Unrecognized myocardial infarction (MI) is frequent in the general population. Its prognosis is reported to be at least as unpropitious as that of recognized MI, particularly in men. However, contemporary data with long follow-up are lacking. The aims of this study were to investigate the long-term prognosis of unrecognized MI with respect to all-cause and cause-specific mortality and to investigate possible differences in prognosis by gender. In the population-based Rotterdam Study (2,672 men and 3,862 women), the presence of unrecognized MI and recognized MI was determined at baseline (1990 to 1993). The cohort was followed for nearly 2 decades for all-cause and cause-specific mortality. During 82,268 patient-years of follow-up (median 15.6 years) 3,412 patients died (1,300 from cardiovascular causes). Men and women with recognized and unrecognized MIs had increased total mortality rates compared with those without MIs. Hazard ratios (HRs) for men and women were 1.57 (95% confidence interval [CI] 1.36 to 1.81) and 1.89 (95% CI 1.56 to 2.30) for recognized MI and 1.72 (95% CI 1.43 to 2.07) and 1.36 (95% CI 1.14 to 1.61) for unrecognized MI. Unrecognized MI was associated with increased risks for cardiovascular mortality (men: HR 2.19, 95% CI 1.66 to 2.91; women: HR 1.36, 95% CI 1.03 to 1.81) and noncardiovascular mortality (men: HR 1.47, 95% CI 1.14 to 1.89; women: HR 1.39, 95% CI 1.10 to 1.75). In conclusion, the long-term prognosis of patients with unrecognized MIs is worse compared with those without MIs and applies not only to cardiovascular mortality but also to noncardiovascular mortality. In men, the prognosis is as unfavorable as that of patients with recognized MIs.
According to several reports, 20% to 70% of all myocardial infarctions (MIs) in the general elderly population are asymptomatic or remain clinically unrecognized. Because of the absence of typical symptoms, affected subjects may never seek and receive medical care. Consequently, the diagnosis of MI in these subjects is likely to be delayed or never made. This explains why up to 6% of the general elderly population may have had unrecognized MIs. Several studies have shown that the prognosis of subjects with unrecognized MIs with respect to future cardiovascular events, such as recurrent MI, is worse than that of healthy individuals. Similar results have been reported with respect to the risk for death. A number of studies have shown that the prognosis of subjects with unrecognized MIs is at least as unfavorable as that of patients with recognized MIs. However, advances in primary prevention have been made over the past years, and recent data on the prognosis of unrecognized MI are lacking. In this study, we report results from the Rotterdam Study, a population-based cohort study in subjects aged ≥55 years ongoing since 1990. Our aim was to determine the long-term prognosis of subjects with unrecognized MI with respect to all-cause mortality and cause-specific mortality. We also sought to answer the question of whether the prognosis is different between men and women.
Methods
The Rotterdam Study is a prospective, population-based cohort study in subjects aged ≥55 years. A more detailed description of the Rotterdam Study and its data collection has been given elsewhere. From 1990 to 1993, all inhabitants of Ommoord, a suburb of the city of Rotterdam, were invited to take part in the study. A total of 7,983 subjects participated (response rate 78%). Once participants entered the Rotterdam Study, they were continuously monitored for mortality and morbidity. The medical ethics committee of Erasmus Medical Center approved the study, and written informed consent was obtained to participate and to permit access to information from treating physicians.
At baseline, participants were asked if they had ever experienced a heart attack. Furthermore, a 12-lead electrocardiogram was recorded using an ACTA electrocardiograph (Esaote, Florence, Italy) at a sampling frequency of 500 Hz. All electrocardiograms were digitized and processed using the Modular ECG Analysis System (MEANS) to obtain electrocardiographic (ECG) measurements and interpretations. The MEANS has been extensively evaluated previously. The MEANS uses a comprehensive set of criteria, partly derived from the Minnesota codes, to determine MI. The diagnosis of MI is based mainly on measurements on pathologic Q waves and on auxiliary criteria, such as QR ratio and R-wave progression. Subsequently, 2 research physicians, blinded to other clinical information, validated the electrocardiograms that were diagnosed by MEANS as indicating possible, probable, or certain MI. A cardiologist, specializing in ECG methods, ascertained the final diagnosis of MI. A history of “recognized MI” included subjects with self-reported MIs confirmed by clinical data or ECG evidence of MI. A history of “unrecognized MI” included all participants without documented or self-reported MIs but with ECG characteristics matching an MI. Subjects without indications of MI on electrocardiography and no self-reports of earlier MIs were classified as “no MI.”
At the start of the Rotterdam Study, we did not report the presence of unrecognized MI to participants or general practitioners at baseline (1990 to 1993). The decision was based on the previous perception in The Netherlands that an unrecognized MI was less severe than a recognized MI and was motivated by a lack of evidence for treatment after unrecognized MI to effectively reduce the risk for subsequent cardiovascular events. From the third follow-up visit onward (January 2002), we reported new findings of ECG unrecognized MI to participants and their general practitioners.
Participants underwent an extensive interview at home by a trained research assistant using a questionnaire to obtain information on medical history and current health status. Labels of all medications used by participants were copied during this interview. At the research center, blood pressure was measured twice in the right upper arm in a sitting position using a random-zero sphygmomanometer. In the analyses, the average of these 2 measurements was used. Diabetes mellitus was defined as random or postload serum glucose level >11.0 mmol/L or the use of oral blood glucose–lowering drugs or insulin. We calculated body mass index as weight in kilograms divided by the square of height in meters. Serum total cholesterol and high-density lipoprotein cholesterol were determined by means of an automated enzymatic procedure in nonfasting blood samples.
Participants’ vital status was ascertained from the moment of enrollment into the Rotterdam Study until January 1, 2009. The information was acquired on a weekly basis from the municipal authorities of Rotterdam. Additionally, the general practitioners in the suburb of Ommoord reported deaths on a continuing basis. Reported deaths were verified by specially trained study personnel who checked the medical records. When an event was reported, additional information was collected (e.g., hospital records, nursing home records). Deaths were classified as cardiovascular or noncardiovascular. The methods of adjudication and the underlying definition of cardiovascular mortality have been described previously. This classification focuses on the underlying cause rather than on mode of death. In short, a research physician weighed all available clinical information in each potentially cardiovascular death according to predefined criteria to adjudicate the underlying cause of death as being cardiovascular or noncardiovascular. All cases were verified by a physician specializing in cardiology, whose judgment was considered final. We excluded 830 subjects who did not visit the research center at baseline. ECG data were missing for 619 subjects, mainly for logistic reasons. The population for analysis consisted of 6,534 subjects. The 1,449 excluded subjects were older (8.7 years) and more likely to be men (14% of women and 21% of men were excluded).
Because previous reports suggested a difference in prognosis of unrecognized MI between men and women, analysis was done separately in men and women. All analyses were adjusted for age. Differences in baseline characteristics between subjects without MI, those with recognized MI, and those with unrecognized MI were evaluated using linear and logistic regression models adjusted for age.
We used Cox proportional-hazards models to calculate the hazard ratios for total mortality and cause-specific mortality associated with unrecognized MI and recognized MI at baseline. Subjects without MIs were used as the reference group. To examine whether the association was significantly different in men and women, we introduced an interaction term to the model. We first investigated all-cause mortality and subsequently cardiovascular and noncardiovascular mortality separately. Kaplan-Meier plots were generated to illustrate the survival differences over time among different groups. Missing values were imputed using an expectation maximization algorithm.
Results
Table 1 lists the baseline characteristics of the study population, stratified by gender. Men with unrecognized MIs had significantly higher body mass indexes and were more often diagnosed as hypertensive. Women had significantly higher body mass indexes, had higher systolic and diastolic blood pressure, had lower high-density lipoprotein cholesterol, and more often reported being current smokers. The comparisons were adjusted for age and gender.
| Variable | Men | Women | ||||
|---|---|---|---|---|---|---|
| No MI (n = 2,200) | Unrecognized MI (n = 165) | Recognized MI (n = 307) | No MI (n = 3,527) | Unrecognized MI (n = 205) | Recognized MI (n = 130) | |
| Age (yrs) | 67.6 ± 8.1 | 70.7 ± 8.6 ∗ | 69.7 ± 7.5 ∗ | 69.2 ± 9.2 | 74.4 ± 9.4 ∗ | 75.4 ± 8.4 ∗ |
| Smokers | ||||||
| Current | 29.9% | 39.4% | 21.5% | 18.1% | 18.5% ∗ | 16.9% ∗ |
| Former | 61.5% | 53.3% | 73.6% ∗ | 27.9% | 26.3% | 29.2% |
| Body mass index (kg/m 2 ) | 25.6 ± 2.9 | 26.0 ± 3.5 ∗ | 26.0 ± 3.0 | 26.7 ± 4.0 | 27.9 ± 5.0 ∗ | 27.1 ± 4.2 |
| Diabetes mellitus | 9.1% | 17.0% ∗ | 17.3% ∗ | 10.2% | 15.1% | 19.2% |
| Total cholesterol (mmol/L) | 6.3 ± 1.2 | 6.2 ± 1.2 | 6.5 ± 1.1 ∗ | 6.8 ± 1.2 | 6.8 ± 1.3 | 6.8 ± 1.4 |
| Total cholesterol (mg/dl) | 243 ± 45 | 240 ± 47 | 250 ± 44 ∗ | 265 ± 46 | 262 ± 50 | 263 ± 52 |
| HDL cholesterol (mmol/L) | 1.24 ± 0.33 | 1.21 ± 0.33 | 1.10 ± 0.26 ∗ † | 1.45 ± 0.36 | 1.36 ± 0.33 ∗ | 1.29 ± 0.35 ∗ |
| HDL cholesterol (mg/dl) | 48 ± 13 | 47 ± 13 | 42 ± 10 ∗ † | 56 ± 14 | 53 ± 13 ∗ | 50 ± 14 ∗ |
| Systolic blood pressure (mm Hg) | 139 ± 22 | 144 ± 21 | 135 ± 20 ∗ † | 140 ± 23 | 147 ± 20 ∗ | 138 ± 26 ∗ † |
| Diastolic blood pressure (mm Hg) | 75 ± 11 | 76 ± 13 | 71 ± 10 ∗ † | 73 ± 11 | 75 ± 12 ∗ | 69 ± 14 ∗ † |
| Hypertension | 51.1% | 63.0% ∗ | 59.9% ∗ | 57.0% | 67.8% | 65.4% |
| Use of blood pressure–lowering drugs | 22.5% | 28.5% | 70.7% ∗ † | 31.6% | 36.6% | 82.3% ∗ † |
| Aspirin | 11.1% | 12.1% | 35.5% ∗ † | 7.9% | 10.2% | 32.6% ∗ † |
| Nitrates | 4.2% | 4.8% | 32.6% ∗ † | 5.0% | 3.9% | 52.7% ∗ † |
| Statins | 1.4% | 1.2% | 9.4% ∗ † | 1.7% | 1.0% | 8.5% ∗ † |
∗ Significantly different from subjects without MI (age adjusted if applicable).
† Significantly different from subjects with recognized MI (age adjusted if applicable).
During 82,268 patient-years of follow-up (median 15.6 years) a total of 3,412 patients died. Of these deaths, 1,300 were due to cardiovascular diseases, 1,956 were due to noncardiovascular diseases, and 156 were due to uncertain causes because of limited information. Table 2 lists the association of recognized and unrecognized MI with all-cause mortality. Recognized MI and unrecognized MI were associated with an increased risk for all-cause mortality. In men, unrecognized MI showed a somewhat stronger association with all-cause mortality compared with recognized MI. In women, however, recognized MI was more strongly associated with all-cause mortality than unrecognized MI. The gender difference in the strength of associations was not statistically significant for unrecognized MI (p for interaction = 0.053), or recognized MI (p for interaction = 0.080). Additional adjustment for cardiovascular risk factors did not materially change the results. Figure 1 shows the Kaplan-Meier curves for all-cause mortality in men and women. Table 3 lists the associations of recognized and unrecognized MI with cardiovascular and noncardiovascular mortality. Unrecognized MI was associated with cardiovascular mortality in men and women. The association was significantly stronger in men than in women (p for interaction = 0.024). Conversely, recognized MI increased the risk for noncardiovascular mortality in women but not in men (p for interaction = 0.054).
| Group | Number (Deaths) | Mortality Rate ∗ | Hazard Ratio (95% Confidence Interval) | |
|---|---|---|---|---|
| Age and Gender Adjusted | Multivariate Adjusted † | |||
| Men | ||||
| No MI | 2,200 (1,179) | 43.1 | 1.00 (reference) | 1.00 (reference) |
| Unrecognized MI | 165 (126) | 80.6 | 1.72 (1.43–2.07) | 1.57 (1.30–1.89) |
| Recognized MI | 307 (230) | 73.1 | 1.57 (1.36–1.81) | 1.67 (1.45–1.94) |
| Women | ||||
| No MI | 3,527 (1,630) | 34.8 | 1.00 (reference) | 1.00 (reference) |
| Unrecognized MI | 205 (137) | 62.5 | 1.36 (1.14–1.61) | 1.33 (1.11–1.58) |
| Recognized MI | 130 (110) | 93.9 | 1.89 (1.56–2.30) | 1.87 (1.54–2.28) |
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