The relationship between severity of coronary artery disease and vital exhaustion

Journal of Psychosomatic Research, Vol. 40, No. 4, pp. 397-405, 1996 Copyright © 1996 Elsevier Science Inc. All rights reserved. 0022-3999/96 $15.00 + .00

ELSEVIER

0022-3999(95)00613-3

THE RELATIONSHIP BETWEEN SEVERITY OF CORONARY ARTERY DISEASE A N D VITAL E X H A U S T I O N W . J . K O P , *t A . P . W . M . A P P E L S , t C. F. MENDES

d e L E O N ~ a n d F. W . B , ~ R ~

(Received 3 March 1995; accepted 12 October 1995) Abstract-The present study investigates the association between the severity of coronary artery disease

(CAD) and feelings,of exhaustion. Vital exhaustion consists of three major components: lack of energy, increased irritability, and demoralization. Previous studies showed that exhaustion is of predictive value for first myocardial infarction (MI). However, these studies could not rule out that the state of exhaustion prior to MI was the result of underlying CAD. To examine this issue, severity of CAD and cardiac pump function were related to feelings of exhaustion in 307 patients who underwent coronary angiography. It was found that exhaustion, as assessed by means of the Maastricht Questionnaire (MQ), was not related to the severity of CAD (F= i. 17; p = 0.15). Furthermore, a poor left ventricular function did not relate to MQ scores (N= 138; F< 1; NS). On the other hand, clinical variables (duration of complaints, exercise performance, peripheral vascular disease, and dyspnea), use of medication (nitrates, 13-blocking agents, calcium antagonists, and diuretics), and demographic characteristics (gender and education) were associated with MQ scores. Multiple regression analysis showed that demographic variables (lower education, younger age, and female gender) were the predominant predictors of exhaustion. In addition, dyspnea, peripheral vascular disease, and the use of medication related significantly to exhaustion scores (R 2= 0.13; F = 4.8; p<0.001). We conclude that neither the extent of CAD nor impaired cardiac pump function is related to feelings of exhaustion in patients referred for coronary angiography. Therefore, the previously reported association between exhaustion and future M1 is not likely to be caused by underlying coronary disease.

Keywords:

Vital exhaustion; Coronary artery disease; Left ventricular ejection fraction.

INTRODUCTION Excessive fatigue and feelings of general malaise are among the most prevalent premonitory symptoms of myocardial infarction and sudden cardiac death [1-6]. Psychological a n a l y s i s o f t h e t i r e d n e s s p r i o r t o m y o c a r d i a l i n f a r c t i o n r e v e a l e d t h a t it t y p i c a l l y

* Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. t Department of Medical Psychology, Cardiovascular Research Institute Maastricht, University of Limburg, the Netherlands. ~tDepartment of Cardiology, Cardiovascular Research Institute Maastricht, University of Limburg, the Netherlands. § Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, Connecticut, USA. The opinions and assertions expressed herein are those of the authors and should not be construed as reflecting those of the USUHS or of the Department of Defense. Address for correspondence: Willem Johan Kop, Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, F. Edward H6bert School of Medicine, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA; Tel. ( + 1) 301-295-3270; Fax ( + 1) 301-295-3034. 397

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consists of 3 components: lack of energy, increased irritability, and demoralization. We have labeled this state previously as "vital exhaustion" [7]. A case-control study [8] and two prospective studies [9,10] showed that feelings of exhaustion were predictive of first myocardial infarction in apparently healthy individuals. Moreover, this association was independent of the known risk factors for coronary artery disease (CAD) such as blood pressure and cholesterol. The origin of vital exhaustion as a premonitory symptom of clinical manifestations of CAD is still not well understood. In the late 1950s, Selye postulated that a state of exhaustion reflects a breakdown in adaptation to prolonged psychological stress [11]. In the late 1960s, Bruhn and colleagues [5] already suggested that myocardial infarction could be conceived as the result of a history of "emotional drain," which they characterized as " . . . a nearly constant state of mental preparedness on the part of the individual to cope w i t h . . , c o n f l i c t . . , to the point where the total organism is left in a state of physical and mental exhaustion." Congruent with this notion is the observation by Falger and colleagues [8], in which a number of stressful life events preceded exhaustion in patients who suffered myocardial infarction. Alternatively, it may be that exhaustion prior to myocardial infarction is caused by underlying CAD or a reduced pump function of the heart. In the prospective study of Appels and Mulder [9, 12], subjects were excluded if they had anginal complaints or signs of past myocardial infarction according to the 12-lead electrocardiogram at rest. However, this procedure is obviously not adequate to rule out the presence or absence of coronary disease. Therefore, the observed association between exhaustion and myocardial infarction might have been confounded by undetected underlying CAD. That is, subjects who had narrowed coronary arteries due to atherosclerosis and who were for that reason at the highest risk of developing clinical endpoints, may also have reported feelings of exhaustion more often. The purpose of the present study was to investigate the relationship between the severity of C A D and cardiac pump function on the one hand, and vital exhaustion on the other hand. To this end, a group of patients who underwent diagnostic coronary angiography was evaluated for feelings of exhaustion. In order to examine the possibility that feelings of exhaustion prior to myocardial infarction reflect underlying CAD, the following hypothesis was tested: Feelings o f exhaustion are positively associated with the extent of coronary artery disease and reduced cardiac pump function. If exhaustion and CAD are found to be strongly related, then there would be little need to search for alternative explanations for the tiredness prior to myocardial infarction. METHOD Patients

The study sample consisted of 322 consecutivepatients referred for diagnostic coronary angiography. Patients had to giveinformed consent and the followinginclusion criteria were applied: 1) age ~70 years; 2) no previous revascularization by coronary angioplasty or bypass surgery; and 3) absence of severe co-morbidity(e.g., valvulardisease, heart failure, cancer,or psychiatricdisorder). A subset of these patients was describedelsewhere [13]. Fifteen patients refused to participate or returned an invalid questionnaire for the assessment of vital exhaustion, leaving 307 patients for further analysis (response rate 95%). Vital exhaustion

The Maastricht Questionnaire (MQ) was used to assess feelings of exhaustion. The MQ consists of 21 items and has a high internal consistency(Crombach'stt = 0.89). In a healthy population, the mean MQ scoreis 8.8 (SD= 8.7, median = 6, possiblescorerange:0-42). In patients whoare hospitalized for noncardiac

Vital exhaustion and coronary artery disease

399

diseases, the MQ tends to he slightly elevated (mean= 11.7, sD=9.8) [9]. In the current study, patients were asked to report how they had felt during the 3 months preceding the current admission.

Coronary artery disease and left ventricular function Coronary angiograms were evaluated by a panel of experienced cardiologists. Two indices of CAD severity were used. The first was the number of vessels with a lesion >50070 (i.e., right coronary artery, left anterior descending artery, and/or circumflex artery). The possible range of this variable (VD) is 03. The other, more informative, measure of CAD takes the severity of the coronary lesions as well as the number of diseased vessels into account [14], making use of the following criteria: 0 = no coronary artery disease; 1 = clinically minor disease in one or more coronary arteries (i.e., lesion <70070); 2 = >70070 stenosis in one coronary artery; 3 = >70°70 stenosis in two coronary arteries; 4 = >70070 stenosis in 3 coronary arteries; 5 = >70070 stenosis in the left main artery. This variable is referred to as CADSEV. Cardiac pump function was evaluated using the standard procedure for left ventricular angiography. The left ventricular ejection fraction (LVEF) is calculated by dividing the stroke volume (i.e., the difference between the end-diastolic and end-systolic volume of the left ventricle) by the end-diastolic volume. The normal value for the LVEF in healthy persons is 67 + 807o. A distinction was made between patients with a "poor" (LVEF<40%), "moderate" (4060%) cardiac pump function. Left ventricular function was determined in 138 (45070) of the 307 patients.

Clinical and demographic characteristics Information about patient characteristics was obtained from the medical record. Duration of cardiac complaints and exercise performance were investigated to assess the impact of the patient's clinical condition prior to admission on feelings of exhaustion. Maximal exercise performance was evaluated using the Bruce protocol [15] if the test was done within 3 months prior to admission. Exercise performance was defined as "poor" if patients reached stage I or II, and as "good" if stage III, IV, or V was reached. The presence of peripheral vascular disease, a positive history of myocardial infarction (i.e., occurring more than I month before hospitalization), hypertension, and diabetes mellitus were also considered as relevant indicators of the clinical condition prior to hospitalization. The diagnosis on admission could be either stable angina, unstable angina, or myocardial infarction. Unstable angina was defined as angina at rest, progressive angina, or recent onset angina. Myocardial infarction was diagnosed on the basis of the electrocardiogram and subsequent enzyme rise. The New York Heart Association classification criteria for angina and dyspnea were used to assess the severity of cardiac complaints. Because fatigue can be a possible side-effect of several types of medications that are frequently prescribed to coronary patients, we registered the use of nitrates, I]-blocking agents, calcium antagonists, platelet aggregation inhibitors, coumarins, and diuretics. Demographic variables included age, gender, education, and marital status. Education was divided into 3 categories: low (less than 8 years), middle (8 to 12 years), and high (more than 12 years). Marital status was categorized as married or living with a spouse, single, divorced, or widowed.

Statistical analysis Analyses of variance were used to examine the association between the severity of CAD, clinical variables, and demographic variables as between-subject factors, with vital exhaustion as the dependent variable. Multiple correlation coefficients (R2) were used to assess the explained variance of the MQ scores. R 2 is also referred to as the "coefficient of determination" because it provides an indication of the extent to which a set of predictor variables accounts for the variation of a dependent variable (i.e., the exhaustion score). Because R 2 tends to increase when the number of predictor variables increases, the adjusted R ~ was used as a measure of association. Analyses were repeated while excluding patients without clinically significant coronary disease because of the purported exceptional status of these patients [16].

RESULTS T h e m e a n a g e o f t h e s t u d y p o p u l a t i o n w a s 55.9 + 8.5 y e a r s , a n d 63 p a t i e n t s ( 2 1 % ) w e r e w o m e n . T h e m e a n M Q s c o r e w a s 19.1 _+ 10.1, w h i c h is m a r k e d l y h i g h e r t h a n w h a t is f o u n d i n h e a l t h y s u b j e c t s a n d h o s p i t a l i z e d p a t i e n t s w i t h n o n c a r d i a c d i s e a s e s . T h e r e l a t i o n s h i p b e t w e e n e x t e n t o f C A D a n d e x h a u s t i o n is s h o w n i n T a b l e I. T h e number of diseased vessels (VD) was not associated with the mean MQ score, nor was there a relationship between the more informative variable CADSEV and exhaustion.

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W. J. KOP et

al.

Table I.-Coronary artery disease and left ventricular function as related to vital exhaustion

Vessel disease 0 1

2 3 CADSEV 0 1 2 3 4 5 Left ventricular function good moderate poor

N

Mean

SD

F

p

14 143 97 53

21.2 17.7 20.5 20.4

12.3 10.4 10.9 10.4

1.77

0.15

12 11 160 79 41 4

18.5 20.3 18.4 20.9 18.9 21.1

11.2 14.1 10.5 11.0 9.7 12.9

0.64

0.67

106 18 14

18.1 19.8 19.0

10.9 10.4 10.7

0.23

0.79

CADSEV = a measure of the severity of coronary disease (see text for explanation).

Because the association between VD and vital exhaustion was stronger than the association between CADSEV and vital exhaustion, the former variable was used in the multiple regression analyses as an indicator of the extent of CAD. When the data were analyzed while excluding patients without significant atherosclerosis (i.e., VD ~0), it was found that patients with multivessel disease tended to have higher exhaustion scores ( F = 2.4; p = 0.09). Left ventricular ejection fraction was obtained in 138 patients (45°70). Table I shows that poor left ventricular function was not very prevalent in the present sample ( N = 14). LVEF was more often assessed in patients with multivessel disease, myocardial infarction on admission, more severe angina, peripheral disease, or longer duration of cardiac complaints. This indicates a less favorable clinical status of patients in whom the LVEF was calculated. Nonetheless, MQ scores did not differ between patients with and without LVEF evaluation. It was found that patients with a poor or moderate LVEF did not have higher MQ scores than patients with a good left ventricular function (Table I). As for the relationship between the clinical condition prior to admission and exhaustion, Table II shows that longer duration of cardiac complaints and poor exercise performance were associated with higher exhaustion scores. The presence o f peripheral vascular disease was also related to more severe exhaustion. Hypertension and diabetes mellitus did not influence exhaustion scores, but in the case of diabetes, the insignificant effect may have been caused by a lack of statistical power. With regard to the diagnosis and severity of cardiac complaints on admission, it was found that patients with unstable angina tended to have higher MQ scores than patients with myocardial infarction or stable angina, but the severity of anginal complaints was not related to MQ scores. Furthermore, patients who had dyspnea (class II, III, or IV) had clearly elevated exhaustion scores. Higher MQ scores were observed when patients used one o f the following medications: nitrates, 13-blocking agents, calcium antagonists, or diuretics. Sixty patients

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Table I I . - Bivariate associations between clinical characteristics and vital exhaustion

Complaint duration ~<1 week x1 month Exercise performance good poor Peripheral disease no yes History of mycardial infarction no yes Hypertension no yes Diabetes mellitus no yes Diagnosis stable angina unstable angina infarction Angina class I

II III IV Dyspnea class I

II Ill/IV

N

Mean

SD

F

p

48 70 188

17.4 16.7 20.5

8.2 11.6 10.7

4.07

0.02

106 87

17.8 21.1

11.0 10.0

4.69

0.03

274 33

18.6 23.9

10.7 9.5

7.17

0.001

223 84

18.9 20.0

10.7 10.6

0.59

0.44

221 86

18.7 20.5

10.5 11.2

1.76

0.19

302 5

19.1 24.4

10.6 16.4

1.22

0.27

80 150 77

18.6 20.6 17.2

11.7 10.8 8.9

2.68

0.07

8

77 131 90

14.0 18.4 20.7 18.2

10.2 12.2 10.7 9.2

1.86

0.14

216 65 26

17.6 23.1 22.5

10.5 10.3 10.2

8.35

0.001

were n o t o n a n y m e d i c a t i o n o n a d m i s s i o n ; this g r o u p h a d l o w e r e x h a u s t i o n scores t h a n patients w h o used o n e o r m o r e m e d i c a t i o n s ( m e a n M Q scores 14.4_+ 9.1 a n d 20.4 + 10.7, respectively; F = 15.8; p < 0 . 0 0 1 ) . T h e d e m o g r a p h i c characteristics were positively related to e x h a u s t i o n in the sense t h a t w o m e n scored higher o n the M Q t h a n m e n did ( m e a n M Q s 23.4 + 10.3 a n d 18.1 _+ 10.5; F = 12.8; p < 0 . 0 0 1 ) . P a t i e n t s with a low level o f e d u c a t i o n h a d higher M Q scores c o m p a r e d to t h o s e with a m i d d l e o r high level o f e d u c a t i o n ( m e a n M Q scores: 22.5 + 11.4, 19.6 + 10.0, a n d 15.6 + 10.2, respectively; F = 10.3;/9<0.001). A g e was n o t c o r r e l a t e d with e x h a u s t i o n scores (r = 0.01), a n d there was no r e l a t i o n s h i p b e t w e e n m a r i t a l status a n d e x h a u s t i o n . R e g r e s s i o n analyses were carried o u t to e s t i m a t e the c o n t r i b u t i o n o f the severity o f C A D a n d o t h e r p a t i e n t characteristics to the p r e d i c t i o n o f e x h a u s t i o n scores. First, V D was e n t e r e d as p r e d i c t o r v a r i a b l e o f the M Q score. It a p p e a r e d t h a t V D e x p l a i n e d less t h a n 1% o f the v a r i a n c e o f e x h a u s t i o n scores (RZ=0.003; F = 2 . 1 ; p = 0 . 1 5 ) . Next, extent o f C A D (VD), clinical characteristics, n u m b e r o f m e d i c a t i o n s used, a n d d e m o g r a p h i c v a r i a b l e s were e n t e r e d s i m u l t a n e o u s l y into o n e m o d e l . It was f o u n d t h a t the overall e x p l a i n e d v a r i a n c e was 13% (R ~ = 0.13; F = 4.8; p < 0 . 0 0 1 ; exercise

402

W. J. KOP et al. Table Ili. - The prediction of vital exhaustion from clinical and demographic characteristics

Age Peripheral VD Education Dyspnea Gender Medication

[3

t

p

-0.097 0.128 - 0.173 0.171 0.112 0.117

- 1.73 2.34 - 3.00 3.07 1.90 2.04

0.085 0.020 0.003 0.002 0.059 0.042

13 = standardized regression coefficient in the multiple regression model. VD = vessel disease; Medication = total number of cardiac medications used (1-6). performance and LVEF were not included because of too m a n y missing data; diabetes was not included because of its low prevalence). Table III shows the variables that remained in the multivariate model after backward removal of predictor variables. It appeared that all demographic variables (younger age, low level of education, and female gender), peripheral vascular disease, dyspnea, and medication contributed to the prediction of exhaustion scores. When analyses were repeated while excluding patients without evidence of coronary disease [16], the bivariate association between extent of CAD and MQ scores increased (R 2 = 0.01; p = 0.05). Multivariate regression analysis revealed the same predictors of exhaustion scores, with the addition of diagnosis on admission (p = 0.03). DISCUSSION Although feelings of unusual tiredness and exhaustion are a m o n g the most prevalent premonitory symptoms of myocardial infarction and sudden cardiac death, the exact origin of these feelings is not known. The current study shows that there is not a marked relationship between the severity of coronary disease and exhaustion. Less than 1% of the variance in exhaustion scores could be explained by the severity of CAD. Multiple regression analysis revealed that the demographic variables were the best predictors of feelings of exhaustion in patients with coronary artery disease. The cross-sectional design of the present study causes some inferential problems. One possible confound is related to patient-based and physician-based referral bias. It is obvious that patients with coronary disease are overrepresented in the present sample in comparison with the prevalence of C A D in the general population. Furthermore, it is possible that cardiologists consider complaints of undue tiredness as angina equivalents and hence refer individuals with these symptoms more often for coronary angiography. In other words, there is an overselection of the disease a n d of the exposure. This may cause both overestimation and underestimation of the true relationship between severity of C A D and exhaustion, depending on the configuration of the selection fractions [17]. The current observation that the association between vital exhaustion and extent of CAD gained strength after exclusion o f patients without evidence of coronary lesions at coronary angiography is in line with this objection. However, these estimation errors are not likely to account for the very low magnitude of the association between severity of coronary artery disease and feelings o f exhaustion. There are several other plausible explanations for the presence of vital exhaustion

Vital exhaustion and coronary artery disease

403

in patients referred for coronary angiography. Impaired left ventricular function may be one of the possible causes of exhaustion. Although no association was found between reduced left ventricular function and exhaustion scores, it should be noted that the pump function was assessed making use of the ventricular angiogram at rest. Thus, this study cannot exclude the possibility that insufficient increase of the cardiac pump function during exercise or mental activity is associated with feelings of exhaustion. We examined various clinical characteristics that might affect vital exhaustion. It was shown that a longer duration of complaints, reduced exercise performance, peripheral vascular disease, and dyspnea were related to increased feelings of exhaustion. In addition to the implication that these factors promoted extreme tiredness, it is conceivable that an additional process plays an amplifying role. That is, both a patient's physical condition and the psychological reaction to it may be mutually reinforcing phenomena. For example, reduced exercise performance is likely to induce feelings of tiredness and exhaustion. This may result in a person's refraining from physical activity, which in turn decreases exercise performance. In this way a gradual but persistent worsening of the physical and psychological well-being develops. Support for this argument is found in the present observation that exhaustion is related to the duration of complaints and not to the severity of underlying coronary artery disease. The biopsychological mechanisms by which vital exhaustion may promote progression of coronary disease require further investigation. In addition to the importance of blood-clotting factors, platelet adhesion and aggregation, and lipids, evidence is accumulating that deficiencies in the immune system may contribute to the progression of atherosclerosis by affecting growth-mediating processes in the vessel wall [18, 19]. It has been shown that immunological factors are related to the blood clotting process and fibrinolysis [20]. Prolonged psychological stress may impair immune function [21-23], and hence it is possible that vital exhaustion unfavorably affects components of the immune system. The interaction of inflammatory and hemostatic components of progressive atherosclerosis may provide a new area of research in cardiovascular behavioral medicine. Other factors may play a more direct role in the association between vital exhaustion and coronary events. These factors may relate to reduced coronary blood supply (e.g., lowered threshold for coronary vasoconstriction, increased disposition for formation of coronary blood clots), increased cardiac demand (stress-induced elevation o f heart rate and blood pressure), or increased engagement in risk behaviors such as smoking, all of which may promote acute coronary syndromes. The present o b s e r v a t i o n - t h a t vital exhaustion is not an epiphenomenon of severity o f coronary artery disease or impaired left ventricular f u n c t i o n - c o r r e s p o n d s to similar findings in previous studies [24, 25]. From another perspective, it is important to note that fatigue is a nonspecific complaint and that vital exhaustion shares characteristics with depression and other manifestations of psychological distress. In a study of 478 men with coronary disease, Denollet [26] showed that negative affect accounted for 50% of the variance in fatigue scores. On the other hand, we have previously shown that exhausted individuals do not qualify for a psychiatric diagnosis of depression and that vital exhaustion is unrelated to sadness as measured by the Profile Of Mood States and to depression as assessed by the Beck Depression Inventory [27]. However, further research is needed to elucidate the differences and similarities between vital exhaustion and depression. In conclusion, previous prospective studies showed that feelings of exhaustion are

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W.J. KOP et al.

of predictive value for f u t u r e m y o c a r d i a l i n f a r c t i o n [7-10, 12]. U n t i l now, we could n o t exclude the possibility t h a t this association was c o n f o u n d e d b y subclinical u n d e r l y i n g c o r o n a r y artery disease. F r o m the present study it can be inferred that feelings of e x h a u s t i o n are n o t likely to be the direct result o f impaired c o r o n a r y p e r f u s i o n due to c o r o n a r y artery disease. Therefore, vital e x h a u s t i o n has to be distinguished from the typical picture of tiredness o n exertion in c o r o n a r y patients t h a t is caused by insufficient c o r o n a r y supply. Recently, we d e m o n s t r a t e d that vital e x h a u s t i o n is of prognostic value for new cardiac events in patients with successful c o r o n a r y angioplasty d u r i n g 1.5 years o f follow-up [13]. It was f o u n d that new events occurred in 35% of exhausted patients c o m p a r e d to 17% o f n o n e x h a u s t e d patients ( O R = 2.7; ,0<0.02). This predictive value c o n t i n u e d to be significant when severity o f c o r o n a r y disease was controlled for, which provides s u p p o r t for the n o t i o n that vital exhaustion is o f prognostic value i n d e p e n d e n t o f u n d e r l y i n g c o r o n a r y artery disease. It has also been shown that psychologically stress ful life events (including familial a n d j oh-related problems) c o n t r i b u t e to the d e v e l o p m e n t o f vital e x h a u s t i o n prior to m y o c a r d i a l i n f a r c t i o n [8]. Therefore, the c o m b i n e d a n d m u t u a l l y reinforcing actions o f exhaustion as a n end stage o f p r o l o n g e d psychological stress a n d deficiencies in b l o o d clotting factors a n d the i m m u n e - s y s t e m - d e p e n d e n t growth mediators might c o n t r i b u t e to the d e v e l o p m e n t of acute m a n i f e s t a t i o n s of c o r o n a r y artery disease. Acknowledgments-This study was supported by grants of the Dutch Heart Foundation and the Dutch

Organization for ScientificResearch.

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