Cardiovascular Disease, Genetic Susceptibility, and Risk of Psychiatric Disorders and Suicide Attempt: A Community‐Based Matched Cohort Study Based on the UK Biobank

Jie Yang; Yu Zeng; Huazhen Yang; Yuanyuan Qu; Xin Han; Wenwen Chen; Yajing Sun; Yao Hu; Zhiye Ying; Di Liu; Huan Song

doi:10.1161/JAHA.123.031280

. 2024 Jul 31;13(15):e031280. doi: 10.1161/JAHA.123.031280

Cardiovascular Disease, Genetic Susceptibility, and Risk of Psychiatric Disorders and Suicide Attempt: A Community‐Based Matched Cohort Study Based on the UK Biobank

Jie Yang ^1,², Yu Zeng ^2,³, Huazhen Yang ^2,³, Yuanyuan Qu ^2,³, Xin Han ^2,³, Wenwen Chen ^2,³, Yajing Sun ^2,³, Yao Hu ^2,³, Zhiye Ying ^2,³, Di Liu ⁴, Huan Song ^2,^3,^5,^✉

PMCID: PMC11964004 PMID: 39082195

Abstract

Background

The associations between cardiovascular disease (CVD) and multiple psychiatric disorders and suicide attempt, and whether different genetic susceptibilities affect such links, have not been investigated clearly.

Methods and Results

Based on the UK Biobank, we conducted a matched cohort study involving 63 923 patients who were first hospitalized with a CVD diagnosis between 1997 and 2020, and their 127 845 matched unexposed individuals. Cox models were used to examine the subsequent risk of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress‐related disorder, substance misuse, psychotic disorder, and suicide behaviors) following CVD. We further performed stratified analyses by polygenic risk score for each studied psychiatric condition to detect the possible effects of genetic susceptibility on the observed associations. We found an increased risk of any psychiatric disorders and suicide attempt among CVD patients, compared with matched unexposed individuals, particularly within 1 year following the CVD (fully adjusted hazard ratio [HR] within 1 year, 1.83 [95% CI, 1.58–2.12]; HR after 1 year, 1.24 [95% CI, 1.16–1.32]). By subtype, the risk elevations existed for any psychiatric disorders and suicide attempt following most categories of CVDs. Analyses stratified by polygenic risk score revealed little impact of genetic predisposition to studied psychiatric conditions on these observed links.

Conclusions

Patients hospitalized for CVD were at increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, especially in the first year after hospitalization, irrespective of their genetic susceptibilities to studied psychiatric conditions, and these findings underscore the necessity of developing timely psychological interventions for this vulnerable population.

Keywords: cardiovascular disease, genetic susceptibility, polygenic risk score, psychiatric disorders and suicide attempt

Subject Categories: Cardiovascular Disease, Mental Health

Nonstandard Abbreviations and Acronyms

CCI: Charlson comorbidity index
PRS: polygenic risk score

Clinical Perspective.

What Is New?

The subsequent risk of multiple types of psychiatric conditions significantly increased following a cardiovascular disease hospitalization, especially in the first year after the hospitalization, irrespective of their genetic susceptibilities.

What Are the Clinical Implications?

Timely assessment and psychological interventions were necessary for this vulnerable population, irrespective of the genetic susceptibility level.
Not only is it important to focus on cardiovascular disease itself, but the role of cardiologists in the psychiatric–psychological attention of patients with cardiovascular disease is also important.

Psychiatric disorders are various degrees of impairments of cognition, emotion, behavior, and other mental activities due to disturbance of brain function activity, mainly including anxiety, depression, stress‐related disorder, substance misuse, and psychotic disorder. Because psychiatric disorders are increasingly prevalent worldwide (eg, an increase of 25.6% in anxiety and an increase of 27.6% in depression due to the COVID‐19 pandemic), the disease burden and social influence induced by psychiatric disorders have attracted increasing research interest. ¹ Furthermore, studies have demonstrated that, beyond psychological impacts, individuals with psychiatric disorders might experience a series of physiological alterations, resulting in subsequent risks of developing many major somatic diseases, including autoimmune disease, infection, neurodegenerative disease, and cardiovascular disease (CVD). ² , ³ , ⁴ , ⁵ Likewise, suicide behaviors, including intentional self‐harms or life‐threatening attempts, are also major public health problems, resulting in ≈1 million suicide‐related deaths worldwide per year. ⁶ Therefore, in addition to improving medical/disease care for individuals already diagnosed with the above‐mentioned psychiatric disorders and suicide attempt, early identification and timely prevention are also important for populations at high risk of these psychiatric conditions.

CVD is one of the most prevalent somatic diseases, with substantial contributions to disease‐related death and disability worldwide. ⁷ , ⁸ Additionally, elevated psychological stress, representing an increased risk of various psychiatric disorders (eg, anxiety, depression, and posttraumatic stress disorder), has been suggested among patients with CVD, compared with either individuals without CVD or the general population. ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ Moreover, the occurrence of anxiety and depression following CVD might in turn lead to more severe adverse cardiovascular outcomes via behavioral changes (such as a less healthy diet and low physical activity) or physiologic changes (such as inflammation and platelet dysfunction). ¹⁵ , ¹⁶ Thus, the psychopathological changes among patients with CVD cannot be ignored. However, due to the limited sample size and the lack of some important covariates (such as environmental or lifestyle factors) in most of the previous studies, these analyses cannot control for other important covariates. ¹⁷ , ¹⁸ Additionally, the potential role of other specific CVD categories, including cerebrovascular disease, emboli/thrombosis, and arrhythmia/conduction disorder, in the development of psychiatric conditions remains unexplored. Furthermore, less attention has been given to the short and long‐term effects of CVD on psychiatric conditions, especially their different specific types, leading to certain difficulties in effective and accurate prevention of different psychiatric conditions following CVD. Moreover, several previous genome‐wide association studies have revealed that genetic susceptibility played a role in the development of multiple specific psychiatric disorders (eg, the estimated heritability of depression was 37%, and the estimated heritability of schizophrenia was ≈80%–85%). ¹⁹ , ²⁰ , ²¹ In addition, there might be a genetic component influencing psychiatric disorders, and this genetic component also had an impact on CVD. ²² , ²³ , ²⁴ Thus, we thought that it was plausible that genetic factors could modify the risk of psychiatric disorders following a CVD diagnosis, and the potential effects of different individuals' genetic susceptibilities to corresponding psychiatric conditions required consideration to assess the association clearly and comprehensively between CVD and different psychiatric conditions.

According to previous research findings, we hypothesized that patients hospitalized for CVD might be at an increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, and such links might be potentially modified by different individuals' genetic susceptibilities to corresponding psychiatric conditions. In the present study, benefiting from the enriched data of UK Biobank, including information on medical diagnosis; demographic, socioeconomic, and lifestyle factors; and complete follow‐ups on a wide range of health‐related outcomes, we conducted a matched cohort study to assess the association between CVD and any subsequent psychiatric disorders and suicide attempt. Specifically, our study was featured by comprehensive explorations on the risk of multiple specific psychiatric conditions, including suicide attempt, following any and different categories of CVDs, in both the short and long term. Furthermore, due to the availability of individual‐level genotypic data from the UK Biobank, we examined whether the observed associations could be further modified by different genetic susceptibilities to corresponding psychiatric conditions.

Methods

Data Availability

Data from the UK Biobank (http://www.ukbiobank.ac.uk/) are available to all researchers upon making an application.

Study Design

The UK Biobank is a large, detailed, and community‐based cohort study that recruited >500 000 participants aged 40–69 years between 2006 and 2010 through 22 assessment centers across the United Kingdom. ²⁵ At recruitment, information about sociodemographic data, family history and early life exposures, environmental factors, and lifestyles was collected. Health‐related data for all participants were also obtained periodically through linkages to national data sets, including hospital inpatient, primary care, cancer registries, and death registers. In addition to the above‐mentioned phenotypic information, genome‐wide genotypic information was also derived from blood samples collected at baseline. ²⁶

In the present study, we first identified an exposed cohort of individuals in the UK Biobank who were first hospitalized with a primary diagnosis of CVD between January 1, 1997, and January 31, 2020 (n=71 900; Figure 1), from the hospital inpatient data. We further excluded patients who had a history of any psychiatric disorders and suicide attempt before CVD diagnosis (n=7977), leaving 63 923 patients for the analysis. For each exposed patient with CVD (ie, the index patient), we then randomly selected 2 unexposed individuals from all eligible participants who were free of CVD and free of any psychiatric disorders and suicide attempt at the diagnosis date of the index patient (ie, index date) using the method of incidence density sampling. Exposed patients and unexposed individuals were individually matched by birth year, sex, and Charlson comorbidity index (CCI, 0 or ≥1).

All study participants were followed up from the index date until the first diagnosis of any or specific type of psychiatric disorders (ie, anxiety, depression, stress‐related disorder, substance misuse, psychotic disorder, or suicide behaviors) and suicide attempt, death, or the end of follow‐up (January 31, 2020), whichever occurred first. The follow‐up of the matched unexposed cohort was additionally censored if they were later diagnosed with CVD during follow‐up.

Ethics Approval and Consent to Participate

The UK Biobank study has full ethical approval from the National Health Service National Research Ethics Service (16/NW/0274), and all participants recruited in UK Biobank gave written informed consent. The present study was also approved by the biomedical research ethics committee of West China Hospital (2019–1171).

Ascertainment of CVD

We defined CVD (any or 6 major categories, including ischemic heart disease, cerebrovascular disease, emboli/thrombosis, heart failure, arrhythmia/conduction disorder, and others) as any first hospitalization with a primary diagnosis of corresponding International Classification of Diseases, Tenth Revision (ICD‐10) codes (I00‐I02, I05‐I09, I20‐ I28, I30‐I52, I60‐I70 [excluding I67.4], and I73.0, I74, Table S1) on the basis of UK Biobank hospital inpatient data between January 1, 1997, and January 31, 2020. Additionally, we identified patients with acute CVDs (see Table S1), presumably as a group of patients with severe and acute cardiovascular events that are less likely to be influenced by delayed diagnosis and treatment (ie, a long time interval between disease onset and hospitalization).

Ascertainment of Psychiatric Disorders and Suicide Attempt

We identified cases of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress‐related disorder, substance misuse, psychotic disorder, or suicide behaviors), according to corresponding ICD‐10 codes for primary diagnosis in hospital inpatient data and read_3 codes in primary care, or underlying cause of death in death register data (see Tables S1 and S2). The validity of administrative data for diagnoses of psychiatric conditions, from Hospital Episode Statistics in England and the equivalent data sets in Scotland and Wales, have been studied. It showed a good validity for some diagnoses of psychiatric conditions, especially depression and anxiety (positive predictive value, 75%), ²⁷ , ²⁸ , ²⁹ and lifetime psychiatric disorder (positive predictive value, 100%). ³⁰ Moreover, Davis and colleagues reported that every study included agreed that in a cohort with a diagnosis of psychotic illness recorded in secondary care, at least 80% are likely to meet research criteria for this, and most suggested >90%. ³¹

Genetic Susceptibility to Corresponding Psychiatric Disorders and Suicide Attempt

The polygenic risk score (PRS) for each specific type of studied psychiatric disorders and suicide attempt was calculated to represent the different genetic contributions of a genotype to the corresponding psychiatric condition, which was used to classify individuals into different genetic risk groups. A standard genome‐wide association studies quality control was conducted from 487 409 individuals with imputed gene data. ³² Then, we excluded 34 158 individuals with non‐European ancestry and 34 089 related individuals with a kinship coefficient >0.0884, ³³ leaving 418 168 eligible participants for further analyses. We used available single‐nucleotide polymorphisms from the base data set (the genome‐wide association studies summary statistics of psychiatric disorders and suicide attempt [ie, anxiety, ³⁴ depression, ³⁵ stress‐related disorder, ³⁶ substance misuse, ³⁷ psychotic disorder, ³⁸ and suicide behaviors ³⁹ ]) and target data set (the UK Biobank genotyping data, which passed the assessment of quality control). According to the summary statistics (ie, effect sizes and standard errors for the variants) of the genome‐wide association studies results, the PRS for each psychiatric adversity was constructed as the weighted sum of the risk alleles using summary statistics and a reference panel in a penalized regression framework called least absolute shrinkage and selection operator, which could allow heavy shrinkage in the effect estimates of single‐nucleotide polymorphisms via regularization methods. ⁴⁰ Before we used PRS calculated, the association between PRS and the corresponding phenotype was validated using a logistic regression model with adjustment for birth year, sex, genotyping array, and first 10 principal components for population heterogeneity. The results of the validation demonstrated that PRS for each specific type of psychiatric disorders and suicide attempt showed a strong association with the corresponding phenotype (see Table S3).

Covariates

Demographic characteristics (age, sex, and race), socioeconomic characteristics (Townsend deprivation index, educational attainment, and annual household income), and lifestyle factors (smoking status and alcohol drinking status) were collected at baseline using questionnaires. Body mass index was calculated through height and weight measured at the assessment center. Townsend deprivation index was used to represent economic deprivation, with high scores usually representing great deprivation. ⁴¹ The Charlson comorbidity index was calculated using hospital inpatient data to represent baseline information about somatic comorbidities (see Table S1). ⁴² Family history of psychiatric disorders was defined as any psychiatric disorders among any immediate relatives (biological parents and full siblings) according to questionnaires at the assessment center. All missing data of covariates in the present study was classified into a separate classification coded as “unknown.”

Statistical Analysis

We first visualized the time‐dependent association of CVD with the risk of any psychiatric disorders and suicide attempt since the index date by flexible parametric survival models. ⁵ Because the risk of any psychiatric disorders and suicide attempt over the short term after CVD diagnosis was significantly increased, compared with thereafter, we separately assessed the associations during the first year and beyond the 1‐year period (≤1 or >1 year of follow‐up, ie, short and long term) after CVD diagnosis, using hazard ratios (HRs) with 95% CIs derived from Cox regression models (see Data S1), which were stratified by matching identifiers (birth year, sex, and CCI) and partially or fully adjusted for age at index date (as continuous variable), sex (male or female), race (White, non‐White, unknown), Townsend deprivation index (<−3.1, −3.1 to 0.6, >0.6, or unknown), educational attainment (college or university degree, A level, O levels, certificate of secondary education or equivalent, national vocation qualifications or equivalent, other professional qualifications, or unknown), annual household income (<£18 000, £18 000–£51 999, >£52 000, or unknown), body mass index (<18.5, 18.5–23.9, ≥24.0 kg/m², or unknown), smoking status (never, previous, current, or unknown), alcohol drinking status (never, previous, current, or unknown), CCI (0 or ≥ 1), and family history of psychiatric disorders (yes or no).

We first performed analyses for any cases of psychiatric disorders and suicide attempt, and then for different specific subtypes of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress‐related disorder, substance misuse, psychotic disorder, and suicide behaviors) separately. In addition to considering all diagnoses of CVD as a whole group, the analyses for 6 major categories of CVDs (ischemic heart disease, cerebrovascular disease, emboli/thrombosis, heart failure, arrhythmia/conduction disorder, and other CVDs) were also separately conducted to examine the associations between different categories of CVDs and any psychiatric disorders and suicide attempt. The main analyses using the diagnoses of acute cardiovascular events (acute myocardial infarction, certain current complications following acute myocardial infarction, other acute ischemic heart diseases, intracerebral hemorrhage, and cerebral infarction) or the CCI as a continuous variable were repeated as sensitivity analyses to test the robustness of the results. In addition, because the competing risk of death existed to some extent due to the relative high risk of death in patients with CVD, we also computed the competing risk models, which account for death as sensitivity analyses to test the robustness of the main results. In the stratification analyses, the HRs were calculated separately by age at index date (median, <63 or ≥63), sex (male or female), and CCI (0 or ≥1) to examine such associations in different demographic characteristics.

To further investigate the role of different genetic susceptibilities in studied associations between CVD and subsequent risk of psychiatric disorders and suicide attempt, the stratified analyses were conducted by PRS for specific psychiatric disorders and suicide attempt (low genetic risk, less than first tertile; intermediate genetic risk, first tertile to second tertile; and high genetic risk, greater than second tertile).

All the data analyses in the present study were performed by R version 4.0 software (R Foundation for Statistical Computing, Vienna, Austria). A 2‐sided test with P<0.05 was considered statistically significant.

Results

Among the eligible individuals from the UK Biobank, 63 923 patients with CVD were included in the exposed cohort, and 127 845 individuals who were free of CVD and free of psychiatric disorders and suicide attempt at the index date were matched as the unexposed cohort (see Figure 1). The median follow‐up durations in the exposed and unexposed cohorts were 7.6 and 7.3 years, respectively. The median age at the index date was 63 years (see Table 1). Compared with the unexposed individuals, exposed patients had a higher Townsend deprivation index, body mass index, and proportion of smoking status and family history of psychiatric disorders but lower educational attainment levels and annual household income.

Table 1.

Basic Characteristics of Study Cohorts

Characteristics	Exposed cohort (N=63 923)	Matched unexposed cohort (N=127 845)	Total (N=191 768)
Follow‐up time, y	7.6 (3.2–13.3)	7.3 (3.3–12.9)	7.4 (3.3–13.0)
Age at index date, y	63.0 (57.0–69.0)	63.0 (57.0–69.0)	63.0 (57.0–69.0)
Male, n (%)	40 715 (63.7)	81 430 (63.7)	122 145 (63.7)
Race, n (%)
White	58 412 (91.4)	117 183 (91.7)	175 595 (91.6)
Non‐White	5086 (8.0)	9953 (7.8)	15 039 (7.8)
Unknown	425 (0.7)	709 (0.6)	1134 (0.6)
Townsend deprivation index, n (%)
< −3.1	20 205 (31.6)	45 632 (35.7)	65 837 (34.3)
−3.1 to 0.6	20 916 (32.7)	43 409 (34.0)	64 325 (33.6)
>0.6	22 730 (35.6)	38 664 (30.2)	61 394 (32.0)
Unknown	72 (0.1)	140 (0.1)	212 (0.1)
Educational attainment, n (%)
College or university degree	16 175 (25.3)	39 344 (30.8)	55 519 (29.0)
A level	5837 (9.1)	12 614 (9.9)	18 451 (9.6)
O level	12 315 (19.3)	25 063 (19.6)	37 378 (19.5)
Certificate of secondary education or equivalent	2579 (4.0)	4581 (3.6)	7160 (3.7)
National vocation qualifications or equivalent	5143 (8.0)	9707 (7.6)	14 850 (7.7)
Other professional qualifications	3759 (5.9)	7408 (5.8)	11 167 (5.8)
Unknown	18 115 (28.3)	29 128 (22.8)	47 243 (24.6)
Annual household income, £, n (%)
<18 000	16 845 (26.4)	27 407 (21.4)	44 252 (23.1)
18 000–51 999	26 590 (41.6)	56 888 (44.5)	83 478 (43.5)
>52 000	9264 (14.5)	23 176 (18.1)	32 440 (16.9)
Unknown	11 224 (17.6)	20 347 (15.9)	31 598 (16.5)
Body mass index, n (%)
<18.5	193 (0.3)	489 (0.4)	682 (0.4)
18.5–23.9	9189 (14.4)	25 483 (19.9)	34 672 (18.1)
≥24.0	53 947 (84.4)	101 143 (79.1)	155 090 (80.9)
Unknown	594 (0.9)	730 (0.6)	1324 (0.7)
Smoking status, n (%)
Never	29 229 (45.7)	66 738 (52.2)	96 032 (50.1)
Previous	27 180 (42.5)	49 650 (38.8)	76 830 (40.1)
Current	6997 (10.9)	10 670 (8.3)	17 667 (9.2)
Unknown	517 (0.8)	787 (0.6)	1304 (0.7)
Alcohol drinking status, n (%)
Never	3273 (5.1)	4898 (3.8)	8171 (4.3)
Previous	3141 (4.9)	4140 (3.2)	7281 (3.8)
Current	57 251 (89.6)	118 453 (92.7)	175 704 (91.6)
Unknown	258 (0.4)	354 (0.3)	612 (0.3)
Charlson comorbidity index, n (%)
0	55 500 (86.8)	111 000 (86.8)	166 500 (86.8)
≥1	8423 (13.2)	16 845 (13.2)	25 268 (13.2)
Charlson comorbidity index	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)
Family history of psychiatric disorders,^* n (%)
No	13 578 (21.2)	21 651 (16.9)	35 229 (18.4)
Yes	7199 (11.3)	13 574 (10.6)	20 773 (10.8)
Unknown	43 146 (67.5)	92 620 (72.4)	135 766 (70.8)
Category of first‐onset CVD, n (%)
Ischemic heart disease	30 422 (47.6)	…
Cerebrovascular disease	8285 (13.0)	…
Emboli/thrombosis	4589 (7.2)	…
Heart failure	1826 (2.9)	…
Arrhythmia/conduction disorder	14 241 (22.3)	…
Other CVDs	4560 (7.1)	…

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CVD indicates cardiovascular disease.

This characteristic included only severe depression.

We checked the proportional hazards assumption graphically by the change of the relative risk for any psychiatric disorders and suicide attempt over follow‐up time using flexible parametric survival models. Briefly, the relative risk of any psychiatric disorders and suicide attempt varied by time; we therefore conducted separate analyses for the follow‐up period ≤1 year and thereafter (ie, >1 year) and found no violation of the assumption. We found that the risk of any psychiatric disorders and suicide attempt within 1 year following CVD diagnosis was relatively greater than thereafter and the magnitude of the HRs tended to be constant after 1 year (see Figure S1). Within the first year of follow‐up, the incidence rate of any psychiatric disorders and suicide attempt in exposed patients was nearly twice that of the unexposed individuals (7.5 versus 3.6 per 1000 person‐years), and the corresponding HR was 1.83 (95% CI, 1.58–2.12) after controlling for all covariates (see Table 2 and Table S4). After 1 year of follow‐up, the similar positive association was also observed between CVD and any psychiatric disorders and suicide attempt: The HR was 1.24 (95% CI, 1.16–1.32) after controlling for all covariates (see Table 2 and Table S4). Likewise, we further found that the risk of several specific psychiatric disorders (such as anxiety, depression, stress‐related disorder, or suicide behaviors) and suicide attempt significantly increased among exposed patients. The associations between multiple specific categories of CVDs and subsequent risk of any psychiatric disorders and suicide attempt were also investigated in the present study. Patients with ischemic heart disease, cerebrovascular disease, and arrhythmia/conduction disorder all had a significantly increased risk of any psychiatric disorders and suicide attempt either within or after the first year of follow‐up (see Table 3). Among them, patients with cerebrovascular disease had the most marked risk elevation of any psychiatric disorders and suicide attempt (≤1 year: HR, 3.65 [95% CI, 2.38–5.61]; >1 year: HR, 1.49 [95% CI, 1.24–1.80]).

Table 2.

Incidence Rates and Hazard Ratios With 95% CIs for Any or Different Specific Psychiatric Disorders and Suicide Attempt Among Patients With CVD Diagnosis, Compared With Matched Unexposed Individuals by the Time of Follow‐Up (≤1 or >1 Year)

Outcome	≤1‐y follow‐up		>1‐y follow‐up
	No of cases (IR^*) in exposed patients/matched unexposed individuals	Hazard ratio	No of cases (IR^*) in exposed patients/matched unexposed individuals	Hazard ratio
		(95% CI)		(95% CI)
Any psychiatric disorders and suicide attempt	448 (7.5)/444 (3.6)	1.83 (1.58–2.12)	2163 (4.4)/2926 (3.1)	1.24 (1.16–1.32)
Anxiety	137 (2.3)/86 (0.7)	3.24 (2.38–4.41)	545 (1.1)/735 (0.8)	1.26 (1.12–1.42)
Depression	120 (2.0)/88 (0.7)	2.63 (1.94–3.58)	594 (1.2)/817 (0.9)	1.28 (1.14–1.44)
Stress‐related disorder	42 (0.7)/61 (0.5)	1.26 (0.76–2.09)	246 (0.5)/378 (0.4)	1.19 (1.01–1.42)
Substance misuse	137 (2.3)/222 (1.8)	1.12 (0.85–1.48)	1024 (2.1)/1501 (1.6)	1.06 (0.96–1.18)
Psychotic disorder	10 (0.2)/12 (0.1)	1.65 (0.67–4.05)	64 (0.1)/73 (0.1)	1.75 (0.99–3.08)
Suicide behaviors	29 (0.5)/26 (0.2)	2.44 (1.39–4.27)	230 (0.5)/268 (0.3)	1.39 (1.14–1.70)

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Cox proportional hazards regression models were stratified by matching identifiers (sex, birth year, and Charlson comorbidity index) and adjusted for sex, age at index date, race, Townsend deprivation index, educational attainment, annual household income, body mass index, smoking status, alcohol drinking status, Charlson comorbidity index, and family history of psychiatric disorders, when applicable.

CVD indicates cardiovascular disease; and IR, incidence rate.

Incidence rate per 1000 person‐years.

Table 3.

Incidence Rates and Hazard Ratios With 95% CIs for Any Psychiatric Disorders and Suicide Attempt Among Patients With Different Categories of CVD Diagnoses, Compared With Matched Unexposed Individuals by the Time of Follow‐Up (≤1 or >1 Year)

Exposure	≤1‐y follow‐up		>1‐y follow‐up
	No. of cases (IR^*) in exposed patients/matched unexposed individuals	Hazard ratio	No. of cases (IR^*) in exposed patients/matched unexposed individuals	Hazard ratio
		(95% CI)		(95% CI)
Ischemic heart disease	225 (7.7)/226 (3.8)	1.68 (1.35–2.08)	1222 (4.6)/1572 (3.1)	1.24 (1.14–1.35)
Cerebrovascular disease	89 (12.2)/49 (3.1)	3.65 (2.38–5.61)	279 (5.5)/317 (3.2)	1.49 (1.24–1.80)
Emboli/thrombosis	25 (6.2)/43 (5.0)	1.21 (0.55–2.66)	139 (4.9)/167 (3.0)	1.35 (1.03–1.77)
Heart failure	10 (6.3)/8 (2.4)	3.00 (1.01–8.89)	40 (4.2)/53 (2.7)	1.28 (0.74–2.24)
Arrhythmia/conduction disorder	73 (5.5)/87 (3.2)	2.08 (1.44–3.01)	349 (3.5)/565 (3.0)	1.21 (1.05–1.40)
Other CVDs	26 (6.1)/31 (3.6)	0.96 (0.42–2.22)	134 (4.1)/252 (4.0)	0.95 (0.74–1.21)

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CVD indicates cardiovascular disease; and IR, incidence rate.

Incidence rate per 1000 person‐years.

To examine the robustness of the results of the main analyses, the sensitivity analyses using the diagnoses of acute cardiovascular events, using competing risk models, and using the CCI as a continuous variable were conducted. The sensitivity analyses demonstrated that the studied associations were robust (see Tables S5–S7), and the risk of any psychiatric disorders and suicide attempt within 1 year of follow‐up in patients with acute CVDs was higher (HR, 2.74 95% CI 2.05–3.67, see Table S5), compared with the main analyses (HR, 1.83 [95% CI, 1.58–2.12]). During the whole follow‐up, we further found similar positive associations across age at index date and sex (see Table S8). In addition, either within or after the first year of follow‐up, stronger positive associations were observed among individuals without a history of somatic diseases (CCI, 0).

Figure 2 demonstrates the potential role of different genetic susceptibilities in the associations between CVD and subsequent risk of 6 specific types of psychiatric disorders and suicide attempt. Individuals with high genetic susceptibility to anxiety had a higher risk of developing anxiety after CVD exposure (HR, 1.52 [95% CI, 1.07–2.16]) than either low or intermediate genetic risk (low: HR, 1.17 [95% CI, 0.81–1.70]; intermediate: HR, 1.28 [95% CI, 0.88–1.86]), whereas the P value for interaction was 0.858. Thus, the association between CVD and anxiety was not significantly modified by different degrees of genetic susceptibilities. Moreover, the associations between CVD and either depression, stress‐related disorder, substance misuse, psychotic disorder, or suicide behaviors were also not significantly modified by different corresponding genetic susceptibilities.

Cox proportional hazards regression models were stratified by matching identifiers (sex, birth year, and Charlson comorbidity index) and adjusted for sex, age at index date, race, Townsend deprivation index, educational attainment, annual household income, body mass index, smoking status, alcohol drinking status, Charlson comorbidity index, and family history of psychiatric disorders, when applicable. CVD indicates cardiovascular disease.

Discussion

Based on a large‐sample cohort comprising patients first hospitalized with a primary diagnosis of CVD and their randomly selected unexposed individuals from the UK Biobank, we assessed the short‐ and long‐term risk of developing any or multiple specific psychiatric disorders and suicide attempt following CVD diagnosis (including different specific categories of CVDs) and further examined the effects of different genetic susceptibilities to the studied conditions on the observed associations. The present study demonstrated that patients with CVD were at an increased subsequent risk of any or multiple specific psychiatric disorders and suicide attempt after adjustment for many important covariates. The relative risks were higher within the first year of follow‐up than thereafter, indicating that the period close to the CVD diagnosis was a high‐risk time window to develop/diagnose psychiatric disorders and suicide attempt. Furthermore, the associations between CVD and different specific psychiatric disorders and suicide attempt were not significantly modified by different corresponding genetic susceptibilities. These findings suggested that timely assessment and psychological interventions were important for this vulnerable population, irrespective of genetic susceptibility to different psychiatric conditions.

The findings of the present study, which demonstrated that an increased risk of multiple psychiatric disorders and suicide attempt among patients diagnosed with CVD were consistent with previous studies. For instance, patients diagnosed with acute myocardial infarction had a 50% increased risk of depression or anxiety, and older patients or females were more likely to experience such psychiatric disorders. ¹⁸ Anxiety also affected ≈20% of patients with more advanced heart failure, and this proportion elevated to 40% among patients who had undergone implantation of a cardioverter‐defibrillator. ⁴³ , ⁴⁴ , ⁴⁵ Similarly, the risk of suicide increased following heart failure, and such risk was particularly higher within the first 6 months of follow‐up. ⁴⁶ Although previous studies have suggested the positive association between CVD and several psychiatric disorders or suicide, few studies have thoroughly controlled for many important confounders due to a lack of abundant data, and less attention has been given to the long‐term effects of any or different categories of CVDs on account of not long enough follow‐up. Therefore, the present study improved the previous studies' limitations, and demonstrated a robust association between CVD (including different categories) and multiple psychiatric disorders and suicide attempt, independent of many environmental and lifestyle factors. We further assessed the short‐ and long‐term effects of CVD on multiple psychiatric disorders and suicide attempt on the basis of a large‐sample cohort with a complete follow‐up of >10 years. The risk of both psychiatric disorders and suicide attempt increased in the short and long term, while a higher risk existed in the short term following CVD diagnosis. Our findings indicated that the period close to the date of CVD diagnosis was a high‐risk time window to develop/diagnose psychiatric disorders and suicide attempt. Moreover, the possibility that patients had symptoms of psychiatric disorders (ie, these symptoms were self‐reported and not enough to become clinically diagnosed) before CVD events might also exist. Because these symptoms might worsen following CVD and become clinically relevant and diagnosed, these individuals should be noted. Thus, screening for symptoms of psychiatric disorders in patients with CVD might be necessary.

In regard to the effect of genetic background, there might be a genetic component influencing psychiatric disorders, and this genetic component also had an impact on CVD. ²² , ²³ Shen et al used a large population‐based sibling‐controlled cohort to investigate that patients with CVD were at an increased risk of psychiatric disorders, independent of shared familial factors. ⁴⁷ Moreover, we explored such effect through perspective of genetic susceptibilities by different levels of the PRS. The present study conducted a thorough assessment on the effects of different genetic susceptibilities to corresponding psychiatric conditions on the studied associations after adjustment for many important confounders, and this novel finding demonstrated that the risk of different specific psychiatric disorders and suicide attempt following CVD did not differ by corresponding genetic susceptibilities. These results suggested that environmental factors, such as traumatic life events, might be more influential, in terms of promoting or triggering the development of psychiatric disorders, and timely assessment and psychological interventions were necessary for this vulnerable population, irrespective of different genetic susceptibilities. Besides standard psychological care, the role of the cardiologist in its management is also essential. For example, cardiologists should consider that irritability may mask some depressive presentation in these patients, which could lead to misdiagnosis (eg, while benzodiazepines attenuate depressive symptoms, they do not achieve effective remission, so the depression tends to become chronic), and apply more rigorous evaluations to detect these cases to further refer the patient to a specialized treatment or even introduce an antidepressant. ⁴⁸ It is also necessary to restore the humanistic and psychological role of the cardiologist (eg, cardiologists should focus on patients achieving a healthier lifestyle and a better quality of life in short and avoid that patients may come back to the lifestyle they were leading before their disease), focused on the cardiologist–patient relationship. ⁴⁹ Therefore, for psychiatric–psychological attention, cardiologists are important for patients with CVD. In addition, along with the rising burden of CVD, psychiatric condition concerns are increasingly being recognized as a comorbidity to address in the CVD management. Apart from a high prevalence of psychiatric conditions following CVD, the role of different symptoms and changing health behaviors and the broader impacts of illness require specialized behavioral health expertise (eg, optimal communication, care coordination between entities, continuity of care, medication reconciliation, and communication among the multidisciplinary elements), and this expertise should be integrated within specialty cardiovascular care. ⁵⁰

The underlying mechanisms of the association between CVD and subsequent risk of psychiatric disorders and suicide attempt are not entirely clear. However, several possible explanations were initially investigated. The diagnosis of CVD generally results in severe stress for patients, and corresponding physiological changes (eg, immune homeostasis disruption, neuroplasticity in the brain, metabolic disorder of purine in CD4+ T cells, and increased inflammatory markers) induced by stress reaction might be major drivers of psychiatric disorders and suicide attempt. ¹⁵ , ⁵¹ , ⁵² , ⁵³ Additionally, hyperactivity of the hypothalamic–pituitary–adrenal axes due to cardiovascular events would release inflammatory cytokines, cortisol, and vasoactive substances (eg, norepinephrine and epinephrine) to induce neuron injury, metabolic disorders of the neurotransmitter, and cerebral vascular injury, which could lead to mental and psychological abnormalities. ⁵⁴ A misunderstanding of CVD was likely to significantly impact on mental health, and patients with greater misconceptions were usually more anxious and depressed. ⁵⁵ Moreover, patients with CVD might experience several problems as follows, such as social function limitations, economic burdens, CVD‐related complications, and indetermination of diseases and treatment, which aggravated their mental and psychological status.

The major merits of the present study included the use of a community‐based matched study design and the use of the large‐sample UK Biobank database, which enabled the comprehensive assessment on the risk of multiple specific psychiatric disorders and suicide attempt following any or different categories of CVDs and related stratified analyses by different characteristics. Because of enriched information from baseline questionnaire surveys and electronic medical records, the present study could consider a wide range of important factors and control them in analyses, such as demographic, socioeconomic, environmental, lifestyle factors, and somatic comorbidity, in the analyses. Moreover, benefiting from the complete duration of follow‐up >10 years in the UK Biobank, the short‐ and long‐term effects of CVD on psychiatric disorders and suicide attempt could be comprehensively assessed. Finally, we took advantage of individual genotype data and further calculated the corresponding genetic susceptibilities to different specific psychiatric conditions by the level of PRS, which could be used to assess the potential effects of different disease susceptibilities on studied links.

Several notable limitations existed in the present study. First, timing for the diagnosis of non‐acute cardiovascular events might be delayed to some degree, possibly leading to an underestimation of the risk of psychiatric disorders and suicide attempt following CVD diagnosis. Second, when a patient started engaging with the health system, new diagnoses of CVD might be also leading to subsequent diagnoses of psychological conditions that might have been present previously. Third, CVD diagnoses in the present study were derived only from hospital inpatient admission data, which might result in lower detection of CVD, especially less severe CVD conditions. Hence, our findings might not be directly generalized to all populations with CVD and the generalizability of the study required to be tested. Fourth, many important confounders involved in the present study (eg, socioeconomic and lifestyle factors) were only measured or surveyed at the baseline stage, and misclassification of these factors might exist on account of a lack of enough information about repeated measurements. Fifth, even though multiple confounders (eg, age at index date, sex, race) were adjusted for in the Cox models, there were still confounding factors unmeasured, such as medication use or family history of other psychiatric disorders (eg, anxiety, stress‐related disorder, substance misuse). This might be one of the limitations in our study. Finally, participants in the UK Biobank cannot completely represent the general UK population due to only 5.5% participating in the baseline assessment, so this limitation should be noticed. ⁵⁶ However, despite a low response rate existing in the UK Biobank, associations between risk factors and outcomes seem to be generalizable. ⁵⁷ Moreover, this study did not include individuals with non‐European ancestry, and additional research based on individuals with other ancestries were further required.

In conclusion, based on the community‐based, large longitudinal cohort in the UK Biobank, the present study indicated that patients hospitalized for CVD were at an increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, especially in the first year after hospitalization. In addition, such links were not significantly modified by different genetic susceptibilities to corresponding psychiatric conditions. Thus, timely assessment and psychological interventions were necessary for this vulnerable population, irrespective of the genetic susceptibility level. In addition, the role of cardiologists in the psychiatric–psychological attention of patients with CVD is also important, and cardiologists should not only focus on CVD itself, but also should focus on patients achieving a healthier lifestyle and a better quality of life in brief and avoid patients returning to the lifestyle they were leading before their disease. Therefore, future research and developing interventions for this patient population would be useful and necessary.

Sources of Funding

This work is supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYYC21005 to Dr Song).

Disclosures

None.

Supporting information

Data S1

Tables S1‐S8

Figure S1

JAH3-13-e031280-s001.pdf^{(277.7KB, pdf)}

Acknowledgments

This research was conducted using the UK Biobank Resource under Application 54803. This work uses data provided by patients and collected by the National Health Service as part of their care and support. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref: MC_PC_20029 and MC_PC_20058). The authors thank the team members involved in West China Biomedical Big Data Center for their support for the present study.

Author Contributions: Dr Song was responsible for the study's concept and design. Y. Zeng, H. Yang, Y. Qu, Y. Sun, Y. Hu, and Z. Ying did the data and project management. Drs Yang, Han, and Chen and Y. Zeng, H. Yang, did the data cleaning and analysis. Drs Yang, Han, Chen, and Song interpreted the data. Drs Yang, Liu, and Song drafted the manuscript. All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This manuscript was sent to Tiffany M. Powell‐Wiley, MD, MPH, Associate Editor, for review by expert referees, editorial decision, and final disposition.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.123.031280

For Sources of Funding and Disclosures, see page 11.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1

Tables S1‐S8

Figure S1

JAH3-13-e031280-s001.pdf^{(277.7KB, pdf)}

Data Availability Statement

Data from the UK Biobank (http://www.ukbiobank.ac.uk/) are available to all researchers upon making an application.

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PERMALINK

Cardiovascular Disease, Genetic Susceptibility, and Risk of Psychiatric Disorders and Suicide Attempt: A Community‐Based Matched Cohort Study Based on the UK Biobank

Jie Yang, MD

Yu Zeng, MS

Huazhen Yang, MS

Yuanyuan Qu, MA

Xin Han, MD

Wenwen Chen, MD

Yajing Sun, MSc

Yao Hu, MSc

Zhiye Ying, MSc

Di Liu, PhD

Huan Song, MD, PhD

Abstract

Background

Methods and Results

Conclusions

Nonstandard Abbreviations and Acronyms

Clinical Perspective.

What Is New?

What Are the Clinical Implications?

Methods

Data Availability

Study Design

Figure 1.

Ethics Approval and Consent to Participate

Ascertainment of CVD

Ascertainment of Psychiatric Disorders and Suicide Attempt

Genetic Susceptibility to Corresponding Psychiatric Disorders and Suicide Attempt

Covariates

Statistical Analysis

Results

Table 1.

Table 2.

Table 3.

Figure 2. The risk of multiple specific types of psychiatric disorders and suicide attempt among patients with CVD diagnoses, compared with matched unexposed individuals, stratified by different genetic risks.

Discussion

Sources of Funding

Disclosures

Supporting information

Acknowledgments

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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