Introduction: Patients with type 2 diabetes mellitus (T2DM), have significantly higher risk of cardiovascular events, including heart failure (HF). Cardiorespiratory fitness (CRF) has been shown to favorably modify comorbidities of HF and lower the risk of HF. However, the independent effect of CRF on HF incidence in patients with T2DM has not been assessed. Methods: We identified 6,263 patients (aged 58.1+10.0 years) with T2DM and no HF or evidence of ischemia prior to an exercise treadmill testing (ETT). We established four fitness categories, based on age-stratified quartiles of peak metabolic equivalents (METs) achieved Least-Fit (4.7±1.1 METs; n= 1,547); Low-Fit (6.6±1.2 METs; n=2,104) Moderate-Fit (8.0±1.3 METs; n=1,454) and Fit (10.9±2.3 METs; n=1,160). Cox proportional hazards model was constructed to assess HF incidence risk associated with exercise capacity. The model was adjusted for age, BMI, race, comorbidities, and medications. The Least-Fit category served as the reference group. P-values <0.05 using two sided tests were considered statistically significant for all test. Results: During a follow-up of 12.9+7.1 years, 1,429 or 21.5% of these patients developed HF accounting for 13.5 events per 1,000 person-years of observation. The CRF-CHF risk association was inverse and graded. Risk decreased by 16% (HR: 0.84; CI: 0.82-0.87; p<0.001) for each 1-MET increase in CRF. When CRF categories were considered, HF risk declined progressively by 38% (HR: 0.62; CI: 0.55-0.71; p<0.001) for those in the Low-Fit; 49% in the Moderate-Fit (HR: 0.51; CI: 0.44-0.59; p<0.001), and 64% (HR: 0.36; CI: 0.30-0.43; p<0.001) for individuals in the Fit category. Conclusions: High levels of CRF were protective against HF incidence in Veterans with T2DM. The CRF-HF association was graded and independent of other risk factors. Disclosure C. Faselis: None. J.N. Myers: None. P. Narayan: Research Support; Self; AstraZeneca, Eli Lilly and Company. P. Karasik: None. H. Moore: None. A. Ahmed: None. H.M. Sheriff: None. E. Nylen: None. P. Kokkinos: None.

Introduction: Obesity and poor cardiorespiratory fitness (CRF) commonly coexists in type 2 diabetes (T2DM). Moreover, CRF has been associated with lower mortality risk in T2DM patients. In this study, we assessed the modulatory impact of fitness on mortality risk in T2DM patients across the obesity spectrum. Methods: We identified 6,888 T2DM patients (age 58.3+10.1 years) with no evidence of ischemia as indicated by a maximal standardized exercise treadmill test. We established two CRF categories based on age-adjusted median peak metabolic equivalents (METs) achieved: Unfit (5.4±1.3 METs; n=3,474) and Fit (9.0±2.3 METs; n=3414). We also defined the cohort based on body mass index (BMI) normal-weight (BMI 18.5-24.9 kg/m2); over-weight (BMI 25.0-29.9 kg/m2); and obese (BMI ≥30 kg/m2). We then combined the BMI and CRF categories to form a total of six groups CRF-BMI categories. Cox proportional hazards models, adjusted for known risk factors were constructed to assess the association between CRF-BMI interaction and mortality risk. Results: During a follow-up of 14.2+6.9 years, 2,495 patients died, accounting for 25.5 events/1,000 person-years of observation. When CRF-BMI groups were considered, the normal-weight-Fit category was used as the referent. Mortality risk in the normal-weight but Unfit patients was 64% higher compared to their Fit counterparts (HR 1.64; 95% CI: 1.35-2.00). In the overweight category, mortality risk was 20% lower in the Fit (HR 0.80; 95% CI: 0.67-0.94) and 28% higher (HR 1.28; 95% CI: 1.09-1.51) in Unfit patients. In obese category the risk was 29% lower for the Fit (HR 0.71; 95% CI: 0.60-0.86) and 23% higher for the Unfit patients (HR 1.23; 95% CI: 1.05-1.45). Conclusion: Increased CRF favorably modulates mortality risk across the obesity spectrum in T2DM patients. Poor fitness had a substantially greater and negative impact on Normal than over-weight and obese individuals. Disclosure E. Nylen: None. P. Kokkinos: None. C. Faselis: None. P. Narayan: Research Support; Self; AstraZeneca, Eli Lilly and Company. P. Karasik: None. J.N. Myers: None.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide, affecting more than 30% of general population. High-fat diets, physical inactivity and obesity, all prevalent in the western societies, are strongly associated with the development and progression of NAFLD. Current drug therapies have not consistently shown substantial beneficial effects. Thus, lifestyle modification appears to be the optimal intervention in combating the disease. Accordingly, several studies have concluded that weight loss, via increase in physical activity, and dietary interventions could potential ameliorate biochemical, histological, and structural abnormalities of non-alcoholic fatty liver disease. The aim of this review is to summarize the findings of these lifestyle intervention studies and discuss the implementation of each intervention, and its effectiveness in the management of the disease in everyday clinical practice.

Objective: Left ventricular hypertrophy (LVH) increases the risk of cardiac events. Exercise blood pressure (BP) and ambulatory BP (ABPM) are associated with LVH, while cardiorespiratory fitness (CRF) is associated with lower BP at absolute workloads. This suggests that abnormally elevated BP during daily activities may be the stimulus for LVH. Thus, we assessed the association between exercise BP, ABPM and LVH in normotensive individuals based on office BP. Design and method: We assessed cardiac structure and function, ABPM, and CRF in 1,022 normotensive men (n = 697; age: 51 ± 10) and women (n = 325; age: 54 ± 10), not treated by any medications. Results: LVH was present in 24.7% with women having approximately 3 times higher prevalence (14.9% vs 45.5%). The strongest predictors of LVH were the increase in SBP from resting to exercise at Bruce I (5 METs), (OR = 1.17; p < 0.001); the difference between resting and SBP at 3 min of exercise (OR = 1.17; p < 0.001, and daytime ABPM (OR = 1.16; p < 0.001). There was also a 44% reduction in the risk for LVH for every 1 MET increase in the workload (OR: 0.56; P < 0.001). Cut-off analysis revealed a threshold for LVH > 150mmHg for SBP at 5 METs and 15 mm Hg increase beyond resting BP at Stage I and 140 mm Hg for daytime SBP. The LVH risk increased by approximately 5-fold for every 10 mm Hg increases beyond these thresholds. To account for the impact of CRF on LVH, we stratified the cohort into age-specific fitness quartiles and compared cardiac parameters (Table).Conclusions: Systolic BP response during workloads of approximately 5 METs provides the stimulus for increased left ventricular mass and LVH. CRF attenuates the BP response and the development of LVH.

An inverse association between cardiorespiratory fitness and the incidence of chronic disease has been established by large, well-designed epidemiologic studies. Collectively, the findings support that these health benefits are realized at relatively moderate levels of exercise or physical activity and increase in a dose-response fashion. This supports the concept that physical activity should be promoted by health care professional for optimal health. This review is focused on the influence of physical activity and cardiorespiratory fitness on the incidence of cardiometabolic risk factors and diseases.

Introduction: An association exists between being overweight and obese and an increased risk of certain types of cancers. In recent years even though there has been a decline in cancer rates in the general population, cancer rates in the overweight and obese have increased. Specific factors that may protect obese individuals against cancer have not been identified. Hypothesis: We assessed the hypothesis that improved cardiorespiratory fitness (CRF) will attenuate the risk of obesity associated cancer. Methods: We studied a total of 6,830 obese Veterans aged 56.2 ±10.4 years, of whom 67.2% (6471 of 6830) were African-American, 94.7% (4581 of 6830) males, 57.4% (3921 of 6830 smokers, 94.4% (6439 of 6830) with a past history of alcohol or drug use and 60.0% (4100 of 6830) were on statins. Obesity was defined as body mass index (BMI) ≥30.0 kg/m 2 and mean BMI for the cohort was 34.4±4.2 kg/m 2 . None of the patients had a diagnosis of cancer at baseline. Participants completed a maximal exercise tolerance test (ETT) as a part of clinical evaluation at either the Department of Veterans Affairs Medical Centers in Washington, DC or Palo Alto, CA and metabolic equivalents (METs) were estimated based on peak exercise time and treadmill grade. Based on these METs achieved on ETT, patients were divided into 4 age-based CRF categories (mean ± SD): least-fit (4.8±1.3 METs; n=1978), low-fit (6.8±1.2 METs; n=2210), moderately-fit (8.3±1.2 METs; n=1674), and high-fit (11.1±2.2 METs; n=968). Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incidence of cancer across these age-based fitness categories for the entire obese cohort, using least-fit as the reference group. The models were adjusted for age, race, gender, smoking, alcohol and drug use. Results: During a median follow-up of 11.1 years, 9.5% (646 of 6830) of the cohort developed cancer with an event rate of 8.0 per 1000-person years of follow-up. An inverse and graded association was observed between CRF and cancer rates. The adjusted risk of cancer was 15% lower for each 1-MET increase in exercise capacity (HR=0.85; CI: 0.82-0.89). When incidence rates were assessed across CRF categories using the least fit as the referent group, the incidence of cancer was 31% lower in the moderately-fit group (HR=0.69; 95% CI: 0.56-0.86) and 81% lower in the high-fit group (HR=0.19; 95% CI: 0.12-0.29). Conclusions: CRF was inversely associated with rate of cancer in obese Veterans. For each 1-MET increase in fitness, cancer rate was 15% lower.

Introduction: Obesity, defined as body mass index (BMI) ≥30 kg/m 2 , is associated with increased incidence of heart failure (HF). Increased cardiorespiratory fitness (CRF), as indicated by increased exercise capacity, is associated with lower risk of cardiovascular disease and HF. However, the CRF-BMI-HF interaction has not been fully explored. Hypothesis: We assessed the hypothesis that the risk of HF associated with increased BMI is moderated by increased CRF. Methods: We identified 19,881 Veterans (mean age: 58.0±11.3 years) who completed an exercise tolerance test (ETT) to assess either CRF status or suspected ischemia at two VA Medical Centers (Washington DC and Palo Alto, CA). None had documented HF at baseline or evidence of ischemia during the ETT. We established four BMI categories: <25 kg/m 2 ; 25-29.9 kg/m 2 ; 30-34.9 kg/m 2 ; and ≥35 kg/m 2 . In addition, we established four CRF categories based on age-stratified quartiles of peak metabolic equivalents (METs) achieved (mean ± SD): Least-Fit (4.5±1.2 METs; n=4,743); Low-Fit (6.6±1.3; n=5,103); Moderate-Fit (8.0±1.3 METs; n=5,084); and High-Fit (11.1±2.4 METs; n=4,951). Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals [CI] for incidence of HF across BMI categories for the entire cohort, using BMI 25-29.9 kg/m 2 (lowest HF rate) as the reference group. We then stratified the cohort by the four BMI categories and assessed HF risk across CRF categories within each stratum, using the Least-fit category as the reference group. The models were adjusted for age, race, gender, cardiac risk factors, sleep apnea, alcohol dependence, medications. Results: During follow-up (median=11.8 years), 2,193 developed HF (10.5 per 1,000 person-years of follow-up). The HF risk for normal weight individuals (18.5-24.9 kg/m2) was 10% higher (p=0.93). For obese individuals, the HF risk was 22% higher in those with BMI 30-34.9 kg/m 2 (HR=1.22; 95% CI: 1.09-1.35) and 50% higher (HR=1.50, 95% CI: 1.32-1.72) for those with BMI ≥35 kg/m 2 . When CRF (peak METs achieved) was introduced in the model, the risk for those with BMI 30-34.9 was reduced from 22% to 16% (HR=1.16; 95% CI: 1.04-1.29) and from 50% to 29% (HR=1.29; 95% CI: 1.13-1.48) among those with ≥35 kg/m 2 . For every 1-MET increase in exercise capacity, HF risk was 15% lower (HR=0.85; 95% CI: 0.83-0.87). We then assessed the impact of CRF on the risk of HF within each of the four BMI categories. The HF risk declined progressively (range: 25% to 69%; p<0.01) with increasing fitness within all BMI categories. Conclusions: The obesity-associated increased risk of HF was attenuated by increased CRF. The HF risk was progressively decreased with increased CRF within all BMI categories.

Patients with resistant systemic hypertension have poorer outcomes than nonresistant hypertensives. The purpose of this study was to evaluate the association between cardiorespiratory fitness and all-cause mortality in black male Veterans with resistant systemic hypertension. Patients were identified from a cohort undergoing exercise tolerance test at the department of Veterans Affairs Medical Center in Washington, DC. Patients were divided into 4 cardiorespiratory fitness categories based on age-specific peak metabolic equivalents achieved on a standard Bruce protocol. Multivariate Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality across all fitness categories. A total of 1,276 patients out of 9,068 hypertensives had resistant hypertension defined as systolic and/or diastolic blood pressure >140 and/or >90 mm Hg, respectively, on 3 antihypertensive medications, one of which was a diuretic or use of >4 antihypertensive medications. During a follow-up of 9.5 +/- 4.2 years, an inverse association was observed between cardiorespiratory fitness and all-cause mortality in patients with resistant hypertension. Compared with the least-fit group, mortality was reduced by 21% in the low-fit group (HR 0.79, CI 0.60 to 1.05; p value: 0.280), 36% in the moderate-fit group (HR 0.64, CI 0.48 to 0.87; p value 0.001), and 62% in the high-fit group (HR 0.38, CI 0.25 to 0.56; p value <0.001). In conclusion, an inverse association was observed between the level of cardiorespiratory fitness and all-cause mortality in patients with resistant systemic hypertension. Compared with the least-fit referent group, the high-fit group had a significant 62% lower risk of all-cause mortality. (C) 2017 Elsevier Inc. All rights reserved.

Introduction: Stroke incidence is significantly higher in hypertensive patients compared to normotensive subjects. Cardiorespiratory fitness (CRF) is associated with a more favorable cardiovascular health. The CRF-stroke incidence association in hypertensive patients has not been fully explored. Hypothesis: We assessed the hypothesis that CRF is inversely and independently associated with stroke incidence in hypertensive patients. Methods: From 1985 to 2014, we identified 12,933 hypertensive patients (mean age: 60±11 years) with a normal response to an exercise tolerance test and no prior history of stroke. We established five fitness categories based on age-stratified quintiles of peak metabolic equivalents (MET) achieved: Least-Fit (4.1±1.0 METs; n=2,516); Low-Fit (5.6±1.0; n=2,772); Moderate-Fit (7.0±1.0 METs; n=2,803); Fit (8.4±1.3 METs; n=3,282); and High-Fit (11.4±2.0 METs; n=1,560). A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals [CI] for incidence of stroke across fitness categories. The model was adjusted for age, resting blood pressure, BMI, atrial fibrillation, gender, race, other cardiac risk factors, alcohol dependence and medications. The Least-fit category was used as the reference group. Results: During follow-up (median=11.4 years; 152,408 person-years), 694 individuals (4.5 events per 1,000 person-years) developed stroke. The risk for stroke was 5% lower for each 1-MET increase in exercise capacity (HR=0.95, CI: 0.92-0.98; p<0.001). When considering fitness categories, stroke risk was lower by 28% (HR=0.72; CI: 0.57-0.90) for the Moderate-Fit and Fit individuals (HR=0.72; CI: 0.58-0.89) and 33% for High-Fit individuals (HR= 0.67; CI: 0.50-0.88). Conclusions: Increased CRF was inversely related to stroke incidence in hypertensive patients. The association was independent and graded.

The association between physical activity and health has been recognized since antiquity. Yet daily physical activity in modern societies, especially for the last 100 years, has declined greatly. Additionally, people tend to become less physically active as they age. This is unfortunate because of the known link between physical activity and health. Physical inactivity can lead to many physiologic maladaptations that can increase the risk of cardiometabolic abnormalities and death. This manuscript reviews the influence of physical activity on cardiometabolic health and mortality.

BACKGROUND: Impact of cardiorespiratory fitness on statin-related incidence of type 2 diabetes has not been assessed. We assessed the cardiorespiratory fitness and diabetes incidence association in dyslipidemic patients on statins.METHODS: We identified dyslipidemic patients with a normal exercise test performed during 1986 and 2014 at the Veterans Affairs Medical Centers in Washington, DC or Palo Alto, Calif. The statin-treated patients (n = 4092; age = 58.8 +/- 10.9 years) consisted of 2701 Blacks and 1391 Whites. None had evidence of type 2 diabetes prior to statin therapy. We formed 4 fitness categories based on age and peak metabolic equivalents achieved: Least-fit (n = 954), Low-fit (n = 1201), Moderate-fit (n = 1242), and High-fit (n = 695). The non-statin-treated cohort (n = 3001; age = 57.2 +/- 11.2 years) with no evidence of type 2 diabetes prior to the exercise test served as controls.RESULTS: Diabetes incidence was 24% higher in statin-treated compared with non-statin-treated patients (P <. 001). In the statin-treated cohort, 1075 (26.3%) developed diabetes (average annual incidence rate of 30.6 events/1000 person-years). Compared with the Least-fit, adjusted risk decreased progressively with increasing fitness and was 34% lower for High-fit patients (hazard ratio [HR] 0.66; 95% confidence interval [CI], 0.53-0.82; P <. 001). Compared with the nonstatin cohort, elevated risk was evident only in the Least-fit (HR 1.50; 95% CI, 1.30-1.73; P <. 001) and Low-fit patients (HR 1.22; 95% CI, 1.06-1.41; P =.006).CONCLUSIONS: Risk of diabetes in statin-treated dyslipidemic patients was inversely and independently associated with cardiorespiratory fitness. The increased risk was evident only in relatively low-fitness patients. Improving fitness may modulate the potential diabetogenic effects of statins. Published by Elsevier Inc.

Objective: Stroke incidence in hypertension and obesity increase significantly higher in hypertensive patients compared to normotensive subjects. Cardiorespiratory fitness (CRF) is associated with a more favorable cardiovascular health. The CRF-stroke incidence association in hypertensive patients has not been fully explored. Design and method: We assessed the hypothesis that CRF is inversely and independently associated with stroke incidence in hypertensive patients. From 1985 to 2014, we identified 9,885 hypertensive overweight or obese patients (mean age: 59 ± 10 years) with a normal response to an exercise tolerance test (ETT) and no prior history of stroke. We established five fitness categories based on age-stratified quintiles of peak metabolic equivalents (MET) achieved: Least-Fit (4.4 ± 1.2 METs; n = 2,032); Low-Fit (5.9 ± 1.1; n = 2,347); Moderate-Fit (7.2 ± 1.1 METs; n = 2,152); Fit (8.4 ± 1.2 METs; n = 2,060); and High-Fit (11.0 ± 2.0 METs; n = 1,317). A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals [CI] for incidence of stroke across fitness categories. The model was adjusted for age, resting blood pressure, atrial fibrillation, gender, race, other cardiac risk factors, alcohol dependence and medications. The Least-fit category was used as the reference group. Results: During follow-up (median = 11.5 years; 117,429 person-years), 517 individuals (4.4 events per 1,000 person-years) developed stroke. The risk for stroke was 6% lower for each 1-MET increase in exercise capacity (HR = 0.94, CI: 0.90–0.98; p < 0.004). When considering fitness categories, stroke risk was lower by 28% (HR = 0.72; CI: 0.61–0.99) for the Low-fit individuals and approximately 34% for the Moderate-fit, Fit and High-Fit (HR = 0.66; CI: 0.49–0.90). Conclusions: Increased CRF was inversely related to stroke incidence in hypertensive patients. The association was independent and graded.

Systemic hypertension and physical exercise are both associated with cardiac adaptations. The impact is most prominent on the left side of the heart, which hypertrophies leading to left ventricular hypertrophy. This article reviews structural and functional cardiac changes seen in hypertensive and athlete's hearts.