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Exercise Counteracts the Cardiotoxicity of Psychosocial Stress

  • Evan L. O'Keefe
    Affiliations
    Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA
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  • James H. O'Keefe
    Affiliations
    University of Missouri–Kansas City and Saint Luke's Mid America Heart Institute, New Orleans, LA
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  • Carl J. Lavie
    Correspondence
    Correspondence: Address to Carl J. Lavie, MD, FCCP, Medical Director, Cardiac Rehabilitation, Director, Exercise Laboratories, John Ochsner Heart and Vascular Institute, Ochsner Clinical School - The University of Queensland School of Medicine, 1514 Jefferson Hwy, New Orleans, LA 70121-2483.
    Affiliations
    Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA

    Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, New Orleans, LA
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      Abstract

      Physical inactivity and psychosocial stress are prevalent in residents of the United States. The purpose of this article is to review the interaction between these 2 conditions and examine the effects of exercise on stress and cardiovascular (CV) health. A query of scientific references between 1974 to 2018 was performed using the PubMed search engine accessing the MEDLINE database using the search terms psychosocial stress, CV disease (CVD), physical activity, exercise, cardiac rehabilitation, and team sports. Psychosocial stress is a strong independent risk factor for adverse CV events. Conversely, people who experience CV events subsequently have drastically elevated rates of new-onset mental health disorders, including depression and anxiety. Psychosocial stress and CVD often trigger self-reinforcing feedback loops that can worsen mental health and cardiac prognosis. Exercise predictably improves CV health and prognosis and also is effective at lowering levels of psychosocial stress. Group exercise in particular seems to provide social support while at the same time boosting fitness levels and, thus, may be the single most important intervention for patients with concomitant CVD and emotional stress. Collaborative physical activity, such as group exercise, team sports, interactive physical play, and cardiac rehabilitation programs, have the potential to improve mental health and CV prognosis.

      Abbreviations and Acronyms:

      ANS (autonomic nervous system), CHD (congestive heart disease), CV (cardiovascular), CVD (cardiovascular disease), HDL (high-density lipoprotein), HPA (hypothalamus-pituitary-adrenal), HR (heart rate), HTN (hypertension), MI (myocardial infarction), SNS (sympathetic nervous system), SSRI (selective serotonin reuptake inhibitor)
      Article Highlights
      • Psychosocial stress is an independent risk factor for adverse CV events.
      • Cardiovascular disease elevates rates of new-onset mental health disorders.
      • Both psychosocial stress and CVD often trigger self-reinforcing feedback loops that worsen both prognoses.
      • Exercise predictably improves CV health and effectively lowers levels of psychosocial stress.
      • New evidence suggests social exercise involving interactive physical play may be the single most important intervention for patients afflicted by concomitant CVD and emotional stress.
      Human existence is, by nature, sometimes a struggle—survival of the fittest where life and death competition is grist for the evolutionary mill of natural selection. In the past century, however, that struggle for survival has been transformed entirely. What once played out largely outside in a natural setting is now taking place indoors in man-made urban surroundings; walking and physical work have been generally supplanted by vehicular travel and cognitive tasks; and violence, starvation, and infection have been superseded by noncommunicable diseases such as diabetes, obesity, and cancer. This cultural evolution has ushered in a general decline in physical fitness while simultaneously triggering a steep rise in the incidence of cardiovascular (CV) disease (CVD) and mental illness (Table).
      Institute of Medicine
      Cardiovascular Disability: Updating the Social Security Listings.
      • Tejada V.B.
      • Bastian B.
      • Arias E.
      Mortality Trends in the United States, 1900–2015.
      • Bloom D.E.
      • Cafiero E.T.
      • Jane-Llopis E.
      • et al.
      The Global Economic Burden of Noncommunicable Diseases.
      • Church T.S.
      • Thomas D.M.
      • Tudor-Locke C.
      • et al.
      Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
      GBD 2015 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      • Kohl III, H.W.
      • Craig C.L.
      • Lambert E.V.
      • et al.
      The pandemic of physical inactivity: global action for public health.
      TableOverview of CVD, Mental Illness, and Physical Inactivity
      CVD in America
       Approximately 1 in 3 American adults, >80 million people, have CVD, and half of those affected are not yet 60 years old.
       CVD has been the leading cause of death in the United States since the early 1920s, when it surpassed pneumonia, tuberculosis, and dysentery, the 3 most common causes of death until then.
      Mental illness in America
       Depression is the third leading cause of chronic disability.
       Mental health and behavioral disorders are among the top 5 contributors to the global burden of disease.
      Physical inactivity in 2018
       Physical inactivity is currently the fourth leading cause of death worldwide.
       During the past 50 y, there has been a persistent decrease in adults working in occupations requiring at least moderate levels of physical activity.
      CVD = cardiovascular disease.
      Evidence indicates that psychosocial stress, often associated with depression, anxiety, and hostility, is a strong independent risk factor for CVD events and that the mind-heart connection likely accounts for a substantial portion of the attributable risk of CVD.
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      • Curtis B.M.
      • O'Keefe Jr., J.H.
      Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
      A large and accumulating body of research suggests that psychosocial stress not only precipitates acute adverse CV events such as myocardial infarction (MI) and stroke but also perpetuates chronic CVD,
      • Barefoot J.C.
      Depression and coronary heart disease.
      with a clinical effect comparable to other major CVD risk factors, such as smoking, low physical activity, and hypertension (HTN).
      • Dimsdale J.E.
      Psychological stress and cardiovascular disease.
      • Figueredo V.M.
      The time has come for physicians to take notice: the impact of psychosocial stressors on the heart.
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.H.
      • Lavie T.J.
      Impact of exercise training on psychological risk factors.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      On the other hand, after being diagnosed as having CVD or diabetes mellitus individuals subsequently experience drastically elevated rates of new-onset mental health disorders.
      • Lavie C.J.
      • Milani R.V.
      Cardiac rehabilitation and exercise training programs in metabolic syndrome and diabetes.
      • Milani R.V.
      • Lavie C.J.
      Behavioral differences and effects of cardiac rehabilitation in diabetic patients following cardiac events.
      Some studies suggest that up to half of all patients early after MI or coronary artery bypass surgery experience symptoms of depression.
      • Das S.
      • O'Keefe J.H.
      Behavioral cardiology: recognizing and addressing the profound impact of psychosocial stress on cardiovascular health.
      • Lett H.S.
      • Blumenthal J.A.
      • Babyak M.A.
      • et al.
      Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.
      Moreover, psychosocial stress can catalyze a downward spiral of worsening morbidity and can shorten life expectancy.
      • Milani R.V.
      • Lavie C.J.
      Behavioral differences and effects of cardiac rehabilitation in diabetic patients following cardiac events.
      • Lavie C.J.
      • Milani R.V.
      Prevalence of anxiety in coronary patients with improvement following cardiac rehabilitation and exercise training.
      • Milani R.V.
      • Lavie C.J.
      • Cassidy M.M.
      Effects of cardiac rehabilitation and exercise training programs on depression in patients after major coronary events.
      • Rozanski A.
      • Blumenthal J.A.
      • Kaplan J.
      Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.
      This article explores the evidence suggesting bidirectional feedback-loop relationships between psychosocial stress and CVD; it also explores how physical activity, group exercise, and interactive physical play can potentially confer beneficial effects that largely neutralize the adverse effects of psychosocial stress.

      Stress Triggers CV Events

      In the hours to days after the 9/11 attacks on the Twin Towers of the World Trade Center, New York City citizens experienced a 2.3-fold increase in ventricular fibrillation and ventricular tachycardia.
      • Steinberg J.S.
      • Arshad A.
      • Kowalski M.
      • et al.
      Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack.
      Similar elevations in risks of sudden cardiac death and acute MI were documented in the Taiwanese survivors after their deadly 1999 earthquake,
      • Huang J.L.
      • Chiou C.W.
      • Ting C.T.
      • Chen Y.T.
      • Chen S.A.
      Sudden changes in heart rate variability during the 1999 Taiwan earthquake.
      as well as in the Israeli survivors of the 18 Iraqi missile attacks during the Persian Gulf War.
      • Meisel S.R.
      • Kutz I.
      • Dayan K.I.
      • et al.
      Effect of Iraqi missile war on incidence of acute myocardial infarction and sudden death in Israeli civilians.
      Even in the context of healthy coronary arteries, psychosocial stress can cause strikingly abnormal electrocardiographic changes usually associated with myocardial ischemia despite the absence of clinically detectable congestive heart disease (CHD).
      • Brotman D.J.
      • Golden S.H.
      • Wittstein I.S.
      The cardiovascular toll of stress.
      • Wittstein I.S.
      • Thiemann D.R.
      • Lima J.A.
      • et al.
      Neurohumoral features of myocardial stunning due to sudden emotional stress.
      Moreover, simply answering “yes” to the question, “During the last month have you felt so sad, discouraged, hopeless, or had so many problems that you wondered if anything was worthwhile?” signifies a 5-fold risk of developing significant CHD.
      • Anda R.
      • Williamson D.
      • Jones D.
      • et al.
      Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults.
      The possible pathophysiologic mechanisms by which psychosocial stress triggers acute CV events include sympathetic surges that lower the arrhythmic threshold, spike the blood pressure, increase inflammation, and cause hypercoaguability.
      • Kivimaki M.
      • Steptoe A.
      Effects of stress on the development and progression of cardiovascular disease.
      In addition, psychosocial stress has been shown to often provoke high-risk, maladaptive behaviors and to impair general functioning.
      • Das S.
      • O'Keefe J.H.
      Behavioral cardiology: recognizing and addressing the profound impact of psychosocial stress on cardiovascular health.
      For example, psychosocial stress may instigate self-destructive behaviors, including substance abuse, noncompliance with medication, and failure to maintain a wholesome diet and prudent lifestyle.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Das S.
      • O'Keefe J.H.
      Behavioral cardiology: recognizing and addressing the profound impact of psychosocial stress on cardiovascular health.
      • DiMatteo M.R.
      • Lepper H.S.
      • Croghan T.W.
      Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence.
      This excessive adrenergic tone makes psychosocial stress one of the most pervasive and pernicious risk factors for CVD.
      • Curtis B.M.
      • O'Keefe Jr., J.H.
      Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
      Chronic imbalance of the autonomic nervous system with sustained sympathetic nervous system prominence and insufficient vagal tone causes elevation of heart rate (HR), delayed HR recovery, loss of normal beat-to-beat variability in HR, and blunted peak exercise HR, all of which increases risk of CVD and all-cause mortality.
      • Curtis B.M.
      • O'Keefe Jr., J.H.
      Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
      Chronic imbalance of the autonomic nervous system also predisposes to inflammation, endothelial dysfunction, hypercoagulability, platelet activation, insulin resistance, coronary spasm, left ventricular hypertrophy, and cardiac arrhythmias.
      • Curtis B.M.
      • O'Keefe Jr., J.H.
      Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
      • Barefoot J.C.
      Depression and coronary heart disease.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Kop W.J.
      • Gottdiener J.S.
      • Tangen C.M.
      • et al.
      Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.
      • Lavie C.J.
      • Milani R.V.
      Prevalence of hostility in young coronary artery disease patients and effects of cardiac rehabilitation and exercise training.
      • Lavie C.J.
      • Milani R.V.
      Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
      • Milani R.V.
      • Lavie C.J.
      Impact of cardiac rehabilitation on depression and its associated mortality.
      The landmark INTERHEART study, after collecting and analyzing data from more than 50 countries and 11,000 patients, found that psychosocial stress is the third most important modifiable risk factor for CHD and MI, ranking behind only lipids and smoking (Figure 1).
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      In addition, the INTERHEART study showed that psychosocial stress accounts for approximately one-third of the attributable risk of CHD.
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      This means that psychosocial stress is a stronger risk factor for CHD than many other widely recognized CVD risk factors, including obesity, diabetes mellitus, HTN, poor diet, and sedentary lifestyle.
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Rugulies R.
      Depression as a predictor for coronary heart disease: a review and meta-analysis.
      In the total group of patients with previously diagnosed CHD, those who self-reported high levels of psychosocial stress had a 5-fold increased risk of major CVD events within 6 months, a 4-fold increase in medical costs, and a 2.5-fold increased risk of additional hospitalizations.
      • Allison T.G.
      • Williams D.E.
      • Miller T.D.
      • et al.
      Medical and economic costs of psychologic distress in patients with coronary artery disease.
      The mind-heart connection is so profound that severe emotional trauma experienced as a child can predispose to CHD as an adult, decades later.
      • Dong M.
      • Giles W.H.
      • Felitti V.J.
      • et al.
      Insights into causal pathways for ischemic heart disease: adverse childhood experiences study.
      The severity of psychosocial stress lies on a continuum, with robust evidence indicating the existence of a dose-response relationship between psychosocial stress and premature mortality.
      • Rugulies R.
      Depression as a predictor for coronary heart disease: a review and meta-analysis.
      • Puustinen P.J.
      • Koponen H.
      • Kautiainen H.
      • Mantyselka P.
      • Vanhala M.
      Psychological distress measured by the GHQ-12 and mortality: a prospective population-based study.
      • Robinson K.L.
      • McBeth J.
      • Macfarlane G.J.
      Psychological distress and premature mortality in the general population: a prospective study.
      • Russ T.C.
      • Stamatakis E.
      • Hamer M.
      • Starr J.M.
      • Kivimaki M.
      • Batty G.D.
      Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies.
      Figure thumbnail gr1
      Figure 1The odds of experiencing a myocardial infarction for individuals in the INTERHEART study. An odds ratio greater than 1 indicates an increased risk of heart attack, and an odds ratio less than 1 indicates a reduction in heart attack risk. Adapted with permission from Lancet.
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      In the INTERHEART study,
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      psychosocial stress was assessed using 4 simple questions asking participants about their subjective perception of stress at work, stress at home, financial stress, and major life events they may have experienced in the past year. Two other questions assessed their locus of control and the presence of depression. Other more detailed assessments of self-reported measures of experienced stress are often deployed in psychological research on stress and its consequences.
      • Morgan E.S.
      • Umberson K.
      • Hertzog C.
      Construct validation of self-reported stress scales.

      Depression and CVD

      Depression is one of the most prevalent forms of psychosocial stress, and it has been consistently identified as a strong independent risk factor for CVD.
      • Huffman J.C.
      • Celano C.M.
      • Beach S.R.
      • Motiwala S.R.
      • Januzzi J.L.
      Depression and cardiac disease: epidemiology, mechanisms, and diagnosis.
      Agatisa et al
      • Agatisa P.K.
      • Matthews K.A.
      • Bromberger J.T.
      • Edmundowicz D.
      • Chang Y.F.
      • Sutton-Tyrrell K.
      Coronary and aortic calcification in women with a history of major depression.
      studied individuals with a history of major recurrent depression and reported an increased relative risk of 2.7 for severe coronary calcification and 3.4 for severe aortic calcification. Other studies confirm that chronic depression independently increases the risk of CVD development by approximately 2-fold compared with nondepressed matched cohorts.
      • Anda R.
      • Williamson D.
      • Jones D.
      • et al.
      Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults.
      • Ferketich A.K.
      • Schwartzbaum J.A.
      • Frid D.J.
      • Moeschberger M.L.
      Depression as an antecedent to heart disease among women and men in the NHANES I study: National Health and Nutrition Examination Survey.
      • Penninx B.W.
      • Beekman A.T.
      • Honig A.
      • et al.
      Depression and cardiac mortality: results from a community-based longitudinal study.
      Correspondingly, depression is also an independent risk factor for the development of HTN, type 2 diabetes mellitus, and adverse CHD events.
      • Dimsdale J.E.
      Psychological stress and cardiovascular disease.
      • Figueredo V.M.
      The time has come for physicians to take notice: the impact of psychosocial stressors on the heart.
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.H.
      • Lavie T.J.
      Impact of exercise training on psychological risk factors.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Lavie C.J.
      • Milani R.V.
      • Artham S.M.
      • Gilliland Y.
      Psychological factors and cardiac risk and impact of exercise training programs: a review of Ochsner studies.
      • Menezes A.R.
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.
      • Lavie T.J.
      Psychological risk factors and cardiovascular disease: is it all in your head?.
      • Scott K.M.
      • Lim C.
      • Al-Hamzawi A.
      • et al.
      Association of mental disorders with subsequent chronic physical conditions: World Mental Health Surveys from 17 countries.
      In addition to its tendency to disturb autonomic nervous system balance, depression can also cause dysfunction in the hypothalamus-pituitary-adrenal (HPA) axis.
      • Akil H.
      • Haskett R.F.
      • Young E.A.
      • et al.
      Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin.
      • Kasckow J.W.
      • Baker D.
      • Geracioti Jr., T.D.
      Corticotropin-releasing hormone in depression and post-traumatic stress disorder.
      Such irregularities in the HPA axis are correlated with many of the disturbances that compose the metabolic syndrome—elevated blood pressure, truncal obesity, hypertriglyceridemia, and hyperglycemia.
      • Agabiti-Rosei E.
      • Alicandri C.
      • Beschi M.
      • et al.
      Relationships between plasma catecholamines, renin, age and blood pressure in essential hypertension.
      • Rosmond R.
      • Bjorntorp P.
      The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke.
      Furthermore, patients with major depression often exhibit persistently elevated baseline levels of cortisol.
      • Ehlert U.
      • Gaab J.
      • Heinrichs M.
      Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis.
      Severe depression accompanied by a sense of hopelessness is an especially lethal condition that predisposes to sudden cardiac death and CV mortality.
      • Bruhn J.G.
      • Paredes A.
      • Adsett C.A.
      • Wolf S.
      Psychological predictors of sudden death in myocardial infarction.
      • Grace S.L.
      • Abbey S.E.
      • Kapral M.K.
      • Fang J.
      • Nolan R.P.
      • Stewart D.E.
      Effect of depression on five-year mortality after an acute coronary syndrome.
      In patients free of CHD at baseline, Penninx et al
      • Penninx B.W.
      • Beekman A.T.
      • Honig A.
      • et al.
      Depression and cardiac mortality: results from a community-based longitudinal study.
      found that those with major depressive disorder were 3.9 times more likely to die of CVD causes compared with those without major depressive disorder at baseline. Middle-aged and older individuals are approximately twice as likely to fall victim to premature mortality and CVD death if they are concomitantly experiencing high levels of depressive symptoms.
      • Geerlings S.W.
      • Beekman A.T.
      • Deeg D.J.
      • Twisk J.W.
      • Van Tilburg W.
      Duration and severity of depression predict mortality in older adults in the community.
      A Norwegian epidemiologic study reported that depression is as potent as smoking as a risk factor for all-cause mortality.
      • Mykletun A.
      • Bjerkeset O.
      • Overland S.
      • Prince M.
      • Dewey M.
      • Stewart R.
      Levels of anxiety and depression as predictors of mortality: the HUNT study.
      Although antismoking campaigns, graphic warnings, taxation, and smoking bans/restrictions now help the general public to understand and avoid the dangers of tobacco, depression continues, unfortunately, to undermine the well-being of our population, and, tragically, the CV toxicity of major depressive disorder remains largely unrecognized by health care providers and patients alike.

      Anxiety and CVD

      Evolutionarily intended as an early warning signal to keep us safe, anxiety now endures predominantly as a chronic maladaptive emotional response that not only fails to protect us from danger but also can paradoxically induce mental and physical disease. Cardiovascular disease often induces high levels of anxiety in afflicted patients,
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.H.
      • Lavie T.J.
      Impact of exercise training on psychological risk factors.
      • Lavie C.J.
      • Milani R.V.
      Prevalence of anxiety in coronary patients with improvement following cardiac rehabilitation and exercise training.
      • Lavie C.J.
      • Milani R.V.
      Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
      and, inversely, long-term excessive anxiety is associated with increased risk of CVD.
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.H.
      • Lavie T.J.
      Impact of exercise training on psychological risk factors.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Kawachi I.
      • Sparrow D.
      • Vokonas P.S.
      • Weiss S.T.
      Symptoms of anxiety and risk of coronary heart disease: the Normative Aging Study.
      Patients who reported high anxiety also recorded increased body weight, percentage body fat, and triglyceride levels and also showed trends for higher low-density lipoprotein to high-density lipoprotein (HDL) ratios and triglyceride to HDL ratios, as well as lower HDL levels.
      • Lavie C.J.
      • Milani R.V.
      Prevalence of anxiety in coronary patients with improvement following cardiac rehabilitation and exercise training.
      Accordingly, several studies have suggested that patients with CVD are at least 2-fold more likely to experience future adverse CVD events if they struggle with concomitant anxiety.
      • Frasure-Smith N.
      In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men.
      • Frasure-Smith N.
      • Lesperance F.
      Depression and anxiety as predictors of 2-year cardiac events in patients with stable coronary artery disease.
      Likewise, for the post-MI patient, the psychological strain induced by severe anxiety is associated with a worse prognosis and increased mortality.
      • Strik J.J.
      • Denollet J.
      • Lousberg R.
      • Honig A.
      Comparing symptoms of depression and anxiety as predictors of cardiac events and increased health care consumption after myocardial infarction.
      • Wrenn K.C.
      • Mostofsky E.
      • Tofler G.H.
      • Muller J.E.
      • Mittleman M.A.
      Anxiety, anger, and mortality risk among survivors of myocardial infarction.
      By disturbing both the sympathetic nervous system and the HPA axis, anxiety reduces HR variability and impairs vagal tone, which can increase vulnerability to sudden cardiac death.
      • Rozanski A.
      • Blumenthal J.A.
      • Davidson K.W.
      • Saab P.G.
      • Kubzansky L.
      The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
      • Lavie C.J.
      • Milani R.V.
      Prevalence of anxiety in coronary patients with improvement following cardiac rehabilitation and exercise training.
      • Kawachi I.
      • Sparrow D.
      • Vokonas P.S.
      • Weiss S.T.
      Symptoms of anxiety and risk of coronary heart disease: the Normative Aging Study.
      • Kawachi I.
      • Colditz G.A.
      • Ascherio A.
      • et al.
      Prospective study of phobic anxiety and risk of coronary heart disease in men.
      • Lucini D.
      • Norbiato G.
      • Clerici M.
      • Pagani M.
      Hemodynamic and autonomic adjustments to real life stress conditions in humans.
      However, the evidence for anxiety-causing CVD remains speculative, with some notable studies reporting an inverse relationship between heightened anxiety levels and reduced CVD mortality rates.
      • Meyer T.
      • Buss U.
      • Herrmann-Lingen C.
      Role of cardiac disease severity in the predictive value of anxiety for all-cause mortality.
      • Mykletun A.
      • Bjerkeset O.
      • Dewey M.
      • Prince M.
      • Overland S.
      • Stewart R.
      Anxiety, depression, and cause-specific mortality: the HUNT study.
      Similarly, Parker et al
      • Parker G.
      • Hyett M.
      • Hadzi-Pavlovic D.
      • Brotchie H.
      • Walsh W.
      GAD is good? generalized anxiety disorder predicts a superior five-year outcome following an acute coronary syndrome.
      found that increased anxiety correlated with improved outcomes after an acute coronary syndrome. However, the health consequences of psychosocial stress seem to be highly variable with respect to individual susceptibilities, types of stressors, and coping mechanisms used.
      • Bonanno G.A.
      • Papa A.
      • Lalande K.
      • Westphal M.
      • Coifman K.
      The importance of being flexible: the ability to both enhance and suppress emotional expression predicts long-term adjustment.
      An apt example is illustrated by the highly variable rates of CHD among caregivers. The psychological strain experienced by caregivers is often substantial and long term, yet those caregivers engaged in an emotionally fulfilling relationship have no associated increase in mortality.
      • Schulz R.
      • Beach S.R.
      Caregiving as a risk factor for mortality: the Caregiver Health Effects Study.
      It is only caregivers providing for others in the context of a hostile or emotionally distant relationship in whom increased risk for early mortality is observed.
      • Schulz R.
      • Beach S.R.
      Caregiving as a risk factor for mortality: the Caregiver Health Effects Study.

      Hostility and CVD

      Psychosocial stress stemming from individual character traits also plays a detrimental role in health outcomes. A large body of evidence indicates that hostility is a particularly toxic emotion that encompasses several negative emotions, including anger, resentment, cynicism, and mistrust.
      • Rozanski A.
      • Blumenthal J.A.
      • Kaplan J.
      Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.
      In contrast to most chronic illnesses and noncommunicable diseases, hostility arises disproportionately in adolescents and younger adults rather than in older individuals. Using psychometric testing, Lavie and Milani
      • Lavie C.J.
      • Milani R.V.
      Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
      found that compared with elderly patients with CHD, younger patients with CHD had a 94% increase in hostility, a 52% increase in anxiety, and a 24% increase in depression.
      As previously stated, psychosocial stress directly induces a host of physiologic derangements via the sympathetic nervous system and the HPA axis, including elevated blood pressure during waking hours and sometimes during sleep. Hostility and other types of adverse psychosocial stress are linked to elevations in resting HR and amplified elevations in blood pressure, often in response to even mundane, generally nonthreatening environmental stimuli.
      • Curtis B.M.
      • O'Keefe Jr., J.H.
      Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
      Individuals with high levels of hostility tend to respond to stress with exaggerated adrenergic responses, which not only can increase blood pressure but also can cause coronary vasoconstriction, increase inflammation, and activate platelets, all of which could trigger MI, stroke, or CV death.
      • Wong J.M.
      • Na B.
      • Regan M.C.
      • Whooley M.A.
      Hostility, health behaviors, and risk of recurrent events in patients with stable coronary heart disease: findings from the Heart and Soul Study.
      In addition, psychosocial stress leads to hypercortisolemia and higher levels of circulating catecholamines
      • Suarez E.C.
      • Kuhn C.M.
      • Schanberg S.M.
      • Williams Jr., R.B.
      • Zimmermann E.A.
      Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge.
      and lower levels of vagal tone, particularly in the CV system.
      • Sloan R.P.
      • Shapiro P.A.
      • Bigger Jr., J.T.
      • Bagiella E.
      • Steinman R.C.
      • Gorman J.M.
      Cardiac autonomic control and hostility in healthy subjects.
      Importantly, in addition to these involuntary responses, psychosocial stress can indirectly degrade health and well-being by triggering maladaptive coping strategies and self-destructive behaviors. Indeed, hostility has been linked to poor diet, obesity, sleep disturbances, and abuse of alcohol, tobacco, and other addictive substances, and it can lead to unhealthy levels of social isolation.
      • Everson S.A.
      • Kauhanen J.
      • Kaplan G.A.
      • et al.
      Hostility and increased risk of mortality and acute myocardial infarction: the mediating role of behavioral risk factors.
      • Kawachi I.
      • Sparrow D.
      • Spiro III, A.
      • Vokonas P.
      • Weiss S.T.
      A prospective study of anger and coronary heart disease: the Normative Aging Study.
      Hostility has been associated with elevated risks of HTN, coronary artery calcification,
      • Iribarren C.
      • Sidney S.
      • Bild D.E.
      • et al.
      Association of hostility with coronary artery calcification in young adults: the CARDIA study: coronary artery risk development in young adults.
      coronary atherosclerosis,
      • Williams Jr., R.B.
      • Haney T.L.
      • Lee K.L.
      • Kong Y.H.
      • Blumenthal J.A.
      • Whalen R.E.
      Type A behavior, hostility, and coronary atherosclerosis.
      peripheral atherosclerosis,
      • Deary I.J.
      • Fowkes F.G.
      • Donnan P.T.
      • Housley E.
      Hostile personality and risks of peripheral arterial disease in the general population.
      • Knox S.S.
      • Adelman A.
      • Ellison R.C.
      • et al.
      Hostility, social support, and carotid artery atherosclerosis in the National Heart, Lung, and Blood Institute Family Heart Study.
      dyslipidemia, and obesity, as well as elevated levels of tumor necrosis factor α
      • Suarez E.C.
      • Lewis J.G.
      • Kuhn C.
      The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men.
      and platelet reactivity.
      • Markovitz J.H.
      • Matthews K.A.
      • Kiss J.
      • Smitherman T.C.
      Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls.
      High levels of hostility have also been linked to a 4-fold increased incidence of symptomatic CHD and a 5-fold increase in adverse CVD events.
      • Lavie C.J.
      • Milani R.V.
      • O'Keefe J.H.
      • Lavie T.J.
      Impact of exercise training on psychological risk factors.
      • Haynes S.G.
      • Feinleib M.
      • Kannel W.B.
      The relationship of psychosocial factors to coronary heart disease in the Framingham Study, III: eight-year incidence of coronary heart disease.
      • Rosenman R.H.
      • Brand R.J.
      • Jenkins D.
      • Friedman M.
      • Straus R.
      • Wurm M.
      Coronary heart disease in Western Collaborative Group Study: final follow-up experience of 8 1/2 years.
      Hostility as a CVD risk factor is especially prevalent in younger males, where psychosocial stress and high levels of hostility are associated with increased risks of all-cause mortality and CVD (Figure 2).
      • Boyle S.H.
      • Williams R.B.
      • Mark D.B.
      • Brummett B.H.
      • Siegler I.C.
      • Barefoot J.C.
      Hostility, age, and mortality in a sample of cardiac patients.
      • Todaro J.F.
      • Con A.
      • Niaura R.
      • Spiro III, A.
      • Ward K.D.
      • Roytberg A.
      Combined effect of the metabolic syndrome and hostility on the incidence of myocardial infarction (the Normative Aging Study).
      Figure thumbnail gr2
      Figure 2Age-adjusted annual rates of adverse events as a function of hostility. Quartile I (lightest shade of green) is the least hostile group, with each sequential quartile increasing in level of hostility. Increased levels of hostility were significantly associated with rates of all-cause mortality and any event, which is a composite of stroke or transient ischemic event (TIA), myocardial infarction, heart failure, and death. Data from Am J Cardiol.
      • Boyle S.H.
      • Williams R.B.
      • Mark D.B.
      • Brummett B.H.
      • Siegler I.C.
      • Barefoot J.C.
      Hostility, age, and mortality in a sample of cardiac patients.

      CVD Inciting Mental Illness

      Cardiovascular disease and psychosocial stress often coexist in bidirectional, self-catalyzing relationships whereby adverse CVD events such as MI, heart failure, arrhythmias, and stroke often worsen or even cause psychiatric issues, such as major depression or generalized anxiety disorder. Regardless of demographic characteristics, clinically unrecognized depression is prevalent in CVD.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      The psychosocial stress associated with depression can lead patients to “catastrophize” their condition, which can cause them to become hypervigilant about their health. In turn, this can predispose to unnecessary visits to the emergency department, an increased use of outpatient services, and increased hospitalizations.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      Psychosocial stress, particularly depressive symptoms, also can be associated with a learned helplessness, which often increases days spent in bed and long-lasting functional disability.
      • Egede L.E.
      Major depression in individuals with chronic medical disorders: prevalence, correlates and association with health resource utilization, lost productivity and functional disability.
      Compared with the general public, depression is approximately 3 times more common in patients with CHD, heart failure, or acute MI.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      • Thombs B.D.
      • Bass E.B.
      • Ford D.E.
      • et al.
      Prevalence of depression in survivors of acute myocardial infarction.
      Cardiovascular disease is accompanied by major depression disorder in approximately 25% of patients, with estimations of minor depression and elevated depressive symptoms afflicting almost half of all patients with diagnosed CVD.
      • Das S.
      • O'Keefe J.H.
      Behavioral cardiology: recognizing and addressing the profound impact of psychosocial stress on cardiovascular health.
      Major depression occurs with a prevalence rate of approximately 6% to 7% in the general population, yet, in cohorts of patients with heart failure or diabetes mellitus with poor glycemic control, the rates of diagnosed depression range from 20% to 40%.
      • Guck T.P.
      • Elsasser G.N.
      • Kavan M.G.
      • Barone E.J.
      Depression and congestive heart failure.
      • Lustman P.J.
      • Anderson R.J.
      • Freedland K.E.
      • de Groot M.
      • Carney R.M.
      • Clouse R.E.
      Depression and poor glycemic control: a meta-analytic review of the literature.
      This body of evidence indicates that in patients with chronic CVD, depression is being grossly underaddressed.

      Exercise Effects on CVD

      The adoption of a consistent exercise regimen is one of the most effective steps that a patient struggling with psychosocial stress can take to reduce mental suffering and physical disability. Increased physical activity, regular exercise, and improved levels of cardiorespiratory fitness have the power to ameliorate many of the adverse physiologic effects of psychosocial stress. Cardiorespiratory exercise training programs have been shown to improve autonomic nervous system function,
      • Lucini D.
      • Milani R.V.
      • Costantino G.
      • Lavie C.J.
      • Porta A.
      • Pagani M.
      Effects of cardiac rehabilitation and exercise training on autonomic regulation in patients with coronary artery disease.
      inflammation,
      • Lavie C.J.
      • Church T.S.
      • Milani R.V.
      • Earnest C.P.
      Impact of physical activity, cardiorespiratory fitness, and exercise training on markers of inflammation.
      metabolic syndrome,
      • Lavie C.J.
      • Milani R.V.
      Cardiac rehabilitation and exercise training programs in metabolic syndrome and diabetes.
      • Milani R.V.
      • Lavie C.J.
      Prevalence and profile of metabolic syndrome in patients following acute coronary events and effects of therapeutic lifestyle change with cardiac rehabilitation.
      blood rheology,
      • Church T.S.
      • Lavie C.J.
      • Milani R.V.
      • Kirby G.S.
      Improvements in blood rheology after cardiac rehabilitation and exercise training in patients with coronary heart disease.
      brain plasticity, mood, and cognition.
      • McAuley E.
      • Kramer A.F.
      • Colcombe S.J.
      Cardiovascular fitness and neurocognitive function in older adults: a brief review.
      Evidence indicates that this exercise training–induced realignment of blood rheology and the autonomic nervous system could, in part, result from improvements in psychological and behavioral factors.
      • Church T.S.
      • Lavie C.J.
      • Milani R.V.
      • Kirby G.S.
      Improvements in blood rheology after cardiac rehabilitation and exercise training in patients with coronary heart disease.
      Typically, an exercise regimen over time lowers stress, improves functionality, and reduces subsequent rehospitalization costs.
      • Ades P.A.
      • Huang D.
      • Weaver S.O.
      Cardiac rehabilitation participation predicts lower rehospitalization costs.
      Exercise training improves many of the systemic derangements associated with depression, including improvements in HR variability, baroreflex reactivity, QT prolongation, autonomic balance, inflammation, hypercoagulability, and endothelial function.
      • Wenger N.K.
      Current status of cardiac rehabilitation.
      Yet, it is in the most crucial category of all—mortality rates—where patients stand to benefit the most from increased physical activity.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      Compared with inactive patients, those with consistent levels of adequate physical activity after experiencing an MI have half the risk of dying during follow-up.
      • Gerber Y.
      • Myers V.
      • Goldbourt U.
      • Benyamini Y.
      • Scheinowitz M.
      • Drory Y.
      Long-term trajectory of leisure time physical activity and survival after first myocardial infarction: a population-based cohort study.
      Individuals with heart failure had a 59% lower incidence of mortality if they participated in exercise cardiac rehabilitation. The cumulative data indicate that increased physical activity, exercise training, and formal cardiorespiratory exercise training each seem to decrease morbidity and markedly improve patient well-being and overall survival rates.
      • Milani R.V.
      • Lavie C.J.
      Impact of cardiac rehabilitation on depression and its associated mortality.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      • O'Connor G.T.
      • Buring J.E.
      • Yusuf S.
      • et al.
      An overview of randomized trials of rehabilitation with exercise after myocardial infarction.
      • Lavie C.J.
      • Menezes A.R.
      • De Schutter A.
      • Milani R.V.
      • Blumenthal J.A.
      Impact of cardiac rehabilitation and exercise training on psychological risk factors and subsequent prognosis in patients with cardiovascular disease.

      Effect of Exercise on Stress

      Exercise training reduces cortisol levels, HR, and anxiety responses to stress.
      • von Haaren B.
      • Haertel S.
      • Stumpp J.
      • Hey S.
      • Ebner-Priemer U.
      Reduced emotional stress reactivity to a real-life academic examination stressor in students participating in a 20-week aerobic exercise training: a randomised controlled trial using ambulatory assessment.
      Furthermore, improved cardiorespiratory fitness reduces reactivity of the autonomic nervous system to psychosocial stress.
      • von Haaren B.
      • Haertel S.
      • Stumpp J.
      • Hey S.
      • Ebner-Priemer U.
      Reduced emotional stress reactivity to a real-life academic examination stressor in students participating in a 20-week aerobic exercise training: a randomised controlled trial using ambulatory assessment.
      The Aerobics Center Longitudinal Study reported that low levels of negative emotions were associated with a 30% lower risk of all-cause mortality. Even more impressively, when low levels of negative emotions were coupled with high cardiorespiratory fitness, all-cause mortality dropped by 63%.
      • Ortega F.B.
      • Lee D.C.
      • Sui X.
      • et al.
      Psychological well-being, cardiorespiratory fitness, and long-term survival.
      Exercise not only mitigates CVD risk factors but also curbs emotional distress, anxiety, hostility. and depression.
      • Milani R.V.
      • Lavie C.J.
      Behavioral differences and effects of cardiac rehabilitation in diabetic patients following cardiac events.
      • Milani R.V.
      • Lavie C.J.
      • Cassidy M.M.
      Effects of cardiac rehabilitation and exercise training programs on depression in patients after major coronary events.
      • Blumenthal J.A.
      • Sherwood A.
      • Babyak M.A.
      • et al.
      Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial.
      • Lavie C.J.
      • Milani R.V.
      • Cassidy M.M.
      • Gilliland Y.E.
      Effects of cardiac rehabilitation and exercise training programs in women with depression.
      Although psychosocial stress disproportionally afflicts younger patients with CVD,
      • Todaro J.F.
      • Con A.
      • Niaura R.
      • Spiro III, A.
      • Ward K.D.
      • Roytberg A.
      Combined effect of the metabolic syndrome and hostility on the incidence of myocardial infarction (the Normative Aging Study).
      • Cole J.H.
      • Miller III, J.I.
      • Sperling L.S.
      • Weintraub W.S.
      Long-term follow-up of coronary artery disease presenting in young adults.
      Lavie and Milani
      • Lavie C.J.
      • Milani R.V.
      Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
      reported that these same individuals have the most to gain. After formal cardiac rehabilitation programs, the younger cohort had the greatest improvements in both body mass index and oxygen consumption, in addition to 50% to 80% reductions in hostility, anxiety, and depression.
      • Lavie C.J.
      • Milani R.V.
      Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
      Recent studies suggest that in patients of all ages who have experienced an MI, exercise has the ability to treat existing depression or prevent future depression.
      • Ernstsen L.
      • Rangul V.
      • Nauman J.
      • et al.
      Protective effect of regular physical activity on depression after myocardial infarction: the HUNT Study.
      • Marmot M.G.
      • Bosma H.
      • Hemingway H.
      • Brunner E.
      • Stansfeld S.
      Contribution of job control and other risk factors to social variations in coronary heart disease incidence.
      • Babyak M.
      • Blumenthal J.A.
      • Herman S.
      • et al.
      Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months.
      • Milani R.V.
      • Lavie C.J.
      Reducing psychosocial stress: a novel mechanism of improving survival from exercise training.
      • Vankim N.A.
      • Nelson T.F.
      Vigorous physical activity, mental health, perceived stress, and socializing among college students.
      Moreover, 57% of exercise training participants who exhibited significant improvements in oxygen consumption demonstrated parallel reductions in their levels of depression.
      • Marmot M.G.
      • Bosma H.
      • Hemingway H.
      • Brunner E.
      • Stansfeld S.
      Contribution of job control and other risk factors to social variations in coronary heart disease incidence.
      A substantial body of research now supports the assertion that for depression, exercise is as effective as antidepressant medications.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      • Babyak M.
      • Blumenthal J.A.
      • Herman S.
      • et al.
      Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months.
      Milani and Lavie
      • Milani R.V.
      • Lavie C.J.
      Reducing psychosocial stress: a novel mechanism of improving survival from exercise training.
      also reported that in 522 patients, nearly all mortality during follow-up occurred in the cohort of patients with high psychosocial stress who failed to increase their exercise capacity (Figure 3). Furthermore, the cohort of patients with heart failure with persistent depressive symptoms after formal cardiorespiratory exercise training have a 4-fold higher mortality rate compared with their nondepressed counterparts.
      • Milani R.V.
      • Lavie C.J.
      Impact of cardiac rehabilitation on depression and its associated mortality.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      Yet, even individuals with persistent depression after successfully completing cardiorespiratory exercise training had half of the all-cause mortality rate as depressed patients who dropped out of exercise training.
      • Milani R.V.
      • Lavie C.J.
      • Mehra M.R.
      • Ventura H.O.
      Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
      Figure thumbnail gr3
      Figure 3Actuarial cumulative hazard plot for survival time based on changes in exercise capacity (high exercise change vs low exercise change) after exercise training split by baseline psychosocial stress (high psychosocial stress vs low psychosocial stress; n=522). Individuals with high psychosocial stress who did not increase their exercise were at markedly higher risk for mortality during follow-up. In contrast, those with high psychosocial stress who increased their exercise had the lowest risk of mortality. Reprinted with permission from Am J Med.
      • Milani R.V.
      • Lavie C.J.
      Reducing psychosocial stress: a novel mechanism of improving survival from exercise training.

      The Power of Physical Play

      Studies show that the stress reduction benefits of physical activity are magnified when exercise is performed in social settings such as group workouts, team sports, and interactive play.
      • Vankim N.A.
      • Nelson T.F.
      Vigorous physical activity, mental health, perceived stress, and socializing among college students.
      A recent, very large cross-sectional study found that people who exercised regularly had approximately 43% fewer days of poor mental health compared with matched sedentary individuals.
      • Chekroud S.R.
      • Gueorguieva R.
      • Zheutlin A.B.
      • et al.
      Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
      The mental health improvements were strongest for those who exercised 30 to 45 minutes per session, 3 to 5 times per week. Group sports such as soccer, basketball, volleyball, and other popular team sports showed the strongest associations with good mental health.
      • Chekroud S.R.
      • Gueorguieva R.
      • Zheutlin A.B.
      • et al.
      Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
      As with other studies on the topic of exercise and health, more is not always better; the mental health benefits of exercise were markedly diminished in those who exercised more than 24 times per month, or longer than 90 minutes per session (Figure 4).
      • Chekroud S.R.
      • Gueorguieva R.
      • Zheutlin A.B.
      • et al.
      Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
      Figure thumbnail gr4
      Figure 4Mental health burden as a function of exercise frequency. People who exercised 12 to 24 times per month had the lowest mental health burden. Frequencies of less than 3 per week (12 sessions per month) or more than 6 per week (24 sessions per month) were associated with worse mental health. Reprinted with permission from Lancet Psychiatry.
      • Chekroud S.R.
      • Gueorguieva R.
      • Zheutlin A.B.
      • et al.
      Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
      A large longitudinal prospective study of Danish adults showed that the leisure-time physical activities that are most effective for improving life expectancy are those that require 2 or more individuals to play together, such as racquet sports, golf, and soccer (Figure 5).
      • Schnohr P.
      • O'Keefe J.H.
      • Holtermann A.
      • et al.
      Various leisure-time physical activities associated with widely divergent life expectancies: the Copenhagen City Heart Study.
      These physical activities that require interactive play increased life expectancy much better than solitary exercises such as running and workouts on a treadmill or elliptical trainer.
      Figure thumbnail gr5
      Figure 5Survival improvement calculated using multivariable Cox proportional hazards regression analysis adjusted for age, sex, educational level, income, alcohol intake, tobacco smoking, diabetes, and weekly volume of other leisure-time physical activities. Compared with sedentary lifestyle (control group), all the different leisure-time physical activities significantly improved survival time except health club activities (treadmill, elliptical trainer, weights, etc). Adapted with permission from Mayo Clin Proc.
      • Schnohr P.
      • O'Keefe J.H.
      • Holtermann A.
      • et al.
      Various leisure-time physical activities associated with widely divergent life expectancies: the Copenhagen City Heart Study.

      Interventions to Improve Stress and CV Health

      Thus, CVD is both a cause and a result of psychosocial stress. Exercise, especially when performed in interactive sports or social settings, increases life expectancy and markedly improves overall health and well-being.
      • Chekroud S.R.
      • Gueorguieva R.
      • Zheutlin A.B.
      • et al.
      Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
      • Schnohr P.
      • O'Keefe J.H.
      • Holtermann A.
      • et al.
      Various leisure-time physical activities associated with widely divergent life expectancies: the Copenhagen City Heart Study.
      Thus, increased physical activity is a potent, natural, and practical therapy for alleviating stress and improving overall prognosis (Figure 6). In addition to standard CVD pharmacology, the following 3-pronged approach is aimed at bolstering psychological health while also promoting CV wellness and longevity.
      Figure thumbnail gr6
      Figure 6The complex interactions among stress, cardiovascular (CV) disease (CVD), and exercise. ANS = autonomic nervous system; HPA = hypothalamus-pituitary-adrenal; SNS = sympathetic nervous system; SSRI = selective serotonin reuptake inhibitor.

      Enhanced Cardiac Rehabilitation

      Cardiac rehabilitation that uses a program to emphasize interpersonal support for stress reduction has been shown to bestow synergistic CV health benefits beyond those provided by solitary exercise.
      • Blumenthal J.A.
      • Sherwood A.
      • Smith P.J.
      • et al.
      Enhancing cardiac rehabilitation with stress management training: a randomized clinical efficacy trial.
      Furthermore, group exercise seems to provide social support while at the same time improving fitness levels, and thus may be the single most important intervention for patients afflicted by concomitant psychosocial stress and CVD because it has the potential to improve outcomes for both conditions.
      • Lavie C.J.
      • Menezes A.R.
      • De Schutter A.
      • Milani R.V.
      • Blumenthal J.A.
      Impact of cardiac rehabilitation and exercise training on psychological risk factors and subsequent prognosis in patients with cardiovascular disease.
      • Kachur S.
      • Menezes A.R.
      • De Schutter A.
      • Milani R.V.
      • Lavie C.J.
      Significance of comorbid psychological stress and depression on outcomes after cardiac rehabilitation.
      Of concern, patients presenting with persistently high estimated cardiorespiratory fitness matched with persistently high depressive symptoms demonstrate no attenuation in mortality risk.
      • Carlsen T.
      • Salvesen O.
      • Sui X.
      • et al.
      Long-term changes in depressive symptoms and estimated cardiorespiratory fitness and risk of all-cause mortality: the Nord-Trondelag Health Study.
      In essence, unremittingly high levels of psychosocial stress can thwart some of the health benefits of long-term exercise training.
      With this in mind, we recommend that the standard cardiorespiratory exercise training regimen should be revamped with increased emphasis on interpersonal interaction during and after the formal exercise classes. Cardiac rehabilitation exercises in general are predominantly solitary activities, such as walking on a treadmill or strength training. The physical activities performed during cardiac rehabilitation training could be easily transitioned to be interactive group exercise sessions.

      Lifestyle Modification

      Behavioral cardiology has gained traction due to myriad CVD risk factors that stem from psychosocial stress and self-destructive lifestyles. For example, an inadequate social support network has been implicated in increasing mortality rates in patients with CVD. Specifically, psychosocial stress factors such as social isolation
      • Ruberman W.
      • Weinblatt E.
      • Goldberg J.D.
      • Chaudhary B.S.
      Psychosocial influences on mortality after myocardial infarction.
      as well as living alone,
      • Case R.B.
      • Moss A.J.
      • Case N.
      • McDermott M.
      • Eberly S.
      Living alone after myocardial infarction: impact on prognosis.
      lacking a confidant,
      • Williams R.B.
      • Barefoot J.C.
      • Califf R.M.
      • et al.
      Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease.
      low emotional support,
      • Berkman L.F.
      • Leo-Summers L.
      • Horwitz R.I.
      Emotional support and survival after myocardial infarction: a prospective, population-based study of the elderly.
      lack of available support,
      • Gorkin L.
      • Schron E.B.
      • Brooks M.M.
      • et al.
      Psychosocial predictors of mortality in the Cardiac Arrhythmia Suppression Trial-1 (CAST-1).
      and low perceived support
      • Frasure-Smith N.
      • Lesperance F.
      • Gravel G.
      • et al.
      Social support, depression, and mortality during the first year after myocardial infarction.
      all increase long-term mortality rates. Other subjective contributors to adverse clinical outcomes include excessive job strain
      • Rosengren A.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
      • Kivimaki M.
      • Leino-Arjas P.
      • Luukkonen R.
      • Riihimaki H.
      • Vahtera J.
      • Kirjonen J.
      Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees.
      • Matthews K.A.
      • Gump B.B.
      Chronic work stress and marital dissolution increase risk of posttrial mortality in men from the Multiple Risk Factor Intervention Trial.
      and a low socioeconomic status, particularly when linked with poor health habits, indigent housing conditions, and financial instability.
      • Marmot M.G.
      • Bosma H.
      • Hemingway H.
      • Brunner E.
      • Stansfeld S.
      Contribution of job control and other risk factors to social variations in coronary heart disease incidence.
      Furthermore, evidence suggests that a strained marital relationship also adversely affects CV health.
      • Matthews K.A.
      • Gump B.B.
      Chronic work stress and marital dissolution increase risk of posttrial mortality in men from the Multiple Risk Factor Intervention Trial.
      • Orth-Gomer K.
      • Wamala S.P.
      • Horsten M.
      • Schenck-Gustafsson K.
      • Schneiderman N.
      • Mittleman M.A.
      Marital stress worsens prognosis in women with coronary heart disease: the Stockholm Female Coronary Risk Study.
      Unfortunately, various types of psychosocial stress tend to cluster together in a vulnerable person and precipitate cumulative effects.
      • Mausner-Dorsch H.
      • Eaton W.W.
      Psychosocial work environment and depression: epidemiologic assessment of the demand-control model.
      Ruberman et al
      • Ruberman W.
      • Weinblatt E.
      • Goldberg J.D.
      • Chaudhary B.S.
      Psychosocial influences on mortality after myocardial infarction.
      reported that in post-MI patients, high levels of life stress and social isolation were each individually associated with a 2-fold increase in subsequent CVD events, but when those insults occurred simultaneously, the individual's CV risk was magnified 4-fold.
      Research shows that approximately 95% of Americans believe in God or some spiritual higher power. Faith and hope confer beneficial effects on the mind-heart axis as well as the CV system, especially when combined with attendance at regularly scheduled in-person gatherings.
      • Zimmer Z.
      • Jagger C.
      • Chiu C.T.
      • Ofstedal M.B.
      • Rojo F.
      • Saito Y.
      Spirituality, religiosity, aging and health in global perspective: a review.
      In part, a person's outlook on life is volitional so that one can consciously choose to adopt a more optimistic attitude, a friendlier and more trusting manner, and an altruistic demeanor, all of which are associated with improvements in mental health and physical well-being.
      • Maruta T.
      • Colligan R.C.
      • Malinchoc M.
      • Offord K.P.
      Optimism-pessimism assessed in the 1960s and self-reported health status 30 years later.
      Notably, the presence of a pet (particularly a dog) in the home or regularly tending a garden are 2 additional methods of lowering stress and improving long-term CV health and overall well-being.
      • Mubanga M.
      • Byberg L.
      • Nowak C.
      • et al.
      Dog ownership and the risk of cardiovascular disease and death: a nationwide cohort study.
      • O'Keefe J.H.
      • O'Keefe E.L.
      • Lavie C.J.
      The goldilocks zone for exercise: not too little, not too much.
      Heat therapy, such as sauna bathing, seems to lower the risk of fatal CV events and has also been used to reduce subjective stress.
      • Laukkanen T.
      • Kunutsor S.K.
      • Khan H.
      • Willeit P.
      • Zaccardi F.
      • Laukkanen J.A.
      Sauna bathing is associated with reduced cardiovascular mortality and improves risk prediction in men and women: a prospective cohort study.
      Meditation, tai chi, and yoga have also been found to be effective for lowering stress, although definitive studies have not been performed to prove that these interventions improve CV outcomes.
      • Goyal M.
      • Singh S.
      • Sibinga E.M.
      • et al.
      Meditation programs for psychological stress and well-being: a systematic review and meta-analysis.
      • O'Keefe J.H.
      • O'Keefe E.L.
      • Lavie C.J.
      Socially interactive exercise improves longevity: the power of playing with friends.

      Pharmacologic Intervention

      A recently published randomized trial suggested that a selective serotonin reuptake inhibitor might improve long-term outcome after an acute MI. Of 300 patients with depression after recent acute MI, 6 months of treatment with escitalopram compared with placebo resulted in a reduced risk of major adverse CV events after follow-up of 8 years.
      • Kim J.M.
      • Stewart R.
      • Lee Y.S.
      • et al.
      Effect of escitalopram vs placebo treatment for depression on long-term cardiac outcomes in patients with acute coronary syndrome: a randomized clinical trial.
      The selective serotonin reuptake inhibitor class of antidepressant medication has been found to be safe for patients with CVD and could prove useful as an adjunct in some individuals, although further randomized trials are needed to clarify this potential indication.
      Omega-3 fats, particularly those derived from marine life, are critically important for optimal functioning of the brain
      • Mocking R.J.
      • Harmsen I.
      • Assies J.
      • Koeter M.W.
      • Ruhe H.G.
      • Schene A.H.
      Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.
      as well as the CV system.
      • Elagizi A.
      • Lavie C.J.
      • Marshall K.
      • DiNicolantonio J.J.
      • O'Keefe J.H.
      • Milani R.V.
      Omega-3 polyunsaturated fatty acids and cardiovascular health: a comprehensive review.
      Approximately 90% US adults are deficient in omega-3, and this predisposes to adverse CV events, depression, and other mental disorders.
      • Richter C.K.
      • Bowen K.J.
      • Mozaffarian D.
      • Kris-Etherton P.M.
      • Skulas-Ray A.C.
      Total long-chain n-3 fatty acid intake and food sources in the United States compared to recommended intakes: NHANES 2003-2008.
      Increased omega-3 content in the cell membranes and blood induced by eating fish or consuming omega-3 supplements may, in part, exert cardioprotective effects via improvement in mood and overall brain functioning.
      • Mocking R.J.
      • Harmsen I.
      • Assies J.
      • Koeter M.W.
      • Ruhe H.G.
      • Schene A.H.
      Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.
      • Elagizi A.
      • Lavie C.J.
      • Marshall K.
      • DiNicolantonio J.J.
      • O'Keefe J.H.
      • Milani R.V.
      Omega-3 polyunsaturated fatty acids and cardiovascular health: a comprehensive review.
      • O'Keefe J.H.
      • Jacob D.
      • Lavie C.J.
      Omega-3 fatty acid therapy: the tide turns for a fish story.
      β-Blockers can be useful in treating some specific types of stress, such as panic attacks and performance anxiety. β-Blockers have been found to be as effective as benzodiazepines for the treatment of panic disorder and do not carry the high risk of sedation, cognitive impairment, dependence, and tolerance seen with benzodiazepines.
      • Steenen S.A.
      • van Wilk A.J.
      • van Westrhenen R.
      • de Lange J.
      Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis.
      Propranolol also seems to be useful for the treatment of performance anxiety, wherein the β-blocker blunts the adrenergic hypersensitivity, thereby diminishing the fear response.
      • Steenen S.A.
      • van Wilk A.J.
      • van Westrhenen R.
      • de Lange J.
      Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis.
      β-Blockers do not treat the underlying psychological causes of anxiety but can help reduce physical manifestations of excess adrenergic tone such as tremor, sinus tachycardia, diaphoresis, and dizziness. By decreasing the body's physical reactions to stress, β-blockers can help lessen the subjective sense of anxiety during stressful times.

      Conclusion

      Psychosocial stress and CVD often coexist in bidirectional self-reinforcing associations that can exert toxic effects on long-term mental and physical health. It is our strong assertion that cardiorespiratory exercise training programs and increased physical activity, especially when performed in socially interactive settings, such as interactive play, have the potential to reduce the burden of noncommunicable diseases in general and specifically to reduce psychosocial stress while at the same time improving CV prognosis. Much of the data on this topic are observational, and, thus, randomized controlled trials are necessary to prove which types of interactive exercise are most beneficial for mental and CV health.

      Supplemental Online Material

      References

        • Institute of Medicine
        Cardiovascular Disability: Updating the Social Security Listings.
        The National Academies Press, Washington, DC2010
        • Tejada V.B.
        • Bastian B.
        • Arias E.
        Mortality Trends in the United States, 1900–2015.
        CDC/National Center for Health Statistics, Atlanta, GA2015
        • Bloom D.E.
        • Cafiero E.T.
        • Jane-Llopis E.
        • et al.
        The Global Economic Burden of Noncommunicable Diseases.
        World Economic Forum, Geneva, Switzerland2011
        • Church T.S.
        • Thomas D.M.
        • Tudor-Locke C.
        • et al.
        Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
        PLoS One. 2011; 6: e19657
        • GBD 2015 Disease and Injury Incidence and Prevalence Collaborators
        Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet. 2016; 388: 1545-1602
        • Kohl III, H.W.
        • Craig C.L.
        • Lambert E.V.
        • et al.
        The pandemic of physical inactivity: global action for public health.
        Lancet. 2012; 380: 294-305
        • Rosengren A.
        • Hawken S.
        • Ounpuu S.
        • et al.
        Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study.
        Lancet. 2004; 364: 953-962
        • Curtis B.M.
        • O'Keefe Jr., J.H.
        Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.
        Mayo Clin Proc. 2002; 77: 45-54
        • Barefoot J.C.
        Depression and coronary heart disease.
        Cardiologia. 1997; 42: 1245-1250
        • Dimsdale J.E.
        Psychological stress and cardiovascular disease.
        J Am Coll Cardiol. 2008; 51: 1237-1246
        • Figueredo V.M.
        The time has come for physicians to take notice: the impact of psychosocial stressors on the heart.
        Am J Med. 2009; 122: 704-712
        • Lavie C.J.
        • Milani R.V.
        • O'Keefe J.H.
        • Lavie T.J.
        Impact of exercise training on psychological risk factors.
        Prog Cardiovasc Dis. 2011; 53: 464-470
        • Rozanski A.
        • Blumenthal J.A.
        • Davidson K.W.
        • Saab P.G.
        • Kubzansky L.
        The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology.
        J Am Coll Cardiol. 2005; 45: 637-651
        • Lavie C.J.
        • Milani R.V.
        Cardiac rehabilitation and exercise training programs in metabolic syndrome and diabetes.
        J Cardiopulm Rehabil. 2005; 25: 59-66
        • Milani R.V.
        • Lavie C.J.
        Behavioral differences and effects of cardiac rehabilitation in diabetic patients following cardiac events.
        Am J Med. 1996; 100: 517-523
        • Das S.
        • O'Keefe J.H.
        Behavioral cardiology: recognizing and addressing the profound impact of psychosocial stress on cardiovascular health.
        Curr Atheroscler Rep. 2006; 8: 111-118
        • Lett H.S.
        • Blumenthal J.A.
        • Babyak M.A.
        • et al.
        Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment.
        Psychosom Med. 2004; 66: 305-315
        • Lavie C.J.
        • Milani R.V.
        Prevalence of anxiety in coronary patients with improvement following cardiac rehabilitation and exercise training.
        Am J Cardiol. 2004; 93: 336-339
        • Milani R.V.
        • Lavie C.J.
        • Cassidy M.M.
        Effects of cardiac rehabilitation and exercise training programs on depression in patients after major coronary events.
        Am Heart J. 1996; 132: 726-732
        • Rozanski A.
        • Blumenthal J.A.
        • Kaplan J.
        Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.
        Circulation. 1999; 99: 2192-2217
        • Steinberg J.S.
        • Arshad A.
        • Kowalski M.
        • et al.
        Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack.
        J Am Coll Cardiol. 2004; 44: 1261-1264
        • Huang J.L.
        • Chiou C.W.
        • Ting C.T.
        • Chen Y.T.
        • Chen S.A.
        Sudden changes in heart rate variability during the 1999 Taiwan earthquake.
        Am J Cardiol. 2001; 87 (A249): 245-248
        • Meisel S.R.
        • Kutz I.
        • Dayan K.I.
        • et al.
        Effect of Iraqi missile war on incidence of acute myocardial infarction and sudden death in Israeli civilians.
        Lancet. 1991; 338: 660-661
        • Brotman D.J.
        • Golden S.H.
        • Wittstein I.S.
        The cardiovascular toll of stress.
        Lancet. 2007; 370: 1089-1100
        • Wittstein I.S.
        • Thiemann D.R.
        • Lima J.A.
        • et al.
        Neurohumoral features of myocardial stunning due to sudden emotional stress.
        N Engl J Med. 2005; 352: 539-548
        • Anda R.
        • Williamson D.
        • Jones D.
        • et al.
        Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults.
        Epidemiology. 1993; 4: 285-294
        • Kivimaki M.
        • Steptoe A.
        Effects of stress on the development and progression of cardiovascular disease.
        Nat Rev Cardiol. 2018; 15: 215-229
        • DiMatteo M.R.
        • Lepper H.S.
        • Croghan T.W.
        Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence.
        Arch Intern Med. 2000; 160: 2101-2107
        • Kop W.J.
        • Gottdiener J.S.
        • Tangen C.M.
        • et al.
        Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.
        Am J Cardiol. 2002; 89: 419-424
        • Lavie C.J.
        • Milani R.V.
        Prevalence of hostility in young coronary artery disease patients and effects of cardiac rehabilitation and exercise training.
        Mayo Clin Proc. 2005; 80: 335-342
        • Lavie C.J.
        • Milani R.V.
        Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation.
        Arch Intern Med. 2006; 166: 1878-1883
        • Milani R.V.
        • Lavie C.J.
        Impact of cardiac rehabilitation on depression and its associated mortality.
        Am J Med. 2007; 120: 799-806
        • Rugulies R.
        Depression as a predictor for coronary heart disease: a review and meta-analysis.
        Am J Prev Med. 2002; 23: 51-61
        • Allison T.G.
        • Williams D.E.
        • Miller T.D.
        • et al.
        Medical and economic costs of psychologic distress in patients with coronary artery disease.
        Mayo Clin Proc. 1995; 70: 734-742
        • Dong M.
        • Giles W.H.
        • Felitti V.J.
        • et al.
        Insights into causal pathways for ischemic heart disease: adverse childhood experiences study.
        Circulation. 2004; 110: 1761-1766
        • Puustinen P.J.
        • Koponen H.
        • Kautiainen H.
        • Mantyselka P.
        • Vanhala M.
        Psychological distress measured by the GHQ-12 and mortality: a prospective population-based study.
        Scand J Public Health. 2011; 39: 577-581
        • Robinson K.L.
        • McBeth J.
        • Macfarlane G.J.
        Psychological distress and premature mortality in the general population: a prospective study.
        Ann Epidemiol. 2004; 14: 467-472
        • Russ T.C.
        • Stamatakis E.
        • Hamer M.
        • Starr J.M.
        • Kivimaki M.
        • Batty G.D.
        Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies.
        BMJ. 2012; 345: e4933
        • Morgan E.S.
        • Umberson K.
        • Hertzog C.
        Construct validation of self-reported stress scales.
        Psychol Assess. 2014; 26: 90-99
        • Huffman J.C.
        • Celano C.M.
        • Beach S.R.
        • Motiwala S.R.
        • Januzzi J.L.
        Depression and cardiac disease: epidemiology, mechanisms, and diagnosis.
        Cardiovasc Psychiatry Neurol. 2013; 2013: 695925
        • Agatisa P.K.
        • Matthews K.A.
        • Bromberger J.T.
        • Edmundowicz D.
        • Chang Y.F.
        • Sutton-Tyrrell K.
        Coronary and aortic calcification in women with a history of major depression.
        Arch Intern Med. 2005; 165: 1229-1236
        • Ferketich A.K.
        • Schwartzbaum J.A.
        • Frid D.J.
        • Moeschberger M.L.
        Depression as an antecedent to heart disease among women and men in the NHANES I study: National Health and Nutrition Examination Survey.
        Arch Intern Med. 2000; 160: 1261-1268
        • Penninx B.W.
        • Beekman A.T.
        • Honig A.
        • et al.
        Depression and cardiac mortality: results from a community-based longitudinal study.
        Arch Gen Psychiatry. 2001; 58: 221-227
        • Lavie C.J.
        • Milani R.V.
        • Artham S.M.
        • Gilliland Y.
        Psychological factors and cardiac risk and impact of exercise training programs: a review of Ochsner studies.
        Ochsner J. 2007; 7: 167-172
        • Menezes A.R.
        • Lavie C.J.
        • Milani R.V.
        • O'Keefe J.
        • Lavie T.J.
        Psychological risk factors and cardiovascular disease: is it all in your head?.
        Postgrad Med. 2011; 123: 165-176
        • Scott K.M.
        • Lim C.
        • Al-Hamzawi A.
        • et al.
        Association of mental disorders with subsequent chronic physical conditions: World Mental Health Surveys from 17 countries.
        JAMA Psychiatry. 2016; 73: 150-158
        • Akil H.
        • Haskett R.F.
        • Young E.A.
        • et al.
        Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin.
        Biol Psychiatry. 1993; 33: 73-85
        • Kasckow J.W.
        • Baker D.
        • Geracioti Jr., T.D.
        Corticotropin-releasing hormone in depression and post-traumatic stress disorder.
        Peptides. 2001; 22: 845-851
        • Agabiti-Rosei E.
        • Alicandri C.
        • Beschi M.
        • et al.
        Relationships between plasma catecholamines, renin, age and blood pressure in essential hypertension.
        Cardiology. 1983; 70: 308-316
        • Rosmond R.
        • Bjorntorp P.
        The hypothalamic-pituitary-adrenal axis activity as a predictor of cardiovascular disease, type 2 diabetes and stroke.
        J Intern Med. 2000; 247: 188-197
        • Ehlert U.
        • Gaab J.
        • Heinrichs M.
        Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis.
        Biol Psychol. 2001; 57: 141-152
        • Bruhn J.G.
        • Paredes A.
        • Adsett C.A.
        • Wolf S.
        Psychological predictors of sudden death in myocardial infarction.
        J Psychosom Res. 1974; 18: 187-191
        • Grace S.L.
        • Abbey S.E.
        • Kapral M.K.
        • Fang J.
        • Nolan R.P.
        • Stewart D.E.
        Effect of depression on five-year mortality after an acute coronary syndrome.
        Am J Cardiol. 2005; 96: 1179-1185
        • Geerlings S.W.
        • Beekman A.T.
        • Deeg D.J.
        • Twisk J.W.
        • Van Tilburg W.
        Duration and severity of depression predict mortality in older adults in the community.
        Psychol Med. 2002; 32: 609-618
        • Mykletun A.
        • Bjerkeset O.
        • Overland S.
        • Prince M.
        • Dewey M.
        • Stewart R.
        Levels of anxiety and depression as predictors of mortality: the HUNT study.
        Br J Psychiatry. 2009; 195: 118-125
        • Kawachi I.
        • Sparrow D.
        • Vokonas P.S.
        • Weiss S.T.
        Symptoms of anxiety and risk of coronary heart disease: the Normative Aging Study.
        Circulation. 1994; 90: 2225-2229
        • Frasure-Smith N.
        In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men.
        Am J Cardiol. 1991; 67: 121-127
        • Frasure-Smith N.
        • Lesperance F.
        Depression and anxiety as predictors of 2-year cardiac events in patients with stable coronary artery disease.
        Arch Gen Psychiatry. 2008; 65: 62-71
        • Strik J.J.
        • Denollet J.
        • Lousberg R.
        • Honig A.
        Comparing symptoms of depression and anxiety as predictors of cardiac events and increased health care consumption after myocardial infarction.
        J Am Coll Cardiol. 2003; 42: 1801-1807
        • Wrenn K.C.
        • Mostofsky E.
        • Tofler G.H.
        • Muller J.E.
        • Mittleman M.A.
        Anxiety, anger, and mortality risk among survivors of myocardial infarction.
        Am J Med. 2013; 126: 1107-1113
        • Kawachi I.
        • Colditz G.A.
        • Ascherio A.
        • et al.
        Prospective study of phobic anxiety and risk of coronary heart disease in men.
        Circulation. 1994; 89: 1992-1997
        • Lucini D.
        • Norbiato G.
        • Clerici M.
        • Pagani M.
        Hemodynamic and autonomic adjustments to real life stress conditions in humans.
        Hypertension. 2002; 39: 184-188
        • Meyer T.
        • Buss U.
        • Herrmann-Lingen C.
        Role of cardiac disease severity in the predictive value of anxiety for all-cause mortality.
        Psychosom Med. 2010; 72: 9-15
        • Mykletun A.
        • Bjerkeset O.
        • Dewey M.
        • Prince M.
        • Overland S.
        • Stewart R.
        Anxiety, depression, and cause-specific mortality: the HUNT study.
        Psychosom Med. 2007; 69: 323-331
        • Parker G.
        • Hyett M.
        • Hadzi-Pavlovic D.
        • Brotchie H.
        • Walsh W.
        GAD is good? generalized anxiety disorder predicts a superior five-year outcome following an acute coronary syndrome.
        Psychiatry Res. 2011; 188: 383-389
        • Bonanno G.A.
        • Papa A.
        • Lalande K.
        • Westphal M.
        • Coifman K.
        The importance of being flexible: the ability to both enhance and suppress emotional expression predicts long-term adjustment.
        Psychol Sci. 2004; 15: 482-487
        • Schulz R.
        • Beach S.R.
        Caregiving as a risk factor for mortality: the Caregiver Health Effects Study.
        JAMA. 1999; 282: 2215-2219
        • Wong J.M.
        • Na B.
        • Regan M.C.
        • Whooley M.A.
        Hostility, health behaviors, and risk of recurrent events in patients with stable coronary heart disease: findings from the Heart and Soul Study.
        J Am Heart Assoc. 2013; 2: e000052
        • Suarez E.C.
        • Kuhn C.M.
        • Schanberg S.M.
        • Williams Jr., R.B.
        • Zimmermann E.A.
        Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge.
        Psychosom Med. 1998; 60: 78-88
        • Sloan R.P.
        • Shapiro P.A.
        • Bigger Jr., J.T.
        • Bagiella E.
        • Steinman R.C.
        • Gorman J.M.
        Cardiac autonomic control and hostility in healthy subjects.
        Am J Cardiol. 1994; 74: 298-300
        • Everson S.A.
        • Kauhanen J.
        • Kaplan G.A.
        • et al.
        Hostility and increased risk of mortality and acute myocardial infarction: the mediating role of behavioral risk factors.
        Am J Epidemiol. 1997; 146: 142-152
        • Kawachi I.
        • Sparrow D.
        • Spiro III, A.
        • Vokonas P.
        • Weiss S.T.
        A prospective study of anger and coronary heart disease: the Normative Aging Study.
        Circulation. 1996; 94: 2090-2095
        • Iribarren C.
        • Sidney S.
        • Bild D.E.
        • et al.
        Association of hostility with coronary artery calcification in young adults: the CARDIA study: coronary artery risk development in young adults.
        JAMA. 2000; 283: 2546-2551
        • Williams Jr., R.B.
        • Haney T.L.
        • Lee K.L.
        • Kong Y.H.
        • Blumenthal J.A.
        • Whalen R.E.
        Type A behavior, hostility, and coronary atherosclerosis.
        Psychosom Med. 1980; 42: 539-549
        • Deary I.J.
        • Fowkes F.G.
        • Donnan P.T.
        • Housley E.
        Hostile personality and risks of peripheral arterial disease in the general population.
        Psychosom Med. 1994; 56: 197-202
        • Knox S.S.
        • Adelman A.
        • Ellison R.C.
        • et al.
        Hostility, social support, and carotid artery atherosclerosis in the National Heart, Lung, and Blood Institute Family Heart Study.
        Am J Cardiol. 2000; 86: 1086-1089
        • Suarez E.C.
        • Lewis J.G.
        • Kuhn C.
        The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men.
        Brain Behav Immun. 2002; 16: 675-684
        • Markovitz J.H.
        • Matthews K.A.
        • Kiss J.
        • Smitherman T.C.
        Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls.
        Psychosom Med. 1996; 58: 143-149
        • Haynes S.G.
        • Feinleib M.
        • Kannel W.B.
        The relationship of psychosocial factors to coronary heart disease in the Framingham Study, III: eight-year incidence of coronary heart disease.
        Am J Epidemiol. 1980; 111: 37-58
        • Rosenman R.H.
        • Brand R.J.
        • Jenkins D.
        • Friedman M.
        • Straus R.
        • Wurm M.
        Coronary heart disease in Western Collaborative Group Study: final follow-up experience of 8 1/2 years.
        JAMA. 1975; 233: 872-877
        • Boyle S.H.
        • Williams R.B.
        • Mark D.B.
        • Brummett B.H.
        • Siegler I.C.
        • Barefoot J.C.
        Hostility, age, and mortality in a sample of cardiac patients.
        Am J Cardiol. 2005; 96: 64-66
        • Todaro J.F.
        • Con A.
        • Niaura R.
        • Spiro III, A.
        • Ward K.D.
        • Roytberg A.
        Combined effect of the metabolic syndrome and hostility on the incidence of myocardial infarction (the Normative Aging Study).
        Am J Cardiol. 2005; 96: 221-226
        • Milani R.V.
        • Lavie C.J.
        • Mehra M.R.
        • Ventura H.O.
        Impact of exercise training and depression on survival in heart failure due to coronary heart disease.
        Am J Cardiol. 2011; 107: 64-68
        • Egede L.E.
        Major depression in individuals with chronic medical disorders: prevalence, correlates and association with health resource utilization, lost productivity and functional disability.
        Gen Hosp Psychiatry. 2007; 29: 409-416
        • Thombs B.D.
        • Bass E.B.
        • Ford D.E.
        • et al.
        Prevalence of depression in survivors of acute myocardial infarction.
        J Gen Intern Med. 2006; 21: 30-38
        • Guck T.P.
        • Elsasser G.N.
        • Kavan M.G.
        • Barone E.J.
        Depression and congestive heart failure.
        Congest Heart Fail. 2003; 9: 163-169
        • Lustman P.J.
        • Anderson R.J.
        • Freedland K.E.
        • de Groot M.
        • Carney R.M.
        • Clouse R.E.
        Depression and poor glycemic control: a meta-analytic review of the literature.
        Diabetes Care. 2000; 23: 934-942
        • Lucini D.
        • Milani R.V.
        • Costantino G.
        • Lavie C.J.
        • Porta A.
        • Pagani M.
        Effects of cardiac rehabilitation and exercise training on autonomic regulation in patients with coronary artery disease.
        Am Heart J. 2002; 143: 977-983
        • Lavie C.J.
        • Church T.S.
        • Milani R.V.
        • Earnest C.P.
        Impact of physical activity, cardiorespiratory fitness, and exercise training on markers of inflammation.
        J Cardiopulm Rehabil Prev. 2011; 31: 137-145
        • Milani R.V.
        • Lavie C.J.
        Prevalence and profile of metabolic syndrome in patients following acute coronary events and effects of therapeutic lifestyle change with cardiac rehabilitation.
        Am J Cardiol. 2003; 92: 50-54
        • Church T.S.
        • Lavie C.J.
        • Milani R.V.
        • Kirby G.S.
        Improvements in blood rheology after cardiac rehabilitation and exercise training in patients with coronary heart disease.
        Am Heart J. 2002; 143: 349-355
        • McAuley E.
        • Kramer A.F.
        • Colcombe S.J.
        Cardiovascular fitness and neurocognitive function in older adults: a brief review.
        Brain Behav Immun. 2004; 18: 214-220
        • Ades P.A.
        • Huang D.
        • Weaver S.O.
        Cardiac rehabilitation participation predicts lower rehospitalization costs.
        Am Heart J. 1992; 123: 916-921
        • Wenger N.K.
        Current status of cardiac rehabilitation.
        J Am Coll Cardiol. 2008; 51: 1619-1631
        • Gerber Y.
        • Myers V.
        • Goldbourt U.
        • Benyamini Y.
        • Scheinowitz M.
        • Drory Y.
        Long-term trajectory of leisure time physical activity and survival after first myocardial infarction: a population-based cohort study.
        Eur J Epidemiol. 2011; 26: 109-116
        • O'Connor G.T.
        • Buring J.E.
        • Yusuf S.
        • et al.
        An overview of randomized trials of rehabilitation with exercise after myocardial infarction.
        Circulation. 1989; 80: 234-244
        • Lavie C.J.
        • Menezes A.R.
        • De Schutter A.
        • Milani R.V.
        • Blumenthal J.A.
        Impact of cardiac rehabilitation and exercise training on psychological risk factors and subsequent prognosis in patients with cardiovascular disease.
        Can J Cardiol. 2016; 32: S365-S373
        • von Haaren B.
        • Haertel S.
        • Stumpp J.
        • Hey S.
        • Ebner-Priemer U.
        Reduced emotional stress reactivity to a real-life academic examination stressor in students participating in a 20-week aerobic exercise training: a randomised controlled trial using ambulatory assessment.
        Psychol Sport Exerc. 2015; 20: 67-75
        • Ortega F.B.
        • Lee D.C.
        • Sui X.
        • et al.
        Psychological well-being, cardiorespiratory fitness, and long-term survival.
        Am J Prev Med. 2010; 39: 440-448
        • Blumenthal J.A.
        • Sherwood A.
        • Babyak M.A.
        • et al.
        Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial.
        JAMA. 2005; 293: 1626-1634
        • Lavie C.J.
        • Milani R.V.
        • Cassidy M.M.
        • Gilliland Y.E.
        Effects of cardiac rehabilitation and exercise training programs in women with depression.
        Am J Cardiol. 1999; 83 (A1487): 1480-1483
        • Cole J.H.
        • Miller III, J.I.
        • Sperling L.S.
        • Weintraub W.S.
        Long-term follow-up of coronary artery disease presenting in young adults.
        J Am Coll Cardiol. 2003; 41: 521-528
        • Ernstsen L.
        • Rangul V.
        • Nauman J.
        • et al.
        Protective effect of regular physical activity on depression after myocardial infarction: the HUNT Study.
        Am J Med. 2016; 129: 82-88
        • Marmot M.G.
        • Bosma H.
        • Hemingway H.
        • Brunner E.
        • Stansfeld S.
        Contribution of job control and other risk factors to social variations in coronary heart disease incidence.
        Lancet. 1997; 350: 235-239
        • Babyak M.
        • Blumenthal J.A.
        • Herman S.
        • et al.
        Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months.
        Psychosom Med. 2000; 62: 633-638
        • Milani R.V.
        • Lavie C.J.
        Reducing psychosocial stress: a novel mechanism of improving survival from exercise training.
        Am J Med. 2009; 122: 931-938
        • Vankim N.A.
        • Nelson T.F.
        Vigorous physical activity, mental health, perceived stress, and socializing among college students.
        Am J Health Promot. 2013; 28: 7-15
        • Chekroud S.R.
        • Gueorguieva R.
        • Zheutlin A.B.
        • et al.
        Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: a cross-sectional study.
        Lancet Psychiatry. 2018; 5: P739-P746
        • Schnohr P.
        • O'Keefe J.H.
        • Holtermann A.
        • et al.
        Various leisure-time physical activities associated with widely divergent life expectancies: the Copenhagen City Heart Study.
        Mayo Clin Proc. 2018; 93: 1775-1785
        • Blumenthal J.A.
        • Sherwood A.
        • Smith P.J.
        • et al.
        Enhancing cardiac rehabilitation with stress management training: a randomized clinical efficacy trial.
        Circulation. 2016; 133: 1341-1350
        • Kachur S.
        • Menezes A.R.
        • De Schutter A.
        • Milani R.V.
        • Lavie C.J.
        Significance of comorbid psychological stress and depression on outcomes after cardiac rehabilitation.
        Am J Med. 2016; 129: 1316-1321
        • Carlsen T.
        • Salvesen O.
        • Sui X.
        • et al.
        Long-term changes in depressive symptoms and estimated cardiorespiratory fitness and risk of all-cause mortality: the Nord-Trondelag Health Study.
        Mayo Clin Proc. 2018; 93: 1054-1064
        • Ruberman W.
        • Weinblatt E.
        • Goldberg J.D.
        • Chaudhary B.S.
        Psychosocial influences on mortality after myocardial infarction.
        N Engl J Med. 1984; 311: 552-559
        • Case R.B.
        • Moss A.J.
        • Case N.
        • McDermott M.
        • Eberly S.
        Living alone after myocardial infarction: impact on prognosis.
        JAMA. 1992; 267: 515-519
        • Williams R.B.
        • Barefoot J.C.
        • Califf R.M.
        • et al.
        Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease.
        JAMA. 1992; 267: 520-524
        • Berkman L.F.
        • Leo-Summers L.
        • Horwitz R.I.
        Emotional support and survival after myocardial infarction: a prospective, population-based study of the elderly.
        Ann Intern Med. 1992; 117: 1003-1009
        • Gorkin L.
        • Schron E.B.
        • Brooks M.M.
        • et al.
        Psychosocial predictors of mortality in the Cardiac Arrhythmia Suppression Trial-1 (CAST-1).
        Am J Cardiol. 1993; 71: 263-267
        • Frasure-Smith N.
        • Lesperance F.
        • Gravel G.
        • et al.
        Social support, depression, and mortality during the first year after myocardial infarction.
        Circulation. 2000; 101: 1919-1924
        • Kivimaki M.
        • Leino-Arjas P.
        • Luukkonen R.
        • Riihimaki H.
        • Vahtera J.
        • Kirjonen J.
        Work stress and risk of cardiovascular mortality: prospective cohort study of industrial employees.
        BMJ. 2002; 325: 857
        • Matthews K.A.
        • Gump B.B.
        Chronic work stress and marital dissolution increase risk of posttrial mortality in men from the Multiple Risk Factor Intervention Trial.
        Arch Intern Med. 2002; 162: 309-315
        • Orth-Gomer K.
        • Wamala S.P.
        • Horsten M.
        • Schenck-Gustafsson K.
        • Schneiderman N.
        • Mittleman M.A.
        Marital stress worsens prognosis in women with coronary heart disease: the Stockholm Female Coronary Risk Study.
        JAMA. 2000; 284: 3008-3014
        • Mausner-Dorsch H.
        • Eaton W.W.
        Psychosocial work environment and depression: epidemiologic assessment of the demand-control model.
        Am J Public Health. 2000; 90: 1765-1770
        • Zimmer Z.
        • Jagger C.
        • Chiu C.T.
        • Ofstedal M.B.
        • Rojo F.
        • Saito Y.
        Spirituality, religiosity, aging and health in global perspective: a review.
        SSM Popul Health. 2016; 2: 373-381
        • Maruta T.
        • Colligan R.C.
        • Malinchoc M.
        • Offord K.P.
        Optimism-pessimism assessed in the 1960s and self-reported health status 30 years later.
        Mayo Clin Proc. 2002; 77: 748-753
        • Mubanga M.
        • Byberg L.
        • Nowak C.
        • et al.
        Dog ownership and the risk of cardiovascular disease and death: a nationwide cohort study.
        Sci Rep. 2017; 7: 15821
        • O'Keefe J.H.
        • O'Keefe E.L.
        • Lavie C.J.
        The goldilocks zone for exercise: not too little, not too much.
        Mo Med. 2018; 115: 98-105
        • Laukkanen T.
        • Kunutsor S.K.
        • Khan H.
        • Willeit P.
        • Zaccardi F.
        • Laukkanen J.A.
        Sauna bathing is associated with reduced cardiovascular mortality and improves risk prediction in men and women: a prospective cohort study.
        BMC Med. 2018; 16: 219
        • Goyal M.
        • Singh S.
        • Sibinga E.M.
        • et al.
        Meditation programs for psychological stress and well-being: a systematic review and meta-analysis.
        JAMA Intern Med. 2014; 174: 357-368
        • O'Keefe J.H.
        • O'Keefe E.L.
        • Lavie C.J.
        Socially interactive exercise improves longevity: the power of playing with friends.
        Yoga Phys Ther Rehabil. 2018; 1 (YPTR-152)
        • Kim J.M.
        • Stewart R.
        • Lee Y.S.
        • et al.
        Effect of escitalopram vs placebo treatment for depression on long-term cardiac outcomes in patients with acute coronary syndrome: a randomized clinical trial.
        JAMA. 2018; 320: 350-358
        • Mocking R.J.
        • Harmsen I.
        • Assies J.
        • Koeter M.W.
        • Ruhe H.G.
        • Schene A.H.
        Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder.
        Transl Psychiatry. 2016; 6: e756
        • Elagizi A.
        • Lavie C.J.
        • Marshall K.
        • DiNicolantonio J.J.
        • O'Keefe J.H.
        • Milani R.V.
        Omega-3 polyunsaturated fatty acids and cardiovascular health: a comprehensive review.
        Prog Cardiovasc Dis. 2018; 61: 76-85
        • Richter C.K.
        • Bowen K.J.
        • Mozaffarian D.
        • Kris-Etherton P.M.
        • Skulas-Ray A.C.
        Total long-chain n-3 fatty acid intake and food sources in the United States compared to recommended intakes: NHANES 2003-2008.
        Lipids. 2017; 52: 917-927
        • O'Keefe J.H.
        • Jacob D.
        • Lavie C.J.
        Omega-3 fatty acid therapy: the tide turns for a fish story.
        Mayo Clin Proc. 2017; 92: 1-3
        • Steenen S.A.
        • van Wilk A.J.
        • van Westrhenen R.
        • de Lange J.
        Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis.
        J Psychopharmacol. 2016; 30: 128-139