Charles Faselis

All Publications

• Target-Dose Versus Below-Target-Dose ACE Inhibitors and Lower Risk of Kidney Failure in U.S. Veterans with HFrEF. European journal of heart failure Ahmed, A. A., Lu, F., Zhang, S., Raman, V. K., Patel, S. S., Morgan, C. J., Faselis, C., Lam, P. H., Fonarow, G. C., Heidenreich, P. A., Ahmad, T., Anker, S. D., Metra, M., Pitt, B., Butler, J., Zullo, A. R., Moore, H. J., Vargas, J. D., Arundel, C., Sánchez-Vallejo, C. A., Deedwania, P., Sheriff, H. M., Zeng-Treitler, Q., Wu, W. C., Ahmed, A. 2026

  Abstract

  In patients with heart failure with reduced ejection fraction (HFrEF), target-dose (vs. below-target-dose) angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve clinical outcomes but worsen kidney function. Less is known about their effect on kidney failure (KF), especially in those with advanced chronic kidney disease (CKD), the examination of which was the objective of our study.Of the 154,945 Veterans with HFrEF (EF≤40%) and no baseline KF, 134,046 were initiated on ACEIs (target-dose, n=37,667) and 20,899 were initiated on ARBs (target-dose, n=4017) during 2000-2018. While remaining blinded to study outcomes, we assembled two propensity score-matched cohorts: ACEI (N=70,860; target-dose, n=35,430) and ARB (N=7900; target-dose, n=3950), balanced on 76 baseline characteristics. Hazard ratios (95% CIs) associated with target doses were estimated for 5-year KF and all-cause mortality, up to December 31, 2023. In the ACEI cohort, target-dose was associated with a 18% lower risk of KF (HR, 0.82; 95% CI, 0.75-0.89) and a 6% lower risk of death (HR, 0.94; 95% CI, 0.92-0.97). Subgroup and spline analyses showed that while the KF association was significant for those with baseline eGFR <35 ml/min/1.73m2, the mortality association was significant for those with eGFR ≥35 ml/min/1.73m2. In the ARB cohort, target-dose had no association with outcomes.In patients with HFrEF, target-dose (vs. below-target-dose) ACEIs, but not ARBs, were associated with lower risk of KF, which was significant in those with advanced CKD. The survival benefit was modest and limited to those without advanced CKD.

  View details for DOI 10.1093/ejhf/xuag076

  View details for PubMedID 41797492

• Serum Magnesium and Outcomes in U.S. Veterans with Heart Failure. The American journal of medicine Yin, Y., Morgan, C. J., Costello, R. B., Fonarow, G. C., Cheng, Y., Tekle, S., Faselis, C., Lam, P. H., Sheriff, H. M., Rosanoff, A., Anker, S. D., Raman, V. K., Moore, H. J., Vargas, J. D., Patel, S. S., Sen, S., Liu, S., Zullo, A., Heidenreich, P. A., Gottlieb, S. S., Deedwania, P., Wu, W. C., Zeng-Treitler, Q., Ahmed, A. 2026

  Abstract

  Magnesium is essential for myocardial function and rhythm. Although typically well-regulated, patients with heart failure are prone to deficiency. Most clinical laboratories define normal serum magnesium as 1.6-2.6 mg/dL, but this range may include chronic latent magnesium deficiency. The Magnesium Global Network (MaGNet) recommends 2.1-2.3 as optimal. We examined outcomes in heart failure patients across and outside these ranges.Using ambulatory serum magnesium, we categorized 627,349 Veterans with heart failure (2001-2023) into <1.6 (6%), 1.6-1.7 (11%), 1.8-2.0 (39%), 2.1-2.3 (34%; reference) and >2.3 (10%) mg/dL. Cox models estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for one-year mortality. Restricted cubic spline models assessed nonlinear associations between serum magnesium as a continuous variable, using two reference values, the lower limits of current (1.6) and MaGNet (2.1) ranges.All-cause mortality occurred in 15.4%, 13.3%, 11.6%, 11.5%, and 16.2% of the patients with serum magnesium <1.6, 1.6-1.7, 1.8-2.0, 2.1-2.3, and >2.3 respectively. Corresponding adjusted HRs (95% CIs) were 1.36 (1.32-1.41), 1.23 (1.20-1.26), 1.07 (1.05-1.09), 1.00 (reference), and 1.23 (1.20-1.26), respectively. When the lower limit of current clinical range was used as the reference, restricted cubic spline analysis revealed a U-shaped association, with the lowest HR between 1.6-2.5 (which included the MaGNet optimal range of 2.1-2.3 mg/dL), with significantly higher risks outside these ranges.In US Veterans with heart failure, ambulatory serum magnesium levels showed a U-shaped, independent association with one-year mortality, with the lowest risk observed between 1.6-2.5 mg/dL, consistent with current clinical range of normal values, and higher risks at both lower and higher levels.

  View details for DOI 10.1016/j.amjmed.2026.02.021

  View details for PubMedID 41802533

• Long-term changes in cardiorespiratory fitness and incidence of Alzheimer's disease and related dementias among US Veterans. Alzheimer's & dementia (New York, N. Y.) Kokkinos, P., Cheng, Y., Zamrini, E., Faselis, C., Sui, X., Morgan, C. J., Sheriff, H. M., Myers, J., Franklin, B., Alderman, B., Zeng-Treitler, Q. 2025; 11 (4): e70171

  Abstract

  Alzheimer's disease and related dementias (ADRD) remain a leading cause of morbidity and mortality. Poor cardiorespiratory fitness (CRF) has been identified as a potential risk factor for ADRD. Since CRF is a modifiable risk factor, we evaluated the association between CRF changes over time and ADRD risk.Our cohort consisted of US Veterans (mean age 60.7±9.0 years; male, n = 128,749; and female, n = 5,421). All completed two standardized exercise treadmill tests (ETT) between 2000 and 2017, at least 1 year apart (mean 3.5±2.7 years), with no evidence of ADRD at the time of both ETTs. We assigned participants to one of three age- and gender-specific CRF categories based on peak metabolic equivalents (METs) achieved during the initial ETT and five categories based on CRF changes at the final ETT. Cox proportional hazard models adjusted for age, comorbidities, and medications were used to evaluate ADRD risk across CRF categories.During the up to 15.0 years of follow-up (mean 7.2 years; interquartile range [IQR] 4.3-9.9 years), totaling 966,337 person-years, 10,699 ADRD cases occurred (11.1 events/1000 person-years). Compared to the Low-fit group, ADRD risk decreased progressively with increased CRF and was 22% lower (hazard ratio [HR] 0.78; 95% confidence interval [CI]: 0.75-0.81; p<0.0001) for Moderate-fit individuals and 30% lower (HR 0.70, 95% CI: 0.67-0.73; p<0.0001) for High-fit individuals. Compared to Low-fit individuals with no CRF change, an increase of 0.1-<2.0 METs was associated with a 13% lower ADRD risk (HR 0.87, 95% CI 0.79-0.95; p<0.0001), while an increase of ≥2.0 METs was associated with a 24% lower risk (HR 0.76, 95% CI 0.70-0.83; p<0.0001).We observed an inverse and independent association between CRF and ADRD risk. An improvement in CRF of approximately ≥1.0 MET led to a lower risk of ADRD in Low-fit individuals. These findings may have considerable clinical and public health significance in reducing ADRD risk.Poor cardiorespiratory fitness (CRF) has been identified as a potential risk factor for Alzheimer's disease and related dementias (ADRD). Thus, we assessed the potential impact of changes in CRF over time on ADRD risk.CRF changes reflected inverse and proportional changes in ADRD risk.Low-fit individuals who improved their CRF by ≥0.1 metabolic equivalents (METs) had a 13%-24% lower ADRD risk. Conversely, a decline in CRF by ≥2.0 METs was associated with a 14% increased ADRD risk among Moderate-fit and a 18% increase among High-fit individuals.

  View details for DOI 10.1002/trc2.70171

  View details for PubMedID 41409742

  View details for PubMedCentralID PMC12706117

• Oral magnesium and outcomes in US veterans with heart failure. European heart journal Yin, Y., Costello, R. B., Fonarow, G. C., Heidenreich, P. A., Morgan, C. J., Faselis, C., Cheng, Y., Zullo, A. R., Liu, S., Lam, P. H., Rosanoff, A., Vargas, J. D., Gottlieb, S. S., Deedwania, P., Moore, H. J., Shao, Y., Sheriff, H. M., Wu, W. C., Zeng-Treitler, Q., Ahmed, A. 2025

  Abstract

  Magnesium deficiency is associated with poor outcomes in patients with heart failure (HF), but less is known about the impact of oral magnesium therapy. This study aimed to examine the association of oral magnesium with outcomes in patients with HF and whether it depends on baseline serum magnesium.Of 54 696 Veterans with HF (2001-2023) and hypomagnesemia (serum magnesium <1.7 mg/dL), 10 695 were initiated on oral magnesium (median dose, 420 mg/day). A propensity score-matched cohort of 21 098 patients (treated, n = 10 549) balanced on 71 baseline characteristics was assembled while remaining outcome-blinded. This process was repeated to assemble a matched cohort of 11 634 patients (treated, n = 5817) with normomagnesemia (serum magnesium, 1.7-2.3 mg/dL). Hazard ratios (HR) (95% confidence intervals [CIs]) for one-year outcomes associated with oral magnesium were estimated.In the hypomagnesemia cohort, HF hospitalization or death occurred in 21.7% of patients not receiving and 20.1% receiving oral magnesium (HR: 0.91; 95% CI: 0.86-0.97). Respective HRs (95% CIs) in subgroups with serum magnesium 1.6 (n = 5929), 1.3-1.5 (n = 11 293) and <1.3 (n = 3876) mg/dL were 0.99 (0.88-1.12), 0.91 (0.84-0.98; interaction P = .20), and 0.81 (0.71-0.93; interaction P = .03). Respective rates in the normomagnesemia cohort were 17.8% and 19.5% (HR: 1.11; 95% CI: 1.02-1.21). Spline regression analysis revealed that HRs were lower at serum magnesium <1.5 mg/dL, higher at >1.8 mg/dL, and not significant at 1.5-1.8 mg/dL.Oral magnesium therapy was associated with a lower risk of HF hospitalization or death in patients with HF and hypomagnesemia. Future clinical trials need to confirm these findings.

  View details for DOI 10.1093/eurheartj/ehaf881

  View details for PubMedID 41338273

• Explaining subgroup findings using spline regression: Risk of kidney failure in patients with heart failure and normal kidney function receiving RAS inhibitors. The American journal of medicine Patel, S. S., Heidenreich, P. A., Morgan, C. J., Faselis, C., Zhang, S., Wu, W. C., Lam, P. H., Palant, C. E., Zeng-Treitler, Q., Fonarow, G. C., Ahmed, A. 2025

  View details for DOI 10.1016/j.amjmed.2025.10.002

  View details for PubMedID 41219087

• Diabetes Incidence According to Statin Intensity Regimen, Body Mass Index, and Cardiorespiratory Fitness. Mayo Clinic proceedings Kokkinos, P., Faselis, C., Pittaras, A., Samuel, I. B., Cadenas-Sánchez, C., Nylen, E., Lavie, C., Barry, F., Malin, S. K., Murphy, R., Myers, J. 2025

  Abstract

  To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and type 2 diabetes mellitus (T2DM).A nationwide cohort of dyslipidemic patients (n=311,269; age 60.8±9.2 years) was treated with statins for 6 months or longer, with no T2DM before statin initiation. All completed a standardized exercise treadmill test between October 1, 1999, and September 3, 2020, with no evidence of ischemia. We formed age- and gender-specific five CRF categories according to peak metabolic equivalents (METs) achieved, four BMI categories, and two statin intensity categories.During a median follow-up of 10.9 years (3,421,650 person-years of observation), 56,994 developed T2DM (incidence rate 16.7 events/1000-person-years). The adjusted risk was 23% higher in patients on high-intensity compared with those on low-intensity statins (HR, 1.23; 95% CI, 1.21 to 1.25). The T2DM risk increased progressively with higher BMI and high-intensity statin regimen to a 4.44-fold increase (HR, 4.44; 95% CI, 4.22 to 4.67) for obese patients. Conversely, the CRF-T2DM association was inverse and graded regardless of BMI or static-intensity regimen and was approximately 30% to 60% lower risk for patients achieving greater than or equal to 8.4±1.2 METs. Compared with least-fit/low-intensity statin-treated patients, T2DM risk was 21% higher for least-fit/high-intensity statin-treated patients (HR, 1.21; 95% CI, 1.18 to 1.25), and 47% lower (HR, 0.53; 95% CI, 0.51 to 0.56) in highly fit/high-intensity statin-treated patients.High-intensity statin therapy was associated with an increased risk of T2DM. The risk increased progressively with higher BMI and decreased with higher CRF. Strategies to improve fitness and weight loss in patients on high-intensity statins can potentially lower T2DM risk.

  View details for DOI 10.1016/j.mayocp.2025.06.004

  View details for PubMedID 41031997

• Cardiorespiratory Fitness and Colorectal Cancer Incidence in US Veterans: A Cohort Study. Mayo Clinic proceedings Ali, A., Howard, D. E., Samuel, I. B., Murphy, R., Pittaras, A., Campbell, S., Becker, O. M., Mrkoci, N., Myers, J., Lavie, C., Ladas, A., Faselis, C., Kokkinos, P. 2025

  Abstract

  To evaluate the association between cardiorespiratory fitness (CRF), objectively measured by standardized exercise treadmill test (ETT), and colorectal cancer incidence.The study involved 643,583 US veterans nationwide (41,968 women) from the Exercise Testing and Health Outcomes Study (ETHOS) cohort. None had cancer diagnosis before ETT or had cancer other than colorectal after ETT. Participants completed an ETT (Bruce) with no evidence of ischemia and were stratified into CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved: least fit (n=119,673; METs: 4.8±1.5), low fit (n=157,059; METs: 7.3±1.4), moderate fit (n=122,194; METs: 8.6±1.4), fit (n=170,324; METs: 10.5±1.0), and high fit (n= 74,333; METs: 13.6±1.8).During a median follow-up period of 10.0 years, totaling 6,632,561 person-years, 8190 participants had colorectal cancer (12.4 events per 10,000 person-years). Cardiorespiratory fitness was inversely associated to colorectal cancer risk, independent of comorbidities, with a 9% risk reduction per 1-MET higher in CRF (hazard ratio [HR], 0.91; 95% CI, 0.90 to 0.92), for men and women and across all races. Compared with least fit, the risk of those in the next CRF category (low fit) was 14% lower (HR, 0.86; 95% CI, 0.81 to 0.91). The risk declined progressively with increased CRF and was 57% lower (HR, 0.43; 95% CI, 0.29 to 0.48) for those in the high-fit group.We observed an inverse and graded association between CRF and colorectal cancer incidence, across races and sexes, independent of comorbidities. The lower risk was evident in those with a peak CRF of approximately 8.5 to 10.5 METs, a relatively moderate CRF status attainable by most middle-aged and older individuals.

  View details for DOI 10.1016/j.mayocp.2025.03.015

  View details for PubMedID 40719661

• Translation of clinical practice to research: the VETS and ETHOS epidemiologic prospective cohorts. Frontiers in cardiovascular medicine Myers, J., Kokkinos, P., Samuel, I. B., Faselis, C., Fletcher, R., Froelicher, V. 2025; 12: 1577931

  Abstract

  For >30 years, the Exercise Testing and Health Outcomes Study (ETHOS) and the Veterans Exercise Testing Study (VETS) cohorts have contributed significantly to the understanding of the association between cardiorespiratory fitness (CRF), health outcomes, and the prevention of chronic disease. Multiple reports from these studies have consistently shown an inverse and graded association between higher CRF and the incidence of chronic conditions including cardiovascular disease, site-specific cancers, chronic kidney disease, rhythm disturbances, and neurological conditions. In addition, higher CRF is inversely related to health care costs. Among individuals whose CRF level improves over periods of time ranging from 5 to 7 years, improvements in health outcomes have been observed, and the converse is true among those who decrease CRF over time. The Veterans Administration Health Care System (VAHCS) has pioneered electronic medical records that have facilitated epidemiologic research and have provided the foundation for the ETHOS and VETS cohorts. The VAHCS is particularly suited for epidemiologic studies because patients can be accurately traced through VAHCS benefits services. These studies have helped formulate guidelines on exercise testing as well as recommendations from national and international health organizations on physical activity. In addition, they have provided strong support for efforts to reduce sedentary behavior, promote physical activity, and enhance CRF by public health organizations and healthcare systems in order to reduce the risk of chronic disease. This paper outlines the development of the ETHOS and VETS cohorts and highlights key studies contributing to our understanding of CRF as a critical health determinant.

  View details for DOI 10.3389/fcvm.2025.1577931

  View details for PubMedID 40709207

  View details for PubMedCentralID PMC12288094

• Higher Risk of Kidney Failure Associated with Angiotensin Receptor Blockers Versus ACE Inhibitors in Patients with Heart Failure. The American journal of medicine Moore, H. J., Wu, W. C., Heidenreich, P. A., Rossignol, P., Patel, S. S., Lu, F., Lam, P. H., Ahmed, A. A., Faselis, C., Butler, J., Palant, C. E., Pitt, B., Weir, M. R., Deedwania, P., Atkins, D., Raman, V. K., Rangaswami, J., Vargas, J. D., Zhang, S., Morgan, C. J., Sheriff, H. M., Zeng-Treitler, Q., Fonarow, G. C., Ahmed, A. 2025

  Abstract

  Renin-angiotensin system (RAS) inhibition with angiotensin-covering enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is associated with a lower risk of kidney failure in patients with heart failure. We examined whether this association varies between ACEIs and ARBs.From 300,361 Veterans with heart failure without kidney failure initiated on ACEIs (n=256,224) or ARBs (n=44,137), we assembled a propensity score-matched cohort of 88,178 patients while remaining blinded to study outcomes. Hazard ratio (95% CI) for 5-year kidney failure in patients in the ARB group was estimated. Kidney failure was defined as receipt of kidney replacement therapy or persistent drop in baseline estimated glomerular filtration rate (eGFR) to <15 mL/min/1.73m2.Matched patients had mean age 71 years, ejection fraction 44%, eGFR 70 mL/min/1.73m2, 97% were male, 18% African American, 23% received ACEIs or ARBs in high doses, and were balanced on 76 baseline characteristics. Kidney failure occurred in 4.4% (1961/44,089) and 5.4% (2389/44,089) of the patients in the ACEI and ARB groups, respectively. When accounted for the competing risk of death, patients in the ARB group had a 20% (95% CI, 13-28%) higher risk of kidney failure, which was similar in low-dose and high-dose subgroups. The associated risk of death was 5% (95% CI, 3-7%) lower in the ARB group, which was only significant in the low-dose group (7% vs 0%; interaction p, 0.007).In patients with heart failure, ARBs (vs. ACEIs) are associated with a higher risk of incident kidney failure. These findings need to be confirmed in future clinical trials.

  View details for DOI 10.1016/j.amjmed.2025.05.024

  View details for PubMedID 40419103

• Renin Angiotensin Inhibition and Lower Risk of Kidney Failure in Patients with Heart Failure: Subtitle: RAS inhibition and kidney failure in heart failure. The American journal of medicine Patel, S. S., Raman, V. K., Zhang, S., Sheriff, H. M., Fonarow, G. C., Heidenreich, P. A., Faselis, C., Lam, P. H., Morgan, C. J., Moore, H., Atkins, D., Cheng, Y., Shao, Y., Deedwania, P., Palant, C. E., Sauer, B. C., Mehta, R. L., Love, T. E., Allman, R. M., Heimall, M. S., Wu, W., Zeng-Treitler, Q., Ahmed, A. 2025

  Abstract

  BACKGROUND: Renin-angiotensin system (RAS) inhibitors reduce risk of kidney failure in patients with chronic kidney disease, but worsen kidney function in heart failure patients, especially in those with chronic kidney disease. Less is known about risk of kidney failure in heart failure patients receiving RAS inhibitors.METHODS: We used propensity score matching for outcome-blinded assembly of 168,860 Veterans with heart failure phenotyped by artificial intelligence who were balanced on 77 baseline characteristics and initiated on RAS inhibitors. Hazard ratio (95% CI) for 5-year kidney failure in high-dose (versus low-dose) RAS inhibitor group was estimated, accounting for competing risk of death. Kidney failure was defined as kidney replacement therapy or estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2.RESULTS: New-onset kidney failure occurred in 4.1% (3455/84,430) and 3.5% (2966/84,430) of patients in low-dose and high-dose RAS inhibitor groups, respectively (HR, 0.85; 95%CI, 0.81-0.89). Respective HRs (95%CIs) in eGFR subgroups ≥60, 45-59 and 15-44 mL/min/1.73m2 were 1.21 (1.08-1.36), 0.93 (0.82-1.05) and 0.82 (0.77-0.87). The association was similar across ejection fraction subgroups. There was a lower risk of death in the subgroup with ejection fraction ≤40%.CONCLUSIONS: Patients with heart failure receiving high-dose (versus low-dose) RAS inhibitors had a lower associated risk of kidney failure, which was driven by the subgroup with chronic kidney disease. This new information may help to inform future guideline recommendations and clinical practice regarding RAS inhibitor use in these patients. Future studies need to examine this association in those with normal kidney function.

  View details for DOI 10.1016/j.amjmed.2025.04.038

  View details for PubMedID 40345511

• Cardiorespiratory Fitness and Mortality in Patients With Chronic Kidney Disease: A Prospective Cohort Study. Mayo Clinic proceedings Sui, X., Kokkinos, P., Faselis, C., Samuel, I. B., Pittaras, A., Gollie, J., Patel, S., Lavie, C. J., Zhang, J., Myers, J. 2025

  Abstract

  To assess the association between objectively measured cardiorespiratory fitness (CRF) and mortality in patients with chronic kidney disease (CKD).From a large cohort of US veterans (n=750,302) based on the ETHOS (Exercise Testing and Health Outcomes) study, we identified 45,674 men and women aged 30 to 95 years (mean, 65.1 ± 8.8 years) who completed an exercise treadmill test (ETT) within the Veterans Affairs hospitals across the United States. All were diagnosed with CKD before the ETT by International Classification of Diseases 9th and 10th revision codes. Age- and-sex-specific CRF categories (quintiles) were established based on peak metabolic equivalents (METs) achieved during the ETT. We computed HRs and 95% CIs with Cox regression analyses adjusted for comorbidities and medications.During 15.9 years of follow-up, 24,310 individuals (53.2%) died. The adjusted association between CRF and mortality risk was inverse and graded. For each 1-MET increase in CRF, the adjusted HR for mortality was 12% lower (HR, 0.88; 95% CI, 0.875 to 0.885; P<.001). When risk was assessed across CRF categories using the least-fit CRF category as the referent, the adjusted HRs and CIs were 0.76 (95% CI, 0.73 to 0.78), 0.63 (95% CI, 0.61 to 0.66), 0.49 (95% CI, 0.47 to 0.51), and 0.33 (95% CI, 0.30 to 0.35), for low-fit, moderate-fit, fit, and high-fit individuals, respectively. The pattern of the CRF mortality risk association was similar regardless of age, race, or sex.In this large multiethnic study, we found an independent, inverse, and graded association between CRF and mortality in CKD patients. These findings underscore the importance of increasing CRF in CKD patients to lower the risk of mortality.

  View details for DOI 10.1016/j.mayocp.2024.09.023

  View details for PubMedID 40186598

• Outcomes of KDIGO-Defined CKD in U.S. Veterans With HFpEF, HFmrEF, and HFrEF. JACC. Heart failure Patel, S., Raman, V. K., Faselis, C., Fonarow, G. C., Lam, P. H., Ahmed, A. A., Heidenreich, P. A., Anker, S. D., Deedwania, P., Morgan, C. J., Zhang, S., Moore, H., Rangaswami, J., Bakris, G., Butler, J., Sheriff, H. M., Allman, R. M., Zeng-Treitler, Q., Wu, W. C., Ahmed, A. 2025

  Abstract

  Chronic kidney disease (CKD) is defined by the KDIGO (Kidney Disease: Improving Global Outcomes) guideline as abnormal kidney structure or function, present for >3 months, with implications for health. KDIGO-defined CKD is associated with poor outcomes in patients with heart failure (HF). Less is known about whether these associations vary by left ventricular ejection fraction.To determine the prevalence and outcomes of KDIGO-defined CKD in heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF).Of the 1,446,053 veterans with an HF diagnosis (1991-2017) in the national Veterans Affairs electronic health record data, 365,000 with data on EF had KDIGO-defined CKD or normal kidney function (NKF). CKD was defined as 2 values measured 90 days apart of estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (categorized into 4 eGFR stages based on the last eGFR: 45-59 mL/min/1.73 m2, 30-44 mL/min/1.73 m2, 15-29 mL/min/1.73 m2, and <15 mL/min/1.73 m2) or urinary albumin-to-creatinine ratio (uACR) >30 mg/g (albuminuria). NKF was defined as 2 values measured >90 days apart of eGFR ≥60 mL/min/1.73 m2, without eGFR <60 mL/min/1.73 m2 or albuminuria for 3 years before HF diagnosis. Patients were categorized into HFpEF (EF ≥50%, n = 85,855), HFmrEF (EF 41%-49%, n = 39,397), and HFrEF (EF ≤40%, n = 139,748). HRs and 95% CIs for 5-year all-cause mortality and HF hospitalization through December 31, 2022, associated with the 5 CKD groups (vs NKF) were estimated using Cox regression.Among patients with HF and NKF, mortality occurred in 39%, 37%. and 41%, and HF hospitalization occurred in 12%, 15%, and 21% of those with HFpEF, HFmrEF. and HFrEF, respectively. Compared with NKF, CKD was associated with 16%, 19%, and 26% higher multivariable-adjusted risks for death in patients with HFpEF, HFmrEF, and HFrEF, respectively. Respective risks for HF hospitalization were 31%, 33%, and 32% higher. The eGFR-associated risks were incrementally higher with decreasing eGFR, except for eGFR <15 mL/min/1.73 m2, likely because of the initiation of dialysis during follow-up. Albuminuria was associated with 16%, 10%, and 12% higher multivariable-adjusted risks for death and 29, 30%, and 24% for HF hospitalization in HFpEF, HFmrEF, and HFrEF, respectively. All associations were statistically significant.These findings based on KDIGO-defined CKD and NKF provide new information about the best estimates of true prevalence and outcomes of CKD in HFpEF, HFmrEF, and HFrEF.

  View details for DOI 10.1016/j.jchf.2024.11.007

  View details for PubMedID 39918536

• RASI'S IN RECOMMENDED HIGHER TARGET DOSES MAY LOWER RISK OF DEATH AND KIDNEY FAILURE IN OCTOGENARIANS WITH HFREF Ahmed, A., Heidenreich, P., Aronow, W., Allman, R., Faselis, C., Sin, M., Lam, P., Fonarow, G. OXFORD UNIV PRESS. 2024: 1369

  View details for DOI 10.1093/geroni/igae098.4365

  View details for Web of Science ID 001388294900001

• Lower Risk of Death and Kidney Failure Associated with Higher Target (vs. Below-Target) Doses of RAS Inhibitors in Octogenarians with HFrEF. The American journal of medicine Sin, M. K., Allman, R. M., Faselis, C., Aronow, W. S., Brown, C. J., Lam, P. H., Wu, W. C., Zeng-Treitler, Q., Patel, S. S., Raman, V. K., Zhang, S., Sheriff, H. M., Morgan, C. J., Heidenreich, P. A., Fonarow, G. C., Ahmed, A. 2024

  Abstract

  Renin-angiotensin system inhibitors (RASIs) at higher target doses reduce the risk of death in patients with heart failure with reduced ejection fraction (HFrEF). Less is known about their effectiveness in octogenarians, the examination of which was the objective of this study.Of 32,964 Veterans ≥80 years with HFrEF (ejection fraction ≤40%) receiving RASIs, 6655 received target-dose. Using propensity scores for target-dose, calculated for each of 32,964 patients, we assembled a matched cohort of 13,284 patients balanced on 66 baseline characteristics. Hazard ratios (95% CI) for 5-year mortality and kidney failure associated with target (vs. below-target) dose RASI were estimated in the matched cohort. Kidney failure was defined as receipt of kidney replacement therapy or estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2 measured twice >30 days apart.Patients had mean(±SD) age 84.5(±3.4) years, EF 31.3(±8.2) %, and eGFR 58.5(±18.2) mL/min/1.73m2. All-cause mortality occurred in 71.2% and 69.5% of matched patients in below-target and target dose RASI groups, respectively (HR associated with target-dose RASI, 0.95; 95% CI, 0.91-0.99; p=0.009). Respective rates for kidney failure were 1.8% and 1.5%, with a trend toward a lower risk in the target-dose group (HR, 0.80; 95% CI, 0.61-1.04; p=0.094). Consequently, there was a lower risk of the composite endpoint of kidney failure or death (HR, 0.94; 95% CI, 0.91-0.98; p=0.004).These findings provide evidence that in octogenarians with HFrEF, the use of RASIs in higher target (vs. below-target) doses was associated with lower risks of death and kidney failure.

  View details for DOI 10.1016/j.amjmed.2024.10.019

  View details for PubMedID 39551174

• Impact of Cardiorespiratory Fitness on COVID-19-Related Outcomes: The Exercise Testing and Health Outcomes Study (ETHOS) MAYO CLINIC PROCEEDINGS Myers, J., Kokkinos, P., Cadenas-Sanchez, C., Liappis, A., Lavie, C. J., Goraya, N. K., Weintrob, A., Pittaras, A., Ladas, A., Heimall, M., Faselis, C. 2024; 99 (11): 1744-1755

  Abstract

  To assess the association between cardiorespiratory fitness (CRF) and COVID-19-related health outcomes including mortality, hospitalization, and mechanical ventilation.In a retrospective analysis of 750,302 patients included in the Exercise Testing and Health Outcomes Study, we identified 23,140 who had a positive result on COVID-19 testing between March 2020 and September 2021 and underwent a maximal exercise test in the Veterans Affairs Health Care System between October 1, 1999 to September 3, 2020. The association between CRF and risk for severe COVID-19 outcomes, including mortality, hospitalization due to COVID-19, and need for intubation was assessed after adjustment for 15 covariates. Patients were stratified into 5 age-specific CRF categories (Least-Fit, Low-Fit, Moderate-Fit, Fit, and High-Fit), based on peak metabolic equivalents achieved.During a median of follow-up of 100 days, 1643 of the 23,140 patients (7.1%) died, 4995 (21.6%) were hospitalized, and 927 (4.0%) required intubation for COVID-19-related reasons. When compared with the Least-Fit patients (referent), the Low-Fit, Moderate-Fit, Fit, and High-Fit patients had hazard ratios for mortality of 0.82 (95% CI, 0.72 to 0.93), 0.73 (95% CI, 0.63 to 0.86), 0.61 (95% CI, 0.53 to 0.72), and 0.54 (95% CI, 0.45 to 0.65), respectively. Patients who were more fit also had substantially lower need for hospital admissions and intubation. Similar patterns were observed for elderly patients and subgroups with comorbidities including hypertension, diabetes, cardiovascular disease, and chronic kidney disease; for each of these conditions, those in the High-Fit category had mortality rates that were roughly half those in the Low-Fit category.Among patients positive for COVID-19, higher CRF had a favorable impact on survival, need for hospitalization, and need for intubation regardless of age, body mass index, or the presence of comorbidities.

  View details for DOI 10.1016/j.mayocp.2024.07.004

  View details for Web of Science ID 001350204600001

  View details for PubMedID 39243247

• Digoxin Discontinuation in Patients with HFrEF on Beta-Blockers: Implication for Future "Knock-Out Trials" in Heart Failure. The American journal of medicine Lam, P. H., Liu, K., Ahmed, A. A., Butler, J., Heidenreich, P. A., Anker, M. S., Faselis, C., Deedwania, P., Aronow, W. S., Kanonidis, I., Masson, R., Gill, G. S., Morgan, C. J., Arundel, C., Allman, R. M., Wu, W., Fonarow, G. C., Ahmed, A. 2024

  Abstract

  BACKGROUND: National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers.METHODS: In OPTIMIZE-HF, of 2,477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for one-year outcomes were estimated.RESULTS: Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85-1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85-1.25) or death (HR, 0.91; 95% CI, 0.72-1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25-2.04), 1.62 (1.18-2.22) and 1.43 (1.08-1.89).CONCLUSIONS: Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.

  View details for DOI 10.1016/j.amjmed.2024.10.015

  View details for PubMedID 39424217

• Stroke Incidence in Patients With Hypertension According to Cardiorespiratory Fitness. Hypertension (Dallas, Tex. : 1979) Kokkinos, P., Faselis, C., Pittaras, A., Samuel, I. B., Lavie, C. J., Ross, R., LaMonte, M., Franklin, B. A., Grassos, C., Zaprini, E., Murphy, R., Myers, J. 2024

  Abstract

  Hypertension and physical inactivity are risk factors for stroke. The effect of cardiorespiratory fitness (CRF) on stroke risk in patients with hypertension has not been assessed. We evaluated stroke incidence in patients with hypertension according to CRF and changes in CRF.We included 483 379 patients with hypertension (mean age±SD; 59.4±9.0 years) and no evidence of unstable cardiovascular disease as indicated by a standardized exercise treadmill test. Patients were assigned to 5 age- and sex-specific CRF categories based on peak metabolic equivalents achieved at the initial exercise treadmill test and in 4 categories based on metabolic equivalent changes over time (n=110 576). Multivariable Cox models, adjusted for age, and comorbidities were used to estimate hazard ratios and 95% CIs for stroke risk.During a median follow-up of 10.6 (interquartile range, 6.6-14.6) years, 15 925 patients developed stroke with an average yearly rate of 3.1 events/1000 person-years. Stroke risk declined progressively with higher CRF and was 55% lower for the High-fit individuals (hazard ratio, 0.45 [95% CI, 0.42-0.48]) compared with the Least-fit. Similar associations were observed across the race, sex, and age spectra. Poor CRF was the strongest predictor of stroke risk of all comorbidities studied (hazard ratio, 2.24 [95% CI, 2.10-2.40]). Changes in CRF reflected inverse and proportional changes in stroke risk.Poor CRF carried a greater risk than any of the cardiac risk factors in patients with hypertension, regardless of age, race, or sex. The lower stroke risk associated with improved CRF suggests that increasing physical activity, even later in life, may reduce stroke risk.

  View details for DOI 10.1161/HYPERTENSIONAHA.124.23066

  View details for PubMedID 38841839

• The Association between Cardiorespiratory Fitness and the Risk of Breast Cancer in Women MEDICINE & SCIENCE IN SPORTS & EXERCISE Katsaroli, I., Sidossis, L., Katsagoni, C., Sui, X., Cadenas-sanchez, C., Myers, J., Faselis, C., Murphy, R., Samuel, I., Kokkinos, P. 2024; 56 (6): 1134-1139

  Abstract

  Studies have shown an inverse association between the risk of breast cancer in women and physical activity. However, information on the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized test and the risk of developing breast cancer is limited.To examine the CRF-breast cancer risk association in healthy females.This retrospective study was derived from the Exercise Testing and Health Outcomes Study cohort ( n = 750,302). Female participants ( n = 44,463; mean age ± SD; 55.1 ± 8.9 yr) who completed an exercise treadmill test evaluation (Bruce protocol) at the Veterans Affairs Medical Centers nationwide from 1999 to 2020 were studied. The cohort was stratified into four age-specific CRF categories (Least-fit, Low-fit, Moderate-fit, and Fit), based on the peak METs achieved during the exercise treadmill test.During 438,613 person-years of observation, 994 women developed breast cancer. After controlling for covariates, the risk of breast cancer was inversely related to exercise capacity. For each 1-MET increase in CRF, the risk of cancer was 7% lower (HR, 0.93; 95% CI, 0.90-0.95; P < 0.001). When risk was assessed across CRF categories with the Least-fit group as the referent, the risk was 18% lower for Low-fit women (HR, 0.82; 95% CI, 0.70-0.96; P = 0.013), 31% for Moderate-fit (HR, 0.69; 95% CI, 0.58-0.82; P < 0.001), and 40% for Fit (HR, 0.60; 95% CI, 0.47-0.75; P < 0.001).We observed an inverse and graded association between CRF and breast cancer risk in women. Thus, encouraging women to improve CRF may help attenuate the risk of developing breast cancer.

  View details for DOI 10.1249/MSS.0000000000003385

  View details for Web of Science ID 001226554900022

  View details for PubMedID 38196147

• Identification and outcomes of KDIGO-defined chronic kidney disease in 1.4 million U.S. Veterans with heart failure. European journal of heart failure Patel, S. S., Raman, V. K., Zhang, S., Deedwania, P., Zeng-Treitler, Q., Wu, W. C., Lam, P. H., Bakris, G., Moore, H., Heidenreich, P. A., Rangaswami, J., Morgan, C. J., Cheng, Y., Sheriff, H. M., Faselis, C., Mehta, R. L., Anker, S. D., Fonarow, G. C., Ahmed, A. 2024

  Abstract

  According to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, the definition of chronic kidney disease (CKD) requires the presence of abnormal kidney structure or function for >3 months with implications for health. CKD in patients with heart failure (HF) has not been defined using this definition, and less is known about the true health implications of CKD in these patients. The objective of the current study was to identify patients with HF who met KDIGO criteria for CKD and examine their outcomes.Of the 1 419 729 Veterans with HF not receiving kidney replacement therapy, 828 744 had data on ≥2 ambulatory serum creatinine >90 days apart. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (n = 185 821) or urinary albumin-to-creatinine ratio (uACR) >30 mg/g (n = 32 730) present twice >3 months apart. Normal kidney function (NKF) was defined as eGFR ≥60 ml/min/1.73 m2, present for >3 months, without any uACR >30 mg/g (n = 365 963). Patients with eGFR <60 ml/min/1.73 m2 were categorized into four stages: 45-59 (n = 72 606), 30-44 (n = 74 812), 15-29 (n = 32 077), and <15 (n = 6326) ml/min/1.73 m2. Five-year all-cause mortality occurred in 40.4%, 57.8%, 65.6%, 73.3%, 69.7%, and 47.5% of patients with NKF, four eGFR stages, and uACR >30mg/g (albuminuria), respectively. Compared with NKF, hazard ratios (HR) (95% confidence intervals [CI]) for all-cause mortality associated with the four eGFR stages and albuminuria were 1.63 (1.62-1.65), 2.00 (1.98-2.02), 2.49 (2.45-2.52), 2.28 (2.21-2.35), and 1.22 (1.20-1.24), respectively. Respective age-adjusted HRs (95% CIs) were 1.13 (1.12-1.14), 1.36 (1.34-1.37), 1.87 (1.84-1.89), 2.24 (2.18-2.31) and 1.19 (1.17-1.21), and multivariable-adjusted HRs (95% CIs) were 1.11 (1.10-1.12), 1.24 (1.22-1.25), 1.46 (1.43-1.48), 1.42 (1.38-1.47), and 1.13 (1.11-1.16). Similar patterns were observed for associations with hospitalizations.Data needed to define CKD using KDIGO criteria were available in six out of ten patients, and CKD could be defined in seven out of ten patients with data. HF patients with KDIGO-defined CKD had higher risks for poor outcomes, most of which was not explained by abnormal kidney structure or function. Future studies need to examine whether CKD defined using a single eGFR is characteristically and prognostically different from CKD defined using KDIGO criteria.

  View details for DOI 10.1002/ejhf.3210

  View details for PubMedID 38700246

• CHRONIC KIDNEY DISEASE INCIDENCE AND CARDIORESPIRATORY FITNESS ASSOCIATION IN HYPERTENSIVE PATIENTS Kokkinos, P., Pittaras, A., Faselis, C., Samuel, I., Patel, S., Doumas, M., Gollie, J., Grassos, H., Myers, J. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for DOI 10.1097/01.hjh.0001019524.70331.9d

  View details for Web of Science ID 001256619700048

• Cardiorespiratory Fitness and Risk of Heart Failure with Preserved Ejection Fraction. European journal of heart failure Kokkinos, P., Faselis, C., Pittaras, A., Samuel, I. B., Lavie, C. J., Vargas, J. D., Lamonte, M., Franklin, B., Assimes, T. L., Murphy, R., Zhang, J., Sui, X., Myers, J. 2023

  Abstract

  Preventive strategies for heart failure (HF) with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence.We assessed CRF in US Veterans (624,551 men; mean age 61.2 ± 9.7 years and 43,179 women; mean age 55.0±8.9 years) by a standardized ETT performed between 1999-2020 across US Veterans Affairs Medical Centers. All had no evidence of HF or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age-and-gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n=139,434) ≥1.0 year apart. During the median follow-up of 10.1 years (IQR 6.0-14.3 years), providing 6,879,229 person-years, there were 16,493 HFpEF events with an average annual rate of 2.4 events per 1,000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% CI 0.46-0.51) compared with least fit (≤ 4.9 METs; referent). Being unfit carried the highest risk (HR, 2.88; 95% CI, 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit.Higher CRF levels are independently associated with lower HRpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.3117

  View details for PubMedID 38152843

• Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy. Mayo Clinic proceedings Kokkinos, P., Nylen, E., Faselis, C., Pittaras, A., Samuel, I. B., Lavie, C., Doumas, M., Heimall, M. S., Murphy, R., Myers, J. 2023

  Abstract

  To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM).Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test.During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75).In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

  View details for DOI 10.1016/j.mayocp.2023.05.005

  View details for PubMedID 37389516

• COVID-19 AND MORTALITY IN HYPERTENSIVE PATIENTS ACCORDING TO CARDIORESPIRATORY FITNESS Faselis, C., Doumas, M., Pittaras, A., Samuel, I., Gorsuch, B., Ladas, A., Lavie, C., Myers, J., Kokkinos, P. LIPPINCOTT WILLIAMS & WILKINS. 2023: E32

  View details for Web of Science ID 001023756600075

• Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease. Journal of the American College of Cardiology Kokkinos, P., Faselis, C., Samuel, I. B., Lavie, C. J., Zhang, J., Vargas, J. D., Pittaras, A., Doumas, M., Karasik, P., Moore, H., Heimal, M., Myers, J. 2023; 81 (12): 1137-1147

  Abstract

  The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined.This study sought to evaluate changes in CRF and all-cause mortality.We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality.During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD.Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

  View details for DOI 10.1016/j.jacc.2023.01.027

  View details for PubMedID 36948729

• Cardiorespiratory Fitness and Mortality Risk Across the Spectra of Age, Race, and Sex. Journal of the American College of Cardiology Kokkinos, P., Faselis, C., Samuel, I. B., Pittaras, A., Doumas, M., Murphy, R., Heimall, M. S., Sui, X., Zhang, J., Myers, J. 2022; 80 (6): 598-609

  Abstract

  Cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality. However, the association of CRF and mortality risk for different races, women, and elderly individuals has not been fully assessed.The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex.A total of 750,302 U.S. veterans aged 30 to 95 years (mean age 61.3 ± 9.8 years) were studied, including septuagenarians (n = 110,637), octogenarians (n = 26,989), African Americans (n = 142,798), Hispanics (n = 35,197), Native Americans (n = 16,050), and women (n = 45,232). Age- and sex-specific CRF categories (quintiles and 98th percentile) were established objectively on the basis of peak METs achieved during a standardized exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for mortality across the CRF categories.During follow-up (median 10.2 years, 7,803,861 person-years of observation), 174,807 subjects died, averaging 22.4 events per 1,000 person-years. The adjusted association of CRF and mortality risk was inverse and graded across the age spectrum, sex, and race. The lowest mortality risk was observed at approximately 14.0 METs for men (HR: 0.24; 95% CI: 0.23-0.25) and women (HR: 0.23; 95% CI: 0.17-0.29), with no evidence of an increase in risk with extremely high CRF. The risk for least fit individuals (20th percentile) was 4-fold higher (HR: 4.09; 95% CI: 3.90-4.20) compared with extremely fit individuals.The association of CRF and mortality risk across the age spectrum (including septuagenarians and octogenarians), men, women, and all races was inverse, independent, and graded. No increased risk was observed with extreme fitness. Being unfit carried a greater risk than any of the cardiac risk factors examined.

  View details for DOI 10.1016/j.jacc.2022.05.031

  View details for PubMedID 35926933

• Cardiorespiratory Fitness And Mortality Risk Among Individuals With Sleep Apnea Spaeth, A. M., Samuel, I., Sidossis, L., Faselis, C., Myers, J., Kokkinos, P. LIPPINCOTT WILLIAMS & WILKINS. 2021: 201

  View details for Web of Science ID 000693128400599

• Exercise blood pressure, cardiorespiratory fitness and mortality risk. Progress in cardiovascular diseases Kokkinos, P., Faselis, C., Sidossis, L., Zhang, J., Samuel, I. B., Ahmed, A., Karasik, P., Pittaras, A., Doumas, M., Grassos, C., Rosenberg, S., Myers, J. 2021; 67: 11-17

  Abstract

  To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk.We assessed CRF in 15,004 US Veterans (mean age 57.5 ± 11.2 years) who completed a standardized treadmill test between January 1, 1988 and July 28, 2017 and had no evidence of ischemia. They were classified as Unfit or Fit according to the age-specific metabolic equivalents (METs) achieved <50% (6.2 ± 1.6 METs; n = 8440) or ≥ 50% (10.5 ± 2.4 METs; n = 6264). To account for the impact of resting systolic BP (SBP) on outcomes, we calculated the difference (Peak SBP-Resting SBP) and termed it SBP-Reserve. We noted a significant increase in mortality associated with SBP-Reserve ≤52 mmHg and stratified the cohort accordingly (SBP-Reserve ≤52 mmHg and > 52 mmHg). We applied multivariable Cox models to estimate hazard ratios (HR) and 95% confidence interval (CIs) for outcomes.Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve >52 mmHg (HR = 1.35; CI: 1.24-1.46; P < 0.001). We then assessed the CRF and SBP-Reserve interaction on mortality risk with Fit individuals with SBP-Reserve >52 mmHg serving as the referent. Mortality risk was 92% higher (HR = 1.92%; 95% CI: 1.77-2.09; P < 0.001) in Unfit individuals with SBP-Reserve ≤52 mmHg and 47% higher (HR = 1.47; 95% CI: 1.33-1.62; P < 0.001) in those with SBP-Reserve >52 mmHg.Low CRF was associated with increased mortality risk regardless of peak exercise SBP. The risk was substantially higher in individuals unable to augment their exercise SBP >52 mmHg beyond resting levels.

  View details for DOI 10.1016/j.pcad.2021.01.003

  View details for PubMedID 33513410

• Cardiorespiratory fitness, body mass index and heart failure incidence EUROPEAN JOURNAL OF HEART FAILURE Kokkinos, P., Faselis, C., Franklin, B., Lavie, C. J., Sidossis, L., Moore, H., Karasik, P., Myers, J. 2019; 21 (4): 436-444

  Abstract

  Obesity is associated with increased risk of heart failure (HF). This risk may be modulated by improved cardiorespiratory fitness (CRF) as CRF is associated with favourable health outcomes. Thus, we assessed the interaction between body mass index (BMI), CRF and HF.Cardiorespiratory fitness and BMI were assessed in 20 254 US male veterans (mean age 58.0 ± 11.3 years), who completed a maximal exercise treadmill test between 1987 and 2017. All had no evidence of ischaemia or HF prior to the exercise test. They were classified based on age-stratified quartiles of peak metabolic equivalents (METs) achieved as: least-fit (4.5 ± 1.3), low-fit (6.7 ± 1.3), moderate-fit (8.1 ± 1.1), and high-fit (11.2 ± 2.4); and according to BMI as normal weight (18.5-24.9 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥ 30.0 kg/m2 ). During a median follow-up of 13.4 years, there were 2979 HF events (10.8 events/1000 person-years). HF risk was significantly higher in the obese category [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.10-1.36; P < 0.001], but was no longer significant after further adjustment for METs. When compared to the least-fit, HF risk declined progressively with increased CRF within all BMI categories. The risk was 63% (HR 0.37, 95% CI 0.30-0.47; P < 0.001), 66% (HR 0.37, 95% CI 0.28-0.40; P < 0.001), and 73% (HR 0.27, 95% CI 0.22-0.34; P < 0.001) lower for high-fit individuals within normal weight, overweight and obese categories, respectively.Increased CRF was associated with progressively lower HF risk regardless of BMI, suggesting that the elevated HF risk associated with obesity may be modulated by improved CRF.

  View details for DOI 10.1002/ejhf.1433

  View details for Web of Science ID 000468038100006

  View details for PubMedID 30779281

• Cardiorespiratory Fitness and Health Outcomes: A Call to Standardize Fitness Categories MAYO CLINIC PROCEEDINGS Kokkinos, P., Myers, J., Franklin, B., Narayan, P., Lavie, C. J., Faselis, C. 2018; 93 (3): 333-336

  Abstract

  An inverse association between physical activity or fitness status and health outcomes has been reported by several cohort studies. When fitness categories are established in quartiles or quintiles based on the peak exercise capacity achieved, the association is graded. Although significant health benefits of increased cardiorespiratory fitness (CRF) have been uniformly reported, the degree of protection has varied substantially between studies. This variability is likely due to varying methods used to define CRF categories, and not considering age, despite its strong effect on CRF. To ameliorate these methodological discrepancies, we propose standardized guidelines by which age-specific CRF categories should be defined.

  View details for DOI 10.1016/j.mayocp.2017.10.011

  View details for Web of Science ID 000426558100013

  View details for PubMedID 29174511

• Impact of Cardiorespiratory Fitness on Mortality in Black Male Veterans With Resistant Systemic Hypertension AMERICAN JOURNAL OF CARDIOLOGY Narayan, P., Doumas, M., Kumar, A., Faselis, C. J., Myers, J. N., Pittaras, A., Kokkinos, P. F. 2017; 120 (9): 1568–71

  Abstract

  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.

  View details for DOI 10.1016/j.amjcard.2017.07.055

  View details for Web of Science ID 000414386500018

  View details for PubMedID 28886854

• Cardiorespiratory Fitness and Incidence of Type 2 Diabetes in United States Veterans on Statin Therapy AMERICAN JOURNAL OF MEDICINE Kokkinos, P., Faselis, C., Narayan, P., Myers, J., Nylen, E., Sui, X., Zhang, J., Lavie, C. J. 2017; 130 (10): 1192-1198

  Abstract

  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.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.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).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.

  View details for DOI 10.1016/j.amjmed.2017.04.042

  View details for Web of Science ID 000410998300037

  View details for PubMedID 28552431

• Cardiorespiratory Fitness and Reclassification of Risk for Incidence of Heart Failure The Veterans Exercise Testing Study CIRCULATION-HEART FAILURE Myers, J., Kokkinos, P., Chan, K., Dandekar, E., Yilmaz, B., Nagare, A., Faselis, C., Soofi, M. 2017; 10 (6)

  Abstract

  It is well established that cardiorespiratory fitness (CRF) is inversely associated with cardiovascular and all-cause mortality. However, little is known regarding the association between CRF and incidence of heart failure (HF).Between 1987 and 2014, we assessed CRF in 21 080 HF-free subjects (58.3±11 years) at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, CA. Subjects were classified by age-specific quintiles of CRF. Multivariable Cox models were used to determine the association between HF incidence and clinical and exercise test variables. Reclassification characteristics of fitness relative to standard clinical risk factors were determined using the category-free net reclassification improvement and integrated discrimination improvement indices. During the follow-up (mean 12.3±7.4 years), 1902 subjects developed HF (9.0%; average annual incidence rate, 7.4 events per 1000 person-years). When CRF was considered as a binary variable (unfit/fit), low fitness was the strongest predictor of risk for HF among clinical and exercise test variables (hazard ratio, 1.91; 95% confidence interval, 1.74-2.09; P<0.001). In a fully adjusted model with the least-fit group as the reference, there was a graded and progressive reduction in risk for HF as fitness level was higher. Risks for developing HF were 36%, 41%, 67%, and 76% lower among increasing quintiles of fitness compared with the least-fit subjects (P<0.001). Adding CRF to standard risk factors resulted in a net reclassification improvement of 0.37 (P<0.001).CRF is strongly, inversely, and independently associated with the incidence of HF in veterans referred for exercise testing.

  View details for DOI 10.1161/CIRCHEARTFAILURE.116.003780

  View details for Web of Science ID 000403652100003

  View details for PubMedID 28572213

• Cardiorespiratory Fitness and Incidence of Major Adverse Cardiovascular Events in US Veterans: A Cohort Study MAYO CLINIC PROCEEDINGS Kokkinos, P. F., Faselis, C., Myers, J., Narayan, P., Sui, X., Zhang, J., Lavie, C. J., Moore, H., Karasik, P., Fletcher, R. 2017; 92 (1): 39-48

  Abstract

  To assess the association between exercise capacity and the risk of major adverse cardiovascular events (MACEs).A symptom-limited exercise tolerance test was performed to assess exercise capacity in 20,590 US veterans (12,975 blacks and 7615 whites; mean ± SD age, 58.2±11.0 years) from the Veterans Affairs medical centers in Washington, District of Columbia, and Palo Alto, California. None had a history of MACE or evidence of ischemia at the time of or before their exercise tolerance test. We established quintiles of cardiorespiratory fitness (CRF) categories based on age-specific peak metabolic equivalents (METs) achieved. We also defined the age-specific MET level associated with no risk for MACE (hazard ratio [HR], 1.0) and formed 4 additional CRF categories based on METs achieved below (least fit and low fit) and above (moderately fit and highly fit) that level. Multivariate Cox models were used to estimate HR and 95% CIs for mortality across fitness categories.During follow-up (median, 11.3 years; range, 0.3-33.0 years), 2846 individuals experienced MACEs. The CRF-MACE association was inverse and graded. The risk for MACE declined precipitously for those with a CRF level of 6.0 METs or higher. When considering CFR categories based on the age-specific MET threshold, the risk increased for those in the 2 CFR categories below that threshold (HR, 1.95; 95% CI, 1.73-2.21 and HR, 1.41; 95% CI, 1.27-1.56 for the least-fit and low-fit individuals, respectively) and decreased for those above it (HR, 0.77; 95% CI, 0.68-0.87 and HR, 0.57; 95% CI, 0.48-0.67 for moderately fit and highly fit, respectively).Increased CRF is inversely and independently associated with the risk for MACE. When an age-specific MET threshold was defined, the risk for MACE increased significantly for those below that threshold and decreased for those above it (P<.001).

  View details for DOI 10.1016/j.mayocp.2016.09.013

  View details for Web of Science ID 000393912300011

  View details for PubMedID 27876315

• Exercise Capacity and Atrial Fibrillation Risk in Veterans: A Cohort Study MAYO CLINIC PROCEEDINGS Faselis, C., Kokkinos, P., Tsimploulis, A., Pittaras, A., Myers, J., Lavie, C. J., Kyritsi, F., Lovic, D., Karasik, P., Moore, H. 2016; 91 (5): 558-566

  Abstract

  To assess the association between exercise capacity and the risk of developing atrial fibrillation (AF).A symptom-limited exercise tolerance test was conducted to assess exercise capacity in 5962 veterans (mean age, 56.8±11.0 years) from the Veterans Affairs Medical Center, Washington, DC. None had evidence of AF or ischemia at the time of or before undergoing their exercise tolerance test. We established 4 fitness categories based on age-stratified quartiles of peak metabolic equivalent task (MET) achieved: least fit (4.9±1.10 METs; n=1446); moderately fit (6.7±1.0 METs; n=1490); fit (7.9±1.0 METs; n=1585), and highly fit (9.3±1.2 METs; n=1441). Multivariable Cox proportional hazards regression models were used to compare the AF-exercise capacity association between fitness categories.During a median follow-up period of 8.3 years, 722 (12.1%) individuals developed AF (14.5 per 1000 person-years; 95% CI, 13.9-15.9 per 1000 person-years). Exercise capacity was inversely related to AF incidence. The risk was 21% lower (hazard ratio, 0.79; 95% CI, 0.76-0.82) for each 1-MET increase in exercise capacity. Compared with the least fit individuals, hazard ratios were 0.80 (95% CI, 0.67-0.97) for moderately fit individuals, 0.55 (95% CI, 0.45-0.68) for fit individuals, and 0.37 (95% CI, 0.29-0.47) for highly fit individuals. Similar trends were observed in those younger than 65 years and those 65 years or older.Increased fitness is inversely and independently associated with the reduced risk of developing AF. The decrease in risk was graded and precipitous with only modest increases in exercise capacity. These findings counter previous suggestions that even moderate increases in physical activity, as recommended by national and international guidelines, increase the risk of AF, with marked protection against AF noted with increasing levels of fitness.

  View details for DOI 10.1016/j.mayocp.2016.03.002

  View details for Web of Science ID 000375877200008

  View details for PubMedID 27068670

• Exercise Capacity and Risk of Chronic Kidney Disease in US Veterans: A Cohort Study MAYO CLINIC PROCEEDINGS Kokkinos, P., Faselis, C., Myers, J., Sui, X., Zhang, J., Tsimploulis, A., Chawla, L., Palant, C. 2015; 90 (4): 461-468

  Abstract

  To assess the association between exercise capacity and the risk of developing chronic kidney disease (CKD).Exercise capacity was assessed in 5812 male veterans (mean age, 58.4±11.5 years) from the Veterans Affairs Medical Center, Washington, DC. Study participants had an estimated glomerular filtration rate of 60 mL/min per 1.73 m(2) or more 6 months before exercise testing and no evidence of CKD. Those who developed CKD during follow-up were initially identified by the International Classification of Diseases, Ninth Revision and further verified by at least 2 consecutive estimated glomerular filtration rate values of less than 60 mL/min per 1.73 m(2) 3 months or more apart. Normal kidney function for CKD-free individuals was confirmed by sequential normal eGFR levels. We established 4 fitness categories on the basis of age-stratified quartiles of peak metabolic equivalents (METs) achieved: least-fit (≤25%; 4.8±0.90 METs; n=1258); low-fit (25.1%-50%; 6.5±0.96 METs; n=1614); moderate-fit (50.1%-75%; 7.7±0.91 METs; n=1958), and high-fit (>75%; 9.5±1.0 METs; n=1436). Multivariable Cox proportional hazard models were used to assess the association between exercise capacity and CKD.During a median follow-up period of 7.9 years, 1010 developed CKD (20.4/1000 person-years). Exercise capacity was inversely related to CKD incidence. The risk was 22% lower (hazard ratio, 0.78; 95% CI, 0.75-0.82; P<.001) for every 1-MET increase in exercise capacity. Compared with the least-fit individuals, hazard ratios were 0.87 (95% CI, 0.74-1.03) for low-fit, 0.55 (95% CI, 0.47-0.65) for moderate-fit, and 0.42 (95% CI, 0.33-0.52) for high-fit individuals.Higher exercise capacity attenuated the risk of developing CKD. The association was independent and graded.

  View details for DOI 10.1016/j.mayocp.2015.01.013

  View details for Web of Science ID 000352197900009

  View details for PubMedID 25792243

• Age-Specific Exercise Capacity Threshold for Mortality Risk Assessment in Male Veterans CIRCULATION Kokkinos, P., Faselis, C., Myers, J., Sui, X., Zhang, J., Blair, S. N. 2014; 130 (8): 653-658

  Abstract

  Mortality risk decreases beyond a certain fitness level. However, precise definition of this threshold is elusive and varies with age. Thus, fitness-related mortality risk assessment is difficult.We studied 18 102 male veterans (8305 blacks and 8746 whites). All completed an exercise test between 1986 and 2011 with no evidence of ischemia. We defined the peak metabolic equivalents (METs) level associated with no increase in all-cause mortality risk (hazard ratio, 1.0) for the age categories of <50, 50 to 59, 60 to 69, and ≥70 years. We used this as the threshold group to form additional age-specific fitness categories based on METs achieved below and above it: least-fit (>2 METs below threshold; n=1692), low-fit (2 METs below threshold; n=4884), moderate-fit (2 METs above threshold; n=4646), fit (2.1-4 METs above threshold; n=1874), and high-fit (>4 METs above threshold; n=1301) categories. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality across fitness categories. During follow-up (median=10.8 years), 5102 individuals died. Mortality risk for the cohort and each age category increased for the least-fit and low-fit categories (HR, 1.51; 95% CI, 1.37-1.66; and HR, 1.21; 95% CI, 1.12-1.30, respectively) and decreased for the moderate-fit; fit and high-fit categories (HR, 0.71; 95% CI, 0.65-0.78; HR, 0.63; 95% CI, 0.56-0.78; and HR, 0.49; 95% CI, 0.41-0.58, respectively). The trends were similar for 5- and 10-year mortality risk.We defined age-specific exercise capacity thresholds to guide assessment of mortality risk in individuals undergoing a clinical exercise test.

  View details for DOI 10.1161/CIRCULATIONAHA.114.009666

  View details for Web of Science ID 000341300100013

  View details for PubMedID 24938279

• Exercise Capacity and All-Cause Mortality in Male Veterans With Hypertension Aged ≥70 Years HYPERTENSION Faselis, C., Doumas, M., Pittaras, A., Narayan, P., Myers, J., Tsimploulis, A., Kokkinos, P. 2014; 64 (1): 30-35

  Abstract

  Aging, even in otherwise healthy subjects, is associated with declines in muscle mass, strength, and aerobic capacity. Older individuals respond favorably to exercise, suggesting that physical inactivity plays an important role in age-related functional decline. Conversely, physical activity and improved exercise capacity are associated with lower mortality risk in hypertensive individuals. However, the effect of exercise capacity in older hypertensive individuals has not been investigated extensively. A total of 2153 men with hypertension, aged ≥70 years (mean, 75 ± 4) from the Washington, DC, and Palo Alto Veterans Affairs Medical Centers, underwent routine exercise tolerance testing. Peak workload was estimated in metabolic equivalents (METs). Fitness categories were established based on peak METs achieved, adjusted for age: very-low-fit, 2.0 to 4.0 METs (n=386); low-fit, 4.1 to 6.0 METs (n=1058); moderate-fit, 6.1 to 8.0 METs (n=495); high-fit >8.0 METs (n=214). Cox proportional hazard models were applied after adjusting for age, body mass index, race, cardiovascular disease, cardiovascular medications, and risk factors. All-cause mortality was quantified during a mean follow-up period of 9.0 ± 5.5 years. There were a total of 1039 deaths or 51.2 deaths per 1000 person-years of follow-up. Mortality risk was 11% lower (hazard ratio, 0.89; 95% confidence interval, 0.86-0.93; P<0.001) for every 1-MET increase in exercise capacity. When compared with those achieving ≤4.0 METs, mortality risk was 18% lower (hazard ratio, 0.82; 95% confidence interval, 0.70-0.95; P=0.011) for the low-fit, 36% for the moderate-fit (hazard ratio, 0.64; 95% confidence interval, 0.52-0.78; P<0.001), and 48% for the high-fit individuals (hazard ratio, 0.52; 95% confidence interval, 0.39-0.69; P<0.001). These findings suggest that exercise capacity is associated with lower mortality risk in elderly men with hypertension.

  View details for DOI 10.1161/HYPERTENSIONAHA.114.03510

  View details for Web of Science ID 000337700400009

  View details for PubMedID 24821944

• Cardiorespiratory Fitness and the Paradoxical BMI-Mortality Risk Association in Male Veterans MAYO CLINIC PROCEEDINGS Kokkinos, P., Faselis, C., Myers, J., Pittaras, A., Sui, X., Zhang, J., McAuley, P., Kokkinos, J. 2014; 89 (6): 754-762

  Abstract

  To assess the effect of fitness status on the paradoxical body mass index (BMI)-mortality risk association.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.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).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.

  View details for DOI 10.1016/j.mayocp.2014.01.029

  View details for Web of Science ID 000338846400010

  View details for PubMedID 24943694

• Statin Therapy, Fitness, and Mortality Risk in Middle-Aged Hypertensive Male Veterans AMERICAN JOURNAL OF HYPERTENSION Kokkinos, P., Faselis, C., Myers, J., Kokkinos, J., Doumas, M., Pittaras, A., Kheirbek, R., Manolis, A., Panagiotakos, D., Papademetriou, V., Fletcher, R. 2014; 27 (3): 422-430

  Abstract

  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.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.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.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.

  View details for DOI 10.1093/ajh/hpt241

  View details for Web of Science ID 000331842300019

  View details for PubMedID 24436326

• Heart Rate at Rest, Exercise Capacity, and Mortality Risk in Veterans AMERICAN JOURNAL OF CARDIOLOGY Pittaras, A. M., Faselis, C., Doumas, M., Myers, J., Kheirbek, R., Kokkinos, J., Tsimploulis, A., Aiken, M., Kokkinos, P. 2013; 112 (10): 1605-1609

  Abstract

  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.

  View details for DOI 10.1016/j.amjcard.2013.07.042

  View details for Web of Science ID 000327224300013

  View details for PubMedID 24035162

• Statins Modulate the Mortality Risk Associated With Obesity and Cardiorespiratory Fitness in Diabetics JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Nylen, E. S., Faselis, C., Kheirbek, R., Myers, J., Panagiotakos, D., Kokkinos, P. 2013; 98 (8): 3394-3401

  Abstract

  Statins are commonly prescribed to avert cardiovascular disease in diabetics. Little information, however, exists about the interrelationship of obesity, fitness, and statin treatment on mortality.Our objective was to evaluate the influence of statin therapy on body mass index (BMI), cardiorespiratory fitness, and all-cause mortality risk in diabetics.We gathered prospective observational data from Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California, on type 2 diabetic male veterans (n = 3775; mean age = 58.9 ± 9.9 years) who underwent an exercise tolerance test during the period of 1986 to 2011.There were 930 deaths during a mean follow-up period of 10.5 years (37 826 person-years), with an average annual mortality of 24.6 events per 1000 person-years of observation. Adjusted Cox proportional hazard analysis revealed that mortality risk was 34% lower (hazard ratio [HR] = 0.66; confidence interval [CI] = 0.57-0.77) for individuals treated with statins compared with those not on statins. There was a paradoxical BMI-mortality association, with the highest mortality in those with a BMI of 18.5 to 24.9 kg/m(2) (HR = 1.54; CI = 1.26-1.87, P < .0001) compared with obese subjects (BMI of 30-34.9 kg/m(2)). However, this paradoxical association was evident only in those not treated with statins (HR = 1.79; CI = 1.39-2.29; P < .001) vs those on statins (HR = 1.06; CI = 0.75-1.54; P = .70). When statin therapy and fitness status were combined, mortality risk was 44% higher (HR = 1.44; CI = 1.16-1.78) in the least-fit not treated with statins compared with the least-fit treated with statins. Mortality risk declined progressively with increased fitness to 60% lower (HR = 0.40; CI = 0.24-0.66) and 49% lower (HR = 0.51; CI = 0.38-0.68) for the most highly fit individuals (>9 metabolic equivalents) treated and not treated with statins, respectively.Statin therapy was associated with increased survival in diabetic veterans, which was further enhanced when fitness and statin therapy were combined. In addition, statin therapy eliminated the increased mortality risk associated with BMI <25 kg/m(2). The presence of a paradoxical BMI-mortality risk association, which is modulated by statin therapy has novel clinically relevant implications.

  View details for DOI 10.1210/jc.2013-1431

  View details for Web of Science ID 000322781300058

  View details for PubMedID 23783095

• Statin and exercise prescription reply LANCET Kokkinos, P., Faselis, C., Myers, J., Panagiotakos, D., Doumas, M. 2013; 381 (9878): 1622-1623

  View details for DOI 10.1016/S0140-6736(13)61018-1

  View details for Web of Science ID 000319112400019

  View details for PubMedID 23663943

• Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study LANCET Kokkinos, P. F., Faselis, C., Myers, J., Panagiotakos, D., Doumas, M. 2013; 381 (9864): 394-399

  Abstract

  Statins are commonly prescribed for management of dyslipidaemia and cardiovascular disease. Increased fitness is also associated with low mortality and is recommended as an essential part of promoting health. However, little information exists about the combined effects of fitness and statin treatment on all-cause mortality. We assessed the combined effects of statin treatment and fitness on all-cause mortality risk.In this prospective cohort study, we included dyslipidaemic veterans from Veterans Affairs Medical Centers in Palo Alto, CA, and Washington DC, USA, who had had an exercise tolerance test between 1986, and 2011. We assigned participants to one of four fitness categories based on peak metabolic equivalents (MET) achieved during exercise test and eight categories based on fitness status and statin treatment. The primary endpoint was all-cause mortality adjusted for age, body-mass index, ethnic origin, sex, history of cardiovascular disease, cardiovascular drugs, and cardiovascular risk factors. We assessed mortality from Veteran's Affairs' records on Dec 31, 2011. We compared groups with Cox proportional hazard model.We assessed 10,043 participants (mean age 58·8 years, SD 10·9 years). During a median follow-up of 10·0 years (IQR 6·0-14·2), 2318 patients died, with an average yearly mortality rate of 22 deaths per 1000 person-years. Mortality risk was 18·5% (935/5046) in people taking statins versus 27·7% (1386/4997) in those not taking statins (p<0·0001). In patients who took statins, mortality risk decreased as fitness increased; for highly fit individuals (>9 MET; n=694), the hazard ratio (HR) was 0·30 (95% CI 0·21-0·41; p<0·0001) compared with least fit (≤5 METs) patients (HR 1; n=1060). For those not treated with statins, the HR for least fit participants (n=1024) was 1·35 (95% CI 1·17-1·54; p<0·0001) and progressively decreased to 0·53 (95% CI 0·44-0·65; p<0·0001) for those in the highest fitness category (n=1498).Statin treatment and increased fitness are independently associated with low mortality among dyslipidaemic individuals. The combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone, reinforcing the importance of physical activity for individuals with dyslipidaemia.None.

  View details for DOI 10.1016/S0140-6736(12)61426-3

  View details for Web of Science ID 000314578900036

  View details for PubMedID 23199849

• BMI-Mortality Paradox and Fitness in African American and Caucasian Men With Type 2 Diabetes DIABETES CARE Kokkinos, P., Myers, J., Faselis, C., Doumas, M., Kheirbek, R., Nylen, E. 2012; 35 (5): 1021-1027

  Abstract

  To assess the association between BMI, fitness, and mortality in African American and Caucasian men with type 2 diabetes and to explore racial differences in this association.We used prospective observational data from Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Our cohort (N = 4,156; mean age 60 ± 10.3 years) consisted of 2,013 African Americans (mean age, 59.5 ± 9.9 years), 2,000 Caucasians (mean age, 60.8 ± 10.5 years), and 143 of unknown race/ethnicity. BMI, cardiac risk factors, medications, and peak exercise capacity in metabolic equivalents (METs) were assessed during 1986 and 2010. All-cause mortality was assessed across BMI and fitness categories.There were 1,074 deaths during a median follow-up period of 7.5 years. A paradoxic BMI-mortality association was observed, with significantly higher risk among those with a BMI between 18.5 and 24.9 kg/m(2) (hazard ratio [HR] 1.70 [95% CI 1.36-2.1]) compared with the obese category (BMI ≥ 35 kg/m(2)). This association was accentuated in African Americans (HR 1.95 [95% CI 1.44-2.63]) versus Caucasians (HR 1.53 [1.0-2.1]). The fitness-mortality risk association for the entire cohort and within BMI categories was inverse, independent, and graded. Mortality risks were 12% lower for each 1-MET increase in exercise capacity, and ~35-55% lower for those with an exercise capacity >5 METs compared with the least fit (≤ 5 METs). CONCLUSIONS A paradoxic BMI-mortality risk association was observed in African American and Caucasian patients with diabetes. The exercise capacity-mortality risk association was inverse, independent, and graded in all BMI categories but was more potent in those with a BMI ≥ 25 kg/m(2).

  View details for DOI 10.2337/dc11-2407

  View details for Web of Science ID 000303218900016

  View details for PubMedID 22399701

  View details for PubMedCentralID PMC3329828

• Heart rate recovery, exercise capacity, and mortality risk in male veterans EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Kokkinos, P., Myers, J., Doumas, M., Faselis, C., Pittaras, A., Manolis, A., Kokkinos, J., Narayan, P., Papademetriou, V., Fletcher, R. 2012; 19 (2): 177-184

  Abstract

  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.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.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).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.

  View details for DOI 10.1177/1741826711398432

  View details for Web of Science ID 000302449500006

  View details for PubMedID 21450594

• Prognostic Effect of Exercise Capacity on Mortality in Older Adults with Diabetes Mellitus JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Nylen, E. S., Kokkinos, P., Myers, J., Faselis, C. 2010; 58 (10): 1850-1854

  Abstract

  To investigate the prognostic effect of exercise capacity in older individuals with diabetes mellitus.Retrospective data review in a clinic-based cohort.Veterans Affairs Medical Centers in Washington, District of Columbia, and Palo Alto, California.Two thousand eight hundred sixty-seven men aged 50 to 87 with type 2 diabetes mellitus.Exercise tolerance testing with fitness categories based on peak metabolic equivalents of task (METs) achieved adjusted for age. All-cause mortality in age groups 50 to 65 (Group 1; n=1,658) and older than 65 (Group 2; n=1,209) was analyzed using adjusted Cox proportional hazards models.After a mean ± standard deviation follow-up period of 7.8 ± 5.1 years, there were 324 deaths in Group 1 (20%) and 464 in Group 2 (38%). For each 1-MET increase in exercise capacity, mortality was 18% lower for the entire cohort (hazard ratio (HR)=0.82, 95% confidence interval (CI)=0.79-0.86), 23% lower for Group 1 (HR=0.77, 95% CI=0.73-0.82), and 16% lower for Group 2 (HR=0.84, 95% CI=0.8-0.89). When fitness categories were considered, the mortality risk was 30% to 80% lower for those who achieved more than 4 METs in both age groups.Augmented exercise capacity is associated with lower risk of mortality in people with type 2 diabetes mellitus aged 50 to 65 as well as in those older than 65. Thus, physical fitness, as represented by exercise capacity, lowers mortality risk in people with diabetes mellitus irrespective of age. These findings suggest that healthcare providers should be cognizant of the level of exercise capacity in individual patients and encourage a physically active lifestyle regardless of age.

  View details for DOI 10.1111/j.1532-5415.2010.03068.x

  View details for Web of Science ID 000282690900003

  View details for PubMedID 20929462

• Exercise Capacity and Mortality in Older Men A 20-Year Follow-Up Study CIRCULATION Kokkinos, P., Myers, J., Faselis, C., Panagiotakos, D. B., Doumas, M., Pittaras, A., Manolis, A., Kokkinos, J., Karasik, P., Greenberg, M., Papademetriou, V., Fletcher, R. 2010; 122 (8): 790-797

  Abstract

  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.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.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.

  View details for DOI 10.1161/CIRCULATIONAHA.110.938852

  View details for Web of Science ID 000281193100006

  View details for PubMedID 20697029

• Exercise Capacity and All-Cause Mortality in Prehypertensive Men AMERICAN JOURNAL OF HYPERTENSION Kokkinos, P., Myers, J., Doumas, M., Faselis, C., Manolis, A., Pittaras, A., Kokkinos, J. P., Singh, S., Fletcher, R. D. 2009; 22 (7): 735-741

  Abstract

  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.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 (10 METs). The trends were similar but more pronounced among younger than older individuals.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.

  View details for DOI 10.1038/ajh.2009.74

  View details for Web of Science ID 000267346100009

  View details for PubMedID 19373216

• Exercise Capacity and All-Cause Mortality in African American and Caucasian Men With Type 2 Diabetes DIABETES CARE Kokkinos, P., Myers, J., Nylen, E., Panagiotakos, D. B., Manolis, A., Pittaras, A., Blackman, M. R., Jacob-Issac, R., Faselis, C., Abella, J., Singh, S. 2009; 32 (4): 623-628

  Abstract

  The purpose of this study was to assess the association between exercise capacity and mortality in African Americans and Caucasians with type 2 diabetes and to explore racial differences regarding this relationship.African American (n = 1,703; aged 60 +/- 10 years) and Caucasian (n = 1,445; aged 62 +/- 10 years) men with type 2 diabetes completed a maximal exercise test between 1986 and 2007 at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California. Three fitness categories were established (low-, moderate-, and high-fit) based on peak METs achieved. Subjects were followed for all-cause mortality for 7.3 +/- 4.7 years.The adjusted mortality risk was 23% higher in African Americans than in Caucasians (hazard ratio 1.23 [95% CI 1.1-1.4]). A graded reduction in mortality risk was noted with increased exercise capacity for both races. There was a significant interaction between race and METs (P < 0.001) and among race and fitness categories (P < 0.001). The association was stronger for Caucasians. Each 1-MET increase in exercise capacity yielded a 19% lower risk for Caucasians and 14% for African Americans (P < 0.001). Similarly, the risk was 43% lower (0.57 [0.44-0.73]) for moderate-fit and 67% lower (0.33 [0.22-0.48]) for high-fit Caucasians. The comparable reductions in African Americans were 34% (0.66 [0.55-0.80]) and 46% (0.54 [0.39-0.73]), respectively.Exercise capacity is a strong predictor of all-cause mortality in African American and Caucasian men with type 2 diabetes. The exercise capacity-related reduction in mortality appears to be stronger and more graded for Caucasians than for African Americans.

  View details for DOI 10.2337/dc08-1876

  View details for Web of Science ID 000264819800020

  View details for PubMedID 19196898

  View details for PubMedCentralID PMC2660444

• Exercise Capacity and Mortality in Hypertensive Men With and Without Additional Risk Factors HYPERTENSION Kokkinos, P., Manolis, A., Pittaras, A., Doumas, M., Giannelou, A., Panagiotakos, D. B., Faselis, C., Narayan, P., Singh, S., Myers, J. 2009; 53 (3): 494-499

  Abstract

  We assessed the association between exercise capacity and mortality in hypertensive men with and without additional cardiovascular risk factors. A cohort of 4631 hypertensive veterans, who successfully completed a graded exercise test at the Veterans Affairs Medical Center in Washington, DC, and Palo Alto, California, was followed for 7.7+/-5.4 years (35,629 person-years) for all-cause mortality. Fitness categories were established based on peak metabolic equivalent (MET) levels achieved. In each fitness category, we defined individuals with and without additional cardiovascular risk factors. Exercise capacity was the strongest predictor of all-cause mortality. The adjusted mortality risk was 13% lower for every 1-MET increase in exercise capacity. Compared with the very low fit (< or =5.0 MET), the adjusted risk was 34% lower for those achieving 5.1 to 7.0 MET (low fit; hazard ratio: 0.66; CI: 0.58 to 0.76; P<0.001), 59% lower for the moderate fit (7.1 to 10.0 MET; hazard ratio: 0.41; CI: 0.35 to 0.50; P<0.001), and 71% lower for the high-fit category (>10.0 MET; hazard ratio: 0.29; CI: 0.21 to 0.40; P<0.001). Within the very-low-fit category, mortality risk was 47% higher for those with additional risk factors compared with individuals with no risk factors. This risk was eliminated for those in the next fitness category (5.1 to 7.0 MET) and was progressively reduced for the moderate and high-fit categories regardless of the presence or absence of additional risk factors. In conclusion, exercise capacity was the strongest predictor of all-cause mortality in hypertensive men. The increased risk imposed by low fitness and additional cardiovascular risk factors was eliminated by relatively small increases in exercise capacity and declined progressively with higher exercise capacity.

  View details for DOI 10.1161/HYPERTENSIONAHA.108.127027

  View details for Web of Science ID 000264341200014

  View details for PubMedID 19171789

• A graded association of exercise capacity and all-cause mortality in males with high-normal blood pressure BLOOD PRESSURE Kokkinos, P., Doumas, M., Myers, J., Faselis, C., Manolis, A., Pittaras, A., Kokkinos, J., Papademetriou, V., Singh, S., Fletcher, R. D. 2009; 18 (5): 261-267

  Abstract

  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.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.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.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.

  View details for DOI 10.1080/08037050903272859

  View details for Web of Science ID 000271186400005

  View details for PubMedID 19919397