Endothelin-1 Release and Stimulation of the Inflammatory Cascade: Is Acute Coronary Syndrome Triggered by Watching Spectator Sports?

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 (eg, cocaine use and intense physical activity), environmental events (eg, natural disasters), and emotional reactions (eg, 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, Wilbert-Lampen and colleagues(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 non–stress-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-1 (ET-1, a potent vasoconstrictor) and monocyte chemotactic 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 α, 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 individuals, peripheral ET-1–mediated endothelial dysfunction can last for longer than 90 minutes 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) while 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.

Limits of the Present Study

The study included only a small number of individuals (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 prior to 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 Takotsubo 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 don’t 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 level of emotional distress by cases and controls unknown in this study.(4,6) We also do not know if 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 individuals were genetically or otherwise vulnerable to increased levels of ET-1 and inflammation. Suk Danik and others⁽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 those at risk of emotion-triggered ACS should be tested in future studies.

Implications for Therapy

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 (eg, 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 multi-disciplinary approach to target the type of ACS triggers and underlying pathophysiology reported in this interesting line of research.