Psychosocial risk factors affect disease processes via biobehavioral pathways, for example through unhealthy behaviors like smoking, inactivity or adverse dietary patterns with increased risk for obesity, hypertension and the metabolic syndrome, or through biologic characteristics like increased cardiovascular/neuroendocrine reactivity in response to acute or chronic stress, increased platelet activation, increased inflammatory cytokines or demonstrable progress in atherosclerosis. In patients with established cardiovascular disease, psychosocial factors can affect treatment adherence and lifestyle improvement.

Several studies indicate that adverse psychosocial factors are associated with higher levels of risk factors.^5–7 Chronic stress may be a contributory factor to a positive energy balance leading to obesity and to the metabolic syndrome, as prospective investigations in the Whitehall II cohort have shown.^8,9 However, associations between adverse risk factor patterns and psychosocial risk factors are not consistently found. For example, with respect to socioeconomic status, higher rates of current and ever smoking among less well-educated subjects were found in some but not all of 11 European countries investigated.¹⁰ In a Swedish study high occupational status was associated with better lipid levels and lower blood pressure in women, but not men.¹¹

By and large, two methods for investigating psychobiologic pathways are used: laboratory or clinical studies of acute physiologic stress responses, and observational studies involving the effect of chronic or recurrent psychosocial stimuli on morphology or physiologic function. An extensive literature in this area exists and has been reviewed,¹² with the conclusion that disturbed psychobiologic reactivity as in, for example, lower socioeconomic status adults is present for some stimuli but not others, and interactions need to be studied. One investigation cited, relevant to this, is the study by Everson et al in which progression of carotid atherosclerosis over 4 years was greatest among middle-aged men who were high stress responders, and had also been exposed to the chronic stress of high work place demands.¹³

Several other studies pertaining to stress tests in relation to other psychosocial factors have been published. Prolonged impairment of endothelial function was demonstrated to occur in healthy men after a brief episode of mental stress, potentially representing a link between stress and the atherogenic process.¹⁴ In 34 male survivors of acute myocardial infarction (AMI), platelet activation in response to a stress test was heightened in men who had stated acute negative emotion in the two hours before the event.¹⁵ Coronary flow velocity reserve was significantly reduced in healthy men during and after a mental stress test.¹⁶ A recent study investigating 22 healthy middle-aged men who underwent a mental stress test demonstrated significant changes in coagulation measures, indicating that stress may elicit a hypercoagulable state.¹⁷ These data corroborate an extensive earlier review which critically reviewed 68 articles, investigating psychosocial factors in both experimental and observational settings, with the conclusion that associations between psychologic factors and several coagulation and fibrinolysis variables provide a plausible biobehavioral link to coronary artery disease.¹⁸

Several observational studies have also investigated associations between psychosocial factors and putative pathophysiologic mediators. A Dutch study in 109 male white-collar workers investigated cardiovascular reactivity in relation to effort – reward imbalance and overcommitment (including inability to unwind after work). High imbalance was associated with a higher heart rate during work and directly after work, a higher systolic blood pressure during work and leisure time, and a lower 24-hour vagal tone.¹⁹

Following the results of early animal studies on psychosocial influences on atherosclerosis,²⁰ a recent US cross-sectional study, which investigated the effect of psychosocial measures on coronary calcification using electron beam tomography in 783 middle-aged men and women, found that indicators of social isolation were independently associated with elevated risk for the presence of calcification,²¹ whereas there was no independent association with socio-economic status. However, in a study of 155 healthy women with measures of positive and negative affect/cognitions, coronary calcification was unrelated to these measures whereas there was evidence of associations of psychosocial attributes with aortic calcification.²² Depressive symptoms, anger, anxiety, and chronic stress burden were not associated with coronary calcification in asymptomatic adults.²³

The effects of acute psychologic stress on circulating inflammatory factors in humans have been reviewed in a meta-analysis suggesting a modest increase in circulating inflammatory markers following laboratory-induced psychologic stress.²⁴ Additionally, in a recent overview, potential additional mechanisms for the association between stress and cardiovascular morbidity were extensively reviewed.²⁵

In a systematic review updated until 2001, aiming to assess the relative strength of the epidemiologic evidence for causal links between psychosocial factors and CHD incidence among healthy populations, and prognosis among CHD patients, over 100 prospective cohort studies were included.²⁶ A previous systematic review, by the same team of researchers, was published in 1999.² For inclusion, papers had to meet four quality criteria relating to design, size, psychosocial variable specification and outcomes. Only prospective studies were accepted and they had to include at least 500 participants (etiologic studies in healthy populations) or 100 participants (for prognosis in patients with established CHD). Psychosocial factors were included if they were reported in at least two eligible study populations. In this review, unspecified “stress” was not included because it was considered too vague to be informative. Valid outcomes were limited to fatal CHD, sudden cardiac death, non-fatal myocardial infarction (MI), incident angina, incident heart failure and all-cause mortality (for prognostic studies only). In the first review,² 65 papers were included while the updated review identified an additional 71 papers, of which 41 were published between 1998 and June 2001. The factors evaluated were type A behavior pattern and hostility, depression, anxiety and distress, and psychosocial work characteristics.

With respect to type A behavior and hostility, both eliciting much interest because of early positive reports from North American populations,^27,28 18 prospective studies were included in the review. The majority (12/18) of the studies did not support type A/hostility as a risk factor, and the studies did not show hostility alone to be a risk factor either. Whether type A might predict incident CHD was again investigated in a more recent study in middle-aged men. Over a nine-year follow-up, there was no overall increased risk of CHD associated with any type A score, but further analysis showed an increase in risk over the first five-year period and a decreased risk between five and nine years, indicating that type A may be a potential trigger, rather than affecting the process of atherosclerosis.²⁹ Other personality types incude type D personality, a construct which has not been widely studied as a potential risk factor but which nevertheless has attracted attention. Type D personality is characterized by a propensity for experiencing negative emotions, while simultaneously inhibiting these emotions in social contacts with others.^30,31 Although potentially indicating worse prognosis in cardiac patients, there are no data to support that type D personality predicts cardiovascular events in healthy populations.

In a systematic search of the literature on depression and risk of CHD to May 2000, Rugulies identified 11 studies.³² Depression was associated with a significant increased risk of CHD in seven of the 11 studies, with clinical depression a stronger and more consistent predictor than depressive mood. A subsequent systematic review by Kuper et al found 22 prospective studies which investigated the association between depression and CHD in healthy populations.²⁶ Roughly one-third found no clear association, with the rest finding moderate or strong effects. There was no apparent difference in strength of association between studies with shorter or longer follow-up, indicating that findings from studies with shorter follow-up were probably not confounded by early disease causing depression. In another, more recent systematic review of studies of depression as a risk factor for coronary disease in people without clinical evidence of prior heart disease and with at least four years follow-up, and which also controlled for other major coronary disease risk factors, 10 studies met inclusion criteria. Nine reported significantly increased risk, including two with mixed results; one study reported no increased risk. The combined overall relative risk of depression for the onset of coronary disease was 1.64.³³ Since this review appeared, additional studies have been published, further supporting depression as a risk factor for CHD.^34,35 A concept which is related to depression, but where there is little conclusive evidence for effects over and above depression, or pre-existing disease, is vital exhaustion.^36,37

Anxiety and/or stress were investigated in eight studies identified by Kuper et al, with inconsistent results, and studies with longer follow-up less likely to find an association.²⁶ Other than these, the INTERHEART Study, the largest study reported so far, which used a case – control design in 11 119 patients with a first MI from 52 countries and 13 648 controls matched for age, sex, and region, found that stress was more commonly reported by cases than by controls.³⁸ Psychosocial stress during the previous 12 months was assessed with two single-item questions about stress at work and stress at home. In these questions stress was defined as feeling irritable or anxious, or as having disturbed sleep because of conditions at home or at work. Compared with controls, cases reported more frequent periods of stress at home during the previous 12 months as well as more frequent periods of stress at work.

This study is limited because of the retrospective case – control design, where cases were interviewed during hospitalization following an acute MI and were asked to report on psychosocial risks during the 12 months before the event. However, prospective studies using similar questions on self-perceived stress have also been performed, providing additional, albeit moderate, support for the contention that stress is related to CHD. One study, using the same question as in INTERHEART, found self-perceived stress to predict CHD as well as cardiovascular mortality over a 12-year follow-up period from baseline,³⁹ with an odds ratio of 1.7 for cardiovascular disease (CVD) death after adjustment for occupational class and other relevant risk factors, although the predictive power for CHD incidence waned after two decades.⁴⁰

Number of work stressors has been associated with increased cardiovascular mortality in the Multiple Risk Factor Intervention Trial.⁴¹ During a nine-year follow-up of 12 336 men, those with three or more work stressors had an increased risk of CVD death of 26%, while the experience of divorce increased risk by 33%. Similar results were observed in a large prospective study involving 281 cases in 73 424 Japanese men and women.⁴² An extreme stressor, such as the death of a child, was associated with an increased risk of MI in parents, particularly for fatal MI.⁴³ Even so, there are also several studies with no or very limited relation between various measures of stress and CHD^44–46 and the concept of stress as an independent risk factor has also been criticized on the grounds that self-reported stress is related to health-related behaviors and largely due to confounding by socioeconomic position⁴⁷ or by a greater propensity to report symptoms and to be hospitalized.⁴⁸

The review of studies on work stress presented a particular challenge because of the wide variety of measures and lack of standardization. However, of the 13 etiologic studies reviewed by Kuper et al, only three did not find a clear association, whereas 10 were moderately supportive, supportive for at least a subset or showed strong evidence for an effect of work stress on incidence of CHD.²⁶ Several studies have been added to the literature since this review. Within the Whitehall II Study, a ratio of high efforts to rewards predicted higher risk of CHD, though only modestly so.⁴⁹ In a multinational study of six European cohorts from four European countries (Belgium, France, Spain and Sweden) consisting of 21111 middle-aged male subjects, the Karasek job strain model of psychologic demands was used.⁵⁰ This model emerged as a moderate but independent predictor of acute coronary events. Recent findings from the Framingham Offspring Study did not, however, support high job strain as a significant risk factor for CHD in men or women.⁵¹ Possibly, effects for women differ from those for men, with recent prospective studies not showing a relation between job stress and CHD for women.^52,53

Social supports and networks relate to the number and quality of a person’ s social contacts, including emotional support. Heterogeneous approaches have been used to measure this construct. The systematic review by Kuper et al included nine studies, with three not showing an association, four moderately supportive, and two strongly supportive.²⁶ In one of the latter, a subsequent follow-up found that both social integration and emotional support protected against CHD over an extended follow-up of 15 years.⁵⁴ In a prospective cohort study of 9011 British civil servants, negative aspects of close relationships were weakly but independently associated with future CHD events, including angina pectoris, over a 12-year follow-up period.⁵⁵ Further confirmation for the role of social support is provided in a review by Lett et al,⁵⁶ although more research is needed to determine which types of functional and structural support are most strongly related to outcome.

There is a large body of literature concerning socioeco-nomic status (SES) and coronary heart disease. A much-cited review published in 1993⁵⁷ indicated that there is a substantial body of evidence for a consistent relation between SES and the incidence and prevalence of cardiovascular disease, secular trends in cardiovascular mortality, survival with cardiovascular disease, and the prevalence of cardiovascular risk factors. By and large, more recent findings have not challenged these conclusions, at least not for Western populations.

There are several ways of measuring SES, with education, income, and occupational position most often used, but there is an increasing awareness that these variables cannot be used interchangeably.⁵⁸ In a study using Swedish and German register data, correlations between education, income, and occupational class were only low to moderate.⁵⁹ Which of these yielded the strongest effects on health depended on the type of health outcome in question. MI morbidity and mortality showed a mixed picture, with steeper gradients in the German than in the Swedish population. In mutually adjusted analyses each social dimension had an independent effect on each health outcome in both countries. The authors concluded that treating education, income, and occupational class as indicators of the same fundamental cause will understate their independent and distinct contributions to health.

Because there are differences in the distribution of risk factors, there has been a debate whether the effect of SES merely reflects these differences or whether there is an independent effect.^60,61