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Endurance exercise training (ET) is an effective treatment in heart failure with preserved ejection fraction (HFpEF), but the efficacy of resistance training in this patient population has been only scarcely evaluated. In this multicenter, randomized trial, we evaluated the effects of combined endurance and resistance training over 12 months in patients with HFpEF. The primary endpoint was a modified Packer score, including all-cause mortality, hospitalizations classified as potentially related to heart failure or exercise and changes in peak oxygen consumption ( V ̇ O 2 ), diastolic function (E/e'), New York Heart Association (NYHA) class and global self-assessment (GSA). In total, 322 patients (mean age, 70 years; 192 females (59.6%) and 130 males (40.4%)) were randomized (1:1) to ET or usual care (UC). At 12 months, the modified Packer score showed an improvement in 33 ET patients (20.5%) and in 13 UC patients (8.1%) and showed a worsening in 69 ET patients (42.9%) and in 71 UC patients (44.1%) (Kendall's tau-b = -0.073, P = 0.17). Although the primary endpoint was not met, clinically relevant differences favoring the ET group as compared to the UC group were observed for the following secondary endpoints: changes in peak V ̇ O 2 (mean difference, 1.3 ml kg -1  min -1 (95% confidence interval (CI): 0.4-2.1)) and NYHA class (odds ratio = 7.77 (95% CI: 3.73-16.21)). No significant between-group differences were observed for other secondary endpoints, including change in E/e', change in GSA, time to cardiovascular hospitalization or all-cause mortality. In conclusion, 1 year of combined endurance and resistance ET did not result in a significantly better modified Packer score, but it did result in improvements in important clinical parameters, such as peak V ̇ O 2 and NYHA class, as compared to UC. ISRCTN registration: ISRCTN86879094 ., Competing Interests: Competing interests: F.E. reports personal fees from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, CVRx, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma; non-financial support from Novartis; and grants from AstraZeneca, Boehringer Ingelheim, Servier and Thermo Fisher Scientific, outside the submitted work. R.W. reports receiving personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Pharmacosmos and Servier and research support from Boehringer Ingelheim, Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, the European Union and Medtronic, outside the submitted work. S.M. reports personal fees from Bristol Myers Squibb (consulting services), outside the submitted work. E.P.-K. holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services) and is a part-time employee of this company and reports receiving minor personal fees from AstraZeneca. H.-D.D. reports receiving personal fees from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Merck, Merck Sharp & Dohme, Novartis and Servier, outside the submitted work. H.-D.D. also holds shares in SCIRENT GmbH and d.o.o. (Clinical Trials Services). C.H.-L. reports a personal fee from Novartis; royalties from Hogrefe Publishing Group; and research grants from the German Ministry of Education and Research, the German Research Foundation and the EU Commission. K.E. reports personal fees from Bristol Myers Squibb and Boehringer Ingelheim (honoraria for lectures), outside the submitted work. A.H. reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Daiichi Sankyo, GE Healthcare and Novartis. G.H. reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Corvia, Impulse Dynamics, Novartis, Servier and Vifor Pharma; being a co-principal investigator for Impulse Dynamics; and business ownership of Avocet Bio GmbH. B.P. reports institutional grants from AstraZeneca, Bayer Healthcare and Boston Scientific and personal fees for steering committee, consulting and speaker services from Bayer Healthcare, Merck Sharp & Dohme, AstraZeneca, Boehringer Ingelheim, Novartis, Boston Scientific and Abbott, outside the submitted work. B.P. also holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). M.H. reports receiving personal fees from Abbott, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Sanofi-Aventis, Novartis and Medical Park (consulting fees and honoraria for lectures) and being the past president of the European Association of Preventive Cardiology (2020–2022), outside the submitted work. No other potential conflicts of interest were reported. Additional collaborators: Stephan Gielen, Stephan von Haehling, Stefan Störk, Tobias D. Trippel, Stefan Anker, Hugo Saner, Mitja Lainscak, Andrea Berghold, Daniel Morris, Evgeny Belyavski, Martin Kropf and Aravind Kumar Radhakrishnan., (© 2025. The Author(s).)

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.

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.)

Competing Interests: Disclosures None.

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.

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.)

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.)

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.)

Reduced exercise tolerance and fatigue are hallmark features in both breast cancer (BC) and heart failure with preserved ejection fraction (HFpEF) and are associated with decreased physical function and quality of life. This brief review focuses on the mechanisms of exercise intolerance in women with BC across the survivorship continuum and highlights how these disturbances within the oxygen transport cascade are similar to that of HFpEF patients. Specifically, the role that impaired cardiac, peripheral vascular and skeletal muscle function play in limiting peak oxygen uptake are discussed. We propose that women with BC are at increased risk of developing HFpEF potentially due to the adverse effects of chemotherapy and concurrent adverse lifestyle behaviors on cardiovascular and skeletal muscle function., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of HF and is associated with high morbidity and mortality. The primary chronic symptom in HFpEF is exercise intolerance, associated with reduced quality of life. Emerging evidence implicates left atrial (LA) dysfunction as an important pathophysiologic mechanism. Here we extend prior observations by relating LA dysfunction to peak oxygen uptake (peak VO 2 ), physical function (distance walked in 6 minutes [6MWD]) and quality of life (Kansas City Cardiomyopathy Questionnaire)., Methods and Results: We compared 75 older, obese, patients with HFpEF with 53 healthy age-matched controls. LA strain was assessed by magnetic resonance cine imaging using feature tracking. LA function was defined according to its 3 distinct phases, with the LA serving as a reservoir during systole, as a conduit during early diastole, and as a booster pump at the end of diastole. The LA stiffness index was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e', by Doppler ultrasound examination) and LA reservoir strain. HFpEF had a decreased reservoir strain (16.4 ± 4.4% vs 18.2 ± 3.5%, P = .018), lower conduit strain (7.7 ± 3.3% vs 9.1 ± 3.4%, P = .028), and increased stiffness index (0.86 ± 0.39 vs 0.53 ± 0.18, P < .001), as well as decreased peak VO 2 , 6MWD, and lower quality of life. Increased LA stiffness was independently associated with impaired peak VO 2 (β = 9.0 ± 1.6, P < .001), 6MWD (β = 117 ± 22, P = .003), and Kansas City Cardiomyopathy Questionnaire score (β = -23 ± 5, P = .001), even after adjusting for clinical covariates., Conclusions: LA stiffness is independently associated with impaired exercise tolerance and quality of life and may be an important therapeutic target in obese HFpEF., Registration: NCT00959660., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome., Methods and Results: A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow-up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan-Meier analyses compared to those with no remodelling, log-rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction., Conclusions: Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long-term outcomes whereas change in left ventricular ejection fraction did not., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

This study tested the hypothesis that early left ventricular (LV) relaxation is impaired in older obese patients with heart failure with preserved ejection fraction (HFpEF), and related to decreased peak exercise oxygen uptake (peak V̇o 2 ). LV strain and strain rate were measured by feature tracking of magnetic resonance cine images in 79 older obese patients with HFpEF (mean age: 66 yr; mean body mass index: 38 kg/m 2 ) and 54 healthy control participants. LV diastolic strain rates were indexed to cardiac preload as estimated by echocardiography derived diastolic filling pressures ( E/e' ), and correlated to peak V̇o 2 . LV circumferential early diastolic strain rate was impaired in HFpEF compared with controls (0.93 ± 0.05/s vs. 1.20 ± 0.07/s, P = 0.014); however, we observed no group differences in early LV radial or longitudinal diastolic strain rates. Isolating myocardial relaxation by indexing all three early LV diastolic strain rates (i.e. circumferential, radial, and longitudinal) to E/e' amplified the group difference in early LV diastolic circumferential strain rate (0.08 ± 0.03 vs. 0.13 ± 0.05, P < 0.0001), and unmasked differences in early radial and longitudinal diastolic strain rate. Moreover, when indexing to E/e' , early LV diastolic strain rates from all three principal strains, were modestly related with peak V̇o 2 ( R  = 0.36, -0.27, and 0.35, respectively, all P < 0.01); this response, however, was almost entirely driven by E/e' itself, ( R = -0.52, P < 0.001). Taken together, we found that although LV relaxation is impaired in older obese patients with HFpEF, and modestly correlates with their severely reduced peak exercise V̇o 2 , LV filling pressures appear to play a much more important role in determining exercise intolerance. NEW & NOTEWORTHY Using a multimodal imaging approach to uncouple tissue deformation from atrial pressure, we found that left ventricular (LV) relaxation is impaired in older obese patients with HFpEF, but only modestly correlates with their severely reduced peak V̇o 2 . In contrast, the data show a much stronger relationship between elevated LV filling pressures and exercise intolerance, refocusing future therapeutic priorities.

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects., Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF., Design, Setting, and Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded., Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise)., Main Outcomes and Measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months., Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%)., Conclusions and Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.

Background: Obesity plays an important role in functional impairment in HFpEF. The mechanisms underlying decreased functional capacity in obese HFpEF are not clear. We assessed the cardiac and peripheral determinants of exercise performance in HFpEF patients with class 2 obesity in the upright position, representative of posture when performing functional activities., Methods and Results: Thirty-two HFpEF patients were divided into two groups by presence of class 2 obesity (C2, BMI ≥ 35 kg/m 2 , n = 14) and non-C2 (BMI < 35 kg/m 2 , n = 18). Participants performed a bout of submaximal exercise followed by incremental stages of treadmill exercise to determine peak aerobic power (peak VO 2 ). Peak VO 2 and Ve/VCO 2 were measured using Douglas bags while cardiac output (Qc) and stroke volume (SV) were measured by acetylene rebreathing. The C2 group were younger than the non-C2 group (67 ± 6 versus 73 ± 6 years; p = .009). Comorbid condition burden was similar between groups. Peak VO 2 indexed to body mass was not significantly different between groups. Absolute peak VO 2 was higher in the C2 group secondary to a larger peak Qc (14.3 versus 11.0 L/min; p = .012). SV reserve was also higher in the C2 group (72 versus 49%; p = .038)., Conclusion: HFpEF patients with severe obesity had similar cardiorespiratory fitness compared to patients with lower BMI with similar comorbidity burden. Absolute VO 2 was actually higher in the severely obese driven by larger Qc and SV reserve arguing against significant effects from obesity per se on aerobic performance. The presence of a larger "cardiac engine" may offer potential for fat-loss strategies to improve impairments in functional capacity in obese patients with HFpEF., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Aims: The aim of this study is to determine factors associated with long-term recovery of left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF) and if further recovery also occurs in this group., Methods and Results: Among 621 participants enrolled in the Alberta Heart Failure Etiology and Analysis Team (HEART) Study, 316 with Stage C HF underwent comprehensive imaging and biomarker testing at enrolment and at 1-year follow up. Using pre-enrolment data, HF with recovered EF (HFrecEF) was defined as an absolute improvement ≥5% in LVEF from the prior lowest LVEF value, with a final LVEF value > 35% at or prior to study baseline. Participants with all LVEF > 40% were included for comparison. Hospitalization-free survival to 5 years was performed. The median cohort age was 66 years, and time from diagnosis was 4 years; 82% were male patients. Of the 316 patients, 95 (30%) patients had HFrecEF and 56 (18%) patients pHFrEF. On multivariate analysis, only shorter duration of HF was predictive of HFrecEF status. Over 1 year, LVEF increased in the HFrecEF group 4.0% (0.15-7.90, P = 0.042) as compared with persistent HFrEF, who in turn demonstrated higher baseline serum high sensitivity Troponin-T with further increase at follow up 0.55(0.33-0.86, P = 0.011). No change in any parameter in the HFpEF/HFmrEF group at follow up was observed., Conclusions: Patients with HFrecEF demonstrate evidence of additional late improvement in LVEF and unchanged troponin levels, in contrast to those with persistent HFrEF, where LVEF does not improve and serum troponin rises over time. These data help to inform mechanisms relating to late LV remodelling., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure in the United States. The cardinal feature of HFpEF is reduced exercise tolerance (peak oxygen uptake, (Equation is included in full-text article.)O2peak) secondary to impaired cardiac, vascular, and skeletal muscle function. There are currently no evidence-based drug therapies to improve clinical outcomes in patients with HFpEF. In contrast, exercise training is a proven effective intervention for improving (Equation is included in full-text article.)O2peak, aerobic endurance, and quality of life in HFpEF patients. This brief review discusses the pathophysiology of exercise intolerance and the role of exercise training to improve (Equation is included in full-text article.)O2peak in clinically stable HFpEF patients. It also discusses the mechanisms responsible for the exercise training-mediated improvements in (Equation is included in full-text article.)O2peak in HFpEF. Finally, it provides evidence-based exercise prescription guidelines for cardiac rehabilitation specialists to assist them with safely implementing exercise-based cardiac rehabilitation programs for HFpEF patients.

Background: Pulmonary edema is a cardinal feature of heart failure but no quantitative tests are available in clinical practice. The goals of this study were to develop a simple cardiovascular magnetic resonance (CMR) approach for lung water quantification, to correlate CMR derived lung water with intra-cardiac pressures and to determine its prognostic significance., Methods: Lung water density (LWD, %) was measured using a widely available single-shot fast spin-echo acquisition in two study cohorts. Validation Cohort: LWD was compared to left ventricular end-diastolic pressure or pulmonary capillary wedge pressure in 19 patients with heart failure undergoing cardiac catheterization. Prospective Cohort: LWD was measured in 256 subjects, including 121 with heart failure, 82 at-risk for heart failure and 53 healthy controls. Clinical outcomes were evaluated up to 1 year., Results: Within the validation cohort, CMR LWD correlated to invasively measured left-sided filling pressures (R = 0.8, p < 0.05). In the prospective cohort, mean LWD was 16.6 ± 2.1% in controls, 17.9 ± 3.0% in patients at-risk and 19.3 ± 5.4% in patients with heart failure, p < 0.001. In patients with or at-risk for heart failure, LWD >  20.8% (mean + 2 standard deviations of healthy controls) was an independent predictor of death, hospitalization or emergency department visit within 1 year, hazard ratio 2.4 (1.1-5.1, p = 0.03)., Conclusions: In patients with heart failure, increased CMR-derived lung water is associated with increased intra-cardiac filling pressures, and predicts 1 year outcomes. LWD could be incorporated in standard CMR scans.

Aims: Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline-mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long-term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy., Methods: The primary objective of Ex-VAD is to investigate whether a 12-week supervised ET can improve peak oxygen uptake (peakVO 2 ) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO 2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow-up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac-specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries., Conclusions: The Ex-VAD trial will assess the effects of a supervised ET programme on peakVO 2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD-supported patients with advanced HF., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The role of exercise training modality to attenuate left ventricular (LV) remodeling in heart failure patients with reduced ejection fraction (HFrEF) remains uncertain. The authors performed a systematic review and meta-analysis of published reports on exercise training (moderate-intensity continuous aerobic, high-intensity interval aerobic, and resistance exercise) and LV remodeling in clinically stable HFrEF patients., Methods: We searched MEDLINE, Cochrane Central Registry of Controlled Trials, CINAHL, and PubMed (2007 to 2017) for randomized controlled trials of exercise training on resting LV ejection fraction (EF) and end-diastolic and end-systolic volumes in HFrEF patients., Results: 18 trials reported LV ejection fraction (LVEF) data, while 8 and 7 trials reported LV end-diastolic and LV end-systolic volumes, respectively. Overall, moderate-intensity continuous training (MICT) significantly increased LVEF (weighted mean difference, WMD = 3.79%; 95% confidence interval, CI, 2.08 to 5.50%) with no change in LV volumes versus control. In trials ≥6 months duration, MICT significantly improved LVEF (WMD = 6.26%; 95% CI 4.39 to 8.13%) while shorter duration (<6 months) trials modestly increased LVEF (WMD = 2.33%; 95% CI 0.84 to 3.82%). High-intensity interval training (HIIT) significantly increased LVEF compared to control (WMD = 3.70%; 95% CI 1.63 to 5.77%) but was not different than MICT (WMD = 3.17%; 95% CI -0.87 to 7.22%). Resistance training performed alone or combined with aerobic training (MICT or HIIT) did not significantly change LVEF., Conclusions: In clinically stable HFrEF patients, MICT is an effective therapy to attenuate LV remodeling with the greatest benefits occurring with long-term (≥6 months) training. HIIT performed for 2 to 3 months is superior to control, but not MICT, for improvement of LVEF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Exercise intolerance is a hallmark feature in heart failure with preserved ejection fraction (HFpEF). Prior heavy exercise ("priming exercise") speeds pulmonary oxygen uptake (V̇o 2p ) kinetics in older adults through increased muscle oxygen delivery and/or alterations in mitochondrial metabolic activity. We tested the hypothesis that priming exercise would speed V̇o 2p on-kinetics in patients with HFpEF because of acute improvements in muscle oxygen delivery. Seven patients with HFpEF performed three bouts of two exercise transitions: MOD1, rest to 4-min moderate-intensity cycling and MOD2, MOD1 preceded by heavy-intensity cycling. V̇o 2p , heart rate (HR), total peripheral resistance (TPR), and vastus lateralis tissue oxygenation index (TOI; near-infrared spectroscopy) were measured, interpolated, time-aligned, and averaged. V̇o 2p and HR were monoexponentially curve-fitted. TPR and TOI levels were analyzed as repeated measures between pretransition baseline, minimum value, and steady state. Significance was P < 0.05. Time constant (τ; tau) V̇o 2p (MOD1 49 ± 16 s) was significantly faster after priming (41 ± 14 s; P = 0.002), and the effective HR τ was slower following priming (41 ± 27 vs. 51 ± 32 s; P = 0.025). TPR in both conditions decreased from baseline to minimum TPR ( P < 0.001), increased from minimum to steady state ( P = 0.041) but remained below baseline throughout ( P = 0.001). Priming increased baseline ( P = 0.003) and minimum TOI ( P = 0.002) and decreased the TOI muscle deoxygenation overshoot ( P = 0.041). Priming may speed the slow V̇o 2p on-kinetics in HFpEF and increase muscle oxygen delivery (TOI) at the onset of and throughout exercise. Microvascular muscle oxygen delivery may limit exercise tolerance in HFpEF.

Purpose of Review: This review summarizes recent developments highlighting the clinical utility of diastolic stress testing along the heart failure continuum., Recent Findings: Invasive hemodynamic assessment of cardiac filling pressures during physiological stress is the gold-standard technique for unmasking diastolic dysfunction. Non-invasive surrogate techniques, such as Doppler ultrasound, have shown excellent agreement with invasive approaches and are now recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. While cycle exercise is often advocated, recent evidence supports the use of isometric handgrip as a viable alternative stressor. Diastolic stress testing is a powerful tool to enhance detection of diastolic dysfunction, is able to differentiate between cardiac and non-cardiac pathology, and should be incorporated into routine clinical assessment.

Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and refractory to available pharmacotherapies. Our understanding of HFpEF has evolved from a disorder of diastolic dysfunction to a constellation of physiologic impairments that lead to elevated left ventricular filling pressures and exercise intolerance. Accordingly, the therapeutic and preventive focus has shifted to identifying lifestyle factors that may have more pleotropic effects on the pathophysiologic mechanisms that define HFpEF. Recent studies have demonstrated that physical inactivity, low fitness, and obesity are potential modifiable targets for prevention as well as management of HFpEF. In this review, we have discussed the emerging epidemiological, mechanistic, and clinical evidence that support the role of these lifestyle factors as key determinants of development and progression of HFpEF. We also summarize the available evidence and major knowledge gaps with regard to developing exercise training and weight loss as unique and effective therapeutic strategies for management of HFpEF., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To discuss the impact of deleterious changes in skeletal muscle morphology and function on exercise intolerance in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as the utility of exercise training and the potential of novel treatment strategies to preserve or improve skeletal muscle morphology and function., Recent Findings: Both HFrEF and HFpEF patients exhibit a reduction in percent of type I (oxidative) muscle fibers and oxidative enzymes coupled with abnormal mitochondrial respiration. These skeletal muscle abnormalities contribute to impaired oxidative metabolism with an earlier shift towards glycolytic metabolism during exercise that is strongly associated with exercise intolerance. In both HFrEF and HFpEF patients, peripheral "non-cardiac" factors are important determinants of the improvement in exercise tolerance following aerobic exercise training. Adjunctive strategies that include nutritional supplementation with amino acids and/or anabolic drugs to stimulate anabolic molecular pathways in skeletal muscle show great promise for improving exercise tolerance and treating heart failure-associated sarcopenia, but these efforts remain early in their evolution, with no immediate clinical applications. There is consistent evidence that heart failure is associated with multiple skeletal muscle abnormalities which impair oxygen uptake and utilization and contribute greatly to exercise intolerance. Exercise training induces favorable adaptations in skeletal muscle morphology and function that contribute to improvements in exercise tolerance in patients with HFrEF. The contribution of skeletal muscle adaptations to improved exercise tolerance following exercise training in HFpEF remains unknown and warrants further investigation.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. Among elderly women, HFpEF comprises more than 80% of incident HF cases. Adverse outcomes-exercise intolerance, poor quality of life, frequent hospitalizations, and reduced survival-approach those of classic HF with reduced EF (HFrEF). However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and despite intensive efforts, optimal therapy remains uncertain, as most trials to date have been negative. This is in stark contrast to management of HFrEF, where dozens of positive trials have established a broad array of effective, guidelines-based therapies that definitively improve a range of clinically meaningful outcomes. In addition to providing an overview of current management status, we examine evolving data that may help explain this paradox, overcome past challenges, provide a roadmap for future success, and that underpin a wave of new trials that will test novel approaches based on these insights.

Objectives: This study sought to test the hypothesis that older obese patients with heart failure with preserved ejection fraction (HFpEF) have significantly greater abdominal, cardiac, and intermuscular fat than healthy, age-matched controls, out of proportion to total body fat, and that these abnormalities are associated with objective measurements of physical function., Background: Recent studies indicate that excess total body adipose tissue contributes to exercise intolerance in patients with HFpEF. However, the impact of the pattern of regional (abdominal, cardiac, intermuscular) adipose deposition on exercise intolerance in patients with HFpEF is unknown., Methods: We measured total body adiposity (using dual-energy x-ray absorptiometry) and regional adiposity (using cardiac magnetic resonance), peak oxygen uptake (Vo 2 ), 6-min walk distance (6MWD), short physical performance battery (SPPB), and leg press power in 100 older obese patients with HFpEF and 61 healthy controls (HCs) and adjusted for age, sex, race, and body surface area., Results: Peak Vo 2 (15.7 ± 0.4 ml/kg/min vs. 23.0 ± 0.6 ml/kg/min, respectively; p < 0.001), 6MWD (427 ± 7 m vs. 538 ± 10 m, respectively; p < 0.001), SPPB (10.3 ± 0.2 vs. 10.9 ± 0.2, respectively; p < 0.05), and leg power (117 ± 5 W vs. 152 ± 9 W, respectively; p = 0.004) were significantly lower in patients with HFpEF than HCs. Total fat mass, total percent fat, abdominal subcutaneous fat, intra-abdominal fat, and thigh intermuscular fat were significantly higher, whereas epicardial fat was significantly lower in patients with HFpEF than in HC. After we adjusted for total body fat, intra-abdominal fat remained significantly higher, while epicardial fat remained significantly lower in patients with HFpEF. Abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intermuscular fat:skeletal muscle ratio were inversely associated, whereas epicardial fat was directly associated with peak Vo 2 , 6MWD, SPPB, and leg power. Using multiple stepwise regression, we found intra-abdominal fat was the strongest independent predictor of peak Vo 2 and 6MWD., Conclusions: In metabolic obese HFpEF, the pattern of regional adipose deposition may have important adverse consequences beyond total body adiposity. Interventions targeting intra-abdominal and intermuscular fat could potentially improve exercise intolerance. (Exercise Intolerance in Elderly Patients With Diastolic Heart Failure [SECRET]; NCT00959660)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: This paper highlights the dynamic relationship between cardiorespiratory fitness (CRF) and heart failure (HF). As heart failure with preserved ejection fraction (HFpEF) surpasses heart failure with reduced ejection fraction (HFrEF) in prevalence, our void in understanding how to treat this syndrome becomes less justifiable. As such, significant attention has been given to the role that obesity and physical inactivity play, as both risk factors for heart failure, and therapeutic targets for its treatment., Recent Findings: Previous findings have shown that low CRF, obesity, and physical inactivity are all risk factors for HF. More recently, it has been discovered that these factors are even more significant when applied to HFpEF, even after accounting for traditional cardiovascular risk factors. As such, new investigations have attempted to discover whether improvements in CRF could be utilized as a tool for prevention of HF. In addition, small studies have shown that interventions to improve CRF in patients with HF could improve both quality of life and fitness. The role of CRF, PA, and obesity in the development of HF is now well established; however, our ability to attenuate that risk is yet to be determined. Observational data have signaled a correlation between improvements in PA, CRF and lower risk of HF however, large randomized controlled trials are still required to truly determine whether exercise training could be used in the prevention and treatment of HF, particularly HFpEF.

A 32-year-old man born with double inlet left ventricle (DILV) and other significant cardiac abnormalities underwent surgical palliation at 1 day, 2 years and 20 years, before receiving a donor heart at 29 years. To our knowledge, there are no case reports or cohort studies of the effect of exercise training on exercise capacity and peak oxygen uptake (VO 2 peak) following heart transplantation (HTx) for individuals born with DILV. The patient accessed our clinical exercise physiology service for assessment, advice and support for exercise training over a 7-year period spanning pre-HTx and post-HTx. An individualised exercise plan, together with careful assessment and monitoring, and the patient's own motivation have contributed to him achieving an outstanding post-HTx doubling of VO 2 peak and exercise capacity., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: The aim of this study was to compare the relative impairment in different exercise hemodynamic reserve parameters in patients with heart failure with preserved ejection fraction (HFpEF) and control patients using a study-level meta-analysis., Background: A cardinal manifestation of chronic HFpEF is severely decreased exercise capacity. Developing effective therapies for exercise intolerance in HFpEF requires optimal understanding of the factors underlying exercise intolerance., Methods: Data were included from 17 unique cohorts that measured peak oxygen uptake and hemodynamic or echocardiographic parameters during exercise in patients with HFpEF and control subjects in this meta-analysis. Standardized mean differences (SMDs) in the exercise reserve (exercise - resting) measures of hemodynamic or echocardiographic parameters between the HFpEF and control groups were pooled in a random-effects meta-analysis., Results: The pooled analysis included 910 patients with HFpEF and 476 control subjects. In pooled analysis, patients with HFpEF had significantly lower peak oxygen uptake (SMD: -2.13; 95% confidence interval [CI]: -2.68 to -1.57). Among hemodynamic exercise reserve parameters, the largest impairment was observed in chronotropic response reserve (change in heart rate from rest to peak exercise; SMD: -1.87; 95% CI: -2.44 to -1.29), followed by exaggerated increase in pulmonary capillary wedge pressure with exercise (SMD: 1.78; 95% CI: 1.46 to 2.09). Significant abnormalities were also observed in the arteriovenous oxygen difference reserve and stroke volume reserve between the HFpEF and control groups., Conclusions: The most consistent and severe hemodynamic reserve abnormalities observed in patients with HFpEF were impairment in chronotropic reserve and exaggerated increase in pulmonary capillary wedge pressure with exercise. These may be important targets for therapeutic strategies to improve exercise tolerance in patients with HFpEF., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is a major health care burden associated with high morbidity and mortality. Approximately 50% of HF patients have reduced ejection fraction (HFrEF) while the remainder of patients have preserved ejection fraction (HFpEF). A hallmark of both HF phenotypes is dyspnoea upon exertion and severe exercise intolerance secondary to impaired oxygen delivery and/or use by exercising skeletal muscle. Exercise training is a safe and effective intervention to improve peak oxygen uptake (VO 2peak ) and quality of life in clinically stable HF patients, however, evidence to date suggests that the mechanism of this improvement appears to be related to underlying HF phenotype. The purpose of this review is to discuss the role of exercise training to improve VO 2peak , and how the central and peripheral adaptations that mediate the improvements in exercise tolerance may be similar or differ by HF phenotype (HFrEF or HFpEF)., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The hallmark symptom of chronic heart failure (HF) is severe exercise intolerance. Impaired perfusive and diffusive O 2 transport are two of the major determinants of reduced physical capacity and lowered maximal O 2 uptake in patients with HF. It has now become evident that this syndrome manifests at least two different phenotypic variations: heart failure with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively). Unlike HFrEF, however, there is currently limited understanding of HFpEF pathophysiology, leading to a lack of effective pharmacological treatments for this subpopulation. This brief review focuses on the disturbances within the O 2 transport pathway resulting in limited exercise capacity in both HFpEF and HFrEF. Evidence from human and animal research reveals HF-induced impairments in both perfusive and diffusive O 2 conductances identifying potential targets for clinical intervention. Specifically, utilization of different experimental approaches in humans (e.g., small vs. large muscle mass exercise) and animals (e.g., intravital microscopy and phosphorescence quenching) has provided important clues to elucidating these pathophysiological mechanisms. Adaptations within the skeletal muscle O 2 delivery-utilization system following established and emerging therapies (e.g., exercise training and inorganic nitrate supplementation, respectively) are discussed. Resolution of the underlying mechanisms of skeletal muscle dysfunction and exercise intolerance is essential for the development and refinement of the most effective treatments for patients with HF.

Background: The benefits of regular physical activity (PA) are well documented in patients with heart failure (HF), however the amount and intensity of objectively measured PA and sedentary behaviour in HF with preserved (HFPEF) or reduced ejection fraction (HFREF) is not well known., Methods: In a cross-sectional observational study the energy expenditure of 151 participants (HFPEF: n = 53; HFREF: n = 16; at-risk for HF: n = 48; control participants: n = 34) using SenseWear Mini Armbands (Body Media, Inc, Pittsburgh, PA) were monitored. PA outcomes included time spent in different PA intensities (light and moderate-vigorous PA), sedentary time, steps per day, total daily energy expenditure, PA energy expenditure, and the patterns of PA in bouts of ≥ 10 minutes of moderate-vigorous PA., Results: The patients with HFPEF had the lowest volume of activity across the 4 groups. After adjusting for covariates, only steps per day remained significantly different across groups (P = 0.0005). A comparison of HFPEF vs HFREF indicated a higher amount of time in bouts of ≥ 10 minutes of moderate-vigorous PA for patients with HFREF (median, 2.4 [interquartile range, 0-13.5] vs 26 [3.7-46.8]; P = 0.0075). In the at-risk group, PA was lower than the recommended levels in the guidelines., Conclusions: Our findings suggest step count as the most robust outcome in evaluating daily PA in this population. Also, patients with HFPEF showed to be the least active group in the HF continuum. Monitoring volume and pattern of PA for those at risk of HF and patients with HFPEF could help to identify sedentary individuals and to develop tailored behavioural interventions for them., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure with preserved ejection fraction (HFpEF) exhibit a range of cardiovascular phenotypic profiles modified by several common comorbidities. In particular, patients with HFpEF tend to be older; however, it is unclear whether the effects of cardiovascular aging per se modify the expression of HFpEF. We therefore sought to investigate the interaction between age and physiologic profile in patients with HFpEF., Methods and Results: We assessed the hemodynamic and metabolic profile of 40 patients with HFpEF. Patients underwent right heart catheterization at rest and during supine cycle ergometry, and were segregated into 2 groups by the median age of the cohort. Older patients with HFpEF demonstrated reduced resting cardiac output (4.8±1.2 L/min versus 5.7±1.1 L/min). With exercise, older patients demonstrated a marked rise in arteriovenous oxygen content difference (10.8±1.8 versus 7.9±2.4 mL, P ≤0.001), driven by enhanced oxygen extraction. There was no significant difference in peak pulmonary capillary wedge pressure (30±7 mm Hg versus 27±6, P =0.135), including when indexed to workload (pulmonary capillary wedge pressure/W, 0.88 mm Hg/W versus 0.92; P =0.83)., Conclusions: Older patients with HFpEF display a different physiological phenotype compared with younger patients, with enhanced oxygen extraction and lower increment in cardiac output to increase oxygen consumption from rest to peak supine exercise. This finding highlights the importance in considering age when considering therapeutic options in patients with HFpEF., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Heart failure (HF) is a common end point for numerous cardiovascular conditions, including coronary artery disease, valvular disease, and hypertension. HF predominantly affects older individuals (aged ≥70 years), particularly those living in developed countries. The pathophysiological sequelae of HF progression have a substantial negative effect on physical function. Diminished physical function in older patients with HF, which is the result of combined disease-related and age-related effects, has important implications on health. A large body of research spanning several decades has demonstrated the safety and efficacy of regular physical activity in improving outcomes among the HF population, regardless of age, sex, or ethnicity. However, patients with HF, especially those who are older, are less likely to engage in regular exercise training compared with the general population. To improve initiation of regular exercise training and subsequent long-term compliance, there is a need to rethink the dialogue between clinicians and patients. This Review discusses the need to improve physical function and exercise habits in patients with HF, focusing on the older population.

Objectives: To systematically examine the relative magnitude and predictors of responses to exercise training in older adult with heart failure (HF) with reduced ejection fraction (HFrEF), and preserved EF (HFpEF)., Design: Secondary analysis of a randomized controlled trial., Setting: Outpatient cardiac rehabilitation program., Participants: Individuals with HF (24 HFrEF, 24 HFpEF) who underwent supervised exercise training., Measurements: The study included individual-level data from the exercise training arms of a randomized controlled trial that evaluated the effect of 16 weeks of supervised moderate-intensity endurance exercise training in older adults with chronic, stable HFpEF and HFrEF. Changes in peak oxygen uptake (VO 2peak ) in response to supervised training in individuals with HFpEF were compared with that of individuals with HFrEF. The significant clinical predictors of changes in VO 2peak with exercise training were assessed using univariate and multivariate regression models., Results: Training-related improvement in VO 2peak was higher in participants with HFpEF than in those with HFrEF (change: 18.7 ± 17.6% vs -0.3 ± 15.4%, P < .001). In univariate analysis, echocardiographic abnormalities in left ventricular structure and function and lower body mass index were associated with blunted response of VO 2peak with exercise training. In multivariate regression analysis using stepwise selection, submaximal exercise systolic blood pressure, and resting early deceleration time were independent predictors of change in VO 2peak ., Conclusion: The change in VO 2peak in response to endurance exercise training in older adults with HF differs significantly according to HF subtype, with greater VO 2peak improvement in HFpEF than HFrEF. These results suggest that the current Centers for Medicare and Medicaid Services policy excluding individuals with HFpEF from reimbursement from cardiac rehabilitation may need to be revisited., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

The goals of the current study were to compare leg blood flow, oxygen extraction and oxygen uptake (VO2) after constant load sub-maximal unilateral knee extension (ULKE) exercise in patients with heart failure with reduced ejection fraction (HFrEF) compared to those with preserved ejection fraction (HFpEF). Previously, it has been shown that prolonged whole body VO2 recovery kinetics are directly related to disease severity and all-cause mortality in HFrEF patients. To date, no study has simultaneously measured muscle-specific blood flow and oxygen extraction post exercise recovery kinetics in HFrEF or HFpEF patients; therefore it is unknown if muscle VO2 recovery kinetics, and more specifically, the recovery kinetics of blood flow and oxygen extraction at the level of the muscle, differ between HF phenotypes. Ten older (68±10yrs) HFrEF (n = 5) and HFpEF (n = 5) patients performed sub-maximal (85% of maximal weight lifted during an incremental test) ULKE exercise for 4 minutes. Femoral venous blood flow and venous O2 saturation were measured continuously from the onset of end-exercise, using a novel MRI method, to determine off-kinetics (mean response times, MRT) for leg VO2 and its determinants. HFpEF and HFrEF patients had similar end-exercise leg blood flow (1.1±0.6 vs. 1.2±0.6 L/min, p>0.05), venous saturation (42±12 vs. 41±11%, p>0.05) and VO2 (0.13±0.08 vs. 0.11±0.05 L/min, p>0.05); however HFrEF had significantly delayed recovery MRT for flow (292±135sec. vs 105±63sec., p = 0.004) and VO2 (95±37sec. vs. 47±15sec., p = 0.005) compared to HFpEF. Impaired muscle VO2 recovery kinetics following ULKE exercise differentiated HFrEF from HFpEF patients and suggests distinct underlying pathology and potential therapeutic approaches in these populations., Competing Interests: The authors have declared that no competing interests exist.

The primary chronic symptom in patients with clinically stable heart failure (HF) is reduced exercise tolerance, measured as decreased peak aerobic power (peak oxygen consumption [Vo 2 ]), and is associated with reduced quality of life and survival. Exercise-based cardiac rehabilitation (EBCR) is a safe and effective intervention to improve peak Vo 2 , muscle strength, physical functional performance, and quality of life and is associated with a reduction in overall and HF-specific hospitalization in clinically stable patients with HF. Despite these salient benefits, fewer than one-tenth of eligible patients with HF are referred for EBCR after hospitalization. In this review, selection for and timing of EBCR for patients with HF, as well as exercise prescription guidelines with special emphasis on the optimal exercise training intensity to improve peak Vo 2 , are discussed., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to examine skeletal muscle mitochondria content, oxidative capacity, and the expression of key mitochondrial dynamics proteins in patients with heart failure with preserved ejection fraction (HFpEF), as well as to determine potential relationships with measures of exercise performance., Background: Multiple lines of evidence indicate that severely reduced peak exercise oxygen uptake (peak VO2) in older patients with HFpEF is related to abnormal skeletal muscle oxygen utilization. Mitochondria are key regulators of skeletal muscle metabolism; however, little is known about how these organelles are affected in HFpEF., Methods: Both vastus lateralis skeletal muscle citrate synthase activity and the expression of porin and regulators of mitochondrial fusion were examined in older patients with HFpEF (n = 20) and healthy, age-matched control subjects (n = 17)., Results: Compared with age-matched healthy control subjects, mitochondrial content assessed by porin expression was 46% lower (p = 0.01), citrate synthase activity was 29% lower (p = 0.01), and Mfn2 (mitofusin 2) expression was 54% lower (p <0.001) in patients with HFpEF. Expression of porin was significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.48, p = 0.003 and r = 0.33, p = 0.05, respectively). Expression of Mfn2 was also significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.40, p = 0.02 and r = 0.37, p = 0.03 respectively)., Conclusions: These findings suggest that skeletal muscle oxidative capacity, mitochondrial content, and mitochondrial fusion are abnormal in older patients with HFpEF and might contribute to their severe exercise intolerance., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether a relatively low single dose or a week-long dosage of dietary inorganic nitrate could improve exercise tolerance in patients with heart failure with preserved ejection fraction (HFpEF)., Background: Exercise intolerance is the primary manifestation of HFpEF and is largely due to noncardiac factors that reduce oxygen delivery to active skeletal muscles. A recent study showed improved exercise capacity in patients with HFpEF after a single, acute dose of beetroot juice (BRJ) (12.9 mmol inorganic nitrate) while another recent study showed neutral and negative effects of an organic nitrate., Methods: Twenty HFpEF patients (69 ± 7 years of age ) were enrolled in an initial cross-over design comparing a single, acute dose of BRJ (6.1 mmol nitrate) to a nitrate-depleted placebo BRJ. A second phase, 1 week of daily doses, used an all-treated design in which patients consumed BRJ for an average of 7 days. The primary outcome of the study was submaximal aerobic endurance, measured as cycling time to exhaustion at 75% of measured maximal power output., Results: No adverse events were associated with the intervention. Submaximal aerobic endurance improved 24% after 1 week of daily BRJ dosing (p = 0.02) but was not affected by the single, acute dose of the BRJ compared to placebo. Consumption of BRJ significantly reduced resting systolic blood pressure and increased plasma nitrate and nitrite in both of the dosing schemes., Conclusions: One week of daily dosing with BRJ (6.1 mmol inorganic nitrate) significantly improves submaximal aerobic endurance and blood pressure in elderly HFpEF patients., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: More than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL)., Objective: To determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF., Design, Setting, and Participants: Randomized, attention-controlled, 2 × 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 declined participation)., Interventions: Twenty weeks of diet, exercise, or both; attention control consisted of telephone calls every 2 weeks., Main Outcomes and Measures: Exercise capacity measured as peak oxygen consumption (V̇O2, mL/kg/min; co-primary outcome) and QOL measured by the Minnesota Living with Heart Failure (MLHF) Questionnaire (score range: 0-105, higher scores indicate worse heart failure-related QOL; co-primary outcome)., Results: Of the 100 enrolled participants, 26 participants were randomized to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 participants completed the trial. Exercise attendance was 84% (SD, 14%) and diet adherence was 99% (SD, 1%). By main effects analysis, peak V̇O2 was increased significantly by both interventions: exercise, 1.2 mL/kg body mass/min (95% CI, 0.7 to 1.7), P < .001; diet, 1.3 mL/kg body mass/min (95% CI, 0.8 to 1.8), P < .001. The combination of exercise + diet was additive (complementary) for peak V̇O2 (joint effect, 2.5 mL/kg/min). There was no statistically significant change in MLHF total score with exercise and with diet (main effect: exercise, -1 unit [95% CI, -8 to 5], P = .70; diet, -6 units [95% CI, -12 to 1], P = .08). The change in peak V̇O2 was positively correlated with the change in percent lean body mass (r = 0.32; P = .003) and the change in thigh muscle:intermuscular fat ratio (r = 0.27; P = .02). There were no study-related serious adverse events. Body weight decreased by 7% (7 kg [SD, 1]) in the diet group, 3% (4 kg [SD, 1]) in the exercise group, 10% (11 kg [SD, 1] in the exercise + diet group, and 1% (1 kg [SD, 1]) in the control group., Conclusions and Relevance: Among obese older patients with clinically stable HFPEF, caloric restriction or aerobic exercise training increased peak V̇O2, and the effects may be additive. Neither intervention had a significant effect on quality of life as measured by the MLHF Questionnaire., Trial Registration: clinicaltrials.gov Identifier: NCT00959660.

This mini-review summarizes the literature regarding the mechanisms of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction (HFREF and HFPEF, respectively). Evidence to date suggests that the reduced peak pulmonary oxygen uptake (pulm V̇o₂) in patients with HFREF compared with healthy controls is due to both central (reduced convective O₂ transport) and peripheral factors (impaired skeletal muscle blood flow, decreased diffusive O₂ transport coupled with abnormal skeletal morphology, and metabolism). Although central and peripheral impairments also limit peak pulm V̇o₂ in HFPEF patients compared with healthy controls, emerging data suggest that the latter may play a relatively greater role in limiting exercise performance in these patients. Unlike HFREF, currently there is limited evidence-based therapies that improve exercise capacity in HFPEF patients, therefore future studies are required to determine whether interventions targeted to improve peripheral vascular and skeletal muscle function result in favorable improvements in peak pulm and leg V̇o2 and their determinants in HFPEF patients., (Copyright © 2015 the American Physiological Society.)

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Exercise training is an established adjuvant therapy in heart failure; however, the effects of high-intensity interval training (HIIT) in HFpEF are unknown. We compared the effects of HIIT vs. moderate-intensity aerobic continuous training (MI-ACT) on peak oxygen uptake (V̇o₂peak), left ventricular diastolic dysfunction, and endothelial function in patients with HFpEF. Nineteen patients with HFpEF (age 70 ± 8.3 yr) were randomized to either HIIT (4 × 4 min at 85-90% peak heart rate, with 3 min active recovery) or MI-ACT (30 min at 70% peak heart rate). Fifteen patients completed exercise training (HIIT: n = 9; MI-ACT: n = 6). Patients trained 3 days/wk for 4 wk. Before and after training patients underwent a treadmill test for V̇o₂peak determination, 2D-echocardiography for assessment of left ventricular diastolic dysfunction, and brachial artery flow-mediated dilation (FMD) for assessment of endothelial function. HIIT improved V̇o₂peak (pre = 19.2 ± 5.2 ml·kg(-1)·min(-1); post = 21.0 ± 5.2 ml·kg(-1)·min(-1); P = 0.04) and left ventricular diastolic dysfunction grade (pre = 2.1 ± 0.3; post = 1.3 ± 0.7; P = 0.02), but FMD was unchanged (pre = 6.9 ± 3.7%; post = 7.0 ± 4.2%). No changes were observed following MI-ACT. A trend for reduced left atrial volume index was observed following HIIT compared with MI-ACT (-3.3 ± 6.6 vs. +5.8 ± 10.7 ml/m(2); P = 0.06). In HFpEF patients 4 wk of HIIT significantly improved V̇o₂peak and left ventricular diastolic dysfunction. HIIT may provide a more robust stimulus than MI-ACT for early exercise training adaptations in HFpEF., (Copyright © 2015 the American Physiological Society.)

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults. The primary chronic symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance. Cardiac and peripheral functions contribute equally to exercise intolerance in HFpEF, though the latter has been the focus of fewer studies. Of note, multiple studies with exercise training have shown that exercise intolerance can improve significantly in the absence of improvements in exercise cardiac output, indicating a role of peripheral, noncardiac adaptations. In addition, clinical drug trials performed to date in HFpEF, all of which have focused on influencing cardiovascular function, have not been positive on primary clinical outcomes and most have not improved exercise capacity. Mounting evidence indicates that sarcopenic obesity, characterized by the coexistence of excess fat mass and decreased muscle mass, could contribute to the pathophysiology of exercise intolerance in older HFpEF patients and may provide avenues for novel treatments.