| Objective:The evelopment of coronary heart disease(CHD)related depression involves complex biological pathways,and the specific pathophysiology mechanism has not been clear.In this study,we detected the levels of hypoxia inducible factor-1?(HIF-1?),interleukin-6(IL-6),tumor necrosis factor-?(TNF-?),and insulin(INS)in plasma,and assayed the level of HIF-1?gene promoter methylation.The present study aimed to explore the pathophysiological mechanisms of patients with CHD suffering from depression,in order to provide strategys and theoretical guidance for the prevention,diagnosis and clinical treatment of depression in patients with CHD.Methods:The patients who were diagnosed with CHD(vessel stenosis exceeding 50%of single or multiple branches by coronary angiography)in the department of cardiovascular intervention of the Fifth Affiliated Hospital of Sun Yat-sen University from May2019 to January 2020 were selected,and all subjects who were emotionally stable had no history of depression-related symptoms or antidepressant treatment before the diagnosis of CHD.All patients who met the admission criteria were included.General demographic data of patients were collected,and Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA)and Pittburgh Sleep Quality Index(PSQI)were assessed,and 5 m L of peripheral blood samples were collected.HAMD-C1,HAMD-C2,HAMD-C3,HAMD-C4,and HAMD-C5 respectively represent the five factors of HAMD means mental/somatization,weight,cognitive impairment,block,and sleep disorders,and the sum of the five factors is the global scores of HAMD.The patients were divided into combined depression(CD)group and non-combined depression(NCD)group according to the global scores of HAMD,and there were 32 patients in the CD group and 30 patients in the NCD group,respectively.Patients in CD group did not have the history of drug-use to intervene their depression symptoms.The first scales assesement and blood samples collection were regarded as baseline data of CD group,and the patients in the CD group were followed after 6 weeks.The HAMD,HAMA,and PSQI scales were re-evaluated and blood samples were collected again.Due to the uncontrollable factors during this period,only 11 patients were followed for the 6th-week end in the CD group.Patients in the NCD group were not followed.Enzyme-linked immunosorbent assay was used to measure HIF-1?,IL-6,TNF-?,and INS levels in plasma of patients in NCD,CD with baseline and the 6th-week end.The homeostasis model assessment(HOMA-IR)was used to assess insulin resistence(IR)degree.Massarray mass spectrometry detection technology was used to measure the methylation of HIF-1?gene promoter of patients in CD with baseline and the 6th-week end.Results:1.The analysis of patients in the NCD group and the baseline CD group.(1)The comparison of general data between the two groups showed that,the patients in the baseline CD group were older,a longer course of disease and a lower body mass index(BMI),and the differences were statistically significant(P<0.05).(2)The scores of HAMA and PSQI were different between the two groups.The results showed that the global scores of HAMA and PSQI in the CD group were significantly higher than those in the NCD group,and the differences were statistically significant(P<0.05).(3)The biomarkers concentration in plasma were compared between the two groups,and the results showed that IL-6,INS,and HOMA-IR in the CD group were higher than those in the NCD group,and the differences were statistically significant(P<0.05).(4)The correlation analysis was performed in the NCD group,the results showed that:(1)HAMD-C1 scores were positively correlated with the global scores of HAMA(P<0.05).(2)The scores of HAMD-C5 and HAMD were positively correlated with the global scores of HAMA and PSQI,respectively(P<0.05).(5)The correlation was performed within the baseline in CD group,the results showed that:(1)HAMD-C1 scores were positively correlated with IL-6 levels in plasma(P<0.05).(2)The scores of HAMD-C4,HAMD-C5,and HAMD were positively correlated with the global scores of HAMA,respectively(P<0.05).(6)Multivariate analysis used binary logistic regression analysis was calculated with depression as the dependent variable,the results showed that IL-6 and BMI were the risk factors for depression in patients with CHD.According to the graph of ROC,we evaluated the two risk factors by the area under curve(AUC)and 95%confidence interval(CI)for diagnosed depression in patients with coronary heart disease,and the result showed IL-6(AUC=0.796,95%CI:0.684?0.908,P<0.01)and BMI(AUC=0.663,95%CI:0.526?0.799,P<0.01).The maximum correct indices and diagnostic thresholds displayed IL-6(0.483,23.79pg/m L)and BMI(0.325,24kg/m~2),respectively.Under the optimal threshold,the sensitivity and specificity of IL-6 correspond to 75%and 73.3%,and the sensitivity and specificity of BMI correspond to62.5%and 70%.2.The analysis were performed in scales,biomarkers concentration in plasma,and the methylation of HIF-1?gene promoter between baseline and the 6th-week end in CD group,(1)Compared scales,biomarkers concentration in plasma,and the methylation between baseline and the 6th-week end.The results showed that,the baseline scores of HAMD-C1,HAMD-C2,HAMD-C3,HAMD-C4,HAMD,HAMA,PSQI,and the methylation of Cp G49 site were higher than counterpart at the 6th-week end,and the differences were statistically significant(P<0.05).(2)The correlation were analyzed among baseline HAMD scores with the methylation,HAMA,PSQI,biomarkers concentration in plasma,and the results showed that:(1)Baseline HAMD-C1 scores were positively correlated with IL-6 levels in plasma(P<0.05).(2)Baseline scores of HAMD-C2 and HAMD-C5 were negatively correlated with HIF-1?levels in plasma(P<0.05).(3)Baseline HAMD-C3 scores were positively correlated with the methylation of Cp G3,Cp G30,and Cp G48 sites(P<0.05),and the correlation with the methylation of Cp G48 site was significantly higher to baseline HAMD-C3 scores(?=0.786,P<0.05).(4)Baseline scores of HAMD-C4,HAMD-C5,and HAMD were positively correlated with HAMA scores(P<0.05).(3)The correlations were analyzed among HAMD scores with biomarkers concentration in plasma,the methylation,HAMA scores,and PSQI scores at the6th-week end,and the results showed that:(1)HAMD-C1 scores were positively correlated with IL-6 levels in plasma at the 6th-week end(P<0.05).(2)HAMD-C1 scores were negatively correlated with the average methylation in Cp G41,42,43 sites at the 6th-week end(P<0.05).(3)The HAMD scores were negatively correlated with the average methylation in Cp G4,5 and Cp G41,42,43 sites at the 6th-week end(P<0.05),and the correlation with the average methylation in Cp G4,5 sites was significantly higher to HAMD scores(?=-0.708,P<0.05).(4)The scores of HAMD-C3 and HAMD were positively correlated with the HAMA scores at the 6th-week end(P<0.05).(4)The correlations were analyzed among baseline biomarkers concentration in plasma,the methylation,the scores of HAMA,PSQI,and HAMD at the 6th-week end,and the results showed that:(1)HAMD-C1 scores at the 6th-week end were negatively correlated with the average methylation in Cp G18,19,20 sites(P<0.05).(2)HAMD-C3 scores at the 6th-week end were positively correlated with the methylation in Cp G3 and Cp G48 sites at baseline,and the correlation with the methylation in Cp G3 sites at baseline was significantly higher to HAMD-C3 scores at the 6th-week end(?=0.675,P<0.05).(3)HAMD-C3scores at the 6th-week end were positively correlated with HAMA scores at baseline(P<0.05).Conclusion:1.The occurrence and development of depression in patients with CHD may be caused by the combination of high levels of IL-6 and low BMI.When the plasma IL-6concentration is higher than 23.79pg/m L and the BMI is less than 24kg/m~2,the occurrence of depression can be predicted in patients with CHD in the early stage.2.The degree of depression in patients with CHD will be improved with the recovery of CHD,but it is not obvious in the improvement of depression at the end of 6th-week.For this kind of patients,it is recommended that antidepressants should be performed as the treatment for CHD.3.Increased methylation levels at some sites in the promoter region of the HIF-1?gene may lead to changes in depression in patients with coronary heart disease and depression,and a larger sample size is need to confirm. |
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