The Time Has Come for Physicians to Take Notice: The Impact of Psychosocial Stressors on the Heart

Work Stress and Cardiovascular Disease 

Chronic work stress, defined as high psychologic demands and low decision latitude, was associated with cardiovascular disease events (relative risk=1.68) in 10,308 middle-aged London-based civil servants.9 Associations were found between work stress and negative behaviors, such as low physical activity and poor diet, and pathophysiologic consequences, such as decreased heart rate variability and higher morning increase in morning cortisol. The authors concluded that work stress might be an important determinant of cardiovascular disease among the working-age population, mediated through indirect effects on health behaviors and direct effects on neuroendocrine pathways.

Recurrent cardiovascular disease events among 972 patients with myocardial infarction returning to work were examined in a prospective cohort study.10 High job strain (high psychologic demands and low decision latitude) was an independent predictor of recurrent cardiovascular disease in a multivariate model adjusted for 26 potentially confounding factors (hazard ratio=2.00).

Marital Stress and Cardiovascular Disease 

A longitudinal analysis of 192 couples over 17 years in Tecumseh, Michigan, placed couples into the following categories: both partners communicate their anger, one spouse expresses anger while the other spouse suppresses anger, and both husband and wife suppress their anger and brood.11 In 26 pairs in whom both suppressed their anger, there were 13 deaths: In 27% of couples 1 partner died, and in 23% of couples both partners died. In the remaining 166 pairs (1 or both spouses communicate anger), there were 41 deaths: In 19% of couples 1 partner died, and in 6% of couples both partners died.

In the Healthy Women Study, 393 women completed a 7-item measure of relationship quality.12 B-mode carotid ultrasound measured plaque burden after 11 years. Greater plaque burden was found in those who reported low satisfaction with marital quality compared with satisfied wives (Figure 2). Unmarried women were intermediate in plaque burden. Three years later, a subset who reported low marital satisfaction had significant progression to moderate-to-severe levels of plaque burden compared with satisfied women. The authors conclude that high-quality marriages might protect against cardiovascular disease. Further study will hopefully confirm these findings.

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Figure 2. A, Percent of each marital status/quality group with a plaque score of≥2 at the first scan (N=376). B, Percent of each group showing an increase in plaque score from 0 or 1 to 2 or more. *Groups differ significantly at P<.05. Reprinted with permission from Gallo LC, Troxel WM, Kuller LH, Sutton-Tyrrell K, Edmundowicz D, Matthews KA. Marital status, marital quality, and atherosclerotic burden in postmenopausal women. Psychosom Med. 2003;65:952-962.

Acute Stress and Cardiovascular Disease 

Subjects from the Multicenter Investigation of the Limitation of Infarct Size study were questioned about possible triggers for their myocardial infarction.13 Of 849 subjects, 49% reported a possible trigger; the most common being emotional upset, followed by physical activity, lack of sleep, and overeating.

The Northridge earthquake struck Los Angeles on January 17, 1994. The Los Angeles County Coroner reported a sharp increase in cardiovascular disease-related sudden deaths on the day of the earthquake.14 During the previous week, sudden death occurred 4.6 times per day. On the day of the earthquake, there were 24 sudden cardiac deaths.

Two hundred New York area patients with implantable cardioverter-defibrillators had their stored electrocardiograms reviewed for ventricular tachyarrhythmias triggering implantable cardioverter-defibrillator therapy before and after the World Trade Center attack of September 11, 2001.15 There was a 2.3-fold increase in ventricular tachyarrhythmias during the month after 9/11, relative to other months between May 2001 and October 2002.

An interesting example of the effect of acute emotional stress on the heart is tako-tsubo or transient left ventricular apical ballooning syndrome. Patients present after acute emotional distress with symptoms and electrocardiographic changes consistent with acute myocardial infarction. Left ventriculogram reveals apical ballooning and a hypercontractile basal segment, a shape reminiscent of the pot (tsubo) that Japanese fishermen use to catch octopus (tako). Recent data implicate massive catecholamine release causing stress-induced myocardial stunning. In a study of 22 patients with tako-tsubo syndrome,16 psychologic stressors included death of relative, domestic abuse, arguments, catastrophic medical diagnosis, and devastating financial or gambling losses.

In addition to severe emotional upset, catastrophic events have been found to trigger myocardial infarction, earthquakes, missile attacks, and a person's favorite team losing a World Cup football game in a penalty shootout. Carroll et al17 studied myocardial infarction admissions in London after England lost to Argentina in a penalty shootout during the 1998 World Cup. On the day of the match, there was a 25% increase in myocardial infarction admissions compared with the same day in previous years. Increased admissions persisted for 2 days after England's loss, returning to baseline by day 3.

Similarly, in a study examining daily cardiovascular disease events in Munich during the 2006 World Cup, cardiovascular emergencies increased 2.7 times in men and 1.8 times in women on the days when Germany was participating in the quarterfinals and semifinals.18 On these days, myocardial infarction and major arrhythmia admissions increased 3 times compared with the same day in previous years (Figure 3). The highest incidence of cardiac events occurred during the first 2 hours of the games.

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Figure 3. Daily cardiovascular events in the study population from May 1 to July 31 in 2003, 2005, and 2006. The FIFA World Cup 2006 in Germany started on June 9, 2006, and ended on July 9, 2006. The 2006 World Cup matches with German participation are indicated by the numbers 1 to 7: match 1, Germany vs Costa Rica; match 2, Germany vs Poland; match 3, Germany vs Ecuador; match 4, Germany vs Sweden; match 5, Germany vs Argentina; match 6, Germany vs Italy; and match 7, Germany vs Portugal (for third-place standing). Match 8 was the final match, Italy vs France. Reprinted with permission from Wilbert-Lampen U, Leistner D, Greven S, et al. Cardiovascular events during World Cup soccer. N Engl J Med. 2008;358:475-483.

Pathophysiologic Mechanisms of Psychosocial Factors and Cardiovascular Disease 

2007 European Guidelines on Cardiovascular Disease Prevention and Clinical Practice 

The Fourth Joint Task Force of the European Society of Cardiology on Cardiovascular Disease Prevention and Clinical Practice concluded, “there is increasing scientific evidence that psychosocial factors contribute independently to the risk of coronary heart disease, even after statistical control for the effects of standard risk factors.”29 Further, “in addition to increasing the risk of a first event and worsening the prognosis of cardiovascular disease, these factors might act as barriers to treatment adherence and efforts to improve lifestyle.” From a mechanistic standpoint, psychosocial risk factors not only portend to risky health behaviors but also result in pathophysiologic characteristics, such as autonomic, endocrine, and inflammatory changes involved in promoting cardiovascular disease.

2008 American Heart Association Science Advisory on Depression and Coronary Heart Disease 

Endorsed by the American Psychiatric Association, an American Heart Association Scientific Advisory was recently published, entitled “Depression and Coronary Heart Disease: Recommendations for Screening, Referral, and Treatment.”30 This multispecialty consensus document reports that 20% of patients with myocardial infarction meet criteria for major depression, and an even greater number demonstrate elevated depressive symptom levels. Recognizing that, beyond the pathophysiologic effects on the heart, depression is associated with decreased adherence to medications and injurious behaviors, the Advisory proposes an algorithm and Patient Health Questionnaires that healthcare practitioners can use in patients with cardiovascular disease to determine whether depression is present (Figure 4; Table 1, Table 2). They recommend starting with Patient Health Questionnaire-2 (Table 1). If the patient answers yes to either question, then continue with Patient Health Questionnaire-9 (Table 2). Questions are scored not at all=0; several days=1; more than half the days=2; and nearly every day=3, and then added together to obtain a depression severity score. The Advisory stresses that although there is currently no direct evidence that depression screening leads to improved outcomes in patients with cardiovascular disease, depression is linked with increased cardiovascular disease morbidity and mortality, poorer risk factor modification, and lower medication and cardiac rehabilitation compliance. Treatment options are proposed, including antidepressant pharmacotherapy, cognitive behavioral therapy, and cardiac rehabilitation. The Advisory stresses that patients with positive screening should be evaluated by a mental health professional. Thus, coordination of care between healthcare providers is essential in patients with combined medical and mental health diagnoses.

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Figure 4. American Heart Association Science Advisory on Depression and Coronary Heart Disease algorithm screening for depression in patients with cardiovascular disease. *Meets diagnostic criteria for major depression, has a Patient Health Questionnaire-9 score of 10 to 19, has had no more than 1 or 2 prior episodes of depression, and screens negative for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problems. †Meets the diagnostic criteria for major depression and has a Patient Health Questionnaire-9 score≥20; or has had 3 or more prior depressive episodes; or screens positive for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problem. ‡If “Yes” to Q.9 “suicidal,” immediately evaluate for acute suicidality. If safe, refer for more comprehensive clinical evaluation; if at risk for suicide, escort the patient to the emergency department. Reprinted with permission Lichtman JH, Bigger JT Jr, Blumenthal JA, et al. Depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2008;118:1768-1775. Epub 2008 Sep 29. PHQ=Patient Health Questionnaire.

Table 1. Patient Health Questionnaire-2

	Over the past 2 weeks, how often have you been bothered by any of the following problems?
	Little interest or pleasure in doing things.
	Feeling down, depressed, or hopeless.

Table 2. Patient Health Questionnaire-9

	Over the past 2 weeks, how often have you been bothered by any of the following problems?
	Little interest or pleasure in doing things.
	Feeling down, depressed, or hopeless.
	Trouble falling asleep, staying asleep, or sleeping too much.
	Feeling tired or having little energy.
	Poor appetite or overeating.
	Feeling bad about yourself, feeling that you are a failure, or feeling that you have let yourself or your family down.
	Trouble concentrating on things such as reading the newspaper or watching television.
	Moving or speaking so slowly that other people could have noticed. Or being so fidgety or restless that you have been moving around a lot more than usual.
	Thinking that you would be better off dead or that you want to hurt yourself in some way.

Psychosocial and Behavioral Intervention Trials 

A recent meta-analysis reporting on the psychologic treatment of patients with cardiac disease identified 43 randomized trials, 23 of which reported mortality data for 9856 patients.31 When comparing psychologic treatment plus usual care with usual care alone, the odds ratio is 0.72 for all-cause mortality at 2 years. Mortality benefits only applied to men. However, only 10 studies allowed gender analysis. Psychologic treatment was statistically superior to control for reduction of heart rate and total cholesterol. Psychologic treatment was superior to control in improving both social support and quality of life.

In the Myocardial Ischemia Intervention Trial, 107 patients with coronary artery disease with ischemia during mental stress testing or ambulatory electrocardiographic monitoring were randomized to a 4-month program of exercise or stress management.32 Patients living a distance from the facility formed a nonrandom, usual care comparison group. Exercise training consisted of aerobic exercise 3 times per week for 16 weeks. Stress management included sixteen 1.5-hour cognitive behavioral therapy group sessions conducted by a clinical psychologist. Sessions included education, cognitive and behavioral skills training, progressive muscle relaxation, and at least 2 individual biofeedback sessions. Stress management was associated with a lower risk of adverse cardiac events at 5 years compared with usual care (relative risk=0.26; Figure 5). Exercise was associated with a nonsignificant lowering of cardiac event risk (relative risk=0.68).

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Figure 5. Cumulative time to cardiovascular event curves for exercise, stress management, and usual care groups. After adjusting for age, baseline left ventricular ejection fraction, and history of myocardial infarction, stress management was associated with a significantly lower risk (relative risk, 0.26; P=.04) of an adverse cardiac event compared with usual care. Exercise was also associated with a lower relative risk compared with usual care, but this difference was not statistically significant (relative risk, 0.68; P=.34). *Significantly different from usual care at P<.05. Reprinted with permission from Blumenthal JA, Jiang W, Babyak MA, et al. Stress management and exercise training in cardiac patients with myocardial ischemia. Effects on prognosis and evaluation of mechanisms. Arch Intern Med. 1997;157:2213-2223.

Blumenthal et al33 followed this study with a randomized control trial comparing aerobic exercise and stress-management training with routine medical care in 134 patients with stable coronary artery disease with exercise-induced ischemia. Patients in the exercise and stress management groups versus usual care had less depression (Beck Depression Inventory) and reduced distress (General Health Questionnaire). Exercise and stress management groups had smaller reductions in left ventricular ejection fraction during mental stress testing versus usual care. In a subset of patients with significant stress-induced wall motion abnormalities at baseline, exercise and stress management groups had lower wall motion abnormality rating scores and greater improvements in brachial flow-mediated dilation versus usual care. In a subgroup study, patients receiving stress management had improved baroreflex sensitivity and increases in heart rate variability. The authors concluded that exercise and stress management training reduced emotional distress and improved cardiovascular risk markers more than usual medical care in patients with stable coronary artery disease.

Milani and Lavie34 compared 522 patients with coronary artery disease who were enrolled in a cardiac rehabilitation program 2000 to 2005 with 179 patients who did not complete rehabilitation. Outpatient cardiac rehabilitation consisted of 12 weeks of 36 educational and exercise sessions. The prevalence of depressive symptoms (Kellner Symptom Questionnaire) decreased 63% after rehabilitation (17% to 6%). After rehabilitation, depressed patients had a significant increased mortality at 3.5 years versus nondepressed patients (22% vs 5%). Depressed patients who completed rehabilitation had a 73% lower mortality compared with control-depressed subjects who did not complete rehabilitation. A reduction in depressive symptoms was related to improvement in fitness, as evidenced by improved peak oxygen consumption during exercise.

Not all studies have demonstrated a benefit of cognitive behavioral therapy after myocardial infarction. In the Enhancing Recovery in Coronary Heart Disease Patients trial, 2481 patients post-myocardial infarction were randomized to cognitive behavioral therapy or usual medical care.35 Cognitive behavioral therapy was initiated at a median of 17 days after myocardial infarction for 6 months, plus group therapy when feasible, and selective serotonin reuptake inhibitors for patients scoring higher than 24 on the Hamilton Rating Scale for Depression. The main outcome measure was a composite end point of death or recurrent myocardial infarction. Secondary outcomes included change in the Hamilton Rating Scale for Depression or Enhancing Recovery in Coronary Heart Disease Patients Social Support Instrument scores. Cognitive behavioral therapy did not increase event-free survival. It did improve depression and social isolation scores. Of note, the relative improvement in the psychologic intervention group compared with the usual care group was less than expected because of substantial improvement in the usual care patients. A nonrandomized, post hoc analysis of the Enhancing Recovery in Coronary Heart Disease Patients trial found that patients treated with a selective serotonin reuptake inhibitor, whether assigned to receive cognitive behavioral therapy or usual care, had a 42% reduction in death or recurrent myocardial infarction compared with depressed patients not receiving an selective serotonin reuptake inhibitor.36

The Sertraline AntiDepressant Heart Attack Trial investigation demonstrated that sertraline is safe and efficacious in depressed patients with ischemic heart disease but was underpowered to detect a mortality difference between sertraline and placebo.37

Therefore, although encouraging data suggest intervention can affect patients with coronary artery disease with psychosocial stressors, further study will be required to determine which treatments definitively provide benefit. In addition, future studies prospectively assessing therapies for specific stressors and their ability to decrease events offer the best chance to further elucidate potential pathophysiologic versus behavioral mechanisms underlying this relationship.