| Backgrounds and purposes Coronary artery disease(CAD)is one of the major cardiovascular diseases(CVD)threatening human health and life in today’s society,and the second leading cause of death of CVD in China.Coronary heart disease is a complex disease caused by the interaction of genetic and environmental factors,and the pathogenesis of CAD has not yet been fully explained.Smoking,obesity,hypertension,hyperlipidemia and family history of CAD are known risk factors for CAD,but these factors cannot fully explain the pathogenesis of CAD.Early detection of the risk factors related to coronary heart disease not only helps to reduce the mortality of cardiovascular diseases,but also can reduce the social medical burden.Clinical studies over the past20 years have shown that telomere length(TL)is closely related to the risk of CAD,and the exact mechanism is still unknown.The purpose of this study was to investigate the relationship among telomeres,DNA damage,methionine cycle products(homocysteine,S-adenosylhomocysteine;S-adenosylmethionine)and coronary heart disease,and Here to evaluate the relationship between methionine cycle products and the severity of coronary artery lesions and explore the predictive value of homocysteine combined with S-adenosylhomocysteine for CAD,to provide a reference for CAD prevention.More importantly,in this study,we aimed to explore the relationship between telomeres and homocysteine in patients with coronary heart disease and to explore the contribution of elevated Hcy level to LTL shortening in CAD patients and the underlying mechanism.Methods Participants(n = 250;aged 40–80 years)with chest pain and suspected CAD underwent coronary angiography(CAG)for assessment of coronary artery stenosis,and the degree of coronary lesion was evaluated by the Gensini scoring system.Then patients were assigned to to either the control subjects or CAD group,respectively.The fasting whole blood of the above patients was collected to measure the telomere length,8-Oxo G concentration and plasma Hcy,SAH and s-adenosine methionine(SAM)concentration in peripheral blood were also measured,and the SAH/SAM ratio was calculated.In the first part,Spearman correlation analysis was used to evaluate the correlation among plasma Hcy,SAM,SAH concentration and SAH/SAM ratio and severity of coronary artery lesions assessed by Gensini score.Multivariate Logistic regression was used to analyze the influence of the above indicators on CAD.The receiver operating characteristic(ROC)curve was conducted to evaluate the value of Hcy,SAM,SAH concentration,SAH/SAM and combination of Hcy and SAH in predicting CAD.In the second part,Spearman correlation analysis and partial correlation analysis were used to analyze the relationship between LTL,8-Oxo G and Hcy.Linear regression analysis was used to test whether the potential mediating effect of 8-Oxo G on the relationship between Hcy and LTL was consistent with the standard proposed by Baron and Kenny.Mediation analysis was conducted to exam whether the relationship between Hcy and LTL was mediated by 8-Oxo G.Results1.Compared with the control group,patients in the CAD group had significantly shortened telomeres,significantly increased blood 8-Oxo G concentration,increased plasma Hcy concentration and plasma SAH concentration which are methionine circulating products,and increased inverse ratio of methylation index SAH/SAM,with statistically significant differences(P<0.05).SAM concentration in CAD group was also higher than that in normal coronary group,but the difference was not statistically significant(P>0.05).2.There was a positive correlation between SAH/SAM(r=0.388,P<0.05)and Gensini score,and a stronger positive correlation between plasma SAH concentration(r=0.634,P<0.05)and Gensini score in the CAD group.But the plasma Hcy and SAM concentrations in the CAD group and the control group showed no significant correlation with Gensini score(P>0.05).The results showed that the plasma SAH level significantly increased with the aggravation of coronary stenosis,and the plasma SAH level was positively correlated with the severity of coronary artery disease.3.After adjusting for gender,age,smoking status,drinking history,history of hypertension,history of diabetes,fasting blood glucose,TG,HDL-C,hs-CRP and other factors,multiple Logistic regression analysis showed that plasma Hcy,SAH and SAH/SAM levels were independent risk factors for CAD(OR values were 1.058,1.09,28.5 respectively,P<0.05).And telomeres are a protective factor for coronary heart disease.4.The area under the ROC curve of Hcy,SAH and SAH/SAM were 0.626,0.768 and0.572,respectively,while the area under the ROC curve of Hcy and SAH jointly predicted CAD was 0.780,which was not better than that of SAH alone.The sensitivity and specificity of SAH alone in predicting coronary heart disease were79.86% and 67.57%,respectively.This result suggests that SAH may be a novel biomarker for the early prediction and diagnosis of coronary heart disease,which further validated our previous research results.5.The correlation analysis and the multiple linear regression analysis among plasma Hcy,SAM,SAH concentration,SAM/SAH,blood 8-Oxo G concentration and LTL in the two groups showed that the plasma Hcy and blood 8-Oxo G concentration in the CAD patients were negatively correlated with telomere length,and the plasma Hcy was positively correlated with blood 8-Oxo G concentration in the CAD patients.These results suggest the mechanism among telomere shortening,plasma Hcy concentration and blood 8-Oxo G concentration in CAD.6.The plasma Hcy concentration ≥15 μmol/L was used as the boundary to stratify homocysteine into a hyperhomocysteine group as HHcy group and a Non hyperhomocysteine group as Non HHcy group.Then all subjects were divided into four groups: control with Non HHcy group,control with HHcy group,CAD with Non HHcy group and CAD with HHcy group.The results showed that compared with the control group(with or without hyperhomocysteine)and CAD patients without hyperhomocysteine,CAD patients with hyperhomocysteine had significantly shorter telomeres and significantly higher blood 8-Oxo G concentrations,with statistically significant differences(P<0.05).7.In order to further explore the underlying mechanism among shorter peripheral blood leukocyte telomere length,higher plasma homocysteine concentrations,and increased blood concentrations of 8–Oxo G in the CAD patients,mediation analysis was conducted to examine whether the relationship between Hcy and LTL was mediated by 8-Oxo G,and adjusting for other factors such as age,gender,body mass index,smoking history,drinking history,history of hypertension,diabetes mellitus,family history of CAD,TG,TC,LDL,HDL-C,the results show that the mediating effect mediated by 8–Oxo G accounted for 25.09% in all subjects(P < 0.0001).But in CAD patients,the effect of 8–Oxo G on LTL was 28.45%(P < 0.0001),and the mediating effect of 8–Oxo G on the relationship between Hcy and LTL in CAD patients was higher than that of all subjects.However,in the control group,the mediating effect of 8–Oxo G on the relationship between Hcy and LTL was not statistically significant.These results indicate that the effect of Hcy on LTL is partially mediated by 8–Oxo G in CAD patients,but not in the control group.Conclusions1.From the metabolites of methionine cycle,the results showed that the level of plasma Hcy levels and plasma SAH were all independent risk factor for coronary artery disease,but plasma concentration of SAH was increased with the deterioration of the extent of coronary stenosis.Detection of SAH is simple and convenient and can also predict the severity of coronary lesions,which may be a better indicator than Hcy as a reference for prophase prevention of CAD,which further validated our previous research results.2.Telomere is a protective factor for coronary atherosclerosis and coronary artery disease.The shortened telomere length in patients with coronary artery disease may be related to increased plasma homocysteine concentration and blood 8–Oxo G concentration.3.The results of mediation analysis showed that 8–Oxo G may play a partial role role in the relationship between plasma Hcy and telomere length in patients with coronary artery disease.8–Oxo G appeared to mediate the effect of LTL by 28.45%.Increased homocysteine may cause DNA damage through the oxidation of guanine to8-hydroxy-2’-deoxyguanosine,thereby contributing to leukocyte telomere length(LTL)shorten in CAD patients and loss of its protective effect on CAD. |
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