Background
Diabetes mellitus (DM) is a major risk factor for cardiovascular morbidity and mortality [
1‐
5]. Accordingly, both the American Heart Association and American College of Cardiology define DM as an equivalent to previous coronary artery disease (CAD) for cardiovascular risk [
5]. When associated with other cardiovascular risk factors, DM increases the rate of macrovascular complications.
The mean annual mortality rate of asymptomatic patients with multiple cardiovascular risk factors is 3% [
6]. In diabetic patients, chronic CAD frequently presents reduced subjective symptoms, unless ventricular dysfunction is present [
7]. Recognition of subclinical ischemic disease in diabetic patients and stratification of risk are important to select therapeutic interventions and to reduce the complications of cardiac events [
2,
7‐
10].
Exercise echocardiography (EE) is a valuable method for diagnosis, risk stratification and prognosis of CAD [
3,
11‐
14]. This technique has the advantages of wide availability, safety and low cost, provides information on left ventricular function, exercise capacity, and presence, location and extension of wall motion abnormalities [
15]. The sensitivity of EE to detect coronary arteries obstructions varies between 70 and 100% [
15,
16]. EE is similar to myocardial perfusion scintigraphy in diagnosing CAD and even superior in determining its extension [
15]. This is particularly relevant, as the extension of ischemia and the severity of wall motion abnormalities are considered independent and cumulative predictors of prognosis in patients with CAD [
3,
9].
The aim of the present study was to evaluate the prognostic value of EE in diabetic patients.
Discussion
Identification of patients with subclinical disease and high risk of future cardiac events occurrence is a strategy that aims to reduce the risk of complications of CAD [
2,
8]. The value of EE in prognostic stratification of diabetic patients with known or suspected CAD has been previously reported [
3,
27].
In the present study, the number of positive EE was higher than reported in the general population [
14], confirming the higher risk of CAD in diabetic patients. A higher number of patients with normal EE reached above maximal age-predicted heart rate (P = 0.004). Patients with ischemic EE presented higher levels of WMSI at rest and during peak of exercise (P < 0.0001). Resting ejection fraction was lower in diabetics with positive EE (0.64 ± 0.07 vs. 0.66 ± 0.05, P = 0.01), although both fell within normal values, suggesting that the G1 group did not have heart failure.
The rate of cardiac events was higher in patients with ischemic EE in comparison to those with a normal result, despite comparable metabolic control. In a similar study, Elhendy et al. [
3] followed up 563 diabetic patients with known or suspected ischemic heart disease who underwent EE for a median period of three years. Fifty patients (9%) experienced cardiac events during the follow-up. Similar to our study, the rate of events was higher in patients with positive EE, in comparison to patients with normal results (11.9%
vs. 1.8% in three years). The frequency of hard events was higher than ours, possibly related to the socio-economic profile of our patients, with access to private health insurance services and high quality of medical care. Alternatively, the high number of LMR may have reduced the number of hard events in our group. In their study, none of the patients with normal EE presented cardiac events in the first two years of follow up. However, the rate of events increased gradually after two years, achieving 7.6% by the end of the fifth year. Our patients behaved similarly, since in patients with normal EE only one event occurred during the first year of follow-up, and the rate of events increased gradually after the second year and reached 15.8% by the end of the fifth year. The authors related this finding to progression of ischemic disease and recommended repeating EE after two years, as a strategy for reassessing the risk status of patients with an initial normal result. Our data suggest that it is better to repeat the EE each year, because one MI occurred 10 months and one LMR 12 months after a normal EE. We also found by multivariate analysis that sedentary lifestyle and positive EE were predictors for cardiac events, while to Elhendy et al., MI, ejection fraction at rest, and percentage of ischemic segments during exercise were the most important predictors [
3].
Garrido et al. [
11] assessed the value of EE for prediction of cardiac events in 214 patients with DM. Twenty-eight developed cardiac events (15 cardiac deaths and 13 MI) during a follow-up of 44 ± 16 months. This study described the following independent risk factors as predictor of future cardiac events: use of insulin, ventricular ejection fraction in peak exercise and, similar to our study, myocardial ischemia detected by EE. More recently, Cortigiani et al. [
28] studied the prognostic value of pharmacological stress echocardiography in 149 diabetic and 786 non-diabetic patients with chest pain and intermediate to high threshold positive exercise results, with a median follow-up of 26 months. They recorded 51 deaths, 29 MI and 79 LMR, with a rate of major events of 26% in diabetics, higher than our global rate of 13.5%, probably due to more severe cardiovascular disease in the entry of that study. They concluded that a non-ischemic test predicts a 6-month period free of major events, and a 2% major event rate at 1-year-follow-up in both populations, with marked increase of major events rate in diabetic patients afterwards. These data are in agreement with our finding of a gradual increase in risk after the second year and a 15.8% rate by the end of the fifth year.
Sozzi et al demonstrated that an abnormal dobutamine stress echocardiography was associated with a higher mortality compared with a normal dobutamine stress echocardiogram (p = 0.03) in asymptomatic diabetic patients with no previous CAD [
27].
The last consensus of stress echocardiography experts [
29] stated that inducible myocardial ischemia in echocardiography by physical or pharmacological stress present a comparable prognostic value. It has also been suggested that patients with ischemic left ventricular dysfunction and a significant amount of viable myocardium have better prognosis, with lower perioperative mortality, greater improvements in global and regional left ventricular function and higher long-term survival after revascularization than patients with non-viable myocardium. In addition to that, coronary flow reserve and wall motion analysis offer complementary data during stress echocardiography. The combination of these two parameters improves the prognostic value. A reduced coronary flow reserve is a parameter of ischemic severity in risk stratification of EE response whereas patients with a negative test for wall motion criteria and normal coronary flow reserve have a favorable outcome during dypiridamole stress echocardiography.
At this moment, our echocardiography laboratory has a larger data base than the one used in this manuscript, and a research is currently being developed concerning prognostic value of EE in all the patients, diabetic and non-diabetic. Therefore, in this study, we cannot assess the impact of revascularization procedures in both groups. Previous reports demonstrated that diabetic patients with a normal EE result present worse outcomes in comparison to their age-matched non-diabetic counterparts [
30]. In addition to that, Cortigiani et al found abnormal coronary flow reserve in the left anterior descending to be a strong, independent and additive prognostic indicator in a large cohort of diabetic and non-diabetic patients with known or suspected CAD and negative dypiridamole stress echocardiography. Thus, a negative test was less prognostically benign in diabetic patients than in age-matched non-diabetic patients [
31].
Our study has some important limitations. One is the lack of data on the duration of DM. Second, the group of diabetics studied was formed by middle-class patients, with access to private health insurance services. Therefore, the results of this study may not be valid to populations of different socio-economic backgrounds. Third, post-test bias could not be eliminated, since the EE results were available to the treating physicians. Therefore, a test result positive for myocardial ischemia may have influenced the decision of performing myocardial revascularization, so that patients with a higher risk may have undergone revascularization, possibly reducing the rate of hard events. In addition, positive results in EE may have influenced in the choice of medication for these patients, also reducing the possibility of occurrence of cardiac events. These interventions, however, would reduce rather than increase the risk of ischemic events. Finally, we cannot rule out that a subset of subjects that we could not locate may have died. However, the prevalence of normal and abnormal EE in this group was almost identical, making it unlikely that this factor may have altered significant our findings.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors contributed to this work, read and approved the final manuscript.