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Background and Aims: Promising associations have been demonstrated between delayed last eating occasion and cardiorespiratory fitness in adults with heart failure (HF), however, it is unknown if time of eating is associated with clinical endpoints such as mortality. This study aimed to examine associations between time of eating variables and all-cause and cardiovascular mortality in the National Health and Nutrition Examination Survey (NHANES)., Methods and Results: Participants self-disclosed HF diagnosis. Two dietary recalls were obtained and categorical variables were created based on mean time of first eating occasion (8:31 AM), last eating occasion (7:33 PM) and eating window (11.02 h). Mortality was obtained through linkage to the National Death Index. Covariate-adjusted Cox proportional hazard regression models were created examining the association between time of eating and mortality. Participants (n = 991) were 68 (95 % CI 67-69) years of age, 52.6 (95 % CI 49.0-56.3)% men and had a body mass index of 32.5 (95 % CI 31.8-33.2) kg/m 2 with follow up time of 68.9 (95 % CI 64.8-72.9) person-months. When models were adjusted for time of eating variables and all other covariates, extending the eating window beyond 11.02 h was associated with decreased risk of cardiovascular (HR 0.36 [95 % CI 0.16-0.81]), but not all-cause mortality. Time of first and last eating occasions were not associated with mortality., Conclusions: In adults with HF, an extended eating window is associated with reduced risk for cardiovascular mortality. Randomized controlled trials should examine if extending the eating window can improve prognostic indicators such as cardiorespiratory fitness in this population., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Despite the advancement in blood pressure (BP) lowering medications, uncontrolled hypertension persists, underscoring a stagnation of effective clinical strategies. Novel and effective lifestyle therapies are needed to prevent and manage hypertension to mitigate future progression to cardiovascular and chronic kidney diseases. Chrono-nutrition, aligning the timing of eating with environmental cues and internal biological clocks, has emerged as a potential strategy to improve BP in high-risk populations. The aim of this review is to provide an overview of the circadian physiology of BP with an emphasis on renal and vascular circadian biology. The potential of Chrono-nutrition as a lifestyle intervention for hypertension is discussed and current evidence for the efficacy of time-restricted eating is presented., (© 2024 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Several human studies have used the mitochondrial antioxidant MitoQ. Recent in vitro data indicating that MitoQ may induce nephrotoxicity caused concern regarding the safety of MitoQ on the kidneys, but the doses were supraphysiological. Therefore, we sought to determine whether acute MitoQ elicits changes in urinary biomarkers associated with tubular injury in healthy adults with our hypothesis being there would be no changes. Using a randomized crossover design, 32 healthy adults (16 females and 16 males, 29 ± 11 yr old) consumed MitoQ (100-160 mg based on body mass) or placebo capsules. We obtained serum samples and a 4- to 6-h postcapsule consumption urine sample. We assessed creatinine clearance and urine kidney injury biomarkers including the chitinase 3-like-1 gene product YKL-40, kidney-injury marker-1, monocyte chemoattractant protein-1, epidermal growth factor, neutrophil gelatinase-associated lipocalin, interleukin-18, and uromodulin using multiplex assays. We used t tests, Wilcoxon tests, and Hotelling's T 2 to assess global differences in urinary kidney injury markers between conditions. Acute MitoQ supplementation did not influence urine flow rate ( P = 0.086, r rb = 0.39), creatinine clearance ( P = 0.085, r rb = 0.42), or urinary kidney injury markers ( T 2 2,8 = 30.6, P = 0.121, univariate ps > 0.064). Using exploratory univariate analysis, MitoQ did not alter individual injury markers compared with placebo (e.g., placebo vs. MitoQ: YKL-40, 507 ± 241 vs. 442 ± 236 pg/min, P = 0.241; kidney injury molecule-1, 84.1 ± 43.2 vs. 76.2 ± 51.2 pg/min, P = 0.890; and neutrophil gelatinase-associated lipocalin, 10.8 ± 10.1 vs. 9.83 ± 8.06 ng/min, P = 0.609). In conclusion, although longer-term surveillance and data are needed in clinical populations, our findings suggest that acute high-dose MitoQ had no effect on urinary kidney injury markers in healthy adults. NEW & NOTEWORTHY We found acute high-dose mitochondria-targeted antioxidant (MitoQ) supplementation was not nephrotoxic and had no effect on markers of acute kidney injury in healthy adults. These findings can help bolster further confidence in the safety of MitoQ, particularly for future investigations seeking to examine the role of mitochondrial oxidative stress, via acute MitoQ supplementation, on various physiological outcomes.

Patients with chronic kidney disease (CKD) have an exacerbated prevalence of cardiovascular disease (CVD). Vascular dysfunction, characterized by impaired endothelial function and arterial stiffness, and markedly low cardiorespiratory fitness levels are hallmark manifestations of the disease that contribute to the CVD burden. Despite advancements in blood pressure and lipid lowering pharmacological therapies, CVD remains markedly prevalent across the spectrum of CKD. This highlights a stagnation in effective clinical strategies to improve cardiovascular health and reinforces the critical need for adjuvant lifestyle strategies such as physical activity and exercise training to be incorporated into routine clinical care. This narrative review provides an overview of the known effects of exercise on vascular and cardiopulmonary function across the spectrum of CKD. The physiological mechanisms of vascular dysfunction that serve as exercise-specific therapeutic targets are highlighted and future perspectives are discussed.

Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare.

High sodium diets (HSD) can cause vascular dysfunction, in part due to increases in reactive oxygen species (ROS). Melatonin reduces ROS in healthy and clinical populations and may improve vascular function. The purpose was to determine the effect of melatonin supplementation on vascular function and ROS during 10 days of a HSD. We hypothesized that melatonin supplementation during a HSD would improve vascular function and decrease ROS levels compared to HSD alone. Twenty-seven participants (13 M/14 W, 26.7 ± 2.9 years, BMI: 23.6 ± 2.0 kg/m 2 , BP: 110 ± 9/67 ± 7 mmHg) were randomized to a 10-day HSD (6900 mg sodium/d) supplemented with either 10 mg of melatonin (HSD + MEL) or a placebo (HSD + PL) daily. Brachial artery flow-mediated dilation, a measure of macrovascular function, (HSD + PL: 7.1 ± 3.8%; HSD + MEL: 6.7 ± 3.4%; p = 0.59) and tissue oxygenation index (TSI) reperfusion rate, a measure of microvascular reactivity, (HSD + PL: 0.21 ± 0.06%/s; HSD + MEL: 0.21 ± 0.08%/s; p = 0.97) and TSI area under the curve (HSD + PL: 199899 ± 10,863 a.u.; HSD + MEL: 20315 ± 11,348 a.u.; p = 0.17) were similar at the end of each condition. Neither nitroxide molarity (HSD + PL: 7.8 × 10 -5  ± 4.1 × 10 -5 mol/L; HSD + MEL: 8.7 × 10 -5  ± 5.1 × 10 -5 mol/L; p = 0.55) nor free radical number (HSD + PL: 8.0 × 10 15  ± 4.4 × 10 15 ; HSD + MEL: 9.0 × 10 15  ± 4.9 × 10 15 ; p = 0.51) were different between conditions. Melatonin supplementation did not alter vascular function or ROS levels while on a HSD in this sample of young healthy normotensive adults., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objectives: Cardiorespiratory fitness (CRF) is influenced by body composition quantity and quality in heart failure with preserved ejection fraction (HFpEF) and obesity. Bioelectrical impedance analysis (BIA) provides a noninvasive quantitative and qualitative body composition assessment. The aim of this study was to determine the role of phase angle (PhA), a BIA-measure of skeletal muscle quality and body cell mass, on CRF in patients with obesity and HFpEF., Methods: Fifty-nine consecutive outpatients with HFpEF underwent cardiopulmonary exercise testing to measure CRF. Single-frequency segmental BIA was used to measure PhA and body composition quantity. Resting Doppler echocardiography and biomarkers were measured to assess cardiac function and systemic inflammation., Results: Compared with patients with lower PhA, patients with higher PhA (above mean 5.8°) presented a greater absolute peak oxygen consumption (VO 2 ; 1.83 [1.3-2.1] versus 1.39 [1.1-1.6] L/min, P = 0.003), VO 2 peak adjusted for body weight (17.5 [12.3-18.1] versus 13.3 [12.7-15.2] mL/kg/min, P = 0.040), and a lower edema index (48.7 [2.9] versus 51.4% [2.7], P < 0.001) and N-terminal pro-B-type natriuretic peptide (NT-proBNP; 64 [50-121] versus 183 [68-343.5] pg/dL, P < 0.001). In the overall sample, PhA was correlated with absolute VO 2 peak (r = 0.468, P < 0.001), VO 2 peak adjusted for body weight (r = 0.368, P = 0.004), VO 2 peak adjusted for fat-free mass (r = 0.315, P = 0.015), edema index (r = -0.508, P < 0.001), and NT-proBNP (r = -0.579, P < 0.001). PhA remained a significant predictor for CRF even after adjustment for potential confounders and HFpEF severity., Conclusion: In patients with obesity and HFpEF, a greater PhA is an independent predictor for favorable CRF., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Salvatore Carbone reports financial support was provided by American Heart Association. Salvatore Carbone reports financial support was provided by National Institutes of Health. Danielle Kirkman reports financial support was provided by American Heart Association. Danielle Kirkman reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

High-sodium diets (HSDs) can cause exaggerated increases in blood pressure (BP) during physiological perturbations that cause sympathetic activation, which is related to cardiovascular risk. Melatonin supplementation has been shown to play a role in BP regulation. Our aim was to examine the effects of melatonin taken during an HSD on 24-h BP and BP reactivity during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT). Twenty-two participants (11 men/11 women, 26.5 ± 3.1 yr, BMI: 24.1 ± 1.8 kg/m 2 , BP: 111 ± 9/67 ± 7 mmHg) were randomized to a 10-day HSD (6,900 mg sodium/day) that was supplemented with either 10 mg/day of melatonin (HSD + MEL) or placebo (HSD + PL). Twenty-four-hour ambulatory BP monitoring was assessed starting on day 9 . Mean arterial pressure (MAP) was quantified during the last 30 s of IHG at 40% of maximal voluntary contraction and CPT, and during 3 min of PEI. Melatonin did not change 24-h MAP (HSD + PL: 83 ± 6 mmHg; HSD + MEL: 82 ± 5 mmHg; P = 0.23) but decreased nighttime peripheral (HSD + PL: 105 ± 10 mmHg; HSD + MEL: 100 ± 10 mmHg; P = 0.01) and central systolic BP (HSD + PL: 97 ± 9 mmHg; HSD + MEL: 93 ± 8 mmHg; P = 0.04) on the HSD compared with the HSD + PL. The absolute and percent change in MAP during IHG was not different between conditions (all P > 0.05). In conclusion, melatonin supplementation did not alter BP reactivity to the perturbations tested on an HSD but may be beneficial in lowering BP in young healthy normotensive adults. NEW & NOTEWORTHY BP reactivity was assessed during isometric handgrip (IHG) exercise, postexercise ischemia (PEI), and the cold pressor test (CPT) after 10 days of a high-sodium diet with and without melatonin supplementation. Melatonin did not alter BP reactivity in healthy normotensive men and women. However, melatonin did decrease nighttime peripheral and central systolic BP, suggesting it may be beneficial in lowering BP even in those with a normal BP.

Mitochondria-derived oxidative stress has been implicated in vascular and skeletal muscle abnormalities in chronic kidney disease (CKD). The purpose of this study was to investigate the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in CKD. In this randomized controlled trial, 18 patients with CKD (means ± SE, age: 62 ± 3 yr and estimated glomerular filtration rate: 45 ± 3 mL/min/1.73 m 2 ) received 4 wk of 20 mg/day MitoQ (MTQ group) or placebo (PLB). Outcomes assessed at baseline and follow-up included macrovascular function measured by flow-mediated dilation, microvascular function assessed by laser-Doppler flowmetry combined with intradermal microdialysis, aortic hemodynamics assessed by oscillometry, and exercise capacity assessed by cardiopulmonary exercise testing. Compared with PLB, MitoQ improved flow-mediated dilation (baseline vs. follow-up: MTQ, 2.4 ± 0.3% vs. 4.0 ± 0.9%, and PLB, 4.2 ± 1.0% vs. 2.5 ± 1.0%, P = 0.04). MitoQ improved microvascular function (change in cutaneous vascular conductance: MTQ 4.50 ± 2.57% vs. PLB -2.22 ± 2.67%, P = 0.053). Central aortic systolic and pulse pressures were unchanged; however, MitoQ prevented increases in augmentation pressures that were observed in the PLB group ( P = 0.026). MitoQ did not affect exercise capacity. In conclusion, this study demonstrates the potential for a MitoQ to improve vascular function in CKD. The findings hold promise for future investigations of mitochondria-targeted therapies in CKD. NEW & NOTEWORTHY In this randomized controlled pilot study, we investigated the effects of a mitochondria-targeted ubiquinol (MitoQ) on vascular function and exercise capacity in chronic kidney disease. Our novel findings showed that 4-wk supplementation of MitoQ was well tolerated and improved macrovascular endothelial function, arterial hemodynamics, and microvascular function in patients with stage 3-4 chronic kidney disease. Our mechanistic findings also suggest that MitoQ improved microvascular function in part by reducing the NADPH oxidase contribution to vascular dysfunction.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean ± SD; age, 56 ± 13 yr) and 10 female (age, 63 ± 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1 ) Ringer's solution; 2 ) superoxide dismutase mimetic, Tempol; and 3 ) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). Central pulse pressure (mean ± SE; 62 ± 9 vs. 46 ± 3 mmHg; P = 0.01) and augmentation index (36 ± 3 vs. 26 ± 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 ± 9 vs. 131 ± 3 mmHg; P = 0.06). Females reported higher forward (39 ± 4 vs. 29 ± 2 mmHg; P = 0.004) and reflected (27 ± 3 vs. 19 ± 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 ± 3 vs. 89 ± 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females. NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

Patients with heart failure with preserved ejection fraction (HFpEF) suffer from a high rate of cardiometabolic comorbidities with limited pharmaceutical therapies proven to improve clinical outcomes and cardiorespiratory fitness (CRF). Nonpharmacologic therapies, such as exercise training and dietary interventions, are promising strategies for this population. The aim of this narrative review is to present a summary of the literature published to date and future directions related to the efficacy of nonpharmacologic, lifestyle-related therapies in HFpEF, with a focus on exercise training and dietary interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Delayed time of evening meal is associated with favorable cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. It is unknown, however, if increasing daily non-fasting time or delaying the midpoint of energy intake may also be associated with CRF., Objective: Our aim was to examine whether a longer non-fasting time, delayed midpoint of energy intake, or both, are associated with greater CRF in patients with HFpEF and obesity., Methods: We measured peak oxygen consumption (VO 2 ), a measure of CRF, in 32 patients with HFpEF and obesity with cardiopulmonary exercise testing, and dietary intake using a five-pass 24-h dietary recall. Participants were divided into groups by having lesser (<11.6) or greater (≥11.6) periods of non-fasting time than the median and similarly, with earlier (<2:15 PM) or later (≥2:15 PM) than median midpoint of energy intake., Results: Median non-fasting time was 11.6 [10.6-12.9] hours and midpoint of energy intake was 2:15 [1:04-3:00] PM. There were no differences in CRF between those with a shorter (<11.6) or longer (≥11.6) non-fasting time. Participants with a delayed midpoint of energy intake (≥2:15 PM) had greater peak VO 2 and exercise time. Midpoint of energy intake (r = 0.444, P = 0.011) and time of last meal (r = 0.550, P = 0.001) displayed a positive association with peak VO 2 , but not non-fasting time nor time of first meal., Conclusions: Delaying the midpoint of energy intake by postponing last meal is associated with better peak VO 2 and exercise time in patients with HFpEF and obesity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Lean mass abnormalities are highly prevalent in patients referred for cardiac rehabilitation (CR). As such, current guidelines recommend incorporating resistance exercise (RE) into the exercise prescription of Phase II-IV CR. The effects of RE on health-related outcomes in patients with cardiovascular (CV) disease (CVD) have not been extensively investigated in comparison to aerobic exercise, the traditional modality of exercise implemented in CR. The purpose of this review is to highlight the growing prevalence of lean mass abnormalities such as dynapenia and sarcopenia in CVD and briefly outline the contributing pathophysiology of these impairments as potential targets for RE training. An update on the current evidence pertaining to the effects of RE on exercise capacity, skeletal muscle strength, body composition, CV health, and quality of life in CR patient populations is provided. The current recommendations for RE training in CR are discussed. Future directions for research and clinical practice in this field are highlighted, and included the need to identify the most efficacious principles of resistance training for different health related outcomes in CVD, as well as the suggested drive towards a 'personalized medicine' approach to exercise prescription in CR., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Patients with chronic kidney disease have reduced cardiorespiratory fitness levels that contribute to mortality., Objectives: The purpose of this study was to investigate the effects of aerobic exercise on cardiopulmonary function in patients with chronic kidney disease., Methods: A total of 36 patients (mean [SD] estimated glomerular filtration rate 44 [12] ml/min/1.73m 2 ) were randomly allocated to an exercise training or a control arm over 12 weeks. The exercise training group performed aerobic exercise for 45min 3 times/week at 65% to 80% heart rate reserve. The control group received routine care. Outcome measures were assessed at baseline and 12 weeks. Cardiopulmonary exercise testing was performed on a cycle ergometer with workload increased by 15W/min. A battery of physical function tests were administered. Habitual physical activity levels were recorded via accelerometry. Data are mean [SD]., Results: Exercise training improved VO 2peak as compared with the control group (exercise: 17.89 [4.18] vs 19.98 [5.49]; control: 18.29 [6.49] vs 17.36 [5.99] ml/kg/min; P<0.01). Relative O 2 pulse improved following exercise, suggestive of improved left ventricular function (exercise: 0.12 [0.02] vs 0.14 [0.04]; control: 0.14 [0.05] vs 0.14 [0.04] ml/beat/kg; P=0.03). Ventilation perfusion mismatching (V E /VCO2) remained evident after exercise (exercise: 32 [5] vs 33 [5]; control: 32 [7] vs 34 [5] AU; P=0.1). Exercise did not affect the ventilatory cost of oxygen uptake (V E /VO 2 ; exercise: 40 [7] vs 42 [8]; control: 3 [7] vs 41 [8] AU; P=0.5) and had no effect on autonomic function assessed by maximal and recovery heart rates. We found no changes in physical function or habitual physical activity levels., Conclusions: Cardiopulmonary adaptations appeared to be attenuated in patients with chronic kidney disease and were not fully restored to levels observed in healthy individuals. Improvements in exercise capacity did not confer benefits to physical function. Interventions coupled with exercise may be required to enhance adaptations in chronic kidney disease. Performed according to CONSORT guidelines; ClinicalTrials.gov: NCT02050035., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Our objective was to examine the impact of caloric intake before or after the mean time of evening meal on cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity., Methods and Results: Twelve patients with HFpEF and obesity completed a cardiorespiratory exercise test to measure CRF, defined as peak oxygen consumption (VO 2 ). Three five-pass 24-h dietary recalls were performed for each participant and mean evening meal time was determined for each participant individually as well as the group. Participants were divided into those who ate before (Group I) and after (Group II) the mean time of evening meal, 7:25 PM. Peak VO 2 and exercise time were significantly greater in Group II compared to Group I, moreover, delaying time of evening meal was associated with greater peak VO 2 ., Conclusion: Caloric intake after the mean time of evening meal was associated with better CRF in patients with HFpEF and concomitant obesity. Later nutrient intake may help prevent fasting related stress associated with cardiac metabolic disturbances present in HFpEF. Based on these findings, prospective trials aimed at examining the effects of later evening meal times in patients with HFpEF and obesity are warranted., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has presented a global public health emergency. Although predominantly a pandemic of acute respiratory disease, corona virus infectious disease-19 (COVID-19) results in multi-organ damage that impairs cardiopulmonary (CP) function and reduces cardiorespiratory fitness. Superimposed on the CP consequences of COVID-19 is a marked reduction in physical activity that exacerbates CP disease (CPD) risk. CP exercise testing (CPET) is routinely used in clinical practice to diagnose CPD and assess prognosis; assess cardiovascular safety for rehabilitation; and delineate the physiological contributors to exercise intolerance and exertional fatigue. As such, CPET plays an important role in clinical assessments of convalescent COVID-19 patients as well as research aimed at understanding the long-term health effects of SARS-CoV-2 infection. However, due to the ventilatory expired gas analysis involved with CPET, the procedure is considered an aerosol generating procedure. Therefore, extra precautions should be taken by health care providers and exercise physiologists performing these tests. This paper provides recommendations for CPET testing during the COVID-19 pandemic. These recommendations include indications for CPET; pre-screening assessments; precautions required for testing; and suggested decontamination protocols. These safety recommendations are aimed at preventing SARS-CoV-2 transmission during CPET., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2021. Published by Elsevier Inc.)

Cardiovascular disease (CVD) affects one in three adults and remains the leading cause of death in America. Advancing age is a major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high-income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age- and disease-related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondrial-derived reactive oxygen species, impaired mitochondrial quality control, and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.

Exertional fatigue, defined as the overwhelming and debilitating sense of sustained exhaustion that impacts the ability to perform activities of daily living, is highly prevalent in chronic kidney disease (CKD) and end-stage renal disease (ESRD). Subjective reports of exertional fatigue are paralleled by objective measurements of exercise intolerance throughout the spectrum of the disease. The prevalence of exercise intolerance is clinically noteworthy, as it leads to increased frailty, worsened quality of life, and an increased risk of mortality. The physiological underpinnings of exercise intolerance are multifaceted and still not fully understood. This review aims to provide a comprehensive outline of the potential physiological contributors, both central and peripheral, to kidney disease-related exercise intolerance and highlight current and prospective interventions to target this symptom. In this review, the CKD-related metabolic derangements, cardiac and pulmonary dysfunction, altered physiological responses to oxygen consumption, vascular derangements, and sarcopenia are discussed in the context of exercise intolerance. Lifestyle interventions to improve exertional fatigue, such as aerobic and resistance exercise training, are discussed, and the lack of dietary interventions to improve exercise tolerance is highlighted. Current and prospective pharmaceutical and nutraceutical strategies to improve exertional fatigue are also broached. An extensive understanding of the pathophysiological mechanisms of exercise intolerance will allow for the development of more targeted therapeutic approached to improve exertional fatigue and health-related quality of life in CKD and ESRD.

Background: Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients., Methods and Results: In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m 2 ) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 μM vs. 28.4 ± 6.6 μM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO 2peak (p = 0.35)., Conclusions: Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The role of body composition in patients with heart failure (HF) has been receiving much attention in the last few years. Particularly, reduced lean mass (LM), the best surrogate for skeletal muscle mass, is independently associated with abnormal cardiorespiratory fitness (CRF) and muscle strength, ultimately leading to reduced quality of life and worse prognosis. While in the past, reduced CRF in patients with HF was thought to result exclusively from cardiac dysfunction leading to reduced cardiac output at peak exercise, current evidence supports the concept that abnormalities in LM may also play a critical role. Abnormalities in the LM body composition compartment are associated with the development of sarcopenia, sarcopenic obesity, and cachexia. Such conditions have been implicated in the pathophysiology and progression of HF. However, identification of such conditions remains challenging, as universal definitions for sarcopenia, sarcopenic obesity, and cachexia are lacking. In this review article, we describe the most common body composition abnormalities related to the LM compartment, including skeletal and respiratory muscle mass abnormalities, and the consequences of such anomalies on CRF and muscle strength in patients with HF. Finally, we discuss the potential nonpharmacologic therapeutic strategies such as exercise training (ie, aerobic exercise and resistance exercise) and dietary interventions (ie, dietary supplementation and dietary patterns) that have been implemented to target body composition, with a focus on HF., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is a public health epidemic that is projected to double over the next two decades. Despite the high prevalence of HFpEF, there are currently no FDA approved therapies for health-related outcomes in this clinical syndrome making it one the greatest unmet needs in cardiovascular medicine. Aging and obesity are hallmarks of HFpEF and therefore there is a high incidence of sarcopenic obesity (SO) associated with this syndrome. The presence of SO in HFpEF patients is noteworthy as it is associated with co-morbidities, worsened cardiovascular health, hospitalizations, quality of life, and mortality. Furthermore, SO plays a central role in exercise intolerance, the most commonly reported clinical symptom of this condition. The aim of this review is to provide insights into the current knowledge pertaining to the contributing pathophysiological mechanisms and clinical outcomes associated with HFpEF-related SO. Current and prospective therapies to address SO in HFpEF, including lifestyle and pharmaceutical approaches, are discussed. The urgent need for future research aimed at better understanding the multifaceted physiological contributions to SO in HFpEF and implementing interventional strategies to specifically target SO is highlighted., (Copyright © 2020 Kirkman, Bohmke, Billingsley and Carbone.)

This review discusses the associations of muscular strength (MusS) with cardiovascular disease (CVD), CVD-related death, and all-cause mortality, as well as CVD risk factors, such as metabolic syndrome, diabetes, obesity, and hypertension. We then briefly review the role of resistance exercise training in modulating CVD risk factors and incident CVD.The role of MusS has been investigated over the years, as it relates to the risk to develop CVD and CVD risk factors. Reduced MusS, also known as dynapenia, has been associated with increased risk for CVD, CVD-related mortality, and all-cause mortality. Moreover, reduced MusS is associated with increased cardiometabolic risk. The majority of the studies investigating the role of MusS with cardiometabolic risk, however, are observational studies, not allowing to ultimately determine association versus causation. Importantly, MusS is also essential for the identification of nutritional status and body composition abnormalities, such as frailty and sarcopenia, which are major risk factors for CVD.

Dialysis adequacy is an independent predictor of high mortality rates in hemodialysis patients. Intradialytic exercise is a potential strategy to increase uremic solute removal by increasing blood flow to low perfusion tissue beds. The purpose of this review is to establish the efficacy of intradialytic exercise for hemodialysis adequacy. Additionally, this review aims to provide practical information to aid health care professionals implement intradialytic exercise for dialysis adequacy. Database and hand searches identified 15 published interventional studies that implemented intradialytic exercise for dialysis adequacy as a primary outcome measure in adult maintenance hemodialysis patients. Data pertaining to dialytic solute clearance of urea, creatinine, beta 2 microglobulin, phosphate, and potassium were extracted. Mean differences, normalized to percentages, and effect sizes were calculated and reported. The current data pertaining to the use of intradialytic exercise for improving dialysis adequacy in terms of Kt/V urea or small molecule uremic toxin clearance are equivocal. Limited data showed that intradialytic exercise has no effect middle molecule toxin (beta 2 - microglobulin) clearance. Intradialytic exercise favored increased phosphate removal showing medium to large effects for reduced serum concentrations, reduced rebound and increased clearance. In summary, supervised light to moderate intradialytic aerobic cycling appears to be beneficial for increasing phosphate removal and may be an adjunct therapy for patients failing to meet clinical phosphate targets. Further work is required to establish the effect of intradialytic exercise on Kt/V urea and other middle molecule and protein bound solutes. Research aimed at establishing the most effective exercise prescription for improved solute clearance is warranted., (© 2019 Wiley Periodicals, Inc.)

Exercise intolerance is the cardinal symptom of heart failure (HF) and is of crucial relevance, because it is associated with a poor quality of life and increased mortality. While impaired cardiac reserve is considered to be central in HF, reduced exercise and functional capacity are the result of key patient characteristics and multisystem dysfunction, including aging, impaired pulmonary reserve, as well as peripheral and respiratory skeletal muscle dysfunction. We herein review the different modalities to quantify exercise intolerance, the pathophysiology of HF, and comorbid conditions as they lead to reductions in exercise and functional capacity, highlighting the fact that distinct causes may coexist and variably contribute to exercise intolerance in patients with HF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Endothelial dysfunction and arterial stiffness are nontraditional risk factors of chronic kidney disease (CKD)-related cardiovascular disease (CVD) that could be targeted with exercise. This study investigated the effect of moderate to vigorous aerobic exercise on vascular function in nondialysis CKD. In this randomized, controlled trial, 36 nondialysis patients with CKD (means ± SE, age: 58 ± 2 yr, estimated glomerular filtration rate: 44 ± 2 ml·min -1 ·1.73 m -2 ) were allocated to an exercise training (EXT) or control (CON) arm. The EXT group performed 3 × 45 min of supervised exercise per week at 60-85% heart rate reserve for 12 wk, whereas the CON group received routine care. Outcomes were assessed at 0 and 12 wk. The primary outcome, microvascular function, was assessed via cutaneous vasodilation during local heating measured by laser-Doppler flowmetry coupled with microdialysis. Participants were instrumented with two microdialysis fibers for the delivery of 1 ) Ringer solution and 2 ) the superoxide scavenger tempol. Conduit artery function was assessed via brachial artery flow-mediated dilation. Aortic pressure waveforms and pulse wave velocity were acquired with tonometry and oscillometry. Microvascular function improved after EXT ( week 0 vs . week 12 , EXT: 87 ± 2% vs. 91 ± 2% and CON: 86 ± 2% vs. 84 ± 3%, P = 0.03). At baseline, pharmacological delivery of tempol improved microvascular function (Ringer solution vs. tempol: 86 ± 1% vs. 90 ± 1%, P = 0.02) but was no longer effective after EXT (91 ± 2% vs. 87 ± 1%, P = 0.2), suggesting that an improved redox balance plays a role in EXT-related improvements. Brachial artery flow-mediated dilation was maintained after EXT (EXT: 2.6 ± 0.4% vs. 3.8 ± 0.8% and CON: 3.5 ± 0.6% vs. 2.3 ± 0.4%, P = 0.02). Central arterial hemodynamics and arterial stiffness were unchanged after EXT. Aerobic exercise improved microvascular function and maintained conduit artery function and should be considered as an adjunct therapy to reduce CVD risk in CKD.

Chronic kidney disease (CKD) is an independent risk factor for the development of cardiovascular disease and is characterized by reduced nitric oxide (NO) bioavailability and vascular dysfunction, typically assessed using brachial artery flow-mediated dilation (FMD). It has been previously reported that passive leg movement (PLM)-induced hyperemia, an assessment of lower extremity vascular function, is highly dependent on NO, but has not yet been utilized to assess vascular function in patients with CKD. The purpose of this study was to comprehensively assess vascular function in patients with CKD using PLM, in addition to the traditional FMD technique. Assessment of vascular function via PLM and FMD was performed on 12 patients (CKD, 66 ± 3 years) and 16 age-matched healthy controls (CON, 60 ± 2 years). Blood velocity and artery diameters during PLM and FMD were measured using duplex ultrasound of the femoral and brachial arteries, respectively. Habitual physical activity, assessed by accelerometry, was performed in a subset of each group. CKD patients had reduced peak leg blood flow (LBF) (384 ± 39 vs. 569 ± 77 mL/min, P < 0.05) and change in LBF from baseline to peak (∆peakLBF) (143 ± 22 vs. 249 ± 34 mL/min, P < 0.05) during PLM compared to CON. Additionally, PLM responses were significantly associated with kidney function and physical activity levels. As anticipated, FMD was significantly attenuated in CKD patients (5.2 ± 1.1 vs. 8.8 ± 1.2%, P < 0.05). In conclusion, both upper and lower extremity measures of vascular function indicate impairment in CKD patients when compared to controls. PLM appears to be a novel and feasible approach to assessing lower extremity vascular function in CKD., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background Reductions in exercise capacity associated with exercise intolerance augment cardiovascular disease risk and predict mortality in chronic kidney disease. This study utilized cardiopulmonary exercise testing to (a) investigate mechanisms of exercise intolerance; (b) unmask subclinical abnormalities that may precede cardiovascular disease in chronic kidney disease. Design The design of this study was cross-sectional. Methods Cardiopulmonary exercise testing was carried out in 31 Stage 3-4 chronic kidney disease patients (60 ± 11 years; estimated glomerular filtration rate 43 ± 13 ml/min/1.73 m 2 ) and 21 matched healthy individuals (healthy controls; 56 ± 5 years; estimated glomerular filtration rate>90 ml/min/1.73 m 2 ) on a cycle ergometer with workload increased by 15 W every minute until volitional fatigue. Breath-by-breath respiratory gas analysis was performed with an automated gas analyzer and averaged over 10 s intervals. Results Peak oxygen uptake was reduced in chronic kidney disease compared to healthy controls (17.43 ± 1.03 vs 28 ± 2.05 ml/kg/min; p < 0.01), as was oxygen uptake at the ventilatory threshold (9.44 ± 0.53 vs15.55 ± 1.34 ml/kg/min; p < 0.01). A steeper minute ventilation rate/carbon dioxide production slope (32 ± 0.8 vs 28 ± 1; p < 0.01) and a lower expired carbon dioxide pressure in chronic kidney disease (27 ± 0.6 vs 31 ± 0.9 vs 0.9; p < 0.01) indicated ventilation perfusion mismatching in these patients. The ventilatory cost of oxygen uptake was higher in chronic kidney disease (37 ± 0.8 vs 33 ± 1; p < 0.01). Maximum heart rate (134 ± 5 vs 159 ± 3 bpm) and one-minute heart rate recovery (15 ± 1 vs 20 ± 2 bpm) were reduced in chronic kidney disease ( p < 0.01). Conclusion This study suggests that both central and peripheral limitations likely contribute to reduced exercise capacity in non-dialysis chronic kidney disease. Additionally, cardiopulmonary exercise testing revealed subclinical cardiopulmonary abnormalities in these patients in the absence of overt cardiovascular disease. Cardiopulmonary exercise testing could potentially be a tool for unmasking cardiopulmonary abnormalities preceding cardiovascular disease in chronic kidney disease.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg -1 ·1.73 m -2 ] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg -1 ·1.73 m -2 ). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F 2 -isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F 2 -isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVC max ; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVC max ; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.

Endothelial dysfunction occurs in chronic kidney disease (CKD) and increases the risk for cardiovascular disease. The mechanisms of endothelial dysfunction seem to evolve throughout kidney disease progression, culminating in reduced L-arginine transport and impaired nitric oxide bioavailability in advanced disease. This review examines the hypothesis that aerobic exercise may reverse endothelial dysfunction by improving endothelial cell L-arginine uptake in CKD.

Background: The anabolic response to progressive resistance exercise training (PRET) in haemodialysis patients is unclear. This pilot efficacy study aimed to determine whether high-intensity intradialytic PRET could reverse atrophy and consequently improve strength and physical function in haemodialysis patients. A second aim was to compare any anabolic response to that of healthy participants completing the same program., Methods: In a single blind controlled study, 23 haemodialysis patients and 9 healthy individuals were randomly allocated to PRET or an attention control (SHAM) group. PRET completed high-intensity exercise leg extensions using novel equipment. SHAM completed low-intensity lower body stretching activities using ultra light resistance bands. Exercises were completed thrice weekly for 12 weeks, during dialysis in the haemodialysis patients. Outcomes included knee extensor muscle volume by magnetic resonance imaging, knee extensor strength by isometric dynamometer and lower body tests of physical function. Data were analysed by a per protocol method using between-group comparisons., Results: PRET elicited a statistically and clinically significant anabolic response in haemodialysis patients (PRET-SHAM, mean difference [95 % CI]: 193[63 to 324] cm(3)) that was very similar to the response in healthy participants (PRET-SHAM, 169[-41 to 379] cm(3)). PRET increased strength in both haemodialysis patients and healthy participants. In contrast, PRET only enhanced lower body functional capacity in the healthy participants., Conclusions: Intradialytic PRET elicited a normal anabolic and strength response in haemodialysis patients. The lack of a change in functional capacity was surprising and warrants further investigation.

Physical activity levels are low in patients with chronic kidney disease (CKD). Evidence indicates that a sedentary lifestyle contributes to increased morbidity and mortality risk; thus, increasing physical activity is an undeniable aspect of a healthy lifestyle. Despite the myriad of health benefits associated with exercise, as well as clinical guidelines in its favor, exercise is still not prescribed as part of routine care in the CKD patient population. This article briefly discusses the benefits of regular exercise implemented across all stages of CKD on independent predictors of survival such as cardiorespiratory fitness, cardiovascular health and protein-energy wasting. Health care providers of the multidisciplinary nephrology team play a pivotal role in the encouragement and implementation of increasing physical activity levels. In order to increase physical activity counseling and enhance healthcare providers' confidence in prescribing exercise for CKD patients, general recommendations for physical activity in these patients are provided.

Background/aims: According to mathematical modeling, intradialytic exercise of sufficient intensity and duration implemented in the second half of dialysis should be as efficacious as increasing dialysis time for dialysis adequacy. This assumption has not been tested in vivo., Methods: In this controlled trial, 11 hemodialysis (HD) patients (mean (SD) age 56 (13) years) were recruited. Each patient completed three trial arms in a randomized order: routine care (CONT), increased HD time of 30 min (TIME), and intradialytic exercise (EXER), 60 min of cycling at 90% of the lactate threshold in the last 90 min of HD. The primary outcome was eKt/Vurea. Secondary outcomes included reduction and rebound ratios of urea, creatinine, phosphate and β2-microglobulin. Outcomes were calculated from blood sampling collected pre-, post- and 30 min post-HD and confirmed with dialysate sampling., Results: Exercise was not as efficacious as increased HD time for eKt/Vurea (EXER vs. CONT, mean change (95% CI): 0.03 (-0.05 to 0.12); TIME vs. CONT: 0.15 (0.05-0.26)). Exercise was less efficacious at improving reduction ratios of urea and creatinine. However, exercise was more efficacious than increased dialysis time for phosphate reduction ratio (EXER vs. CONT: 8.6% (0.5-16.7); TIME vs. CONT: 5.0% (-1.0 to 11.1))., Conclusion: This study utilized a rigorously controlled in vivo design to test mathematical models and assumptions regarding dialysis adequacy. Intradialytic exercise towards the end of HD cannot replace the prescription of increased HD time for dialysis adequacy, but may be an adjunctive therapy for serum phosphate control., (© 2013 S. Karger AG, Basel.)