Luo-Xi XIAO,Zi-Yu WANG,Jiang-Tao LI,Hai-Mei WANG,Yi-Ming HAO,Pan ZHOU,Yu-Lin HUANG,Qiu-Ju DENG,Yong-Chen HAO,Na YANG,Li-Zhen HAN,Zhao YANG,Ping-Ping JIA,Yue QI ,Jing LIU

Center for Clinical and Epidemiologic Research,Beijing Anzhen Hospital,Capital Medical University,Beijing Institute of Heart,Lung and Blood Vessel Diseases,Beijing Municipal Key Laboratory of Clinical Epidemiology,Beijing,China

ABSTRACT BACKGROUND Hypertension usually clusters with multiple comorbidities.However,the association between cardiometabolic multimorbidity (CMM) and mortality in hypertensive patients is unclear.This study aimed to investigate the association between CMM and all-cause and cardiovascular disease (CVD) mortality in Chinese patients with hypertension.METHODS The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors (CONSIDER),which comprised 5006 participants aged 19–91 years.CMM was defined as the presence of one or more of the following morbidities: diabetes mellitus,dyslipidemia,chronic kidney disease,coronary heart disease,and stroke.Cox proportional hazard models were used to calculate the hazard ratios (HR) with 95% CI to determine the association between the number of CMMs and both all-cause and CVD mortality.RESULTS Among 5006 participants [mean age: 58.6 ± 10.4 years,50% women (2509 participants)],76.4% of participants had at least one comorbidity.The mortality rate was 4.57,4.76,8.48,and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one,two,and three or more morbidities,respectively.In the fully adjusted model,hypertensive participants with two cardiometabolic diseases (HR=1.52,95% CI: 1.09–2.13) and those with three or more cardiometabolic diseases (HR=2.44,95% CI: 1.71–3.48) had a significantly elevated risk of all-cause mortality.The findings were similar for CVD mortality but with a greater increase in risk magnitude.CONCLUSIONS In this study,three-fourths of hypertensive patients had CMM.Clustering with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients,suggesting more intensive treatment and control in this high-risk patient group.

Aging of the global population has brought about a rapid increase in the prevalence of multimorbidity,especially cardiometabolic multimorbidity (CMM),which refers to the coexistence of at least two cardiometabolic diseases (CMDs) in one individual.[1]Research conducted on populations from around the world,including Europe,the United States,and China,has demonstrated a cumulative increase in the risk of all-cause mortality and a decrease in life expectancy associated with CMM.[1–3]Given its extensive prevalence and poor prognosis,CMM is becoming a major global public health challenge that requires immediate attention.

Hypertension is the most common component of CMM.[4]In the United Kingdom Biobank database,70%,64%,and 57% of patients diagnosed with chronic kidney disease (CKD),diabetes mellitus (DM),and stroke,respectively,were also diagnosed with hypertension.[4]Moreover,one in four patients with hypertension also develop CMM.[5]With comorbidity of DM and cardiovascular disease (CVD),the risk of all-cause mortality in hypertensive patients increases significantly from 7% to 30% and to 136%,respectively.[3]These data strongly suggest that CMM is extremely common in individuals with hypertension,leading to a heavy burden of disease.Research evidence indicates that in the general population,a dose–response relationship exists between the number of chronic diseases and mortality.[6–9]

According to current understanding,there is a research gap regarding the association between the number of CMMs and mortality in patients with hypertension.There is an urgent need for in-depth research to elucidate this relationship in hypertensive populations.This study aimed to investigate the association of the number of CMMs with both all-cause mortality and CVD mortality in hypertensive patients to provide clinicians with a clear basis for risk assessment,thereby optimizing patient management and treatment strategies.

METHODS

Study Design and Population

In this study,we used data from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors (CONSIDER),a national multi-center collaborative study conducted in 46 hospitals across China,focusing on hypertensive outpatients.The study design has been described previously.[10]In the baseline national survey conducted between June and December 2009,a total of 5206 hypertensive patients aged 19–91 years were recruited from 46 hospitals in 22 cities.On 31 December 2019,we linked the survey data with the National Vital Registration System to obtain mortality data prior to this date.We excluded 200 patients who had incomplete data on baseline disease diagnoses and health factors,leaving 5006 participants included in the final analysis.This study was approved by the Institutional Review Boards of all participating institutions,and written informed consent was obtained from all participants.This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Data Collection

A standard questionnaire was employed to collect information on demographic characteristics,smoking status,drinking status,and medical history,including hypertension,DM,coronary heart disease (CHD),stroke,CKD,and dyslipidemia.Physical examinations were conducted to acquire anthropometric measurements and blood pressure.Blood pressure was measured in the right arm of seated patients using a mercury sphygmomanometer after at least 5 min of rest,with an average of three consecutive readings being recorded.Patients were measured for height and weight in a barefoot and light clothing state.Body mass index was calculated as weight in kilograms divided by the square of height in meters.Waist circumference was measured once,at the midpoint between the lower rib margin and the iliac crest,with participants semi-clothed.Educational level was categorized as low (primary school),medium-low(junior high school),medium-high (high school),and high (college or university or higher).Occupation was classified as mental,physical,retiree,unemployed,or other.Current smoking was defined as smoking once or more cigarettes per day for three months.Current drinking was defined as drinking once or more per week.Exercise was defined as engaging in physical activity for more than 30 min per day for more than three times every week.Waist circumference was measured at the level midway between the lower rib margin and iliac crest.Ideal use of medications was defined as patients with hypertension,DM,CHD,or stroke receiving guideline-recommended medications for the corresponding diseases.

Laboratory Tests

Venous blood samples were taken after an overnight fast for the laboratory assessment of serum lipid levels and fasting plasma glucose.After the fasting blood samples were collected,each participant,except those with a confirmed history of DM,underwent 75 g oral glucose tolerance test.The oral glucose tolerance test was conducted by dissolving 75 g of glucose in 300 mL of warm water,which was then consumed by the patients within 5 min.A venous blood sample was taken 2 h later to measure postprandial glucose levels.Total cholesterol,triglycerides,and fasting plasma glucose were determined using the enzymatic method.Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were measured using the homogeneous assay (Daiichi,Tokyo,Japan).

Ascertainment of CMM

CMM is commonly defined as the coexistence of 2 or more CMDs,including hypertension,DM,CHD,stroke,CKD,and dyslipidemia.[11]Because all participants included in this study were hypertensive,we defined CMM as having one or more of the following: DM,CHD,stroke,CKD,or dyslipidemia.Hypertension,DM,dyslipidemia,and CKD were defined according to (1)a documented or self-reported history,or (2) receiving medication for the corresponding disease,or (3) clinical or laboratory examination (blood pressure ≥ 140/90 mmHg on repeated measurements for a diagnosis of hypertension,[12]fasting plasma glucose level ≥ 7.0 mmol/L or 2-hour postprandial blood glucose level ≥11.1 mmol/L for a diagnosis of DM,[13]total cholesterol ≥6.2 mmol/L,or triglyceride ≥ 2.3 mmol/L,or low-density lipoprotein cholesterol level ≥ 4.1 mmol/L,or highdensity lipoprotein cholesterol level <1.0 mmol/L for a diagnosis of dyslipidemia,[14]and estimated glomerular filtration rate <60 mL/min per 1.73 m2for a diagnosis of CKD,which was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.[15]CHD and stroke histories were defined through a standardized questionnaire-based survey.

在彈體打擊巖石條件下，彈靶間形成應(yīng)力波并向地下傳播，在沖擊波或接近于沖擊波的短應(yīng)力波中，巖石介質(zhì)壓縮行為是在受限條件下發(fā)生的[7]，從物理力學(xué)本質(zhì)上講，巖石介質(zhì)的變形狀態(tài)可以用剛性壁圓筒中的單軸壓縮描述。設(shè)沿圓筒的軸向應(yīng)力σr為垂直于彈靶接觸面的法向應(yīng)力；沿圓筒的徑向應(yīng)力σθ為平行于彈靶接觸面的切向應(yīng)力。由于應(yīng)變僅發(fā)生在軸向，因此，這時(shí)，體積應(yīng)變ε約等于軸向應(yīng)變εr，徑向應(yīng)變εθ約為0。

Ascertainment of Mortality

Death information for participants was mainly obtained by linking with the National Vital Registration System.We used each participant’s unique identification number to link with their health information up to 31 December 2019.The cause of death was coded using the International Statistical Classification of Diseases and Related Health Problems,Tenth Revision,Clinical Modification (ICD-10-CM).The outcome used in this study was death from all causes and cause-specific death from CVDs according to ICD-10 death diagnoses (ICD-10 codes: I00–I99).[16]

Statistical Analysis

All participants’ baseline characteristics are presented as mean ± SD or counts (percentages) and categorized by the number of CMDs (0,1,2,and ≥ 3) among hypertensive patients.Categorical variables were analyzed using the Pearson’s chi-squared test,parametric continuous variables with analysis of variance,and nonparametric continuous variables using the Kruskal–Wallis test.The crude mortality rate per 1000 person-years was calculated as follows: the number of deaths in each group divided by the total number of person-years in that group,and then multiplied by 1000.Person-years were calculated from the baseline date to death or 31 December 2019,whichever came first.A Poisson regression model was used to calculate 95% CI of the crude mortality rate.Cox proportional hazard models were used to calculate the hazard ratios (HR) with 95% CI to examine the association between the number of CMDs and death.In multivariable modeling,covariates were adjusted including age,sex,education level,occupation,current smoking,current drinking,exercise,waist circumference,and the ideal use of medications.

All analyses were conducted with R statistical software 4.3.0 (The R Project for Statistical Computing,Vienna,Austria).Two-sidedP-value <0.05 were considered statistically significant.

RESULTS

Baseline Characteristics

Among 5006 study participants,the mean age was 58.6 ± 10.4 years;the sex ratio was roughly 1:1 (2509 participants were women).There were 63.8% of participants with dyslipidemia,24.4% of participants with DM,21.3% of participants with CHD,10.4% of participants with CKD,and 9.1% of participants with a history of stroke.The counts of participants with 0,1,2,and ≥ 3 types of CMM were 1183 participants (23.6%),1924 participants (38.4%),1297 participants (25.9%),and 602 participants (12.0%),respectively.Compared with participants who had no CMMs,those with more than one CMM were typically older,predominantly male,and less inclined to have a mental occupation.Additionally,these individuals had higher body mass index and waist circumference values,as well as lower estimated glomerular filtration rate values.Participants with more than one CMM were more likely to have dyslipidemia as well as elevated fasting blood glucose and 2-hour postprandial blood sugar levels,and a lower proportion had the ideal use of medications (Table 1).

Table 1 Baseline characteristics of study participants according to the number of CMMs.

Association of CMM with Mortality

Figure 1 Adjusted survival curves for all-cause mortality (A) and cardiovascular disease mortality (B) by cardiometabolic multimorbidity in hypertensive patients. The survival curves were adjusted for age,sex,education level,occupation,current smoking,current drinking,exercise,waist circumference,and the ideal use of medications was additionally adjusted.

A graded increased risk of all-cause mortality was observed with the number of CMDs.In the fully adjusted model,hypertensive patients with one CMD did not show a significant difference compared with those who had no comorbidities.However,participants with twoCMDs (HR=1.52,95% CI: 1.09–2.13) and those with three or more CMDs (HR=2.44,95% CI: 1.71–3.48) had a significantly elevated risk of all-cause mortality.Table 3 and Figure 1B depict the association between CMM and CVD mortality.The crude mortality rate for participants without any CMDs was 1.91 (95% CI: 1.21–2.87) deaths per 1000 person-years.The rate for those with one CMD was 2.51 (95% CI: 1.85–3.31) deaths per 1000 person-years,the rate with two CMDs was 4.32 (95% CI:3.26–5.61) deaths per 1000 person-years,and the crude mortality rate with three or more CMDs was 9.38 (95%CI: 7.07–12.21) deaths per 1000 person-years.In the fully adjusted model,similar to the association with all-cause mortality,hypertensive participants with one CMD showed no significant difference compared with those who did not have any comorbidities.However,participants with two CMDs (HR=1.83,95% CI: 1.10–3.06) and those with three or more CMDs (HR=3.22,95% CI: 1.89–5.48)had a notably increased risk of CVD mortality.

Table 3 Association of CMM with cardiovascular disease mortality among hypertensive patients in the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors study.

DISCUSSION

In this prospective cohort study of hypertensive patients,our results showed that the risks of all-cause and CVD mortality increased significantly with an increased number of CMDs.Participants with three or more CMDs had the highest risks.For these participants,the unadjusted risk of all-cause mortality increased 2.6-fold and the risk of CVD mortality increased 4-fold.This result remained statistically significant after adjusting for potential confounders.After adjustment,the risk of all-cause mortality was increased 1.4-fold and the risk of CVD mortality was increased 2.2-fold.Therefore,even after adjusting for known cardiovascular risk factors,the number of cardiometabolic conditions remained signifi-cantly associated with increased risks of all-cause and CVD mortality in patients with hypertension.

To the best of our knowledge,no studies have focused on CMDs within a population that has hypertension.We compared hypertensive patients from the CONSIDER study with the general population in the China Kadoorie Biobank study.[9]In the CONSIDER study,the crude all-cause mortality rate for participants without any CMDs with no CMMs was 4.6 deaths per 1000 person-years;the crude mortality rate for CVD deaths was roughly half that of all-cause deaths.In contrast,in the China Kadoorie Biobank study,for individuals without any chronic diseases,the all-cause mortality rate was 4.1 deaths per 1000 person-years.However,for individuals with one or more CMMs in our study,the crude mortality rate was even lower.This might be attributed to hypertensive patients receiving regular medical followups,medication treatments,and frequent medical examinations,which could lead to more timely and superior treatment and earlier detection of potential issues,thereby reducing their risk of death.In most studies,CMM is characterized by comorbidity with CHD,DM,hypertension,or stroke.[17–20]In our study,we included DM,CHD,and stroke in hypertensive patients.In comparison with the general population,hypertensive patients have a higher prevalence of these diseases and higher long-term mortality.In the present research,we additionally incorporated dyslipidemia and CKD,which are both risk factors for metabolic diseases.Over half of the adult hypertensive patients in China have concurrent dyslipidemia,significantly increasing the risk of CVDs.[21]Moreover,the prevalence of hypertension in non-dialysis patients with CKD in China stands at 67.3%,[22]which substantially elevates the incidence and mortality rates of CVDs.

Regarding the HRs for mortality in our study,we compared our findings with those of other studies.In the general population,multimorbidity is associated with a high risk of mortality.[23–25]A study involving 1.2 million participants from population cohorts primarily in the United States and Europe,and covering more than 90 cohort studies,found that the risk of death was two times higher for participants with one disease,four times higher for those with two diseases,and eight times higher for those with three diseases.With each additional disease,the risk of death approximately doubled.[11]However,hypertension,CKD,and dyslipidemia were not included in that evaluation.In contrast,in our study among hypertensive patients,with one CMD,the all-cause mortality risk was not significantly increased in comparison with participants without any CMDs that only had hypertension;with two CMDs,the all-cause mortality risk increased by 53.5%;and with three or more CMDs,the all-cause mortality risk relative to the risk of two CMDs increased by 60.5%.Similarly,in the associations with CVD mortality,with one CMD,the CVD mortality risk was not significantly increased in comparison with participants without any CMDs that only had hypertension;with two CMDs,the CVD mortality risk increased by 53.8%;and with three or more CMDs,the CVD mortality risk relative to the risk of two CMDs was increased by 76.0%.

The above data suggest that although the risk increases with the number of CMDs,its rate of increase is not as steep as described in the general population.One reason for this might be that hypertensive patients inherently have a higher risk of mortality,and thus the relative increase in risk might not be as pronounced as that in the general population.

STRENGTH AND LIMITATIONS

The strength of our study lies in our large-scale national multicenter collaborative research initiated by the Cardiovascular Disease Branch of the Chinese Medical Association.This research involved 46 hospitals in 22 provinces and cities across China,including 14 secondary hospitals and 32 tertiary hospitals,ensuring representativeness of the sample.All study participants were outpatients with hypertension and our findings will help to deepen and clarify understanding regarding the impact of CMM on the health of individuals with hypertension.This cross-regional,multi-level healthcare institution data ensures the broad representativeness of our samples,thereby enhancing the generalizability of the research findings.We conducted a baseline survey involving five different CMDs to provide comprehensive information for the analysis.The follow-up time was as long as 10.4 years,providing a sufficient time window to analyze long-term trends and assess patients’ survival status.

The study also had several limitations.The diagnosis of CMD is confirmed at baseline,and its incidence was not updated during the follow-up period.This may limit our understanding of how the disease changes over time and with the course of the illness and may affect our estimates of how the risk of death changes over time.Additionally,we did not specifically explore the different types of multimorbidity patterns and their relationship with mortality.Considering the feasibility of data analysis,if we were to examine various comorbidity patterns in detail,the sample size for some groups might not be sufficient for robust statistical analysis (supplemental material,Table 1S).Thus,we may have missed some key information that may be important for understanding the mortality risk in patients with hypertension and specific comorbidity patterns.This is an important research area because understanding these relationships may help to better prevent and manage hypertension and its related CMMs.Overall,this study has many advantages in design and implementation,as well as some limitations that should be addressed in future research.

CONCLUSIONS

This cohort study revealed a novel association between CMMs and all-cause and CVD mortality risk among hypertensive patients in China.An increased number of CMMs was associated with an increased risk of all-cause mortality among hypertensive patients,with a greater magnitude of association for CVD mortality.Given the rising prevalence of cardiometabolic conditions among hypertensive patients,coupled with the recent surge in cardiovascular mortality,there is urgent need to expedite the development and implementation of preventive measures to reduce CMDs and enhance care and treatment for those patients with such conditions.Our findings highlight the need for a complementary strategy in primary and secondary prevention of CMDs among hypertensive patients in China.

ACKNOWLEDGMENTS

This study was supported by the National Key Research and Development Program of China (2022YFC 3602501) and the Pfizer Inc.(New York,USA) offices in Beijing,China.All authors had no conflicts of interest to disclose.