| Objective:Hypertensive heart disease(HHD)is a major cause of global morbidity and mortality.Understanding the distribution features and trends of HHD burden among various countries and populations,and exploring potential therapeutic targets,are crucial for making prevention and control policies,and delaying or reversing HHD process.However,there are only a few epidemiological studies that could provide effective guidance for HHD-related public health policy making.In addition,the causal relationship between metabolites and HHD remains to be further clarified.Therefore,the aims of this study were:1)to analyze and predict the levels and trends of HHD burden in different countries and populations,and explore potential risk factors to provide a sound scientific basis for future HHD prevention and control policies;2)to screen metabolites that may be involved in the progression from hypertension to HHD,which may provide potential therapeutic targets for HHD.Methods:(1)Based on data from the global burden of disease,descriptive analyses were performed on the prevalent cases,deaths,disability-adjusted life years(DALYs)and corresponding age-standardized rates of HHD by year,age,sex,location,and quintile of sociodemographic index(SDI).The changing trend of HHD burden was analyzed by Joinpoint regression model.The expected relationship between SDI and HHD burden was determined by locally weighted regression model.Changes in HHD DALY numbers due to population growth,population aging,age-specific prevalence,and disease severity were quantified by a decomposition method established by Das Gupta.(2)Based on data from the global burden of disease and global demographics,Bayesian age-period-cohort model was used to further predict the burden of HHD and its changing trend in various countries and populations from 2018 to 2035.(3)Data were from a large-scale metabolome-genome-wide association analysis,and the genome-wide association analyses for HHD and essential hypertension in the Finn Gen database.To identify metabolites which may be causally linked to HHD and essential hypertension,twosample Mendelian randomization analysis was performed by inversevariance weighted method(IVW),MR-Egger regression method,weighted median method,and weighted mode method,respectively.Pleiotropy test was performed by MR-Egger intercept and MR-PRESSO Global test.Heterogeneity was tested by Cochrane’s Q test.Criteria for a causal relationship are as follows:(1)the IVW method had a P value <0.05,and the q value after False Discovery Rate(FDR)correction was still <0.05;(2)other MR methods showed the same effect directions and similar effect sizes to IVW;(3)there was no evidence of horizontal pleiotropy(P >0.05).Results:(1)Trends in the global burden of hypertensive heart disease(1)From 1990 to 2017,the global age-standardized prevalence rate of HHD increased from 202.8/100,000 to 217.9/100,000,with an average annual percent change(AAPC)of 0.27%.In contrast,there was a decrease in the global age-standardized mortality and DALY rates of HHD from1990 to 2017,with an AAPC of-0.79% and-1.01%,respectively.(2)The age-standardized prevalence rate of HHD was higher in women,and the prevalence rate gradually increased with age.(3)There were great discrepancies in the distributions and trends of HHD burden among different countries and territories.Bolivia and Maldives had the fastest increases in age-standardized prevalence rates between 1990 and 2017,while Estonia and Latvia had the fastest increases in age-standardized mortality and DALY rates over the same period.In addition,there was a correlation between the discrepancies and SDI levels.Generally,the agestandardized prevalence rate was relatively high in countries and territories with middle SDI,while the age-standardized mortality and DALY rates decreased with increasing SDI.(4)Population growth and aging were important factors leading to the increase in the total number of global HHD burden.Globally,the number of DALYs due to HHD increased by 49.3%between 1990 and 2017,with population growth and aging contributing42.6% and 43.6%,respectively,while the contribution of improved disease severity(-48.0%)was completely offset.(2)Projection of the global burden of hypertensive heart disease(1)The global age-standardized prevalence rate of HHD is expected to further increase from 219.1/100,000 in 2018 to 224.6/100,000 in 2035,with an AAPC of 0.15%.The age-standardized mortality and DALY rates will further decline between 2018 and 2035,with an AAPC of-0.26% and-0.33%,respectively.However,the total number of global HHD burden will continue to increase.By 2035,the total number of prevalent cases,deaths,and DALYs will reach to 20.03 million,1.04 million,and 17.62 million,respectively.(2)The prevalence gaps between men and women will widen further during 2018-2035,with the age-standardized prevalence rate decreasing in men(AAPC:-0.23%)and increasing in women(AAPC:0.35%).However,from 2018 to 2035,more decreases in age-standardized mortality and DALY rates were observed in women than in men.(3)There are still large discrepancies in the future burden of HHD and its changing trend among different countries and territories.Bolivia,Thailand,and Costa Rica will be the countries with the fastest increases in agestandardized prevalence,mortality,and DALY rates between 2018 and2035,respectively.(3)The role of circulating metabolites in the progression of hypertensive heart disease(1)Based on the IVW method,21 of the 309 known metabolites were found to have a potential causal effect on HHD(P <0.05).After FDR correction,only three metabolites had a clear causal effect on HHD.Among them,docosahexaenoate reduced the risk of HHD with an odds ratio(OR)of 0.31(FDR q = 0.036),while 2-hydroxyglutarate and alphahydroxyisovalerate increased the risk of HHD,with an OR of 2.25(FDR q= 0.016)and 2.04(FDR q = 0.036),respectively.(2)All the three metabolites with clear causal effects on HHD were not causally associated with essential hypertension(FDR q >0.05),suggesting that they play the role in the disease progression from hypertension to HHD.(3)The causal relationships of docosahexaenoate,2-hydroxyglutarate and alphahydroxyisovalerate with HHD were further verified using MR-Egger regression method,weighted median method and weighted mode method,which showed the same directions and similar effect sizes to IVW method.Pleiotropy test and heterogeneity test suggested that there was no evidence of horizontal pleiotropy and heterogeneity.Conclusion:(1)HHD remains a major public health challenge worldwide with an increasing age-standardized prevalence rate from 1990 to 2017.The levels and trends of HHD burden varied substantially by location,sex,and age,and were associated with SDI.Population growth and aging were important factors leading to the increase in total number of global HHD burden.(2)By 2035,it is estimated that the global age-standardized prevalence rate of HHD will further increase,and the discrepancies in HHD burden among different locations,genders,and age groups are still significant.More targeted and effective efforts,especially for vulnerable populations and countries with high or rapidly increasing HHD burden,are necessary.(3)Docosahexaenoate,2-hydroxyglutarate,and alpha-hydroxyisoval erate are metabolites with clear causal effects on HHD,and modulating their levels in hypertensive patients may reduce the HHD burden. |
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