John Peter Kokkinos

Exercise Capacity and Mortality in Older Men A 20-Year Follow-Up Study

BACKGROUND Epidemiological findings, based largely on middle-aged populations, support an inverse and independent association between exercise capacity and mortality risk. The information available in older individuals is limited. METHODS AND RESULTS Between 1986 and 2008, we assessed the association between exercise capacity and all-cause mortality in 5314 male veterans aged 65 to 92 years (mean+/-SD, 71.4+/-5.0 years) who completed an exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. We established fitness categories based on peak metabolic equivalents (METs) achieved. During a median 8.1 years of follow-up (range, 0.1 to 25.3), there were 2137 deaths. Baseline exercise capacity was 6.3+/-2.4 METs among survivors and 5.3+/-2.0 METs in those who died (P<0.001) and emerged as a strong predictor of mortality. For each 1-MET increase in exercise capacity, the adjusted hazard for death was 12% lower (hazard ratio=0.88; confidence interval, 0.86 to 0.90). Compared with the least fit individuals (< or =4 METs), the mortality risk was 38% lower for those who achieved 5.1 to 6.0 METs (hazard ratio=0.62; confidence interval, 0.54 to 0.71) and progressively declined to 61% (hazard ratio=0.39; confidence interval, 0.32 to 0.49) for those who achieved >9 METs, regardless of age. Unfit individuals who improved their fitness status with serial testing had a 35% lower mortality risk (hazard ratio=0.65; confidence interval, 0.46 to 0.93) compared with those who remained unfit. CONCLUSIONS Exercise capacity is an independent predictor of all-cause mortality in older men. The relationship is inverse and graded, with most survival benefits achieved in those with an exercise capacity >5 METs. Survival improved significantly when unfit individuals became fit.

Exercise Capacity and Progression From Prehypertension to Hypertension

Prehypertension is likely to progress to hypertension. The rate of progression is determined mostly by age and resting blood pressure but may also be attenuated by increased fitness. A graded exercise test was performed in 2303 men with prehypertension at the Veterans Affairs Medical Centers in Washington, DC. Four fitness categories were defined, based on peak metabolic equivalents (METs) achieved. We assessed the association between exercise capacity and rate of progression to hypertension (HTN). The median follow-up period was 7.8 years (mean (± SD) 9.2±6.1 years). The incidence rate of progression from prehypertension to hypertension was 34.4 per 1000 person-years. Exercise capacity was a strong and independent predictor of the rate of progression. Compared to the High-Fit individuals (>10.0 METs), the adjusted risk for developing HTN was 66% higher (hazard ratio, 1.66; 95% CI, 1.2 to 2.2; P=0.001) for the Low-Fit and, similarly, 72% higher (hazard ratio, 1.72; 95% CI, 1.2 to 2.3; P=0.001) for the Least-Fit individuals, whereas it was only 36% for the Moderate-Fit (hazard ratio, 1.36; 95% CI, 0.99 to 1.80; P=0.056). Significant predictors for the progression to HTN were also age (19% per 10 years), resting systolic blood pressure (16% per 10 mm Hg), body mass index (15.3% per 5 U), and type 2 diabetes mellitus (2-fold). In conclusion, an inverse, S-shaped association was shown between exercise capacity and the rate of progression from prehypertension to hypertension in middle-aged and older male veterans. The protective effects of fitness were evident when exercise capacity exceeded 8.5 METs. These findings emphasize the importance of fitness in the prevention of hypertension.

Exercise Capacity and All-Cause Mortality in Prehypertensive Men

BACKGROUND Prehypertension is associated with increased risk for mortality, a fact that generated a debate regarding the use of antihypertensive therapy in prehypertensives. Increased exercise capacity is associated with lower mortality risk, but little is known about its effects in prehypertensives. Thus, we evaluated the association between exercise capacity and all-cause mortality in prehypertensives. METHODS A graded exercise test was performed in 4,478 prehypertensive men at the Veterans Affairs Medical Centers in Washington, DC and Palo Alto, CA. Four fitness categories (quartiles) were defined based on peak metabolic equivalents (METs) achieved. All-cause mortality was assessed for both younger (<or=60 years) and older individuals. The mean follow-up period was 9.0 +/- 6.0 years. RESULTS Exercise capacity was a strong predictor of all-cause mortality, independent of traditional risk factors. The adjusted risk for all-cause mortality was reduced by 15% for every 1-MET increase in exercise capacity in the entire cohort, 18% for younger and 12% for older individuals. Compared to the Very-Low-Fit individuals (<or=6 METs) the adjusted mortality risk was 40% lower in Low-Fit (6.1-8.0 METs); 58% lower in Moderate-Fit (8.1-10 METs), and 73% lower in High-Fit individuals (>10 METs). The trends were similar but more pronounced among younger than older individuals. CONCLUSIONS A strong, inverse and graded association between exercise capacity and all-cause mortality was observed in prehypertensive individuals. The protective effects of increased fitness were more pronounced in younger than older individuals, suggesting that age should be more closely considered when assessing fitness and mortality relationships.

A graded association of exercise capacity and all-cause mortality in males with high-normal blood pressure

Abstract Introduction. Information regarding the effect of exercise capacity on mortality risk in individuals with high-normal blood pressure is severely limited. Thus, we evaluated the association of exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Methods. Exercise test was performed in 1727 males with high-normal blood pressure at two Veteran sites (Washington, DC, and Palo Alto, CA). Fitness status was assessed in metabolic equivalents (METs) at exercise peak. All-cause mortality was recorded for a mean follow-up period of 9.8±6.0 years. Results. Exercise capacity was inversely associated with all-cause mortality, and the association was independent of traditional cardiovascular risk factors. For each 1 MET increase in exercise capacity, the adjusted mortality risk was reduced by 13%, underscoring the strong predictive value of exercise capacity that was confirmed by ROC analysis. Data analysis according to fitness levels revealed a threshold level of 4 METs, over which the mortality risk was progressively reduced by 30% (hazard ratio=0.70; CI 0.51–0.95) for those who achieved 4.1–6.0 METs and 61% (hazard ratio=0.39; CI 0.26–0.57) for those who achieved 8.1–10 METs. No additional reductions in risk were noted until the MET level achieved exceeded 12 METs. Conclusions. We observed a strong, inverse, graded and independent association between exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Our findings indicate that a shift of the fitness curve to the right is associated with significant survival benefits, and even slight differences in fitness levels are associated with substantial reductions in mortality risk.

Heart rate recovery, exercise capacity, and mortality risk in male veterans

Background: Both impaired heart rate recovery (HRR) and low fitness are associated with higher mortality risk. In addition, HRR is influenced by fitness status. The interaction between HRR, mortality, and fitness has not been clearly defined. Thus, we sought to evaluate the association between HRR and all-cause mortality and to assess the effects of fitness on this association. Methods: Treadmill exercise testing was performed in 5974 male veterans for clinical reasons at two Veterans Affairs Medical Centers (Washington, DC and Palo Alto, CA). HRR was calculated at 1 and 2 min of recovery. All-cause mortality was determined over a mean 6.2-year follow-up period. Results: Mortality risk was significantly and inversely associated with HRR, only at 2 min. A cut-off value of 14 beats/min at 2 min recovery was the strongest predictor of mortality for the cohort (hazard ratio = 2.4; CI 1.6–3.5). The mortality risk was overestimated when exercise capacity was not considered. When both low fitness and low HRR were present (≤6 metabolic equivalents and ≤14 beats/min), mortality risk was approximately seven-fold higher compared to the High-fit + High-HRR group (>6 metabolic equivalents and >14 beats/min). Conclusions: HRR at 2 min post exercise is strongly and inversely associated with all-cause mortality. Exercise capacity affects HRR-associated mortality substantially and should be considered when applying HRR to estimate mortality.

Cardiorespiratory Fitness and the Paradoxical BMI-Mortality Risk Association in Male Veterans

OBJECTIVE To assess the effect of fitness status on the paradoxical body mass index (BMI)-mortality risk association. PATIENTS AND METHODS From February 1, 1986, through December 30, 2011, we assessed fitness and BMI in 18,033 male veterans (mean age, 58.4 ± 11.4 years) in 2 Veterans Affairs Medical centers. We established 3 fitness categories on the basis of peak metabolic equivalents achieved during an exercise test as well as 5 BMI categories. The primary outcome was all-cause mortality. RESULTS During the follow-up period (median, 10.8 years, comprising a total of 207,168 person-years), 5070 participants (28%) died. After adjusting for age, risk factors, muscle-wasting diseases, medications, and year of entry, mortality risk was higher for individuals with a BMI of 20.1 to 23.9 kg/m(2) (hazard ratio [HR], 1.21; 95% CI, 1.12-1.30) and 18.5 to 20.0 kg/m(2) (HR, 1.56; 95% CI, 1.37-1.77) than for those with a BMI of 24.0 to 27.9 kg/m(2); mortality risk was not increased for those with a BMI of 28.0 kg/m(2) or greater. When stratified by fitness, the trend was similar for low-fit and moderate-fit individuals. However, mortality risk was not increased for high-fit individuals across BMI categories. When fitness status was considered within each BMI category, mortality risk increased progressively with decreased fitness and was more pronounced for moderate-fit (HR, 2.52; 95% CI, 2.06-3.08) and low-fit (HR, 2.48; 95% CI, 2.0-3.06) individuals with a BMI of 18.5-20.0 kg/m(2). Mortality risk was not significantly increased for high-fit individuals (HR, 1.17; 95% CI, 0.78-1.78; P=.45). CONCLUSION A high mortality risk associated with low BMI levels was observed only in moderate-fit and low-fit individuals, and not in high-fit individuals. Thus, fitness greatly affects the paradoxical BMI-mortality risk association. Furthermore, our findings indicate that lower BMI levels do not increase the risk for premature death as long as they are associated with high fitness. Thus, the paradoxically higher mortality risk observed with lower body weight as represented by lower BMI is likely the result of unhealthy reduction in body weight and, perhaps most importantly, considerable loss of lean body mass.

Statin Therapy, Fitness, and Mortality Risk in Middle-Aged Hypertensive Male Veterans

BACKGROUND Hypertension often coexists with dyslipidemia, accentuating cardiovascular risk. Statins are often prescribed in hypertensive individuals to lower cardiovascular risk. Higher fitness is associated with lower mortality, but exercise capacity may be attenuated in hypertension. The combined effects of fitness and statin therapy in hypertensive individuals have not been assessed. Thus, we assessed the combined health benefits of fitness and statin therapy in hypertensive male subjects. METHODS Peak exercise capacity was assessed in 10,202 hypertensive male subjects (mean age = 60.4 ± 10.6 years) in 2 Veterans Affairs Medical Centers. We established 4 fitness categories based on peak metabolic equivalents (METs) achieved and 8 categories based on fitness status and statin therapy. RESULTS During the follow-up period (median = 10.2 years), there were 2,991 deaths. Mortality risk was 34% lower (hazard ratio (HR) = 0.66; 95% confidence interval (CI) = 0.59-0.74; P < 0.001) among individuals treated with statins compared with those not on statins. The fitness-related mortality risk association was inverse and graded regardless of statin therapy status. Risk reduction associated with exercise capacity of 5.1-8.4 METs was similar to that observed with statin therapy. However, those achieving ≥8.5 METs had 52% lower risk (HR = 0.48; 95% CI = 0.37-0.63) when compared with the least-fit subjects (≤5 METs) on statin therapy. CONCLUSIONS The combination of statin therapy and higher fitness lowered mortality risk in hypertensive individuals more effectively than either alone. The risk reduction associated with moderate increases in fitness was similar to that achieved by statin therapy. Higher fitness was associated with 52% lower mortality risk when compared with the least fit subjects on statin therapy.

Heart Rate at Rest, Exercise Capacity, and Mortality Risk in Veterans

Heart rate (HR) at rest has been associated inversely with mortality risk. However, fitness is inversely associated with mortality risk and both increased fitness and β-blockade therapy affect HR at rest. Thus, both fitness and β-blockade therapy should be considered when HR at rest-mortality risk association is assessed. From 1986 to 2011, we assessed HR at rest, fitness, and mortality in 18,462 veterans (mean age = 58 ± 11 years) undergoing a stress test. During a median follow-up period of 10 years (211,398 person-years), 5,100 died, at an average annual mortality of 24.1 events/1,000 person-years. After adjusting for age, body mass index, cardiac risk factors, medication, and exercise capacity, we noted approximately 11% increase in risk for each 10 heart beats. To assess the risk in a wide and clinically relevant spectrum, we established 6 HR at rest categories per 10 heart beat intervals ranging from <60 to ≥100 beats. Mortality risk was significantly elevated at a HR at rest of ≥70 beats/min (hazard ratio 1.14, confidence interval 1.04 to 1.25; p <0.006) and increased progressively to 49% (hazard ratio 1.49, confidence interval 1.29 to 1.73; p <0.001) for those with a HR at rest of ≥100 beats/min. Similar trends were noted when for subjects aged <60 and ≥60 years and those treated with β blockers. In all assessments, mortality risk was consistently overestimated when fitness was not considered. In conclusion, HR at rest-mortality risk association was direct and independent. A progressive increase in risk was noted >70 beats/min for the entire cohort, those treated with β blockers, and those aged <60 and ≥60 years. Mortality risk was overestimated slightly when fitness status was not considered.