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(Circulation. 2008;117:614-622.)
© 2008 American Heart Association, Inc.
Exercise Physiology |
From the Veterans Affairs Medical Center, Cardiology Department (P. Kokkinos, J.P.K., A.P., P.N., A.M., P. Karasik, M.G., V.P.) and Georgetown University School of Medicine (P. Kokkinos, S.S.), Washington, DC, and Veterans Affairs Palo Alto Health Care System, Cardiology Division, and Stanford University, Stanford, Calif (J.M.).
Correspondence to Peter F. Kokkinos, PhD, Veterans Affairs Medical Center/Cardiology Division, 50 Irving St NW, Washington, DC 20422. E-mail peter.kokkinos{at}med.va.gov
Received August 17, 2007; accepted November 8, 2007.
| Abstract |
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Methods and Results— We assessed the association between exercise capacity and mortality in black (n=6749; age, 58±11 years) and white (n=8911; age, 60±11 years) male veterans with and without cardiovascular disease who successfully completed a treadmill exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. Fitness categories were based on peak metabolic equivalents (METs) achieved. Subjects were followed up for all-cause mortality for 7.5±5.3 years. Among clinical and exercise test variables, exercise capacity was the strongest predictor of risk for mortality. The adjusted risk was reduced by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.88; P<0.001). Compared with those who achieved <5 METs, the mortality risk was
50% lower for those with an exercise capacity of 7.1 to 10 METs (hazard ratio, 0.51; 95% confidence interval, 0.47 to 0.56; P<0.001) and 70% lower for those achieving >10 METs (hazard ratio, 0.31; 95% confidence interval, 0.26 to 0.36; P<0.001). The findings were similar for those with and without cardiovascular disease and for both races.
Conclusions— Exercise capacity is a strong predictor of all-cause mortality in blacks and whites. The relationship was inverse and graded, with a similar impact on mortality outcomes for both blacks and whites.
Key Words: African Americans epidemiology exercise tolerance mortality exercise test
| Introduction |
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Clinical Perspective p 622
It is well documented that the age-adjusted all-cause mortality rates in blacks are as much as 60% higher than those of whites.11,12 This has been attributed in part to the fact that race and income are reported to negatively influence access to medical care.13 The Veterans Health Administration in the US Department of Veterans Affairs Health Care System is unique in that it ensures equal access to care independently of a patients financial status.14 Improved access to care and higher-quality health have been demonstrated in the Veterans Affairs Health Care System.14 In addition, the Veterans Affairs electronic healthcare database is uniquely suited to determine mortality and other outcomes accurately and facilitates risk-adjustment models to study outcomes.15 Thus, the system provides a unique opportunity to assess the association between mortality and exercise capacity in blacks and whites while minimizing the influence of disparities in medical care.
In the present study, we assessed the prognostic value of exercise capacity among black and white patients referred for an exercise test for clinical reasons. We addressed the following questions: Is exercise capacity an independent predictor of overall mortality for both black and white men? And are there racial differences in how exercise capacity influences the risk of mortality?
| Methods |
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The 15 660 participants included in the study were either black (n=6749) or white (n=8911) men. All subjects gave written consent before the exercise tolerance test. The study was approved by the Internal Review Board at each institution. All demographic, clinical, and medication information was obtained from patients computerized medical records just before the exercise tolerance test. Each individual also was asked to verify the computerized information with regard to history of chronic disease, current medications, and cigarette smoking habits. Body weight and height were recorded before the test. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Demographic data are included in Table 1. Individuals with CVD were defined as those with a history of myocardial infarction, angiographically documented coronary artery disease, coronary angioplasty, coronary bypass surgery, chronic heart failure, and/or peripheral vascular disease.
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We recorded death dates from the Veterans Affairs Beneficiary Identification and Record Locator System File. This system, used to determine benefits to survivors of veterans, is complete and accurate.19 The Social Security Death Index was used to match all subjects to their record according to Social Security number. Vital status was determined as of June 30, 2007.
Exercise Assessments
The exercise capacity for the individuals at the Veterans Affairs Medical Center (Washington, DC) was assessed by the standard Bruce protocol. For the individuals assessed at the Veterans Affairs Palo Alto Health Care System, an individualized ramp protocol was used as described elsewhere.20 Peak exercise time was recorded in minutes. Peak workload was estimated as metabolic equivalents (METs). One MET is defined as the energy expended at rest, which is equivalent to an oxygen consumption of 3.5 mL/kg body weight per minute.21 Exercise capacity (in METs) was estimated on the basis of exercise time via a commonly used equation for the Bruce protocol22 and based on American College of Sports Medicine equations for the ramp protocol.21 Subjects were encouraged to exercise until volitional fatigue in the absence of symptoms or other indicators of ischemia.16 The use of handrails during the exercise test was discouraged. Age-predicted peak exercise HR was determined with standardized methods.23 Medications were not changed or stopped before testing.
Supine resting HR and blood pressure (BP) were assessed after 5 minutes of rest. Exercise BP was recorded at 2 minutes of each exercise stage, at peak exercise, and during recovery. Indirect arm-cuff sphygmomanometry was used for all BP assessments. ST-segment depression was measured visually. ST depression
1.0 mm that was horizontal or downsloping was considered suggestive of ischemia.
Determination of Fitness Categories
Four fitness categories were established on the basis of the MET level achieved. For practical reasons, the MET cutoffs used to define the fitness categories were based on the approximate MET level for each stage of the Bruce protocol. Subjects who achieved <5 METs made up the low fitness category (Low-Fit; n=3170); those who achieved 5 to 7 METs were in the moderate fitness category (Moderate-Fit; n=5153); those who achieved 7.1 to 10 METs made up the high fitness category (High-Fit; n=5075); and those who achieved >10 METs made up the highest fit category (Very-High-Fit; n=2261).
Statistical Analysis
Continuous variables are presented as mean±SD; categorical variables are expressed as absolute and relative frequencies (percent). Associations between categorical variables were tested with Pearsons
2 test. One-way ANOVA was applied to determine age and BMI differences between the 2 races and among fitness categories. Post hoc procedures also were used to discern differences between fitness categories. The Bonferroni rule to correct for the inflation in the type I error was applied with multiple comparisons. Equality of variances between treatment groups was tested by the Levenes test. ANCOVA was used to assess whether exercise variables were associated with race.
The relative risk for mortality was calculated for each fitness category. We considered individuals with an exercise capacity of <5 METs as Low-Fit; these subjects made up the reference group. Survival analysis was performed with the use of Kaplan-Meier curves, and Cox proportional-hazard models were used to determine the variables that were independently and significantly associated with mortality. The analyses were adjusted for age in years, BMI, cardiovascular medications (aspirin, angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, vasodilators, and statins), and risk factors (hypertension, diabetes, dyslipidemia, and smoking) as categorical variables. Receiver-operating characteristic curves (ROCs) were constructed to compare the MET level achieved, age, BMI, and cardiovascular risk factors in terms of their discriminatory accuracy in predicting survival and to determine an optimal MET level threshold for mortality. Logistic regression (forward stepwise) was applied to determine the relative risk for mortality based on this threshold.
Values of P<0.05 using 2-sided tests were considered statistically significant. All statistical analyses were performed with SPSS software (SPSS version 15.0, SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
| Results |
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Comparisons between fitness categories revealed that age was significantly lower (P<0.001) for the more fit versus the less fit categories (51±11, 56±10; 62±10, and 66±10 years, respectively). Similar findings were observed for both races. BMI was lower (P<0.001) in the 2 highest fitness categories compared with the Moderate-Fit and Low-Fit categories (28.2±5.7 versus 28.7±5.5, 28.3±4.7, and 27±4 kg/m2, respectively). Thus, age and BMI were used as covariates when assessing differences in resting and exercise HR, BP, and MET levels among the fitness categories.
Demographic and Clinical Characteristics
Participant characteristics and exercise data for the entire cohort and for each race are presented in Table 1. Blacks were younger than whites (58±11 versus 60±11 years; P<0.001) and had higher resting systolic and diastolic BPs. They also were more likely to smoke; to be obese; and to have CVD, hypertension, diabetes, and dyslipidemia. Accordingly, they were more likely to be treated with angiotensin-converting enzyme inhibitors and diuretics. Whites had a higher prevalence of a previous myocardial infarction and were more likely to be treated with β-blockers and nitrates. After adjustment for age and resting BP, the peak exercise systolic and diastolic BPs and HR were significantly higher in blacks compared with whites, whereas peak MET level was higher in whites.
Racial Differences in Mortality
After adjustments for racial differences in age, resting BP, smoking habits, myocardial infarction, cardiovascular risk factors, and cardiac medications (Table 2), mortality was 11% higher in blacks than in whites (hazard ratio, 1.11; 95% confidence interval [CI], 1.01 to 1.18; P=0.001). Blacks who died were significantly older (63±10 versus 56±11 years; P<0.001) and had higher resting HRs (74±14 versus 72±14 bpm) and systolic BPs (139±22 versus 132±20 mm Hg; P<0.001) compared with those alive. They also had lower BMI (27.1±5.4 versus 28.8±5 kg/m2; P<0.001), peak exercise HR (130±25 versus 145±25 bpm; P<0.001), peak systolic BP (180±34 versus 188±31 mm Hg; P<0.001), and MET level achieved (5.6±1.9 versus 7.2±2.4; P<0.001); were more likely to smoke; and had a higher prevalence of diabetes, CVD, and previous myocardial infarction.
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Similarly, whites who died were older (65±10 versus 58±11 years; P<0.001) and had a higher resting HR (75±14 versus 73±14 bpm; P<0.001) and systolic BP (134±23 versus 131±20 mm Hg; P<0.001) than those alive. In addition, they had significantly lower BMI (27.0±4.8 versus 28.5±5.1 kg/m2; P<0.001), peak exercise HR (127±27 versus 140±25 bpm; P<0.001), peak systolic BP (170±32 versus 178±30 mm Hg; P<0.001), and MET level achieved (6.1±2.7 versus 8.0±3.1; P<0.001) and were more likely to have hypertension and CVD and less likely to have dyslipidemia.
Predictors of All-Cause Mortality for the Entire Cohort
Hazard ratios for exercise capacity for the entire cohort and for each race are presented in Table 2. Exercise capacity was the strongest predictor of mortality (hazard ratio, 0.87) (ROC area, 0.71; P<0.001), followed by age (hazard ratio, 1.04; 95% CI, 1.03 to 1.04; P<0.001) (ROC area, 0.67; P<0.001), cardiovascular risk factors (hazard ratio, 1.16; 95% CI, 1.08 to 1.24; P<0.001) (ROC area, 0.50; P<0.001), and BMI (hazard ratio, 0.96; 95% CI, 0.96 to 0.97; P<0.001) (ROC area, 0.41; P<0.001).
Cox proportional-hazards analysis revealed a 13% reduction in mortality risk for every 1-MET increase in exercise capacity (hazard ratio, 0.87). The findings were similar (P=0.60) when individuals receiving β-blockers (n=2448) were excluded from the analysis (hazard ratio, 0.87; 95% CI, 0.86 to 0.88; P<0.001) or were analyzed separately (hazard ratio, 0.87; 95% CI, 0.84 to 0.90; P<0.001).
When predictors of mortality for each race were explored, each 1-MET increase in exercise capacity conferred a 14% lower risk for mortality among blacks (hazard ratio, 0.86) and a 12% lower risk for whites (hazard ratio, 0.88). The mortality risk reduction for each 1-MET increase in exercise capacity was similar (P=0.49) for both blacks and whites.
A MET level of 7.0 was the optimal threshold for increased risk in mortality (sensitivity, 75%; specificity, 55%). Those below this threshold had a 2.6-fold increase in risk for mortality (95% CI, 2.4 to 2.8; P<0.001) compared with those above it. The findings were similar for blacks and whites.
Predictors of All-Cause Mortality for Individuals With and Without CVD
Exercise capacity and other clinical predictors of mortality for the CVD cohort are presented in Table 3. Exercise capacity was the strongest predictor of mortality. The adjusted risk for the entire group was lowered by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87).
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In blacks, the mortality risk was lowered by 15% per 1 MET (hazard ratio, 0.85), whereas the mortality risk was lowered by 12% per 1 MET in whites (hazard ratio, 0.88). The mortality risk reduction for each 1-MET increase in exercise capacity was similar in a comparison of blacks and white (P=0.86) or when individuals receiving β-blockers (n=928) were excluded from analysis (hazard ratio, 0.87) or were analyzed separately (hazard ratio, 0.86) (P=0.60).
Similar findings were observed in individuals with no CVD (Table 4). The adjusted risk of mortality for the entire cohort was lowered by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87). The mortality risk was lowered by 14% in blacks (hazard ratio, 0.86) and 12% in whites (hazard ratio, 0.88) for each 1-MET increase in exercise capacity. The mortality risk reduction for each 1-MET increase in exercise capacity was similar for both blacks and whites (P=0.97).
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Among those without CVD, the optimal threshold for increased risk of mortality was 6.0 METs (sensitivity, 70%; specificity, 60%). A 2.3-fold increase in the risk for mortality was noted for subjects below this threshold (relative risk, 2.3; 95% CI, 2.0 to 2.6; P<0.001). The relative mortality risk for those achieving a MET level below versus above 6.0 METs was 2.7 (95% CI, 2.2 to 3.3; P<0.001) for blacks and 2.0 (95% CI, 1.6 to 2.3; P<0.001) for whites.
Risk of Mortality Across Fitness Categories: Entire Cohort
Survival curves across fitness categories and relative risks for the entire cohort and for each race are presented in Figures 1 through 4![]()
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. Relative risks across fitness categories for the CVD and no CVD cohorts and for each race are presented in Figures 5 and 6
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For the entire cohort, the adjusted relative risks for those who achieved peak exercise capacity levels of 5 to 7, 7.1 to 10, and >10 METs compared with those in the Low-Fit category (<5 METs) are shown in Figure 4. The relative risk of mortality was progressively lower as exercise capacity increased to 5 to 7 METs (hazard ratio, 0.80; 95% CI, 0.74 to 0.86; P<0.001), 7.1 to 10 METs (hazard ratio, 0.51; 95% CI, 0.47 to 0.56; P<0.001), and >10 METs (hazard ratio, 0.31; 95% CI, 0.26 to 0.36; P<0.001).
For blacks, the relative risk also was progressively lower for those achieving 5 to 7 METs (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P<0.001), 7.1 to 10 METs (hazard ratio, 0.50; 95% CI, 0.43 to 0.58; P<0.001), and >10 METs (hazard ratio, 0.26; 95% CI, 0.18 to 0.37; P<0.001). Among whites, the corresponding relative risks were 0.79 (95% CI, 0.71 to 0.87; P<0.001), 0.52 (95% CI, 0.46 to 0.58; P<0.001), and 0.34 (95% CI, 0.28 to 0.41; P<0.001).
Risk of Mortality Across Fitness Categories for Subjects With and Without CVD
For individuals with CVD, the adjusted relative risks for those in each fitness category are shown in Figure 5. For the entire CVD cohort, the relative risk of mortality was progressively lower for those achieving 5 to 7 METs (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P<0.001), 7.1 to 10 METs (hazard ratio, 0.50; 95% CI, 0.43 to 0.58; P<0.001), and >10 METs (hazard ratio, 0.42; 95% CI, 0.31 to 0.56; P<0.001).
In blacks, the relative risk was similar for individuals who achieved <5 and 5 to 7 METs (hazard ratio, 0.86; 95% CI, 0.73 to 1.0; P=0.07). Significantly higher risk was noted only for individuals achieving 7.1 to 10 METs (hazard ratio, 0.46; 95% CI, 0.36 to 0.59; P<0.001) and >10 METs (hazard ratio, 0.34; 95% CI, 0.18 to 0.63; P<0.001). For whites, the relative risk was progressively lower for those achieving 5 to 7 METs (hazard ratio, 0.78; 95% CI, 0.67 to 0.91; P=0.002), 7.1 to 10 METs (hazard ratio, 0.53; 95% CI, 0.44 to 0.65; P<0.001), and >10 METs (hazard ratio, 0.46; 95% CI, 0.33 to 0.64; P<0.001). For those with no CVD (Figure 6), the findings were similar to those of the entire cohort.
| Discussion |
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The risk for mortality was 13% lower for every 1-MET increase in exercise capacity for the entire cohort, with similar reductions observed for those with and without CVD. The findings did not change significantly when individuals treated with β-blockers were included or excluded in the analysis. When fitness tertiles were considered, the relative risk for all-cause mortality for the entire cohort was
20% lower in those with an exercise capacity of 5 to 7 METs (Moderate-Fit category) compared with those achieving <5 METs. For those with an exercise capacity >7 METs, the mortality risk was
50% to 70% lower compared with those achieving <5 METs (Figure 4). This gradient for a reduction in mortality with increasing fitness was similar in blacks and whites in the entire cohort (Figure 4) and in individuals with and without CVD (Figures 5 and 6
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Low levels of physical activity, as determined by self-reported activity questionnaires, have been associated with an increased risk of mortality.3–6,9 These observations have been supported by studies using exercise capacity, a more objective assessment of fitness, to classify the physical status of apparently healthy men1,2,8,10,27 and women.1,2,8–10,27 Our findings support these previous reports.1–10,27 In particular, the 13% reduction in mortality risk for every 1-MET increase in exercise capacity we observed is similar to the 12% reduction reported previously in a veteran cohort10 but somewhat lower than the 17% to 20% reduction reported in women.25,27
Several aspects about the present study are unique. First, the 15 660 subjects make it the largest to assess the association between fitness and mortality in a clinically referred cohort. Second, our findings make a unique contribution to existing knowledge by providing needed information on the association between exercise capacity and mortality in a relatively large cohort of blacks and compare them with whites. Moreover, we had the opportunity to examine the association between exercise capacity and mortality in blacks and whites with CVD. In this regard, subtle differences were observed among those with CVD and those without CVD. For example, for every 1-MET increase in exercise capacity, the risk for all-cause mortality was 15% lower in blacks compared with 12% in whites. Another finding with potentially important clinical implications was the mortality risk differences between tertiles in the CVD cohort. Specifically, the relative risk among individuals with CVD and an exercise capacity between 5 and 7 METs was significantly lower only in whites, whereas among blacks, significant reductions were realized only when exercise capacity exceeded 7 METs (Figure 6). This suggests that blacks with CVD may require a higher fitness level for the same cardiovascular protection.
Third, most information on the association between physical activity, exercise capacity, and health is derived from populations of middle to upper socioeconomic strata.1–4,6,9 Such individuals are likely to have greater access to health-related information and may be in a better position to participate in and maintain a healthy lifestyle. Thus, the association between fitness and mortality may be accentuated in such individuals. In contrast, most of the individuals in the present study were of relatively low socioeconomic strata. The 50% lower mortality risk for those with an exercise capacity >7 METs versus <5 METs is similar to that reported by Blair and coworkers1,2 in middle to upper socioeconomic strata populations. Thus, our findings and those reported earlier10 in a similar population (patients from 2 Veterans Affairs Medical Centers) strengthen the evidence that higher exercise capacity is associated with lower all-cause mortality regardless of factors related to socioeconomic strata.
Our finding of a slightly higher overall mortality in blacks compared with whites is in contrast to a recent report demonstrating higher mortality rates in white veterans compared with blacks and Hispanics.28 The different findings in the 2 studies may be explained by differences in age and baseline comorbidities between the races. In the earlier study,28 whites were 6.4 years older than blacks, whereas in the present study, the difference in age was only 2 years. With regard to baseline comorbidities, the prevalence of CVD in the present study was significantly higher in blacks than in whites, whereas the prevalence of all other comorbidities was similar.
Our study has several limitations. The inverse relationship between fitness and mortality does not demonstrate cause. Although similar relationships have been demonstrated for CVD mortality, we had information only on all-cause mortality, not cardiovascular interventions. In addition, we did not have information on the physical activity level of the individuals in our study; the extent to which exercise capacity reflects the physical activity pattern in our sample is unknown. The onset of chronic diseases, their severity, and duration of therapy were not evaluated in our study because of incomplete records. In addition, it is likely that direct measurements of oxygen uptake would yield more precise findings. The use of 2 different exercise protocols to assess fitness also is a potential limitation. Our previous work suggests that the ramp protocol is somewhat more accurate in predicting measured METs.20 We analyzed the data separately from both locations and found that for every 1-MET increment, the Bruce protocol yielded an
14% reduction in risk and the ramp protocol yielded a 13% reduction in mortality. Thus, the differences in protocols did not have a substantial impact on results. Finally, our findings are based on men only and cannot be extrapolated to women.
Our findings have a number of clinical applications. These results extend the public health message about the health benefits of fitness and physical activity.29–31 Because higher exercise capacity is associated with a lower risk of mortality, physicians and other healthcare professionals should encourage individuals to initiate and maintain a physically active lifestyle consisting of moderate-intensity activities (brisk walking or similar activities). Such programs are likely to improve exercise capacity and lower the risk of mortality. Exercise capacity as assessed by an exercise test is a standardized procedure used throughout the world. Thus, inferences can be made for the many patients undergoing this procedure, and the prognostic power of exercise capacity applies equally to blacks and whites. In fact, a salient finding is that mortality risk was 50% lower for both blacks and whites who achieved an exercise capacity of 7 to 10 METs compared with those who achieved <5 METs regardless of CVD status (Figures 4 through 6![]()
). These findings also expand the clinical applications of the relationship between fitness and mortality to patients treated with β-blockers. Collectively, these results support the concept that exercise capacity should be given as much attention by clinicians as other major risk factors.
| Acknowledgments |
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None.
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CLINICAL PERSPECTIVE
The findings of the present study reinforce the concept that the fitness status of an individual is inversely and strongly related to mortality in individuals with and without cardiovascular disease, regardless of factors related to socioeconomic strata. The gradient for a reduction in mortality with increasing fitness was similar in blacks and whites. Specifically, mortality was 13% lower for every 1-MET increase in exercise capacity and 50% lower for both blacks and whites who achieved a moderate exercise capacity (7 to 10 metabolic equivalents [METs]) compared with those who achieved a poor exercise capacity (<5 METs) regardless of cardiovascular disease status. Because exercise capacity as assessed by an exercise test is a standardized procedure used throughout the world, inferences can be made for the many patients undergoing this procedure. The prognostic power of exercise capacity applies equally to blacks and whites and to those with and without cardiovascular disease. It also expands the clinical applications of the relationship between fitness and mortality to patients treated with β-blockers. Collectively, the results of the present and other recent studies support the concept that exercise capacity should be given as much attention by clinicians as other major risk factors.
Circulation 2008 117: 589-591.
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