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A questionnaire to assess premonitory symptoms of myocardial infarction
International
15
Journal of Cardiology, 17 (1987) 15-24
Elsevier
IJC 00578
A questionnaire to assess premonitory symptoms of myocardial infarction A. Appels ‘, P. HGppener I, P. Mulder 2 ’ Department of Medical Psychologv, Rijksuniversiteit 2 Institute of Biostatistics, (Received
Erasmus
2 February
Limburg Maastricht, The Netherlandr; University, Rotterdam, The Netherlands
1987; revision
accepted
15 April 1987)
Appels A, Hoppener P, Mulder P. A questionnaire to assess premonitory of myocardial infarction. Int J Cardiol 1987;17:15-24.
symptoms
To test the hypothesis that feelings of vital exhaustion precede the onset of myocardial infarction, and to develop a short questionnaire to assess these feelings, a prospective study was done among 3877 males, aged 39-65 years. During a 4.2-year follow-up period, 59 fatal or non-fatal infarctions occurred. The mean score of future coronary causes as determined by a questionnaire assessing feelings of vital exhaustion was significantly higher than the mean score of a control group matched for age, blood pressure, cholesterol and smoking. Given the validity of the model, it was possible to reduce markedly the size of the questionnaire. Key words: Stress
Myocardial
infarction;
Vital
exhaustion;
Maastricht
Questionnaire;
Introduction During the past two decades, it has become more evident infarction and sudden cardiac death are foreshadowed by a number symptoms [l-6]. Studies suggest that these prodromal symptoms major categories: chest pain, dyspnea, and feelings of fatigue or The feelings of fatigue are often vague and nonspecific and frequently than any other premonitory symptom. In spite of this,
that myocardial of premonitory fall into three general malaise. yet occur more and of the fact
Correspondence to: Prof. Dr. A. Appels, Dept. of Medical Psychology, Rijksuniversiteit Box 616, 6200 MD Maastricht, The Netherlands. This study was supported by grant no. 83.069 of the Dutch Heart Foundation.
0167-5273/87/$03.50
0 1987 Elsevier Science Publishers
B.V. (Biomedical
Division)
Limburg,
P.O.
16
that unusual tiredness is often the only complaint voiced by persons who, in the near future, develop myocardial infarction, the exact nature of these feelings has yet to be studied in depth. The scientific study of these symptoms is hampered by several facts. The major one is that most studies dealing with this subject are retrospective. As such, one must take into consideration a series of factors which might negatively influence the reliability of the data. As a WHO working group stated in 1971: “Useful though retrospective studies are, their value as guides to prediction is open to doubt, firstly because hindsight assists in the interpretation of atypical symptoms, and secondly because they do not supply information on how often “prodromal” symptoms are not followed by heart attacks [7]. The study of the symptoms is also hampered by the fact that it is not yet known just what kinds of questions should be directed to patients with coronary arterial disease or to the relatives of those who have died suddenly. This is an unsatisfactory situation which calls for a specification of those feelings which have prognostic relevance in order to make them measurable and to determine to what extent they increase the risk of contracting heart disease. Clinical experience regarding personality factors and life events associated with the risk of future coronary arterial disease suggests that future patients face so many situations which are hard to control that they gradually develop a condition in which a chronic overburdening assumes the form of fatigue and exhaustion, and in which an increasing feeling of helplessness results in a subclinical depression [S-lo]. This general model suggests that the increased emotional tension is reflected in a state of exhaustion and depression which precedes the onset of myocardial infarction and sudden cardiac death. The primary purpose of the study reported below was to test the hypothesis that feelings of exhaustion and depression are predictive of future myocardial infarction, independent of past myocardial infarction, angina pectoris and the classic risk factors of smoking, high blood pressure, and high cholesterol level. A second goal was to develop a short questionnaire to assess these feelings. Both goals require a prospective study. Such a study was conducted in Rotterdam and will hence be referred to as the Rotterdam Civil Servants Study. The Rotterdam Civil Servants Study In 1979, the municipal health authority of the city of Rotterdam started a voluntary, periodic health check of the city’s employees. Between January 1978 and December 1980, 3877 employees participated. For local reasons, the invitation to participate was sent to persons in two specific age groups: 39-45 years and 54-65 years. The medical examination was conducted according to the protocol of the A detailed description of this project has been given “Consultatiebureau-project”. elsewhere [ll]. The examination included the measurement of blood pressure, relative weight, smoking habits (assessed on an cholesterol, glucose tolerance, eight-point scale) and an assessment of the presence or absence of angina pectoris using the Rose Questionnaire. A resting electrocardiogram completed the cardiovascular screening.
17
Feelings of exhaustion and/or depression were assessed by a newly designed questionnaire, part of which was developed in the Imminent Myocardial Infarction Rotterdam study. In that study, 37 items were found to discriminate between future cases of coronary arterial disease and a healthy control group [12]. To these items, 21 new questions, derived from clinical interviews, were added. The questionnaire was labelled the Maastricht Questionnaire so as to give it a neutral name. It was regarded as an item pool to be reduced after the completion of the prospective study. The cohort was followed for an average period of 4.2 years (SD = 0.7). Because employee absence due to illness is registered in a central system together with the medical diagnosis, case-finding for myocardial infarction could be achieved by checking out employee absence longer than one week attributable to cardiac problems. During the follow-up period, 1541 of the participants in the study left their jobs. Each one of them received a questionnaire asking about any heart trouble they had experienced after screening. Whenever the sick leave register or the responses to the questionnaire indicated that a former participant might have suffered from coronary arterial disease, a medical doctor contacted the hospital and family physician to verify the diagnosis. Appendix 1 shows the system used to classify the information obtained. In those cases where a former participant had died, the cause of death was obtained from the death certificate.
Data Analysis Those subjects who probably or possibly suffered from angina pectoris at screening, and those who had suffered a myocardial infarction in the past according to the electrocardiogram (Minnesota code I 1.2) were excluded from the prospective analyses, as were non-respondents to the questionnaire and those whose deaths were not linked to cardiac causes. The last group was excluded because they might have suffered from coronary arterial disease between screening and the moment of their death. Such information is, however, lacking. Finally, subjects with missing data at entrance or follow-up were excluded from the analyses. “Hard” coronary events were defined, following the criteria in Appendix 1, as probable or certain myocardial infarction or cardiac death. “Soft” coronary events were defined as possible myocardial infarction, angina pectoris, or bypass surgery. Only hard events were used to test the validity of the model and for construction of the scale, because the behavioral factors associated with hard and soft events are not identical [13]. Stage 1: Testing the Validity of Vital Exhaustion Heart Disease and Other Serious Illnesses
as a Risk Factor for Coronary
As noted above, the 58-item Maastricht Questionnaire used in this study was mainly an item pool to be reduced after completion of the follow-up study. This raises the problem of circularity, that is of developing and testing a model in the
18
same study. To avoid this problem the test of the hypothesis was restricted to the 37 items previously found to be discriminative. If the model were found to be valid, item analyses could proceed using the entire item pool. To test whether vital exhaustion is associated with other diseases too, each new case of a disease developing during the follow-up period was simultaneously matched with three non-cases, free of that disease, on relevant risk factors. Hypothesis testing was limited to diseases occurring in at least twenty participants. Differences in mean scores were tested using Student’s t-test. This design was chosen because it is well suited to test whether a factor is predictive of diseases which have a low incidence rate. Stage 2: Construction
of a Shorter Measure of Vital Exhaustion
To reduce the 5%item pool, the age-adjusted relative risk of each item for myocardial infarction was computed. Items found to be predictive were selected for the construction of the scale and summed to give a new scale score. In order to obtain an indication of the risk associated with an elevated score, subjects were divided into tertiles of the reduced scale. Confounding was controlled by stratification on age, blood pressure, cholesterol level and smoking, separately. The statistical significance of the standardized relative risks was tested using the Mantel-Haenszel &i-square. The uniformity of the rate ratios across strata was tested using a heterogeneity &i-square. Results The data base of the follow-up study is presented in Table 1. It shows that 7% of all participants had to be excluded from data analysis because of past or present heart disease at screening. This figure might be influenced by a slight overestimation of the prevalence of angina pectoris. Due to migration, unknown address or missing observations at entrance, 119 subjects were lost to follow-up and could not be included in the data analysis.
TABLE 1 Data base of the Rotterdam Civil Servants Study.
1. Excluded from follow-up due to diagnosed or probable history of coronary arterial disease at entrance 2. Missing information (entrance or follow-up) 3. Non-respondent morbidity questionnaire 4. Angina (including possible myocardial infarction) 5. Fatal or non-fatal myocardial infarction 6. Non-cardiac or unknown cause of death 7. Free from coronary arterial disease
266 119 95 54 59 74 3 210
07 03 02 01 02 02 83
Total
3 877
loo
19
The morbidity questionnaire, sent to those employees who had left their jobs during follow-up, was answered by 1446 subjects (94%). No differences were found between respondents and non-respondents on any of the somatic risk factors or on the Maastricht Questionnaire. Both groups were equal with respect to past or present heart disease at screening. The mean age of the non-respondents, however, was two years lower than the mean age of the respondents (t = 2.75; P = 0.01). The death of 64 subjects was not linked to cardiac causes. Permission to verify the cause of death was not obtained in 10 cases. Among those subjects free of coronary arterial disease at screening, 21 subjects died of myocardial infarction, while well-documented non-fatal myocardial infarctions occurred in 38 subjects. The Validity of the Model The results of the analysis to test the validity of vital exhaustion as a risk factor for myocardial infarction are shown in Table 2. Cases and controls are found to be almost equal in age, blood pressure, cholesterol level and smoking, indicating the adequacy of the matching. The mean scores on the 37-item Maastricht Questionnaire differ significantly in the predicted direction. This confirms the validity of the model. During follow-up, 38 subjects died of cancer and 24 subjects were diagnosed as suffering from cancer. Each case was matched with three non-cases on age and smoking. Those who had already suffered from cancer before screening, according to the sick-leave register, or those in whom a carcinoma of the lung was detected at screening by an X-ray analysis, were excluded from the analysis. No significant
TABLE
2
Mean values of future infarction measuring vital exhaustion.
cases and matched
N
Age
controls
Mean 56.3 56.3
on somatic
risk factors
and on a scale
1
P
6.5 6.5
0.00
1.00
2.3 2.3
0.22
0.83
SD
(years)
cases controls
59 177
Smoking (8-point scale)
cases controls
59 177
systolic blood pressure
cases controls
59 177
148.4 148.2
19.9 18.5
0.08
0.94
Diastolic blood pressure
cases controls
59 177
84.4 83.5
11.8 11.2
0.49
0.62
Cholesterol (mmol/liter)
cases controls
59 177
6.5 6.4
0.9 0.8
1.15
0.25
Exhaustion (37-item MQ)
cases controls
59 177
20.0 14.9
14.5 12.4
2.58
0.01
4.46 4.38
20
difference in mean Maastricht Questionnaire scores between future cancer patients and controls was found. According to the sick leave register, duodenal ulcers occurred in 22 subjects. Each case was matched with three non-cases on age. Those who had suffered from duodenal ulcer before screening were excluded from the analysis. No significant difference between future duodenal ulcer patients and controls was found. This conclusion is, however, only tentative since diagnoses of ulcer were usually accepted in the absence of roentgenologic evidence. The incidence of other major somatic diseases was too small to be studied. The Construction
of a Scale to Measure Vital Exhaustion
Twenty-four of the 58 items were found to be predictive of future hard coronary events. Sixteen of these belonged to the 37-item form used to test the validity of the model and eight to the 21 newly administered items. Two items were predictive in the first year of follow-up only. The fact that these items were not predictive over a longer period may indicate either that they are truly prodromal or that their association with near future coronary arterial disease is based upon some random variations in the data. Because their predictive power decreased when the number of cases increased, they were not selected for the final scale. One item (“In the past year did you have spells of shaking and trembling all over?‘) was excluded because of some doubts about its conceptual validity. This item was found to discriminate between future infarction cases and matched controls in a study by Klatsky and his colleagues [14]. While such a positive replication merits attention, the item is ambiguous since it can be interpreted both as an element and as a consequence of the state of vital exhaustion. The elimination of these three items brought the Maastricht Questionnaire down to 21 items. They are listed in Appendix 2. The items have a high internal consistency (Cronbach’s alpha is 0.89) and may, therefore, be considered to form one scale. Its correlation with the 37-item form is 0.92. This high correlation is due to the fact that both forms have 16 common items. The standardized risk for myocardial infarction
TABLE
3
Standardized relative risk for myocardial infarction associated with a score in the first, second tertile of the Maastricht Questionnaire, adjusted for somatic risk factors separately. Tertile
Ane Cholesterol Systolic blood pressure Diastolic blood pressure Smoking * P-=0.01:
df=l.
1
2
3
X&!l
1.00 1.00 1.00 1.00 1.00
1.86 2.19 2.11 2.34 2.31
3.55 4.58 4.43 4.67 4.60
12.53 19.85 19.10 20.52 19.71
Xl% + * * * *
0.57 1.23 0.06 0.63 1.22
and third
21
associated with a score in the first, second or third tertile of the 21-item Maastricht Questionnaire is 1.00, 2.26 and 4.69, respectively. These rates drop only slightly when adjusted for the somatic risk factors (Table 3). None of the heterogeneity cm-squares is significant, indicating that the rate ratios of the strata are comparable and that no major interaction between vital exhaustion and the somatic risk factors exists. No association was found between the 21-item Maastricht Questionnaire and cancer or duodenal ulcers.
Discussion The data from this prospective study support the hypothesis that feelings of vital exhaustion precede the onset of fatal and non-fatal myocardial infarction. The item pool was reduced to a short scale which measures a specific construct. Unlike the test of the general validity of the model using the 37-item Maastricht Questionnaire, the strength of the association between the 21-item Maastricht Questionnaire and future coronary arterial disease is somewhat influenced by the method used in the construction of the scale. The data shown in Table 3 are presented mainly to document the findings of the prospective study. Their absolute values should be interpreted carefully. More important than the estimation of the relative risk is the specification of these feelings and complaints, which have prognostic relevance. A major question concerns the length of the follow-up period. The cardiological literature describes exhaustion as one of the prodromal states or premonitory symptoms existing in the relatively short period before a myocardial infarction or a sudden death. No study has yet investigated the duration of such feelings prior to a coronary event. Most patients who were asked during the preparatory stage of this study how long they had felt exhausted before their infarction replied that they could not easily answer the question. The best they could do was to say that they had grown increasingly tired during the 12 to 18 months prior to the infarction and that they had experienced a gradual decline in total functioning. Just when this decline had begun they could not say. For statistical reasons, two items predictive of myocardial infarction occurring in the first year of follow-up only were not included in the final scale. These were: “Have you felt strange bodily sensations lately? (Yes)“; “Recently I shrink from my regular work as if it were a mountain to climb (Yes)“. As noted above, these items might truly be prodromal and of possible clinical relevance. Contrary to our expectations, almost none of the items referring to depression (guilt feelings; lowered self esteem) had any predictive power. This is the reason why we now say the Maastricht Questionnaire measures “vital exhaustion” rather than “a syndrome of vital exhaustion and depression” as in preliminary reports [12]. Many patients, clinically diagnosed as depressed, feel exhausted. Only a minority of these who are vitally exhausted are depressed in the clinical sense. Corrected by the outcomes of the prospective study, we now describe vital exhaustion as: “a state which is present when an individual not only complains of unusual fatigue and decreasing energy but also by feeling dejected or defeated. Feeling exhausted when
22
waking up is highly characteristic of the condition. Vital exhaustion is often associated with increased irritability and loss of libido. Symptoms of depression may be associated with vital exhaustion but not necessarily so. Usually self esteem is not lowered and guilt feelings are absent”. This epidemiological study does not give insight into the origins of exhaustion, or into the mechanisms linking vital exhaustion to coronary arterial disease. The data show that only a minority of those individuals having elevated Maastricht Questionnaire scores are destined for myocardial infarction in the near future. Only 5% of those scoring in the upper tertile of the Maastricht Questionnaire suffered from a hard or soft coronary event during follow-up. A state of vital exhaustion is clearly not a sufficient cause of coronary arterial disease. Unless the heart has already become vulnerable, due to atherosclerosis or some other degeneration, an exhausted individual would most likely go through a period of mental strain but not fall ill. We think of vital exhaustion as a strong wind which may stir up an already existing fire. We speculate that a deteriorated cardiac condition and a state of exhaustion are mutually reinforcing factors that can produce a “spiralling down” towards myocardial infarction. The Maastricht Questionnaire is a research tool that allows one to confirm and refute these and other conceptions and hypotheses.
Acknowledgments We want to express our gratitude to the Municipal Health Authority Centre of Rotterdam for their support of this study; to Dr. CD. Jenkins for his comments on an early draft of this paper; and to P. Falger-Cohen for her editorial assistance.
References 1 Stowers M, Short D. Warning symptoms before myocardial infarction. Br Heart J 1970;32:833-838. 2 Romo M. Factors related to sudden death in acute ischaemic heart disease. A community study in Helsinki. Acta Med Stand 1973;547:5-92. 3 Kuller LH. Prodromata of sudden death and myocardial infarction. Adv Cardiol 1978;25:61-72. 4 Feinleib M, Simon A, Gillum R, Majolis J. Prodromal symptoms and signs of sudden death. Circulation 1975; (suppl vol 51 and 52):155-159. 5 Rissanen V, Romo M, Siltanen P. Premonitory symptoms and stress factors preceding sudden death from ischaemic heart disease. Acta Med Stand 1978;20:389-396. 6 Alonzo AA, Simon AB, Feinleib M. Prodromata of myocardial infarction and sudden death. Circulation 1975;52:1056-1062. 7 World Health Organization, regional office for Europe. The prodromal symptoms of myocardial infarction and sudden death. Report of a working group. Copenhagen. 1971. 8 Nixon PGF. The human function curve. Practitioner 1976;217:765-770, 935-944. 9 Crisp AH, Queenan M. D’Suvza. Myocardial infarction and the emotional climate. Lancet 1984; March 17:616-619. 10 Byrne DG. Attributed responsibility for life events in survivors of myocardial infarction. Psychother Psychosom 1980;33:7-13. 11 Arntzenius AC. Intervention results in high risk individuals of the CB heart project in the Netherlands. In: Haus W, Wisster R, Lehman R, eds. State of prevention and therapy in human arteriosclerosis and in animal models. Opladen: Westdeutscher Verlag, 1978.
23 12 Appels A. Psychological prodromata of myocardial infarction and sudden death. Psychother Psychosom 1980;34:187-195. 13 Jenkins CD. Psychosocial risk factors for coronary heart disease. Acta Med Stand 1982;660:123-136. 14 Klatsky A, Friedman G, Siegelaub A. Medical history questions predictive of myocardial infarction. J Chron Dis 1976;29:683-696.
APPENDIX
1
Definition of Myocardial Infarction Medical history, electrocardiographic a number of points.
and enzyme findings
were used to make a classification
based upon
Myacardial Infarction A. Medical History Chest pain - sudden start or increase _ unrelated to physical effort _ duration longer than 20 minutes - pressing or spastic character _ no reaction to nitroglycerine _ radiation One characteristic = 1 point Two characteristics = 2 points B. Ekctrocardiogram - presence of “injury current” - Minnesota code 1.1 or 1.2 (Q-wave deviations) and/or 7.1 (left bundle block; in the case of first myocardial infarction) _ description by cardiologist as “typical myocardial infarction” One of these characteristics: 2 points _ Minnesota code 1.3 (moderate Q-wave deviations and/or 5.1 or 5.2 (negative T) _ description by the cardiologist “ myocardialinfarction suspected” One of these characteristics: 1 point C. Enzyme Levels _ If SGOT and CPK elevated above those values considered to be normal in the hospital: 2 points _ If either the value of SGOT or the value of CPK was above the value to be considered normal in the hospital: 1 point - If the course of the enzyme values made the diagnosis Coding A. In case all data are available O-l point: no myocardial infarction 2-3 points: possible myocardial infarction 4 points: probable myocardial infarction 5-6 points: certain myocardial infarction B. In case only two criteria are available O-l point: no myocardial infarction 2 points: possible myocardial infarction 3-4 points: probable myocardial infarction C. In case only a general clinical diagnosis is available _ probable myocardial infarction
myocardial
infarction
probable:
1 point
24 Angina
Pectoris (AP)
Medical history by cardiologist indicative of AP: possible AP Medical history by cardiologist indicative of AP and ECG deviations during pain or during physical exercise testing : probable AP Medical history by cardiologist indicative of AP and occlusions found during catheterization : certain AP
APPENDIX
2
The Maastricht Questionnaire Medical research is constantly trying to track down the causes of disease. You would help this research by answering the following questions about how you feel lately. Please mark the answers that are true for you. If you don’t know or cannot decide circle the ?. There are no “right” or “wrong” answers. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
Do you often feel tired? Do you often have trouble falling asleep? Do you wake up repeatedly during the night? Do you feel weak all over? Do you have the feeling that you haven’t been accomplishing much lately? Do you have the feeling that you can’t cope with everyday problems as well as you used to? Do you believe that you have come to a “dead end”? Do you lately feel more listless than before? I enjoy sex as much as ever Have you experienced a feeling of hopelessness recently? Does it take more time to grasp a difficult problem than it did a year ago? Do little things irritate you more lately than they used to? Do you feel you want to give up trying? I feel fine Do you sometimes feel that your body is like a battery that is losing its power? Would you want to be dead at times? Do you have the feeling these days that you just don’t have what it takes any more? Do you feel dejected? Do you feel like crying sometimes? Do you ever wake up with a feeling of exhaustion and fatigue? Do you have increasing difficulty in concentrating on a single subject for long?
yes yes yes yes
? ? ? ?
no no no no
yes
?
no
yes
?
no
yes yes yes
? ? ?
no no no
yes
?
no
yes
?
no
yes yes yes
? ? ?
no no no
yes yes
? ?
no no
yes yes yes
? ? ?
no no no
yes
?
no
yes
?
no
Scoring Each confirmation of a complaint is coded as 2. All question marks are coded as 1. A negative answer coded as 0. Note that questions 9 and 14 are reversed (No = 2; ? = 1; Yes = 0). The scale score obtained by summing the answers.
is is
15
Journal of Cardiology, 17 (1987) 15-24
Elsevier
IJC 00578
A questionnaire to assess premonitory symptoms of myocardial infarction A. Appels ‘, P. HGppener I, P. Mulder 2 ’ Department of Medical Psychologv, Rijksuniversiteit 2 Institute of Biostatistics, (Received
Erasmus
2 February
Limburg Maastricht, The Netherlandr; University, Rotterdam, The Netherlands
1987; revision
accepted
15 April 1987)
Appels A, Hoppener P, Mulder P. A questionnaire to assess premonitory of myocardial infarction. Int J Cardiol 1987;17:15-24.
symptoms
To test the hypothesis that feelings of vital exhaustion precede the onset of myocardial infarction, and to develop a short questionnaire to assess these feelings, a prospective study was done among 3877 males, aged 39-65 years. During a 4.2-year follow-up period, 59 fatal or non-fatal infarctions occurred. The mean score of future coronary causes as determined by a questionnaire assessing feelings of vital exhaustion was significantly higher than the mean score of a control group matched for age, blood pressure, cholesterol and smoking. Given the validity of the model, it was possible to reduce markedly the size of the questionnaire. Key words: Stress
Myocardial
infarction;
Vital
exhaustion;
Maastricht
Questionnaire;
Introduction During the past two decades, it has become more evident infarction and sudden cardiac death are foreshadowed by a number symptoms [l-6]. Studies suggest that these prodromal symptoms major categories: chest pain, dyspnea, and feelings of fatigue or The feelings of fatigue are often vague and nonspecific and frequently than any other premonitory symptom. In spite of this,
that myocardial of premonitory fall into three general malaise. yet occur more and of the fact
Correspondence to: Prof. Dr. A. Appels, Dept. of Medical Psychology, Rijksuniversiteit Box 616, 6200 MD Maastricht, The Netherlands. This study was supported by grant no. 83.069 of the Dutch Heart Foundation.
0167-5273/87/$03.50
0 1987 Elsevier Science Publishers
B.V. (Biomedical
Division)
Limburg,
P.O.
16
that unusual tiredness is often the only complaint voiced by persons who, in the near future, develop myocardial infarction, the exact nature of these feelings has yet to be studied in depth. The scientific study of these symptoms is hampered by several facts. The major one is that most studies dealing with this subject are retrospective. As such, one must take into consideration a series of factors which might negatively influence the reliability of the data. As a WHO working group stated in 1971: “Useful though retrospective studies are, their value as guides to prediction is open to doubt, firstly because hindsight assists in the interpretation of atypical symptoms, and secondly because they do not supply information on how often “prodromal” symptoms are not followed by heart attacks [7]. The study of the symptoms is also hampered by the fact that it is not yet known just what kinds of questions should be directed to patients with coronary arterial disease or to the relatives of those who have died suddenly. This is an unsatisfactory situation which calls for a specification of those feelings which have prognostic relevance in order to make them measurable and to determine to what extent they increase the risk of contracting heart disease. Clinical experience regarding personality factors and life events associated with the risk of future coronary arterial disease suggests that future patients face so many situations which are hard to control that they gradually develop a condition in which a chronic overburdening assumes the form of fatigue and exhaustion, and in which an increasing feeling of helplessness results in a subclinical depression [S-lo]. This general model suggests that the increased emotional tension is reflected in a state of exhaustion and depression which precedes the onset of myocardial infarction and sudden cardiac death. The primary purpose of the study reported below was to test the hypothesis that feelings of exhaustion and depression are predictive of future myocardial infarction, independent of past myocardial infarction, angina pectoris and the classic risk factors of smoking, high blood pressure, and high cholesterol level. A second goal was to develop a short questionnaire to assess these feelings. Both goals require a prospective study. Such a study was conducted in Rotterdam and will hence be referred to as the Rotterdam Civil Servants Study. The Rotterdam Civil Servants Study In 1979, the municipal health authority of the city of Rotterdam started a voluntary, periodic health check of the city’s employees. Between January 1978 and December 1980, 3877 employees participated. For local reasons, the invitation to participate was sent to persons in two specific age groups: 39-45 years and 54-65 years. The medical examination was conducted according to the protocol of the A detailed description of this project has been given “Consultatiebureau-project”. elsewhere [ll]. The examination included the measurement of blood pressure, relative weight, smoking habits (assessed on an cholesterol, glucose tolerance, eight-point scale) and an assessment of the presence or absence of angina pectoris using the Rose Questionnaire. A resting electrocardiogram completed the cardiovascular screening.
17
Feelings of exhaustion and/or depression were assessed by a newly designed questionnaire, part of which was developed in the Imminent Myocardial Infarction Rotterdam study. In that study, 37 items were found to discriminate between future cases of coronary arterial disease and a healthy control group [12]. To these items, 21 new questions, derived from clinical interviews, were added. The questionnaire was labelled the Maastricht Questionnaire so as to give it a neutral name. It was regarded as an item pool to be reduced after the completion of the prospective study. The cohort was followed for an average period of 4.2 years (SD = 0.7). Because employee absence due to illness is registered in a central system together with the medical diagnosis, case-finding for myocardial infarction could be achieved by checking out employee absence longer than one week attributable to cardiac problems. During the follow-up period, 1541 of the participants in the study left their jobs. Each one of them received a questionnaire asking about any heart trouble they had experienced after screening. Whenever the sick leave register or the responses to the questionnaire indicated that a former participant might have suffered from coronary arterial disease, a medical doctor contacted the hospital and family physician to verify the diagnosis. Appendix 1 shows the system used to classify the information obtained. In those cases where a former participant had died, the cause of death was obtained from the death certificate.
Data Analysis Those subjects who probably or possibly suffered from angina pectoris at screening, and those who had suffered a myocardial infarction in the past according to the electrocardiogram (Minnesota code I 1.2) were excluded from the prospective analyses, as were non-respondents to the questionnaire and those whose deaths were not linked to cardiac causes. The last group was excluded because they might have suffered from coronary arterial disease between screening and the moment of their death. Such information is, however, lacking. Finally, subjects with missing data at entrance or follow-up were excluded from the analyses. “Hard” coronary events were defined, following the criteria in Appendix 1, as probable or certain myocardial infarction or cardiac death. “Soft” coronary events were defined as possible myocardial infarction, angina pectoris, or bypass surgery. Only hard events were used to test the validity of the model and for construction of the scale, because the behavioral factors associated with hard and soft events are not identical [13]. Stage 1: Testing the Validity of Vital Exhaustion Heart Disease and Other Serious Illnesses
as a Risk Factor for Coronary
As noted above, the 58-item Maastricht Questionnaire used in this study was mainly an item pool to be reduced after completion of the follow-up study. This raises the problem of circularity, that is of developing and testing a model in the
18
same study. To avoid this problem the test of the hypothesis was restricted to the 37 items previously found to be discriminative. If the model were found to be valid, item analyses could proceed using the entire item pool. To test whether vital exhaustion is associated with other diseases too, each new case of a disease developing during the follow-up period was simultaneously matched with three non-cases, free of that disease, on relevant risk factors. Hypothesis testing was limited to diseases occurring in at least twenty participants. Differences in mean scores were tested using Student’s t-test. This design was chosen because it is well suited to test whether a factor is predictive of diseases which have a low incidence rate. Stage 2: Construction
of a Shorter Measure of Vital Exhaustion
To reduce the 5%item pool, the age-adjusted relative risk of each item for myocardial infarction was computed. Items found to be predictive were selected for the construction of the scale and summed to give a new scale score. In order to obtain an indication of the risk associated with an elevated score, subjects were divided into tertiles of the reduced scale. Confounding was controlled by stratification on age, blood pressure, cholesterol level and smoking, separately. The statistical significance of the standardized relative risks was tested using the Mantel-Haenszel &i-square. The uniformity of the rate ratios across strata was tested using a heterogeneity &i-square. Results The data base of the follow-up study is presented in Table 1. It shows that 7% of all participants had to be excluded from data analysis because of past or present heart disease at screening. This figure might be influenced by a slight overestimation of the prevalence of angina pectoris. Due to migration, unknown address or missing observations at entrance, 119 subjects were lost to follow-up and could not be included in the data analysis.
TABLE 1 Data base of the Rotterdam Civil Servants Study.
1. Excluded from follow-up due to diagnosed or probable history of coronary arterial disease at entrance 2. Missing information (entrance or follow-up) 3. Non-respondent morbidity questionnaire 4. Angina (including possible myocardial infarction) 5. Fatal or non-fatal myocardial infarction 6. Non-cardiac or unknown cause of death 7. Free from coronary arterial disease
266 119 95 54 59 74 3 210
07 03 02 01 02 02 83
Total
3 877
loo
19
The morbidity questionnaire, sent to those employees who had left their jobs during follow-up, was answered by 1446 subjects (94%). No differences were found between respondents and non-respondents on any of the somatic risk factors or on the Maastricht Questionnaire. Both groups were equal with respect to past or present heart disease at screening. The mean age of the non-respondents, however, was two years lower than the mean age of the respondents (t = 2.75; P = 0.01). The death of 64 subjects was not linked to cardiac causes. Permission to verify the cause of death was not obtained in 10 cases. Among those subjects free of coronary arterial disease at screening, 21 subjects died of myocardial infarction, while well-documented non-fatal myocardial infarctions occurred in 38 subjects. The Validity of the Model The results of the analysis to test the validity of vital exhaustion as a risk factor for myocardial infarction are shown in Table 2. Cases and controls are found to be almost equal in age, blood pressure, cholesterol level and smoking, indicating the adequacy of the matching. The mean scores on the 37-item Maastricht Questionnaire differ significantly in the predicted direction. This confirms the validity of the model. During follow-up, 38 subjects died of cancer and 24 subjects were diagnosed as suffering from cancer. Each case was matched with three non-cases on age and smoking. Those who had already suffered from cancer before screening, according to the sick-leave register, or those in whom a carcinoma of the lung was detected at screening by an X-ray analysis, were excluded from the analysis. No significant
TABLE
2
Mean values of future infarction measuring vital exhaustion.
cases and matched
N
Age
controls
Mean 56.3 56.3
on somatic
risk factors
and on a scale
1
P
6.5 6.5
0.00
1.00
2.3 2.3
0.22
0.83
SD
(years)
cases controls
59 177
Smoking (8-point scale)
cases controls
59 177
systolic blood pressure
cases controls
59 177
148.4 148.2
19.9 18.5
0.08
0.94
Diastolic blood pressure
cases controls
59 177
84.4 83.5
11.8 11.2
0.49
0.62
Cholesterol (mmol/liter)
cases controls
59 177
6.5 6.4
0.9 0.8
1.15
0.25
Exhaustion (37-item MQ)
cases controls
59 177
20.0 14.9
14.5 12.4
2.58
0.01
4.46 4.38
20
difference in mean Maastricht Questionnaire scores between future cancer patients and controls was found. According to the sick leave register, duodenal ulcers occurred in 22 subjects. Each case was matched with three non-cases on age. Those who had suffered from duodenal ulcer before screening were excluded from the analysis. No significant difference between future duodenal ulcer patients and controls was found. This conclusion is, however, only tentative since diagnoses of ulcer were usually accepted in the absence of roentgenologic evidence. The incidence of other major somatic diseases was too small to be studied. The Construction
of a Scale to Measure Vital Exhaustion
Twenty-four of the 58 items were found to be predictive of future hard coronary events. Sixteen of these belonged to the 37-item form used to test the validity of the model and eight to the 21 newly administered items. Two items were predictive in the first year of follow-up only. The fact that these items were not predictive over a longer period may indicate either that they are truly prodromal or that their association with near future coronary arterial disease is based upon some random variations in the data. Because their predictive power decreased when the number of cases increased, they were not selected for the final scale. One item (“In the past year did you have spells of shaking and trembling all over?‘) was excluded because of some doubts about its conceptual validity. This item was found to discriminate between future infarction cases and matched controls in a study by Klatsky and his colleagues [14]. While such a positive replication merits attention, the item is ambiguous since it can be interpreted both as an element and as a consequence of the state of vital exhaustion. The elimination of these three items brought the Maastricht Questionnaire down to 21 items. They are listed in Appendix 2. The items have a high internal consistency (Cronbach’s alpha is 0.89) and may, therefore, be considered to form one scale. Its correlation with the 37-item form is 0.92. This high correlation is due to the fact that both forms have 16 common items. The standardized risk for myocardial infarction
TABLE
3
Standardized relative risk for myocardial infarction associated with a score in the first, second tertile of the Maastricht Questionnaire, adjusted for somatic risk factors separately. Tertile
Ane Cholesterol Systolic blood pressure Diastolic blood pressure Smoking * P-=0.01:
df=l.
1
2
3
X&!l
1.00 1.00 1.00 1.00 1.00
1.86 2.19 2.11 2.34 2.31
3.55 4.58 4.43 4.67 4.60
12.53 19.85 19.10 20.52 19.71
Xl% + * * * *
0.57 1.23 0.06 0.63 1.22
and third
21
associated with a score in the first, second or third tertile of the 21-item Maastricht Questionnaire is 1.00, 2.26 and 4.69, respectively. These rates drop only slightly when adjusted for the somatic risk factors (Table 3). None of the heterogeneity cm-squares is significant, indicating that the rate ratios of the strata are comparable and that no major interaction between vital exhaustion and the somatic risk factors exists. No association was found between the 21-item Maastricht Questionnaire and cancer or duodenal ulcers.
Discussion The data from this prospective study support the hypothesis that feelings of vital exhaustion precede the onset of fatal and non-fatal myocardial infarction. The item pool was reduced to a short scale which measures a specific construct. Unlike the test of the general validity of the model using the 37-item Maastricht Questionnaire, the strength of the association between the 21-item Maastricht Questionnaire and future coronary arterial disease is somewhat influenced by the method used in the construction of the scale. The data shown in Table 3 are presented mainly to document the findings of the prospective study. Their absolute values should be interpreted carefully. More important than the estimation of the relative risk is the specification of these feelings and complaints, which have prognostic relevance. A major question concerns the length of the follow-up period. The cardiological literature describes exhaustion as one of the prodromal states or premonitory symptoms existing in the relatively short period before a myocardial infarction or a sudden death. No study has yet investigated the duration of such feelings prior to a coronary event. Most patients who were asked during the preparatory stage of this study how long they had felt exhausted before their infarction replied that they could not easily answer the question. The best they could do was to say that they had grown increasingly tired during the 12 to 18 months prior to the infarction and that they had experienced a gradual decline in total functioning. Just when this decline had begun they could not say. For statistical reasons, two items predictive of myocardial infarction occurring in the first year of follow-up only were not included in the final scale. These were: “Have you felt strange bodily sensations lately? (Yes)“; “Recently I shrink from my regular work as if it were a mountain to climb (Yes)“. As noted above, these items might truly be prodromal and of possible clinical relevance. Contrary to our expectations, almost none of the items referring to depression (guilt feelings; lowered self esteem) had any predictive power. This is the reason why we now say the Maastricht Questionnaire measures “vital exhaustion” rather than “a syndrome of vital exhaustion and depression” as in preliminary reports [12]. Many patients, clinically diagnosed as depressed, feel exhausted. Only a minority of these who are vitally exhausted are depressed in the clinical sense. Corrected by the outcomes of the prospective study, we now describe vital exhaustion as: “a state which is present when an individual not only complains of unusual fatigue and decreasing energy but also by feeling dejected or defeated. Feeling exhausted when
22
waking up is highly characteristic of the condition. Vital exhaustion is often associated with increased irritability and loss of libido. Symptoms of depression may be associated with vital exhaustion but not necessarily so. Usually self esteem is not lowered and guilt feelings are absent”. This epidemiological study does not give insight into the origins of exhaustion, or into the mechanisms linking vital exhaustion to coronary arterial disease. The data show that only a minority of those individuals having elevated Maastricht Questionnaire scores are destined for myocardial infarction in the near future. Only 5% of those scoring in the upper tertile of the Maastricht Questionnaire suffered from a hard or soft coronary event during follow-up. A state of vital exhaustion is clearly not a sufficient cause of coronary arterial disease. Unless the heart has already become vulnerable, due to atherosclerosis or some other degeneration, an exhausted individual would most likely go through a period of mental strain but not fall ill. We think of vital exhaustion as a strong wind which may stir up an already existing fire. We speculate that a deteriorated cardiac condition and a state of exhaustion are mutually reinforcing factors that can produce a “spiralling down” towards myocardial infarction. The Maastricht Questionnaire is a research tool that allows one to confirm and refute these and other conceptions and hypotheses.
Acknowledgments We want to express our gratitude to the Municipal Health Authority Centre of Rotterdam for their support of this study; to Dr. CD. Jenkins for his comments on an early draft of this paper; and to P. Falger-Cohen for her editorial assistance.
References 1 Stowers M, Short D. Warning symptoms before myocardial infarction. Br Heart J 1970;32:833-838. 2 Romo M. Factors related to sudden death in acute ischaemic heart disease. A community study in Helsinki. Acta Med Stand 1973;547:5-92. 3 Kuller LH. Prodromata of sudden death and myocardial infarction. Adv Cardiol 1978;25:61-72. 4 Feinleib M, Simon A, Gillum R, Majolis J. Prodromal symptoms and signs of sudden death. Circulation 1975; (suppl vol 51 and 52):155-159. 5 Rissanen V, Romo M, Siltanen P. Premonitory symptoms and stress factors preceding sudden death from ischaemic heart disease. Acta Med Stand 1978;20:389-396. 6 Alonzo AA, Simon AB, Feinleib M. Prodromata of myocardial infarction and sudden death. Circulation 1975;52:1056-1062. 7 World Health Organization, regional office for Europe. The prodromal symptoms of myocardial infarction and sudden death. Report of a working group. Copenhagen. 1971. 8 Nixon PGF. The human function curve. Practitioner 1976;217:765-770, 935-944. 9 Crisp AH, Queenan M. D’Suvza. Myocardial infarction and the emotional climate. Lancet 1984; March 17:616-619. 10 Byrne DG. Attributed responsibility for life events in survivors of myocardial infarction. Psychother Psychosom 1980;33:7-13. 11 Arntzenius AC. Intervention results in high risk individuals of the CB heart project in the Netherlands. In: Haus W, Wisster R, Lehman R, eds. State of prevention and therapy in human arteriosclerosis and in animal models. Opladen: Westdeutscher Verlag, 1978.
23 12 Appels A. Psychological prodromata of myocardial infarction and sudden death. Psychother Psychosom 1980;34:187-195. 13 Jenkins CD. Psychosocial risk factors for coronary heart disease. Acta Med Stand 1982;660:123-136. 14 Klatsky A, Friedman G, Siegelaub A. Medical history questions predictive of myocardial infarction. J Chron Dis 1976;29:683-696.
APPENDIX
1
Definition of Myocardial Infarction Medical history, electrocardiographic a number of points.
and enzyme findings
were used to make a classification
based upon
Myacardial Infarction A. Medical History Chest pain - sudden start or increase _ unrelated to physical effort _ duration longer than 20 minutes - pressing or spastic character _ no reaction to nitroglycerine _ radiation One characteristic = 1 point Two characteristics = 2 points B. Ekctrocardiogram - presence of “injury current” - Minnesota code 1.1 or 1.2 (Q-wave deviations) and/or 7.1 (left bundle block; in the case of first myocardial infarction) _ description by cardiologist as “typical myocardial infarction” One of these characteristics: 2 points _ Minnesota code 1.3 (moderate Q-wave deviations and/or 5.1 or 5.2 (negative T) _ description by the cardiologist “ myocardialinfarction suspected” One of these characteristics: 1 point C. Enzyme Levels _ If SGOT and CPK elevated above those values considered to be normal in the hospital: 2 points _ If either the value of SGOT or the value of CPK was above the value to be considered normal in the hospital: 1 point - If the course of the enzyme values made the diagnosis Coding A. In case all data are available O-l point: no myocardial infarction 2-3 points: possible myocardial infarction 4 points: probable myocardial infarction 5-6 points: certain myocardial infarction B. In case only two criteria are available O-l point: no myocardial infarction 2 points: possible myocardial infarction 3-4 points: probable myocardial infarction C. In case only a general clinical diagnosis is available _ probable myocardial infarction
myocardial
infarction
probable:
1 point
24 Angina
Pectoris (AP)
Medical history by cardiologist indicative of AP: possible AP Medical history by cardiologist indicative of AP and ECG deviations during pain or during physical exercise testing : probable AP Medical history by cardiologist indicative of AP and occlusions found during catheterization : certain AP
APPENDIX
2
The Maastricht Questionnaire Medical research is constantly trying to track down the causes of disease. You would help this research by answering the following questions about how you feel lately. Please mark the answers that are true for you. If you don’t know or cannot decide circle the ?. There are no “right” or “wrong” answers. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
Do you often feel tired? Do you often have trouble falling asleep? Do you wake up repeatedly during the night? Do you feel weak all over? Do you have the feeling that you haven’t been accomplishing much lately? Do you have the feeling that you can’t cope with everyday problems as well as you used to? Do you believe that you have come to a “dead end”? Do you lately feel more listless than before? I enjoy sex as much as ever Have you experienced a feeling of hopelessness recently? Does it take more time to grasp a difficult problem than it did a year ago? Do little things irritate you more lately than they used to? Do you feel you want to give up trying? I feel fine Do you sometimes feel that your body is like a battery that is losing its power? Would you want to be dead at times? Do you have the feeling these days that you just don’t have what it takes any more? Do you feel dejected? Do you feel like crying sometimes? Do you ever wake up with a feeling of exhaustion and fatigue? Do you have increasing difficulty in concentrating on a single subject for long?
yes yes yes yes
? ? ? ?
no no no no
yes
?
no
yes
?
no
yes yes yes
? ? ?
no no no
yes
?
no
yes
?
no
yes yes yes
? ? ?
no no no
yes yes
? ?
no no
yes yes yes
? ? ?
no no no
yes
?
no
yes
?
no
Scoring Each confirmation of a complaint is coded as 2. All question marks are coded as 1. A negative answer coded as 0. Note that questions 9 and 14 are reversed (No = 2; ? = 1; Yes = 0). The scale score obtained by summing the answers.
is is