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Chronic and Acute Psychological Risk Factors for Clinical Manifestations of Coronary Artery Disease

From the Uniformed Services University of the Health Sciences, Bethesda, MD.

Address reprint requests to: Willem J. Kop, PhD, Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814.

	ABSTRACT

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Psychological factors are known to affect biological processes involved in the progression of coronary artery disease. This article focuses on psychological risk factors for progression of coronary artery disease and its clinical manifestations. Recent research on the adverse cardiovascular consequences of feelings of exhaustion and acute psychological arousal is reviewed, and a classification of psychological risk factors is presented distinguishing (1) chronic psychological risk factors, such as hostility; (2) episodic risk factors, such as exhaustion, with a duration ranging from several months to 2 years; and (3) acute psychological triggers, including mental activity and anger. The distinctive pathophysiological mechanisms by which these psychological risk factors promote coronary disease progression and cardiac ischemia are described, including hemodynamic reactivity, blood clotting, and inflammatory processes.

Key Words: coronary artery disease • vital exhaustion • hostility • myocardial infarction • psychology • risk factors

Abbreviations: CAD = coronary artery disease; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of MentalDisorders, fourth edition; MQ = Maastricht Questionnaire; NS = not significant; RR = relative risk; SES =socioeconomic status.

	INTRODUCTION

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A growing body of research suggests that acute coronary syndromes, such as myocardial infarction and sudden cardiac death, are triggered by exogenous factors rather than occur randomly (1, 2). In vulnerable patients, acute triggers (eg, physical exercise and mental arousal) may precipitate clinical coronary syndromes, such as myocardial ischemia, myocardial infarction, and sudden cardiac death (2, 3). This vulnerability for cardiac events is primarily determined by underlying CAD in combination with other cardiovascular risk factors, such as hypertension and hyperlipidemia. A three-category classification of psychological risk factors is proposed here. The classification is based on the duration of the risk factors and their temporal proximity to the occurrence of coronary syndromes: (1) chronic psychological risk factors promote gradual progression of coronary artery disease (eg, hostility); (2) episodic psychological risk factors have a duration lasting from several months to 2 years and tend to recur (eg, exhaustion); and (3) acute psychological risk factors (eg, outbursts of anger or mental activity) may act as triggers of cardiac events within 1 hour by provoking sudden pathophysiological responses in the hemodynamic, neuroendocrine, and hemostatic systems (Figure 1).

View larger version (33K): [in this window] [in a new window]   Fig. 1. Pathophysiological model of the relationships between chronic, episodic, and acute psychological risk factors for coronary syndromes. Acute psychological factors result in physiological responses, leading to cardiac effects (ie, electrical instability, increased cardiac demand, and decreased coronary supply). In vulnerable patients, these cardiac effects may have pathophysiological results, including arrhythmias, myocardial ischemia, thrombus formation, and plaque rupture. Episodic psychological factors have physiological correlates that are involved in the progression of severe coronary disease to acute coronary syndromes. Chronic psychological factors promote the onset of early atherosclerosis, especially in the setting of genetic vulnerability, adverse health behaviors, and other environmental risk factors. In addition, chronic psychological factors are related to increased frequency and response magnitude of acute psychological factors and promote the risk of developing episodic factors. BP = blood pressure; HR = heart rate. Modified from Krantz et al. (1).

	EXHAUSTION AND PROGRESSION OF CORONARY ARTERY DISEASE

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Selye’s general adaptation syndrome postulates that prolonged, uncontrollable physical and/or psychological distress may ultimately result in a state of exhaustion (6). Feelings of extreme tiredness and lack of energy are among the most prevalent premonitory symptoms of myocardial infarction and sudden cardiac death (for reviews, see Refs. 7 and 8). Therefore, it has been hypothesized that the exhaustion preceding cardiac events is the consequence of prolonged psychological distress. Appels et al. (8–10) developed the construct of "vital exhaustion," based on an empirical approach aimed at identifying premonitory symptoms of myocardial infarction rather than applying an existing psychological measure in the setting of CAD. This approach involved evaluation of premonitory symptoms of patients who suffered a myocardial infarction, which were then validated using case–control and prospective studies. A prospective study revealed a subset of 21 items predictive of future myocardial infarction (9). These items (the MQ) were reviewed by a panel of clinical psychologists, who described the overall content as "vital exhaustion" (10), which will be referred to as "exhaustion" in the remainder of this article. Additional case–control studies indicated that the MQ differentiates subjects with myocardial infarction from healthy and hospital control subjects in both men (11) and women (12). In addition, an interview technique for the assessment of exhaustion has been developed (13).

Exhaustion is characterized by lack of energy, increased irritability, and demoralization (10). The predictive value of exhaustion was demonstrated in the Rotterdam Civil Servants Study, in which 3877 initially healthy men were followed up for an average period of 4.2 years. Subjects who were exhausted at study entry were more than twice as likely to have a myocardial infarction during follow-up than subjects who were not exhausted (RR = 2.3; p < .001) (14). Moreover, this predictive value was most obvious in the first year of follow-up (RR = 10.05), less pronounced in years 2 (RR = 2.23) and 3 (RR = 3.04), and absent in year 4 of follow-up (RR = 0.68). This finding indicates that exhaustion is a relatively short-term precursor of myocardial infarction. Other evidence indicates that current exhaustion is associated with a history of exhaustion (15) and that such a history adds to the prediction of myocardial infarction over and above the exhaustion assessed at screening. Thus, exhaustion can be construed to be an episodic (ie, transient and recurring) rather than a chronic risk indicator for adverse cardiac events (3).

Because exhaustion is assumed to result from prolonged and uncontrollable psychological distress, it was further hypothesized that individuals who were hostile or who displayed the type A behavior pattern were more likely to become exhausted (Figure 1) (16). In a case–control study, it was indeed demonstrated that exhaustion was more prevalent among subjects displaying interview-determined type A behavior (17). In addition, the combination of both type A behavior and exhaustion was associated with an excess risk (RR = 11.0) of myocardial infarction compared with type B/nonexhausted reference group (risks associated with type A behavior/nonexhaustion and type B/exhaustion were 2.0 and 7.6, respectively; overall, 2 = 7.05, p < .001) (17). A similar interaction between exhaustion and hostility has been found using the Cook-Medley hostility scale. The irritability component of exhaustion may share common variance with the characteristics of type A behavior/hostility, but in exhaustion, irritability is only scored as present if it has increased within the last 2 years. Given this background of prior research, we next sought to answer two questions: (1) Does exhaustion reflect underlying subclinical CAD? This could account for the short-term elevated risk for adverse cardiovascular outcome. (2) To what extent do the similar clinical features of exhaustion and depression pose a problem for the divergent validity of these constructs?

Predictive Value of Exhaustion in Patients Undergoing Coronary Angioplasty
To examine whether the relationship between exhaustion and future cardiac events is the result of confounding by underlying coronary disease, we conducted a prospective study in patients undergoing coronary angioplasty. Coronary angioplasty is a nonsurgical procedure with a high (>90%) success rate in removing coronary stenoses and related anginal symptoms, even in patients with multivessel CAD (18). The high (20–30%) incidence of recurrent symptoms and/or restenosis of the initially dilated stenoses within 1 year after the procedure remains a problem in patients’ clinical care (19). The main explanation for coronary restenosis is that the angioplasty procedure pushes the atherosclerotic plaque into the vessel wall, resulting in damage to the coronary endothelium and intima and a subsequent proliferative response of the smooth muscle cells in the arterial wall (20). Restenosis may therefore be viewed as a response to arterial injury, the latter also being an important factor in the pathogenesis of atherosclerosis of native coronary arteries (21). For that reason, the clinical course after coronary angioplasty can be considered to reflect a form of accelerated coronary atherosclerosis (22). In this regard, the clinical course after coronary angioplasty is a useful model for investigating biobehavioral predictors of coronary disease progression, because the incidence of new cardiac events after coronary angioplasty is high, the anatomical severity of underlying CAD can be explicitly controlled, and postprocedural psychological assessments can be made in the absence of cardiac symptoms (23).

This study included 127 successful coronary angioplasty patients in whom exhaustion was assessed before and 2 weeks after successful angioplasty (23, 24). Successful angioplasty was defined as a residual stenosis of less than 50% with complete absence of symptoms until 2 weeks after the angioplasty procedure. Patients were then followed up for 1.5 years, and the occurrence of new cardiac events (ie, cardiac death, myocardial infarction, coronary bypass surgery, repeat angioplasty, progression of coronary disease, and new angina with evidence of ischemia) was documented. New cardiac events occurred in 29 (23%) patients, and exhaustion was associated with a more than twofold elevated risk of new cardiac events (RR = 2.7; CI = 1.1–6.3; p = .02) (23). As shown in Figure 2, the increased rate of new cardiac events in the exhausted group was most pronounced in the first 6 months after angioplasty, after which group differences persisted. Other predictors of adverse long-term outcome were severity of coronary disease and history of hypercholesterolemia. Multivariate analysis revealed that these other risk factors for adverse outcome did not account for the predictive value of exhaustion (adjusted RR = 2.3, p = .06).

View larger version (17K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier curves of exhausted (N = 43) and nonexhausted patients (N = 84). The exhausted group (solid line) had a less favorable clinical course after angioplasty compared with the nonexhausted group (dashed line) (p = .02). Reproduced from Kop et al. (23).

Relationship Between Exhaustion and Underlying Cardiac Dysfunction
The relationship between exhaustion and anatomical and functional severity of coronary disease was further investigated in a series of cross-sectional studies. In one study, the association between exhaustion and underlying CAD severity was examined in 307 consecutive patients undergoing coronary angiography (25). Angiograms were coded with regard to the anatomical severity of coronary disease using two indices, the number of diseased vessels and a composite measure of severity including the number, location, and severity of the coronary lesion. Overall, no significant association was found between the severity of coronary disease and exhaustion scores on the MQ. Patients without angiographic evidence of coronary disease had a MQ score of 21.2 ± 12.3, compared with 17.7 ± 10.4 in patients with single-vessel disease, 20.5 ± 10.9 in those with two-vessel disease, and 20.4 ± 10.4 in three-vessel disease (p = .15). A similar negative result was found using the composite disease severity score. Because patients who have undergone coronary angiography and are free of coronary disease may constitute a special category and hence bias the results (26), analyses were repeated excluding disease-free patients. The relationship between disease severity and exhaustion remained nonsignificant (p = .09), and the amount of explained variance of exhaustion scores by CAD severity was quite low (R2 = 0.01) (25). Thus, in patients with coronary disease, no substantial relationship is observed between anatomical disease severity and self-reported feelings of exhaustion.

The hypothesis that exhaustion in CAD patients is a consequence of underlying cardiac pathology may be better investigated by assessment of cardiac pump function rather than anatomical disease severity. Two aspects of cardiac pump function are relevant: overall function at rest and the potential to increase cardiac pump function during physical or mental challenges. Left ventricular function (ejection fraction and ventricular wall motion) can be assessed during cardiac catheterization or with noninvasive techniques, such as echocardiography or radionuclide ventriculography. In the above-mentioned angiography study (25), a subset of patients also underwent assessment of left ventricular pump function at rest. It was found that exhaustion scores were not higher in patients displaying a poor (40%; N = 14) or moderate (40–60%; N = 18) cardiac pump function, compared with those with a good (>60%; N = 106) cardiac pump function (mean MQ scores: 19.0 ± 10.7, 19.8 ± 10.4, and 18.1 ± 10.9, respectively). However, exhaustion was more prevalent among patients with poor exercise tolerance, suggesting that cardiac responsiveness to exogenous challenges such as exercise may be impaired in exhausted individuals.

Cardiac responses to exercise and mental challenges in patients with CAD were examined as part of a larger study of the association between indicators of myocardial ischemia and coronary vasomotion. Subjects performed physical and mental laboratory tasks while cardiac pump function was documented using radionuclide ventriculography; pretask resting images were compared with images obtained during the tasks. Mental tasks (mental arithmetic, anger recall, and a Stroop color–word test) and physical exercise (semisupine bicycle) were performed by 39 patients (27). Stress-induced wall motion abnormalities indicative of ischemia occurred in 18 (46%) patients during mental tasks. Ischemia elicited by the mental tasks was not associated with higher exhaustion scores (21.3 ± 11.4) compared with nonischemic responders (20.8 ± 10.8). Similarly, no association was found between exercise-induced ischemia and exhaustion. In addition, the blood pressure and heart rate responses to mental stress did not differ between exhausted and nonexhausted subjects.

To summarize, these data reveal little support for the notion that exhaustion in patients with cardiac disease reflects the severity of underlying anatomical or functional CAD. In selected cases, however, complaints of exhaustion may reflect severe underlying cardiac pathology that requires immediate cardiological attention (eg (28)). Nonetheless, the data presented here make it unlikely that exhaustion is merely a consequence of the underlying cardiac disease for the majority of patients with CAD. Therefore, a psychological interpretation of exhaustion may be valid and helpful in developing intervention strategies for cardiovascular disease prevention (29, 30).

Similarities and Differences Between Exhaustion and Depression
Given the extensive research on the adverse effects of depression on cardiovascular health outcome (31, 32), there would be little need for exhaustion as a new construct if depression and exhaustion refer to essentially the same condition. DSM-IV (33) uses the following criteria for diagnosis of major depressive disorder: (1) depressed mood, (2) markedly diminished interest or pleasure in activities, (3) weight loss or gain (>5%), (4) insomnia or hypersomnia, (5) psychomotor retardation or agitation, (6) fatigue or loss of energy, (7) feelings of worthlessness or guilt, (8) diminished ability to concentrate or think, and (9) recurrent thoughts of death. Diagnosis is based on the presence of five of these nine criteria, at least one of which should be criterion 1 or 2. The three characteristics of exhaustion (lack of energy, increased irritability, and demoralization) are therefore, by definition, quite prevalent among depressed individuals.

However, some observations suggest certain differences between exhaustion and depression. First, sadness, guilt, and feelings of worthlessness are commonly observed in depression, whereas these affects are not part of the diagnostic criteria for exhaustion and are generally not present among exhausted individuals (34). A second issue relates to potential cultural biases in the definition of the exhaustion construct. Most research on exhaustion has been conducted in northern Europe, primarily in the Netherlands. Although Western cultures share many values, and psychiatric classifications based on the American Psychiatric Association criteria are generally applicable to other cultures, some subtle differences between the expression of emotion between the Dutch and Americans could account for the apparent differences between exhaustion and depression. Preliminary analysis comparing the DSM-IV classification of major depression and criteria for exhaustion in an American sample of 52 patients with CAD indicated that more than half (57%) of the exhausted patients did not meet the criteria of major depression. In contrast, nearly all patients meeting criteria for depression also met criteria for exhaustion. This suggests that most cardiac patients who are depressed are also exhausted but that an additional subset of patients exists who are exhausted but not depressed. The overlap between exhaustion and DSM-IV criteria for minor depression needs further investigation.

Furthermore, secondary analyses were conducted on the aforementioned study of coronary angioplasty patients, examining whether the lack of energy component of exhaustion was a more powerful predictor of adverse cardiac outcome compared with the demoralization component, which is more closely related to the affective state of depression. The risk for new cardiac events associated with the lack of energy component was 2.5 (p = .03), compared with 1.9 (p = .1) for demoralization. Multivariate analysis adjusting for CAD severity and hypercholesterolemia revealed that the lack of energy component was unaffected by control variables (RR = 2.6, p = .08), whereas the demoralization component lost its predictive value (RR = 1.2, p = NS). In this respect, it is relevant to note that the neuroendocrine correlates of depression may vary with its clinical presentation such that melancholia is related to hyperactivity of the hypothalamic–pituitary axis, whereas atypical depression is characterized by hypoactivity (35). It could therefore be that exhaustion is associated with pathophysiological correlates that are distinctive from those of depression.

To summarize, both depression and exhaustion can be construed as episodic psychological risk factors on the basis of their characteristic duration and proximity as risk factors for coronary syndromes. The assessment instruments for exhaustion include many of the depression criteria mentioned above (criteria 1, 2, 4, 6, 8, and 9), and it will therefore be necessary to improve the assessment techniques of exhaustion to better identify this construct. Exhaustion appears to occur more frequently in cardiac patients (approximately 35–60%) than depression (approximately 10–20%), and the detection of exhaustion may further optimize the identification of patients at risk for adverse cardiovascular outcome, although future studies are needed to substantiate this hypothesis.

	ACUTE RISK FACTORS FOR MYOCARDIAL ISCHEMIA AND INFARCTION

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In the prior section, the clinical course after coronary angioplasty was used as a model to examine biobehavioral predictors of coronary disease progression. It was noted that exhaustion is an episodic risk factor for cardiac events with a time span ranging from several months to 2 years. In an analogous manner, studies on stress-induced cardiac ischemia were used as a model for assessing acute psychological risk factors (ie, triggers) of coronary syndromes, such as myocardial infarction. Most coronary syndromes are preceded by acute and sustained myocardial ischemia. Myocardial ischemia occurs when the demands for oxygenated blood required by the heart muscle to exert its pumping activity are not met by the coronary blood supply (36). Therefore, the study of myocardial ischemia may provide important information about the pathophysiological mechanisms by which acute psychological risk factors (ie, mental activity and emotions) can trigger coronary syndromes. Epidemiological research suggests that anger is a potent short-term trigger of myocardial infarction (37). In addition to these immediate adverse effects of acute psychological risk factors, recent prospective studies also support the long-term clinical relevance of ischemia triggered by acute psychological distress, demonstrating that cardiac events occur more often in patients with mental stress–induced ischemia (38–40).

Two main factors determine the onset of cardiac ischemia in patients with CAD: increased cardiac demand and decreased coronary supply. As reviewed elsewhere (1, 41), myocardial ischemia can be induced by mental challenge tasks in 30% to 60% of patients with CAD and is referred to as mental stress–induced ischemia. Several characteristics of mental stress– induced ischemia make it a useful paradigm for biobehavioral research on triggers of coronary syndromes: (1) it can be observed reliably and frequently in patients with CAD; (2) it can be studied in laboratory settings as well as during daily life activities; and (3) because mental stress–induced ischemic episodes are generally asymptomatic (silent), no confounding by concomitant cardiac symptoms occurs. The following sections review our recent field studies on specific acute psychological risk factors for ambulatory cardiac ischemia. This is followed by a summary of investigations on potential pathophysiological mechanism (ie, coronary vasomotion and hemodynamic responses) by which acute psychological risk factors can lead to coronary syndromes.

Behavioral Triggers of Ischemia During Daily Life Activities
Specific behavioral triggers of ambulatory ischemia can be investigated by cross-tabulating patients’ activities as reported in structured diaries with coinciding ischemic events documented by continuous electrocardiographic monitoring. The structured diary inquires about activities (driving, reclining, getting dressed, etc.), posture, physical and mental effort level, mood state, and occurrence of cardiac symptoms. Patients are instructed to complete a new diary page each time a change in their activity occurs. In more recent studies, a beeper is also provided to indicate that a new diary page has to be completed. These diary entries can then be matched with ambulatory ischemic events. Myocardial ischemia during the activities of daily life is defined as ST-segment depression of 1 mm or more for a duration of more than 1 minute. As with mental stress–induced ischemia, most ambulatory ischemic events are silent (41, 42), and this method, therefore, allows assessment of the activities and emotions triggering ambulatory ischemia in the absence of cardiac symptoms.

To determine the associations between physical activities and emotions (eg, anger, sadness, anxiety, and happiness) with ischemia, we examined 63 patients with coronary disease who exhibited evidence of ischemia during daily life (43). It was found that most ischemic events occurred at moderate, not high, levels of activity. However, the average duration of moderate physical effort or mental arousal was significantly longer than the duration of high effort and arousal. When the data were corrected for the duration of activities, it appeared that the highest levels of physical and mental activities were associated with more ischemia. In addition, a circadian variation was observed in the inducibility of ischemia by mental arousal and physical activity such that these triggers were most pronounced during the first 6 hours after awakening (RR = 1.9, CI = 1.0–3.6, p = .05 and RR = 3.7, CI = 2.0–67, p < 0.01, respectively); mental arousal, but not physical activity, preceded ischemic events occurring in the evening hours (RR = 2.0, CI = 1.1–3.9, p = .04 and RR = 1.4, CI = 0.8–2.4, p = NS, respectively) (44). Anger was the emotional state most strongly associated with ischemia (43). However, the heart rate (used as a measure of cardiac demand) at which anger-induced ischemia occurred was only marginally higher than the heart rate at ischemia occurring in the absence of anger (106 ± 18 vs. 96 ± 17 bpm; p < .06). These data demonstrate that acute psychological factors, especially anger, can trigger ischemia during the activities of daily life and that the mechanisms involved are most likely not limited to increased cardiac demand.

Mental Stress–Induced Changes in Cardiac Demand and Coronary Supply
A wide range of studies have examined the effects of acute mental challenge tasks on measures related to increased cardiac demand, including hemodynamic and hemostatic factors (for reviews, see Refs. 45–47). In addition to increasing cardiac demand, mental activities and emotions may induce myocardial ischemia by reducing coronary blood supply. This hypothesis is consistent with the observation that mental stress–induced ischemia occurs at lower levels of cardiac demand than exercise-induced ischemia (see above). Prior research has demonstrated that mental stress can result in a transient reduction of the coronary artery diameter, especially in more severely diseased arteries (48). The diameter of a coronary artery can be measured using quantitative coronary angiography.

In a recent study, patients performed a 2-minute mental arithmetic test after the clinically indicated diagnostic coronary angiography procedure. Preliminary analyses of 33 patients (mean age, 60 ± 10 years; 32 men and 1 woman) revealed that this mental task provoked increases in blood pressure and heart rate (49). The coronary vasomotion responses ranged from 15% constriction to 18% dilation. In contrast to prior observations (48, 50, 51), no overall constrictive response was observed in the diseased coronary segments. Interestingly, however, the magnitude of the blood pressure response was inversely related to the extent of arousal-induced coronary vasomotion, such that high responders displayed more constriction (r = -0.43, p < .01) (49). No relationships between heart rate responses and coronary constriction was observed. This finding indicates that the increases in cardiac demand induced by mental arousal (ie, increased blood pressure) coincide with decreases in coronary supply, both of which promote the likelihood of ischemia.

We also documented one instance of transient complete coronary occlusion as a result of a standard mental challenge task, which was reversed by administration of intracoronary nitroglycerin and a calcium antagonist (Figure 3) (52). These findings indicate that mental stress–induced hemodynamic increases can result in simultaneous paradoxical coronary vasoconstriction. One of the explanatory mechanisms is that the normal arterial dilatory response to increased blood flow is absent or even reversed in patients with CAD because of endothelial dysfunction. The clinical consequences of this phenomenon may be further exaggerated by an impaired dilation response of the coronary microcirculation (eg, Refs. 53 and 54), leading to ischemia at relatively low levels of cardiac demand.

View larger version (57K): [in this window] [in a new window]   Fig. 3. Left anterior descending coronary artery. Initial angiography (left), total occlusion after mental stress (middle), and revascularization after intracoronary administration of nitroglycerin and a calcium antagonist (right). Reproduced from Papademetriou et al. (52).

	PATHOPHYSIOLOGICAL MECHANISMS: CHRONIC, EPISODIC, AND ACUTE PSYCHOLOGICAL RISK FACTORS FOR CORONARY SYNDROMES

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Episodic Risk Factors
The relationships between episodic risk factors, such as exhaustion, and future cardiac events are confined to a relatively short time span (<2 years) (3, 16). Recent evidence further indicates that exhaustion adversely affects cardiovascular risk factors related to homeostasis, such as blood clotting tendency (59, 60), and markers of subclinical inflammation (61), thereby increasing the vulnerability of developing coronary syndromes. Specifically, exhaustion was found to be related to decreased fibrinolytic measures (plasminogen activator inhibitor-1), whereas no effects of exhaustion on blood coagulation factors was found (eg, factor VII and VIII) (59). We also found some evidence of decreased albumin and increased fibrinogen in elderly exhausted subjects (61). Episodic risk factors have pathophysiological correlates that differ from chronic as well as acute psychological risk factors. Chronic psychological risk factors are significantly associated with severity of coronary disease, whereas episodic risk factors do not reveal consistent associations with CAD severity (see above) (24, 25). In addition, most evidence suggests that episodic risk factors are not associated with hemodynamic hyperresponsiveness (27, 32). This lack of association with reactivity may be explained in part by a blunted responsiveness due to prolonged challenges to the cardiovascular system, resulting in what has been described as an increased allostatic load (62, 63).

Evidence suggests that the likelihood of developing episodic risk factors is elevated among individuals who have chronic psychological risk factors. For example, exhaustion is considered to be the end-stage of prolonged uncontrollable psychological distress (6, 10). Consequently, exhaustion is likely to be more prevalent among individuals who experience continued psychological distress (eg, hostile individuals). Several studies have found additive effects of exhaustion superimposed on these chronic sources of psychological distress (3, 11, 64).

Acute Psychological Risk Factors
Mental activities and emotions are potent triggers of myocardial ischemia (1), and epidemiological studies suggest that outbursts of anger can provoke myocardial infarction (37). The pathophysiological consequences of acute psychological risk factors in patients with cardiac disease are described in detail elsewhere (1). In general, the acute factors are associated with a shift toward increased activity of the sympathetic nervous system and a decreased parasympathetic (vagal) activity, accompanied by elevated circulating catecholamines and increased hemodynamic load (eg, heart rate and blood pressure). The pattern of physiological and biological responses to mental activities and emotions is determined by many factors, including demographic characteristics, task characteristics, presence of comorbid conditions, and cardiovascular risk factors. Acute psychological risk factors may result in impaired dilation of the coronary vessels (48, 49), decreases in plasma volume (65), and increased platelet activity and blood clotting tendency (66, 67). These physiological responses result in an imbalance between increased cardiac demand and decreased coronary blood supply and potentially lead to cardiac ischemia. Furthermore, hemodynamic responses to acute stressors can lead to plaque rupture, and increased platelet aggregation may promote acute coronary thrombosis. Acute psychological factors may also elicit electrical instability of the myocardium and cause life-threatening arrhythmias (68).

	FUTURE DIRECTIONS

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Additional studies in cardiovascular behavioral medicine may clarify the pathophysiological mechanisms by which psychological risk factors cause coronary disease progression and its clinical manifestations, such as myocardial infarction. Given the research findings presented above, these mechanisms depend in part on the proximity, duration, and combined effects of the psychological risk factors in relation to the cardiac event. In addition, a wide range of studies have indicated that psychological risk factors are associated with adverse health behaviors, such as smoking (4) and a sedentary lifestyle, as well as known cardiovascular risk factors, such as hypercholesterolemia (5). It is important to note that the magnitude of the chronic and episodic psychological risks associated psychological factors is similar to those reported for traditional cardiovascular risk factors. The triggering role of acute psychological risk factors is generally less potent compared with other known triggers of coronary syndromes, including smoking (43) and strenuous exercise (69). Two selected areas for future research will be discussed here: (1) the effects of behavioral factors and inflammatory processes in CAD and (2) the interaction between the three purported categories of psychological risk factors for coronary syndromes and their pathophysiological correlates.

Inflammation and CAD
As mentioned, coronary disease progression is promoted by inflammatory processes and can be viewed as a "response to injury" (21). Moreover, recent evidence suggests significant associations between exhaustion and other episodic cardiovascular risk factors with measures of (subclinical) inflammation (61, 70). It is therefore hypothesized that the risk associated with episodic risk factors is partially mediated by immunological processes. At present, little is known about the interaction between behavioral factors and inflammatory processes in progressive atherosclerosis. As reviewed elsewhere (71), several lines of evidence indicate that immunological processes play a crucial role in plaque formation. The cascade of events can be summarized as follows. Both acute and chronic psychological factors may promote the expression of adhesion molecules (eg, Ref. 72). These adhesion molecules (eg, intracellular adhesion molecule-1) may cause monocytes and T cells to adhere to the vascular endothelium. Monocytes that infiltrate tissue become macrophages. Two main responses emerge from the penetration of macrophages and T cells into the vascular wall: activation of the cytokine cascade and release of growth factors (eg, insulin-like and platelet-derived growth factor). Cytokines and growth factors accelerate smooth muscle cell proliferation from the intimal layers of the vessel wall and promote progression of atherosclerosis. In the perspective of the pathophysiological model proposed here, it is of interest that both episodic (73, 74) and acute (75) psychological risk factors for coronary syndromes are reported to affect circulating levels of T cells, B cells, and aspects of the cytokine cascade. A major challenge in this area of research relates to the clinical significance of the reported elevated levels of immunological measures. Furthermore, the relationships between immunological processes and the progression of CAD are not fully understood, and it is not clear to what extent circulating immunological measures accurately reflect the processes that occur at the local sites of atherosclerotic plaques. Nonetheless, the relationship between psychological risk factors for coronary syndromes and measures of inflammation may reveal new insights in the pathophysiology of coronary disease progression.

Psychological Factors and CAD
Additional research is also needed to clarify possible interactions among the three categories of psychological risk factors for coronary syndromes. With regard to chronic psychological risk factors, it seems appropriate to further extend research efforts to include factors other than antagonistic traits such as hostility. Although most studies have dichotomized the presence or absence of psychological risk factors for coronary syndromes and cutoff points can be useful in certain settings, it is likely that these constructs are better conceptualized as continuous variables. An important issue relates to the coincidence of various chronic psychological and sociological risk factors for coronary disease, such as the association between hostility and low SES (76). Recent evidence also suggests that the depressive personality type may predispose for recurrent cardiac events (77). Such a predisposition for becoming depressed may account for the reported long-term association between depression and cardiac events (78) as well as the fact that a history of depression (32) and exhaustion (15) adds to the prediction of cardiac events over and above the presence of episodic risk factors at screening.

In conclusion, psychological risk factors for coronary syndromes can be classified into three categories: chronic, episodic, and acute. The reviewed evidence suggests that each of these risk factors is associated with specific pathophysiological characteristics. The assessment of various levels of psychosocial risk factors and their pathophysiological correlates may therefore help to improve the risk stratification of patients with cardiac disease and may guide the development of future intervention strategies (29, 30).

	ACKNOWLEDGMENTS

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Dr. Willem Johan Kop received the 1998 Early Career Award of the American Psychosomatic Society. The research presented in this article was made possible by National Institutes of Health Grants HL47337 and HL58638; Dutch Heart Foundation Grant 94–098; and Uniformed Services University of the Health Sciences Grant RO7233.

This article presents a review of the research conducted in collaboration with my mentors, Dr. Ad Appels, Cardiovascular Research Institute Maastricht, University of Limburg, the Netherlands, and Dr. David Krantz, Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, Bethesda, MD. I benefited tremendously from their guidance, for which I am grateful. I also thank Dr. John Gottdiener and Dr. Ad Vingerhoets for their friendship and scientific support. Dr. David S. Krantz and Dr. Deborah N. Ader are acknowledged for their helpful comments on earlier drafts of this manuscript. The opinions and assertions expressed herein are those of the author and should not be construed as reflecting those of the Uniformed Services University of the Health Sciences or the US Department of Defense.

Received for publication October 21, 1998.

Revision received April 16, 1999.

	REFERENCES

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