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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.