Epidemiology And Metabonomics Study Of Hypertension Combined With Depression In Less Developed Region Northwest China

Objective:(1)To investigate the prevalence of depression and examine the association between depression and risk of hypertension,and hypertension awareness,treatment and control in primary care setting of northwest China;To examine whether combination treatment(antihypertensive + antidepressant)can improve hypertension outcomes in patients with both hypertension and depression.(2)To determine the risk factor of depression in patients with hypertension,and to develop and verify risk nomogram of depression in hypertensive patients based on the risk factors that have significantly predictive depression.(3)Liquid chromatography-tandem mass spectrometry(LC-MS)was used to analyze the differential metabolites between hypertensive patients with depression and without depression by non-targeting metabolomics,which help to understand the molecular mechanism of depression and identify potential biomarkers for diagnosing depression in patients with hypertension.Methods:(1)We used stratified multistage random sampling method to collect subjects aged ?18 years in primary care setting of Emin Xinjiang,China between March and October 2019.Depression was evaluated by Hospital Anxiety and Depression Scale.We compared the difference for the prevalence of depression among different demographic stratification and hypertension status.We related depression to hypertension,adjusting for minimally sufficient adjustment set of variables from literature-based DAG and the optimal adjustment set of variables from the LASSO regression.Furthermore,we evaluated the association between depression and unaware,untreated,and uncontrolled hypertension.Moreover,a meta-analysis was conducted to determine the effect of combination treatment on hypertension in hypertensive patients with depression,with registered study protocol(CRD42020213430).We searched for relevant randomized controlled trials(RCTs)published through December 2020.According to the inclusion and exclusion criteria,literature screening,data extraction and strict quality evaluation were conducted for the included studies.Stata 14.0 software was used for meta-analysis.(2)The patients with hypertension screened out in the first part were randomly divided into a training set with70% samples(n = 1299)and a validation set with 30% samples(n = 557).Using the LASSO regression model,we identified the optimized risk factors of depression in the training set,followed by the establishment of prediction nomogram based on Logistic regression equation.The AUC,calibration curve,Hosmer-Lemeshow test,and DCA were used to assess the discriminative ability,calibration,and clinical usefulness of nomogram.The results were verified by internal validation in validation set.(3)60 subjects aged >18years(30 hypertensive patients with depression and ethnicity-sex-age matched 30 hypertensive patients without depression)were included in this study.Plasma metabolites were detected by LC-MS.Differential plasma metabolites and potential biomarkers were screened by applying statistical analysis(PCA,OPLS-DA,ROC curve,random forest analysis and Logistic regression).Results:(1)Totally 6294 subjects were included with mean age 45.26 ± 13.07 years,and 49.3% women and 52.2% ethnic minorities,which66.8% subjects from agricultural and stock-raising regions.Overall prevalence of depression was 8.9%(95CI: 8.2%-9.6%),and the prevalence of depression in female population was significantly higher than that in male population(10.2% vs.7.7%,P<0.001),significantly higher in those from agricultural and stock-raising regions than in those from urban(9.9% vs.6.9%,P<0.001),and significantly higher in Kazakhs than in Han ethnicity(11.1% vs.7.9%,P<0.001).Different state of hypertension stratified analysis showed that,the prevalence of depression was two fold higher in hypertensive patients than in normotensive subjects(13.7% vs.6.9%,P <0.001).Depression was associated with 1.13 fold increased odds of hypertension [OR 2.13,95%CI: 1.79-2.54],and the odds increased with the degree of depression.This association remained significant even after adjusting for the minimal sufficient adjustment sets and the optimal adjustment set of variables.Depression was significantly associated with untreated and uncontrolled hypertension,but not with unaware hypertension.Twenty seven RCTs(2606subjects)were included in meta analysis.Combination treatment significantly decreased systolic blood pressure(SBP)by 11.27 mm Hg(WMD =-11.27,95%CI:-14.12 to-8.43)and diastolic blood pressure(DBP)by 8.21 mm Hg(WMD =-8.21,95%CI:-10.73 to-5.69),and significantly improved antihypertensive efficient rate by 42%(RR = 1.42,95% CI: 1.32 to 1.52).(2)Seven independent risk factors related to depression were identified and entered into the nomogram including age,region,ethnicity,marital status,physical activity,sleep quality,and control of hypertension.The nomogram displayed robust discrimination with a AUC of 0.760(95% CI: 0.724-0.797)and 0.761(95%CI:0.702-0.819),and good calibration in training set and validation set,respectively.The decision curve analysis and clinical impact curve demonstrated clinical usefulness of predictive nomogram.(3)The different plasma metabolic phenotypes between hypertensive patients with depression(HDP)and hypertensive patients without depression(HT)were identified.In total,62 differential matabolites(VIP > 1 and p < 0.05)between HDP and HT were identified.These differential plasma metabolites mainly revealed disturbance of glycerophospholipid metabolism,tryptophan metabolism and phenylalanine metabolism.A total of 8 metabolites were screened out by random forest analysis and ROC curve analysis(AUC> 0.8)as biomarkers for the screening and diagnosis of depression in patients with hypertension.A panel consisting of 8 plasma metabolite biomarkers was identified.This panel was capable of distinguishing hypertension with depression from hypertension with an AUC of 0.989(95 % CI:0.966-1.000).Conclusions:(1)In the economically less developed northwest of China,the prevalence of depression in the general population is considerable,and the prevalence of depression in Kazakhs,farmers and stock raisers is significantly higher than Han and urban populations.The prevalence of depression in patients with hypertension is twice as high as that in the normotensive population.Depression is significantly associated with hypertension,as well as with untreated and uncontrolled hypertension in primary care setting Northwest China.Pooled evidence suggests that combination treatment in hypertensive patients with depression significantly improves both blood pressure levels and antihypertensive efficient rate.(2)Seven risk factors of depression in patients with hypertension were age,region,marital status,ethnicity,physical activity,sleep quality and control of hypertension.The nomogram developed may help primary care provider assess the risk of depression in hypertensive patients.(3)Plasma metabolic profiles were different between hypertensive patients with depression and without depression and helping to understand underlying metabolic mechanisms.Our results would be helpful in future for developing an objective method to diagnose depression in patients with hypertension.