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Circulation. 1996;93:450-456

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(Circulation. 1996;93:450-456.)
© 1996 American Heart Association, Inc.

Articles

Smoking, Serum Lipids, Blood Pressure, and Sex Differences in Myocardial Infarction

A 12-Year Follow-up of the Finnmark Study

Inger Njølstad, MD; Egil Arnesen, MD; Per G. Lund-Larsen, MD

From the Institute of Community Medicine, University of Tromsø, Norway (I.N., E.A.), and the National Health Screening Service, Oslo, Norway (P.G.L.-L.).


*    Abstract
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 *Abstract
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Background Few epidemiological studies have investigated the relative importance of major coronary risk factors in the two sexes within the same study population. In particular, it is not clear whether smoking carries a similar risk of coronary heart disease in men and women.

Methods and Results The associations between smoking, serum lipids, blood pressure, and myocardial infarction were examined in a population-based prospective study of 11 843 men and women aged 35 to 52 years at entry. During 12 years, 495 cases of first myocardial infarction among men and 103 cases among women were identified. Myocardial infarction incidence was 4.6 times higher among men. The incidence was increased sixfold in women and threefold in men who smoked at least 20 cigarettes per day compared with never-smokers, and the rate in female heavy smokers exceeded that of never-smoking men. Multivariate analysis identified current smoking as a stronger risk factor in women (relative risk, 3.3; 95% confidence interval [CI], 2.1 to 5.1) than in men (relative risk, 1.9; 95% CI, 1.6 to 2.3). Among those under 45 years old at entry, the smoking-related sex difference was more pronounced (in women: relative risk, 7.1; 95% CI, 2.6 to 19.1) (in men: relative risk, 2.3; 95% CI, 1.6 to 3.2). Serum total cholesterol, HDL cholesterol, and systolic blood pressure were also highly significant predictors in both sexes.

Conclusions Smoking was a stronger risk factor for myocardial infarction in middle-aged women than in men. Relative risks associated with serum lipids and blood pressure were similar despite large sex differences in myocardial infarction incidence rates.


Key Words: coronary disease • smoking • blood pressure • epidemiology • lipids


*    Introduction
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 *Introduction
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down arrowResults
down arrowDiscussion
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Serum total cholesterol, HDL cholesterol, smoking, and blood pressure are established major risk factors for coronary heart disease. They are often presumed to apply similarly to both sexes1 despite the current threefold to fivefold higher coronary heart disease mortality among men in industrialized countries2 and despite the scarcity of prospective studies published on risk factors in women. Among the few studies that actually had the potential to explore sex differences in risk factors within the same population, several had a limited number of coronary heart disease cases among women3 4 5 6 or the inclusion of various "soft" disease manifestations in the coronary heart disease end point.7

The present study is the third prospective study8 9 to examine relationships between smoking, other major risk factors, and myocardial infarction incidence in the two sexes. Furthermore, it is the only study restricted to a middle-aged population. Other large studies of smoking and coronary heart disease that included both sexes used mortality as an end point and lacked baseline information on other major risk factors.10 11 12 13 Although thoroughly investigated in men, current knowledge of the relation between smoking and myocardial infarction in women stems mainly from case-control studies14 15 16 and the prospective Nurses' Health Study.17

We examined the relations between smoking, serum lipids, and blood pressure and the incidence of myocardial infarction in a population-based, 12-year follow-up of nearly 12 000 men and women aged 35 to 52 years at study entry. Sex-stratified analyses with validated and identical end points allowed comparisons of risk factor patterns in the two sexes. The dose-response relation between smoking and myocardial infarction and possible risk modifying effects of serum lipids and blood pressure was assessed.


*    Methods
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 *Methods
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Study Population
In 1977, all residents aged 35 to 52 years and a sample of those aged 20 to 34 years in Finnmark County in Northern Norway were invited to a cardiovascular screening. In all, 20 683 subjects were invited through a personal, mailed letter. The survey was organized by the National Health Screening Service, and details of study design and procedures have been published.18 19 The present analysis is limited to age group 35 to 52 years, in which 12 785 subjects (87.8%) attended the screening. Eighty-eight men and 11 women were excluded from the follow-up because of verified myocardial infarction or hospitalization as a result of a severe attack of angina pectoris before screening. Persons with self-reported angina pectoris but no previous infarction-suspect attack (93 men and 71 women) were included, as were 33 male and 23 female diabetics. Baseline values of HDL cholesterol were missing in some subjects, leaving 11 843 subjects available for analysis. Almost 20% of these were of Finnish origin, 13% were Sami, and the rest were Norse (50%) or of mixed ethnicity.

Screening Data and Procedures
Enclosed with the letter of invitation was a questionnaire that covered history and symptoms of cardiovascular disease, ethnicity, and smoking habits. Current and previous smokers were asked about the number of cigarettes smoked per day, number of years smoked, and, in case, time since smoking cessation. The questionnaire was to be completed at home and brought to the examination, where it was checked for consistency.

The examination included measurements of weight, height, and blood pressure and a nonfasting blood sample. Systolic and diastolic blood pressures were measured twice with the patient in the sitting position after 4 minutes' rest. The lower values were used in this analysis.

Details of the laboratory methods have been published.19 20 Briefly, the serum was analyzed for total cholesterol and triglycerides within 2 weeks at Ullevål Hospital in Oslo. Total cholesterol was measured by the Liebermann-Burchard method21 and triglycerides by a fluorimetric method.21 HDL cholesterol was determined in frozen sera at the Institute of Medical Biology, University of Tromsø, after precipitation of LDL and VLDL with the heparin-manganese method.20 Data on cross-sectional relations between HDL cholesterol and other variables in the Finnmark Study have been published previously.20 22

Pearson correlation coefficients between baseline serum lipids were generally similar in the two sexes. Strong intercorrelations were observed between serum triglycerides and total cholesterol (r=.4) and between serum triglycerides and HDL cholesterol (r=-.4). In women, there was no association between total cholesterol and HDL cholesterol (r=-.0), whereas a weak, positive correlation (r=.1, P<.001) was seen in men.

Follow-up and Case Identification
The subjects were followed from screening through December 31, 1989. The national 11-digit identification number enabled a linkage to the Causes of Death Registry at Norway Statistics and ensured a 100% follow-up on vital status. For persons with a death certificate diagnosis according to ICD ninth revision codes 410-414 and 798.1, additional information from the relevant hospital or physician was collected for case validation. Possible cases were also detected through hospital discharge diagnosis lists and a systematic screening of the medical record files in the only two hospitals in Finnmark. For persons with any mention of coronary heart disease, the medical record was reviewed by one of the authors (I.N.) to determine if and when a first event of myocardial infarction had occurred according to preset diagnostic criteria.

To detect ambulant and out-of-county nonfatal events, a questionnaire was sent to all 10 923 participants who were alive by June 1991. The Data Inspectorate did not allow questionnaires to be sent to relatives of deceased persons. Eleven percent of the study population had moved from Finnmark, but linkage to the Central Population Registry of Norway provided updated addresses regardless of area of residency. When a questionnaire reply indicated cardiovascular disease, medical record information from the relevant hospital or attending physician was obtained, with the respondent's written consent. The postal survey response rate was 82% among those who stayed and those who had moved from Finnmark. In all, 97% of the participants were followed up by means of the postal survey and/or official diagnosis registers and hospital record surveys.

Each case was classified as definite or probable myocardial infarction or as sudden death on the basis of the available data. Diagnostic criteria of myocardial infarction were based on symptoms, on ECG changes and changes in cardiac enzymes, and on autopsy results in fatal events, when performed (see "Appendix"). Not included as cases were 49 men and 34 women with uncertain myocardial infarction.

In 1987, 76% of the cohort members attended another county- and population-based cardiovascular screening in Finnmark. This allowed an assessment of changes in smoking habits during follow-up to be made.

Data Analysis
Incidence rates were based on the number of person-years calculated from date of examination until first event of myocardial infarction or sudden death, with date of death from other reasons or December 31, 1989, as the censoring date. Age adjustment of incidence rates was performed directly on 5-year age groups with all attending men and women as the standard population. Sex differentials and other rate ratios of myocardial infarction incidence were assessed with the use of age-adjusted rates.

Some persons combined cigarettes with other smoking habits, leaving 108 men as exclusive pipe or cigar smokers. They were included as current smokers but were left out of analyses of quantity smoked.

Cox proportional hazards analysis was used for multivariate modeling. In models stratified by sex, the following continuous variables were considered: serum total cholesterol, HDL cholesterol and triglycerides, systolic blood pressure, and body mass index (weight/height2). Daily smoking was included as a binary variable. Self-reported angina pectoris, diabetes, and medically treated hypertension were included as covariates, along with ethnic group. Relative risk estimates were determined for units of increase arbitrarily chosen to approximate the standard deviation for both sexes. Probability values less than .05 were regarded as statistically significant. All significance tests were two-tailed. The SAS statistical package version 6.07 was used.


*    Results
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*Results
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Baseline mean values and frequencies are presented in Table 1Down. Noteworthy are the high means of serum total cholesterol and the rather high prevalence of daily smoking in both sexes. Men had a more unfavorable risk profile, with higher mean total cholesterol, triglycerides, and blood pressure and lower HDL cholesterol. Fewer women than men were daily smokers, and female smokers consumed fewer cigarettes per day than their male counterparts. Among current nonsmokers, a larger proportion of men than of women were ex-smokers (63.1% versus 29.8%). Smokers had lower mean serum HDL cholesterol than nonsmokers, and the difference was larger in women (0.10 mmol/L [3.87 mg/dL], 6%) than in men (0.03 mmol/L [1.16 mg/dL], 2%) (data not shown).


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  		Table 1. Baseline Characteristics in Men and Women: The Finnmark Study, 1977-1989

During 12 years of follow-up (139 836 person-years), 495 first events of myocardial infarction and sudden death among men and 103 first events among women were identified (Table 2Down). There was no significant sex difference in case category distribution.


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  		Table 2. Case Categories of Myocardial Infarction by Sex: The Finnmark Study, 1977-1989

The relation between smoking and myocardial infarction incidence is shown in Table 3Down. In both sexes, markedly higher incidence rates were seen among the current smokers. Intermediate rates were observed among ex-smokers yet were significantly higher compared with never-smokers only in men (relative risk, 1.5; 95% confidence interval [CI], 1.1 to 2.4). In each smoking category, men had a higher rate of infarction than did women. However, the risk associated with increasing numbers of cigarettes was greater in women. Women who smoked 20 cigarettes per day or more had a nearly sixfold increased risk of myocardial infarction compared with never-smoking women, while the corresponding ratio in men was less than 3. This reduced the male-to-female ratio from 5.2 in never-smokers to 2.5 in heavy smokers, and the incidence rate among female heavy smokers exceeded that of never-smoking men. The population attributable risk of smoking was close to 50% in both sexes. If incidence rates in the total study population were the same as for never-smokers, 55 events among women and 236 events among men would not have occurred.


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  		Table 3. Age-Adjusted Incidence Rates of Myocardial Infarction per 1000 Person-Years by Smoking Habits and Sex: The Finnmark Study, 1977-1989

Table 4Down presents the age-adjusted myocardial infarction incidence by sex according to smoking and serum total cholesterol. The cutoff points were chosen to divide the total study population into approximate quartiles. Among men, relative risks were similar in smokers and nonsmokers, and the smoker-to-nonsmoker ratios were 1.4 to 2.1 across all total cholesterol strata. Only one case of infarction occurred among nonsmoking women with baseline serum total cholesterol less than 5.7 mmol/L (220 mg/dL), and the lowest cutoff point was chosen at 6.5 mmol/L (250 mg/dL). Only at serum total cholesterol levels of 7.4 mmol/L (285 mg/dL) or more did the incidence rise in women, significantly in smokers only. The ratios between smoking and nonsmoking women were greater than for men at all levels of total cholesterol and ranged from 2.9 to 4.5.


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  		Table 4. Age-Adjusted Incidence Rates of Myocardial Infarction per 1000 Person-Years, Relative Risk, and 95% Confidence Interval According to Serum Total Cholesterol and Smoking Status by Sex: The Finnmark Study, 1977-1989

When examining myocardial infarction incidence in relation to smoking and serum HDL cholesterol (Table 5Down), identical cutoff points were chosen in the two sexes. In all subgroups, the relative risk decreased significantly with increasing HDL cholesterol. The ratio between smokers and nonsmokers was less in men (1.6 to 1.9) compared with women (2.4 to 6.3) in all HDL cholesterol strata.


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  		Table 5. Age-Adjusted Incidence Rates of Myocardial Infarction per 1000 Person-Years, Relative Risk, and 95% Confidence Interval According to Serum HDL Cholesterol and Smoking Status by Sex: The Finnmark Study, 1977-1989

Table 6Down presents relative risks adjusted for age first and then for several risk factors and confounders. Adjusted for age, all variables considered were highly significant predictors in both sexes except body mass index, which was significant in men (relative risk, 1.19; P<.0001) but not in women (relative risk, 1.12; P=.0626). In both sexes, serum triglycerides and body mass index became nonsignificant when adjusted for the other risk factors and were not included in the final model. The relative risk estimates of serum cholesterol, HDL cholesterol, and blood pressure were similar in the two sexes and were virtually unchanged after multivariate adjustment. Daily smoking made a striking exception to the rule. The relative risk associated with current smoking and adjusted for other risk factors was 3.3 (95% CI, 2.1 to 5.1) in women and 1.9 (95% CI, 1.6 to 2.3) in men. A further age-stratified analysis revealed apparent large age-related differences in relative risk estimates. Among women aged 35 to 44 years at study entry (median age at diagnosis, 49 years), the multivariate adjusted relative risk of smoking was 7.1 (95% CI, 2.6 to 19.1). This estimate was based on 31 cases, and the confidence interval was wide. The corresponding relative risk was 2.6 (95% CI, 1.6 to 4.3) in women 45 to 52 years old at entry (median age at diagnosis, 57 years). A much smaller age effect was observed among men. The relative risk estimate was 2.3 (95% CI, 1.6 to 3.2) in the younger age group (median age at diagnosis, 48 years) and 1.7 (95% CI, 1.3 to 2.2) in the older age group (median age at diagnosis, 56 years). The relative risk estimates for serum lipids and blood pressure did not vary substantially between sex and age groups.


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  		Table 6. Risk Factors for Myocardial Infarction, Adjusted Relative Risk, and 95% Confidence Interval by Sex: The Finnmark Study, 1977-1989


*    Discussion
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 up arrowAbstract
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 up arrowMethods
up arrowResults
*Discussion
down arrowAppendix
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This study confirms that smoking, serum lipids, and blood pressure are major risk factors for myocardial infarction in both sexes. The relative risks associated with serum lipids and blood pressure were generally similar, although men were overall 4.6 times more likely to have a myocardial infarction. However, one important sex-related difference was observed. Smoking had a much larger relative detrimental impact in women, and the risk gradient associated with increasing number of daily cigarettes was larger. Women smoking 20 cigarettes or more per day totally eliminated any "female advantage" relative to men who had never smoked. Smoking carried a particularly high risk in younger women.

This study used several sources to detect all incident cases of clinical myocardial infarction in the study population. However, an underregistration of nonfatal events must be expected, mainly among those who had moved from Finnmark and who did not respond to the postal survey in 1991. We estimated the total number of missed events to be less than 15. No attempt was made to register silent myocardial infarctions. Only fatal and nonfatal "hard" coronary heart disease manifestations were included in the end point, thus avoiding a potential source of misleading sex differentials. Long-term outcome of angina pectoris23 24 and survival rate after a myocardial infarction25 appear to be different in the two sexes. Mortality time trends and sex ratio patterns are very different for coronary and cerebrovascular disease.26 This may result in diluted sex differentials if all cardiovascular disease is included in a single end point.

A sex-biased misclassification of smoking status due to sex differences in smoking cessation2 during follow-up possibly could explain some of the observed differences between men and women. We were able to explore this hypothesis indirectly, because 76% of the present cohort attended another cardiovascular screening 10 years after study entry. More men than women reported to have quit smoking since the baseline examination (19.5% versus 16.0%; P<.001). No sex differential in smoking cessation was observed among those with angina pectoris or a myocardial infarction during the 10 years (32.0% in men versus 34.5% in women; NS). Thus, misclassification bias of the exposure variable is unlikely to explain the sex differentials.

Our finding of larger relative risks with increasing amounts smoked among women compared with men is in accordance with the Copenhagen City Heart Study,9 which reported that the relative risk of first myocardial infarction was 9.4 in women and 2.9 in men who smoked at least 30 g tobacco per day compared with nonsmokers. According to Tverdal et al,13 the relative risk of coronary death per 10 cigarettes per day was 1.8 in women and 1.2 in men. Data from case-control studies among young women of fatal14 and nonfatal15 myocardial infarction and from prospective studies confined to one sex also indicate that increasing amounts of smoking may have a more detrimental effect for women than for men. In the Nurses' Health Study, the risk of myocardial infarction increased with number of cigarettes, and a relative risk of 6.0 was observed among women smoking at least 25 cigarettes per day compared with never-smokers.17 Among the men screened for the MRFIT study, cigarette smoking was a significant predictor for coronary death.27 The risk increased with smoking amount but leveled off at 25 cigarettes per day, and the relative risk compared with nonsmokers did not exceed 2.5. On the other hand, in a number of publications, the Framingham Study reported no significant relation between smoking and coronary heart disease among women.28 In the classic American10 and British11 12 studies of coronary mortality, the relative risks associated with daily smoking were similar in the two sexes. Different smoking frequencies, possible sex-specific smoking habits, different age distributions in the study samples, and different end points may all be related to the various study results. Our finding of a higher relative risk associated with smoking in younger rather than older women may contribute to an explanation of previous apparently conflicting study results.

Oral contraceptive use15 29 could have contributed to the strong relation between smoking and myocardial infarction among women but is unlikely to have had any impact in this particular study population. Only three women were below the age of 45 at the time of the event. Median age at diagnosis in the younger age group was 49 years. Oral contraceptives appear to carry no residual risk for myocardial infarction after quitting.29 30 Also, 55% of the women had their first myocardial infarction after 1984, when low-dose estrogen pills totally dominated the market in Norway.31 It is uncertain whether oral contraceptives with <50 µg estrogen are associated with any elevated risk of coronary heart disease.32

Cigarette smoking probably increases myocardial infarction risk through long-term effects on atherosclerosis33 and through readily reversible effects on hemostasis34 and the hemodynamic system.35 Intermediate incidence rates in ex-smokers relative to never-smokers in this and other studies13 17 may be taken in support of a reversibility of smoking-induced risk effects. This may also partly explain why smoking appears to be strongly related to myocardial infarction in case-control studies,14 15 16 while several prospective studies of coronary heart morbidity and mortality found weaker associations.10 11 12 13 In longitudinal studies, smoking status at the time of the event is more prone to be misclassified than in case-control studies. This bias will be more pronounced as length of follow-up increases.

In this study, the role of systolic blood pressure as a major coronary risk factor36 was confirmed. Serum total cholesterol was a strong independent predictor in both sexes. This is accordant with a number of coronary disease studies in men37 and women,38 but the importance of total cholesterol as a coronary risk factor has been questioned.39 40 41 The multivariate model showed a risk increase in both sexes by almost 40% per mmol/L serum cholesterol. The relative risk increased similarly in smokers and nonsmokers across the total cholesterol strata, each sex considered separately. However, in women, an apparent threshold level was observed. The smoker-to-nonsmoker ratios were greater in women than in men at all levels of total cholesterol, again pointing to the hazardous effect of cigarette smoking for women. Few studies among younger women offer data on the combined effect of smoking and serum lipoproteins or history of hypercholesterolemia, and results were inconsistent.15 17

HDL cholesterol has been claimed as a more important risk factor for coronary heart disease than total cholesterol, especially in women,38 while epidemiological studies disagree regarding the role of triglycerides.42 In the present study, HDL cholesterol was a strong predictor for myocardial infarction in both sexes, and relative risks were similar. Serum triglycerides and HDL cholesterol were strongly inversely intercorrelated. Triglycerides were a significant predictor univariately and in models that included total cholesterol but became nonsignificant in both sexes as soon as HDL cholesterol was included in the model. Similar results were reported from several of the few prospective studies (mostly among men) in which both HDL cholesterol and triglycerides were accounted for,6 43 44 but there are exceptions.45

In our study population, baseline serum HDL cholesterol was absolutely and relatively more reduced in female than in male smokers compared with nonsmokers of the same sex. This is in accordance with previous findings.46 47 48 A reduced HDL cholesterol concentration in smokers may be related to sex hormone metabolism,49 50 51 but to our knowledge, the apparently greater reduction in women has been only little explored.48 Stratified by serum HDL cholesterol, the smoker-to-nonsmoker ratios of myocardial infarction were consistently greater in women than in men, and the largest ratio (6.3) was observed among women with serum HDL cholesterol above 1.50 mmol/L. Our data suggest that women who smoke heavily lose relatively more of the protection against myocardial infarction that is associated with HDL cholesterol than their male counterparts do. However, few cases in the female population reduce the power of subgroup analyses. Our data are consistent with a case-control study by Rosenberg et al,15 which estimated the risk of infarction in women who smoked at least 25 cigarettes per day relative to nonsmoking women. In the low HDL cholesterol group (cutoff point at 40 mg/dL [1.03 mmol/L]), Rosenberg et al observed a relative risk of 4.7 compared with 14 in the high HDL cholesterol group.

Exogenous estrogen1 and alcohol52 are potential confounders that could not be assessed in this study, since no baseline data were collected. However, by 1987, only 2% of Finnmark women aged 45 to 62 years used exogenous estrogen.53 More women (40%) than men (13%) were alcohol abstainers.53 Among users, alcohol intake was more frequent in men. Alcohol raises HDL cholesterol,48 52 and moderate alcohol intake appears to be associated with decreased risk of myocardial infarction.52 Sex differences in drinking habits may therefore have influenced our findings.

Possible mechanisms behind the apparently greater hazard of smoking for women were not elucidated by this study. The antiestrogenic effect of cigarette smoking50 51 54 could be the mediator that increases the risk of coronary heart disease in young female smokers relatively more than in men. Added to this is the greater reduction in HDL cholesterol in female smokers than in male smokers. The recent increase in smoking among young women in some countries55 should be of great concern because it may have a serious effect on future coronary heart disease mortality.


*    Acknowledgments
 
This research was supported by grants from the Norwegian Council on Cardiovascular Diseases and from the Norwegian National Programme for Health for all by the year 2000 (Health and Inequalities in Finnmark).


*    Footnotes
 
Reprint requests to Dr Inger Njølstad, Institute of Community Medicine, University of Tromsø, N-9037, Tromsø, Norway. E-mail ingern@ism.uit.no.


*    Appendix
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*Appendix
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Myocardial Infarction Classification Criteria
One of the following must have occurred: (I) Definite myocardial infarction (MI) (290 men, 55 women): (1) dynamic ECG changes typical of MI and lasting more than 24 hours, with or without symptoms and/or cardiac enzyme changes, (2) typical (prolonged chest pain) or atypical symptoms (acute congestive heart failure, syncope) and serial cardiac enzyme elevation exceeding twice the upper limit of reference range, (3) in fatal event: autopsy proved recent MI or fresh coronary artery thrombus. (II) Probable MI (135 men, 37 women): (1) symptoms and a clinical development typical of MI, but death before a definite diagnosis could be given, and no autopsy performed (23 men, 4 women), (2) typical or atypical symptoms and equivocal ECG and/or serial cardiac enzyme elevation between upper and twice the upper limit of reference range (59 men, 18 women), (3) clinical episode with prolonged chest pain and persisting ECG changes typical of MI, but patient examined too late to record dynamic ECG changes and/or enzyme elevation (16 men, 3 women), (4) death certificate or other medical record diagnosis of coronary heart disease (CHD) (ICD-8 and ICD-9 410-414) or sudden death (ICD-8 795, ICD-9 798.1), with no indication of competing cause of death, but confirmative medical information unaccessible (37 men, 12 women). (Case validation was performed in 1990 to 1991, up until 17 years after death of study participants. Norwegian laws permit physician medical records to be destroyed 10 years after the death of the patient.). (III) Sudden death (70 men, 11 women): (1) death within 1 hour after acute collapse or chest pain or since last time seen without symptoms. No indication of competing cause of death (40 men, 5 women), (2) death more than 1 hour or unspecified time after last time seen alive, with no indication that other disease or condition may have caused death (30 men, 6 women); (IV) uncertain MI (49 men, 34 women): symptoms, ECG, and/or enzyme changes indicate MI but criteria of definite or probable MI not fulfilled. (Most cases were hospitalized persons with prolonged chest pain but whose initial ECG changes resolved within 24 hours.)

Received July 17, 1995; revision received September 5, 1995; accepted September 11, 1995.


*    References
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*References
 

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