Unrecognized myocardial infarction is diagnosed objectively using thallium perfusion imaging, radionuclide angiography, or echocardiography; it is most often diagnosed from typical, unequivocal changes on the electro-cardiogram of a patient with symptoms so atypical that neither patient nor physician recognizes the problem as an infarction. Atypical and silent myocardial infarction have traditionally been grouped together as unrecognized myocardial infarction. Patients with silent myocardial infarction seemingly have no symptoms. Half of all patients with unrecognized myocardial infarction recall no symptoms and have therefore had silent myocardial infarctions; the remainder have had atypical myocardial infarctions [8, 9]. Silent myocardial ischemia as an important manifestation in patients with coronary heart disease has been studied in recent decades and clearly affects prognosis unfavorably [10, 11]. Because the prognosis for patients with unrecognized myocardial infarction seems to be as serious as that for patients with recognized myocardial infarction [12, 13], practicing physicians face considerable diagnostic and therapeutic challenges when dealing with the many patients with this condition. Not only is it difficult to choose methods with which to identify these patients, it is also difficult to make decisions about secondary prevention and medical treatment. Detailed knowledge about this disease entity is therefore important and must include a thorough understanding of which patient subgroups are especially vulnerable.

We report the results of a long-term study of a population-based cohort participating in the Reykjavik Study. Our purpose was to determine the incidence, prevalence, and prognosis associated with unrecognized myocardial infarction. We evaluated the risk factor profile for patients with unrecognized myocardial infarction compared with that of patients with recognized myocardial infarction, as well as the prognostic role of angina pectoris in persons with unrecognized myocardial infarction.

Methods

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The design of the Reykjavik study has been described previously [6], and only a brief description is included here. The study is a large population-based cohort study that started in 1967. Men living in the Reykjavik area who were born between 1907 and 1934 were invited to participate. The study has been conducted in several stages: 1967-1968, 1970-1971, 1974-1975, 1979-1980, and 1983-1987. The response rate has varied from 64% to 75%. Since 1969, women have also participated in the study, but their results will be the subject of a separate report. Each participant answered a questionnaire that included the Rose chest pain questionnaire used by the London School of Hygiene and Tropical Medicine [14]; was examined by a physician; and had a standardized 12-lead electrocardiogram recorded and evaluated according to the Minnesota Code [15]. A total of 9141 men participated in the study at least once. Since 1981, data on the incidence of myocardial infarction have been collected as part of the World Health Organization MONICA Project [16]. Hospital records for persons who had had myocardial infarctions before 1981 were reviewed and evaluated according to criteria used in the MONICA study.

Causes of death were determined from all death certificates from the start of the study until 31 December 1987. All autopsy records were also reviewed (autopsy rate, 55%).

Diagnostic categories were defined as follows:

1. Recognized myocardial infarction: Patients who fulfilled the MONICA criteria for definite myocardial infarction [16] were placed in this category. These criteria include electrocardiographic changes (Minnesota codes 1.1.1-1.2.8); typical, atypical, or inadequately described symptoms together with probable electrocardiographic changes and abnormal enzyme levels; and typical symptoms and abnormal enzyme levels with ischemic or noncodable electrocardiographic results.

2. Unrecognized myocardial infarction: Participants in this category had no history or symptoms of heart attack but had electrocardiographic changes that fulfilled the criteria for definite myocardial infarction results (Minnesota codes 1.1.1-1.2.8).

3. Angina pectoris with electrocardiographic manifestations of myocardial ischemia: Participants who fulfilled the Rose questionnaire criteria for angina pectoris and who had either ischemic electrocardiographic results (Minnesota codes 1.3.1-1.3.6, 4.1-4.4, 5.1-5.4) or normal resting electrocardiographic results with a positive exercise stress test result ( 0.2 mV horizontal or down-sloping ST depression) were placed in this category.

4. Angina pectoris with normal resting electrocardiographic results: Participants with normal resting electrocardiographic results who either had normal exercise test results or had had no exercise test were assigned to this category if Rose questionnaire results indicated angina pectoris and if the examining physician could confirm the diagnosis.

5. Angina pectoris by the Rose questionnaire only: Participants fulfilling the Rose questionnaire criteria for angina pectoris, if their electrocardiograms did not indicate ischemia and the investigating physician could not confirm the diagnosis, were placed in this category.

6. No coronary heart disease: Participants in this category had no history or electrocardiographic manifestations of myocardial infarction.

Patients were classified as having recognized myocardial infarction (category 1) on the basis of hospital records. Classification into the other diagnostic categories, including that of unrecognized myocardial infarction, was based on data collected at set intervals when patients attended the study clinic.

Statistical Methods

Three designs were used. In the first, a cross-sectional study, logistic regression was used to compute the prevalence odds of unrecognized myocardial infarction as a function of age and calendar year. It was also used to estimate the dependence of unrecognized and recognized myocardial infarction on simultaneous values of measured variables.

In the second design, a prospective study, Poisson regression was used to compute the incidence of unrecognized myocardial infarction as a function of age and calendar year. It was also used to compute the predictive power of the measured variables for future unrecognized and recognized myocardial infarction. In these computations, consecutive visits were paired and each pair was used; pairs of visits were excluded if myocardial infarction had been diagnosed during the former visit. The risk period was the time elapsed between two visits (3 to 6 years), and age was the participant's age halfway between the visits.

In the third design, a prospective study of survival, Cox regression was used to estimate the simultaneous predictive power for risk for death (cause-specific or from all causes). ß-coefficients were calculated to investigate the prognostic value of risk factors and to form a composite score for individual persons. The composite risk score was the product sum of ß-coefficients and values of risk factors.

Significance testing was two-sided and based on a 5% probability level. The software package used was EGRET (Epidemiologic Graphics, Estimation and Testing) [17].

Results

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Prevalence and Incidence

The overall prevalence of unrecognized myocardial infarction in the first stage of the study was 0.5% in 1968 and 0.4% in 1971, and it increased in later stages of the study. In 1975 and 1980 it was 1.0% and 1.3%, respectively, and in the last stage, in 1986, it was 2.8%. To adjust for changes in age in the participants during the study period, we used logistic regression in which the prevalence odds were modeled as a function of age and either stage number or calendar year. As shown in Figure 1, prevalence increased steeply after age 60 years; it was 0.5% at age 50 years but exceeded 5% at age 75 years. The odds ratio per year was 1.10 (95% CI, 1.07 to 1.12). There was no significant time trend when the computation of prevalence was limited to the first visit of each participant, thus eliminating the bias introduced by the diagnosis of the previously unrecognized infarction.

View larger version (12K): [in this window] [in a new window]   Figure 1. The prevalence of unrecognized myocardial infarction as a function of age. Results of a logistic regression analysis of prevalence odds. The odds ratio per year was 1.10 (95% CI, 1.07 to 1.12).

The incidence rate was obtained from the prospective study using a Poisson regression. The only explanatory variables tried at this stage were age, age squared, and calendar time. The incidence rate did not depend significantly on calendar time. Figure 2 shows that incidence was almost zero before age 40 years and increased steeply from age 40 years to age 60 years, at which it exceeded 300 per year per 100 000 persons. After age 65 years, the incidence rate decreased with age. The odds ratio for age (per year) was 2.06 (CI, 1.23 to 3.46); for age squared it was 0.994 (CI, 0.990 to 0.999). This was a significant (P < 0.05) contribution by age squared to the explanation of the incidence rate and indicated a decrease in the incidence rate of unrecognized myocardial infarction after age 65 years (Figure 2).

View larger version (43K): [in this window] [in a new window]   Figure 2. Incidence of unrecognized myocardial infarction as a function of age. Poisson regression. Each bar represents the annual number of cases per 100 000 persons. The odds ratio for age was 2.06 per year (95% CI, 1.23 to 3.46) and for age squared was 0.994 per year (CI, 0.990 to 0.999).

Risk Factor Profile

Table 1 compares the mean values of some of the baseline characteristics of the cohort that had unrecognized myocardial infarction with those of the cohort that had recognized myocardial infarction. Although more participants with recognized than with unrecognized myocardial infarction were treated for high blood pressure and diabetes mellitus, the differences were not significant. Age and cholesterol, triglyceride, blood glucose, and blood pressure levels were similar in both groups. Differences in smoking habits were not significant.

Table 2 lists the factors that were shown by logistic regression to correlate significantly with both unrecognized and recognized myocardial infarction. The correlation of the two types of myocardial infarction with these variables was similar, except that impaired glucose tolerance (blood glucose levels 90 minutes after oral glucose load) and therapy with digoxin were significantly associated with recognized but not with unrecognized myocardial infarction. Unrecognized and recognized myocardial infarction were both strongly associated with angina pectoris; the odds ratios were 4.7 and 9.3, respectively. Both correlated significantly with age, smoking, serum cholesterol level, cardiomegaly (heart volume > 550 mL/m²), and therapy with diuretic drugs.

Poisson regression multivariate analysis was used in a prospective study to compute the predictive power of the included variables for future unrecognized and recognized infarction. Table 3 shows that age, cholesterol levels, antihypertensive medication, diastolic blood pressure, and smoking were all significantly associated with an increased risk for unrecognized myocardial infarction. Patients with angina pectoris had an increased risk compared with those who had no manifestations of coronary heart disease. Those who had angina pectoris according to the Rose questionnaire had only a 1.8-fold risk for unrecognized infarction (CI, 0.6 to 5.7), and those displaying ischemic electrocardiographic changes had a 3.8-fold risk (CI, 1.5 to 9.5).

Angina Pectoris and Unrecognized Myocardial Infarction

Thirty-four percent (CI, 24% to 45%) of participants with unrecognized myocardial infarction had a history of angina pectoris at the first visit to the clinic compared with 58% (CI, 50% to 66%) of those with recognized myocardial infarction (P < 0.001). Of those patients with unrecognized myocardial infarction who also had angina pectoris, 82% had angina with ischemic electrocardiographic changes, 4% had angina without electrocardiographic changes, and 14% had angina pectoris according to the Rose questionnaire only. The corresponding figures for patients with recognized myocardial infarction were 55%, 29%, and 16%, respectively.

Prognosis

Life-table analysis was done for participants in the first four stages of the study who had either unrecognized or recognized myocardial infarction. The 10- and 15-year survival probabilities with respect to death from coronary heart disease among patients with unrecognized myocardial infarction were 49% and 45%, respectively; for patients with recognized myocardial infarction, these probabilities were 62% and 48%, respectively (Figure 3). Coronary heart disease was the predominant cause of death for patients with unrecognized myocardial infarction, accounting for 87% of deaths, but it caused 80% of deaths among patients with recognized myocardial infarction (Table 4).

View larger version (11K): [in this window] [in a new window]   Figure 3. Survival probability (with respect to coronary heart disease mortality) of participants in the first four stages of the study having had either recognized or unrecognized myocardial infarction. Also shown are the number of patients at risk after 3, 6, 9, and 12 years. 95% confidence intervals are shown for 5- and 10-year survival. MI = myocardial infarction.

The subsequent clinical course of unrecognized myocardial infarction at the ensuing stage of the Reykjavik study, when all participants were reclassified on the basis of clinical and electrocardiographic data obtained at that stage, is shown in Figure 4. Only 1% of patients were classified as having recognized myocardial infarction. Twelve percent were classified as having angina with or without ischemic changes because they no longer fulfilled the electrocardiographic criteria for definite myocardial infarction; this was also true for the 12% classified as having no manifestations of coronary heart disease. The nonattendance rate was 14% among those with unrecognized and 18% among those with recognized myocardial infarction. Furthermore, the mortality in these two groups was similar between two successive visits, ranging from 25% to 26%.

View larger version (32K): [in this window] [in a new window]   Figure 4. The subsequent clinical course of those who had an unrecognized myocardial infarction. Reclassification at the ensuing stage of the Reykjavik Study based on clinical and electrocardiographic data obtained at that stage.

Table 5 shows the relative risk for death from coronary heart disease and from all causes in the different categories of coronary heart disease after adjustment for differences in risk factors (composite risk). The presence of angina pectoris had an especially serious effect on the risk for death, either from coronary heart disease or from all causes, in those who had unrecognized myocardial infarction. The relative risk for death from coronary heart disease increased from 4.6 (CI, 2.4 to 8.6) in patients with unrecognized myocardial infarction and no angina to 16.9 (CI, 9.4 to 30.3) in patients with unrecognized myocardial infarction and angina. The relative risk for death from coronary heart disease in patients with recognized myocardial infarction increased from 6.3 (CI, 3.7 to 10.6) if angina was not present to 8.5 (CI, 5.8 to 12.6) if the patients had a history of angina pectoris.

Discussion

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The reasons why some patients with myocardial infarction present with atypical or no symptoms is unknown. Various theories about possible mechanisms have been discussed. Autonomic neuropathy with altered peripheral nervous function has been suggested as an explanation for the increased incidence of silent myocardial infarction and sudden death associated with diabetes mellitus [5, 18-20]. However, the results of many epidemiologic studies have not confirmed that diabetic patients are more prone to silent myocardial infarction than are other persons [4, 12, 21]. Some correlation seems to exist between silent myocardial ischemia and silent myocardial infarction. Droste and colleagues [22, 23] showed that patients with silent ischemia have a higher pain tolerance to various noxious stimuli (cold, electrical shock, and pressure) than do patients with typical angina pectoris, and they concluded that patients with silent ischemia have altered sensitivity to pain in general. Earlier, Cohn [24] suggested that patients with silent myocardial ischemia have a defective anginal warning system and that humoral, neurologic, psychological, and sociologic factors were all involved in the symptoms arising from myocardial ischemia.

Among the symptoms shown to be associated with unrecognized myocardial infarction are dyspnea, nonproductive cough, fatigue, abdominal or epigastric pain, nausea and vomiting, syncope, and palpitations [8, 13, 25].

Prevalence and Incidence

In the Reykjavik Study, about 30% of myocardial infarctions are unrecognized [6]. Results from other population studies have shown that between 20% and 60% of all myocardial infarctions are unrecognized [2-5, 7, 13]. Prevalence is strongly dependent on age. It is nearly undetectable in the youngest age group and increases exponentially with age to more than 5% in the group aged 75 to 79 years, in which 47% of all infarctions are unrecognized. Incidence was almost zero for those younger than age 40 years and increased steeply from age 40 years to more than 300 cases per year per 100 000 persons at age 60 years. After age 65 years, incidence decreased with age. However, both incidence and prevalence are probably underestimated; it has been shown that the typical electrocardiographic changes used to establish the diagnosis of unrecognized myocardial infarction frequently disappear with time, often within 1 to 2 years [5, 13, 26]. Furthermore, more patients with unrecognized myocardial infarction died before reaching the next stage of the study than did the remainder of the cohort. This could at least partly explain the decline in incidence rate after the age of 65 years, as the observations for this age group were primarily confined to the 6-year interval between stages 4 and 5. The Bronx Aging Study, which began in 1980 and studied patients aged 75 to 85 years, found that 6.4% of its participants had evidence of unrecognized myocardial infarction at study entry [27].

The Israeli Heart Attack study followed 9509 healthy adults for 5 years [4]. Half of those with unrecognized myocardial infarction (85 of 170) did not recall any symptoms or illness and were thought to have had silent myocardial infarctions. The same results were seen in the Framingham study, in which 53% of patients with unrecognized myocardial infarction had silent infarction and 47% had some atypical symptoms [8]. The annual incidence rates in the Israeli Heart Attack study were between 300 and 460 cases per 100 000 persons [4]; in the Framingham study, 130 unrecognized myocardial infarctions occurred among the 2252 men studied, translating into an annual incidence rate of 192 cases per 100 000 persons [8, 13]. These studies show higher incidence rates than did our study, probably because of differences in study design.

Prognosis

Along with the results from many other epidemiologic studies, our results show that the prognosis for patients with unrecognized myocardial infarction is no better than that for patients with recognized myocardial infarction [3, 5]. In contrast, the Israeli Heart Attack Study found annual mortality rates of 17.3 deaths per 1000 persons with unrecognized myocardial infarction and 36.3 deaths per 1000 persons with recognized myocardial infarction [4]. Ten years after detection, 42% of men with unrecognized myocardial infarction in the Framingham cohort were still alive [13]; the 10-year survival probability in our study was 51%.

Angina pectoris seems to affect the risk for death among those having had either recognized or unrecognized myocardial infarction. As shown in Table 5, the combination of angina pectoris and unrecognized myocardial infarction is associated with the worst prognosis, even after accounting for the unfavorable risk factor score. Although angina also adds to the risk for death of persons with recognized myocardial infarction, the 95% CIs for recognized myocardial infarction with and without angina overlap substantially.

It is interesting that only 1% of those with unrecognized myocardial infarction had a recognized myocardial infarction between two succeeding stages in the study (Figure 4). Furthermore, 12% were classified at their next visit as having no coronary heart disease because the electrocardiographic changes used to make the diagnosis had disappeared.

Angina Pectoris and Unrecognized Myocardial Infarction

In the Reykjavik Study, 34% (CI, 24% to 45%) of patients with unrecognized myocardial infarction fulfilled the Rose questionnaire criteria for angina pectoris and 80% of those had electrocardiographic changes indicative of myocardial ischemia. In comparison, 50% of the 58% (CI, 50% to 86%) with angina and recognized myocardial infarction had ischemic electrocardiographic changes. Again, a difference in pain perception between those with recognized and those with unrecognized myocardial infarction is suggested. As previously discussed, those with unrecognized myocardial infarction and angina have an exceptionally poor prognosis, suggesting a particularly severe form of coronary heart disease.

Differences in the prevalence of angina pectoris between those with unrecognized and those with recognized myocardial infarction have been shown in other epidemiologic studies. In the Framingham study, 10.5% of men with unrecognized and 53.4% of those with recognized myocardial infarction also had angina [13]. The Honolulu, Hawaii, Heart Program also showed a lower prevalence of angina pectoris among those with unrecognized myocardial infarction [5].

Risk Factor Profile

With the exception of history of angina pectoris, the Reykjavik Study detected no major differences between the risk factor profiles of those with recognized and those with unrecognized myocardial infarction. Other studies have presented controversial results. The Framingham Study found that the major risk factors predisposing patients to recognized and unrecognized myocardial infarction were largely the same [12]. However, they also showed that diabetes, hypertension, and abnormal electrocardiograms were associated with increased incidence of unrecognized myocardial infarction. This association was not statistically significant and was attributed to the small number of patients (n = 130) studied [13]. In the Israeli Heart Attack Study, 170 cases of unrecognized myocardial infarction in men were studied [4]. In a multivariate analysis, age, left axis deviation, left ventricular hypertrophy, systolic or diastolic blood pressure, peripheral vascular disease or intermittent claudication, and smoking were significantly associated with increased risk for unrecognized myocardial infarction, but diabetes was not [4]. In the Honolulu, Hawaii, Heart Program, certain differences were found when patients with recognized and unrecognized myocardial infarction were compared [5]. Patients with unrecognized myocardial infarction were more likely to be hypertensive, to have diabetes or impaired glucose intolerance, and to smoke cigarettes, but they were less likely to have angina pectoris or hypercholesterolemia. However, these differences were not statistically significant.

The atypical, sometimes totally silent presentation of unrecognized myocardial infarction and the severe prognosis associated with it present a diagnostic and therapeutic challenge to practicing physicians. This is highlighted by recent successes in secondary prevention of coronary heart disease [28]. No consensus has been reached about when and how to search for unrecognized myocardial infarction in the general population and no policy statements have addressed this issue; further research is clearly needed. However, the grave prognosis for patients with unrecognized myocardial infarction and angina pectoris supports the current practice of obtaining regular electrocardiograms from patients with known coronary heart disease. Although our study Figure 4 and several others [5, 13, 26] have shown that typical electrocardiographic changes often disappear with time, limiting the ability of electrocardiography to detect remote myocardial infarction, we would suggest that an electrocardiogram at least be part of the clinical workup offered to any patient with known risk for coronary heart disease and any symptoms, however atypical, that might indicate myocardial infarction.

Conclusions

Our results show that at least one third of all myocardial infarctions among Icelandic men are unrecognized. The risk factor profiles for those with unrecognized and recognized myocardial infarction are largely the same. Those with unrecognized myocardial infarction were less likely to have had angina pectoris, but when they did, the angina was usually associated with ischemic electrocardiographic changes. This might indicate altered pain perception. Furthermore, angina was a marker of worse prognosis. Our results confirm the finding from several other epidemiologic studies that although the presenting symptoms of this form of coronary heart disease may be trivial, the prognosis for patients who have it is similar to that for patients with recognized myocardial infarction. These patients present a diagnostic and therapeutic challenge to practicing physicians and once they are diagnosed they should be given every possible preventive therapy.