EDITORIAL COMMENT
Endothelin-1 Release and Stimulation of the Inflammatory CascadeIs Acute Coronary Syndrome Triggered by Watching Spectator Sports?*
Karina W. Davidson, PhD*,
Matthew Burg, PhD and
Daichi Shimbo, MD
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
* Reprint requests and correspondence: Dr. Karina W. Davidson, Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, PH9 Center, Room 948, New York, New York 10032 (Email: kd2124{at}columbia.edu).
Key Words: emotional stress • atherosclerosis • inflammation • endothelin-1
Exposure to acute emotional stress can occur at any time; indeed, some of us buy tickets to it (1). Regardless of how people are exposed to acute emotional stress, elevated risk of acute coronary syndrome (ACS) can follow (2–4). The role of acute stress in the triggering of cardiovascular events is no longer disputed, thanks to carefully conducted prospective cohort studies (3,5,6). Specific behaviors (e.g., cocaine use and intense physical activity), environmental events (e.g., natural disasters), and emotional reactions (e.g., anger and sadness) have been identified that increase the risk of ACS for a distinct hazard period (2,3). While exposure to acute stress and its emotional concomitants can trigger ACS, until now the underlying pathophysiologic characteristics have not been well defined.
In the latest contribution to this literature, in this issue of the Journal, Wilbert-Lampen et al. (7) presented findings from a substudy of their previous report on ACS events triggered during World Cup soccer matches. In the original study (1), a higher incidence of ACS was found on match days when the outcome of the match was uncertain or of great portent for German fans, compared with days when the German team did not play or when the outcome did not matter. The authors instructed local coronary care units to obtain blood samples from patients presenting to the hospital with possible ACS during the World Cup soccer (1). This approach allowed for a comparison between patients with stress-triggered ACS and both patients with nonstress-triggered ACS (matched on age, sex, and type of ACS) and healthy volunteers (matched on age and sex) (7).
The authors found increased levels of endothelin (ET)-1, a potent vasoconstrictor, and monocyte chemoattractant protein-1, a member of the small inducible gene family involved in the recruitment of monocytes to sites of injury and infection, to be specific and sensitive indicators of the patients with stress-induced ACS. They also found additional differences of note between the cases and controls. Levels of tumor necrosis factor-alpha, known to be regulated in part by a vagal, cholinergic anti-inflammatory pathway (8) and implicated in dysregulated sympathovagal balance during and immediately after acute emotional stress (9), were also higher in the stress-triggered ACS group, while levels of high-sensitivity C-reactive protein, thought to be a risk marker for ACS (10), were not increased.
This study has some exciting features. The majority of studies concerning pathways linking acute stress to ischemic syndromes have been conducted in the laboratory setting with participants far removed from the natural environment. Laboratory mental stress can cause epicardial and coronary microvascular vasoconstriction among patients with coronary artery disease (CAD) (11). Even among healthy persons, peripheral ET-1–mediated endothelial dysfunction can last for >90 min after the laboratory stress is terminated (12). The processes by which stress might modulate ET-1 release of inflammatory processes are not fully understood, yet the study's demonstration that ET-1 is implicated in stress-triggered ACS in the real world provides evidence for the importance of this pathway.
Only certain soccer fans were vulnerable to an acute stress-triggered ACS. Can we identify who might be at risk? There has been considerable interest in identifying individual differences in vulnerability to the potential pathogenic effects of stress, with emphasis on genetic as well as psychological factors (13). Soccer fans with a history of CAD were the most vulnerable to a stress-triggered ACS (1). Among patients with CAD, trait anger increased the risk for emotional stress-provoked myocardial ischemia (14), whereas a tendency to ruminate about past anger-inducing events was associated with a stress-provoked increase in ET-1 levels in the laboratory (15). Other factors that might determine who is vulnerable to acute stress-induced ACS need to be explored.
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Study limitations
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The study included only a small number of subjects (58 in each of the 3 groups). Blood samples were obtained after the ACS event, so we do not know if the levels of ET-1 and other inflammatory markers were elevated in certain patients before the stress exposure, were induced by the stress-provoked ACS event, or merely constituted a marker of the severity of the ACS event. The feasibility of testing this question in a real-world setting is limited for obvious reasons.
Blood was not also assayed for catecholamine levels, which have been linked to stress-provoked Tako-tsubo syndrome (16). It would be interesting to explore the interplay of catecholamines with ET-1 and inflammatory status in the onset of stress-provoked ACS.
We assume, but do not know, that fans were experiencing extreme emotions. Direct measurement of emotional reactions during the soccer match might lead to some insight into who is vulnerable for a stressor-induced ACS, but the level of emotional distress in cases and controls is unknown in this study (4,6). We also do not know whether the fans with ACS suffered from chronic emotion dysregulation (e.g., anger, anxiety, or anger) that rendered them vulnerable to a stress-induced ACS (5). Finally, we do not know if some subjects were genetically or otherwise vulnerable to increased levels of ET-1 and inflammation. Suk Danik et al. (17) have reported that a common allele variant leads to increased levels of C-reactive protein during and after ACS. These hypotheses that acute emotional response, chronic emotional dysregulation, and/or allelic variation mark persons at risk of emotion-triggered ACS should be tested in future studies.
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Implications for therapy
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Tofler and Muller (6) described an approach to prevent stress-triggered ACS: determine the risk of a specific trigger in the patient and then address that risk. For example, sedentary patients with CAD who episodically engage in short bouts of extreme physical exertion (e.g., snow shoveling) might increase daily exercise. Similarly, stress-reduction training, previously found to reduce the risk of emotion-triggered myocardial ischemia in patients with CAD (18), could be suggested for patients prone to chronic anxiety, anger, or overall stress reactivity. Acute stressors that have in the past caused angina can be avoided—painful though that might be for the devoted soccer fan or the doting son-in-law. Clearly, stress-triggered ACS risk prevention in research and practice will require a multidisciplinary approach to target the type of ACS triggers and underlying pathophysiology reported in this interesting line of research.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Wilbert-Lampen U, Leistner D, Greven S, et al. Cardiovascular events during World Cup soccer N Engl J Med 2008;358:475-483.[CrossRef][Medline]2. Kloner RA. Natural and unnatural triggers of myocardial infarction Prog Cardiovasc Dis 2006;48:285-300.[CrossRef][Web of Science][Medline] 3. Strike PC, Steptoe A. Behavioral and emotional triggers of acute coronary syndromes: a systematic review and critique Psychosom Med 2005;67:179-186.[Abstract/Free Full Text] 4. Mittleman MA, Maclure M, Sherwood JB, et al. Determinants of Myocardial Infarction Onset Study Investigators Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study. Circulation 1995;92:1720-1725.[Abstract/Free Full Text] 5. Rozanski A, Blumenthal JA, Davidson KW, Saab PG, 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.[Abstract/Free Full Text] 6. Tofler GH, Muller JE. Triggering of acute cardiovascular disease and potential preventive strategies Circulation 2006;114:1863-1872.[Free Full Text] 7. Wilbert-Lampen U, Nickel T, Leistner D, et al. Modified serum profiles of inflammatory and vasoconstrictive factors in patients with emotional stress-induced acute coronary syndrome during World Cup soccer 2006 J Am Coll Cardiol 2010;55:637-642.[Abstract/Free Full Text] 8. Tracey KJ. The inflammatory reflex Nature 2002;420:853-859.[CrossRef][Medline] 9. Mezzacappa ES, Kelsey RM, Katkin ES, Sloan RP. Vagal rebound and recovery from psychological stress Psychosom Med 2001;63:650-657.[Abstract/Free Full Text] 10. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease N Engl J Med 2004;350:1387-1397.[CrossRef][Web of Science][Medline] 11. Arrighi JA, Burg M, Cohen IS, et al. Myocardial blood-flow response during mental stress in patients with coronary artery disease Lancet 2000;356:310-311.[Web of Science][Medline] 12. Spieker LE, Hurlimann D, Ruschitzka F, et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors Circulation 2002;105:2817-2820.[Abstract/Free Full Text] 13. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease JAMA 2007;298:1685-1687.[Free Full Text] 14. Burg MM, Jain D, Soufer R, Kerns RD, Zaret BL. Role of behavioral and psychological factors in mental stress-induced silent left ventricular dysfunction in coronary artery disease J Am Coll Cardiol 1993;22:440-448.[Abstract] 15. Fernandez A, Soufer R, Collins D, et al. Angry rumination predicts stress-provoked increase in endothelin-1 among patients with coronary artery disease Psychosom Med 2009;71:A132. 16. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress N Engl J Med 2005;352:539-548.[CrossRef][Web of Science][Medline] 17. Suk Danik J, Chasman DI, Cannon CP, et al. Influence of genetic variation in the C-reactive protein gene on the inflammatory response during and after acute coronary ischemia Ann Hum Genet 2006;70:705-716.[CrossRef][Web of Science][Medline] 18. Blumenthal JA, Babyak M, Wei J, et al. Usefulness of psychosocial treatment of mental stress-induced myocardial ischemia in men Am J Cardiol 2002;89:164-168.[CrossRef][Web of Science][Medline]
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Study limitations
Implications for therapy