FUNCTIONAL COMPOSITION AND POLYMORPHISM OF THE MITOCHONDRIAL LEUKOCYTE GENOME IN ISCHEMIC HEART DISEASE COMPLICATED BY RHYTHM DISTURBANCES
Authors:   Research Institute of Cardiology of the Tomsk National Research Medical Center of the Russian Academy of Sciences, Korepanov Vyacheslav Andreevich ,   Tomsk Russian Federation, Atabekov Tariel Abdilazimovich ,   Research Institute of Cardiology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Tomsk Russian Federation, Golubenko Maria Vladimirovna ,   Research Institute of Cardiology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Tomsk Russian Federation, Afanasiev Sergey Aleksandrovich ,   Research Institute of Cardiology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Tomsk Russian Federation
Published: October 2023

Introduction. Ischemic heart disease (CHD) is the most common pathology in the structure of cardiovascular diseases. Ischemia is a trigger for the occurrence of cardiac arrhythmias (HRDs), requiring the implantation of cardioverter-defibrillators. The functioning of cardiomyocytes is closely associated with respiratory processes in mitochondria (Mtx). Normally, all Mtx in the human body carry the same genome - mitochondrial DNA (mtDNA), respectively, the functional capabilities of all Mtx within the body are similar. Carriage of polymorphic variants of genes encoding subunits of respiratory chain complexes and rRNA may affect the functionality of Mthx. Target. To study the respiratory function of Mtx and the features of mtDNA of leukocytes in patients with coronary artery disease, accompanied by life-threatening NRS. Material and methods. Peripheral venous blood was taken from patients with coronary artery disease (n=45) and ischemic heart disease with HRS (n=120). Mtx was obtained by differential centrifugation in a sucrose gradient. Oxygen consumption rates (OCR) (nM O2/min/mg protein) Mthx were measured in two energy states: V3, the presence of oxidation substrate(s) and phosphorylation substrate (ADP) in the incubation buffer; V4 - after the consumption of ADP in the buffer. Succinate and a mixture of pyruvate and malate were used as oxidation substrates. To assess the functional reserve of Mtx, OPC was determined in the presence and in the absence of saturated palmitic acid (PA) in buffer. The coefficient of conjugation of oxidative processes and phosphorylation was calculated - respiratory control (RC) (V3/V4). The mtDNA haplogroup was established, as well as the carriage of polymorphic variants of genes encoding subunits of the respiratory chain complexes and ribosomal RNA (rRNA) (12S and 16S subunits). Statistical evaluation was carried out in the STATISTICA 13 program using the Mann-Whitney test for independent samples and the Wilcoxon test for dependent data groups. Data are presented as medians and quartiles (Me (Q1; Q3). Differences were considered statistically significant at p<0.05. Results. SPK in V3, V4 and DC of mitochondria in CAD and CAD with HRS did not have significant differences in both buffers without PC. When PA was added to the buffer, a significant increase in SEC was observed in Mth patients with isolated CAD. Thus, in the V3 state, SPK in pyruvate-malate buffer increased from 127.7 (85.3; 196.4) to 198.3 (162.7; 234.9) nM O2/min/mg of protein (p=0, 04), and in the V4 state from (46.6 (38.5; 56.3) to 64.4 (60.3; 87.7) nM O2/min/mg protein (p=0.02). the use of succinate buffer and PC, the mitochondrial SPK in patients with uncomplicated coronary artery disease increased slightly (p = 0.07) from 125.5 (64.4; 172.3) to 184.3 (47.3; 406.3) and from 44, 2 (27.5; 71.9) to 86.1 (36.9; 159.4) nM O2 / min / mg protein in V3 and V4, respectively. In the group of CAD with HRS, the addition of PA to the buffer did not affect the SEC in V3 and V4, as well as DC when using both buffers.mtDNA genotyping found that the main haplogroup in patients with IHD and HRS is haplogroup H - 41%.In 90% of cases, patients in this group were carriers of missense polymorphisms of 16S rRNA genes, which correlates with earlier studies of mtDNA in patients with uncomplicated CAD.In almost half of the cases, tRNA polymorphisms were detected in patients with CAD with HRS.Rarely (less than 40%), missense polymorphisms of the respiratory chain complex I genes were found. Polymorphisms of the genes for cytochrome B, cytochrome c oxidase, ATP synthase, and 12S rRNA turned out to be minor in frequency of occurrence. The frequencies of occurrence of all these polymorphic variants of the genes were similar to those in patients with uncomplicated coronary artery disease. The mtDNA of patients with HRS was 1.5 times more likely to have multiple missense polymorphisms in the protein genes of two different respiratory chain complexes. For genes with missense substitutions in three complexes and substitutions simultaneously in 12S and 16S rRNA, the differences between the groups were 1.6 and 1.7 times. Conclusion. Patients with CAD complicated by HRS are characterized by a reduced functional reserve of mitochondria, in contrast to patients with uncomplicated CAD. This may be due to the carriage of polymorphic variants of the mtDNA genes responsible for coding subunits of proteins of the Mth electron transport chain and mitochondrial rRNA. Also, in patients with CAD and HRS, compared with patients with uncomplicated CAD, the combined carriage of several polymorphic variants of the genes encoding these proteins and rRNA was more often detected.