Association of Depressive Symptoms With Incident Cardiovascular Diseases in Middle-Aged and Older Chinese Adults

Key Points Question Are depressive symptoms associated with incident cardiovascular disease among middle-aged and older Chinese adults? Findings In this cohort study of 12 417 Chinese adults, participants with depressive symptoms at baseline had higher incident rates of cardiovascular disease compared with those without such symptoms. Elevated depressive symptoms as a whole and 2 individual symptoms (restless sleep and loneliness) were significantly associated with increased risk of cardiovascular disease after adjusting for potential confounders. Meaning This study suggests that depressive symptoms, particularly restless sleep and loneliness, may be associated with incident cardiovascular disease among middle-aged and older Chinese adults.


Introduction
Depressive symptoms are common among middle-aged and older adults. 1,2 China, like much of Asia, is experiencing an increase in older adults. The prevalence of depressive symptoms in older adults has become an increasingly important public health priority. [3][4][5] A national survey in China 6 showed that approximately 30% of men and 43% of women aged 45 years and older experienced depressive symptoms. Epidemiological studies [7][8][9] have found that depressive symptoms are associated with a range of negative health outcomes, such as coronary heart diseases, stroke, and all-cause mortality.
Some studies 10-12 found that both the history and new onset of depressive symptoms were associated with a series of cardiovascular events, such as angina, myocardial infarction, stroke, heart failure, and coronary death. A meta-analysis 13 of 24 prospective cohort studies found that depressive symptoms could be associated with a 30% excess risk for coronary heart disease. The association between depression and incident cardiovascular disease (CVD) may vary across different depression subtypes 14 and may be bidirectional; for example, depressive symptoms are associated with an increased risk of CVD, 13 whereas cardiovascular risk factors also are associated with depression or depressive symptoms. 15,16 Therefore, to reduce the risk of CVD, it is important to understand its association with depressive symptoms.
Depressive symptoms are usually assessed using validated rating scales with established cutoffs, such as the Center for Epidemiologic Studies Depression Scale (CES-D) 17 and the Geriatric Depression Scale. 18 Although these scales cannot be used to establish the diagnosis of major depression, they are widely used in both research and daily practice, and most confirmatory factor analysis studies 19 support 2 clusters of symptoms: emotional or affective (eg, felt depressed, happy, or lonely) and somatic symptoms (eg, fatigue, appetite, or sleep). Most previous studies 7,12,[20][21][22] on the association between depressive symptoms and CVD risk only analyzed the presence of depressive symptoms as a binary variable (eg, depressed or not) or used its total score, with the assumption that all depressive symptoms are equally good severity indicators, 23 despite the lack of evidence to support this.
To date, the contribution of individual depressive symptoms to incident CVD is still unknown, which gives us the impetus to examine the association between specific depressive symptoms and incident CVD among middle-aged and older adults in China on the basis of the China Health and Retirement Longitudinal Study (CHARLS). We hypothesized that elevated depressive symptoms and certain specific depressive symptoms would be associated with increased risk of CVD.

Study Population
This cohort study was a secondary analysis of the data set of the CHARLS, which is an ongoing nationally representative cohort study. 24 Details of the study design have been described elsewhere. 24,25 In brief, a total of 17 708 participants in 10 257 households were recruited from 150 counties or districts and 450 villages within 28 provinces in China between June 2011 and March 2012, using the multistage stratified probability-proportional-to-size sampling technique. All participants underwent an assessment using a standardized questionnaire to collect data on sociodemographic and lifestyle factors and health-related information. The response rate of the baseline survey was 80.5%. All participants were followed up every 2 years after the baseline survey.
The CHARLS study was approved by the institutional review board of Peking University. Written informed consent was obtained from all participants. This study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. 26

Assessment of Depressive Symptoms
In the baseline survey of the CHARLS, depressive symptoms were measured using the CES-D short form, 17 which is a widely used self-report measure on depressive symptoms in population-based

Ascertainment of Incident CVD Events
The study outcome was incident CVD events. In accordance with previous studies, 28,29 incident CVD events were assessed by the following standardized questions: "Have you been told by a doctor that you have been diagnosed with a heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems?" or "Have you been told by a doctor that you have been diagnosed with a stroke?" Participants who reported heart disease or stroke during the follow-up period were defined as having incident CVD. The date of CVD diagnosis was recorded as being between the date of the last interview and that of the interview reporting an incident CVD. 28,29 Covariates adjusted. To examine the association between specific depressive symptoms (eg, CES-D individual items) and incident CVD events, using the method of Jokela et al, 31 we coded the items as dichotomous variables by defining the responses as occasionally or a moderate amount of time (3)(4) days) and all of the time (5-7 days) as having the specific symptoms. All 10 items were entered simultaneously in model 3.
To further examine the association between the severity of depressive symptoms and incident CVD events, scores of depressive symptoms were split into quintiles and then were included in Cox proportional hazards models with quintile 1 as the reference group. In addition, we explored the potential nonlinear associations using 3-knotted restricted cubic spline regression. Subgroup analyses were conducted to examine whether the potential association between depressive symptoms and CVD events was moderated by the following demographic and clinical characteristics: Three sensitivity analyses were conducted as follows: (1) further adjusting for metabolic biomarkers in model 3 in the sample of 8696 participants who underwent metabolic examinations; (2) repeating all analyses using the complete data set (10 186 participants) without multiple imputations; and (3) using the Fine and Gray competing risk model 32 to account for competing risks due to mortality. Two-sided P < .05 was considered as statistically significant. All analyses were performed using Stata statistical software version 15.1 (StataCorp) and R statistical software version 3.6.1 (R Foundation).

Results
Of the 17 708 CHARLS participants at study baseline, we excluded 484 individuals younger than 45 years, 2789 with heart disease or stroke at baseline, 1878 with incomplete information on depressive symptoms, and 140 with no answers for the questions on the physician-diagnosis CVD during follow-up. Finally, 12 417 participants were included for analysis, and 8696 (70.0%) of them provided blood samples at baseline. A comparison of baseline characteristics between participants included and those who were not included in the analysis is shown in eTable 1 in the Supplement.
A total of 12 417 adults were included in the analyses. The mean (SD) age at baseline was 58.40 (9.51) years; 6113 (49.2%) of the participants were men and 6304 (50.8%) were women. Table 1 shows the characteristics of the participants.   association between the CES-D total score and risk of incident CVD events using restricted cubic spline regression was also found (for nonlinearity, P = .30 for CVD, P = .40 for heart disease, and P = .82 for stroke) (Figure 1).

JAMA Network Open | Cardiology
Of the individual depressive symptoms, the most common ones included feeling hopeless (35.9%), restless sleep (32.7%), and being bothered by little things (31.7%) ( Table 3). Table 3  were significantly associated with incident CVD, after adjusting for potential confounders. Feeling lonely was also significantly associated with stroke (HR, 2.10; 95% CI, 1.43-3.10).  Graphs show HRs for cardiovascular disease (A), heart disease (B), and stroke (C) adjusted for age, sex, residence, marital status, educational level, smoking status, drinking status, systolic blood pressure, and body mass index; history of diabetes, hypertension, dyslipidemia, and chronic kidney disease; and use of hypertension medications, diabetes medications, and lipid-lowering therapy. Data were fitted by a restricted cubic spline Cox proportional hazards regression model. The depressive symptoms score ranges from 0 to 30, with the highest score representing the lowest risk of depressive symptoms. Solid lines indicate HRs, and dashed lines indicate 95% CIs.

Discussion
This study examined the associations between depressive symptoms and incident CVD in a nationally representative cohort of 12 417 adults in China aged 45 years and older with over 4 years of follow-up.
At baseline, 26.0% of the participants experienced depressive symptoms. Depressive symptoms were associated with a 39.0% increased risk of CVD. The presence of certain depressive symptoms (restless sleep and loneliness) were independently associated with incident CVD.
Increasing evidence suggests that the presence of depressive symptoms is associated with an increased risk of CVD. 8,10,[33][34][35] The Jackson Heart Study 20 found an almost 2-fold increase in the risk of coronary heart disease and stroke in patients with major depression. The Reasons for Geographical and Racial Differences in Stroke Study 36 also found that severe depressive symptoms were associated with an increased risk of coronary heart disease, stroke, and mortality. A recent cohort study 22 suggested that time-dependent depressive symptoms were associated with 1.4-fold risk of cardiovascular mortality. In addition, several meta-analyses and systematic reviews 12,13,21 found a positive association between severe depressive symptoms and increased risk of CVD. As expected, the risk of CVD including heart disease and stroke was associated with depressive symptoms in this study.
Although the association between depressive symptoms and incident CVD has been widely examined, the contribution of specific depressive symptoms to incident cardiovascular events is still not clear. This study found that restless sleep and loneliness were independently associated with incident CVD and stroke. Restless sleep or insomnia previously have been associated with CVD. [37][38][39] In the Health and Retirement Study Cohort, 8 2 individual depressive symptoms (everything was an effort and restless sleep) were independently associated with an increased risk of stroke. A recent study 9 also found that a combination of depressive symptoms and sleep problems was associated with an increase in the odds of coronary heart disease at 6-year follow-up. The mechanisms that underlie the association between sleep problems and increased risk of CVD have been widely examined. 38 Some studies found that short sleep duration or nonrestorative sleep could lead to metabolic or endocrine changes through elevated levels of inflammatory cytokines and sympathetic activation, 40,41 poor sleep quality with low levels of slow-wave sleep could impair glucose tolerance and then increase the risk of type 2 diabetes, 42  Apart from differences in methods, we assume that different sociocultural contexts across these countries may partly explain the different findings between studies, 51,52 although convincing findings are needed to support this notion. In China, loneliness among elders may take on a specific relevance.
As China continues to develop, it is less common for young people to comport with traditional Confucian ideals of filial piety, and this, coupled with massive internal migration, may disruptive to care structures for older adults. 53 The underlying mechanisms of the association between depressive symptoms and CVD are multifactorial, involving autonomic nerve dysfunction, inflammation, endothelial dysfunction, platelet activation and thrombosis, life behavior, and cardiac metabolic risk factors. 54 For example, a meta-analysis 55 found that depression may be associated with dietary patterns, which could change the gut microbiome and then increase CVD risk. Furthermore, the association between elevated levels of inflammatory markers, such as high-sensitivity C-reactive protein, and depression are well documented. 56,57 In the current study, after adjusting for high-sensitivity C-reactive protein, the association between depressive symptoms and increased risk of CVD remained, which suggests these findings are robust. In this study, apart from restless sleep and loneliness, other individual depressive symptoms as measured by the CES-D were not significantly associated with incident CVD.

JAMA Network Open | Cardiology
We have no clear explanation about the associations between different individual depressive symptoms and incident CVD except for assuming that the effect size between both restless sleep and loneliness and CVD is, perhaps, greater than those for other individual depressive symptoms because of biological and environmental factors. 38,49 In addition, the associations between other depressive symptoms and CVD may be undetected because of the short study period (4 years).

Strengths and Limitations
The strengths of this study included the prospective design, the long follow-up period, and the inclusion of specific depressive symptoms. However, several limitations need to be addressed. First, some confounding factors of the association between depression and CVD, such as income, social support, isolation, and joblessness, 58,59 were not adjusted in this study. Second, similar to other studies, 60,61 for logistical reasons, the diagnosis of CVD was self-reported. Medical records were not available in the CHARLS; however, some other large-scale studies, 28 such as the English Longitudinal Study of Aging, found that self-reported incident coronary heart disease had a good agreement with medical records (accuracy, 77.5%). Third, only participants from China were involved in this study; thus the findings may not fully generalize to other countries. In addition, time-varying exposures were not included in the present analysis, so residual confounding is a concern.

Conclusions
This study found that the presence of certain depressive symptoms, such as restless sleep and loneliness, could be associated with an increased risk of CVD in middle-aged and older Chinese adults. To reduce the risk of CVD, effective treatment and psychosocial interventions should be delivered targeting these symptoms.