1. Introduction
Cardiovascular disease (CVD), including heart disease and stroke, is the leading cause of death worldwide and in the United States (U.S.) [
1]. The prevalence of CVD in U.S. adults is 49%, and the American Heart Association’s (AHA) 2023 update on Heart Disease and Stroke Statistics reported 928,741 CVD deaths in the US in 2020 [
1]. Furthermore, the World Health Organization’s (WHO) projections estimate that CVD will account for over 22.2 million annual deaths by 2030 [
2]. The economic burden of CVD in the U.S. is estimated at over
$350 billion annually, with a projected increase to over
$950 billion by 2035 [
1,
3]. CVD broadly impacts demographic groups, affecting men and women of all ages and racial backgrounds [
4]. While CVD was previously considered a disease of aging populations, the incidence of CVD in younger persons and working populations is rapidly increasing [
5]. Additionally, although CVD mortality in the U.S. has declined over the course of the past two decades, the rate of decline has stagnated, and CVD continues to exert a heavy mortality burden, with recent data showing an increase again in the later 2010s to 2020 [
1,
6,
7,
8].
Traditional risk factors such as unhealthy diets, smoking, and physical inactivity are unable to fully account for the burden of CVD risk, and recent evidence has identified an urgent need to evaluate the contribution of novel environmental, behavioral, and occupational risk factors to CVD [
9,
10,
11,
12]. Accordingly, the U.S. National Heart, Lung, and Blood Institute’s (NHLBI) Strategic Vision for Research has called for the targeted epidemiological investigation of novel risk factors for CVD [
13]. Such risk factors can be broadly classified as stressors, and a rapidly emerging body of evidence has posited a central role of stress in the etiology and pathophysiology of CVD [
14,
15].
Research efforts have identified a continuum of novel stressors that contribute to CVD across all stages of the life-course, from childhood through adulthood and old age. Notably, psychosocial exposures are a major source of stress and increased CVD risk across the life-course, the effects of which can be dissected according to their associated life stage [
16,
17,
18]. Adverse childhood experiences (ACEs), defined as a constellation of early life adversities such as childhood abuse, neglect, or household dysfunction, have emerged as a severe and causal risk factor for CVD [
19,
20,
21], while in adulthood, social isolation [
16,
22] and job strain have demonstrated extensive and causal associations with CVD [
17,
23,
24,
25,
26]. This collective set of stressors represents a holistic spectrum of work and nonwork related psychosocial stressors evidenced as CVD risk factors, across the life course. While studies have demonstrated the separate associations of such psychosocial exposures with CVD outcomes, there is an extreme lack of evidence covering these stressors in one single study. Importantly, the systematic and integrated investigation of these novel stressors and their aggregate contributions to CVD at different life stages demands a novel conceptual framework. Most recently, the life-course model has emerged as a theoretical framework for effectively characterizing the differential effects of exposures across life stages [
27,
28,
29]. The life-course model has benefitted additionally from integration with the cumulative advantage/disadvantage model, which was developed to assess the issue of multiple overlapping exposures with potential additive or synergistic effects [
30,
31].
While some pioneering research efforts have identified interactions of job strain with other psychosocial factors in the context of mental health outcomes [
32,
33,
34], no study has examined the comprehensive associations of ACEs, social isolation, and job strain with risk of CVD, presenting a research gap. A single study in 2007 assessed the contribution of early-life risk factors (in this case, parental socioeconomic status) to the association of job strain with atherosclerosis, stating that “even the best-designed prospective studies have failed to take into account the cumulative effects of early life factors”, but found no evidence for such effects [
35]. Therefore, this project seeks to address these knowledge gaps via the systematic investigation of work and nonwork related psychosocial exposures across the life course.
The objective of this project is to conduct a systematic epidemiological investigation of ACEs, social isolation, job strain, and their association with CVD mortality in a large, nationally representative, population-based sample of U.S. older employees. This analytic project based on the Health and Retirement Study (HRS) examines the contribution of psychosocial stressors at different life stages (childhood and adulthood) and in different life domains (working life and non-working life) to death from CVD. There is a critical knowledge gap regarding the interaction of work and nonwork related psychosocial stressors in cardiometabolic disease processes. While many studies have evaluated the separate contributions of either work or nonwork related exposures, there is a paucity of empirical evidence assessing their interrelationships, and hence the National Occupational Research Agenda (NORA) has highlighted a need for research on the “relationship of occupational risk factors with known non-occupational risk factors for CVD” [
36]. This project implements a comprehensive exposure assessment model incorporating the work and nonwork related psychosocial factors of ACEs, social isolation, and job strain, from childhood to adulthood and old age, spanning the entirety of the life-course. Our central hypothesis is that ACEs, social isolation, and job strain lead to increased risk of CVD mortality.
4. Discussion
Using the data from the large, nationally representative, population-based HRS study, we examined the prospective associations of ACEs, social isolation, and job strain with CVD mortality. ACEs and job strain were significantly associated with CVD mortality in older employees, while social isolation was related to increased risk of CVD mortality but did not reach statistical significance. Mutual adjustment between the psychosocial exposures of ACEs, social isolation, and job strain did not indicate marked differences compared to models foregoing mutual adjustment. Together, these results suggest a notable influence of psychosocial stressors on deaths due to CVD. Our hypotheses were therefore supported by the findings.
The significant associations of ACEs with CVD mortality detected in the HRS sample are consistent with the literature on the adverse cardiometabolic health impacts of ACEs exposure. Review studies assaying evidence on ACEs and CVD later in life have reported that adults with high exposure to ACEs have a “more than 2-fold higher risk of developing CVD and an almost 2-fold higher risk of premature mortality” [
21]. ACEs are widely implicated in cardiometabolic health conditions, including clinically proven risk factors for CVD such as hypertension [
20,
53,
54]. The AHA has also published scientific statements acknowledging ACEs as a social determinant of CVD risk and cardiometabolic health outcomes and calling for targeted longitudinal investigations—this project suitably addressed this call for further research by providing survival analysis data from prospective cohort studies [
20,
55]. Such findings provide preliminary evidence in support of the “chains of risk” model, where an early stress exposure might lead to further stressful experiences later in life [
56,
57,
58]; ACEs may lead to more adverse working conditions and augment perceptions of stressful work environments in adulthood [
59]. ACEs may also lead to impaired social functioning in adolescence and adulthood, based on neurobiological evidence showing disruptions of neural networks involved in social functioning [
60]. This has been documented to lead to deficits in processing social cues and body language such as facial expressions, with neuroimaging studies of physically abused children showing effects of bias towards angry faces and negative emotions [
61,
62,
63,
64]. Alternative explanations explored by life-course exposure models [
56,
65] and the “biological embedding” model of stress and disease posit that early childhood is a critical period that greatly influences responses to environmental and psychosocial stressors later in life [
66,
67]. Long-term biological consequences of ACEs include disruption of regulatory and homeostatic mechanisms, including the immune, metabolic, neuroendocrine, and autonomic nervous systems [
68]. ACEs have been shown to produce chronic inflammation, as evidenced by elevated proinflammatory signaling molecules such as interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen [
69,
70,
71]. Notably, recent evidence showing efficacy of CVD medications such as PCSK9 inhibitors in ameliorating CVD biomarkers such as low-density lipoprotein cholesterol (LDLC) also demonstrated reductions in psychological distress and improved quality of life, indicating a potential pathway for interventions targeting psychosocial stress and CVD [
72].
While associations of social isolation with CVD mortality did not reach statistical significance in the current analyses, elevated hazard estimates were observed amongst participants with high social isolation, which is in accordance with prior investigations of such psychosocial exposures and CVD. One potential explanation for the insignificant findings may be the fact that the participants were employees, as opposed to retirees or the general population—employed participants may experience social contacts through the work environment, based on engagement in work tasks and with colleagues. Therefore, workplace social support and task involvements may offset the negative effects of nonwork-related social isolation. Social isolation has a plethora of effects that undermine an individual’s health and overall well-being, with recent data aggregated in a comprehensive report disseminated by the U.S. Surgeon General [
73]. Indeed, evidence illustrates a strong connection between social isolation and heart disease and stroke outcomes, with many studies demonstrating significant increases in morbidity and mortality [
74,
75,
76,
77]. Estimates for the effect of social isolation range from 30–50% for increased risk of heart disease and stroke [
16,
22], as well as drastically increased risk of hospitalization (68%) and emergency department visits (57%) related to chronic cardiovascular conditions [
78]. The increased risk of death and healthcare use associated with social isolation clearly demonstrate clinical relevance in CVD. There is also a pragmatic element of social isolation that is relevant to CVD outcomes—instances of fatality from myocardial infarction are less likely when household members or social contacts are able to provide immediate help and calls for medical attention. In context of population-level demographic trends apparent in the U.S., where the percentage of single-person households reached 29% in 2022, these data call attention to social isolation as an urgent and pressing issue of public health significance. The rapidly increasing prevalence of social isolation in the U.S. and the burgeoning body of literature on associated cardiovascular health consequences prompted the AHA to issue a 2022 statement underscoring social isolation as a “common, yet underrecognized determinant of cardiovascular health and brain health” [
77].
Job strain has also been strongly substantiated as a major risk factor for CVD and worsened CVD mortality outcomes. A review of evidence from over 600,000 adults from 27 studies across the U.S., Europe, and Japan found that occupational stressors such as job strain were associated with an up to 40% increased risk of incident coronary heart disease and stroke [
25]. Meta-analyses of over 190,000 participants from 13 European cohort studies found robust associations of job strain with coronary heart disease and stroke, with the population attributable risk for coronary heart disease due to job strain estimated at 3.4% [
79,
80]. Similarly, a multicohort study drawing on data from Finland, France, Sweden, and the United Kingdom with over 100,000 individuals found evidence for excess CVD mortality risk among participants with prevalent cardiometabolic diseases at baseline [
81]. These data highlight the importance of including novel and psychosocial exposures such as social isolation and job strain in investigations of CVD mortality in working populations.
4.1. Strengths
The major strengths of this study are founded upon the large, population-based, nationally representative sample population among older employees. The sample included strong representation of sociodemographic ranges and occupations and provided a long follow-up length of 12 years, thus addressing limitations of previous studies and the lack of longitudinal cohort data highlighted by the AHA’s 2022 scientific statement on ACEs [
20]. Additionally, the older mean age of the sample (61) and long follow-up period likely allowed for the manifestation of CVD deaths and thus detection by the statistical analyses, as the risk of cardiometabolic conditions increases with age [
82,
83]. In a study of over 130,000 Chinese adults, socioeconomic and psychosocial risk factors were found to be prominent determinants of CVD outcomes among participants aged 55 years or above, accounting for 27% of the population attributable risk for mortality [
84].
Furthermore, the measures used were detailed and reliable; job strain measures generally adhered to Karasek’s well-established model job strain [
50], and the well-validated Berkman-Syme Social Network Index was utilized to assess social isolation [
85]—one study using data from the HRS cohort utilizing this approach, showed promising findings regarding outcomes including all-cause mortality and excess Medicare spending [
86]. Job strain data from the HRS study have been successfully implemented in studies of hypertension, depression, drinking behavior, memory function, and long-term mortality [
87,
88,
89,
90]. ACE measures across the studies were also rich and detailed, adequately encompassing the three-factor structure of ACEs with assessments of abuse, household dysfunction, and financial stress. The HRS dataset also provided data on sociodemographic characteristics and health-related behaviors that were used to account for potential confounders.
4.2. Limitations
There are several limitations of this study that may have impacted the findings. While the reliability of adult retrospective reports of ACEs has also come under question due to potential recall bias, studies assessing retrospective reports have observed robust test-retest reliability ranging from 0.45 to 0.90, and adequate kappa coefficients ranging from 0.52 to 0.72 [
91,
92]. Similarly, because all exposure data was collected at baseline, the results may be influenced by exposure misclassification bias due to the possibility of changes in social isolation and job strain during follow-up. In terms of data quality, it is also possible that the use of surveys and administrative data in assessments of CVD and CVD mortality introduced potential bias in the analyses. Furthermore, a substantial number of participants were excluded due to missing data on psychosocial factors, given the special research design in the HRS study, i.e., roughly half of the study sample in 2006 and 2008 were invited to participate in psychosocial surveys, respectively, and we pooled them together to form our baseline sample. As a result, we were unable to rule out the possibility of non-invitation or non-response. Hence, caution should be exercised when generalizing our findings to all older U.S. employees. Additionally, while the sample population was large and included a broad range of demographic strata, most participants were White, with limited representation of Black and other racial groups, limiting the generalizability of the results. Future studies with better representation of racial and ethnic minorities would allow for further extrapolation and comparison of results with broader populations. Finally, while these findings showed significant associations of ACEs and job strain with CVD mortality, they raise further questions regarding the biological mechanisms underlying such observations and the means by which such exposures impact cardiometabolic health. Hence, the contributions of ACEs and job strain to manifested diseases and relevant biomarkers deserve further investigation.