Exercise for patients with chronic kidney disease: from cells to systems to function.

Chronic kidney disease (CKD) is among the leading causes of death and disability, affecting an estimated 800 million adults globally. The underlying pathophysiology of CKD is complex creating challenges to its management. Primary risk factors for the development and progression of CKD include diabetes mellitus, hypertension, age, obesity, diet, inflammation, and physical inactivity. The high prevalence of diabetes and hypertension in patients with CKD increases the risk for secondary consequences such as cardiovascular disease and peripheral neuropathy. Moreover, the increased prevalence of obesity and chronic levels of systemic inflammation in CKD have downstream effects on critical cellular functions regulating homeostasis. The combination of these factors results in the deterioration of health and functional capacity in those living with CKD. Exercise offers protective benefits for the maintenance of health and function with age, even in the presence of CKD. Despite accumulating data supporting the implementation of exercise for the promotion of health and function in patients with CKD, a thorough description of the responses and adaptations to exercise at the cellular, system, and whole body levels is currently lacking. Therefore, the purpose of this review is to provide an up-to-date comprehensive review of the effects of exercise training on vascular endothelial progenitor cells at the cellular level; cardiovascular, musculoskeletal, and neural factors at the system level; and physical function, frailty, and fatigability at the whole body level in patients with CKD.

Cardiorespiratory fitness and risk of Alzheimer's disease and related dementias among American veterans.

INTRODUCTION: Cardiorespiratory fitness (CRF) is associated with improved health and survival. Less is known about its association with Alzheimer's disease and related dementias (ADRD). METHODS: We identified 649,605 US veterans 30 to 95 years of age and free of ADRD who completed a standardized exercise tolerance test between 2000 and 2017 with no evidence of ischemia. We examined the association between five age- and sex-specific CRF categories and ADRD incidence using multivariate Cox regression models. RESULTS: During up to 20 (median 8.3) years of follow-up, incident ADRD occurred in 44,105 (6.8%) participants, with an incidence rate of 7.7/1000 person-years. Compared to the least-fit, multivariable-adjusted hazard ratios (95% confidence intervals) for incident ADRD were: 0.87 (0.85-0.90), 0.80 (0.78-0.83), 0.74 (0.72-0.76), and 0.67 (0.65-0.70), for low-fit, moderate-fit, fit, and high-fit individuals, respectively. DISSCUSSION: These findings demonstrate an independent, inverse, and graded association between CRF and incident ADRD. Future studies may determine the amount and duration of physical activity needed to optimize ADRD risk reduction.

Adherence to the Mediterranean Diet and Successful aging in Greeks living in Greece and abroad: the epidemiological Mediterranean Islands Study (MEDIS).

Background: Whether older immigrant populations from the Mediterranean region, continue to follow the MD long after they immigrated is not known. Aim: Compare adherence to the MD and successful aging levels between Greeks living in Greece (GG) and Greeks living abroad (GA). Methods: Anthropometrical, clinical, psychological, sociodemographic, dietary and lifestyle parameters were assessed in a cross-sectional manner in a sample of 252 GG and 252 GA. Mediterranean Diet Score (MedDietScore range 0-55) was used to assess adherence to the MD. Successful aging was evaluated with the validated successful aging index (SAI range 0-10). Results: GA presented higher adherence to MD (p < 0.001); they were consuming significantly more cereals, legumes, vegetables, and fruits compared to GG. GG consumed significantly more dairy (3.8 ± 2.9 vs. 1.9 ± 2.2, p < 0.001) and potatoes (2.4 ± 1.6 vs. 1.9 ± 1.5, p < 0.001) compared to GA. Meat (p = 0.27), poultry (p = 0.72), fish (p = 0.68), olive oil (p = 0.16) and alcohol consumption (p = 0.05) were comparable between the two groups (all p's > 0.05). MedDietScore was positively associated with SAI among both groups after adjusting for possible confounders (0.041 ± 0.014, p = 0.003 GG and 0.153 ± 0.035, p < 0.001 GA). Also, legumes, cereals, fruits and vegetables were found to be beneficial for successful aging. Conclusion: Adherence to the MD is associated with higher levels of successful aging among people of the same genetic background living in different environments. However, traditional dietary habits are gradually abandoned in their native countries, when, at the same time, are considered cultural heritage and preserved accordingly among immigrants.

Role of Blood Pressure Responses to Exercise and Vascular Insulin Sensitivity with Nocturnal Blood Pressure Dipping in Metabolic Syndrome.

INTRODUCTION: Nocturnal systolic blood pressure (SBP) dipping is independently related to cardiovascular disease risk, but it is unclear if vascular insulin sensitivity associates with SBP dipping in patients with metabolic syndrome (MetS). METHODS: Eighteen adults with MetS (ATP III criteria 3.3 ± 0.6; 53.2 ± 6.5 years; body mass index 35.8 ± 4.5 kg/m2) were categorized as "dippers" (≥10% change in SBP; n = 4 F/3 M) or "non-dippers" (<10%; n = 9 F/2 M). Twenty-four-hour ambulatory blood pressure was recorded to assess SBP dipping. A euglycemic-hyperinsulinemic clamp (40 mU/m2/min, 90 mg/dL) with ultrasound (flow mediated dilation) was performed to test vascular insulin sensitivity. A graded, incremental exercise test was conducted to estimate sympathetic activity. Heart rate (HR) recovery after exercise was then used to determine parasympathetic activity. Metabolic panels and body composition (DXA) were also tested. RESULTS: Dippers had greater drops in SBP (16.63 ± 5.2 vs. 1.83 ± 5.6%, p < 0.01) and experienced an attenuated rise in both SBPslope (4.7 ± 2.3 vs. 7.2 ± 2.5 mm Hg/min, p = 0.05) and HRslope to the incremental exercise test compared to non-dippers (6.5 ± 0.9 vs. 8.2 ± 1.7 bpm/min, p = 0.03). SBP dipping correlated with higher insulin-stimulated flow-mediated dilation (r = 0.52, p = 0.03), although the relationship was no longer significant after covarying for HRslope (r = 0.42, p = 0.09). CONCLUSION: Attenuated rises in blood pressure and HR to exercise appear to play a larger role than vascular insulin sensitivity in SBP dipping in adults with MetS.

Association between cardiorespiratory fitness, obesity, and health care costs: The Veterans Exercise Testing Study.

BACKGROUND/OBJECTIVE: Obesity is a chronic disease, a risk factor for other chronic conditions and for early mortality, and is associated with higher health care utilization. Annual spending among obese individuals is at least 30% higher vs. that for normal-weight peers. In contrast, higher cardiorespiratory fitness (CRF) is related to many health benefits. We sought to examine the association between CRF and health care costs across the spectrum of body mass index (BMI). METHODS: Data from 3,924 men (58.1 ± 11.1 years, 29.2 ± 5.3 kg.m-2) who completed a maximal exercise test for clinical reasons and to estimate CRF were recorded prospectively at the time of testing. Cost data (USD) from each subject during a 6-year period after the exercise test were merged with the exercise database and compared according to BMI and estimated CRF (CRFe). Subjects were categorized as normal-weight (BMI < 25.0 kg.m-2), overweight (BMI 25.0-29.9 kg.m-2), and obese (BMI ≥ 30.0 kg.m-2). We also formed four CRFe categories based on age-stratified quartiles of metabolic equivalents (METs) achieved: least-fit (5.1 ± 1.5 METs; n = 1,044), moderately-fit (7.6 ± 1.5 METs; n = 938), fit (9.4 ± 1.5 METs; n = 988), and highly-fit (12.4 ± 2.2 METs; n = 954). RESULTS: Average annual costs per person adjusted for age and presence of cardiovascular disease were $37,018, $40,572, and $45,683 for normal-weight, overweight, and obese subjects, respectively (p < 0.01). For each 1-MET incremental increase in CRFe, annual cost savings per person were $3,272, $4,252, and $6,103 for normal-weight, overweight, and obese subjects, respectively. Stratified by CRFe categories, annual costs for normal-weight, overweight, and obese subjects in the highest CRFe quartile were $28,028, $31,669, and $32,807 lower, respectively, compared to subjects in the lowest CRFe quartile (p < 0.01). CONCLUSION: Higher CRFe is associated with lower health care costs. Cost savings were particularly evident in obese subjects, suggesting that the economic burden of obesity may be reduced through interventions that target improvements in CRF.

Cardiorespiratory fitness versus physical activity as predictors of all-cause mortality in men.

BACKGROUND: Although both cardiorespiratory fitness (CRF) and physical activity (PA) are associated with mortality, whether they are associated with all-cause mortality independent of each other is unclear. METHODS: CRF was assessed by a maximal exercise test and PA was measured by self-report in 8,171 male veterans. The predictive power of CRF and PA, along with clinical variables, was assessed for all-cause mortality during a mean (±SD) follow-up 8.7 (4.4) years during which there were 1,349 deaths. RESULTS: CRF was associated with mortality after adjusting for clinical variables and remained a strong predictor of mortality after further adjusting for PA (hazard ratio 0.85, 95% CI 0.83-0.87). PA was a significant predictor of mortality after controlling for clinical variables; however, the association was eliminated after further adjusting for CRF (hazard ratio 0.98, 95% CI 0.88-1.10). In CRF-stratified analysis, being active (≥150 min/wk) was not associated with mortality within the unfit or fit categories (P>.4). However, in PA-stratified analysis, subjects categorized as fit (≥7 metabolic equivalents [METS]) had a lower risk of mortality regardless of PA status (P<.001). CONCLUSIONS: In adult men, PA was associated with mortality independent of established risk factors, but not CRF. Conversely, CRF remained a strong predictor of mortality independent of PA status and established risk factors.

Cardiorespiratory fitness, physical activity and cancer mortality in men.

The preventive role of cardiorespiratory fitness (CRF) and physical activity (PA) in cancer mortality is not well-established. This study sought to evaluate the association between CRF, PA and cancer mortality in men. Maximal exercise testing was performed at the VA Palo Alto Health Care System in 5876 male veterans (60.5±11years) free from malignancy at baseline who were followed for mean of 9.9 (range 0.11 to 26.8) years. PA status was assessed in a sub-group of 4034 participants. Relative risks and population attributable risks (PAR%) for cancer-related mortality were determined. During the follow-up, 447 men (7.6%) died from cancer. Forty-nine percent of the sample was considered physically active (defined as meeting the minimal PA guidelines); this group exhibited a 20% reduction in cancer mortality risk [95% confidence interval (0.67-0.97), p=0.02]. CRF was inversely associated with cancer death. For each 1 MET increase in CRF there was a 5% reduction in risk for cancer mortality (p=0.01). Compared to the least fit group (<5.0 METs), subjects with moderate to high CRF exhibited 26-46% reduced risks of cancer mortality (p for trend=0.002). The PARs% for low CRF and inactivity were 6.6% and 8.5%, respectively. Moderate and high CRF levels and meeting the minimal PA guidelines have protective benefits against cancer mortality in men. Eliminating inactivity and low CRF as risk factors could potentially prevent a considerable number of cancer deaths and reduce the associated societal and economic burden.

Age-specific exercise capacity threshold for mortality risk assessment in male veterans.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: We defined age-specific exercise capacity thresholds to guide assessment of mortality risk in individuals undergoing a clinical exercise test.

Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: None.

Glucagon-Like Peptide-1 Receptor Agonists and Sodium Glucose Cotransporter-2 Inhibitors and Cardiorespiratory Fitness Interaction.

INTRODUCTION: Cardiorespiratory fitness (CRF) is a stronger predictor of mortality than traditional risk factors and is a neglected vital sign of health. Enhanced fitness is a cornerstone in diabetes management and is most often delivered concurrently with pharmacological agents, which can have an opposing impact, as has been reported with metformin. Considering the rapid evolution of diabetes medications with improved cardiovascular outcomes, such as glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors, it is of importance to consider the influence of these vis-a-vis effects on CRF. MATERIALS AND METHODS: Combining the words glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter-2 inhibitors with cardiorespiratory fitness, an online search was done using PubMed, Embase, Scopus, Web of Science, Scientific Electronic Library Online, and Cochrane. RESULTS: There were only a few randomized controlled studies that included CRF, and the results were mostly neutral. A handful of smaller studies detected improved CRF using sodium glucose cotransporter-2 inhibitors in patients with congestive heart failure. CONCLUSIONS: Since CRF is a superior prognosticator for cardiovascular outcomes and both medications can cause lean muscle mass loss, the current review highlights the paucity of relevant interactive analysis.

Update to the 2016 American Heart Association cardiorespiratory fitness statement.

In 2016 the American Heart Association published a scientific statement that summarized a large body of evidence concluding that cardiorespiratory fitness (CRF) was a powerful marker of cardiovascular disease (CVD) and CVD-mortality risk; its association with morbidity and mortality was independent of commonly obtained risk factors, and consequently, that it should be a routine measure in all health care settings. Since 2016 the interest in CRF as a prognostic for human health and performance has increased exponentially. This review will summarize a growing body of evidence that reinforces the notion that the assessment of CRF improves patient/client management. Feasible means of CRF assessment in health care settings is considered, and the expected response of CRF to exercise consistent with consensus recommendations is reviewed. The association between CRF and health care costs is also explored. The evidence reviewed will reinforce the conclusions drawn in 2016; that overwhelming evidence demands that CRF should be a routine assessment in all health care settings - a vital sign.

A Novel Explainable AI Method to Assess Associations between Temporal Patterns in Patient Trajectories and Adverse Outcome Risks: Analyzing Fitness as a Risk Factor of ADRD.

We present a novel explainable artificial intelligence (XAI) method to assess the associations between the temporal patterns in the patient trajectories recorded in longitudinal clinical data and the adverse outcome risks, through explanations for a type of deep neural network model called Hybrid Value-Aware Transformer (HVAT) model. The HVAT models can learn jointly from longitudinal and non-longitudinal clinical data, and in particular can leverage the time-varying numerical values associated with the clinical codes or concepts within the longitudinal data for outcome prediction. The key component of the XAI method is the definitions of two derived variables, the temporal mean and the temporal slope, which are defined for the clinical concepts with associated time-varying numerical values. The two variables represent the overall level and the rate of change over time, respectively, in the trajectory formed by the values associated with the clinical concept. Two operations on the original values are designed for changing the values of the two derived variables separately. The effects of the two variables on the outcome risks learned by the HVAT model are calculated in terms of impact scores and impacts. Interpretations of the impact scores and impacts as being similar to those of odds ratios are also provided. We applied the XAI method to the study of cardiorespiratory fitness (CRF) as a risk factor of Alzheimer's disease and related dementias (ADRD). Using a retrospective case-control study design, we found that each one-unit increase in the overall CRF level is associated with a 5% reduction in ADRD risk, while each one-unit increase in the changing rate of CRF over time is associated with a 1% reduction. A closer investigation revealed that the association between the changing rate of CRF level and the ADRD risk is nonlinear, or more specifically, approximately piecewise linear along the axis of the changing rate on two pieces: the piece of negative changing rates and the piece of positive changing rates.

Long-Term Mortality Risk According to Cardiorespiratory Fitness in Patients Undergoing Coronary Artery Bypass Graft Surgery.

The aim of this study was to evaluate the association between cardiorespiratory fitness (CRF) and long-term survival in United States (US) Veterans undergoing CABG. We identified 14,550 US Veterans who underwent CABG at least six months after completing a symptom-limited exercise treadmill test (ETT) with no evidence of cardiovascular disease. During a mean follow-up period of 10.0 ± 5.4 years, 6502 (43.0%) died. To assess the association between CRF and risk of mortality, we formed the following five fitness categories based on peak workload achieved (metabolic equivalents or METs) prior to CABG: Least-Fit (4.3 ± 1.0 METs (n = 4722)), Low-Fit (6.8 ± 0.9 METs (n = 3788)), Moderate-Fit (8.3 ± 1.1 METs (n = 2608)), Fit (10.2 ± 0.8 METs (n = 2613)), and High-Fit (13.0 ± 1.5 METs (n = 819)). Cox proportional hazard models were used to calculate risk across CRF categories. The models were adjusted for age, body mass index, race, cardiovascular disease, percutaneous coronary intervention prior to ETT, cardiovascular medications, and cardiovascular disease risk factors. P-values < 0.05 using two-sided tests were considered statistically significant. The association between cardiorespiratory fitness and mortality was inverse and graded. For every 1-MET increase in exercise capacity, the mortality risk was 11% lower (HR = 0.89; CI: 0.88-0.90; p < 0.001). When compared to the Least-Fit category (referent), mortality risk was 22% lower in Low-Fit individuals (HR = 0.78; CI: 0.73-0.82; p < 0.001), 31% lower in Moderate-Fit individuals (HR = 0.69; CI: 0.64-0.74; p < 0.001), 52% lower in Fit individuals (HR = 0.48; CI: 0.44-0.52; p < 0.001), and 66% lower in High-Fit individuals (HR = 0.34; CI: 0.29-0.40; p < 0.001). Cardiorespiratory fitness is inversely and independently associated with long-term mortality after CABG in Veterans referred for exercise testing.

Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The Association between Cardiorespiratory Fitness and the Risk of Breast Cancer in Women.

INTRODUCTION: 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. PURPOSE: To examine the CRF-breast cancer risk association in healthy females. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction.

AIMS: Preventive strategies for heart failure 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. METHODS AND RESULTS: 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 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure 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 a median follow-up of 10.1 years (interquartile range 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 1000 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% confidence interval [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. CONCLUSIONS: Higher CRF levels are independently associated with lower HFpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.

Stroke Incidence in Patients With Hypertension According to Cardiorespiratory Fitness.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Blood pressure control among US veterans: a large multiyear analysis of blood pressure data from the Veterans Administration health data repository.

BACKGROUND: Hypertension treatment and control remain low worldwide. Strategies to improve blood pressure control have been implemented in the United States and around the world for several years. This study was designed to assess improvement in blood pressure control over a 10-year period in a large cohort of patients in the Department of Veterans Affairs. METHODS AND RESULTS: A cohort of 582 881 hypertensive patients and 260 924 normotensive individuals treated in 15 Department of Veterans Affairs medical centers between 2000 and 2010 were examined. Strategies used system-wide included blood pressure control as a performance measure, automatic notification to healthcare providers, electronic reminders, and a systematic revisit schedule. The main outcome measure was the percentage of hypertensive patients whose hypertension was controlled and the level of blood pressure each month. In the hypertensive cohort (mean age 62.9±13.4 years, 96.0% male), 52.3% of patients were white, 25.1% were black, and 21.1% were Hispanic. Blood pressure control rates improved from 45.7% in September 2000 to 76.3% in August 2010. Improvements were similar across ethnic, racial, age, and sex groups. Average systolic/diastolic blood pressure decreased from 142.6/77.1 mm Hg in 2000 to 131.2/74.8 mm Hg in 2010, a decrease of 11.3/2.3 mm Hg (P<0.0001 for both). Systolic and diastolic blood pressures were lower in summer than in winter, and this trend continued through 2010. On average, control rates increased by 3.0% per year and were 6.8% higher in summer than in winter. CONCLUSIONS: High rates of blood pressure control can be achieved in all age and ethnic groups and in both sexes.

Gender differences in hypertension: myths and reality.

Life expectancy is longer in women compared to men, and cardiovascular events occur at a lower rate and at a later age in females than males. The impact of gender on the prevalence, the presentation, and the long-term outcome of cardiovascular disease has long been a topic of active research. Gender differences have been found in several studies but opposite findings also exist. The impact of gender in hypertension and antihypertensive therapy remains poorly clarified. The prevalence, awareness, treatment, and control rates of hypertension exhibit some differences between the two sexes, which are age-dependent. The female advantage in the cardiovascular risk of hypertensive patients might be attenuated by comorbidities and target organ damage. Another aspect of major clinical importance is whether gender differences exist on the effects of antihypertensive agents in blood pressure reduction and cardiovascular morbidity and mortality. The aim of this review is to critically evaluate recent data regarding gender differences in hypertension and incorporate new data into the body of existing knowledge.

Hybrid Value-Aware Transformer Architecture for Joint Learning from Longitudinal and Non-Longitudinal Clinical Data.

Transformer is the latest deep neural network (DNN) architecture for sequence data learning, which has revolutionized the field of natural language processing. This success has motivated researchers to explore its application in the healthcare domain. Despite the similarities between longitudinal clinical data and natural language data, clinical data presents unique complexities that make adapting Transformer to this domain challenging. To address this issue, we have designed a new Transformer-based DNN architecture, referred to as Hybrid Value-Aware Transformer (HVAT), which can jointly learn from longitudinal and non-longitudinal clinical data. HVAT is unique in the ability to learn from the numerical values associated with clinical codes/concepts such as labs, and in the use of a flexible longitudinal data representation called clinical tokens. We have also trained a prototype HVAT model on a case-control dataset, achieving high performance in predicting Alzheimer's disease and related dementias as the patient outcome. The results demonstrate the potential of HVAT for broader clinical data-learning tasks.