Anger and mental stress–induced myocardial ischemia: Mechanisms and clinical implications Redford B. Williams, MD, Durham, NC
In the current issue of the Journal, Vaccarino et al 1 report that among a sample of 98 post–myocardial infarction (MI) patients between the ages of 38 and 60 years, those with higher levels of state and trait anger were more likely to develop myocardial ischemia during a stress challenge in which they reported a real-life stressful situation that they had experienced while being evaluated by a small audience wearing white coats. It is noteworthy that none of the anger dimensions assessed were associated with ischemia during exercise or pharmacologic stress. Heart rate, systolic and diastolic blood pressures, and rate pressure product all increased during the stress challenge, but these changes were not associated with the anger dimensions nor, presumably, with ischemia. As the authors note, these findings suggest that increased myocardial ischemia during emotional stress among MI patients with a personality trait that predisposes them to experience higher levels of anger—both acutely and chronically—could be placing them at increased risk or adverse clinical outcomes, in which case, they conclude, “New treatments should be evaluated that specifically target anger to reduce risk of future cardiac events.” Consistent with this interpretation is the finding in a sample of 1,328 coronary heart disease (CHD) patients that the mortality rate over a 14-year follow-up was increased by 52% in those with high hostility scores at baseline, but only in those younger than 61.2 years. 2 To develop new treatments targeting anger that have the potential to reduce mortality in CHD patients with high hostility/anger levels, it would be helpful to have some idea of the biological mechanisms that are mediating the impact of anger on prognosis. One such mediator could be increased platelet reactivity to psychological stress, which has been found to be higher in both CHD patients and age-matched healthy controls with higher hostility levels. 3 In this study, there was a trend (Ps b .10) for larger increases in both norepinephrine and diastolic blood pressure during stress to be associated with increased platelet reactivity. Another study in healthy From the and Departments of Psychiatry and Medicine, Duke University Medical Center, Durham, NC. Submitted September 10, 2014; accepted September 12, 2014. Reprint requests: Redford B. Williams, MD, Departments of Psychiatry and Medicine, Duke University Medical Center, Durham, NC E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.09.003
young white men found larger increases in blood pressure, heart rate, norepinephrine, testosterone, and cortisol during a harassment stressor among those with higher hostility levels. 4 Directly documenting the potential for increased cardiovascular reactivity to stress to increase risk in young adults, in the CARDIA study, those with higher blood pressure reactivity were found to have higher levels of coronary artery calcification 13 years later. 5 Although there was no indication that cardiovascular reactivity to the stressor in the current study was associated with the level of stress-induced ischemia, there has to be some biological mediator of the increased ischemia, and identification of that mediator would be a major help in designing interventions to reduce stress-induced myocardial ischemia—and the associated increased mortality/morbidity— in CHD patients. In the meanwhile, there is some evidence supporting the potential of both pharmacologic and behavioral approaches as a means of reducing stress-induced myocardial ischemia and/or associated increased morbidity/mortality in CHD patients. Directly relevant to the findings of Vaccarino et al, in a placebo-controlled, randomized clinical trial, treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram produced a significant reduction in mental stress–induced myocardial ischemia in patients with clinically stable CHD. 6 Also noteworthy in this study and analogous to the lack of association of anger levels to exercise-induced ischemia in the current study, escitalopram did not produce a greater reduction in exercise-induced ischemia than placebo. In a nonrandom sample of patients in both the control and treatment arms of the ENRICHD study, those who were treated with SSRI had a 27% to 28% reduction in recurrent MI or all-cause mortality. 7 Findings like these suggest that it could be worthwhile to undertake a study to evaluate effect of SSRI treatment in patients with elevated state and trait anger levels who exhibit increased levels of mental stress–induced myocardial ischemia. If SSRI treatment reduces their ischemia levels to that of patients with low state and trait anger levels, it would help make the case for a larger clinical trial to determine whether SSRI treatment reduces morbidity/mortality in this patient group. There is also evidence that behavioral interventions such as cognitive behavior stress management (CBSM) have the potential to be an effective means of reducing stress-induced myocardial ischemia and associated morbidity/mortality in patients with high state and trait anger levels. In a randomized controlled trial of group-
American Heart Journal Volume 169, Number 1
based CBSM in men after coronary bypass surgery, compared with men in the attention control arm, those receiving group-based CBSM exhibited significantly larger reductions in trait anger, depression, perceived stress, and blood pressure and heart rate at rest and during and anger-recall stressor—improvements that were maintained or enhanced at 3-month follow-up. 8 There have now been 2 randomized controlled trials evaluating effects of group-based CBSM on morbidity/mortality in CHD patients. In one that included 237 women, those in the active arm had a 66% lower mortality over a 7.1-year follow-up than those in the usual care control arm. 9 The second included 362 men and women and found a 41% lower rate of fatal and nonfatal first recurrent cardiovascular disease events among those in the active arm compared with those in the usual care arm. 10 Combined with these other studies that document pathogenic effects of high anger levels and suggest that SSRI and CBSM treatment approaches have promise as a means of reducing morbidity/mortality that could be mediated by increased stress-induced myocardial ischemia in CHD patients with high levels of state and trait anger, the current study's findings make a case for undertaking preliminary studies to determine whether SSRI or CBSM interventions reduce the increased stressinduced myocardial ischemia in CHD patients with high state and trait anger. If so, it would strengthen the case for undertaking a large simple trial of both these pharmacologic and behavioral approaches to determine their efficacy in reducing morbidity/mortality in this high-risk patient group. Such a trial would help to determine if both approaches have equal clinical benefits as well as whether one or the other is better tolerated among the patients.
Disclosures Redford Williams is a founder and major stockholder of Williams LifeSkills, Inc, and holds a patent on the use of the 5HTTLPR L allele as a marker of stress-related
Williams 5
cardiovascular disease. This work was supported by National Heart, Lung, and Blood Institute grant P01HL36587 and the Duke University Behavioral Medicine Research Center.
References 1. Pimple P, Shah A, Rooks C, et al. Association between anger and mental stress–induced myocardial ischemia. Am Heart J 2014. [current issue]. 2. Boyle SH, Williams RB, Mark DB, et al. Hostility, age, and mortality in a sample of cardiac patients. Am J Cardiol 2005;96(1):64-6. 3. Markovitz JH, Matthews KA, Kiss J, et al. Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls psychosomatic medicine. 1996;58(2):143-9. 4. Suarez EC, Kuhn CM, Schanberg SM, et al. Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge. Psychosom Med 1998;60(1):78-88. 5. Matthews KA, Zhu S, Tucker DC, et al. Blood pressure reactivity to psychological stress and coronary calcification in the coronary artery risk development in young adults study. Hypertension 2006;47(3): 391-5. 6. Jiang W, Velazquez EJ, Kuchibhatla M, et al. Effect of escitalopram on mental stress–induced myocardial ischemia: results of the REMIT trial. JAMA 2013;309(20):2139-49. 7. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005;62(7):792-8. 8. Bishop GD, Kaur D, Tan VLM. Effects of a psychosocial skills training workshop on psychophysiological and psychosocial risk in patients undergoing coronary artery bypass grafting. Am Heart J 2005;150 (3):602-9. 9. Orth-Gomér K, Schneiderman N, Wang HX, et al. Stress reduction prolongs life in women with coronary disease: the Stockholm Women's Intervention Trial for Coronary Heart Disease (SWITCHD). Circ Cardiovasc Qual Outcomes 2009;2(1):25-32. 10. Gulliksson M, Burell G, Vessby B, et al. Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med 2011;171(2):134-40.
In the current issue of the Journal, Vaccarino et al 1 report that among a sample of 98 post–myocardial infarction (MI) patients between the ages of 38 and 60 years, those with higher levels of state and trait anger were more likely to develop myocardial ischemia during a stress challenge in which they reported a real-life stressful situation that they had experienced while being evaluated by a small audience wearing white coats. It is noteworthy that none of the anger dimensions assessed were associated with ischemia during exercise or pharmacologic stress. Heart rate, systolic and diastolic blood pressures, and rate pressure product all increased during the stress challenge, but these changes were not associated with the anger dimensions nor, presumably, with ischemia. As the authors note, these findings suggest that increased myocardial ischemia during emotional stress among MI patients with a personality trait that predisposes them to experience higher levels of anger—both acutely and chronically—could be placing them at increased risk or adverse clinical outcomes, in which case, they conclude, “New treatments should be evaluated that specifically target anger to reduce risk of future cardiac events.” Consistent with this interpretation is the finding in a sample of 1,328 coronary heart disease (CHD) patients that the mortality rate over a 14-year follow-up was increased by 52% in those with high hostility scores at baseline, but only in those younger than 61.2 years. 2 To develop new treatments targeting anger that have the potential to reduce mortality in CHD patients with high hostility/anger levels, it would be helpful to have some idea of the biological mechanisms that are mediating the impact of anger on prognosis. One such mediator could be increased platelet reactivity to psychological stress, which has been found to be higher in both CHD patients and age-matched healthy controls with higher hostility levels. 3 In this study, there was a trend (Ps b .10) for larger increases in both norepinephrine and diastolic blood pressure during stress to be associated with increased platelet reactivity. Another study in healthy From the and Departments of Psychiatry and Medicine, Duke University Medical Center, Durham, NC. Submitted September 10, 2014; accepted September 12, 2014. Reprint requests: Redford B. Williams, MD, Departments of Psychiatry and Medicine, Duke University Medical Center, Durham, NC E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.09.003
young white men found larger increases in blood pressure, heart rate, norepinephrine, testosterone, and cortisol during a harassment stressor among those with higher hostility levels. 4 Directly documenting the potential for increased cardiovascular reactivity to stress to increase risk in young adults, in the CARDIA study, those with higher blood pressure reactivity were found to have higher levels of coronary artery calcification 13 years later. 5 Although there was no indication that cardiovascular reactivity to the stressor in the current study was associated with the level of stress-induced ischemia, there has to be some biological mediator of the increased ischemia, and identification of that mediator would be a major help in designing interventions to reduce stress-induced myocardial ischemia—and the associated increased mortality/morbidity— in CHD patients. In the meanwhile, there is some evidence supporting the potential of both pharmacologic and behavioral approaches as a means of reducing stress-induced myocardial ischemia and/or associated increased morbidity/mortality in CHD patients. Directly relevant to the findings of Vaccarino et al, in a placebo-controlled, randomized clinical trial, treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram produced a significant reduction in mental stress–induced myocardial ischemia in patients with clinically stable CHD. 6 Also noteworthy in this study and analogous to the lack of association of anger levels to exercise-induced ischemia in the current study, escitalopram did not produce a greater reduction in exercise-induced ischemia than placebo. In a nonrandom sample of patients in both the control and treatment arms of the ENRICHD study, those who were treated with SSRI had a 27% to 28% reduction in recurrent MI or all-cause mortality. 7 Findings like these suggest that it could be worthwhile to undertake a study to evaluate effect of SSRI treatment in patients with elevated state and trait anger levels who exhibit increased levels of mental stress–induced myocardial ischemia. If SSRI treatment reduces their ischemia levels to that of patients with low state and trait anger levels, it would help make the case for a larger clinical trial to determine whether SSRI treatment reduces morbidity/mortality in this patient group. There is also evidence that behavioral interventions such as cognitive behavior stress management (CBSM) have the potential to be an effective means of reducing stress-induced myocardial ischemia and associated morbidity/mortality in patients with high state and trait anger levels. In a randomized controlled trial of group-
American Heart Journal Volume 169, Number 1
based CBSM in men after coronary bypass surgery, compared with men in the attention control arm, those receiving group-based CBSM exhibited significantly larger reductions in trait anger, depression, perceived stress, and blood pressure and heart rate at rest and during and anger-recall stressor—improvements that were maintained or enhanced at 3-month follow-up. 8 There have now been 2 randomized controlled trials evaluating effects of group-based CBSM on morbidity/mortality in CHD patients. In one that included 237 women, those in the active arm had a 66% lower mortality over a 7.1-year follow-up than those in the usual care control arm. 9 The second included 362 men and women and found a 41% lower rate of fatal and nonfatal first recurrent cardiovascular disease events among those in the active arm compared with those in the usual care arm. 10 Combined with these other studies that document pathogenic effects of high anger levels and suggest that SSRI and CBSM treatment approaches have promise as a means of reducing morbidity/mortality that could be mediated by increased stress-induced myocardial ischemia in CHD patients with high levels of state and trait anger, the current study's findings make a case for undertaking preliminary studies to determine whether SSRI or CBSM interventions reduce the increased stressinduced myocardial ischemia in CHD patients with high state and trait anger. If so, it would strengthen the case for undertaking a large simple trial of both these pharmacologic and behavioral approaches to determine their efficacy in reducing morbidity/mortality in this high-risk patient group. Such a trial would help to determine if both approaches have equal clinical benefits as well as whether one or the other is better tolerated among the patients.
Disclosures Redford Williams is a founder and major stockholder of Williams LifeSkills, Inc, and holds a patent on the use of the 5HTTLPR L allele as a marker of stress-related
Williams 5
cardiovascular disease. This work was supported by National Heart, Lung, and Blood Institute grant P01HL36587 and the Duke University Behavioral Medicine Research Center.
References 1. Pimple P, Shah A, Rooks C, et al. Association between anger and mental stress–induced myocardial ischemia. Am Heart J 2014. [current issue]. 2. Boyle SH, Williams RB, Mark DB, et al. Hostility, age, and mortality in a sample of cardiac patients. Am J Cardiol 2005;96(1):64-6. 3. Markovitz JH, Matthews KA, Kiss J, et al. Effects of hostility on platelet reactivity to psychological stress in coronary heart disease patients and in healthy controls psychosomatic medicine. 1996;58(2):143-9. 4. Suarez EC, Kuhn CM, Schanberg SM, et al. Neuroendocrine, cardiovascular, and emotional responses of hostile men: the role of interpersonal challenge. Psychosom Med 1998;60(1):78-88. 5. Matthews KA, Zhu S, Tucker DC, et al. Blood pressure reactivity to psychological stress and coronary calcification in the coronary artery risk development in young adults study. Hypertension 2006;47(3): 391-5. 6. Jiang W, Velazquez EJ, Kuchibhatla M, et al. Effect of escitalopram on mental stress–induced myocardial ischemia: results of the REMIT trial. JAMA 2013;309(20):2139-49. 7. Taylor CB, Youngblood ME, Catellier D, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005;62(7):792-8. 8. Bishop GD, Kaur D, Tan VLM. Effects of a psychosocial skills training workshop on psychophysiological and psychosocial risk in patients undergoing coronary artery bypass grafting. Am Heart J 2005;150 (3):602-9. 9. Orth-Gomér K, Schneiderman N, Wang HX, et al. Stress reduction prolongs life in women with coronary disease: the Stockholm Women's Intervention Trial for Coronary Heart Disease (SWITCHD). Circ Cardiovasc Qual Outcomes 2009;2(1):25-32. 10. Gulliksson M, Burell G, Vessby B, et al. Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med 2011;171(2):134-40.
