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Psychosomatic Medicine 66:492-500 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Exaggerated Platelet and Hemodynamic Reactivity to Mental Stress in Men With Coronary Artery Disease

Philip C. Strike, MRCP, Kesson Magid, BSc, Lena Brydon, PhD, Susan Edwards, PhD, Jean R. McEwan, MD and Andrew Steptoe, DPhil

From the Psychobiology Group, Department of Epidemiology and Public Health (P.C.S., K.M., L.B., S.E., A.S.) and the Department of Medicine (J.R.M.), University College London, London, UK.

Address correspondence and reprint requests to Dr. Philip Strike, Department of Epidemiology and Public Health, University College London, 1–19 Torrington Place, London, WC1E 6BT, UK. E-mail p.strike{at}public-health.ucl.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: This study compared the effects of acute mental stress on cardiovascular and subjective responses and platelet activation in male patients with established coronary artery disease (CAD) and age-matched controls.

METHODS: We assessed 17 male CAD patients aged 44 to 59 years and 22 healthy male controls. Blood pressure, heart rate, and hemodynamics were assessed before, during, and up to 2 hours after administration of color/word and mirror tracing tasks. Blood was sampled at baseline, after tasks, and at 30 and 75 minutes after stress, and platelet activation was assessed by measuring platelet-leukocyte aggregates (PLAs) using flow cytometry.

RESULTS: CAD patients showed significantly greater systolic blood pressure stress responses than controls (mean increases of 43.9 and 28.3 mm Hg, adjusted for income, body mass index, waist/hip ratio, and medication), together with larger increases in heart rate (14.1 and 4.7 bpm) and cardiac index. Total peripheral resistance increased during the poststress recovery period in CAD patients but not in controls. PLAs increased with stress in both groups, but remained elevated at 75 minutes in CAD patients, returning to baseline in controls. Heart rate and cardiac index responses were correlated with increases in subjective stress and with depression ratings, whereas PLA responses were associated with ratings of task difficulty.

CONCLUSION: Acute mental stress stimulated heightened cardiovascular responses in CAD patients, coupled with more prolonged platelet activation. These factors may contribute to plaque rupture and thrombogenesis, and partly mediate stress-induced triggering of acute coronary syndromes.

Key Words: coronary artery disease, • mental stress, • platelet activation, • blood pressure, • depression.

Abbreviations: ACS = acute coronary syndromes;; ADP = adenosine diphosphate;; BMI = body mass index;; CAD = coronary artery disease;; HAD = Hospital Anxiety and Depression Scale;; PLAs = platelet-leukocyte aggregates.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Psychosocial factors are relevant both to the long-term etiology of coronary artery disease (CAD), and to the triggering of acute coronary syndromes (ACS) in patients with established disease (1). Heightened physiological reactivity to mental stress has been proposed as a mechanism underlying both of these phenomena. Although the data are inconsistent, there is evidence linking heightened reactivity prospectively with the development of cardiovascular disease (2), and with disease progression and clinical complications in patients with established CAD (3).

Studies of patients with CAD have centered on the induction of transient myocardial ischemia by mental stress. A recent systematic review indicated that across studies, acute stress induces transient myocardial ischemia in 30% to 50% of CAD patients (4). However, inducible myocardial ischemia has a fundamentally different pathophysiological basis from that of ACS. Whereas myocardial ischemia may result from several pathogeneses leading to an imbalance in myocardial oxygen supply and demand, ACS are predominantly due to atherosclerotic plaque rupture and subsequent partial or total occlusion of the coronary artery by platelet-rich thrombus (5).

In the search for potential mechanisms linking psychosocial factors with plaque rupture and subsequent ACS, two processes may be particularly relevant: hemodynamic shear stress across the endothelial wall leading to mitogen-activated protein kinase signaling, activation of nuclear factor kappa B and atherosclerotic plaque rupture (6), and the activation and local aggregation of platelets (7). Studies of cardiovascular stress reactivity are relevant to the first of these processes, but current literature is inconclusive. Although some authors have found that patients with CAD have greater blood pressure responses to stressful tasks than healthy controls (8–10), others have reported no differences (11–14), or heightened pressor responses only in patients who show severe ischemic changes (15). Several factors may account for these inconsistencies. Some studies have assessed cardiovascular reactivity during inherently stressful procedures such as coronary angiography or radionuclide ventriculography (11,12,16) that may themselves affect the magnitude and duration of responses. Most investigators have measured blood pressure with conventional sphygmomanometry, taking readings every 2 to 3 minutes. Such measures estimate blood pressure reactivity on the basis of less than 1% of data, so may not accurately reflect the profile of responses (17). The medication status of CAD patients has been variable and not always statistically controlled (4). Assessment of cardiac output and peripheral vascular resistance responses may also be illuminating. Sundin et al. (10) showed that CAD patients exhibited greater total peripheral resistance responses to stress in comparison with controls, with no poststress return to baseline. In a study involving mental arithmetic and anger recall, Jain et al. (16) reported greater increases in vascular resistance and smaller rises in cardiac output in CAD patients compared with controls, so that the pattern of hemodynamic responses differed even though the resultant blood pressure reactions were similar.

In the present study, we compared the blood pressure, heart rate, cardiac output, and peripheral resistance responses of CAD patients and age-matched healthy controls, using continuous noninvasive measures. We also assessed whether individual subjective appraisal of the stress tasks was associated with biological responses. CAD patients were withdrawn from all cardiac medications except for aspirin, and their medication history was used as a covariate in the analyses. Cardiovascular monitoring continued for 2 hours after stress, so that recovery patterns could be assessed. Two tasks were utilized to elicit stress responses, and we aggregated physiological responses across tasks, because the focus of the study was on group differences rather than between-task response profiles (18,19).

Platelet activation is one of the fundamental factors in the pathogenesis of acute coronary syndromes (20), and may be an important mediator of psychosocial influences on CAD (21). Studies of acute mental stress have measured platelet function with filtragometry, adenosine diphosphate (ADP) and collagen-stimulated platelet aggregation, and assays of the {alpha}-granule proteins platelet factor-4 and ß-thromboglobulin (22–25). Data relating platelet activation with mental stress in CAD patients and controls have been conflicting. Wallen et al. (26) found that platelet aggregability times were reduced in angina patients but not controls in response to mental stress, together with increases in platelet factor 4 and ß-thromboglobulin. However, Markovitz et al. (24) reported a greater mental stress–induced rise in ß-thromboglobulin in healthy controls than in post-myocardial infarction patients, whereas Grignani et al. (27) demonstrated greater ADP and collagen-stimulated platelet activation in response to mental stress in CAD patients vs. controls. Techniques for assessing platelet activation have progressed substantially over recent years, and mefasures of platelet-leukocyte aggregates (PLAs) based on whole blood flow cytometry have become the method of choice (28,29). This technique allows platelets to be assessed directly in their physiological milieu with minimal manipulation, preventing artifactual in vitro activation (30). We therefore used this technique to compare mental stress-induced platelet activation in CAD patients compared with healthy controls.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Participants
Data were collected from 17 male CAD patients and 22 male healthy controls. All participants were white, nonsmokers, and normotensive. CAD patients were recruited from the database of patients who had stable angina and documented coronary artery atherosclerosis and who had undergone percutaneous coronary angiography or coronary intervention in the University College London NHS Trust within the preceding 2 years. Medical notes were examined and the patients interviewed before testing to explain the procedure and ensure that they fulfilled entry criteria. Patients were excluded from recruitment if they were aged less than 30 or more than 65; had poor left ventricular function, unstable or rapidly worsening symptoms, history of malignant arrhythmias, significant comorbid conditions; had other major past medical problems that could affect either hemodynamic, platelet, or immune responses; and were not fluent in English or able to understand the procedure. The actual age range was 44 to 59 years, and all patients were chronically medicated, with 15 taking aspirin, 15 statins, and 12 having ß-blocker medication for cardioprotection. The healthy controls were part of a larger sample of 37 men recruited from London-based Departments of the British civil service for a study of the effects of mental stress on platelet function. They self-certified that they were free of any past or present medical problems and took no regular medications (including aspirin or statins). They were not screened for occult CAD with any test of reversible myocardial ischemia, and all were normocholesterolemic. Results from the larger sample have been published elsewhere (31). The participants in that study were aged 30 to 60 years, and for the present comparison, we included the 22 individuals who were aged 44 and over, and therefore matched the CAD sample in age distribution.

The healthy controls participated in the study before the CAD patients, but the protocols used were identical. Participants in both groups were volunteers who had replied to an invitation to help in research, and all were given identical information about the study and its purposes. There was no financial incentive to participate in either group. The study was approved by the UCL/UCLH Medical Research Ethics Committee.

Measures and Behavioral Tasks
Blood pressure and heart rate were monitored continuously from the finger using a Portapres-2 (32). Cardiac output and stroke volume were determined from the Portapres using the aortic flow waveform method developed by Wesseling and coworkers (33), and utilized in ModelflowTM 2.1 software (TNO, Amsterdam, NL). Stroke volume is calculated from the systolic area—the area under the arterial pressure wave between the onset of the blood pressure rise and the dicrotic notch—on a beat-by-beat basis corrected by a calibration factor that relates to aortic compliance. Total peripheral resistance was predicted from mean pressure and computed aortic flow. Good agreement has been obtained between ModelflowTM computations from intraarterial and finger blood pressure measures, and between finger-based measures and thermodilution (34). Cardiac output was converted to cardiac index by dividing by body surface area. Weight, height, and waist and hip circumference were measured with standard methods, and body fat was assessed using a Bodystat® 1500 bioelectrical impedance body composition analysis device (Bodystat Ltd, Douglas, Isle of Man).

Information concerning employment, marital status, smoking, and alcohol consumption was collected by questionnaire. Physical activity was measured as the number of days in the past week on which participants had been moderately or vigorously active. Socioeconomic status was assessed with two measures. First, participants provided information about their annual income. In the analysis, the sample was divided according to whether annual incomes were above or below £35,000 (US$56,000). Second, participants completed the social "ladder." They were shown a drawing of a ladder with 10 rungs, representing where people stand in society (35). They were told that at the top of the ladder are the people who are best off—those who have the most money, most education, and best jobs. At the bottom are the people who are the worst off, have the least money, least education, and the worst jobs or no job. They were asked to place themselves on the rung on which they felt that they stood.

Depression was assessed using the depression subscale from the Hospital Anxiety and Depression (HAD) scale (36). This measure is widely used for assessing medical patients (37), and consists of seven items, each of which is rated on a 4-point scale, so total scores could range from 0 to 21. Higher scores reflect greater depression, and a score of 11 or more is suggestive of moderate clinical depression. Sleep problems were assessed with the scale developed by Jenkins et al. (38). This consists of four items, asking respondents how often in the past month they had woken up several times in the night, had trouble staying asleep, etc. There were six response options, ranging from 0 = not at all to 5 = 22 to 31 days. The total was computed, so scores could range from 0 to 20.

Psychological stress was induced by two behavioral tasks previously used in this laboratory (39). The first was a computerized color–word interference task developed at the University of Pittsburgh involving the consecutive presentation of target color words (eg, green) printed in another color. At the bottom of the computer screen were names of four colors printed in incongruent colors, and 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 rate of presentation was adjusted to ensure sustained demands. The second task was mirror tracing, involving the tracing of a star that could only be seen in mirror image. Participants were told that the average person completed five circuits of the star in the time available, and were asked to give accuracy priority over speed.

Measures of Platelet Function
Blood for the assessment of PLAs was drawn using 21-gauge Butterfly® needles into Vacutainer® tubes containing sodium citrate as anticoagulant. Whole blood samples (10 µl) were incubated for 20 minutes with 90 µl HEPES buffered saline containing 10 µl each of leukocyte- and platelet-specific antibodies, respectively, 6.25 µg/ml fluorescein isothiocyanate-conjugated mouse anti-human CD45 monoclonal antibody (H130, BD PharMingen, Oxford) and 12.5 µg/ml R-Phycoerythrin-conjugated mouse anti-human CD42a monoclonal antibody (ALMA.16, BD PharMingen). Samples were fixed with 700 µl 0.5% formaldehyde solution diluted from 37% formalin solution (Sigma) after incubation. Within 3 hours, the samples were analyzed using a Becton Dickinson FACScan Flow Cytometer and Cellquest software. The instrument was set up to acquire 10,000 CD45 positive events. Results are expressed as the percentages of leukocyte bound to platelets (30). As detailed previously, control experiments were also carried out to assess nonspecific binding (31). The same methods of sample preparation were used, but a control antibody (R-PE)-conjugated mouse IgG1, kappa isotope was substituted for (RPE)CD42a. The proportion of nonspecific binding averaged <0.6%, and adjusting levels of PLAs for this nonspecific effect did not alter the pattern of results.

Procedure
CAD patients were withdrawn from all medications except aspirin for 72 hours before testing. Healthy controls were asked not to take aspirin for 10 days before testing, but to use paracetamol if they required pain medication. All sessions were carried out in the morning beginning at 9:15 AM. Participants were instructed not to drink tea, coffee, or caffeinated beverages on the morning of the experiment, not to eat a high fat or high protein breakfast, and not to have consumed alcohol or exercised on the evening before or the day of testing. At the beginning of the session, anthropometric measures were taken, a venous cannula was inserted, and the participant rested for 30 minutes. Blood pressure and heart rate were recorded for the last 5 minutes of the rest period using the Portapres, after which two readings were obtained manually with an electronic sphygmomanometer, and the baseline blood sample was drawn. The participant rated feelings of stress on a 7-point scale from 1 = low to 7 = high. The two tasks were then administered each for 5 minutes in fixed order beginning with the color–word interference task. Blood pressure and heart rate were recorded continuously during tasks. At the end of each task, the participant rated task difficulty, involvement, controllability, and feelings of stress on 7-point scales from 1 = low to 7 = high. A second blood sample was drawn immediately after the second task. The participant then rested quietly for the remainder of the experimental session. Five-minute recordings of blood pressure and heart rate were made 25 to 30 minutes, 70 to 75 minutes, and 115 to 120 minutes after stress, and further blood samples were drawn 30 minutes and 75 minutes after stress.

Statistical Analysis
The two groups were compared on anthropometric and background characteristics using analysis of variance and {chi}2 tests as appropriate. The blood pressure, heart rate, cardiac index, and total peripheral resistance data were averaged into 5 periods for analysis: baseline, stress task period, 25 to 30 minutes after stress, 70 to 75 minutes after stress, and 115 to 120 minutes after stress. Data were analyzed using repeated-measures analysis of variance, applying the Greenhouse-Geisser correction of degrees of freedom where the sphericity assumption was violated. Preliminary analyses assessed whether cardiovascular responses were influenced by the medication status of patients. There was no association between use of aspirin or statins and cardiovascular stress responses in the CAD group. Patients who had been taking ß-blockers tended to be less stress reactive in blood pressure and heart rate, so use of ß-blockers was included as a covariate in all cardiovascular analyses. Data were incomplete for some participants because of signal or equipment faults, so the number of participants analyzed was 38 for systolic and diastolic pressure, and 35 for heart rate, cardiac index, and total peripheral resistance.

The percentage of PLAs from each blood sample was calculated. Preliminary analyses indicated that PLAs were not affected by use of ß-blockers, so this was not included as a covariate in analyses. PLAs were analyzed with group (CAD/healthy control) as the between-subject factor, and trial (baseline, stress, 30 minute, 75 minute after task) as the within-subject factor. Responses to the stress tasks were further analyzed by calculating difference scores between baseline and stress trials.

Associations between subjective experiences during the session and cardiovascular and platelet responses were assessed using partial correlations, adjusting for the factors detailed in the Results section. The relationships between depressive symptoms and cardiovascular and platelet responses were analyzed with linear regression, and the unstandardized regression coefficients with 95% confidence intervals are presented. Analyses were carried out using SPSS V 10.0.5, and data are presented in the tables and text as means ± SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
CAD patients and healthy controls did not differ in age (Table 1). However, body mass index (BMI) tended to be greater in CAD patients (F(1,37) = 2.99, p = .092), and waist/hip ratio and percent body fat were significantly greater in CAD patients than controls (F(1,37) = 14.2 and 4.15, respectively, p < .05). There was a tendency for CAD patients to report lower birth weights than healthy controls (F(1,25) = 3.00, p = .096). Similar proportions of patients and controls were married and in paid employment, and there was no difference in the number of hours worked per week. CAD patients were of lower socioeconomic status on both objective and subjective criteria; healthy controls had higher incomes ({chi}2) = 7.65, p < .01), and their ratings on the ladder measure were higher (F(1,37) = 4.22, p < .05). Few of the participants were current smokers, but more CAD patients had smoked in the past ({chi}2) = 7.14, p < .05). Fewer CAD patients than controls drank alcohol regularly ({chi}2 = 7.44, p < .01), while scores on the sleep problems scale were greater in patients (F(1,37) = 6.97, p < .05). There was no group difference on the HAD depression scale, and only one individual scored above the threshold for clinically significant problems. HAD depression and sleep problems were positively correlated (r = 0.51, p < .001). In the light of the differences in socioeconomic status and body size between groups, income, BMI, and waist/hip ratio were included as covariates in the cardiovascular analyses.


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  		TABLE 1. CAD Patients and Healthy Controls: Means ± SD and N (%)
 
Cardiovascular Stress Responses
CAD patients and healthy controls did not differ in baseline blood pressure or heart rate. Levels measured manually averaged 118.4 ± 16.0/72.2 ± 10.8 and 117.0 ± 8.1/72.3 ± 5.4 mm Hg in CAD patients and controls, whereas baseline Portapres levels averaged 117.6 ± 15.8/72.1 ± 10.8 and 117.9 ± 8.6/72.2 ± 5.4 mm Hg, respectively, after adjusting for income, BMI, waist/hip ratio, and use of ß-blockers. Baseline heart rate averaged 64.7 ± 13.8 and 62.3 ± 7.4 bpm in the 2 groups.

Blood pressure responses over the session are summarized in Figure 1. There was a significant group-by-trial interaction in the analysis of systolic pressure (F(4,140) = 3.64, p < .01). The systolic pressure response to tasks was greater in the CAD patients, with adjusted mean increases of 43.9 and 28.3 mm Hg in patients and controls (F (1,32) = 4.45, p < .05). Post hoc analyses indicated there were no differences between groups during the recovery phase. Analysis of diastolic pressure showed a main effect of trial (F(4,140) = 13.4, p < .001), but no interaction with group. The diastolic pressure responses to stress tasks averaged 21.6 and 15.7 mm Hg in the CAD patients and controls, adjusted for covariates. Both systolic and diastolic pressure remained above baseline during the 2-hour posttask period in both groups.



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  		Figure 1. Mean systolic blood pressure (upper panel) and diastolic blood pressure (lower panel) for 5 periods: baseline, average of task trials, and 25 to 30 minutes, 70 to 75 minutes, and 115 to 120 minutes after stress. Solid lines = coronary artery disease patients; dashed lines = healthy controls.

 
Results for heart rate are shown in Figure 2. The heart rate responses to stress tasks was greater in the CAD patients than controls (F(1,33) = 4.27, p < .05), with mean increases of 14.1 and 4.7 bpm adjusted for income, BMI, waist/hip ratio, and use of ß-blockers. Heart rate returned to baseline levels during the posttask period.



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  		Figure 2. Mean heart rate (upper panel) and subjective stress (lower panel) over the 5 trials. For details, see legend to Figure 1. Solid lines = coronary artery disease patients; dashed lines = healthy controls.

 
Neither total peripheral resistance nor cardiac index differed between groups at baseline. The changes in total peripheral resistance and cardiac index over the session are summarized in Figure 3. Peripheral vascular resistance increased with stress and then continued to rise in CAD patients but not controls. Analysis of covariance of the stress and posttask trials showed a main effect for trial in the CAD patients (p < .05) but not in controls. CAD patients had greater peripheral resistance increases than healthy controls between baseline and 30 minutes after stress, and baseline and 120 minutes after stress (both p < .05), but not for the 75 minute poststress trial (p = .093).



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  		Figure 3. Mean total peripheral resistance (upper panel) and cardiac index (lower panel) over the 5 trials. For details, see legend to Figure 1. Solid lines = coronary artery disease patients; dashed lines = healthy controls.

 
Cardiac index also increased between baseline and stress task trials, so the blood pressure stress responses were sustained by a combination of raised peripheral resistance and cardiac output. The increase in cardiac index between baseline and stress trials was greater in CAD patients than controls (adjusted differences of 0.72 and 0.40 l/min, respectively), but did not differ significantly. However, the subsequent decreases in cardiac index between baseline and 30 minutes and 75 minutes after task were significantly greater in CAD patients than controls (F(1,29) = 6.66 and 7.53 respectively, p < .05).

Subjective Stress Responses
Subjective stress ratings showed a highly significant effect of trial (F(4,132) = 140.6, p < .001). As can be seen in Figure 2, ratings on the 7-point scale increased from an average of 1.4 to 4.36 during the stress tasks, returning to baseline levels in the posttask period. CAD patients and controls did not differ in ratings of task difficulty or task controllability, with averages of 5.53 ± 1.0 and 2.82 ± 1.0 on the two scales. However, CAD patients were significantly more involved with the tasks than healthy controls, with mean ratings of 6.12 ± 1.0 and 5.05 ± 1.4, respectively (F(1,37) = 7.52, p < .01).

Platelet Activation
The percentage of PLAs was not related to income or to use of ß-blockers, so data were analyzed with BMI and waist/hip ratio as covariates. CAD patients and healthy controls did not differ in PLAs at baseline, and there were also no differences in white blood cell or platelet counts. However, the group-by-trial interaction was significant (F(3,87) = 5.50, p < .01), and is illustrated in Figure 4. The increase in PLAs in response to stress was the same in the 2 groups, but they diverged in the poststress period. PLAs remained high in the CAD patients, and returned to baseline levels in healthy controls. The difference between groups was significant at 75 minutes after stress (F(1,27) = 7.47, p < . 05). Compared with baseline, the number of PLAs was an average 18.1% higher at 75 minutes after stress in the CAD group, but had decreased by 9.3% in controls (F(1.27) = 5.98, p < . 05).



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  		Figure 4. Mean percentage of platelet-leukocyte aggregates at baseline, stress, 30 minutes after stress, and 75 minutes after stress. Solid lines = coronary artery disease patients; dashed lines = healthy controls. Error bars are standard error of the mean.

 
Associations Between Subjective Factors and Physiological Responses
The stress-induced increases in both heart rate and cardiac index were positively correlated with increases in subjective stress between baseline and stress trials (partial r = 0.41 and 0.46 respectively, p < .05, controlling for income, BMI, waist/hip ratio, use of ß-blockers, and baseline heart rate or cardiac index). Larger cardiac responses were recorded from participants who showed greater subjective stress responses. Heart rate and cardiac index increases between baseline and stress trials were also positively correlated with ratings of task involvement (partial r = 0.46 and 0.37, respectively, p < .05). Changes in PLAs were not related to subjective stress ratings. However, there was a positive correlation between the PLA increase from baseline to 75 minutes post-task and ratings of task difficulty (partial r = 0.39, p < .05, controlling for income, BMI, waist/hip ratio, and baseline PLAs).

Regression analyses indicated that heart rate stress responses were predicted by HAD depression independently of income, BMI, waist/hip ratio, use of ß-blockers, and baseline heart rate (B = 1.03, C.I. 0.18 to 1.87, p < .05). A similar effect was observed for stress-induced increases in cardiac index (B = 0.09, CI 0.02 to 0.17, p < .025). In both cases, higher depression scores predicted heightened cardiac stress responses. HAD depression scores were not associated with blood pressure or PLA responses.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
The principal findings of this study are as follows: CAD patients showed greater systolic pressure, heart rate and cardiac index responses to acute mental stress than age-matched healthy controls; total peripheral resistance increased during the post-task period in CAD patients but not in controls; platelet activation was stimulated by acute stress, and remained elevated for a more extended period after stress in CAD patients compared with controls; and cardiovascular responses were associated with subjective stress and with depression, while platelet activation was correlated with ratings of task difficulty.

The two groups in this study were recruited using different methods. The healthy sample was recruited through their workplaces, while the CAD patients were identified from hospital registers. We made efforts to use identical methods of inviting people and providing information about the study, and neither group received any financial incentive. However, it is possible that patients with a diagnosed disease will approach a research study of this kind with different attitudes to those of healthy volunteers. Ratings of stress experienced before and during the tasks revealed no differences between groups, and they did not differ in ratings of task difficulty or task controllability either. There was one difference in that CAD patients reported greater task involvement than did the healthy group. It is difficult to evaluate the importance of this effect in the absence of differences on three other measures, but it is possible that clinical status affected appraisals of the situation.

The groups were comparable in age, resting blood pressure and hemodynamics, but there were significant differences in waist-hip ratio and in percentage body fat. The CAD patients had lower incomes on average than the controls and their self-rated socioeconomic status was lower. These differences were to be expected, since the incidence of coronary heart disease is inversely related to socioeconomic status, and is associated with abdominal obesity (40). We have previously shown in other studies that lower socioeconomic status predicts impaired post-stress recovery of blood pressure (39) and heightened post-stress total peripheral resistance (41), so this factor was included as a covariate in the analyses along with BMI and waist/hip ratio. The groups did not show any difference in depression, but sleep problem scores were greater in CAD patients than the control group. Associations between poor sleep and coronary heart disease have been described in a number of studies (42), and Leineweber et al. (43) recently demonstrated that sleep problems predicted increased risk of recurrent cardiac events in women with ACS. Heavier persons and individuals with CAD are also at heightened risk from obstructive sleep apnea (44).

Systolic blood pressure increased by an average of 37% in the CAD patients compared with 24% in healthy controls. Heart rate increased by 21.7% versus 7.5% in controls. As noted earlier, variable results have been described in previous comparisons of CAD patients and healthy controls, with elevated blood pressure and heart rate stress reactions in some but not all studies. The computerized color/word task was previously used in the Psychophysiological Investigations of Myocardial Ischemia (PIMI) studies, where systolic pressure increases averaged 21% in CAD patients (45) and 17% in healthy controls (46). However, baseline systolic pressure in the 2 groups differed by 20 mm Hg in that study owing to the presence of hypertension in a substantial minority of patients. As noted earlier, it is unlikely that the differences we observed were due to cardiac patients finding the tests more stressful than the control group. Both groups were equally unfamiliar with the tasks and the assessment setting, and the low ratings of stress during baseline and recovery indicate that neither group reported apprehension or stress under resting conditions. The CAD patients did not show greater increases in subjective stress than controls. One explanation for the magnitude of responses may lie in the use of a continuous measure of blood pressure, which may capture the dynamic profile of stress responses more accurately than sampling from a single cardiac cycle every one or 2 minutes, as is done with conventional cuff measures (17,47).

A critical issue in comparisons between CAD patients and healthy controls is medication. Almost all the patients in this study were taking aspirin and statins, and a substantial minority were prescribed ß-blockers for cardioprotection. A review of 59 studies of the effects of ß-blockers on cardiovascular reactivity showed effects on heart rate but not blood pressure responses (48). In the present study, patients were withdrawn from ß-blockers and statins 72 hours before stress testing. There was a tendency for patients who had been using ß-blockers to be less stress reactive, but the number was too small to analyze as a separate group, so ß-blockade was instead incorporated as a covariate. If ß-blocker withdrawal was a factor then it was not likely to be at its maximum effect after 72 hours withdrawal (49), and for cardioselective drugs the increase in ß-adrenergic sensitivity is small at 72 hours post-cessation. There is little sympathetic hypersensitivity following cessation of atenolol (the most commonly taken drug in our study population) therapy in normotensive CAD patients (50). As far as statins are concerned, lower cholesterol should if anything have reduced cardiovascular stress reactivity (51). Our conclusion is that a genuine elevation of systolic blood pressure and heart rate stress reactivity is present in CAD.

Blood pressure responses were sustained by a combination of changes in cardiac output and total peripheral resistance (Figure 3). The groups did not differ in their cardiac or vascular responses to tasks themselves, although there was a modest difference in cardiac index response, which was presumably responsible for the larger systolic pressure response in the CAD patient group. During the post-stress period, a marked difference in hemodynamics emerged. Healthy controls maintained a moderately elevated total peripheral resistance offset by reduced cardiac index, resulting in small elevations in blood pressure in comparison with baseline. In CAD patients, there were substantially larger increases in peripheral resistance and correspondingly greater reductions in cardiac index. This vascular response is consistent with the results described by Sundin et al. (10) in CAD patients. It may have potentially adverse effects on cardiac patients by increasing afterload. Stress-induced increases in peripheral vascular resistance have been associated with reductions in left ventricular ejection fraction (16). Kop et al. (13) reported that coronary artery constriction in response to mental stress was related to diastolic blood pressure reactivity, and this may be sustained by an underlying abnormality of coronary vasomotion secondary to endothelial dysfunction. It should be noted that the mirror trace task was given last in this study, and as it produces strong increases in TPR with little effect on cardiac output, it may have been partly responsible for the greater degree of elevation seen in CAD patients.

The increases in platelet activation with stress as assessed by PLAs in this study are consistent with earlier work using aggregometry and measures of {alpha}-granule proteins (22,23,25,27). Michelson and coworkers (29) have argued that circulating PLAs are more sensitive indicators of in vivo platelet activation than these measures or platelet surface P-selectin. Circulating degranulated platelets rapidly lose surface P-selectin, yet continue to aggregate with monocytes and macrophages (30). Increases of circulating PLAs but not P-selectin-positive platelets were observed in patients undergoing angioplasty, and have also been shown to be early markers of acute myocardial infarction (52). Huo et al. (53) have recently shown that injection of activated PLAs accelerated atherosclerosis in apolipoprotein E-deficient mice, promoting leukocyte binding of vascular cell adhesion molecule-1 and adhesion to inflamed endothelium.

The 2 groups did not differ in baseline PLA counts. Platelet function at rest has been shown to be similar in CAD patients and controls in previous studies (26). The initial increase in platelet activation with stress was also the same in the 2 groups. However, differences emerged in the duration of responses, with the increase in PLAs persisting 75 minutes after stress in CAD patients, while returning to baseline in controls (Figure 4). The observation of a difference not in the magnitude but in the duration of stress-induced responses may explain why earlier comparisons of cardiac patients and healthy controls have shown mixed effects. These results are consistent with recent work suggesting that psychosocial risk factors for coronary heart disease are related to delayed poststress recovery in other biological responses. For example, low socioeconomic status (a risk factor of coronary heart disease) is associated with delayed poststress recovery of blood pressure and heart rate variability (39), and with prolonged elevations of Factor VIII and plasma viscosity (54). The greater platelet activation 75 minutes after stress is potentially important in the light of the evidence that episodes of anger are associated with increased vulnerability for the development of ACS for 1 to 2 hours (55).

It is interesting that these effects were observed despite use of aspirin by almost all CAD patients. Aspirin treatment has been shown to have little effect on platelet activation with mental stress assessed by filtragometry or platelet factor 4 and ß-thromboglobulin (26). Aspirin also fails to attenuate the PLA response to exercise (56). Recently it has been demonstrated that clopidogrel but not aspirin reduces both P-selectin expression and also the formation of PLAs in patients with atherosclerotic vascular disease (57). It would seem, therefore, that aspirin is not an effective means of eliminating mental stress–induced platelet activation. However, it may be that greater differences between groups would have been seen in the absence of aspirin or on aspirin withdrawal.

Individual differences in psychological responses were also associated with cardiovascular and platelet reactions. Heart rate and cardiac index responses were positively related to increases in subjective stress and to task involvement, whereas changes in PLAs were greater in participants who rated the tasks as being more difficult. These data indicate that in addition to clinical status, the individual’s appraisal of the situation is related to biological responses. In the light of associations between depression and platelet activation in coronary heart disease patients (58), we expected that PLA responses might be related to depression. This was not the case, possibly because levels of depression in this sample were low. Nevertheless, HAD depression scores did predict stress-induced increases in heart rate and cardiac index independently of covariates. An association between depression in the nonclinical range and cardiovascular stress responses has been described in previous research on healthy women (59), and so may be relevant to cardiac patients as well. Unfortunately, in this study we were not able to assess heart rate variability, which would have been interesting in the light of evidence relating impaired parasympathetic cardiac control with depression in postinfarction patients (60).

This study has a number of important limitations. The groups were relatively small, and participation was limited to white male patients less than 60 years old. This is a younger age group than the majority of CAD patients. The exclusion of women is a major limitation. We were concerned that the inclusion of men and women would substantially increase the variability in measures of platelet function, and that with a small study of this type the effects of stress might be obscured. Our current studies include both men and women. As noted earlier, the different methods of recruitment of CAD and controls resulted in groups that differed in socioeconomic profile, so that factor was taken into account statistically rather than through matching. The mean age of the CAD patients in this study is younger than most commonly found in clinical practice, and it may be that more elderly patient would have a different response to mental stress than is shown here. The CAD patients had all recently been taking cardioactive medications, and these might have had enduring effects. Recent use of ß-blockers was related to stress responsivity, but the sample was too small to analyze this as a separate factor. Although the cardiovascular monitoring continued for 2 hours after stress, the last blood sample for the measurement of PLAs was taken 75 minutes after stress. We do not therefore know whether the persistent elevation in platelet activation recorded from cardiac patients would have diminished after 2 hours. Nevertheless, the study indicates that CAD patients may show heightened cardiovascular responses to acute mental stress accompanied by prolonged platelet activation. These processes may be significant in the triggering of ACS and the development of complications in patients with advanced coronary atherosclerosis.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This research was supported by the British Heart Foundation. We are grateful to Bev Murray for her assistance with blood sampling. Flow cytometry was carried out in the Department of Medicine at University College London under the supervision of Dr. Jorge Erusalimsky.

Received for publication July 3, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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