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Psychosocial factors in coronary and cerebral vascular disease

Author: Geoffrey H Tofler, MD
Section Editor: Jonathan M Silver, MD
Deputy Editor: David Solomon, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2019. | This topic last updated: Aug 09, 2019.

INTRODUCTION

Although recent attention has focused on the role of psychosocial factors in the acute precipitation of
myocardial infarction and sudden cardiac death, psychosocial factors may also contribute to the early
development of atherosclerosis [1]. The link between psychologic stress and atherosclerosis may be
both direct, via damage of the endothelium, and indirect, via aggravation of traditional risk factors
such as smoking, hypertension, and lipid metabolism.

Unfortunately, human studies of stress and coronary atherosclerosis have been limited in scope, due
primarily to the difficulty in quantifying the degree of atherosclerosis in asymptomatic subjects. Thus,
although angiographic data suggest that more extensive atherosclerosis is seen in patients with type
A personality [2], confounding issues limit the interpretation. Stronger epidemiologic studies have
linked psychosocial factors such as bereavement, loss of job, and depression with hard end points
such as myocardial infarction and sudden death [3]. One study which followed 1592 men and women
for five years reported that the personality trait of submissiveness, a marker for type B behavior, was
protective against nonfatal and total myocardial infarction, particularly in women (relative risk 0.59
and 0.69, respectively) [4].

Depression screening — Depression is associated with increased morbidity and mortality in patients

with established coronary heart disease. We agree with the 2008 American Heart Association
scientific advisory on Depression and Coronary Heart Disease which recommends screening for
depressive symptoms in such patients [5]. (See "Screening for depression in adults".)

STUDIES IN ANIMALS
The best insights into the role of psychological stress in atherosclerosis come from animal studies, in
particular a series of experiments using cynomolgus monkeys [6]. When fed a diet sufficiently rich in
saturated fat and cholesterol, these monkeys develop atherosclerosis very rapidly with lesions similar
to those seen in humans. Also similar to humans, premenopausal female monkeys are relatively
protected from atherosclerosis.

These animals display complex patterns of social interaction characterized by hierarchies of

dominant (aggressive) and subordinate (submissive) animals. Since the monkeys respond
aggressively to new animals attempting to join their social groupings, the placement of strangers
within groups forms the basis for a stressful challenge.

As an initial experiment, 30 animals consumed an atherogenic diet for 22 months [7]. Half of the
animals were placed in a stable environment while the other half were moved to new animal groups
at one to three month intervals. Animals placed in the latter unstable environment displayed more
extreme versions of their behavior. When the coronary arteries were examined at the end of the study,
the aggressive animals in the unstable group had more extensive atherosclerosis than did any of the
other groups. The development of atherosclerosis was independent of differences in serum
cholesterol or triglycerides or blood pressure. Even in normolipemic animals, there was more
atherosclerosis in the aggressive animals that were placed in the disrupted social environment. In
addition, the arteries of animals housed in an unstable social environment displayed more coronary
vasoconstriction than those in a stable environment [8].

The investigators next evaluated the effect of heart rate reactivity to a standardized stress: displaying
a large monkey catch-glove in a prominent and threatening manner [9]. Based on heart rate response,
the animals were divided into high and low reactors. The high heart reactors had intimal lesions that
were twice as extensive as those seen in low-reactors. In a later report, the administration of
propranolol, in doses that produced a 20 percent reduction in heart rate, resulted in significantly less
atherosclerosis [10].

Another series of studies in rabbits with a genetic defect that results in spontaneous atherosclerosis
also found that the social environment affected the progression of atherosclerosis [11].

STUDIES IN HUMANS

Human studies demonstrate an association between type A personality and exaggerated

cardiovascular responses when the subjects are exposed to frustrating laboratory tasks [12]. While
studies have suggested a larger pressor response to stress among patients with cardiovascular
disease [12-14], the link between hyperreactivity and cardiovascular disease has not yet been
convincingly made. One of the few completed prospective studies of reactivity and disease prediction
found that diastolic blood pressure responses to a cold pressor test were significantly related to the
development of coronary heart disease 23 years later [15].

Among patients with coronary artery disease, myocardial ischemia that occurs in response to mental
stress is associated with subsequent adverse events. A meta-analysis pooled results from five
observational studies in which patients with stable coronary artery disease (n = 555) were tested in a
laboratory for mental stress induced myocardial ischemia and then followed prospectively [16]. The
risk of subsequent coronary artery disease events (eg, myocardial infarction or unstable angina) or
mortality was two times greater in patients with mental stress induced myocardial ischemia.

Development of coronary disease — The association between psychosocial factors and the presence
of asymptomatic coronary heart disease is uncertain. One study evaluated 630 active-duty army
personnel, aged 38 to 45, without known coronary disease who underwent electron beam computed
tomography; there was no correlation between the presence of coronary artery calcification and prior
or current psychiatric disorders, such as anxiety, hostility, and stress [17]. (See "Diagnostic and
prognostic implications of coronary artery calcification".)

In contrast, another study of 1305 men with a mean age of 62 found that symptomatic depression, as
measured by the Minnesota Multiphasic Personality Inventory, was associated with an increased risk
of coronary heart disease and angina pectoris [18].

Other personality traits and affective disorders may be associated with the development of coronary
heart disease [19,20]. The Normative Aging Study followed 1305 men of a mean age of 62 who were
free of coronary heart disease and completed the Minnesota Multiphasic Personality Inventory [18].
After a mean follow-up of 7 to 8 years, those with the highest level of depression, anger, or social
competitiveness (dominance) had an increased risk of coronary heart disease, including nonfatal
infarction and coronary death, compared to those with the lowest levels of these traits (multivariate
adjusted relative risk of 1.46, 3.15, and 1.8, respectively) [18,21,22].

Anger in response to stress may be of particular importance for the development of premature
cardiovascular disease in young men. This issue was addressed in a longitudinal study of 1055 male
medical students that documented anger reactions to stress by self-reporting on a questionnaire
administered in medical school [23]. After a median follow-up of 36 years, those with the highest level
of anger, compared to those with lower levels, had a significant increased risk of premature
cardiovascular disease developing before the age of 55 (adjusted relative risk 3.1), coronary heart
disease (adjusted relative risk 3.5), and myocardial infarction (relative risk 6.4). (See "Coronary heart
disease and myocardial infarction in young men and women".)

The association of psychosocial factors and coronary heart disease may be especially prominent in
individuals at high risk for the development of coronary disease. As an example, the Family Heart
study of 2300 subjects at high risk, based upon the age of onset of coronary heart disease in
biologically related family members, found that, after controlling for other risk factors, hostility was
associated with a history of revascularization in high risk men (odds ratio 1.21) and a history of
myocardial infarction in high risk women (odds ratio 1.39) [24]. A high degree of social support
reduced the odds of a myocardial infarction in high risk women (odds ratio 0.76), but not in high risk
men. There was no association between these outcome and hostility or social support in a random
sample of 2447 individuals.

Coronary heart disease symptoms — There is an association between psychosocial factors and the
presence of symptomatic coronary disease. Mental stress-induced angina results from an increase in
heart rate and blood pressure, which increases cardiac demand, and coronary vasoconstriction,
which reduces coronary blood flow and myocardial oxygen supply [25]. Several clinical studies
illustrate the effects on cardiac symptoms and quality of life. Two approaches have been used: the
frequency of stress in patients who have angina and the frequency of angina in patients with
depression.

● One prospective study compared psychosocial variables in 767 patients who had chronic stable
angina with 50 healthy subjects [26]. The patients with angina experienced more stressful events,
more frequently suffered from disturbed and psychosomatic symptoms, and had higher scores
for hostility and lower levels of over-all well-being. These psychosocial findings were more
common among women than men, although women had less type A behavior and hostility.

● In a review of 1024 patients with stable CHD, 201 had depressive symptoms [27]. Patients with
depressive symptoms were significantly more likely than those without such symptoms to report
monthly or more frequent angina, physical activity limitation, diminished quality of life, and fair to
poor overall health. In contrast to the correlation of depression with these symptom indices,
there was no correlation of either ejection fraction or stress echocardiographic evidence of
ischemia with reported symptom status.

● Similar findings were noted in a series of 1282 patients with coronary heart disease who
completed a Mental Health Inventory and the Seattle Angina Questionnaire [28,29]. Depression
was associated with significantly more frequent angina, physical limitation, less treatment
satisfaction, and a lower perceived quality of life [28,29].

Progression of coronary heart disease — Psychosocial factors may also be important for the
progression of atherosclerosis in patients with documented coronary disease. As an example, one
study of 162 patients who underwent angiography at baseline and after two years found that only
those who had low emotional social support and also expressed anger outwardly were at an
increased risk for the progression of coronary heart disease (odds ratio 30); this association was
independent of medication or other risk factors [30]. In a second study of 292 middle aged women
hospitalized for an acute coronary event and followed for five years, the presence of two or more
depressive symptoms and the lack of social integration were independent predictors of recurrent
cardiac events, including death, myocardial infarction, and revascularization (hazard ratio 1.9 and 2.3
compared to those without these features) [31].

Cardiovascular mortality — Psychosocial factors can contribute to cardiovascular mortality. The

potential magnitude of this effect is illustrated by the following observations:

● The Cardiovascular Health Study of 5201 men and women ≥65 years of age who were followed
for six years found that a high level of depression was associated with a significant increase in
mortality (24 versus 18 percent for low level of depression, adjusted relative risk 1.24) [32].

● Using data from the EPIC-Norfolk United Kingdom Prospective cohort study, the relationship
between death from ischemic heart disease and major depressive disorder was evaluated in over
19,000 men and women initially free of coronary heart disease [33]. After a median follow-up
period of 8.5 years, participants who had major depression in the year prior to enrollment were
2.7 times more likely to die from ischemic heart disease after adjustment for traditional and
other sociodemographic risk factors.

Outcome after CABG — The prevalence of depression after coronary artery bypass graft (CABG)
surgery is 20 to 40 percent and its presence is associated with a poorer outcome after CABG [34-37].
(See "Coronary artery bypass graft surgery: Graft choices".)

The following reports illustrate the range of findings:

● A prospective study of 309 patients, followed for one year after CABG, found that cardiac events
(angina, heart failure, myocardial infarction, cardiac arrest, need for repeat revascularization, and
cardiac mortality) were more common in those with a major depressive disorder (27 versus 10
percent without depression, adjusted risk ratio 2.3) [35].

● A larger prospective analysis of 817 patients followed for a longer interval (five years)
demonstrated an effect of depression on survival [36]. There were 122 deaths (15 percent). The
all-cause mortality rate was higher for patients with moderate to severe depression at baseline
(adjusted hazard ratio 2.4) and for patients with depression of any degree that persisted for six
months (adjusted hazard ratio 2.2).

Carotid artery atherosclerosis — Psychosocial stress may also be associated with the development
of carotid artery atherosclerosis. This issue was examined in the Family Health study of 3617
subjects judged to be high risk, based upon the age of onset of coronary heart disease in biologically
related family members [38]. After adjusting for other risk factors, hostility alone or associated with
low social support increased the odds of carotid lesions in high risk women (odds ratio 1.18 and 1.47,
respectively), but not high risk men or 1026 subjects at low to medium coronary heart disease risk.

Stroke — Depression may be a risk factor for stroke. After adjusting for potential confounding factors
such as smoking and hypertension, a meta-analysis of 17 prospective community or population
studies (206,641 participants, including 6086 cases of stroke) found that stroke occurred in
significantly more participants who were depressed than those not depressed (relative risk 1.3, 95%
CI 1.2-1.5) [39]. Other meta-analyses have also found that depression is associated with a
significantly increased risk of stroke [40].

PATHOPHYSIOLOGY

A brief period of mental stress, similar to that occurring in everyday life, can cause transient
endothelial dysfunction in young healthy individuals without evidence of vascular disease or risk
factors for cardiovascular disease [41,42]. The endothelial dysfunction appears to be mediated by
endothelin, since it can be prevented by a selective endothelin-A receptor antagonist [42], and lasts
for as long as one to four hours [41,42].

Psychological stress, perhaps via activation of the hypothalamic, pituitary and adrenocortical axis,
also produces endothelial injury in animals, an important first step in the generation of
atherosclerosis [43-45]. As an example, an increase in hemodynamic turbulence promotes endothelial
injury in the coronary arteries, particularly at branch points. Damage to the endothelium will promote
the movement of lipoproteins from the circulation to the artery wall, platelet aggregation, and the
release of growth factors that further stimulate atherogenesis.

In addition to the hemodynamic effects of increased sympathetic tone, other factors may contribute
to the endothelial injury associated with stress:

● Cortisol may play a potentiating role on vasoconstriction induced by catecholamines [46]

● The serotoninergic system may modulate sympathetic activity [47]
● Mental stress and increased exposure to epinephrine can lead to platelet activation and
deposition [48-50]
● Psychologic stress can modify macrophage activity and the inflammatory response [51]
● Hypertensive, but not hypercholesterolemic patients, have impaired nitric oxide-dependent
vasodilation during mental stress [52]

Effect on risk factors — Psychosocial factors may also promote atherosclerosis via an effect on
traditional risk factors. As examples, cigarette smokers typically increase their consumption in
response to stress, and the serum cholesterol levels have been shown to rise in stressful situations
[53-55]. The increases range from 8 to 65 percent in situations such as the preparation of tax returns
in April by accountants, the taking of examinations by students, and following job loss or significant
life events [55].

These data suggest an interaction between diet and the stressor. The cholesterol increase may result
from free fatty acid mobilization induced by epinephrine [56].

There is also a correlation between high blood pressure and psychosocial variables of a stressful
nature, such as job loss and demanding occupations. The animal literature provides more compelling
evidence for sustained hypertension resulting from emotional stress [57]. Although an increase in
blood pressure in response to stress is well described in humans, the change tends to return to
normal following removal of the stress [58].

However, a more prolonged response may be seen in those with a genetic predisposition to
hypertension. As an example, individuals with a family history of hypertension show exaggerated
cardiovascular responsiveness to stressors when compared to those with normotensive parents.
Furthermore, hyperreactivity may be a marker for individuals at increased risk for developing
hypertension. The mechanism of the rise in pressure may be related to the increased plasma
catecholamines that have been shown in some hypertensives.

Association with inflammation — The association between inflammatory markers associated with

CHD, such as serum C-reactive protein and interleukin (IL)-6, was evaluated in a report from the
PRIME study of healthy, middle-aged men [59]. The 335 men who subsequently developed CHD were
compared to matched controls. The odds ratio of depressive mood for CHD was 1.35 on univariate
analysis. The depressed men had higher levels of inflammatory markers; however, after adjustment
for these markers, depression was still associated with CHD.

INTERVENTIONS

Although medications such as beta blockers and psychosocial interventions can reduce the
physiologic response to some forms of stress, there are no convincing data on their ability alone to
prevent or regress atherosclerosis in humans. Therefore it would be difficult to justify these
interventions for purposes of prevention of atherosclerosis. However, in patients with known coronary
disease, the cardioprotective effect of beta blockers with regard to myocardial infarction and sudden
cardiac death may be due in part to a diminution of catecholamine and hemodynamic-induced
endothelial damage and a raising of the threshold for ventricular fibrillation. (See "Psychosocial
factors in acute myocardial infarction".)
In patients at risk for cardiovascular events who are under increased psychosocial stress, a stress
management program can be considered as part of an overall preventive strategy. In general the goal
of a stress management program is to reduce the impact in the individual of stressful environmental
events and to better regulate the stress response. Interventions may be considered at several levels
[60]:

● Removal or alteration of the stressor

● Change in perception of the stressful event
● Reduction in the physiologic sequelae of stress
● Use of alternative coping strategies

Stress management techniques typically include components of muscular relaxation, a quiet

environment, passive attitude, and deep breathing with the repetition of a word or phrase. Skills
training is also performed, and involves instruction in acquisition of skills to reduce the affective,
behavioral, and cognitive components of stress [61]. The physiologic changes produced include a
decrease in oxygen consumption, reduced heart rate and respiratory rate and passive attitude and
muscular relaxation. Such changes are consistent with a decrease in sympathetic nervous system
activity.

The potential efficacy of stress management was illustrated in a randomized trial of 134 patients with
stable ischemic heart disease and exercise-induced ischemia [61]. The patients were assigned to
usual medical care alone, with exercise training for 35 minutes three times per week, or with 1.5 hours
of stress management training for 16 weeks. Compared to usual care, the following significant
benefits were noted with active intervention:

● A reduction in depression scores

● A reduction in self-reported measures of general distress
● A smaller reduction in left ventricular ejection fraction during mental stress testing
● A lower mean wall motion abnormality score in patients with significant stress-induced wall
motion abnormalities at baseline

Other measures, such as relaxation techniques and biofeedback, can produce a small reduction in
blood pressure of 5 to 10 mmHg in some patients [62-64]. Behavior modification programs are also
an important adjunct to smoking cessation and have been associated with a reduction in cigarette
consumption [65]. Modifications of type A personality have been less well studied, but behavior
modification or exercise programs may be of benefit [66,67]. Improvements in compliance with
medication regimens may be an additional benefit from stress reduction program [60].

SUMMARY AND RECOMMENDATIONS

● Psychosocial factors may possibly contribute to the early development of atherosclerosis. The
link between psychologic stress and atherosclerosis may be both direct, via damage of the
endothelium, and indirect, via aggravation of traditional risk factors such as smoking,
hypertension, and lipid metabolism. (See 'Introduction' above.)

● Evidence about the association between psychosocial factors and the presence of
asymptomatic coronary heart disease is mixed. Some studies suggest a possible link between
depression, anger, or social competitiveness (dominance) and an increased risk of coronary
heart disease, especially in individuals at high risk for the development of coronary disease by
virtue of other factors, such as family history. (See 'Development of coronary disease' above.)

● There is an association between psychosocial factors and the presence of symptomatic

coronary disease. Mental stress-induced angina results from an increase in heart rate and blood
pressure, which increases cardiac demand, and coronary vasoconstriction, which reduces
coronary blood flow and myocardial oxygen, supply. (See 'Coronary heart disease symptoms'
above.)

● Psychosocial factors may be associated with the progression of atherosclerosis in patients with
documented coronary disease, cardiovascular mortality, poorer outcome after CABG, and the
development of carotid artery atherosclerosis. (See 'Progression of coronary heart disease'
above and 'Cardiovascular mortality' above and 'Outcome after CABG' above and 'Carotid artery
atherosclerosis' above.)

● Psychosocial factors may be involved in coronary and cerebrovascular disease by contributing to

endothelial injury, affecting traditional risk factors (cigarette smoking, diet and serum cholesterol
levels, and high blood pressure). (See 'Pathophysiology' above.)

● For patients with known coronary disease, the cardioprotective effect of beta blockers with
regard to myocardial infarction and sudden cardiac death may be due in part to modifying the
effect of psychosocial factors, such as a diminishing catecholamine and hemodynamic-induced
endothelial damage and raising the threshold for ventricular fibrillation. (See 'Interventions'
above.)

● For patients at risk for cardiovascular events who are under increased psychosocial stress, a
stress management program can be considered as part of an overall preventive strategy. The
goal of a stress management program is to reduce the impact of stressful environmental events
and to better regulate the stress response by removing the stressor, changing the perception of
the stressful event, and reducing the physiologic sequelae of stress. Stress management
techniques typically include muscular relaxation, a quiet environment, passive attitude, deep
 breathing with the repetition of a word or phrase, and skills training to reduce the affective,
behavioral, and cognitive components of stress. (See 'Interventions' above.)

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Topic 4862 Version 8.0

Contributor Disclosures
Geoffrey H Tofler, MD Nothing to disclose Jonathan M Silver, MD Nothing to disclose David Solomon,
MD Nothing to disclose

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