Journal of the American College of Cardiology

Volume 52, Issue 25, December 2008 DOI: 10.1016/j.jacc.2008.08.057
PDF Article

Psychological Distress as a Risk Factor for Cardiovascular Events
Pathophysiological and Behavioral Mechanisms

Mark Hamer, Gerard J. Molloy, Emmanuel Stamatakis

Author + information

vol. 52 no. 25 2156-2162
DOI: 
https://doi.org/10.1016/j.jacc.2008.08.057
Published By: 
Journal of the American College of Cardiology
Print ISSN: 
0735-1097
Online ISSN: 
1558-3597
History: 
  • Received April 30, 2008
  • Revision received July 23, 2008
  • Accepted August 26, 2008
  • Published online December 16, 2008.
Copyright & Usage: 
American College of Cardiology Foundation

Author Information

  1. Mark Hamer, PhD⁎ (m.hamer{at}ucl.ac.uk),
  2. Gerard J. Molloy, PhD and
  3. Emmanuel Stamatakis, PhD
  1. ↵⁎Reprint requests and correspondence:
    Dr. Mark Hamer, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom

Abstract

Objectives This study sought to estimate the extent to which behavioral and pathophysiological risk factors account for the association between psychological distress and incident cardiovascular events.

Background The intermediate processes through which psychological distress increases the risk of cardiovascular disease (CVD) are incompletely understood. An understanding of these processes is important for treating psychological distress in an attempt to reduce CVD risk.

Methods In a prospective study of 6,576 healthy men and women (ages 50.9 ± 13.1 years), we measured psychological distress (using the 12-item version of the General Health Questionnaire ≥4) and behavioral (smoking, alcohol, physical activity) and pathophysiological (C-reactive protein, fibrinogen, total and high-density lipoprotein cholesterol, obesity, hypertension) risk factors at baseline. The main outcome was CVD events (hospitalization for nonfatal myocardial infarction, coronary artery bypass, angioplasty, stroke, heart failure, and CVD-related mortality).

Results Cigarette smoking, physical activity, alcohol intake, C-reactive protein, and hypertension were independently associated with psychological distress. There were 223 incident CVD events (63 fatal) over an average follow-up of 7.2 years. The risk of CVD increased in relation to presence of psychological distress in age- and sex-adjusted models (hazard ratio: 1.54, 95% confidence interval: 1.09 to 2.18, p = 0.013). In models that were adjusted for potential mediators, behavioral factors explained the largest proportion of variance (∼65%), whereas pathophysiological factors accounted for a modest amount (C-reactive protein ∼5.5%, hypertension, ∼13%).

Conclusions The association between psychological distress and CVD risk is largely explained by behavioral processes. Therefore, treatment of psychological distress that aims to reduce CVD risk should primarily focus on health behavior change.

Key Words

The link between psychosocial stress and cardiovascular disease (CVD) has been identified as an important public health issue (1). The presence of psychological distress, measured with screening instruments such as the General Health Questionnaire, has been associated with incident CVD in several prospective cohort studies (2–5), with effect sizes that are comparable to conventional risk factors such as hypertension, obesity, and physical inactivity (6). The value of treating psychological distress using a range of modalities has therefore been an area of considerable interest and intense debate in clinical and research work in CVD (7).

Although the association between psychological distress and CVD risk is well established, the intermediate mechanisms are yet to be fully elucidated. Behavioral changes, such as increased smoking, reduced physical activity, and poor dietary habits may occur as an adaptation or coping response to psychological distress, thus are potentially important intermediate factors in disease processes (8). Psychosocial stress primarily activates the hypothalamic pituitary adrenocortical axis and sympathetic nervous system, which can trigger pathophysiological mechanisms that include inflammation, hemostasis, and altered metabolic and cardiac autonomic control (1). The behavioral and pathophysiological processes that operate between psychological distress and CVD events provide the key to understanding and treating psychological distress that aims to reduce CVD risk. These variables can be thought of as the “causes of the cause” in clinical and research work that starts with the assumption that psychological distress can cause an increase in CVD risk.

Because the mediating variables are many and varied, it is important that the relative contribution of behavioral and pathophysiological processes in accounting for the distress–CVD link be reliably established. This is particularly necessary given the very different treatment modalities that follow from a greater emphasis on either class of process, for example, behavior change and pharmacotherapy. These data would help establish priorities for the allocation of health care and research resources. To date, few studies have compared behavioral and pathophysiological processes in this way. Recent data from the British Whitehall II cohort have shown that traditional and novel CVD risk markers did not account for any of the association between psychological distress and incident coronary heart disease (CHD) (9). However, given that the results from this occupational cohort cannot be generalized to the wider population, it is important that this type of study is replicated in large, representative, community-based samples of asymptomatic adults, because the results will have far-reaching implications for public health efforts to reduce the disease burden of CVD associated with psychological distress.

We analyzed data from the Scottish Health Survey (SHS) to address the following questions: 1) how much of the association between psychological distress and CVD events can be explained by behavioral and pathophysiological processes; and 2) what is the relative contribution of behavioral and pathophysiological processes in explaining the link?

Methods

Participants and study design

The SHS is a periodic survey (typically every 3 to 5 years) that draws a nationally representative sample of the general population living in households. The sample was drawn using multistage stratified probability sampling with postcode sectors selected at the first stage and household addresses selected at the second stage. Different samples were drawn for each survey. The present analyses combined data from the 1998 and 2003 SHS in adults age 30 years and older. Participants from the different survey years were comparable in terms of demographics and risk factors. The overall response rate ranged between 60% and 76% for the different survey years, with approximately 63% of all eligible participants seeing a nurse. Participants gave full informed consent to participate in the study, and ethical approval was obtained from the London Research Ethics Council. Participants who declined the nurse visit or did not consent to blood being taken were excluded from the analyses (n = 4,776). Participants with existing CVD were also removed from the analyses (n = 156), leaving a final sample size of 6,576 (44.9% men, ages 50.9 ± 13.1 years). Excluded participants generally showed poorer health risk profiles with higher body mass index and a greater prevalence of hypertension, CVD, smoking, and psychological distress.

Baseline assessment

Survey interviewers visited eligible households and collected data on demographics, height, weight, and health behaviors (physical activity, smoking, alcohol intake). Physical activity questions inquired about participation in the 4 weeks before the interview. Frequency, duration, and intensity of participation was assessed across 3 domains of activity: leisure time sports (e.g., cycling, swimming, running, aerobics, dancing, and ball sports such as football and tennis), walking for any purpose, and domestic physical activity (e.g., heavy housework, home improvement activities, and manual and gardening work). The physical activity questionnaire has been validated against the output of accelerometers (worn for 2 nonconsecutive weeks over a 1-month period in 106 British adults). On a separate visit, nurses collected information on medical history, waist circumference, and blood samples from consenting adults. Detailed information on the survey method can be found elsewhere (10).

Predictor and outcome variables

Current mental health was assessed from the 12-item version of the General Health Questionnaire (GHQ-12), which is a measure of psychological distress devised for population studies. The questionnaire comprises 12 questions, asking informants about their general level of happiness, experience of depressive and anxiety symptoms, and sleep disturbance over the last 4 weeks. Interpretation of the answers is based on a 4-point response scale scored using a bimodal method (symptom present: not at all = 0, same as usual = 0, more than usual = 1, much more than usual = 1). The GHQ-12 is a highly validated instrument and has been strongly associated with various psychological disorders such as depression and anxiety (11). In the present sample, the GHQ-12 showed good internal reliability (Cronbach α = 0.896). We used a score of ≥4 to define psychological distress according to studies validating the GHQ-12 against standardized psychiatric interviews (12). In addition, we used the GHQ-12 score as a continuous variable to examine linear relationships with CVD events.

The main outcome was fatal or nonfatal cardiovascular events (including myocardial infarction [MI], coronary artery bypass, percutaneous coronary angioplasty, stroke, heart failure). This information was obtained from a patient-based database of CVD hospital admissions and deaths (Information Services Division Scotland) that was linked to the surveys. The Information Services Division database has shown 94% accuracy and 99% completeness when samples of computerized CVD records from the Scottish national database were compared with the original patient case notes. Mortality from cardiovascular causes was coded according to International Classification of Diseases Version 9 (390–459) and the International Classification of Diseases Version 10 (I01–I99). Data on CVD hospital admissions were available between 1980 and September 2006, which allowed us to exclude participants with existing CVD at baseline.

Biological risk markers

Peripheral blood was collected in citrate and serum tubes and spun at room temperature. All blood samples were frozen at −70°C until assay. The analysis of C-reactive protein (CRP) levels from serum was performed using the N Latex high-sensitivity CRP mono immunoassay on the Dade Behring Nephelometer II analyzer (Deerfield, Illinois). The limit of detection was 0.17 mg/l, and the coefficient of variation (CV) was <6% for this assay. Fibrinogen levels were determined using the Organon Teknika MDA 180 analyzer (Durham, North Carolina), using a modification of the Clauss thrombin clotting method, with a CV of <10%. Cholesterol and high-density lipoprotein (HDL) cholesterol were measured using cholesterol oxidase assays on an Olympus Diagnostics 640 analyzer (Tokyo, Japan). All analyses were carried out in the same laboratory according to standard operating procedures by state-registered Medical Laboratory Scientific Officers. Existing hypertension was confirmed from self-reported doctor's diagnosis. Obesity was defined as a body mass index ≥30 kg/m2 and central obesity as waist >102 cm in men and >88 cm in women.

Statistical methods

Cox proportional hazards models were used with months as the time scale to estimate the risk of cardiovascular events according to psychological distress. The data were censored to September 2006 in participants who survived. The proportional hazards assumption was examined by comparing the cumulative hazard plots grouped on exposure, although no appreciable violations were noted. In the basic multivariate model, we adjusted for potential confounders including age and sex. To test the extent to which behavioral and pathophysiological risk factors account for the association between psychological distress and CVD events, we grouped together CVD risk factors considered to be potential mediators on an a priori basis. This included behavioral factors (physical activity, smoking, alcohol), an inflammatory/hemostatic factor (CRP and fibrinogen), a metabolic factor (adiposity measures, cholesterol, HDL cholesterol), and a blood pressure factor (doctor-diagnosed hypertension). We initially adjusted for behaviors and then added pathophysiological factors into the model. The proportion of CVD risk reduction explained by each set of factors was estimated as follows: (HRbasic model − HRadjusted)/HRbasic model − 1) × 100 (13), where HR = hazard ratio. Health behaviors were entered as categorical variables: physical activity was categorized into 5 groups according to frequency of any activity lasting at least 30 min (reference group no activity, <1/week, 1 to 2/week, 3 to 4/week, ≥5/week); smoking was categorized into 4 groups (reference group never smoked, occasional ex-smokers, regular ex-smokers, current smokers); alcohol intake was quantified in units per week (1 U = one-half pint of beer, a small glass of wine, or a measure of spirits) and categorized into 3 sex-specific groups with nondrinkers assigned to the reference group and the highest intake group representing unsafe drinking levels (14+ U for women/21+ U for men). All blood variables were entered as categorical variables; cholesterol, HDL cholesterol, and fibrinogen as tertiles and CRP was categorized according to previously defined cut points (14), representing low-risk (<1 mg/l), medium-risk (1 to <3 mg/l), and high-risk (≥3 mg/l) groups. Analyses were also run entering risk markers as continuous values, although this did not appreciably alter the results. We used analysis of variance tests to examine continuous variables and chi-square tests to examine univariable relationships of the confounders with the exposure measure. We also performed multivariate logistic regression analyses to determine independent associations between the potential mediators and psychological distress. All analyses were performed using SPSS (version 14, SPSS Inc., Chicago, Illinois), and all tests of statistical significance were based on 2-sided probability.

Results

There were a total of 223 incident CVD events (63 fatal) over an average of 7.2 years of follow-up; CHD accounted for 62% of nonfatal events (n = 58 nonfatal MI, n = 15 coronary artery bypass graft, n = 26 percutaneous coronary angioplasty) and 66% of fatal CVD events. At baseline, 14.6% of participants showed psychological distress. Distressed participants were slightly younger, and were more likely to be female, to have poorer health behaviors, and to have higher levels of inflammatory and hemostatic markers and a greater prevalence of hypertension (Table 1). In multivariate analyses, age, sex, cigarette smoking, physical activity, alcohol intake, CRP, and hypertension remained significantly associated with psychological distress (Table 2). These factors were therefore retained for inclusion as potential mediators in modeling the association between psychological distress and incident CVD.

View this table:
Table 1

Descriptive Characteristics of Participants at Baseline by Psychological Distress

View this table:
Table 2

Multivariate Logistic Regression to Examine the Association of Psychological Distress With Behavioral and Pathophysiological Risk Factors

Psychologically distressed participants (GHQ-12 ≥4) were at a higher relative risk of CVD events during follow-up (Table 3). There was also a linear relationship between GHQ-12 score and CVD events, with each standard deviation (2.7) increment in GHQ-12 score being associated with a 7% increased risk (age- and sex-adjusted hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.03 to 1.12, p = 0.002). The addition of potential mediators substantially attenuated the association between psychological distress and risk of CVD events, with all factors collectively explaining an estimated 83.3% of the variance. When behavioral factors were modeled separately, smoking accounted for 40.7%, physical activity 22.3%, and alcohol <2% of the variance. The addition of pathophysiological factors accounted for a further modest proportion of the variance (hypertension explained 13.0%, and CRP 5.5%). When hypertension and CRP were modeled separately, 35.2% of the variance was explained (HR: 1.35, 95% CI: 0.96 to 1.91), although they accounted for only 18.5% of the variance after prior adjustment for behavioral risk factors.

View this table:
Table 3

The Extent to Which Behavioral and Pathophysiological Risk Factors Explain the Association Between Psychological Distress and CVD Events

In further analyses that were stratified by age and sex, there were similar effects of distress on CVD among men and women, although the effects were weaker in older participants (>65 years old) (HR: 1.32, 95% CI: 0.72 to 2.44, p = 0.372) compared with younger adults (HR: 1.63, 95% CI: 1.07 to 2.47, p = 0.023).

Several of the mediating factors were independently associated with CVD events, which included HDL cholesterol ≥1.5 mmol/l (HR: 0.66, 95% CI: 0.47 to 0.94, p = 0.022), CRP ≥3 mg/l (HR: 1.71, 95% CI: 1.09 to 2.68, p = 0.02), hypertension (HR: 2.07, 95% CI: 1.56 to 2.75, p < 0.001), smoking (HR: 2.51, 95% CI: 1.76 to 3.59, p < 0.001), and moderate physical activity levels (HR: 0.47, 95% CI: 0.29 to 0.76, p = 0.003).

There were a total of 247 deaths during follow-up, and there was a relationship between risk of all-cause mortality and psychological distress (HR: 1.88, 95% CI: 1.39 to 2.54) in models adjusted for age, sex, and social economic group. Adjustments for behavioral and pathophysiological risk factors significantly attenuated the association (HR: 1.36, 95% CI: 1.00 to 1.85), collectively explaining 59%.

Discussion

The present investigation confirms the results of previous studies that have shown a robust relationship between psychological distress and CVD risk (2–5). We observed similar associations between men and women, although weaker associations in older participants (>65 years old), which might reflect a greater presence of other age-related CVD risk factors that attenuate the effects of psychological distress. The main aim of the present study was to estimate the extent to which behavioral and pathophysiological factors explain the association between psychological distress and CVD events, which has not been widely examined. Our data suggest that the behavioral factors of smoking and physical activity made the largest contribution to increased risk, with CRP and hypertension making a modest contribution. Interestingly, pathophysiological factors accounted for a considerably lower proportion of the variance after prior adjustment for behavioral risk factors, which might reflect shared variance between these variables. For example, we have recently shown that in the present sample of participants, inflammation and hemostasis are associated with multiple modifiable CVD risk factors, including physical activity, smoking, obesity, and hypertension (15).

Psychological distress was associated with a higher prevalence of hypertension that partly mediated the greater risk of CVD events. Previous work suggests that anger, anxiety, and depression are predictors of hypertension (16), and acute psychological trauma such as terrorist attacks and earthquakes can produce profound and sustained increases in blood pressure (17,18). Because hypertension is a potent risk factor for CVD, it is therefore plausible that the association between psychological distress and CVD is partly mediated through this risk factor. To our knowledge there are a limited number of studies that have examined the role of novel biomarkers in accounting for the distress–CVD relationship. Data from the Whitehall II cohort suggested that inflammatory markers did not explain any of the association between psychological distress and incident CHD (9). Other studies that have directly measured depressive symptoms, one of the components of the GHQ-12, are also equivocal. For example, inflammatory markers (CRP and interleukin-6) and the metabolic syndrome explained approximately 17% and 7%, respectively, of the association between depression and CVD events in women with suspected coronary ischemia (19,20). And, in a previous case control study, various inflammatory markers did not explain any of the association between depressive symptoms and risk of CHD (21). Experimental research, however, underlines the effects of acute psychosocial stress on inflammatory responses (22), and these responses may be amplified by the presence of chronic psychosocial stress (23) and depressive symptoms (24). Acute stress also has been shown to activate nuclear factor kappa B in peripheral blood mononuclear cells and gene expression and protein production of several inflammatory cytokines that is dependent on stimulation of the sympathetic nervous system (25–27). The reliability of different measures may explain why behavior seemed to account for a considerably larger amount of the association between distress and CVD risk than biological factors. That is, biological factors measured from the blood, such as inflammatory markers, are generally estimated from a single sample that may be subject to considerable measurement error and may not reflect chronic levels.

Although the effectiveness of behavioral change and psychological stress reduction has been established clearly in basic research, the evidence to support the efficacy of such interventions that aim to prevent cardiovascular events is limited (7). In one of the largest trials of 2,481 MI patients suffering from depression and low perceived social support, treatment with cognitive behavior therapy had no effect on event-free survival after 29 months of follow-up despite significant improvement in depression and perceived social support (28). However, in a secondary analysis, self-reported exercise in the 6 months after MI was associated with more than a 50% reduction in the risk of subsequent death (29). Other recent data suggest that aggressive lipid lowering can minimize the increased risk of atherosclerotic progression in patients with depressive symptoms (30). These data therefore indicate that treating the intermediate processes, such as health behaviors and pathophysiological factors, is a key aspect of reducing distress-related CVD risk. Further research, however, is required to establish whether physical activity or inactivity, alcohol abuse, and smoking are more accurately conceived of as a set of depressogenic or anxiogenic behaviors or representative of the behavioral phenotype of individuals genetically predisposed to depression or anxiety.

Several limitations of the present study warrant consideration. We have assessed psychological distress only once at baseline, thus we cannot exclude the possibility that changes in distress over time could have influenced our results. Additionally, because the GHQ-12 was administered at the same time point as the measurement of behavioral and pathophysiological factors, we cannot establish the precise nature of the temporal relationship between these factors. For example, recent evidence suggests a bidirectional association between inflammation and depression (31,32). Nevertheless, our analysis supports the main criteria for mediation, that is, psychological distress was associated with behavioral and pathophysiological risk factors (potential mediators), the potential mediators predicted incident CVD, and psychological distress predicted incident CVD; this association was significantly attenuated after adjustment for the mediators. The GHQ-12 is a robust indicator of general psychological distress at a population level, although it cannot be used to distinguish the specific nature of the distress. The present results should therefore be interpreted with caution when making comparisons with studies that have directly assessed depression using standardized methods, and it will be necessary to replicate and extend our findings using more specific clinical assessments of anxiety and depression rather than relying solely on questionnaire scores. Several variables were assessed by self report; thus, it is possible that a more precise assessment of these factors may have affected the results. We were unable to assess all of the potentially important pathophysiological mediators, and these may have accounted for additional unexplained variance. For example, dysregulation of the hypothalamic pituitary adrenal axis, and altered hemodynamic and autonomic nervous system functioning have been implicated in stress and CVD risk (1). The study has notable strengths, including the availability of clinically confirmed CVD events, the exclusion of participants with pre-existing CVD at baseline, and the use of a nationally representative sample from Scotland. In summary, we have observed that pathophysiological and behavioral processes in particular partly explain the association between psychological distress and CVD events.

Footnotes

  • Drs. Hamer and Molloy receive grant funding from the British Heart Foundation, United Kingdom. Dr. Stamatakis receives grant funding from the National Institute for Health Research, United Kingdom. The Scottish Health Survey is funded by the Scottish Executive. The views expressed in this article are those of the authors and not necessarily of the funding bodies.

Abbreviations and Acronyms
CHD
coronary heart disease
CI
confidence interval
CRP
C-reactive protein
CV
coefficient of variation
CVD
cardiovascular disease
GHQ-12
12-item version of the General Health Questionnaire
HDL
high-density lipoprotein
HR
hazard ratio
MI
myocardial infarction
SHS
Scottish Health Survey
  • Received April 30, 2008.
  • Revision received July 23, 2008.
  • Accepted August 26, 2008.

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