There is growing evidence that psychosocial stress can influence the natural history of coronary heart disease (CHD). Established data from both population studies and an experimental animal model confirmed that adverse early life events, in particular during childhood and adolescence, predispose the individual to a greater rate of inflammatory-based diseases such as cardiovascular disease (CVD) in adulthood through epigenetic signature. Several epidemiological studies report that psychosocial factors such as acute and chronic stressors strongly increase the risk for cardiac events, worsening the prognosis in susceptible patients [1].

Since 1910, emotional triggers have been included in the pathogenesis of acute myocardial infarction by Obraztsov and Strazhesko [2]. Heterogeneous community-wide events, such as natural disasters, financial crashes, terrorist attacks, and wars, are associated with an increase in major cardiac events, in addition to positive emotionally charged events, such as sports matches and Christmas and New Year holidays [3].

Chronic stressors have also been linked to a worse prognosis in patients with existing CVD. Meta-analyses of prospective observational studies found that social isolation and loneliness were associated with a 50% increased risk of incident CVD events (pooled relative risk [RR] = 1.5, 95% confidence interval [CI]: 1.2–1.9). The increased risk associated with work-related stress (high work load, low reward) was similar at 40% (pooled RR = 1.4, 95% CI: 1.2–1.8) [4].

Depression has been widely studied as an independent risk factor in patients with coronary artery disease (CAD) and heart failure, demonstrating a close relationship between highly depressive symptoms and a poor prognosis after an acute cardiac event, as established in the 2014 American Heart Association Scientific Statement [5].

Depression is also associated with incident CHD [6], with a pooled adjusted RR of 1.90 (95% CI: 1.49–2.42), and stroke [7], with a pooled adjusted hazard ratio (HR) of 1.45 (95% CI: 1.29–1.63).

A large number of epidemiological studies regarding racial differences in the incidence and mortality of CHD and racial disparities in depressive symptoms could be explained by biological (neuroendocrine stress pattern activation) and behavioral (smoking, physical inactivity, lower socioeconomic status) factors.

In REGARDS, 24,443 US blacks and whites without CHD at baseline were followed up to assess whether depressive symptoms are related to new cardiac events. Blacks who reported depressive symptoms were at a greater risk for the composite end point of CHD or revascularization (HR: 1.36; 95% CI: 1.01–1.81). Depressive symptoms were also associated with incident acute CHD or revascularization among blacks but not whites [8].

In another community-based cohort of blacks, the Jackson Heart Study, 3,309 participants showed, over a 10-year follow-up, that major depressive symptoms were associated with greater risks of incident stroke and CHD. Moreover, the authors found that the association between depressive symptoms and CHD risk was no longer significant after adjustment for coping strategies, demonstrating that coping strategies are particularly important for mitigating the increased CHD risk associated with depressive symptoms [9].

The association between anxiety and onset of CVD is less significant. In a 2010 meta-analysis, great anxiety in healthy individuals is associated with an increased incidence of coronary disease. However, the meta-analytic estimate for the association of anxiety with CHD was not adjusted for depression, which is commonly comorbid with anxiety [10].

Sex differences were found about anxiety disorder and prevalence of CVD. Among 49,321 young military men, those who are diagnosed with anxiety are at an increased risk for experiencing CHD (adjusted HR: 2.17 [95% CI: 1.28–3.67]) and myocardial infarction (HR 2.51 [95% CI: 1.38–4.55]) [11]. A Finnish cohort showed an association between anxiety and an elevated risk of incident CHD over 7 years of follow-up only in women, with an HR of 1.24 (95% CI: 0.91–1.70) [12]. No clear association was found between anxiety and incidence of cardiac events and mortality among CHD patients.

Evidence is better established for psychological trauma and post-traumatic stress disorder (PTSD) with incident CVD events and/or CVD death. Multiple prospective cohort studies have included general population subgroups and veterans. In a Danish study, associations were found between PTSD and CVD events, with limited evidence for gender differences [13]. The recently published Nurses’ Health Study II investigated trauma exposure and PTSD symptoms in 49,978 women, finding that having elevated PTSD symptoms was associated with increased CVD risk, after adjusting for age, family history, and childhood factors (HR: 1.60; 95% CI: 1.20–2.13) [14].

A recently published analysis of active duty US military service members and veterans participating in the Millennium Cohort Study reported that combat deployment is associated with new-onset CHD by self-report or medical record diagnoses, demonstrating that experiences of recent combat exposure may increase the risk for CHD over a relatively short period of time (5.6-year follow-up) [15].

Some studies have focused on the importance of positive thoughts and emotions, along with social cohesion, on health outcome.

Prospective data from the Health and Retirement Study of older US adults included 6,808 participants who were followed for 4 years. Multiple logistic regression models are used to assess if optimism was independently associated with incident heart failure. Greater optimism was associated with a lower risk for incident heart failure over the follow-up period, adjusted for sociodemographic, behavioral, biological, and psychological covariates, with an odds ratio (OR) of 0.74 (95% CI: 0.63–0.85) [16].

Emerging ethnic differences between behavioral factors and the prognosis of CAD are also shown in a Japanese prospective study. Two hundred and one men enrolled in the Eastern Collaborative Group Study who have had CAD and undergone diagnostic coronary angiography were administered the Japanese Coronary-prone Behavior Scale (JCBS), a questionnaire that evaluates 10 psychological items. The authors have found that lower levels of impatience were associated with a 1.4-fold higher multivariable-adjusted risk of incidence of CHD and a 1.5-fold higher multivariable-adjusted risk for the incidence of myocardial infarction and nonfatal coronary disease. The fourth item of JCBS concerns the Japanese mentality, describing the Japanese “Spirit of Wa,” transliterated as “harmonious groupism,” a traditional attitude used to keep order in hierarchically organized social relationships in communities and groups. “Wa” represents a way of living that integrates a person into his or her community or group. Japanese Spirit of “Wa” was independently associated with coronary events (HR: 0.21) at the 7-year follow-up and thus is a preventive factor against coronary events for Japanese men with CAD [17].

Higher perceived neighborhood social cohesion may have a protective effect against myocardial infarction, as demonstrated in a cohort study of 5,276 American middle-aged adults with no history of heart disease, in which an increase in perceived neighborhood social cohesion was associated with a reduced likelihood of incident myocardial infarction (OR = 0.78, 95% CI: 0.63–0.94) over 4 years, even after further adjustments for behavioral, biological, and psychosocial factors [18].

An important method of assessing the effects of stress on cardiac function is Mental Stress-Induced Myocardial Ischemia (MSIMI) [19], a provocative test alternative to exercise and pharmacological stress-induced ischemia, in which the stimulus is psychological rather than physical. A wide range of stimuli were regarded as mental stressors, including mental arithmetic, simulated public speaking tasks, problem-solving tasks, cognitive tasks such as the Stroop color/word interference task, psychomotor challenges such as mirror tracing, and tasks involving the recall of a negative emotion.

Ischemic alterations in MSIMI are induced not by extreme emotional response to stress, but by behavioral challenges similar to those that might be experienced in everyday life. For this reason, anger, both as an emotional state and as a personality trait, is likewise associated with the propensity to develop myocardial ischemia during mental stress, but not during exercise/pharmacological stress [20].

Many different instrumental techniques have been used to assess reversible myocardial ischemic damage induced by psychological testing. Electrocardiogram (ECG) alone or in combination, echocardiography (ECHO), radionuclide ventriculogram, nuclear scintigraphy, positron emission tomography (PET), and quantitative coronary angiography show different characteristics of transient stress-induced ischemia: ST segment depression on ECG, wall motion abnormality on ECHO, left ventricular ejection fraction decrease on ventriculography, segmental hypoperfusion on scintigraphy, abnormal regional myocardial perfusion and reduced coronary flow reserve on PET, and finally coronary vasoconstriction on angiography.

Basing on recent evidence, myocardial perfusion imaging (e.g., with 99mTc-sestamibi SPECT) seems to be more accurate for the detection of MSIMI than methods based solely on electric changes and/or changes in the left ventricular function [21].

The main features of MSIMI are that it occurs more frequently among patients with CAD (about 50%) than in other groups, it is asymptomatic, and it occurs at a lower workload and oxygen demand than exercise-induced ischemia. Recent meta-analysis confirms a strong association between MSIMI and poor cardiovascular prognosis in terms of adverse outcome events in patients with CAD, with a pooled relative risk of 2.24 (95% CI: 1.59–3.15), although MSIMI is not directly related to the severity of coronary atherosclerosis [22].

In healthy controls, both mental and exercise/dipyridamole stress tests induce increased myocardial blood flow in normal coronary vessel, as a result of coronary microvascular dilation. In patients with CAD, coronary flow during mental stress was lower in regions without epicardial stenosis than in those with significant stenosis, suggesting microvascular constriction. In contrast, physical stress-induced ischemia occurred primarily by coronary steal when restricted vasodilation in a stenosed epicardial vessel causes selective hypoperfusion.

Moreover, subjects with exaggerated cardiovascular reactivity during mental stress have a greater likelihood of positive exercise/pharmacologic stress test [23].

Most significant hemodynamic features associated with MSIMI are the increase in systemic vascular resistance, vasoconstriction of normal coronary artery segments, impaired endothelial function, and increased heart rate and/or blood pressure, thereby resulting in myocardial oxygen supply–demand imbalance. Mental stress, through the activation of stress–response systems, increases levels of circulating catecholamines, also inducing cardiac electrical instability, as shown by ST segment and T-wave abnormalities [22].

It has been well established that among young post-myocardial infarction patients, higher levels of cognitive and somatic depressive symptoms are associated with a greater tendency to develop ischemia with MSIMI, but not with physical (exercise or pharmacologically)-induced stress. This association remains robust even after multivariate adjustments for other risk factors and disease severity, and applies to both somatic and cognitive depressive symptoms [24].

Recent research has investigated the role of baseline coping strategies and CVD outcomes, once again in a Japanese population cohort. Analyses of CVD incidence and mortality included 57,017 subjects aged 50–79 years without a history of CVD, who completed a coping behaviors and strategies questionnaire and were included in an approach-oriented behavior strategy or in an avoidance-oriented behavior strategy.

The authors have found that an approach-oriented coping strategy was associated with a significantly reduced incidence of stroke and reduced CVD mortality, in particular among hypertensive individuals. The specific fantasizing behavior avoidance-oriented strategy is only associated with CVD incidence and with increased CVD mortality among hypertensive subjects, whereas a positive reappraisal behavior approach-oriented strategy is associated with reduced CVD mortality [25].

Physiological derangements related to depression include autonomic and hypothalamic–pituitary–adrenal axis dysregulation, altered central and peripheral serotonin homeostasis, an increase in inflammatory signals, stress-related platelet activation [26, 27], and endothelial dysfunction. The results of these derangements may lead to cardiac events and cardiovascular death [28].

Pharmacology-based approaches to depression treatment have been shown to decrease platelet/endothelial activation markers (e.g., platelet factor 4 and β-thromboglobulin), reduce inflammatory markers (e.g., tumor necrosis factor-α and C-reactive protein), improve heart rate variability, and normalize brain serotonin turnover [29].

Among antidepressants, selective serotonin re-uptake inhibitors (SSRIs) are recommended as first-line therapy for the treatment of depression in CVD patients. TCA and IMAO use is discouraged because of the adverse cardiovascular effects [30]. Some SSRIs seem to exert a direct cardioprotective role during acute myocardial infarction, inhibiting myocardial apoptosis in a rat model [31].

The first randomized controlled trial of pharmacological therapy for depression in cardiovascular patients was the Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART). This trial demonstrated that sertraline was safe in CAD patients and resulted in improvements in depressive symptoms and quality of life, without significant effects on cardiovascular outcomes [32]. Indeed, sertraline in depressed patients with congestive heart failure showed no statistical difference in the reduction of depressive symptoms and no difference in all-cause mortality [33].

The subsequent Myocardial Infarction and Depression–Intervention Trial (MIND–IT) involving depressed patients treated with mirtazapine depressed patients with acute myocardial infarction or with placebo, finding no difference in cardiac events rate [34].

The Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) trial randomized 235 primary care patients with depression to a 12-month collaborative care program involving antidepressants and psychotherapy, finding a dramatic 48% lower risk of a CVD event over a 5-year follow-up only among patients without baseline cardiac disease, underlining the importance of integrated stress management in the primary prevention of CVD [35]. A recent randomized controlled trial (RCT) on 24-week escitalopram treatment in patients with depression and recent coronary events, confirmed the antidepressant effect of SSRI drugs without any harmful changes in cardiovascular safety measures. However, the study did not analyze cardiovascular outcomes [36]. Another recent randomized trial, named Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT), on the use of 6-week administration of escitalopram versus placebo among 127 patients with stable coronaropathy and evidence of MSIMI at baseline, resulted in a significantly lower prevalence of MSIMI in the treatment group, with no difference in exercise-induced ischemia [37].

The importance of managing stress to prevent and improve CVD is challenging.

This is particularly true for women. Although female coronary disease occurs later in life, those women who have clinical events at a younger age have a worse prognosis than men. Psychosocial factors have been hypothesized as relevant risk markers in this field. In the context of the Stockholm Female Coronary Risk study, 237 middle-aged women, who had experienced acute myocardial infarction and who underwent coronary artery bypass grafting or percutaneous coronary intervention, were randomized to a group-based psychosocial stress intervention program or usual care for 1 year. Over a mean period of 7 years, women in usual care had a mortality rate of 20%, whereas those in the psychosocial intervention group had a mortality rate of 7% [38].

Behavioral intervention has also been tested among patients with an implantable cardioverter defibrillator (ICD). A comprehensive review of cognitive-behavioral therapies coupled with relaxation strategies (e.g., diaphragmatic breathing, breath counting meditation, progressive muscle relaxation, visualization, self-hypnosis, and autogenic training) showed promising results with respect to reductions in psychological distress, whereas effects on cardiovascular endpoints (e.g., shocks and arrhythmias) remain elusive [39].

A cost-effectiveness analysis of the stress management program in secondary prevention in established CAD patients reveals lower medical costs than usual care in the first 2 years and lower cumulative costs over 5 years for stress management compared with usual care [40].

Psychotherapy also appears effective in treating the psychological symptoms of coronary disease patients, significantly improving quality of life [41].

The largest intervention trial of a non-pharmacology-based approach to depression in CVD is the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial, in which 2,481 patients with an acute myocardial infarction and major depressive disorder, depressive symptoms, or dysthymia were randomized to cognitive-behavioral therapy (CBT) or usual treatment. If the score of the Hamilton scale was greater than 24, they also received an SSRI. CBT was found to significantly improve depression, social isolation, and the overall quality of life, with no effect on cardiac outcomes [42].

The safety and efficacy of CBT were confirmed in a recently published trial involving 158 heart failure patients with a major depressive disorder. At 6 months, depression and the anxiety score were significantly reduced, as along with the rate of hospitalization, but improvement of physical functioning was not observed [43]. Also, collaborative care interventions improve depression and quality of life and in some cases, relieve cardiac symptoms.

A dedicated Cochrane Review on psychological intervention for coronary disease established that psychological treatments are effective in treating the psychological symptoms of CHD patients. Uncertainty remains regarding the subgroups of patients who would benefit most from treatment (there is most evidence for “type A” behavior) and the characteristics of successful interventions [41]. A 2011 comprehensive Cochrane systematic review concluded that both pharmacological and psychological intervention for depression in CVD patients may have a small yet clinically meaningful effect on depression outcomes, without beneficial effects on the reduction of mortality rates and cardiac events, owing to the low number of high-quality trials [44].

The physiology of meditation practices and their role in health and disease have been widely investigated in the last half century, with increased attention given to the effect of meditation on the cardiovascular system [45].

Meditation practice, by reducing the heart rate and respiratory rate (approximately 6 breaths per minute), positively affects autonomic balance, enhancing parasympathetic activity and improving heart rate variability and baroreflex sensitivity, in addition to inducing the vagal anti-inflammatory reflex [46]. Evidence from neurophysiological studies confirms the impact of mindful meditation on stress response in the brain through reduced amygdala activation, increased prefrontal cortex activation, and increased hippocampal gray matter density [47].

A review of RCTs demonstrates that mind–body practices produce encouraging results in patients with cardiac disease; however, the quality of the studies in this field remains low [48].

Transcendental meditation, introduced into the West in the second half of the nineteenth century by Yogi Maharishi Mahesh, is a technique that involves the use of a repeated sound (mantra) for 15–20 min twice per day to achieve a quiet state of awareness. It is estimated that there have been more than 600 studies published examining the impact of transcendental meditation on CVD, although, again, many studies have been criticized for their low quality and possible researcher bias.

A 2013 American Heart Association Statement described TM as a safe and effective alternative treatment to lowering high blood pressure, both in primary and in secondary prevention, with mean blood pressure reduction between 4.7 and 3.2 mmHg among young and older subjects [49]. It was found that a TM program also reduces left ventricular mass on echography, decreases the carotid intima-media thickness in African–American hypertensive adults, and reduces circulating levels of stress hormones norepinephrine and cortisol [50]. However, there are few trials with outcomes that are too limited to draw conclusions about the effectiveness of TM for the primary prevention of CVD [51].

A small group of 23 African–Americans with heart failure randomized to TM and usual care showed a significant increase in the 6-min walking distance in addition to improvement in depression scores and measures of quality of life in the TM group [52]. A more recent, large study involved 201 black patients with stable CAD who demonstrated a 48% risk reduction in the composite of mortality, nonfatal myocardial infarction, and nonfatal stroke, and a significant reduction in blood pressure during an average follow-up of 5.4 years and improvement in psychosocial distress, confirming that the TM program may be clinically useful in the secondary prevention of CVD [53].

Acem meditation is a systematic, nondirected, nonreligious approach to meditation theorized by physicians and psychologists and founded in Norway in 1966 by Are Holen. It subsequently spread worldwide. Acem meditation is based on the use of a simple combination of repeated sounds and release of the spontaneous activities of the mind, providing deep relaxation and free flow of thoughts and feelings. Also, Acem meditation may contribute toward a reduction in cardiovascular risk, as demonstrated in a study conducted recently among 27 middle-aged healthy participants of both genders practicing Acem meditation for 20 min: heart rate variability increased during meditation compared with rest, without a change in respiration and heart rates [54].

Mindfulness is a modern Western movement, derived from the ancient Buddhist Vipassana meditation, founded by Jon Kabat-Zinn in the late 1970s. It is a nonjudgmental practice involving becoming aware moment to moment, improving emotion regulation, and cultivating the attention of mental events in the present moment with openness and acceptance. Mindfulness-based stress reduction (MBSR) is the most popular and validated mindfulness program, with a consistent number of scientific studies. MBSR provides 8 weeks of systematic training in formal mindfulness meditation practices, including a physical session with mindful yoga and a psychoeducational program.