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Rationale: Hyperoxia and normoxic helium independently reduce dynamic hyperinflation and improve the exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). Combining these gases could have an additive effect on dynamic hyperinflation and a greater impact on respiratory mechanics and exercise tolerance. Objective: To investigate whether helium-hyperoxia improves the exercise tolerance and respiratory mechanics of patients with COPD. Methods: Ten males with COPD (FEV(1) = 47 +/- 17%pred [mean +/- SD]) performed randomized constant-load cycling at 60% of maximal work rate breathing air, hyperoxia (40% O(2), 60% N(2)), normoxic helium (21% O(2), 79% He), or helium-hyperoxia (40% O(2), 60% He). Measurements: Exercise time, inspiratory capacity (IC), work of breathing, and exertional symptoms were measured with each gas. Results: Compared with air (9.4 +/- 5.2 min), exercise time was increased with hyperoxia (17.8 +/- 5.8 min) and normoxic helium (16.7 +/- 9.1 min) but the improvement with helium-hyperoxia (26.3 +/- 10.6 min) was greater than both these gases (p = 0.019 and p = 0.007, respectively). At an isotime during exercise, all three gases reduced dyspnea and both helium mixtures increased IC and tidal volume. Only helium-hyperoxia significantly reduced the resistive work of breathing (15.8 +/- 4.2 vs. 10.1 +/- 4.1 L . cm H(2)O(-1)) and the work to overcome intrinsic positive end-expiratory pressure (7.7 +/- 1.9 vs. 3.6 +/- 2.1 L . cm H(2)O(-1)). At symptom limitation, tidal volume remained augmented with both helium mixtures, but IC and the work of breathing were unchanged compared with air. Conclusion: Combining helium and hyperoxia delays dynamic hyperinflation and improves respiratory mechanics, which translates into added improvements in exercise tolerance for patients with COPD. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate the effects of different modalities of aerobic (i.e., interval (INT) and continuous (CONT)) training on cardiorespiratory function and the importance of training-induced blood volume (BV) expansion on aerobic power and LV function. We hypothesized that if modality-mediated differences in cardiorespiratory function exist after INT and CONT, they would be related directly to differences in training-induced hypervolemia. METHODS: We examined the effects of 12 wk of CONT and INT on BV, volume-regulatory hormones (angiotensin II, aldosterone, atrial natriuretic peptide), and cardiorespiratory function in 20 untrained males (mean age 30 +/- 4 (SD)). Participants were stratified (mass and VO2max) and randomly assigned to control, CONT, or INT. RESULTS: There were no significant changes in cardiorespiratory function or BV in the control group. Twelve weeks of continuous and interval training, respectively, resulted in significant changes in VO2max (23 +/- 18 vs 21 +/- 10%), peak stroke volume (20 +/- 18 vs 11 +/- 18%), and BV (12 +/- 9 vs 10 +/- 6%). Changes in VO2max were directly related to changes in BV (r = 0.47). Angiotensin II significantly increased after 1 wk of CONT and INT and thereafter returned to baseline values. There was no significant difference between the CONT and INT groups with regard to changes in vascular volumes, volume-regulatory hormones, and/or cardiorespiratory function. CONCLUSIONS: These data indicate that: 1) 12 wk of CONT and INT result in similar improvements in VO2max, and LV function and 2) training-induced hypervolemia accounts for approximately 47% of the changes in VO2max after CONT and INT. [ABSTRACT FROM AUTHOR]

Long-term resistance training as performed by elite female resistance-trained athletes appears to be an insufficient stimulus to alter left ventricular cavity size, wall thickness, or estimated mass. [ABSTRACT FROM AUTHOR]

Aims: Low cardiorespiratory fitness (CRF) is associated with functional disability, heart failure and mortality. Left ventricular (LV) end-diastolic volume (LVEDV) has been linked with CRF, but its utility as a diagnostic marker of low CRF has not been tested., Methods: This multi-center international cohort examined the relationship between LV size on echocardiography and CRF (peak oxygen uptake [peak VO2] from cardiopulmonary exercise testing) in individuals with LV ejection fraction ≥50%. Absolute and BSA-indexed LVEDV (LVEDVi) were tested as predictors of low CRF and functional disability (peak VO2 <1100ml/min or <18 ml/kg/min) and compared against candidate measures of cardiac structure and function., Results: 2876 individuals (309 endurance athletes, 251 healthy non-athletes, 1969 individuals with unexplained dyspnea, 347 individuals with heart failure with preserved ejection fraction) were included. For the entire cohort, LVEDV had the strongest univariable association with peak VO2 (R2 =0.45, standardized [std]β 0.67, p<0.001) and remained the strongest independent predictor of peak VO2 after adjusting for age, sex and BMI (stdβ 0.30, p<0.001). LVEDV was better at identifying low CRF than most established echocardiographic measures (LVEDV AUC 0.72; LVEDVi AUC 0.71), but equivalent to the E/e' ratio. The probability of achieving a peak VO2 below the functional independence threshold was highest for smaller ventricular volumes, with LVEDV and LVEDVi of 88ml and 57ml/m2 providing the optimal cut-points, respectively., Conclusions: Small resting ventricular size is associated with a higher probability of low CRF and functional disability. LV size is the strongest independent echocardiographic predictor of CRF across the health-disease continuum., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF., Methods and Results: ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change., Conclusion: In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity., Competing Interests: Conflict of interest: Dr Mueller reported personal fees (advisory board) from Bristol Myers Squibb outside the submitted work. Dr Winzer reported grants from Boehringer Ingelheim, and personal fees from Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Novartis and Pfizer outside the submitted work. Dr Gevaert reported receiving lecture/advisory fees paid to his institution by Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Johnson and Johnson, and Menarini outside the submitted work. Dr Edelmann reported personal fees from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, CVRx, Medtronic, Merck, MSD, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma, non-financial support from Novartis, and grants from AstraZeneca, Boehringer Ingelheim, Servier and Thermo Fischer outside the submitted work. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingleheim, NovoNorDisk, Rivus, and St. Luke’s Medical Center; received grant support from US National Institutes of Health (grants U01AG076928; R01AG078153; R01AG045551; R01AG18915; P30AG021332; U24AG059624; and U01HL160272), Novartis, AstraZeneca, Bayer, Pfizer, Novo NorDisk, Rivus, and St. Luke’s Medical Center outside the submitted work; and owns stock in Gilead Sciences. Dr Linke reported grant/research support from Edwards Lifesciences and Novartis, consultant fees from Edwards Lifesciences, Boston Scientific, Abiomed, Novartis, Meril, Pfizer, AstraZeneca, Boehringer Ingelheim, Abbott, MSD, Corvia Medical, and Daiichi Sankyo outside the submitted work, and individual stocks/stock options from Transverse Medical, Picardia and Filterlex. Dr Pieske reported institutional grants from AstraZeneca, Bayer Healthcare and Boston Scientific; personal fees for Steering Committee, consulting, and speaker services from Bayer Healthcare, MSD, AstraZeneca, Boehringer Ingelheim, Novartis, Boston Scientific and Abbott outside the submitted work; and holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). Dr Van Craenenbroeck reported receiving grants from Vifor Pharma outside the submitted work. Dr Halle reported receiving personal fees from Abbott, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, sanofi-aventis, Novartis, Medical Park (consulting fees and honoraria for lectures) and being the past-president of the European Association of Preventive Cardiology (2020–22) outside the submitted work. No other potential conflicts of interest were reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Cardiovascular disease (CVD) is a leading cause of mortality in childhood cancer survivors (CCS) that may be related to the cardiotoxic effects of radiation or chemotherapy and concomitant reductions in cardiorespiratory fitness. Therefore, we sought to compare cardiorespiratory fitness (peak oxygen uptake, V̇O2peak) between CCS and age-matched non-cancer controls (CON). Secondary outcomes included hemodynamics and resting cardiac function., Methods: Embase, Scopus, MEDLINE, CINAHL and SPORTDiscus databases were searched from inception to June 2023 for eligible studies. Cross-sectional studies with V̇O2peak measured in CCS and CON were included. Differences in outcomes and pooled estimates for each outcome were estimated from a fixed effects meta-analysis and between group differences were reported as a weighted mean difference (WMD)., Results: Of 2026 studies identified, 18 reported V̇O2peak (CCS: n=786, 44% female, mean age: 16-years, time post-therapy: 5.8 years; CON: n=1379, 50% female, mean age: 16-years). V̇O2peak was lower in CCS (WMD: -7.08mL/kg/min, 95% CI: -7.75 to -6.42, I2: 79%, n=2,165) with no difference for peak exercise heart rate (WMD: -1.4bpm, 95% CI: -3.0 to 0.2, I2: 63%, n=741). Resting left-ventricular ejection fraction (WMD: -1.61%, 95% CI: -2.60 to -0.62, I2.: 49%, n=222) and systolic blood pressure were lower (WMD: -3.8mmHg, 95% CI: -5.7 to -1.9, I2: 25%, n=184) while resting heart rate was higher in CCS (WMD: 4.9bpm; 95% CI: 1.8 to 7.9, I2: 55%, n=262)., Conclusions: CCS have a marked reduction in cardiorespiratory fitness (7.1ml/kg/min lower than CON) that may have important prognostic implications for their future risk of CVD and mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Heart failure (HF) has a major impact on exercise tolerance that may (in part) be due to abnormalities in body and skeletal muscle composition. This systematic review and meta-analysis aims to assess how differences in whole-body and skeletal muscle composition between patients with HF and non-HF controls (CON) contribute to reduced peak oxygen uptake (VO 2 peak)., Methods and Results: The PubMed database was searched from 1975 to May 2024 for eligible studies. Cross-sectional studies with measures of VO 2 peak, body composition, or muscle biopsies in HF and CON were considered. Out of 709 articles, 27 studies were included in this analysis. Compared with CON, VO 2 peak [weighted mean difference (WMD): -9.96 mL/kg/min, 95% confidence interval (CI): -11.71 to -8.21), total body lean mass (WMD: -1.63 kg, 95% CI: -3.05 to -0.21), leg lean mass (WMD: -1.38 kg, 95% CI: -2.18 to -0.59), thigh skeletal muscle area (WMD: -10.88 cm 2  , 95% CI: -21.40 to -0.37), Type I fibres (WMD: -7.76%, 95% CI: -14.81 to -0.71), and capillary-to-fibre ratio (WMD: -0.27, 95% CI: -0.50 to -0.03) were significantly lower in HF. Total body fat mass (WMD: 3.34 kg, 95% CI: 0.35-6.34), leg fat mass (WMD: 1.37 kg, 95% CI: 0.37-2.37), and Type IIx fibres (WMD: 7.72%, 95% CI: 1.52-13.91) were significantly higher in HF compared with CON. Absolute VO 2 peak was significantly associated with total body and leg lean mass, thigh skeletal muscle area, and capillary-to-fibre ratio., Conclusion: Individuals with HF display abnormalities in body and skeletal muscle composition including reduced lean mass, oxidative Type I fibres, and capillary-to-fibre ratio that negatively impact VO 2 peak., Competing Interests: Conflict of interest: None., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In a 77-year-old former world-record-holding male marathoner (2:08:33.6), this study sought to investigate the impact of lifelong intensive endurance exercise on cardiac structure, function, and the trajectory of functional capacity (determined by maximal oxygen consumption, V̇o 2max ) throughout the adult lifespan. As a competitive runner, our athlete (DC) reported performing up to 150-300 miles/wk of moderate-to-vigorous exercise and sustained 10-15 h/wk of endurance exercise after retirement from competition. DC underwent maximal cardiopulmonary exercise testing in 1970 (aged 27 yr), 1991 (aged 49 yr), and 2020 (aged 77 yr) to determine V̇o 2max . At his evaluation in 2020, DC also underwent comprehensive cardiac assessments including resting echocardiography, and resting and exercise cardiac magnetic resonance to quantify cardiac structure and function at rest and during peak supine exercise. DC's V̇o 2max showed minimal change from 27 yr (69.7 mL/kg/min) to 49 yr (68.1 mL/kg/min), although it eventually declined by 36% by the age of 77 yr (43.6 mL/kg/min). DC's V̇o 2max at 77 yr, was equivalent to the 50th percentile for healthy 20- to 29-yr-old males and 2.4 times the requirement for maintaining functional independence. This was partly due to marked ventricular dilatation (left-ventricular end-diastolic volume: 273 mL), which facilitates a large peak supine exercise stroke volume (200 mL) and cardiac output (22.2 L/min). However, at the age of 78 yr, DC developed palpitations and fatigue and was found to be in atrial fibrillation requiring ablation procedures to revert his heart to sinus rhythm. Overall, this life study of a world champion marathon runner exemplifies the substantial benefits and potential side effects of many decades of intense endurance exercise. NEW & NOTEWORTHY This life study of a 77-yr-old former world champion marathon runner exemplifies the impact of lifelong high-volume endurance exercise on functional capacity (V̇o 2max equivalent to a 20- to 29-yr-old), partly due to extreme ventricular remodeling that facilitates a large cardiac output during exercise despite reduced maximal heart rate. Although it is possible that this extreme remodeling may contribute to developing atrial fibrillation, the net benefits of extreme exercise throughout this athlete's lifespan favor increased health span and expected longevity.

Background & Aims: Accurately estimating resting energy requirements is crucial for optimizing energy intake, particularly in the context of patients with varying energy needs, such as individuals with cancer. We sought to evaluate the agreement between resting energy expenditure (REE) predicted by 40 equations and that measured by reference methods in women undergoing active breast cancer treatment stage (I-IV) and post-completion (i.e., survivors)., Methods: Data from 4 studies were combined. REE values estimated from 40 predictive equations identified by a systematic search were compared with REE assessed by indirect calorimetry (IC) using a metabolic cart (MC-REE N = 46) or a whole-room indirect calorimeter (WRIC-REE N = 44). Agreement between methods was evaluated using Bland-Altman and Lin's concordance coefficient correlation (Lin's CCC)., Results: Ninety participants (24 % survivors, 61.1% had early-stage breast cancer I or II, mean age: 56.8 ± 11 years; body mass index: 28.7 ± 6.4 kg/m 2 ) were included in this analysis. Mean MC-REE and WRIC-REE values were 1389 ± 199 kcal/day and 1506 ± 247 kcal/day, respectively. Limits of agreement were wide for all equations compared to both MC and WRIC (∼300 kcal for both methods), including the most commonly used ones, such as Harris-Benedict and Mifflin ST. Jeor equations; none had a bias within ±10% of measured REE, and all had low agreement per Lin's CCC analysis (<0.90). The Korth equation exhibited the best performance against WRIC and the Lvingston-Kohlstadt equation against MC. Similar patterns of bias were observed between survivors and patients and between patients with stages I-III versus IV cancer., Conclusion: Most equations failed to accurately predict REE at the group level, and none were effective at the individual level. This inaccuracy has significant implications for women with or surviving breast cancer, who may experience weight gain, maintenance, or loss due to inaccurate energy needs estimations. Therefore, our research underscores the need for further efforts to improve REE estimation., Competing Interests: Conflict of interest C.M.P. reports receiving unrelated honoraria and/or paid consultancy from Abbott Nutrition, Nutricia, Nestle Health Science, Pfizer, and AMRA Medical. B.R.S, A.P.P, A.A.K, M.C.G, M.J.H, A.A.J, P.S, E.C, I.P, E.P and R.T. declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation., Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO 2 ) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO 2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO 2 , and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity., Results: Peak VO 2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P =0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO 2 /dL blood; P <0.001). During single leg knee extension, there was no difference in peak leg VO 2 ( P =0.306), but the peripherally limited group had greater blood flow/VO 2 ratio ( P =0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO 2 /dL blood; P =0.013), and lower muscle oxygen diffusive conductance ( P =0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected ( P =0.199)., Conclusions: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O 2 ratio and poor muscle diffusive capacity., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844., Competing Interests: None.

Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear., Methods: A multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3-6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized., Discussion: Long-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease., Study Registration: clinicaltrials.gov (MOIST late cross-sectional study; NCT04525404)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paterson, White, Beaulieu, Sherrington, Prado, Tandon, Halloran, Smith, McCombe, Ritchie, Pituskin, Haykowsky, Coulden, Emery, Tsui, Wu, Oudit, Ezekowitz and Thompson.)

Background: Obesity combined with heart failure with preserved ejection fraction (HFpEF) is the dominant form of HF among older persons. In a randomized trial, we previously showed that a 5-month calorie restriction (CR) program, with or without aerobic exercise training (AT), resulted in significant weight and fat loss and improved exercise capacity. However, little is known regarding the long-term effects of these outcomes after a short-term (5-month) intervention of CR with or without AT in older patients with obesity and HFpEF., Methods: Sixteen participants from either the CR or CR+AT who experienced significant weight loss ≥ 2 kg were reexamined after a long-term follow-up endpoint (28.0 ± 10.8 months) without intervention. The follow-up assessment included body weight and composition via dual-energy X-ray absorptiometry and exhaustive cardiopulmonary treadmill exercise testing., Results: Compared to the 5-month time-point intervention endpoint, at the long-term follow-up endpoint, mean body weight increased +5.2 ± 4.0 kg (90.7 ± 11.2 kg vs 95.9 ± 11.9; P < 0.001) due to increased fat mass (38.9 ± 9.3 vs 43.8 ± 9.8; P < 0.001) with no change in lean mass (49.6 ± 7.1 vs 49.9±7.6; P = 0.67), resulting in worse body composition (decreased lean-to-fat mass). Change in total mass was strongly and significantly correlated with change in fat mass (r = 0.75; P < 0.001), whereas there appeared to be a weaker correlation with change in lean mass (r = 0.50; P = 0.051). Additionally, from the end of the 5-month time-point intervention endpoint to the long-term follow-up endpoint, there were large, significant decreases in VO 2 peak (-2.2 ± 2.1 mL/kg/min; P = 0.003) and exercise time (-2.4 ± 2.6 min; P = 0.006). There appeared to be an inverse correlation between the change in VO 2 peak and the change in fat mass (r = -0.52; P = 0.062)., Conclusion: Although CR and CR+AT in older patients with obesity and HFpEF can improve body composition and exercise capacity significantly, these positive changes diminish considerably during long-term follow-up endpoints, and regained weight is predominantly adipose, resulting in worsened overall body composition compared to baseline. This suggests a need for long-term adherence strategies to prevent weight regain and maintain improvements in body composition and exercise capacity following CR in older patients with obesity and HFpEF., Competing Interests: Disclosures BU has received research funding from Novartis and Corvia. PHB has received honoraria as a consultant for Boston Scientific, Boehringer Ingelheim, Corvia Medical, and Merck. DWK has received honoraria as a consultant for Bayer, Medtronic, Relypsa, Merck, Corvia Medical, Boehringer Ingelheim, Ketyo, Rivus, NovoNordisk, AstraZeneca‚ and Novartis, grant funding from Novartis, Bayer, NovoNordisk‚ and AstraZeneca‚ and has stock ownership in Gilead Sciences. All other authors report no disclosures. The manuscript is not under consideration elsewhere, nor have any of its contents been previously published. All authors have read and approved the manuscript. All authors contributed to the work by ICMJE guidelines. None of the other authors have any financial disclosures or conflicts of interest concerning this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF)., Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood., Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO 2 ) and its determinants. HFpEF was considered likely when the H 2 FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t -test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression., Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO 2 and its determinants. Overall, women had lower peak VO 2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O 2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O 2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m 2 [95% CI: -8 to -11 mL/m 2 ]) and mass (-12 g/m 2 [95% CI: -9 to -14 g/m 2 ]) and more often iron deficiency (55% vs 33%;  P < 0.001)., Conclusions: Women with unexplained dyspnea had significantly lower peak VO 2 , regardless of HFpEF likelihood, attributed to both lower peak exercise O 2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness., Competing Interests: Dr Bekhuis has received funding through the Flanders Research Foundation (FWO-T004420N). Dr Haykowsky is funded by a Research Chair in Ageing and Quality of life in the faculty of Nursing, 10.13039/501100000190University of Alberta. Dr Falter has received funding through the Flanders Research Foundation FWO, file number 1SE1222N. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes., Competing Interests: Dr Howden is supported by the National Heart Foundation of Australia Future Leader Fellowship (102536) and the National Health and Medical Research Council (GNT 1119955). Dr Touyz is supported by a Canada Research Chair, Canadian Institutes of Health Research, and the Dr Phil Gold Chair, McGill University. Dr Herrmann is supported by the National Cancer Institute (CA 233601) and the Miami Heart Research Institute; has received consulting fees from Pfizer, AstraZeneca, and Astellas; and has received royalties from Elsevier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

This systematic review and meta-analysis examined the physiological mechanisms responsible for lower peak exercise leg oxygen uptake (V̇o 2 ) in patients with chronic disease. Studies measuring peak leg V̇o 2 (primary outcome) and its physiological determinants during large (cycle) or small muscle mass exercise (single-leg knee extension, SLKE) in patients with chronic disease were included in this meta-analysis. Pooled estimates for each outcome were reported as a weighted mean difference (WMD) between chronic disease and controls. We included 10 studies that measured peak leg V̇o 2 in patients with chronic disease ( n = 109, mean age: 45 yr; encompassing chronic obstructive pulmonary disease, COPD, heart failure with reduced ejection fraction, HFrEF, or chronic renal failure, RF) and age-matched controls ( n = 88). In pooled analysis, peak leg V̇o 2 (WMD; -0.23 L/min, 95% CI: -0.32 to -0.13), leg oxygen (O 2 ) delivery (WMD: -0.27 L/min, 95% CI: -0.37 to -0.17), and muscle O 2 diffusive conductance (WMD: -5.2 mL/min/mmHg, 95% CI: -7.1 to -3.2) were all significantly lower during cycle and SLKE exercise in chronic disease versus controls. These results highlight that during large and small muscle mass exercise in patients with COPD, HFrEF, or RF, there is no single factor causing peak V̇o 2 limitations. Specifically, the lower peak V̇o 2 in these pathologies is due to not only the expected impairments in convective O 2 delivery but also impairments in muscle oxygen diffusive transport from capillary to mitochondria. Whether impaired muscle O 2 transport is caused solely by inactivity or additional muscle pathology remains in question. NEW & NOTEWORTHY Peripheral (skeletal muscle and vasculature) factors contribute significantly to reduced exercise capacity during both large and small muscle mass exercise in chronic diseases such as COPD, HFrEF, or RF and should be important targets of therapy in addition to the primary organs (lungs, heart, and kidneys) affected by disease.

Purpose: Improvements in diagnosis and treatment mean that the long-term health of breast cancer survivors (BCS) is increasingly dictated by cardiovascular comorbidities. This is partly a consequence of exposure to cardiotoxic therapies, which result in cardiac dysfunction and decreased cardiorespiratory fitness (CRF). Exercise training (ExT) is a key therapeutic strategy for secondary prevention and increasing CRF in adults with established cardiovascular disease. Exercise-based cardio-oncology rehabilitation (CORE) has been proposed as an emerging strategy to address CRF and cardiac impairment in BCS. This review aims to (1) provide an overview of the impact of breast cancer therapy on CRF; (2) provide an up-to-date summary of the effects of ExT on CRF and cardiac function in BCS undergoing cardiotoxic therapy; and (3) discuss how traditional ExT approaches can be adapted for BCS undergoing therapy., Review Methods: A literature review was performed based on an intensive literature search for systematic reviews and meta-analyses, randomized and non-randomized controlled trials and single-arm trials investigating the impact of exercise training or cardiac rehabilitation on CRF and/or cardiac function in BCS who are undergoing or have completed cardiotoxic cancer therapy., Summary: Overall, current evidence suggests that ExT induces clinically meaningful benefits for CRF in BCS during and after therapy. There is also emerging evidence that ExT can improve peak exercise measures of cardiac function; however, there is a need for further research to understand how to adapt these effective ExT approaches into clinical CORE-based settings., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

•Exercise intolerance is common among breast cancer survivors.•Exercise intolerance in breast cancer survivors is related to cardiac, vascular, and skeletal muscle impairments.•Holistic rehabilitation or pharmacological therapies are needed to address these impairments., Competing Interests: Dr Haykowsky is supported by the Faculty of Nursing Research Chair in Aging and Quality of Life at the University of Alberta. Dr Pituskin is supported by a Canada Research Chair. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

With significant improvements in the understanding of cancer biology, improved detection, and the use of novel adjuvant therapies, each year more Canadians are surviving a cancer diagnosis. Despite their effectiveness these therapies often result in short- and long-term deleterious effects to major organ systems, particularly cardiovascular. Cardio-oncology is an emerging field of study with the aim to improve cardiovascular health across the oncology disease spectrum. International guidelines distinguish "cardio-oncology" rehabilitation from "cancer" rehabilitation, but how this is navigated is currently unknown. How such care should be assessed and integrated acutely or in the longer term remains unknown. Accordingly, the aim of this article is to consider the cancer patient's needs beyond the scope of cardio-oncology rehabilitation to holistically integrate cancer rehabilitation across the disease trajectory., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exercise capacity is a spectrum that reflects an individual's functional capacity and the dynamic nature of cardiac remodelling along with respiratory and skeletal muscle systems. The relationship of increasing physical activity, increased cardiac mass and volumes, and improved cardiorespiratory fitness (CRF) is well established in the endurance athlete. However, less emphasis has been placed on the other end of the spectrum, which includes individuals with a more sedentary lifestyle and small hearts who are at increased risk of functional disability and poor clinical outcomes. Reduced CRF is an independent predictor of all-cause mortality and cardiovascular events determined by multiple inter-related exogenous and endogenous factors. In this review, we explore the relationship of physical activity, cardiac remodelling, and CRF across the exercise spectrum, emphasising the critical role of cardiac size in determining exercise capacity. In contrast to the large compliant left ventricle of the endurance athlete, an individual with a lifetime of physical inactivity is likely to have a small, stiff heart with reduced cardiac reserve. We propose that this might contribute to the development of heart failure with preserved ejection fraction in certain individuals, and is key to understanding the link between low CRF and increased risk of heart failure., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Heart transplantation (HTP) is a life-saving therapy for selected individuals with end-stage refractory heart failure. Despite improvements in quality of life and survival, HTP recipients' peak aerobic power (peak VO 2 ) remains up to 50% lower than age-matched healthy control subjects owing to abnormal cardiovascular and skeletal muscle function. Currently, little is known regarding the effect of exercise training (ET) to improve peak VO 2 after HTP. This brief review aims to summarise existing evidence regarding the role of ET on peak VO 2 and its determinants, highlights the upper limits of endurance performance in highly trained HTP athletes, and identifies areas for future HTP exercise rehabilitation research., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures None.

Metabolic dysfunction and excess accumulation of adipose tissue are detrimental side effects from breast cancer treatment. Diet and physical activity are important treatments for metabolic abnormalities, yet patient compliance can be challenging during chemotherapy treatment. Time-restricted eating (TRE) is a feasible dietary pattern where eating is restricted to 8 h/d with water-only fasting for the remaining 16 h. The purpose of this study is to evaluate the effect of a multimodal intervention consisting of TRE, healthy eating, and reduced sedentary time during chemotherapy treatment for early-stage (I-III) breast cancer on accumulation of visceral fat (primary outcome), other fat deposition locations, metabolic syndrome and cardiovascular disease risk (secondary outcomes) compared with usual care. The study will be a two-site, two-arm, parallel-group superiority randomised control trial enrolling 130 women scheduled for chemotherapy for early-stage breast cancer. The intervention will be delivered by telephone, including 30-60-minute calls with a registered dietitian who will provide instructions on TRE, education and counselling on healthy eating, and goal setting for reducing sedentary time. The comparison group will receive usual cancer and supportive care including a single group-based nutrition class and healthy eating and physical activity guidelines. MRI, blood draws and assessment of blood pressure will be performed at baseline, after chemotherapy (primary end point), and 2-year follow-up. If our intervention is successful in attenuating the effect of chemotherapy on visceral fat accumulation and cardiometabolic dysfunction, it has the potential to reduce risk of cardiometabolic disease and related mortality among breast cancer survivors.

BACKGROUND: Patients with kidney failure undergoing hemodialysis experience physical deconditioning and multimorbidity. Exercise interventions may mitigate this outcome, but their clinical role is unclear. METHODS: This multicenter, cluster randomized controlled trial evaluated combined endurance and resistance exercise training during hemodialysis versus usual care in chronic kidney failure. It assessed physical functioning, quality of life, hospitalizations, and overall survival. The primary outcome was the change in the 60-second sit-to-stand test (STS60) between baseline and 12 months. RESULTS: A total of 1211 patients underwent randomization, 917 (65.9±14.4 years; 38.9% female) of whom were included in the full analysis (exercise intervention, n=446; usual care, n=471). At 12 months, the STS60 repetitions improved from 16.2±7.6 to 19.2±9.1 in the exercise group but declined from 16.2±7.1 to 14.7±7.9 in the usual care group (group difference, 3.85 repetitions; 95% confidence interval [CI], 2.22 to 5.48; P<0.0001). The timed up-and-go test (−1.1 seconds; 95% CI, −1.9 to −0.3) and the 6-minute walk test (37.5 m; 95% CI, 14.7 to 60.4) also differed in the exercise group versus usual care group. The physical summary score and vitality subscale of the quality of life questionnaire (i.e., the 36-item Short Form Health Survey) differed in the exercise group versus usual care group, but the other subscales did not change. Adverse events during dialysis sessions were similar in both groups. Median days spent in the hospital annually were 2 in the exercise group and 5 in the usual care group. Mortality and dialysis-specific adverse events were not affected. CONCLUSIONS: Twelve months of intradialytic exercise in patients with kidney failure significantly improved the STS60 compared with usual care. (Funded by the Innovation Fund, Federal Joint Committee; ClinicalTrials.gov number, NCT03885102.)

Background: Cardiac rehabilitation (CR) modeled care is recommended for patients with breast cancer to mitigate risk of cardiotoxicity. However, the cardiovascular impact of CR-modeled interventions has not been studied., Objectives: The purpose of this study was to evaluate if a multidisciplinary model of CR reduces cardiotoxicity and improves cardiovascular risk in patients undergoing breast cancer treatment., Methods: We randomly assigned patients with stage I to III breast cancer scheduled to receive anthracycline and/or trastuzumab-based chemotherapy to the CR intervention (n = 37) or usual care (n = 37). The intervention included guideline-directed management of cardiovascular risk factors, dietary counselling, and supervised exercise for 52 weeks. Cardiac magnetic resonance imaging, cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, and serum biomarkers were acquired at baseline and 52 weeks., Results: There was no difference in the primary outcome, left ventricular ejection fraction (LVEF), between groups at 52 weeks (61% ± 6%). Other markers of cardiotoxicity, including high-sensitivity troponin I and brain natriuretic peptide, were similar between groups. However, total cholesterol (5.2 ± 0.8 mmol/L to 4.7 ± 0.8 mmol/L, P  = 0.002) and low-density lipoprotein (3.0 ± 0.7 mmol/L to 2.4 ± 0.7 mmol/L, P  < 0.001) decreased in the intervention group at 52 weeks and were unchanged in usual care. In all patients, adverse cardiac and metabolic changes occurred over 52 weeks including reductions in LVEF, left ventricular mass, high-density lipoprotein, lean body mass, insulin-like growth factor-1, as well as increased triglycerides, whole-body and truncal fat mass (all P  < 0.050)., Conclusions: The CR-modeled intervention had no effect on LVEF or biomarkers of cardiotoxicity. Future lifestyle intervention trials in patients with breast cancer should consider targeting other risk factors associated with incident cardiovascular disease. (Multidisciplinary Team IntervenTion in CArdio-ONcology [TITAN Study] [TITAN]; NCT01621659)., Competing Interests: This trial was supported by the 10.13039/501100018911University Hospital Foundation, Edmonton, Alberta. During the study, Dr Kirkham was supported by Postdoctoral Fellowships from Susan G. Komen Foundation (PDF17483149) and the 10.13039/501100000024Canadian Institutes of Health Research. Dr Haykowsky is supported by the Faculty of Nursing Research Chair in Aging and Quality of Life at the 10.13039/501100000190University of Alberta. Dr Oudit has received study funding from 10.13039/100002429Amgen. Drs Oudit and Paterson are supported by the 10.13039/501100000024Canadian Institutes of Health Research and/or the 10.13039/100004411Heart and Stroke Foundation of Canada. Drs Dyck and Pituskin are each supported by 10.13039/501100001804Canada Research Chairs. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: There is a lack of international consensus regarding the prescription of high-intensity interval training (HIIT) for people with coronary artery disease (CAD) attending cardiac rehabilitation (CR)., Aims: To assess the clinical effectiveness and safety of low-volume HIIT compared with moderate-intensity steady-state (MISS) exercise training for people with CAD., Methods and Results: We conducted a multi-centre RCT, recruiting 382 patients from 6 outpatient CR centres. Participants were randomized to twice-weekly HIIT (n = 187) or MISS (n = 195) for 8 weeks. HIIT consisted of 10 × 1 min intervals of vigorous exercise (>85% maximum capacity) interspersed with 1 min periods of recovery. MISS was 20-40 min of moderate-intensity continuous exercise (60-80% maximum capacity). The primary outcome was the change in cardiorespiratory fitness [peak oxygen uptake (VO2 peak)] at 8 week follow-up. Secondary outcomes included cardiovascular disease risk markers, cardiac structure and function, adverse events, and health-related quality of life. At 8 weeks, VO2peak improved more with HIIT (2.37 mL.kg-1.min-1; SD, 3.11) compared with MISS (1.32 mL.kg-1.min-1; SD, 2.66). After adjusting for age, sex, and study site, the difference between arms was 1.04 mL.kg-1.min-1 (95% CI, 0.38 to 1.69; P = 0.002). Only one serious adverse event was possibly related to HIIT., Conclusions: In stable CAD, low-volume HIIT improved cardiorespiratory fitness more than MISS by a clinically meaningful margin. Low-volume HIIT is a safe, well-tolerated, and clinically effective intervention that produces short-term improvement in cardiorespiratory fitness. It should be considered by all CR programmes as an adjunct or alternative to MISS., Trial Registration: ClinicalTrials.gov: NCT02784873. https://clinicaltrials.gov/ct2/show/NCT02784873., Competing Interests: Conflict of interest: G.M., L.I., P.B., and S.W.E. have received research grants from the National Institute for Health Research and/or the British Heart Foundation. G.M. and S.E. are Directors of Atrium Health Ltd., a provider of rehabilitation services for the NHS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background & Aim: Phase angle (PhA) obtained from bioelectrical impedance analysis (BIA) is an indicator of cellular integrity and relates to several chronic conditions. The purpose of this secondary analysis was to evaluate the association of PhA with health-related physical fitness, namely, cardiorespiratory fitness, skeletal muscle volume, and myosteatosis (i.e. muscle health) in older breast cancer survivors., Methods: Twenty-two women ≥60 years with a body mass index (BMI) ≥25 kg/m 2 and who completed chemotherapy for early-stage breast cancer were included. BIA, cardiopulmonary exercise tests and magnetic resonance imaging scans were completed before and after eight weeks of time-restricted eating., Results: At baseline, PhA was associated with cardiorespiratory fitness (R 2  = 0.54, p < 0.01) and skeletal muscle volume (R 2  = 0.83, p < 0.01) and myosteatosis (R 2  = 0.25, p = 0.02). Results were similar at follow-up., Conclusion: Findings from this pilot study suggest that higher values of PhA are associated with better health-related physical fitness among older breast cancer survivors., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to the contents of this paper., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is characterized by reduced ability to sustain physical activity that may be due partly to disease-related changes in autonomic function that contribute to dysregulated cardiovascular control during muscular contraction. Thus, we used a combination of static handgrip exercise (HG) and postexercise ischemia (PEI) to examine the pressor response to exercise and isolate the skeletal muscle metaboreflex, respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were assessed during 2-min of static HG at 30 and 40% of maximum voluntary contraction (MVC) and subsequent PEI in 16 patients with HFpEF and 17 healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared with controls during both 30%MVC (Δ11 ± 7 vs. Δ15 ± 8 mmHg) and 40%MVC (Δ19 ± 14 vs. Δ30 ± 8 mmHg), and a similar pattern of response was evident during PEI (30%MVC: Δ8 ± 5 vs. Δ12 ± 8 mmHg; 40%MVC: Δ13 ± 10 vs. Δ18 ± 9 mmHg) (group effect: P = 0.078 and P = 0.017 at 30% and 40% MVC, respectively). Changes in HR, CO, and TPR did not differ between groups during HG or PEI ( P > 0.05). Taken together, these data suggest a reduced pressor response to static muscle contractions in patients with HFpEF compared with similarly aged controls that may be mediated partly by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may reduce an ability to sustain physical activity in HFpEF. NEW & NOTEWORTHY The current investigation has identified a diminution in the exercise-induced rise in arterial blood pressure (BP) that persisted during postexercise ischemia (PEI) in an intensity-dependent manner in patients with heart failure with preserved ejection fraction (HFpEF) compared with older, healthy controls. These findings suggest that the pressor response to exercise is reduced in patients with HFpEF, and this deficit may be mediated, in part, by a blunted muscle metaboreflex, highlighting the consequences of impaired neural cardiovascular control during exercise in this patient group.

Mounting evidence suggests that myocardial steatosis contributes to left ventricular diastolic dysfunction, but definitive evidence in humans is lacking due to confounding comorbidities. As such, we utilized a 48-h food restriction model to acutely increase myocardial triglyceride (mTG) content - measured by 1 H magnetic resonance spectroscopy - in 27 young healthy volunteers (13 men/14 women). Forty-eight hours of fasting caused a more than 3-fold increase in mTG content (P < 0.001). Diastolic function - defined as early diastolic circumferential strain rate (CSRd) - was unchanged following the 48-h fasting intervention, but systolic circumferential strain rate was elevated (P < 0.001), indicative of systolic-diastolic uncoupling. Indeed, in a separate control experiment in 10 individuals, administration of low-dose dobutamine (2 μg/kg/min) caused a similar change in systolic circumferential strain rate as was found during 48 h of food restriction, along with a proportionate increase in CSRd, such that the two metrics remained coupled. Taken together, these data indicate that myocardial steatosis contributes to diastolic dysfunction by impairing diastolic-systolic coupling in healthy adults, and suggest that steatosis may contribute to the progression of heart disease. KEY POINTS: Preclinical evidence strongly suggests that myocardial lipid accumulation (termed steatosis) is an important mechanism driving heart disease. Definitive evidence in humans is limited due to the confounding influence of multiple underlying comorbidities. Using a 48-h food restriction model to acutely increase myocardial triglyceride content in young healthy volunteers, we demonstrate an association between myocardial steatosis and left ventricular diastolic dysfunction. These data advance the hypothesis that myocardial steatosis may contribute to diastolic dysfunction and suggest myocardial steatosis as a putative therapeutic target., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Background: Exercise training improves peak oxygen uptake (V.O 2 peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined., Objectives: The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF., Methods: This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values., Results: At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training., Conclusions: In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V.O 2 peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947)., Competing Interests: Funding Support and Author Disclosures This work was supported by the European Commission, Framework Program 7 (EU-FP7; Brussels, Belgium [grant number: EU 602405-2]); the Deutsche Forschungsgemeinschaft (DFG) through the TUM International Graduate School of Science and Engineering (IGSSE; Garching, Germany) (Flavia Baldassarri, Stephan Mueller, Drs Duvinage and Haykowsky); and the Flanders Research Foundation (FWO; Brussels, Belgium) (senior clinical investigator grant to Dr Van Craenenbroeck). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Gevaert has received personal fees from Abbott, AstraZeneca, Boehringer Ingelheim (lectures), and Novartis (lectures, advisory board) outside the submitted work. Dr Duvinage has received grants from Novartis outside the submitted work. Dr Van De Heyning has received personal fees from Abbott, Daiichi-Sankyo, Bayer, and Edwards Lifesciences (lectures) outside the submitted work. Dr Pieske has received personal fees from AstraZeneca (lectures), Bayer (steering committee, lectures), Bristol-Myers Squibb (lectures), Medscape (lectures), Merck (steering committee, lectures), Novartis (steering committee, lectures), and Servier outside the submitted work. Dr Haykowsky has received grants from Novartis and personal fees from Abbott (advisory board), AstraZeneca, Bayer, Berlin Chemie-Menarini, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Novartis, Roche, Sanofi, and Pfizer; and serves as an advisor for Medical Park SE, Germany; outside the submitted work. Dr Van Craenenbroeck has received grants from Vifor Pharma, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO 2 peak), and prevent cardiac dysfunction., Methods: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO 2 peak and functional disability (VO 2 peak ≤18.0 mL·kg -1 ·min -1 ); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide])., Results: Among 104 participants randomized, greater study attrition was observed among UC participants ( P =0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11-0.94]; P =0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06-1.12]; P =0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P =0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg -1 ·min -1 improvement in VO 2 peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve ( P <0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P =0.002). There were no changes in BNP in either group., Conclusions: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO 2 peak and cardiac reserve., Registration: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.

Objective: This study aimed to evaluate the implementation of telephone-based delivery of weekday-only time-restricted eating (TRE), its preliminary efficacy for metabolic outcomes, and concurrent lifestyle changes., Methods: Twenty-two breast cancer survivors aged 60+ years with overweight/obesity completed an 8-week feasibility study of 12 to 8 p.m. weekday-only ad libitum TRE. The intervention was delivered by one registered dietitian call, twice-daily automated text messages asking about eating start and stop times, and three support phone calls. Magnetic resonance imaging, venipuncture, and 3 days of diet records and accelerometry were performed at baseline and after intervention., Results: Participants had a mean age of 66 (SD 5) years with BMI of 31.8 (4.8) kg/m 2 . Intervention implementation was successful, including excellent adherence (98%), participant acceptability, and a low symptom profile and cost ($63/participant). There were no significant changes in individual components of metabolic syndrome, lipid profile, or hemoglobin A 1c , despite clinically relevant changes occurring within individual participants. Magnetic resonance imaging-derived hepatic steatosis and thigh myosteatosis did not change. Dietary intake changes included reduced energy (-22%) and protein (-0.2 g/kg). Physical activity and sleep did not change., Conclusions: Eight weeks of telephone-delivered weekday TRE is a feasible, acceptable, low-symptom, and low-cost intervention. Future studies may consider a longer intervention length for more consistent metabolic improvements and counseling to enhance protein intake., (© 2023 The Obesity Society.)

Purpose: The objective of this investigation was to compare the acute hemodynamic responses during single-leg knee extension (SLKE) exercise between female breast cancer (BC) survivors previously treated with anthracycline chemotherapy and age- and sex-matched control (CON) subjects., Methods: Fourteen BC survivors (age: 61 ± 7 yr; time post-anthracycline therapy: 12 ± 6 yr) and nine CON subjects (age: 59 ± 7 yr) performed SLKE exercise at 25%, 50%, and 75% of peak power output during which heart rate, blood pressure (BP), leg blood flow (Doppler ultrasonography), and vascular conductance (leg blood flow/mean BP) were measured. Quadriceps mass was estimated from thigh volume and skinfold measures., Results: Breast cancer survivors had lower quadriceps mass compared with CON subjects (1803 ± 607 vs 2601 ± 1102 g, P = .04). No difference was found between groups for maximal SLKE power output (28 ± 11 vs 34 ± 17 W, P = .35), heart rate (109 ± 14 vs 103 ± 13 bpm, P = .36), or mean arterial BP (122 ± 18 vs 119 ± 26 mm Hg, P = .33). Rest and submaximal exercise mean arterial BP, leg blood flow (indexed to quadriceps muscle mass), and leg vascular conductance were not significantly different between BC survivors and CON subjects., Conclusion: Leg blood flow during submaximal SLKE exercise is preserved in long-term BC survivors previously treated with anthracycline chemotherapy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In this secondary analysis of an 8-wk single-arm feasibility study of weekday time-restricted eating (TRE), we explored the effects of TRE on body composition. Women ( n  = 22; ≥60 yr) who had completed chemotherapy for early-stage breast cancer and had a body mass index ≥25 kg/m 2 were enrolled. Bioelectrical impedance analysis was performed before and after 8 wk of TRE, and nutritional status was evaluated by bioelectrical impedance vector analysis (BIVA). Body weight ( p  = 0.01) and total fat mass ( p  = 0.04) decreased with TRE. Phase angle was low (defined as ≤5.6°) in 86% of participants at baseline and did not change. Four participants who initially presented with obesity (>95% ellipse, BIVA) had favorable body composition modifications after TRE. Our study highlighted a less favorable body composition profile, poorer cell integrity and overhydration in these patients. BIVA was a useful method to assess body composition and hydration. A short TRE intervention was associated with decreased estimated fat mass and a favorable change in nutritional status in those with obesity.

Aims: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O 2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O 2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O 2 -pulse (V̇O 2  × HR -1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O 2 , is inversely associated with the change in peak V̇O 2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF., Methods and Results: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O 2 (%) was analysed as a function of baseline peak V̇O 2 and its determinants (absolute peak V̇O 2 , peak O 2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O 2 through changes in peak O 2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O 2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O 2 -pulse explained approximately 72% of the difference in changes in peak V̇O 2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O 2 -pulse on change in peak V̇O 2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O 2 -pulse was associated with a decreased mean change in peak V̇O 2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O 2 (P > 0.05). Change in V̇O 2 at VT1 was not associated with any of the investigated factors (P > 0.05)., Conclusions: In patients with HFpEF, the easily measurable peak O 2 -pulse seems to be a good indicator of the potential for improving peak V̇O 2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O 2 -pulse, patients with high O 2 -pulse may need to use additional therapies to significantly increase peak V̇O 2 ., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Abstract: Bigaran, A, Howden, EJ, Foulkes, S, Janssens, K, Beaudry, R, Haykowsky, MJ, La Gerche, A, Fraser, SF, and Selig, SE. Prescribing exercise in early-stage breast cancer during chemotherapy: a simple periodized approach to align with the cyclic phases of chemotherapy. J Strength Cond Res 36(10): 2934-2941, 2022-To evaluate whether a periodized aerobic and resistance training plan aligned to the anthracycline chemotherapy (AC) cycles would be well tolerated, feasible, and attenuate the decline in peak oxygen uptake (V̇o2peak) in breast cancer (BC) patients. Twenty-eight women with early-stage BC treated with AC self-selected to undertake exercise training (EX 47 ± 9 years, n = 14) or usual care (53 ± 9 years, n = 14) for 12 weeks as part of a nonrandomized controlled trial. The periodized EX was aligned to the cyclic phases of AC, including AC taper and nontaper weeks. Outcome measures included cardiopulmonary exercise testing. Attendance and adherence variables (relative dose intensity [RDI] and volume load) were calculated to quantify the dose of EX completed relative to the amount of EX prescribed. The mean session attendance was 76% (range 46-88%). The mean ± SD prescribed and completed dose of aerobic training was 332.3 ± 48.7 MET h·wk-1 and 380.6 ± 53.2 MET h·wk-1 (p = 0.02), equating to a mean RDI of 89 ± 17%. For resistance training, the prescribed and completed cumulative dose was 128,264 ± 54,578 and 77,487 ± 26,108 kg (p < 0.001), equating to an RDI of 60 ± 11%. Adherence to the AC taper week RDI (52 ± 14%) for resistance training was significantly lower than the non-AC taper week (72 ± 8%, p = 0.02). The most frequent cause for EX interruption was hospitalization (35%), whereas AC-related illness was the most common cause for missed (57%) or modified EX sessions (64%). This periodized approach was mostly well tolerated for patients with BC. We speculate that a periodized approach may be both more palatable and useful, although this requires further investigation in a randomized controlled trial., (Copyright © 2021 National Strength and Conditioning Association.)

Across differing spectrums of cardiac function and cardiac pathologies, there are strong associations between measures of cardiorespiratory fitness and burden of symptoms, quality of life, and prognosis. In this part 2 of a 4-part series, we contend that there is a strong association among physical activity, cardiorespiratory fitness, and cardiac function. We argue that a chronic lack of exercise is a major risk factor for heart failure with preserved ejection fraction in some patients. In support of this hypothesis, increasing physical activity is associated with greater cardiac mass, greater stroke volumes, greater cardiac output and peak oxygen consumption, and fewer clinical events. Conversely, physical inactivity results in cardiac atrophy, reduced output, reduced chamber size, and decreased ability to augment cardiac performance with exercise. Moreover, physical inactivity is a strong predictor of heart failure risk and death. In sum, exercise deficiency should be considered part of the broad heart failure with preserved ejection fraction phenotype., Competing Interests: Funding Support and Author Disclosures Dr La Gerche is supported by the National Heart Foundation of Australia. Dr Howden is supported by the National Heart Foundation of Australia Future Leader Fellowship (102536). Dr Kovacic has received research support from the National Institutes of Health (R01HL148167), New South Wales health grant RG194194, and the Bourne Foundation and Agilent; and is the recipient of an Agilent Thought Leader Award (January 2022), which includes funding for research that is unrelated to the current paper. Dr Levine receieves relevant research funding from National Institutes of Health grant P01HL137630 and NASA grant 80NSSC20K0987. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Regular exercise that meets or exceeds the current physical activity guidelines is associated with a reduced risk of cardiovascular disease (CVD) and mortality. Therefore, exercise training plays an important role in primary and secondary prevention of CVD. In this part 1 of a 4-part focus seminar series, we highlight the mechanisms and physiological adaptations responsible for the cardioprotective effects of exercise. This includes an increase in cardiorespiratory fitness secondary to cardiac, vascular, and skeletal muscle adaptations and an improvement in traditional and nontraditional CVD risk factors by exercise training. This extends to the role of exercise and its prescription in patients with CVDs (eg, coronary artery disease, chronic heart failure, peripheral artery disease, or atrial fibrillation) with special focus on the optimal mode, dosage, duration, and intensity of exercise to reduce CVD risk and improve clinical outcomes in these patients., Competing Interests: Funding Support and Author Disclosures Dr Kovacic is the recipient of an Agilent Thought Leader Award (January 2022), which includes funding for research that is unrelated to the current paper; and has received research support from the National Institutes of Health (R01HL148167), New South Wales health grant RG194194, the Bourne Foundation, and Agilent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: While cardiotoxic chemotherapy is known to negatively impact cardiac function and hemoglobin levels, the impact on skeletal muscle has been understudied among patients. The purpose was to longitudinally characterize myosteatosis (muscle fat), skeletal muscle metabolism, and oxygen (O2) consumption during cardiotoxic chemotherapy for breast cancer., Patients and Methods: Thirty-four patients with stage I-III breast cancer were enrolled before trastuzumab-containing and/or anthracycline-containing chemotherapy. We used magnetic resonance imaging to non-invasively quantify thigh myosteatosis (fat-water imaging), and lower leg metabolism (31P spectroscopy), O2 consumption (custom techniques), and peak power output during single-leg plantarflexion exercise at pre-, mid-, end-chemotherapy, and 1-year. We also measured pulmonary VO2peak and maximal leg press strength., Results: During chemotherapy, VO2peak and leg press strength decreased while peak plantarflexion power output was maintained. At mid-chemotherapy, hemoglobin decreased (16%) and lower leg blood flow increased (37%) to maintain lower leg O2 delivery; exercise Pi:PCr and myosteatosis increased. Between mid- and end-chemotherapy, lower leg O2 extraction (28%) and O2 consumption (21%) increased, while plantarflexion exercise efficiency (watts/O2 consumed) decreased. At one year, VO2peak and leg press strength returned to pre-chemotherapy levels, but lower leg exercise O2 extraction, consumption and Pi:PCr, and myosteatosis remained elevated., Conclusion: Lower leg skeletal muscle blood flow and O2 extraction adapt to compensate for chemotherapy-related hemoglobin reduction for small muscle mass exercise but are insufficient to maintain large muscle mass exercise (pulmonary VO2peak, leg press strength). The excess O2 required to perform work, increased Pi:PCr ratio and myosteatosis together suggest suppressed fat oxidation during chemotherapy., (© The Author(s) 2022. Published by Oxford University Press.)