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Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The NetherlandsDepartment of Cardiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The NetherlandsDepartment of Radiology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The NetherlandsDepartment of Neurology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
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.
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 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.
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.
Table 1Baseline characteristics of the study population
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).
Table 2All-cause mortality in patients with recognized and unrecognized myocardial infarctions
Further adjusted for systolic and diastolic blood pressure, indication for antihypertensive medication, total cholesterol, high-density lipoprotein cholesterol, smoking, body mass index, and type 2 diabetes.
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)
∗ Per 1,000 patient-years.
† Further adjusted for systolic and diastolic blood pressure, indication for antihypertensive medication, total cholesterol, high-density lipoprotein cholesterol, smoking, body mass index, and type 2 diabetes.
This population-based cohort study confirms that unrecognized MI is associated with high all-cause mortality in men and women. In men, the increased risk is even larger than that associated with recognized MI. Furthermore, unrecognized MI was associated with higher risk for cardiovascular as well as noncardiovascular mortality in men and women.
Thus far, several studies have investigated the prognosis of unrecognized MI pertaining to mortality and recurrent ischemic heart disease.
These studies, which were conducted mainly in the 1990s, showed that unrecognized MI is not a benign condition and that patients with unrecognized MIs had increased risk for mortality compared with those without MIs. Recently, we have reported on the prognosis of unrecognized MI with respect to risk for stroke,
In the present study, we report on contemporary data regarding the prognosis of unrecognized MI with respect to all-cause mortality and cause-specific mortality. We hypothesized that changes in lifestyle, better self-awareness of health, and widespread introduction of primary prevention of cardiovascular disease could have changed the prognosis of unrecognized MI over the years. However, our results show that the prognosis of unrecognized MI is still as unfavorable as of recognized MI. We found that men and women with unrecognized MI had an increased risk for all-cause mortality compared with subjects without MI. This is in accordance with previous studies reporting similar results.
A likely explanation for this finding is that lack of preventive cardiovascular treatment and lifestyle advice may have contributed to a poorer prognosis after unrecognized MI compared with the prognosis after recognized MI. Support for this hypothesis comes from the observation in our study that subjects with recognized MIs considerably more often used aspirin, nitrates, statins, and β blockers than those with unrecognized MIs (Table 1). However, it should be noted that the lipid profiles of patients with recognized MIs were slightly worse than the profiles of those with unrecognized MIs. To take such baseline differences into account, we further adjusted the association for major cardiovascular risk factors. However, the prognosis of unrecognized MI remained as unfavorable as of recognized MI. This may indicate that unrecognized MI gives a more comprehensive image of an patient's cardiovascular risk profile than individual cardiovascular risk factors measured only once at baseline.
Although unrecognized MI was followed by an increase in all-cause mortality in men and women, the increase was not to the same extent in men (72%) and women (36%). Although men with unrecognized MIs had >10% increased risk compared with men with recognized MI, women with unrecognized MI had a better prognosis compared with women with recognized MI. This gender difference was observed in former studies
An explanation for this difference between men and women might be the misclassification of unrecognized MI in women. ECG abnormalities that are not caused by coronary artery disease, but can be mistaken for MI, are more often present in women than in men. These abnormalities are possibly caused by difficulties in correctly placing the electrodes because of breast tissue.
Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation.
In agreement with this explanation, we found that the prevalence of unrecognized MI was similar in men and women (6.2% vs 5.3%), while the percentages were far from each other concerning recognized MI (11.5% vs 3.4%). Because of this possible nondifferential misclassification of our unrecognized MI, dilution of the effect might have occurred, and therefore the poor prognosis may have been underestimated in women. Such misclassification is less likely to have occurred for recognized MI, because this diagnosis is also confirmed by clinical information.
We reported that recognized MI was associated with higher cardiovascular mortality in men and women compared with unrecognized MI. It is likely that extensive MIs less often remained unrecognized. In agreement with this conjecture, it has been shown that the infarct size is smaller in unrecognized MI compared with recognized MI.
Quantitative comparison of extent of coronary narrowing and size of healed myocardial infarct in 33 necropsy patients with clinically recognized and in 28 with clinically unrecognized (“silent”) previous acute myocardial infarction.
Therefore, higher cardiovascular mortality in recognized MI may be due to more sever and extensive MI. Another speculation is suboptimal treatment of recognized MI, which can be seen in Table 1. Most of these subjects might have experienced MIs well before the start of this study (1990 to 1993), when coronary revascularization during acute MI was not part of everyday clinical practice. Therefore, the current anticipated improvements in outcomes for recognized MI should not be fully expected in our population.
We report that subjects with unrecognized MIs had significantly higher noncardiovascular mortality. This finding is consistent with those of former studies.
An explanation for the increase in noncardiovascular mortality might be the presence of noncardiovascular morbidities. Such morbidities might lead patients to mistake their infarcts' atypical symptoms for morbidity (e.g., dyspnea in chronic obstructive pulmonary disease) or affect their ability to sense their infarcts (“silent MI”).
We did not report the presence of unrecognized MIs to participants and practitioners until 2002. Therefore, our results reflect in part the situation in the general population, in which a large proportion of MIs remain unrecognized and hence untreated. Since 2002, however, medication use and lifestyles may have changed in those who were still alive as a result of the their awareness about their unrecognized MIs. This may have caused an underestimation of the prognosis of silent MI.
The strengths of our study lie in its large population and long follow-up period. We examined the association separately in men and women and identified gender differences in the prognosis of unrecognized MI. A number of limitations should be acknowledged. First, >500 subjects were excluded from our analysis because of missing electrocardiograms. Given that the missing electrocardiograms were randomly distributed and due mainly to temporary logistic reasons, our results are not likely to have been affected by this problem.
Second, MI on electrocardiography was diagnosed using the MEANS computer program. However, this program has been formerly validated, and diagnoses agree very well with diagnoses made by an experienced cardiologist.
Moreover, any potential misclassification is likely to be nondifferential because MEANS diagnoses were made independent from the prognosis.
Finally, as in a classic cohort study design, we based our analysis only on the status of individuals (recognized or unrecognized MI) at baseline. Given that the follow-up period was rather long (median 15.6 years), this may have caused a nondifferential misclassification of exposure, leading to an underestimation of the effect estimates.
Unrecognized MI remains a problem in clinical practice. It would be worthwhile to search for factors related to the recognition of MI. Such risk factors could help identify those who are more at risk for unrecognized MI and will help more timely recognition of MI cases. In parallel, its diagnosis needs to be improved, especially in the elderly. Given the high prevalence of unrecognized MI in the elderly population and its poor prognosis, studies should investigate to what extent screening for unrecognized MI is feasible, whether it will help reducing mortality rates, and whether it is cost effective or not.
Acknowledgment
We are very grateful to the participants and staff members of the Rotterdam Study, as well as the participating general practitioners and the pharmacists of the Ommoord district, Rotterdam, for help with data collection and validation.
Disclosures
The authors have no conflicts of interest to disclose.
References
Aronow W.S.
Silent MI. Prevalence and prognosis in older patients diagnosed by routine electrocardiograms.
Prognosis after the onset of coronary heart disease. An investigation of differences in outcome between the sexes according to initial coronary disease presentation.
Quantitative comparison of extent of coronary narrowing and size of healed myocardial infarct in 33 necropsy patients with clinically recognized and in 28 with clinically unrecognized (“silent”) previous acute myocardial infarction.
The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University Rotterdam ; the Netherlands Organization for the Health Research and Development ; the Netherlands Organization for Scientific Research (NWO); the Research Institute for Diseases in the Elderly ; the Ministry of Education, Culture and Science ; the Ministry for Health, Welfare and Sports; the European Commission (DG XII) ; and the Municipality of Rotterdam . Dr. Dehghan is supported by Grant VENI 916-12-154 from the NWO and an Erasmus University Rotterdam fellowship . Dr. Leening is supported by Grant 80-82500-98-10208 from the Netherlands Organization for Health Research and Development . Dr. Witteman is supported by Grant VICI 918-76-619 from the NWO.
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