) relative units) was detected in comparison with the heterozygous 145AG genotype (16,3 (11,7; 31,5) relative units). In the studied sample, there was no statistically significant association of p-adrenoreactivity with the carrier of homozygous and heterozygous genotypes of the rs1801253 variant of the ADRB1 gene.Conclusion. The studied rs1801252 and rs1801253 variants of the ADRB1 gene have different associations with impaired diastolic function of the myocardium and desensitization of erythrocyte p-adrenoreceptors

GENOTYPE -786CC OF THE ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE NOS3 AS A FACTOR OF ADVERSE CORONARY HEART DISEASE COURSE AND INCREASED ON-TREATMENT PLATELET AGGREGATION

Aim. To assess the associations of polymorphism T-786C gene NOS3 with the severity of clinical course of coronary heart disease (CHD) and platelet aggregatability in the selection of patients receiving clopidogrel and acetylsalicylic acid (ASA) compounds after selective coronary intervention.Material and methods. In the study, 203 CHD males included, taking ASA and clopidogrel as double antiplatelet therapy for coronary intervention. The test performed, of induced platelet aggregation with adenosine diphosphate (ADP) (2,5 mcM and 5,0 mcM) and epinephrine (0,2 mcM). Genotyping was done with the allele specific polymerase chain reaction (“SNP-express”, SPF Litekh, Russia). Statistics was done with Mann-Whitney test, Kruskal-Wallis test and Pearson chisquare or bi-test by Fisher. Differences were taken as significant at p<0,05.Results. In the studied group, genotypes -786TT, -786TC, -786CC were found with the prevalences 72 (35,4%), 99 (48,8%), 32 (15,8%), respectively. For the carriers of -786CC there was found highest grade of platelet aggregation with ADP 2,5 mcM (p=0,047) and with epinephrine (p=0,008). Carriers of -786TC had the highest left ventricle ejection fraction (p=0,035).Conclusion. In the selection of CHD males taking ASA and clopidogrel, carriage of -786CC polymorphism T-786C gene NOS3 was related to higher platelet aggregation in response to ADP and epinephrine. For these patients, the carriage of genotype -786CC gene NOS3 might be a predictor of thrombotic complications after coronary stenting and more adverse outcome of CHD

Association of polymorphic variants rs6684209 and rs7521023 of the calsequestrin gene (CASQ2) with contractile myocardial function in patients with coronary artery disease

Aim. To study the association between polymorphic rs6684209 and rs7521023 variants of the CASQ2 gene and myocardial contractile function and risk factors for the development of chronic heart failure (CHF).Material and methods. The study included 172 patients with CHF developing on the background of coronary artery disease. We identified polymorphic variants rs6684209 and rs7521023 of the CASQ2 gene by real-time polymerase chain reaction.Results. There was no association of the rs6684209 variant with CHF and the frequency of cardiac arrhythmias. It was revealed that the carriage of the GG genotype of rs7521023 variant is associated with a higher frequency of dilatation of the left atrium (p=0,044) and an increased end-systolic volume (p=0,045).Conclusion. Among patients with coronary artery disease, there was no correlation between the rs7521023 and rs6684209 variants of the calsequestrin gene (CASQ2) with the frequency of cardiac arrhythmias. There was no association of the rs6684209 variant with CHF risk factors and parameters of myocardial contractile function. A relationship was found between the GG genotype of the rs7521023 variant and a higher frequency of left atrium dilatation. Among patients taking beta-blockers, the GG genotype is associated with an increase in end-systolic volume

Polymorphic variants of genes encoding Ca(2+)-transporting sarcoplasmic reticulum proteins in the progression of chronic heart failure

Aim. To study the association between polymorphic rs1860561 variants of Ca(2+)-ATPase SERCA2a (ATP2A2) gene and rs3766871 of ryanodine receptor (RYR2) gene and the severity of chronic heart failure (CHF).Material and methods. We determined rs1860561 and rs3766871 variants of the ATP2A2 and RYR2 genes, respectively, in 168 patients with coronary artery disease (CAD) and CHF using real-time polymerase chain reaction.Results. A statistically significant (p=0,046) decrease in the left ventricular ejection fraction in AA homozygotes of the ATP2A2 gene compared to carriers of the G allele was shown. But among GG homozygotes, patients with FC II CHF prevailed and participants with FC I CHF were less common than among patients with genotype GA (p=0,041).Conclusion. The association of the AA genotype carriage for the rs1860561 variant of the ATP2A2 gene encoding Ca(2+)-ATPase SERCA2a, with a decrease in the left ventricle ejection fraction in patients with CHF and CAD was revealed. At the same time, among the GG homozygotes, FC I CHF was the least prevalent. There was no association of the rY3766871 variant of the RYR2 gene with CHF severity

I/D POLYMORPHISM OF ANGIOTENSINE CONVERTING ENZYME IN CHD PATIENTS OF DIFFERENT AGE AND GENDER

Aim. To analyze spread of alleles and genotypes of ACE gene in CHD patients of different gender and age and to study their realtion with MI risk.Material and methods. Totally 326 individuals of both age, Tomsk city inhabitants, aged 34-79 y. o., included into the study. Of those 173 CHD patients having MI anamnesis and 153 healthy individuals. For the entire group the I/D polymorphism of ACE gene with PCR method using primers by AmpliKit Company (Saint-Petersburg). For the analysis of frequency spread of alleles and genotypes the χ2 criteria used, precise Fischer test and relative risk estimation.Results. By the results of statistic analysis there were no difference between control and patient groups by the prevalence of ACE genes and alleles. While studying women separately there were no siginificant differences between patients and controls in genotypes and alleles. In men with MI in anamesis there was increase of DD genes prevalence comparing to healthy individuals (p=0,038). The analysis of MI prevalence and I/D polymorphism in men and women was performed with relation to age. It is shown that in men younger than 50 y.o. homozygotes there are moreprevalent II and DD genotypes, than in men older than 50 y.o., whom ID genotype is more prevalent (p=0,031). In women group the difference between those younger and older than 55 y.o. the spread of genotypes was similar, but there were more prevalent MIs in older group (p=0,020).Conclusion. The important points of I/D polymorphism of ACE genes influence on MI risk was shown. Among women, sick and healthy, and of various age, there were no significant differences in genitypes prevalence. However there are statistically significant differences in the genotype spread was found in healthy men and men after MI, and in men with the age of 34-50 and 51-79 y.o

Β-адренореактивность мембран эритроцитов у пациентов с дилатацией левого или правого предсердий на фоне фибрилляции предсердий

Hyperactivation of the sympathoadrenal system (SAS) leads to desensitization of β1-adrenergic receptors (β1-AR). This contributes to aggravation of myocardial contractile dysfunction and development of arrhythmias, including atrial fibrillation (AF). An indirect indicator of the viability of β1-AR is β-adrenergic receptor reactivity of erythrocyte membranes (β-ARM).Aim. To evaluate β-ARM in patients with different forms of AF, including left (LAD) or right (RAD) atrial dilation.Materials and methods. The sample included 38 patients, 65.8% of whom had paroxysmal AF, 21% had persistent AF, and 13.2% had long-standing persistent AF. All patients received surgical treatment for AF by radiofrequency ablation or cryoablation. LAD was detected in 39.4% of patients, RAD – in 34.2% of patients. Βeta-ARM was determined before treatment, as well as at 3 days and at 12 months after ablation.Results. The groups of patients with different forms of AF, as well as patients with LAD / RAD and without it showed comparable values of β-ARM at different measurement periods. In the group of patients without LAD / RAD, β-ARM increased 3 days after ablation compared to β-ARM before the treatment (p = 0.002 / p = 0.004) and returned to the pre-treatment level after 3 months. At the same time, in the group of patients with LAD / RAD, β-ARM did not significantly change before the ablation and in different periods after it.Conclusion. In patients with AF without LAD / RAD, we detected an increase in β-ARM 3 days after the ablation compared to the level before the treatment and a decrease in the intensity of SAS 3 months after the surgery. In the presence of LAD / RAD, no changes in the β-ARM were revealed.Гиперактивация симпатоадреналовой системы (САС) приводит к десенситизации β1-адренорецепторов (β1-АР). Это способствует усугублению сократительной дисфункции миокарда и развитию аритмий, в том числе фибрилляции предсердий (ФП). Косвенным показателем состоятельности β1-АР является β-адренореактивность мембран эритроцитов (β-АРМ).Цель: оценка β-АРМ у пациентов с разными формами ФП, в том числе с дилатацией левого (ДЛП) или правого (ДПП) предсердия.Материалы и методы. В выборку включены 38 пациентов, из них 65,8% с пароксизмальной, 21% с персистирующей, 13,2% с длительно персистирующей формами ФП. Всем пациентам проведено оперативное лечение ФП методом радиочастотной или криоаблации. ДЛП выявлена у 39,4% пациентов, ДПП – у 34,2% пациентов. Β-АРМ определяли до лечения, через 3 сут, 3 и 12 мес после аблации.Результаты. Группы пациентов с разными формами ФП, а также пациенты с ДЛП/ДПП и без нее показали сопоставимые значения β-АРМ на разных сроках измерения. В группе без ДЛП/ДПП β-АРМ повышалась через 3 сут после аблации по сравнению с β-АРМ до лечения (р = 0,002/р = 0,004) и через 3 мес вернулась к уровню до лечения. В то же время в группе пациентов с ДЛП/ДПП β-АРМ значимо не менялась до и в разные периоды после аблации.Заключение. У пациентов с ФП без ДЛП/ДПП выявлено повышение β-АРМ через 3 сут после аблации по сравнению с уровнем до лечения и снижение напряженности САС через 3 мес. При наличии ДЛП/ДПП динамика в β-АРМ отсутствовала