Prognostic Value of an Exaggerated Exercise Blood Pressure Response in Patients With Diabetes Mellitus and Known or Suspected Coronary Artery Disease
Article Outline
The prognostic value of an exaggerated exercise systolic blood pressure response (EESBPR) remains controversial. Our aim was to assess whether an EESBPR is associated with the long-term outcome in patients with diabetes mellitus and known or suspected coronary artery disease (CAD). From an initial population of 22,262 patients with known or suspected CAD who underwent treadmill exercise electrocardiography or exercise echocardiography at our institution, 2,591 patients with a history of diabetes mellitus were selected for the present study. EESBPR was defined as systolic blood pressure >220 mm Hg during exercise. The end points were all-cause mortality and hard events (ie, death or myocardial infarction). A total of 236 patients (9.1%) developed an EESBPR during the tests. During a mean follow-up of 6.5 ± 3.9 years, 484 patients died and 646 experienced hard events. The 10-year mortality rate was 16.6% in patients with an EESBPR compared to 30.9% in those without an EESBPR (p <0.001). The 10-year hard event rate was also lower in patients with an EESBPR (23.2% vs 38.9% in patients without an EESBPR; p <0.001). On multivariate analysis, an EESBPR remained independently associated with a lower risk of all-cause mortality (hazard ratio 0.53, 95% confidence interval 0.36 to 0.78, p = 0.001) and hard events (hazard ratio 0.57, 95% confidence interval 0.41 to 0.79; p <0.001). These results remained consistent in the subgroup of patients without a known history of CAD. In conclusion, an EESBPR was associated with improved survival and a lower rate of death or myocardial infarction in patients with diabetes mellitus and known or suspected CAD.
Hypertension at rest is a well-established risk factor for cardiovascular events, particularly in patients with diabetes mellitus (DM).1 The prognostic value of exercise hypertension, however, remains controversial. Although some studies have found an association of an exaggerated exercise blood pressure (BP) response with future hypertension2, 3, 4, 5, 6, 7, 8 and cardiovascular events5, 9, 10, 11 in healthy subjects, studies evaluating patients with known or suspected coronary artery disease (CAD) have reported conflicting results.12, 13, 14 Furthermore, whether exercise hypertension provides prognostic information in patients with DM remains unexplored. Our aim was to assess the value of an exaggerated exercise systolic BP response (EESBPR) for predicting mortality and cardiac events in patients with DM and known or suspected CAD.
Methods
From June 1, 1994 to March 31, 2008, 22,262 patients aged ≥18 years with known or suspected CAD underwent symptom-limited treadmill exercise testing for clinical reasons at our institution. Of these patients, 2,956 had a history of DM. We excluded 326 patients who had received β blockers within 48 hours before the tests15 and 39 patients in whom the systolic BP failed to increase with exercise to greater than the at rest value.16, 17 Thus, 2,591 patients were finally included in the present study. The demographic and clinical data and stress testing results were entered in our prospective database at the time of the procedures. DM was defined as a previous fasting serum glucose ≥126 mg/dl, nonfasting glucose of ≥200 mg/dl, use of antidiabetic drugs, or a self-reported diagnosis. Hypertension was defined as BP at rest of >130/80 mm Hg or a previously established diagnosis. Hypercholesterolemia was defined as a previously known low-density lipoprotein cholesterol level of ≥100 mg/dl, the use of lipid-lowering agents, or a self-reported diagnosis. Patients referred for evaluation of chest pain were classified as having typical angina, atypical/probable angina, or nonischemic chest pain.18 A history of CAD was defined as previous myocardial infarction (MI), previous coronary revascularization, or previous angiographic documentation of any ≥50% coronary stenosis. The electrocardiogram at rest was considered interpretable in the absence of left bundle branch block, pre-excitation, paced rhythm, left ventricular hypertrophy, repolarization abnormalities, or treatment with digoxin. All patients gave informed consent before testing, and the local research ethics committee approved the study.
The heart rate, BP, and a 12-lead electrocardiogram were obtained at baseline and at each stage of the exercise protocol. The patients were encouraged to perform a treadmill exercise test (Bruce protocol 93.9%, modified Bruce 3.2%, Naughton 1.5%, other protocols 1.5%) until they reached an end point. The exercise end points included physical exhaustion, severe angina, exercise-induced ST-segment deviation >2 mm, significant arrhythmia, or severe hypertension (systolic BP >240 mm Hg or diastolic BP >110 mm Hg). An EESBPR was defined as systolic BP >220 mm Hg during exercise.14 Significant ST-segment changes during the tests were defined as the development of ST-segment deviation of ≥1 mm, which was horizontal or sloping away from the isoelectric line 80 ms after the J point. A submaximal test was defined as the failure to achieve 85% of the maximum age-predicted heart rate.
A subset of 1,003 patients underwent treadmill exercise echocardiography; in these cases, the echocardiographic images were acquired at rest, at peak exercise, and immediately after exercise, as previously described.19 Echocardiographic ischemia was defined as the appearance of new or worsening wall motion abnormalities with exercise, except for worsening from akinesia to dyskinesia and isolated hypokinesia of the inferobasal segment.20
Coronary angiography was performed at the discretion of the referring physician. Significant coronary stenosis was defined as a ≥50% lumen stenosis of the left main coronary artery or a ≥70% diameter stenosis of any other major epicardial coronary artery.
The follow-up data were obtained by review of hospital databases, medical records, death certificates, and telephone interviews. The main end points were all-cause mortality and hard events (ie, a composite of death or nonfatal MI). Percutaneous and surgical coronary revascularization procedures were also recorded.
Categorical variables are reported as percentages, and the comparison between groups was based on the chi-square test. Continuous variables are reported as mean ± SD, and the differences were assessed with the unpaired t test or Mann-Whitney U test, as appropriate. Survival free of the end point of interest was estimated using the Kaplan-Meier method, and the survival curves were compared using the log-rank test. The association of an EESBPR with the end points was assessed with Cox's proportional hazard models. Hazard ratios with 95% confidence intervals were estimated. Statistical analysis was performed using the Statistical Package for Social Sciences software, version 15.0 (SPSS, Chicago, Illinois).
Results
The mean age was 63.8 ± 9.9 years, and 1,473 patients (56.9%) were men. Overall, 2,071 patients (80.2%) did not have a history of CAD. The demographic and clinical characteristics of the 2,591 patients are listed in Table 1.
Table 1. Baseline characteristics of 2,591 patients with diabetes mellitus (DM) undergoing treadmill stress testing
| Variable | All Patients (n = 2,591) | EESBPR | p Value | |
|---|---|---|---|---|
| No (n = 2,355) | Yes (n = 236) | |||
| Men | 1,473 (56.9%) | 1,341(56.9%) | 132(55.9%) | 0.77 |
| Age (years) | 63.8±9.9 | 63.9±9.9 | 61.9±9.4 | 0.002 |
| Current smokers | 565(21.8%) | 509(21.6%) | 56(23.7%) | 0.45 |
| Hypertension | 1,584(61.1%) | 1,401(59.5%) | 183(77.5%) | <0.001 |
| Hypercholesterolemia | 1,391(53.7%) | 1,248(53.0%) | 143(60.6%) | 0.03 |
| Family history of coronary artery disease | 320(12.4%) | 273(11.6%) | 47(19.9%) | <0.001 |
| Previous myocardial infarction | 417(16.1%) | 393(16.7%) | 24(10.2%) | 0.009 |
| ≤30 Days before testing | 171(6.6%) | 167(7.1%) | 4(1.7%) | 0.001 |
| ≥30 Days before testing | 258(10.0%) | 238(10.1%) | 20(8.5%) | 0.43 |
| Previous coronary revascularization | 218(8.4%) | 209(8.9%) | 9(3.8%) | 0.008 |
| Percutaneous coronary intervention | 141(5.4%) | 134(5.7%) | 7(3.0%) | 0.08 |
| Coronary artery bypass grafting | 87(3.4%) | 85(3.6%) | 2(0.8%) | 0.02 |
| Atrial fibrillation | 79(3.0%) | 78(3.3%) | 1(0.4%) | 0.01 |
| Left bundle branch block | 98(3.8%) | 92(3.9%) | 6(2.5%) | 0.29 |
| Chest pain | 1,884(72.7%) | 1,704(72.4%) | 180(76.3%) | 0.20 |
| Typical angina | 195(7.5%) | 178(7.6%) | 17(7.2%) | 0.84 |
| Atypical/probable angina | 1,035(39.9%) | 949(40.3%) | 86(36.4%) | 0.25 |
| Nonischemic chest pain | 654(25.2%) | 577(24.5%) | 77(32.6%) | 0.006 |
| Medication | ||||
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 885(34.2%) | 804(34.1%) | 81(34.3%) | 0.96 |
| Calcium channel blockers | 440(17.0%) | 400(17.0%) | 40(16.9%) | 0.99 |
| Nitrates | 681(26.3%) | 626(26.6%) | 55(23.3%) | 0.28 |
| Diuretics | 233(9.0%) | 218(9.3%) | 15(6.4%) | 0.14 |
A total of 236 patients (9.1%) developed an EESBPR during the tests. The patients with an EESBPR were slightly younger and had a greater prevalence of cardiovascular risk factors compared to those not developing an EESBPR. However, the former had a lower likelihood of a history of CAD. There were no significant differences regarding antihypertensive medications between the 2 groups (Table 1). The exercise data are listed in Table 2.
Table 2. Exercise data of 2,591 patients with diabetes mellitus (DM) undergoing treadmill stress testing
| Variable | All Patients (n = 2,591) | EESBPR | p Value | |
|---|---|---|---|---|
| No (n = 2,355) | Yes (n = 236) | |||
| Resting systolic blood pressure (mm Hg) | 139.1±20.6 | 137.5±19.6 | 165.8±18.9 | <0.001 |
| Peak systolic blood pressure (mm Hg) | 178.2±32.0 | 172.0±26.6 | 238.7±10.1 | <0.001 |
| Resting heart rate (beats/min) | 81.2±15.5 | 81.3±15.7 | 81.0±12.0 | 0.89 |
| Peak heart rate (beats/min) | 143±21 | 142.5±20.8 | 145.5±17.7 | 0.01 |
| % of maximum age-predicted heart rate | 91.3±12.3 | 91.2±12.4 | 92.0±10.9 | 0.30 |
| Rate-pressure product (×103 mm Hg beats/min) | 25.5±6.3 | 24.6±5.7 | 34.7±4.4 | <0.001 |
| Sub-maximal test | 686(26.5%) | 641(27.2%) | 45(19.1%) | 0.007 |
| Metabolic equivalents (METs) | 8.1±3.2 | 8.1±2.9 | 8.0±2.5 | 0.57 |
Of the subgroup of 2,285 patients with interpretable electrocardiograms at rest, 470 (20.6%) developed significant exercise-induced ST-segment abnormalities, and the latter occurred less frequently in patients developing an EESBPR (13.2% vs 21.4% in patients without an EESBPR, p = 0.004). In contrast, of the subgroup of 1,003 patients undergoing exercise echocardiography, 419 (41.8%) developed new or worsening wall motion abnormalities during exercise. These were also less likely in patients developing an EESBPR (21.1% vs 43.0% in patients who did not develop an EESBPR, p = 0.001). The left ventricular ejection fraction increased from 55.5 ± 10.3% to 57.3 ± 14.9% in patients without an EESBPR and from 59.9 ± 7.2% to 64.3 ± 11.7% in those with an EESBPR.
A total of 357 patients underwent coronary angiography within 90 days after the treadmill tests. Of them, 288 (80.7%) had significant coronary stenoses. The likelihood of significant coronary stenoses in patients with an EESBPR who had undergone coronary angiography (72.2%) was not significantly different from that of the patients without an EESBPR (81.1%, p = 0.35).
During a mean follow-up of 6.0 ± 3.7 years, 484 patients died, 286 experienced MI, 309 underwent percutaneous coronary intervention, and 206 underwent coronary artery bypass surgery. A total of 646 patients experienced a hard event. The 10-year mortality rate was 16.6% in patients with an EESBPR compared to 30.9% in patients without an EESBPR (p = 0.0001; Figure 1). These results remained consistent when the patients were stratified according to gender and age (Figure 2). The 10-year hard event rate was also lower in patients with an EESBPR (23.2% vs 38.9% in patients without an EESBPR, p <0.0001; Figure 1). On multivariate analysis, EESBPR was independently associated with a lower risk of all-cause mortality and hard events (Table 3).
Figure 1.
(A) All-cause mortality and (B) death or MI curves in patients with and without an EESBPR.
Figure 2.
All-cause mortality curves in patients with and without an EESBPR stratified by (A) gender and (B) age.
Table 3. Prognostic value of exaggerated exercise systolic blood pressure response (EESBPR)
| Adjusted Hazard Ratio (95% CI)⁎ | p Value | |
|---|---|---|
| All-cause mortality | 0.53(0.36–0.78) | 0.001 |
| Death or non-fatal myocardial infarction | 0.57(0.41–0.79) | <0.001 |
| Death, myocardial infarction or coronary revascularization | 0.63(0.48–0.83) | <0.001 |
| Non-fatal myocardial infarction | 0.76(0.48–1.18) | 0.22 |
| Coronary revascularization | 0.84(0.59–1.20) | 0.34 |
⁎Adjusted by age, gender, hypertension, hypercholesterolemia, smoking, family history of CAD, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass grafting, chest pain, left bundle branch block, atrial fibrillation, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, nitrates, calcium channel blockers, diuretics, exercise-induced chest pain, exercise electrocardiographic results, metabolic equivalents, and percentage of maximum age-predicted heart rate. |
In the subgroup of patients without a known history of CAD, those with interpretable electrocardiograms who developed an EESBPR had a lower likelihood of significant electrocardiographic changes during the tests (11.5% vs 19.4%, p = 0.007). In addition, those who underwent exercise echocardiography and developed an EESBPR had a nonsignificant trend toward a lower likelihood of echocardiographic myocardial ischemia (21.6% vs 34.4%, p = 0.06). The 10-year mortality rate in patients without a history of CAD who developed an EESBPR was 12.5% compared to 27.3% in those who did not develop an EESBPR (p <0.001). The 10-year rate of death or nonfatal MI was also lower in patients with an EESBPR (19.2% vs 34.4% in those without an EESBPR, p <0.001; Figure 3). On multivariate analysis, EESBPR remained an independent predictor of a lower risk of all-cause mortality (hazard ratio 0.46, 95% confidence interval 0.30 to 0.75, p = 0.001) and hard events (hazard ratio 0.55, 95% confidence interval 0.37 to 0.80, p = 0.002) in these patients.
Figure 3.
(A) All-cause mortality and (B) death or MI curves for patients without a history of CAD with and without an EESBPR.
Discussion
In our study, EESBPR was associated with improved long-term survival and a lower risk of death or nonfatal MI in patients with DM and known or suspected CAD referred for treadmill stress testing. These results held true even after excluding those patients with a known history of CAD.
The prognostic value of a hypertensive response with exercise remains controversial. Although many studies performed in asymptomatic healthy subjects found that the exercise BP response is associated with a greater risk of cardiovascular events,5, 9, 10, 11 most reports of patients with known or suspected CAD have generally agreed that a hypertensive response to exercise is associated with improved outcomes.12, 13 Lauer et al12 found that an EESBPR was associated with a lower likelihood of significant CAD and a lower adjusted mortality rate. Similarly, Gupta et al13 reported that an increase in systolic BP of ≥44 mm Hg during exercise was independently associated with improved survival. Our study has complemented and expanded such results by addressing the association of EESBPR with outcome in patients with DM. In our study, the mortality rate in patients developing an EESBPR was almost 1/2 that of patients without an EESBPR. We also found an association of an EESBPR with a lower prevalence of electrocardiographic and echocardiographic markers of myocardial ischemia. These results are noteworthy because an EESBPR has been reported to be a cause of false-positive results on exercise echocardiography.21, 22 Our results contrast with those reported by Kane et al,14 who failed to find a significant association between a hypertensive BP response to exercise and exercise-induced ST-segment abnormalities, myocardial perfusion defects, or outcome in symptomatic patients referred for exercise single photon emission computed tomographic myocardial perfusion imaging.
The clinical significance of a hypertensive response to exercise in patients with DM has been poorly explored. Brassard et al23 found that elevated exercise systolic BP was not associated with reduced exercise capacity in patients with type 2 DM without cardiovascular disease. However, to our knowledge, no studies have yet evaluated the prognostic value of a hypertensive response to exercise in patients with DM.
The threshold used in the present study for defining EESBPR was greater than that used in many previous reports. This threshold was selected because the prognostic value of moderate increases in BP during exercise has been well established.24, 25 Also, in contrast to previous studies,12 we did not use a lower threshold for defining an EESBPR in women; nonetheless, in our study, the prevalence and prognostic value of an EESBPR were similar in both genders.
The mechanism accounting for the more favorable outcome in patients developing an EESBPR might be related to the fact that an exercise-induced increase in cardiac output is a major determinant of the BP response during exercise. Thus, an EESBPR might reflect a greater cardiac output reserve, which, in turn, might identify patients with less severe CAD. In contrast, it seems unlikely that high systemic vascular resistance during exercise would account for the better prognosis.
Our study had several limitations. First, this was a single-center observational study and, therefore, unmeasured confounding might have accounted for at least a part of the observed differences in outcomes. Only a small proportion of the patients included in the present study underwent coronary angiography; thus, the association of an EESBPR with the angiographic findings could not be properly assessed. In addition, the reproducibility of an EESBPR has been reported to be low.26 Almost all patients included in our study were white; hence, we could not assess any racial heterogeneity in our cohort. Also, we did not evaluate the cause of death; we assessed all-cause mortality, instead of cardiovascular death, because the latter could be susceptible to bias and misclassification.27 Finally, these results only apply to patients undergoing treadmill stress tests for clinical reasons and should not be extrapolated to patients with asymptomatic DM without known or suspected CAD.
References
- . Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–419
- . Exercise blood pressure response and 5-year risk of elevated blood pressure in a cohort of young adults: the CARDIA study. Am J Hypertens. 1994;7:234–241
- . Response in subjects with high-normal BP: exaggerated blood pressure response to exercise and risk of future hypertension in subjects with high-normal blood pressure. J Am Coll Cardiol. 2000;36:1626–1631
- . Blood pressure response during treadmill testing as a risk factor for new-onset hypertension: the Framingham heart study. Circulation. 1999;99:1831–1836
- . Prognostic significance of exercise-induced systemic hypertension in healthy subjects. Am J Cardiol. 1999;83:371–375
- . The significance of hypertensive response to exercise as a predictor of hypertension and cardiovascular disease. J Hum Hypertens. 2001;15:353–356
- . Blood pressure responses to exercise as predictors of blood pressure level after 5 years. Am J Hypertens. 1997;10:106–116
- . Follow-up of normotensive men with exaggerated blood pressure response to exercise. Am Heart J. 1983;106:316–320
- . Systolic blood pressure response to exercise testing is related to the risk of acute myocardial infarction in middle-aged men. Eur J Cardiovasc Prev Rehabil. 2006;13:421–428
- . Exercise testing of healthy men in a new perspective: from diagnosis to prognosis. Eur Heart J. 2004;25:978–986
- . Exercise blood pressure predicts cardiovascular mortality in middle-aged men. Hypertension. 1994;24:56–62
- . Angiographic and prognostic implications of an exaggerated exercise systolic blood pressure response and rest systolic blood pressure in adults undergoing evaluation for suspected coronary artery disease. J Am Coll Cardiol. 1995;26:1630–1636
- . Prognostic significance of systolic blood pressure increases in men during exercise stress testing. Am J Cardiol. 2007;100:1609–1613
- . Hypertensive response with exercise does not increase the prevalence of abnormal Tc-99m SPECT stress perfusion images. Am Heart J. 2008;155:930–937
- . Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol. 2006;47:794–798
- . Prediction of cardiovascular death by means of clinical and exercise test variables in patients selected for cardiac catheterization. Am Heart J. 1993;125:1717–1726
- . Exercise-induced hypotension in a male population (Criteria, causes, and prognosis). Circulation. 1988;78:1380–1387
- . A clinically relevant classification of chest discomfort. J Am Coll Cardiol. 1983;1:574–575
- . Prediction of mortality and major cardiac events by exercise echocardiography in patients with normal exercise electrocardiographic testing. J Am Coll Cardiol. 2009;53:1981–1990
- . Standardized guidelines for the interpretation of dobutamine echocardiography reduce interinstitutional variance in interpretation. Am J Cardiol. 1998;82:1520–1524
- . Hypertensive response to exercise: a potential cause for new wall motion abnormality in the absence of coronary artery disease. J Am Coll Cardiol. 2002;39:323–327
- . False-positive exercise echocardiograms: impact of sex and blood pressure response. Am Heart J. 2003;146:914–919
- . Elevated peak exercise systolic blood pressure is not associated with reduced exercise capacity in subjects with type 2 diabetes. J Appl Physiol. 2006;101:893–897
- . Variations in and significance of systolic pressure during maximal exercise (treadmill) testing. Am J Cardiol. 1977;39:841–848
- . Prediction of cardiovascular death in men undergoing noninvasive evaluation for coronary artery disease. Ann Intern Med. 1993;118:689–695
- . Reproducibility of exaggerated blood pressure response to exercise in healthy patients. Am Heart J. 2001;141:1014–1017
- . Cause of death in clinical research: time for a reassessment?. J Am Coll Cardiol. 1999;34:618–620
PII: S0002-9149(09)02678-2
doi:10.1016/j.amjcard.2009.10.059
© 2010 Elsevier Inc. All rights reserved.
