Association Of HOGG1 Genotypes And Serum Levels Of 8-OHdG With Ischemic Cardiomyopathy,And Efficacy Of Atorvastatin Treatment On Serum Levels Of 8-Hydroxy-Guanin And Mortality In Patient With Ischemic Cardiomyopathy

Of the oxidative DNA damages, 8-hydroxy deoxyguanosine(8-OHd G) is one of the most typical oxidative damage product of DNA, and it has been widely used as a sensitive biomarker and a indicatrix in the oxidative stress and oxidative DNA damage assessment in the present study,which became a hot topic among medical researchers.More than 130 gene products are involved in DNA repair in humans, including8-oxoguanine glycosylase(h OGG1). Oxoguanine glycosylase, encoded by h OGG1, is a bifunctional DNA glycosylase involved in base excision and repair. The main function of oxoguanine glycosylase is to identify and excise8-hydroxy-deoxyguanosine(8-OHd G) lesions from double-stranded DNA. The h OGG1 Ser326 Cys polymorphism, located at base 1245, in the seventh exon of h OGG1-the 326thcodon-encodes either cysteine(Cys) or serine(Ser). The resulting protein variants exhibit differing enzymatic activities, which might be an issue for individuals with increased levels of oxidative damage.More and more evidence found that oxidative damage is closely linked to the coronary artery heart disease(CAHD) and its complications. Dyslipidosis is the dominant cause of atherosclerosis, which is also a facilitator of increasing reactive oxygen, and will lead the oxidative stress phenomenon, endothelial dysfunction, and cardiovascular complications.Ischemic cardiomyopathy(ICM) is a common type of dilated cardiomyopathy caused by coronary atherosclerotic heart disease(CHD). ICM manifests as systolic or diastolic dysfunction, with clinical symptoms not entirely explained by coronaryartery disease, such as arrhythmia, heart dilatation or stiffness, heart failure, and other manifestations of severe ischemia. Long-term myocardial ischemia can lead to either local or diffuse myocardial fibrosis, resulting in systolic or diastolic dysfunction.With the society enters the stage of population aging, ICM morbidity and mortality rates to rise sharply, about 5 million of patients with heart failure caused by ICM ventricular systolic and diastolic dysfunction at least 3.5 million in the United States.The pathogenesis of ICM has not been fully elucidated, and clinical treatment remains challenging owing to a lack of specific therapeutic interventions at present. The literature increasingly suggests that ICM is a disease with both genetic and environmental causes. The role of oxidative stress, as well as the expression levels and polymorphisms of genes encoding DNA-repair enzymes, are gaining increasing attention.As an antiatherosclerotic drug, atorvastatin can obviously lower the incidence rate of cardiovascular disease, and is extensive used in the secondary prevention of CHD. However, there is very few studies to evaluate the association of h OGG1 genotypes and serum levels of 8-OHd G with ICM and other antioxidation functions of atorvastatin except for blood lipid concentration reduction, and the effect of different doses of atorvastatin usage that related to antioxidation and case-fatality rate among ICM patients. These studies have not been more achieved. This paper is divided into two parts to discuss the association of h OGG1 genotypes and serum levels of 8-OHd G with ICM and the efficacy of different dosis atorvastatin treatment on serum levels of 8-OHd G and case-fatality rate in patient with ICM.Part One Case-control analysis of correlation between h OGG1 genotypes and serum levels of 8-OHd G with Ischemic CardiomyopathyObjective To investigate the correlation of h OGG1 gene Ser326 Cys and serum levels of8-OHd G ICM, accordingly to study the effect of oxidative stress on ICM.Methods The case-control study method was used, 246 patients with ICM were selected as the case group, while patients with normal coronary arteries were selected as the control group based on the 1:1 pairing principle and matched by gender, age(within 5years), and hospitalization during the same time period. The h OGG1 gene Ser326 Cys single nucleotide polymorphisms(SNPs) were determined by polymerase chain reaction–restriction fragment length polymorphism(PCR-RFLP), and serum levels of8-OHd G were measured using a sandwich enzyme-linked immunosorbent assay(ELISA) kit, serum level of 8-OHd G, and related biochemical indexes were detected simultaneously.Results There were no differences in allele frequency(?2 = 2.182 P = 0.140), significant differences were present in the genotype distributions(?2= 12.388 P = 0.002).Compared with carriers of Ser/Cys, the analysis suggested the Cys/Cys correlated strongly with the risk of developing ICM(odds ratio, 2.22; 95% confidence interval,1.40- 3.28). Treating the Ser/Ser and Ser/Cys genotypes as members of the same group increased the predicted ICM risk for patients carrying the Cys/Cys genotype(odds ratio, 1.92; 95% confidence interval, 1.21- 2.88). Levels of 8-OHd G in participants' blood samples were 6.74 ± 1.69 and 3.00 ± 0.77 in the ICM and control groups, respectively(P < 0.05). and significantly increased in those carrying the Cys/Cys genotype in the ICM(8.68 ± 1.73 for the Cys/Cys group, and 4.50 ± 0.83 for the Ser/Ser + Ser/Cys group; P < 0.05).Conclusions1. Patients carrying the Cys/Cys genotype had a significantly increased risk of developing ICM.2. Serum levels of 8-OHd G were increased in patients with ICM, and significantly increased in those carrying the Cys/Cys genotype in the ICM.Part Two Efficacy of Atorvastatin Treatment on Serum Levels of8-OHd G and Mortality in Patient with Ischemic CardiomyopathyObjective The present study was to investigate the differences of 40 mg versus 20 mg atorvastatin on 8-Hydroxrguanin(8-OHd G) and mortality in patients with Ischemic Cardiomyopathy(ICM).Methods Total 246 hospitalized ICM patients were enrolled in this study. The patients were randomly divided into two groups of 20 mg/d atorvastatin treatment group 40mg/d atorvastatin treatment group. Patients could receive other medications during atorvastatin treatment on the basis of their disease conditions. During the period of four year follow-up, adverse drug reaction events and general data and laboratory indexes were recorded in this study. ELISA was applied to measure the human serum8-OHd G and doppler echocardiography to detect heart function.Result A total of 246 patients with ICM were enrolled. We found that the follow-up patients was 74 in 40 mg/d treatment group and 70 in 20 mg/d treatment group, and 6patients discontinued therapy. During the follow-up period of 4 years, we found that the follow-up mortality was 96 patients in treatment groups, there was no significant difference between two treatment groups in the aspect of other medicine usage(P>0.05). Neither of the two treatment groups had drug induced hepatitis or rhabdomyolysis. Adverse drug reaction incidence between two treatment groups had no significant statistical differenc(P>0.05). At the terminal phase of this study, TC and LDL-C in 40 mg/d treatment group and 20 mg/d treatment group was lower after treatment, the difference was statistically significant(P<0.05). 40 mg/d treatment group decreased significantly in hs-CRP, BNP and 8-OHd G before and after the treatment(P<0.05), and these indexes in 40 mg/d treatment group was lower than 20mg/d treatment group after the treatment, the difference was statistically significant(P<0.05). At the commencement of this study, there was no significant change in levels of heart function both in 40 mg/d treatment group and 20 mg/d treatment group(P>0.05). E, E/A ratio was significantly higher whereas A was significantly lower in40 mg/d treatment group than each corresponding values in 20 mg/d treatment group(P<0.05) at the terminal phase of this study, and these indexes in 40 mg/d treatment group also changed significantly after the treatment(P<0.05). By the single factor analysis. We found that the follow-up mortality in 40 mg/d treatment group was slightly lower than 20 mg/d treatment group, the difference had no statistically significant(P>0.05). In patients with same NYHA, the mortality of two treatment groups had no significant difference(P>0.05).Conclusion1. The dosage does affect the efficiency of anti-oxidation among ICM patients by atorvastatin treatment. 40 mg/d atorvastatin treatment group is closely linked to the lower levels of 8-OHd G than 20 mg/d atorvastatin treatment group.2. Atorvastatin is safe and effective in ICM treatment and improve cardiac diastolic function.3. Treatment of different doses atorvastatin had no correlated with the mortality in ICM patients with cardiac function NYHA ?-?.