Individuals with diabetes mellitus have been reported to have a 2 to 4 times higher risk of CVD and death than individuals of the same age who do not have diabetes mellitus.2,3
We previously reported that an abnormal exercise test is associated with higher risk of CHD mortality in asymptomatic men and that this relation is evident within different risk factor groups.12
Exercise testing has not been recommended for patients with diabetes mellitus9
because diabetes mellitus is considered a CHD “risk equivalent,” and it has been assumed that little additional information would be obtained from exercise testing. Therefore, the primary aim of the present report was to expand on our previous report12
and to determine whether exercise testing improves risk stratification in men with diabetes mellitus. Our hypothesis was that an equivocal or abnormal exercise ECG in men with diabetes mellitus would be associated with a higher risk of all-cause, CVD, and CHD mortality than among those who had a normal exercise ECG. We observed a direct gradient of mortality risk across normal, equivocal, and abnormal exercise ECG groups, and this remained significant after adjustment for age, smoking, family history of CVD or diabetes, abnormal resting ECG responses, fasting glucose level, CRF, and factors that may be intermediate in the causal pathway between exercise ECG and CHD (body mass index, hypertension, and hypercholesterolemia). A second major finding was that the association between exercise ECG result and CHD generally was consistent within strata of other CHD predictors. The prognostic value of an abnormal exercise ECG was particularly notable in men with other coexisting risk factors at baseline. A third noteworthy issue was that fit men had a higher survival rate than unfit men within each category of exercise ECG outcome.
Because of their propensity for silent ischemia, patients with diabetes mellitus may require special consideration. Callaham et al10
studied 1747 US veterans with diabetes and showed that exercise-induced ST-segment depression was associated with more CVD events during a mean 2 years of follow-up. Weiner et al11
reported that 45 patients with diabetes mellitus who had exercise-induced silent ischemia had worse outcomes in terms of CVD events than persons without diabetes mellitus but with silent ischemia. May and colleagues23
estimated the prevalence of maximal symptom-limited bicycle ergometer exercise-induced silent ischemia in those with diabetes mellitus was 13.5%. In the present study, ≈20% of men with diabetes had abnormal or equivocal exercise ECG responses. Thus, those with diabetes mellitus and an abnormal ECG may potentially benefit from further attention.
Our finding on the positive relation between abnormal exercise ECG results and higher risk for CHD mortality are in concert with other population-based studies of asymptomatic men with other CVD risk factors.4–7
Laukkanen and colleagues4
examined 1769 middle-aged men using a maximal symptom-limited exercise stress test and found that exercise-induced silent ischemia was associated with adverse outcome largely in those who were at high risk of developing CHD because of the presence of smoking, hypercholesterolemia, or hypertension. The Framingham Heart Study Offspring Study evaluated 3043 asymptomatic men and women, all of whom underwent a symptom-limited exercise test and were followed up for 18.2 years.5
ST-segment depression provided additional prognostic information in age- and Framingham risk score-adjusted models in men, particularly among those in the highest-risk group (10-year predicted CHD risk ≥20%).5
Bruce et al6
found a 3-fold higher risk of CHD among patients with 1 or more risk factors and 2 or more abnormal features on exercise testing. Rywik et al7
reported that abnormal exercise ECG responses (≥1 mm horizontal or downsloping ST-segment depression) were associated with a doubling of risk for CHD events. However, some studies have failed to confirm a positive relation between abnormal exercise ECG testing and CHD outcomes.8
For example, Bodegard et al8
found that impaired breathing, not the exercise ECG result, predicted a high long-term risk of CHD mortality.
A few previous studies have reported the usefulness of exercise testing for predicting CHD in patients with diabetes mellitus.24,25
Elhendy et al24
evaluated the importance of exercise echocardiography for risk stratification of such patients with known or suspected ischemic heart disease. A total of 563 patients underwent symptom-limited treadmill testing that involved 1 of the 3 following protocols: Bruce, Naughton, or modified Bruce. Their data indicated that patients with diabetes mellitus who had an abnormal stress echocardiogram were at greater risk of death or nonfatal myocardial infarction than those with a normal stress echo-cardiogram.24
Lee and colleagues25
sought to determine the characteristics of exercise treadmill testing in patients with diabetes who had angina. They conducted a retrospective analysis of exercise test results in 1282 men who had undergone coronary angioplasty and were without prior myocardial infarction. They concluded that a standard exercise test has similar diagnostic characteristics in patients with diabetes mellitus and in those free of the disease.
Exercise testing is also an important predictor of survival. Prakash et al26
tested 6213 men referred for a standard maximal exercise ECG treadmill test because of complaints of angina or because they had risk factors or signs or symptoms of CHD. They found that abnormal exercise ECGs were significantly more common in those who died during follow-up, and exercise capacity (< 5 METS) was independently and significantly associated with all-cause mortality. The present findings are consistent with this report: Men with higher CRF levels have a higher survival rate than unfit men, and an abnormal exercise ECG is associated with an increased risk of all-cause mortality. These findings further demonstrate the prognostic power of exercise testing, including both the ECG response and the CRF assessment.
Results from the Aerobics Center Longitudinal Study have shown that low levels of CRF are independently associated with increased mortality in men with diabetes mellitus.2,27,28
In the present investigation, we found that men with diabetes who were unfit but had normal ECG testing had lower CHD mortality risk than men with diabetes who were fit but had equivocal or abnormal ECG testing. This finding further demonstrates the prognostic power of the exercise ECG response even in fit men with diabetes mellitus. Strengthening the public health importance of our findings, we observed that 26% of unfit men with diabetes had normal exercise ECG tests, which provides further evidence for the importance of the exercise ECG. To the best of our knowledge, no studies have examined the joint association of exercise ECG results and exercise capacity on CHD risks in men with diabetes mellitus. The present results provide evidence of an intrinsic value in encouraging healthcare professionals to perform a treadmill test to determine diabetic patients’ CRF level and exercise ECG response, which may guide both physical activity counseling and CHD prevention efforts.
Strengths of the present study include the extensive baseline examination to detect subclinical disease, the use of measured risk factors, the variety of mortality end points, the relatively long follow-up (average 15 years), the broad age range of the study population (from 21 to 82 years), and the fact that we studied the prognostic impact of an exercise ECG stress test. In the present study, all stress tests were maximal tests, and ECGs were monitored continually with 12 leads for 10 minutes after the conclusion of each test.12,17
Therefore, our methods ensured that we would capture most, if not all, abnormalities that may have occurred.
One limitation of the present study was the absence of data documenting the duration of diabetes in the study subjects. However, the literature shows that half of the prevalent cases of diabetes mellitus are undiagnosed and exist in patients without typical clinical symptoms.29
Similarly, in the present report, it is difficult to know exactly when these men were diagnosed with diabetes mellitus. Although it is impossible for us to directly assess the impact of the duration of diabetes on the results, we did adjust the examination year when they were identified as having diabetes mellitus. Although we were unable to separate individuals with type 1 versus type 2 diabetes mellitus, previous reports suggest that >90% of adults with diabetes have type 2 diabetes.30
Because the present study consisted of middle-aged men, we suspect most of the cases were type 2 diabetes. Another limitation was the predominantly white, well-educated, middle- to upper-class, and male subject group, which limits the ability to generalize the results of the present study. However, this should not affect the internal validity, and no strong reason exists to assume that the benefits of exercise testing would be any less in women or other ethnic groups. Our previous studies have shown, in analyses in which enough deaths occurred for parallel analyses in women and men, that the inverse gradient of mortality across exercise capacity is similar for the 2 sexes.20,21,28,31
We do not have enough information for Duke treadmill score calculations. The present study did not have information on medication usage, dietary habits, hemoglobin A1C levels, or presence of end-organ damage to include these in our analysis. Although mortality data were primarily obtained from the National Death Index, which has established validity, the possibility still exists of misclassification of CVD and CHD deaths. However, these issues of death certificate analyses are not relevant for all-cause mortality, which in the present study showed results similar to CVD and CHD mortality. The consistency of results for all-cause, CVD, and CHD mortality is reassuring, and therefore, we do not think these issues would cause major misinterpretation of the data. Finally, we do not have available information on the sensitivity of the ECG test. Future studies are needed to include these data to confirm the findings reported here.
In conclusion, abnormal exercise ECG response is a significant determinant of CHD mortality in men with diabetes mellitus. Assessment of exercise ECG by maximal stress testing provides important prognostic information independent of CRF level and traditional CHD risk factors. Exercise stress testing to determine both ECG responses and CRF may be used as a tool for potential CHD risk stratification in men with diabetes mellitus. We encourage clinicians to further consider the diagnostic value of maximal exercise ECG tests for this high-risk group of men.
Although exercise testing is proven to have prognostic value, studies that examine the relationship between exercise ECG (E-ECG) responses and coronary heart disease (CHD) mortality risk in asymptomatic men with existing cardiovascular disease risk factors are inconsistent. Most studies have shown a positive association in high-risk subgroups, although others have not. However, these studies have not focused on individuals with diabetes mellitus, which is considered a CHD risk equivalent. Therefore, the primary aim of our study was to evaluate the relationship between E-ECG testing and CHD mortality in a large population of asymptomatic men with diabetes mellitus. We examined the association between E-ECG responses and mortality in men with documented diabetes who completed a maximal treadmill exercise test and were without a previous cardiovascular disease event at baseline. We observed a direct gradient of mortality risk across normal, equivocal, and abnormal E-ECG groups that remained significant after adjustment for age, smoking, family history of cardiovascular disease or diabetes mellitus, abnormal resting ECG responses, fasting glucose level, cardiorespiratory fitness, and factors that may be intermediate in the causal pathway between E-ECG and CHD (body mass index, hypertension, and hypercholesterolemia). A second major finding was that the association between E-ECG result and CHD generally was consistent within strata of other CHD predictors. A third noteworthy issue was that fit men had a higher survival rate than unfit men within each category of E-ECG outcome. Our data suggest that abnormal E-ECG response is a significant determinant of CHD mortality in men with diabetes mellitus.