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BIOLOGICAL SCIENCES / PSYCHOLOGY
Pathophysiological processes underlying emotional triggering of acute cardiac events

Philip C. Strike, Kesson Magid, Daisy L. Whitehead, Lena Brydon, Mimi R. Bhattacharyya, and Andrew Steptoe^*

Psychobiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, United Kingdom

Edited by Burton H. Singer, Princeton University, Princeton, NJ, and approved December 29, 2005 (received for review August 16, 2005)

	Abstract

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Acute negative emotional states may act as triggers of acute coronary syndrome (ACS), but the biological mechanisms involved are not known. Heightened platelet activation and hemodynamic shear stress provoked by acute stress may contribute. Here we investigated whether patients whose ACS had been preceded by acute anger, stress, or depression would show heightened hemodynamic and platelet activation in response to psychophysiological stress testing. We studied 34 male patients an average of 15 months after they had survived a documented ACS. According to an interview conducted within 5 days of hospital admission, 14 men had experienced acute negative emotion in the 2 h before symptom onset, and 20 men had not experienced any negative emotion. Hemodynamic variables and platelet activation were monitored during performance of challenging color-word interference and public speaking tasks and over a 2-h poststress recovery period. The emotion trigger group showed significantly greater increases in monocyte-platelet, leukocyte-platelet, and neutrophil-platelet aggregate responses to stress than the nontrigger group, after adjusting for age, body mass, smoking status, and medication. Monocyte-platelet aggregates remained elevated for 30 min after stress in the emotion trigger group. The emotion trigger group also showed poststress delayed recovery of systolic pressure and cardiac output compared with the nontrigger group. These results suggest that some patients with coronary artery disease may be particularly susceptible to emotional triggering of ACS because of heightened platelet activation in response to psychological stress, coupled with impaired hemodynamic poststress recovery.

acute coronary syndrome | blood pressure | platelets | stress | myocardial infarction

The pathophysiological basis for these effects is not known. Acute MI is one manifestation of the broader construct of acute coronary syndrome (ACS), encompassing ST elevation MI (STEMI), nonST elevation MI (NSTEMI), and unstable angina (UA) (7). The onset of an ACS is thought to involve the disruption of vulnerable plaques by rupture or erosion, coupled with activation of prothrombotic and inflammatory factors in the blood (8). Platelet activation is a central element in the initiation of ACS (9). Acute emotional stress induces hemodynamic shear stress together with platelet activation and a procoagulant shift in hemostatic processes (10), and blood pressure responses and platelet activation are heightened in patients with coronary artery disease (CAD) compared with healthy controls (11). It is conceivable that some individuals are vulnerable to emotional triggers because of a tendency to react to stressful stimuli with a heightened psychophysiological response profile.

In this study, we investigated the possibility that hemodynamic and platelet responses to stress contribute to the emotional triggering of ACS. Prospective investigation of this problem is difficult, because it would involve psychophysiological testing of large numbers of patients with CAD, only a few of who would experience emotional triggering. We therefore compared the psychophysiological stress responses of patients who reported that their ACS had been preceded by an acute negative emotional state with those who had not experienced an emotional trigger. It was hypothesized that the emotional trigger group would show greater platelet activation and blood pressure stress responses than the nontrigger group.

	Results

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The emotion trigger and nontrigger groups did not differ in age, marital status, education, ethnic distribution, body mass index (BMI), clinical ACS presentation, subsequent treatment, anxiety and depression at the time of stress testing, or anxiety and depression in the interval between admission with ACS and psychophysiological stress testing (Table 1). Waist/hip ratio was greater in the nontrigger group (P < 0.05). There were no significant differences between groups in the proportions of patients medicated with -blockers, aspirin, or statins.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Mean levels of systolic blood pressure (Upper) and cardiac index (Lower) during psychophysiological testing in the emotion trigger (solid line) and nontrigger (dashed line) groups. Values are adjusted for age, BMI, smoking status, and medication with -blockers and aspirin. Error bars are SEM.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Mean proportion of leukocyte-platelet (Top), monocyte-platelet (Middle), and neutrophil-platelet (Bottom) aggregates during psychophysiological testing in the emotion trigger (solid line) and nontrigger (dashed line) groups. Values are adjusted for age, BMI, smoking status, and medication with -blockers and aspirin. Error bars are SEM.

	Discussion

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However, the present investigation is unique in studying a group of patients in which there is evidence of emotional involvement in the triggering of ACS. We reasoned that such a group should be particularly susceptible to the impact of emotional stimuli on pathophysiological processes. Two responses may be relevant to the linkage between emotion, plaque disruption, and subsequent ACS. These responses are the activation and local aggregation of platelets (22) and hemodynamic shear stress across the endothelial wall, leading to mitogen-activated protein kinase signaling, activation of NF-B, and atherosclerotic plaque rupture (23, 24). We hypothesized that platelet activation and blood pressure and cardiac responses to standardized stress would be enhanced in this group in comparison with patients whose ACS was not associated with negative emotional states.

Patients were recruited from a larger clinical cohort that had been interviewed within a few days of admission with a documented ACS, some of whom had reported states of acute negative emotion before symptom onset. It is not known how common emotional triggering of ACS is in clinical practice. Estimates from different studies range from 4% to 52%, depending on the definition of emotional upset and the time frame of assessments (25–27). In the ACCENT (acute coronary syndrome: emotion and trigger) study from which these patients were drawn, 34.6% reported anger, depression, or stress in the 2 h before ACS symptom onset, compared with 41% in the present experiment. However, some of these associations may have been because of retrospective reporting bias, whereas others will have been coincidental (2). The case-crossover statistical methodology was devised to reduce, although not completely eliminate, these biases by comparing the critical hazard period with control time periods on a within-subject basis (28).

Psychophysiological stress testing was carried out an average of 15 months after acute cardiac admission. This long interval was selected to ensure patient stabilization and safety. The study was based on the assumption that biological stress responsivity is a stable trait and that acute responses assessed under laboratory conditions generalize to real-life experience. Differences in responses to standardized challenges may therefore parallel variations in response to emotional stimuli in the hours before ACS onset. In support of this rationale is the substantial evidence that cardiovascular stress responses are moderately stable with repeated testing (29), although it is not yet known whether stress-induced platelet activation is a stable individual characteristic that generalizes to everyday life. Nonetheless, emotional triggering of ACS was associated with heightened psychophysiological responses, specifically greater platelet activation and cardiac output responses to tasks, and delayed poststress recovery of systolic blood pressure and cardiac output. Stress-induced platelet activation previously has been assessed with measures such as collagen-stimulated aggregation and assays of -granule proteins (10). Measures of platelet-leukocyte aggregates by using whole blood flow cytometry are increasingly favored because they allow assessments to be made of platelets in their physiological milieu with minimal manipulation (30). In the present study, the emotional trigger group demonstrated significantly greater stress-induced increases in the proportion of total leukocytes bound to platelets and in monocyte-platelet and neutrophil-platelet aggregates. Monocyte-platelet aggregates increased by 100% during stress and neutrophil-platelet aggregates by 85% in the emotion trigger group, while remaining unchanged in the nontrigger patients. These effects were independent of age, BMI, smoking status, and medication status. Michelson et al. (31) have argued that circulating monocyte-platelet aggregates are particularly sensitive indicators of in vivo platelet activation and have been shown to be early markers of acute MI and other ACS (32, 33). Elevated levels of neutrophil-platelet aggregates are also observed in CAD and correlate with proinflammatory activity (34). These findings suggest that one reason some patients with CAD may be particularly susceptible to emotional triggering of ACS is because of a tendency to heightened platelet activation in response to stress.

It is unlikely that differences are because of the emotion trigger group being more subjectively stressed than the nontrigger group during the psychophysiological testing. The emotion trigger group did not report greater subjective stress, nor did they find the tasks more difficult. There were no differences in standard psychometric measures of anxiety or depression at the time of stress testing, so biological reactivity effects cannot be attributed to current mood state. It is likely, therefore, that differences in the regulation of autonomic and neuroendocrine activation at the subcortical level are responsible for the greater responsivity of the emotional trigger group (35). We do not know the exact mechanisms underlying enhanced platelet activation. Psychological stress stimulates the sympathetic nervous system and leads to increased concentration of circulating catecholamines, and epinephrine and norepinephrine in turn stimulate platelet activation although binding to ₂- and ₂-adrenergic receptors on the platelet surface (36). Alterations in hypothalamic-pituitary-adrenocortical activity and inflammatory cytokine responses may also be involved (24). Emotional stress leads to increased IL-1 gene expression and raised levels of circulating IL-6 (24). These endocrine and inflammatory responses take longer to evolve and persist for longer periods after the end of behavioral challenges than does neural activation and may result in persistent platelet activation. The onset of ACS is characterized by raised inflammatory cytokine levels as well as platelet activation (9), and it is possible that these effects are accentuated by concurrent emotional distress in susceptible individuals.

We also observed differences in the rate of poststress recovery of systolic blood pressure and cardiac output, together with differences in cardiac output responses to the first task (Fig. 1). Variations in cardiovascular reactivity and recovery may be important because they lead to hemodynamic shear stress across the vessel wall and because they relate to coronary vasomotor activity. Kop et al. (37) have demonstrated that coronary artery constriction in stenosed vessels during mental stress is correlated with the magnitude of blood pressure reactions. Delayed cardiovascular recovery after termination of stressful challenges is a marker of physiological dysregulation and allostatic load (38) and has been associated with risk factors for coronary heart disease (CHD) such as low socioeconomic status, family history of hypertension, and increases in blood pressure level over time (39–41). It is plausible that these hemodynamic responses further increase the risk of plaque disruption in ACS. In a previous study, we observed that patients with stable CAD showed more persistent platelet activation after stress than did a healthy comparison group (11), suggesting that failures of poststress recovery may be particularly important in patients with CAD. We do not know what stimulated ACS onset in the 20 patients who did not report emotional triggers. Plaque disruption and thrombus formation may either have occurred spontaneously or in response to unmeasured factors.

This study has a number of limitations. The total sample size was small, and there were too few women in the clinical study from which this sample was drawn to be able to compare emotion trigger and nontrigger groups. The majority of participants were of white European origin, so we do not know whether the findings would be the same in women or other ethnic groups. The analysis was complicated by the inclusion of patients whose medications had been withdrawn and those individuals who continued to take -blockers, angiotensin converting enzyme (ACE) inhibitors, statins, and aspirin at the time of psychophysiological stress testing. Although there were no significant differences in medication status between emotion trigger and nontrigger groups, there was a trend toward lower medication in the emotion trigger group. It is not clear why this trend occurred, because recruitment took place blind to trigger information. The sample was not large enough to carry out separate analyses of patients on and off medication, so this factor was taken into account as a statistical covariate. However, the differences between groups remained significant after controlling for these medication effects.

It could be argued that it would be preferable to carry out psychophysiological stress testing before ACS, predicting that participants with heightened biological response profiles would be more prone to emotional triggering. Our study was reversed, with comparisons between patients who had or had not experienced acute negative emotion in the hours before ACS onset. A strength of this study is that emotional triggering of ACS was measured soon after the cardiac event by using methods that have been established in previous clinical investigations. The groups were not therefore identified through patients’ recall months later, a method that could be vulnerable to long-term memory bias. The investigators were blind to group membership, reducing the possibility that patients were treated differently during psychophysiological stress testing. The precise relationship between the emotional stimuli that preceded ACS onset and the behavioral challenges in the laboratory was not studied, but the laboratory tasks were only moderately stressful. It is likely, therefore, that patients experienced more intense emotional upset in their real lives, and that physiological responses were further accentuated. We therefore conclude that the results provide evidence that patients with CAD who are vulnerable to emotional triggering have distinctive psychophysiological response profiles. Heightened stress-induced platelet activation coupled with impaired hemodynamic recovery after stress may be mechanisms through which emotional states contribute to the acute onset of ACS in susceptible patients.

	Methods

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Participants. The participants in this study were a subsample from the ACCENT study, an investigation of 295 patients admitted with ACS to four hospitals in the London area. They were included in the larger study on the following criteria: a diagnosis of ACS based on the presence of chest pain plus verification by diagnostic electrocardiogram (ECG) and/or cardiac enzyme changes, aged 18–90 years, ability to recall the time of onset of symptoms, and no comorbid conditions that might influence either symptom presentation, mood, or troponin positivity (such as severe psychiatric illness, unexplained anemia, ongoing infection or inflammatory conditions, neoplasia, and renal failure) (42). Patients were interviewed in detail about the circumstances surrounding the onset of acute symptoms an average 2.56 ± 1.5 days after admission to hospital.

We recruited patients for the present experiment an average of 444.9 ± 172 days (range, 183 to 915 days) after their ACS. This interval was chosen to ensure that patients’ clinical condition had stabilized. Patients were not considered for this experiment if they were women (because the ACCENT study had involved an insufficient number of women), had ongoing symptoms of chest pain or breathlessness, had a second ACS or cardiac intervention within the previous 6 months, had severely impaired left ventricular function, were aged over 80, had new comorbidities that might affect hemodynamic or biochemical measurements, or suffered from hypertension, atrial fibrillation, history of late ventricular dysrhythmia, or color blindness. None of the patients were taking antidepressant medication. There were 231 men in the ACCENT study, of who 3 were >80 years old, and 21 experienced onset of ACS after they had been asleep for at least 2 h, so they could not provide trigger information. Of the remainder, 12 lived outside the country or too far away for participation, 50 were hypertensive, 5 were dead, 14 were lost to follow-up, 44 had comorbidities, persisting symptoms, or very poor left ventricular function, and 1 was blind. Eighty-two subjects were therefore eligible for participation, of who 34 were tested within the time available for the study. Patients who participated in psychophysiological stress testing were younger on average than those who were excluded (P = 0.023) but did not differ in clinical presentation, medical management, number of diseased coronary arteries, or other cardiological characteristics. The study was approved by the medical research ethics committees of University College London Hospital, St. George’s Hospital, and Southend Hospital (all based in London), and all patients gave written consent.

Psychophysiological Stress Testing Protocol. The study was carried out in a light- and temperature-controlled clinical laboratory. Eighteen patients were withdrawn from medication after consultation with physicians and patients, whereas 16 patients were taking some form of medication at the time of stress testing (16 -blockers, 11 aspirin, 11 statins, and 8 ACE inhibitors). Patients who were withdrawn from medication stopped taking aspirin 10 days before testing, and statins, -blockers, and ACE inhibitors 72 h before testing. Sessions began at 9:00 a.m., and participants were instructed not to have drunk tea, coffee, or caffeinated beverages on the morning of the study, not to have eaten a high fat or high protein breakfast, and not to have consumed alcohol or exercised on the day before testing. Anthropometric measures were taken at the beginning of the session from which BMI and waist/hip ratio were calculated, a venous cannula was inserted, and the participant rested for 30 min. Blood pressure and heart rate were monitored continuously by using a Portapres-2 [The Netherlands Organization for Applied Scientific Research (TNO) Biomedical Instrumentation, Amsterdam] (43), and cardiac output and stroke volume were determined from the Portapres-2 by using the aortic flow waveform method implemented in MODELFLOW 2.1 software (TNO Biomedical Instrumentation) (44). Readings were taken for the last 5 min of the baseline period, after which a baseline blood sample was drawn, and the patient rated subjective stress on a 7-point scale (1 = low to 7 = high). Two tasks were then administered each for 5 min in fixed order. The first was a CW interference task (11) involving the computer presentation of target color words printed in an incongruous color. The task was to press a computer key that corresponded to the position at the bottom of the screen of the name of the color in which the target word was printed. The second task was presented after an interval of 5 min and involved simulated public speaking as previously used in mental stress testing of cardiac patients (45). Participants were given an imaginary scenario in which they had been accused of theft and were instructed to make a speech in their defense. They were told that the speech was being videotaped and that it would be assessed later for content and fluency. Cardiovascular monitoring continued throughout the tasks, and further subjective stress ratings were obtained at the end of each one. Ratings of task difficulty and involvement were also made after each task on 7-point scales. A second blood sample was drawn immediately after the second task, and the patient then rested quietly for the remainder of the experimental session, reading or watching a nature video. Five-minute recordings of blood pressure and heart rate were made for 25–30 min, 70–75 min, and 115–120 min after stress, and further blood samples were drawn 30 min, 75 min, and 120 min after stress. Laboratory investigators were blind to the clinical details of the study volunteers and whether or not they had reported emotional upset before their ACS.

Measures of Platelet Function. Platelet activation was indexed by measuring the presence of circulating leukocyte-platelet, monocyte-platelet, and neutrophil-platelet aggregates (30, 31). When platelets are activated, P-selectin is released from granules and expressed at the platelet surface, binding to P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes (46). These aggregates can be detected using flow cytometry. After discarding the first 2 ml of each sample, blood was drawn by using a butterfly needle with Luer adapter connected to a sodium citrate Vacutainer (all supplied by 3S Healthcare, Enfield, U.K.). Whole blood samples (10 µl) were incubated for 20 min with 90 µl of Hepes-buffered saline containing 10 µl each of leukocyte- and platelet-specific antibodies, namely 6.25 µg/ml fluorescein isothiocyanate-conjugated mouse anti-human CD45 monoclonal antibody (H130; BD Pharmingen) and 12.5 µg/ml R-phycoerythrin (RPE)-conjugated mouse anti-human CD42a monoclonal antibody (ALMA.16; BD Pharmingen). Samples were fixed and analyzed within 3 h by using a Becton Dickinson FACScan flow cytometer and CELLQUEST software. The instrument was set to acquire 10,000 CD45-positive events. Results are expressed as the percentages of platelet-bound leukocytes. Additionally, the total leukocyte-platelet aggregates were categorized into subpopulations of monocyte-platelet and neutrophil-platelet aggregates according to their specific light scatter properties and levels of CD45 expression. Control experiments were also carried out to assess nonspecific binding, as described in ref. 47. The same methods of sample preparation were used, but a control antibody RPE-conjugated mouse IgG1, isotope) was substituted for RPE-CD42a. The proportion of nonspecific binding averaged <0.6%, and adjusting levels of leukocyte-platelet aggregates for this nonspecific effect did not alter the pattern of results.

Other Measures. Patients were classified on the basis of ECG and biochemical markers to the different forms of ACS [ST elevation MI (STEMI), nonST elevation MI (NSTEMI), and unstable angina (UA)]. Primary treatments were classified as percutaneous transluminal coronary angioplasty (PTCA), medical, or coronary artery bypass graft (CABG). The number of diseased vessels found on coronary angiography was assessed independently by a cardiologist blind to triggering status. Information concerning marital status, educational attainment, and smoking status was obtained by questionnaire. Anxiety and depression at the time of psychophysiological stress testing was measured by using the Hospital Anxiety and Depression scale, a well validated instrument specifically designed to assess mood in medical patients, and previously used with MI patients (48, 49). Each scale consists of seven items rated on 4-point scales, and total scores can range from 0 to 21.

Assessment of Emotional Triggers. A structured triggering interview was conducted, modeled on the procedures used in previous studies (5, 50). Based on these findings (2), we specifically focused on the occurrence of acute emotions in the 2 h before symptom onset. Patients were questioned in detail about the events and circumstances surrounding the onset of acute symptoms. They were asked separately to estimate the level of anger, stress, and sadness or depression they had experienced over these hours, by using rating systems from 0 (none) to 4 (extreme). Information about other periods, including the corresponding 2 h one day before ACS onset, was also collected in the same way for comparison purposes.

Fourteen of the patients reported episodes of anger, depression, stress, or combinations of these emotions in the 2 h before the onset of their ACS. Emotional upset was stimulated by discrete time-limited episodes such as arguments with neighbors, family conflict, anniversaries of bereavements, and frustrating commuting. Findings from case-crossover analyses of triggers in the full ACCENT sample are presented elsewhere (51). The remaining 20 nontrigger cases reported no unusual events or emotional experiences during the hours before ACS onset.

Statistical Analysis. The 14 trigger cases were compared with the remaining 20 nontrigger cases. Comparisons of sociodemographic, clinical, and psychological variables were made with t tests for continuous measures and ² tests for categorical variables.

Blood pressure, heart rate, and cardiac output were averaged into six 5-min trials (baseline, CW task, speech task, 25- to 30-min poststress recovery, 70- to 75-min poststress recovery, and 115- to 120-min poststress recovery). Cardiac output was converted into cardiac index before analysis by correcting for body surface area. Subjective stress ratings were also analyzed across six trials, whereas the analysis of monocyte-platelet, neutrophil-platelet, and leukocyte-platelet aggregates involved five trials (baseline, task, and recovery at 30, 75, and 120 min, respectively). Responses across the session were analyzed by using repeated-measures analysis of variance with trial as the within-subject factor. Cardiovascular and platelet responses to tasks were compared in the two groups by analyzing difference scores between task and baseline trials, covarying for factors that might influence responses, namely age, BMI, smoking status, and medication with -blockers and aspirin. Variations in the rate of poststress recovery were analyzed with difference scores between recovery trials and baseline, covarying for the same factors. Further adjustment for the use of other medications (statins and ACE inhibitors) and clinical characteristics did not influence the results, so these variables were not included in the final analytic models.

	Acknowledgements

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We are grateful to Dr. Jean McEwan (University College Hospital) for her support for the study and to the staff and patients of University College Hospital, St. George’s Hospital, and Southend Hospital. This research was funded by the British Heart Foundation Grant RG2000002.

	Footnotes

 

Abbreviations: ACCENT, acute coronary syndrome: emotion and trigger; ACE, angiotensin converting enzyme; ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CW, color-word; MI, myocardial infarction.

*To whom correspondence should be addressed. E-mail: a.steptoe{at}ucl.ac.uk

Author contributions: P.C.S., D.L.W., L.B., and A.S. designed research; P.C.S., K.M., D.L.W., L.B., and M.R.B. performed research; P.C.S., K.M., D.L.W., L.B., M.R.B., and A.S. analyzed data; and P.C.S., K.M., M.R.B., and A.S. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

© 2006 by The National Academy of Sciences of the USA

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