• Chronic coronary disease
• Epidemiology

Psychological distress is increasingly being recognised as a risk factor for cardiovascular disease. In the past, psychological distress has been investigated as a contributor to the development of coronary heart disease (CHD), as a trigger for acute coronary events or as a prognostic factor following acute events, usually acute myocardial infarction.1 In the INTERHEART (Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) study, individuals who reported psychological distress (at home, at work or both) and those who were under financial stress or had stressful life events were at increased risk of an acute myocardial infarction with an effect size (for severe stress) comparable to that of arterial hypertension or abdominal obesity.2 A recent individual participant pooled analysis of 10 prospective cohort studies with 68 222 participants living in England and free of CHD (at entry) showed a dose–response association between psychological distress and the risk of overall and cardiovascular mortality.3 In a cohort of 4204 patients with acute myocardial infarction, moderate-to-high psychological stress was associated with higher 2-year mortality compared with those having low levels of stress and the association persisted after adjustment for a wide range of potential confounders.4 The increased risk associated with stress was evident despite the fact that patients with increased perceived stress had less cardiovascular risk, potentially suggesting that psychological distress per se contributes to the poor prognosis.4

Despite epidemiological and other lines of evidence linking psychological distress with the risk of coronary events or mortality, many aspects of the association between psychological distress and these outcomes remain poorly investigated. Psychological distress is multifactorial and reaction to exposure and consequently perceived stress differs widely across the individuals. The assessment of psychological distress and CHD or outcome is commonly based on self-reporting whose accuracy depends on recall bias and other factors. Many studies that have investigated the association of psychological distress with CHD or prognosis have included subjects/patients close to an acute event (usually acute myocardial infarction) and were based on a single assessment of depression (or anxiety). In studies that have investigated the association of sustained psychological distress with CHD or prognosis, the definition of stress as chronic or persistent was highly variable. Concerns have also been raised that the association of psychological distress with mortality is attenuated at longer follow-up.3

In their Heart publication, Stewart et al 5 investigated the association between occasional or persistent psychological distress and mortality in 950 subjects with stable CHD obtained from the Long-Term Intervention with Pravastatin in Ischemic Disease trial. All included patients completed the General Health Questionnaire-30 (GHQ-30) at least four times over a 4-year stress assessment period. Psychological distress was stratified according to the level and duration as follows: never distressed, sometimes any severity, persistent mild and persistent moderate distress. The outcome (all-cause or cardiovascular mortality) was assessed over a median of 12.1 years. Persistent moderate or more severe distress was observed in 3.7% of the subjects. This subgroup had an almost four times higher adjusted risk for cardiovascular mortality and an almost three times higher adjusted risk for all-cause mortality compared with subjects with no distress. Subjects belonging to the persistent mild distress category (7.7%) and those showing stress on one or two occasions (26.8%) did not have an increased risk of cardiovascular or all-cause mortality.

The authors are to be commended for this important and elaborative study which helps to uncover the intricate relationship between psychological distress and cardiovascular disease. The study seems to be unique with respect to the subjects investigated (the largest group of patients with CHD), the multiple psychological distress assessment over an extended period and the long-term follow-up. All these indicate a dedicated and laborious work. Furthermore, the study included a well-characterised cohort of subjects in terms of presence of CHD which excludes any confounding effect caused by self-reporting of the disease and focused on an outcome (mortality) that has the highest probability of being correctly documented and reported.

As the authors do well to emphasize, the study has limitations related to the observational design which leaves the question of causality in the relationship between distress and mortality unanswered, was based on the GHQ-30, which although robust cannot distinguish the specific nature of distress, excludes items related to physical illness and is no longer widely used as a stress screening device. Moreover they did not account for the impact of traumatic life events, excluded subjects who died at the time of stress assessment potentially underestimating the association between stress and mortality and could not rule out under-adjustment and consequently residual confounding. The inclusion of a limited number of participants and not accounting for the socioeconomic level—known to amplify the impact of psychological distress on the health—should also be mentioned. Of note, the inclusion of psychological distress in multivariable models only marginally improved the discriminatory power of the models with respect to mortality prediction. Although undesirable, these limitations do not compromise the main findings of the study.

Mechanisms linking psychological distress with CHD disease or mortality are known.1 6 Psychological distress may affect CHD or the outcome of subjects with CHD in at least two ways. First, psychological distress activates the sympathetic system and hypothalamic–pituitary–adrenal axis leading to increased levels of catecholamines and cortisol. Psychological distress, particularly if of high level and prolonged duration, generates a metabolic syndrome-like state consisting of elevated blood pressure, unfavourable lipid profile, elevated levels of C-reactive protein and inflammatory cytokines, endothelial dysfunction, increased platelet activation and prothrombotic state, insulin resistance and activation of nuclear factors leading to gene expression for atherogenic factors. Second, psychological distress produces an unhealthy behaviour response with distressed subjects being less likely to quit smoking or drinking and more likely to become physically inactive, overweight or develop diabetes.7

The question on how psychological distress over a 4-year period impacts on subsequent 12-year mortality deserves commenting. One possibility is that CHD with its tendency to worsen over time is the main source of continuing stress and increased risk of mortality in the subsequent years. In fact, CHD and cardiovascular risk factors are important for the development of long-lasting psychological distress.8 Another hypothesis posits that persistent or recurrent psychological distress leads to permanent alterations in the stress-regulatory systems perpetuating increased cardiometabolic risk even in the absence of stressor itself.9 Repeat episodes of depression have a more robust impact on C-reactive protein than isolated ones.10 In the same vein, persistent psychological distress during the life course was associated with a worse cardiometabolic profile compared with distress occurring in childhood or adulthood alone.11

The question of reverse causality looms largely in studies investigating the association between psychological distress and CHD. The possibility is real that CHD itself is the source of distress and a determinant of poor outcome. In fact, in the study by Stewart et al, 5 angina and dyspnoea increased progressively with the increase in the level of distress. Commonly, these symptoms are perceived as worrisome (and stressful) and as a harbinger of imminent risk (including the risk of death) in subjects experiencing them. Although of particular concern and hard to rule out, reverse causality is not entirely devastating for the association between psychological distress and mortality in patients with CHD. Regardless of the origin of distress, from CHD itself or from external sources, when present, psychological distress aggravates the existing disease and predisposes to a poorer outcome.

The study by Stewart et al 5 found an increased risk of mortality only in subjects in the category of persistent moderate-to-high distress but not in subjects in lower distress categories. These results are not easy to reconcile with prior studies showing a dose–response relationship across all stress strata in which even low levels of stress were associated with increased risk of mortality.3 Nevertheless, some putative explanations may be offered. First, it may be that only advanced and highly symptomatic CHD, but not CHD forms having few or minor symptoms generate high psychological distress. Reasonably, subjects with more severe forms of CHD are at higher risk of mortality compared with subjects having less severe forms of the disease. Second, the study subjects were under secondary prevention measures including statin therapy. Aggressive lipid-lowering therapy can minimise the increased risk of atherosclerosis progression in subjects with depressive symptoms.12 Thus, statin therapy and other secondary prevention measures may have attenuated the association between distress and mortality in low-risk (and less distressed) subjects.

The study by Stewart et al 5 is important for clinicians and healthcare providers. As psychological distress may be dismissed as a reaction to the diagnosis of a serious event like acute myocardial infarction, the study draws attention to screening and eventually treating psychological distress over extended time intervals in patients with stable CHD. The study suggests that persistent psychological distress needs to be addressed with multistep interventions. Clinicians should make the screening of psychological distress, a constituent part of the routine assessment of patients with CHD. Strict implementation of secondary prevention measures and referral of distressed subjects to mental health professionals to strengthen their stress-coping aptitude should be included in the strategy of care, principally for subjects with CHD and persistent moderate-to-high distress.