On the mechanism of the antiarrhythmic action of fabomotizole hydrochloride in alcoholic cardiomyopathy

It is known that the alcoholic cardiomyopathy (ACMP) is the main reason for lethality from chronic alcoholism. For ACMP the risk of development of malignant violations of a heart rhythm which result approximately at 40% of such patients is sudden heart death is extremely high. Materials and methods. Experiments were made on the ACMP translational model developed by us which is formed at rats by the end of the 24th week of compulsory reception of 10 % of ethanol solution. For studying the mechanisms which are the responsible of antiarrhythmic action of a fabomotizole dihydrochloride used a complex of morphohistological, electrophysiological and molecular researches. Results. It is shown that against the background of systematic therapy fabomotizole dihydrochloride (15 mg/kg, i.p.) daily within 28 days after 24 weeks of alcoholization, in comparison with alcoholized control the fat dystrophy of a myocardium significantly decreases and the threshold of electric fibrillation of heart ventricles is restored. According to results of molecular researches, a fabomotizole dihydrochloride significantly suppresses revealed in control alkoholized animals the abnormal mRNA expression of key receptor genes and proteins responsible for maintenance in cardiomyocytes of a homeostasis of ions of Ca++ and regulation of their rhythmic activity: regulatory proteins Epac1 (p = 0.021), Epac2 (p = 0.018), CaM (p = 0.00001) and also RyR2 (p = 0.031), IP3R2 (p = 0.006) receptors. Conclusion. The obtained results suggest that antiarrhythmic action of a fabomotizole dihydrochloride in the conditions of ACMP is connected with its ability to suppress abnormal activity of regulatory proteins Epac2 and RyR2, IP3R2 receptors.

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

Chronic alcohol consumption leads to myocardial injury, ventricle dilation, and cardiac dysfunction, which is defined as alcoholic cardiomyopathy (ACM). To explore the induced myocardial injury and underlying mechanism of ACM, the Liber-DeCarli liquid diet was used to establish an animal model of ACM and histopathology, echocardiography, molecular biology, and metabolomics were employed. Hematoxylin-eosin and Masson’s trichrome staining revealed disordered myocardial structure and local fibrosis in the ACM group. Echocardiography revealed thinning wall and dilation of the left ventricle and decreased cardiac function in the ACM group, with increased serum levels of brain natriuretic peptide (BNP) and expression of myocardial BNP mRNA measured through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR), respectively. Through metabolomic analysis of myocardium specimens, 297 differentially expressed metabolites were identified which were involved in KEGG pathways related to the biosynthesis of unsaturated fatty acids, vitamin digestion and absorption, oxidative phosphorylation, pentose phosphate, and purine and pyrimidine metabolism. The present study demonstrated chronic alcohol consumption caused disordered cardiomyocyte structure, thinning and dilation of the left ventricle, and decreased cardiac function. Metabolomic analysis of myocardium specimens and KEGG enrichment analysis further demonstrated that several differentially expressed metabolites and pathways were involved in the ACM group, which suggests potential causes of myocardial injury due to chronic alcohol exposure and provides insight for further research elucidating the underlying mechanisms of ACM.

Injury caused by alcoholic cardiomyopathy in spontaneous ethanol drinking rats

ABSTRACTWhen speaking of pathologies caused or aggravated by the constant ingestion of ethanol, people with liver and central nervous system diseases soon come to mind, however, the acute intake of large amounts of ethanol and chronic abuse induce toxic effects in the majority of tissues. The heart is highlighted, since alcoholic cardiomyopathy (AC) has prevalence among alcoholics of 23 to 40% and occurs more frequently in men than in women. AC is characterized by dilation and poor contraction of one or both ventricles in the presence of increased ventricular wall thickness, along with a long history of ethanol abuse and no other cause identified. Our aim is to quantify the rate of cardiac tissue replacement, collagen fiber deposition and pro inflammatory cytokines in the left ventricle myocardium of volunteer ethanol drinking rats.

Effect of Candesartan Combined with Rosuvastatin on Myocardial Fibrosis in Rats with Alcoholic Cardiomyopathy by Mediating LOX-1 Expression

Objective: To analyze the effect of candesartan and rosuvastatin on myocardial fibrosis in rats with alcoholic cardiomyopathy by mediating the expression of lectin-like oxidized low-density lipoprotein receptor-1(LOX-1). Methods: The rats were selected as experimental samples, and these rats were randomly divided into observation group and alcohol feeding group (abbreviated as "alcohol group") and desartan combined with rosuvastatin intervention + alcoholic cardiomyopathy group (Referred to as the "intervention group"), the observation group is fed normally, the alcohol group is fed with alcohol, and the intervention group uses two drugs on the basis of the alcohol group to intervene. After 16 weeks of the three groups of experiments, analyze the results of the three groups of experiments. Myocardial structure, myocardial fibrosis and myocardial function. Results: After 16 weeks, the left ventricular short axis shortening rate (FS) and left ventricular ejection fraction in the alcohol group were lower than those in the observation group, while the collagen volume fraction (CVF) and left ventricular end-diastolic diameter (LVEDd) were higher than those in the observation group. The expression of LOX-1 in the intervention group was lower than that in the alcohol group, and the degree of fibrosis was reduced. The expression of LOX-1 in the alcohol group was higher than that in the observation group, and the degree of fiber increased. At the same time, the expression of TN-X and smad-3 protein in the alcohol group (86%± 7%, 83%±9%) were higher than those in the observation group (32%±10%, 30%±7%), while the expression of smad-7 protein (36%±8%) was lower than that in the observation group (78%± 9%), P<0.05 among the three groups of experiments, and there is statistical significance among the groups. Conclusion: Candesartan combined with Rosuvastatin can reduce myocardial fibrosis in rats with alcoholic cardiomyopathy by mediating the expression of LOX-1.