HomeCirculation: Heart FailureVol. 8, No. 1Exercise Training as Therapy for Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBExercise Training as Therapy for Heart FailureCurrent Status and Future Directions Jerome L. Fleg, MD, Lawton S. Cooper, MD, MPH, Barry A. Borlaug, MD, Mark J. Haykowsky, PhD, William E. Kraus, MD, Benjamin D. Levine, MD, Marc A. Pfeffer, MD, PhD, Ileana L. Piña, MD, MPH, David C. Poole, PhD, DSc, Gordon R. Reeves, MD, MPT, David J. Whellan, MD, MHS and Dalane W. Kitzman, MDResults from a National Heart, Lung, and Blood Institute Working Group Jerome L. FlegJerome L. Fleg From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Lawton S. CooperLawton S. Cooper From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Barry A. BorlaugBarry A. Borlaug From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Mark J. HaykowskyMark J. Haykowsky From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , William E. KrausWilliam E. Kraus From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Benjamin D. LevineBenjamin D. Levine From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Marc A. PfefferMarc A. Pfeffer From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Ileana L. PiñaIleana L. Piña From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , David C. PooleDavid C. Poole From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , Gordon R. ReevesGordon R. Reeves From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author , David J. WhellanDavid J. Whellan From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author and Dalane W. KitzmanDalane W. Kitzman From the Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (J.L.F., L.S.C.); Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN (B.A.B.); Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada (M.J.H.); Division of Cardiology, Duke University School of Medicine, Durham, NC (W.E.K.); Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas (B.D.L.); Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.); Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY (I.L.P.); Department of Kinesiology (D.C.P.) and Department of Anatomy and Physiology (D.C.P.), Kansas State University, Manhattan; Division of Cardiology, Jefferson Medical College, Philadelphia, PA (G.R.R., D.J.W.); and Sections on Cardiology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.). Search for more papers by this author and Results from a National Heart, Lung, and Blood Institute Working Group Originally published1 Jan 2015https://doi.org/10.1161/CIRCHEARTFAILURE.113.001420Circulation: Heart Failure. 2015;8:209–220BackgroundDespite a variety of pharmacological and device therapies for persons with chronic heart failure (HF), prognosis and quality of life (QOL) remain poor. The need for new effective strategies to improve outcomes for patients with HF is underscored by persistently high mortality, morbidity, healthcare use, and costs associated with HF, with >1 million US HF hospitalizations at an estimated direct and indirect cost in the US of $40 billion in 2012.1Exercise intolerance is a primary symptom in patients with chronic HF, both those with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and is a strong determinant of prognosis and of reduced QOL.2 Exercise training improves exercise intolerance and QOL in patients with chronic stable HFrEF, and has become an accepted adjunct therapy for these patients (Class B level of evidence) based on a fairly extensive evidence base of randomized trials, mostly small.3The National Heart, Lung, and Blood Institute–funded Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial compared an individualized, supervised, and home-based aerobic exercise program plus guideline-based pharmacological and device therapy with guideline-based therapy alone in persons with HFrEF. The exercise arm showed a modest reduction in cardiovascular hospitalizations and mortality and improved QOL.4,5 However, problems with adherence in the exercise arm probably dampened the potential benefit. This landmark study leaves several unanswered key questions, including the role of exercise dose; the relative benefit of different types of aerobic exercise, including high-intensity interval training (HIIT), and resistance, training relative to aerobic training; combination of exercise training with other therapies; optimization of adherence; benefit for older patients with HF, those with HFpEF or multiple comorbidities, and those with acute decompensated HF.The National Heart, Lung, and Blood Institute convened a working group of experts on June 11, 2012 in Bethesda, MD to identify knowledge gaps and to suggest general approaches to filling those gaps for exercise training as a treatment for HF. The National Heart, Lung, and Blood Institute invited experts in a variety of areas, including basic and clinical exercise physiologists, HF and cardiac rehabilitation (CR) specialists, and clinical trial specialists to address these issues. Workshop participants were asked to identify knowledge gaps and to suggest general approaches in basic and clinical investigation to evaluate, to optimize, and to translate the potential role of exercise training in the treatment of HF.They were asked to address the following specific questions:What more needs to be learned about the pathophysiology of exercise intolerance in HFpEF and HFrEF to design better exercise treatments?What do we need to learn about the mechanisms of exercise training, and of the training-related improvements (or lack thereof)?What do we know about the need to tailor exercise regimens to specific HF population, for example, persons with multiple comorbidities, frail elderly, and women?What evolving, innovative new exercise training modalities and combinations should be tested?Can we begin rehabilitation earlier and in more severe, decompensated patients?How can we improve long-term exercise adherence and maintenance?How can we decrease the cost of exercise training interventions, whereas increasing their generalizability and dissemination (eg, home therapy, community centers, and avoidance of ECG monitoring)?Is there a more efficient, yet clinically meaningful, outcome than mortality or exercise capacity in trials of HFpEF and HFrEF?Given the focus of this article on these questions, the reader is referred to excellent recent reviews of exercise training in HF for additional general information on this topic.6,7Pathophysiology of Exercise Intolerance in HF: Cardiac LimitationsExercise intolerance, typically quantified by the reduction in peak oxygen consumed during maximal effort exercise (peak VO2), is a hallmark of HFpEF and HFrEF.2 According to the Fick principle, VO2 is equal to the product of cardiac output (CO) and arteriovenous oxygen difference (a-vO2 diff). Thus, deficits in reserve capacity, that is, the change from rest to peak effort, in either component or both may cause reduction in peak VO2 in HF. CO reserve limitation has been repeatedly although not invariably observed in HFpEF and HFrEF, and is related to impairments in both heart rate and stroke volume responses.6–10 An earlier study identified limited ability to recruit preload (left ventricular end-diastolic volume [LVEDV]) as the key mechanism limiting peak VO2 in HFpEF,9 but a more recent study observed that EDV reserve is similar in HFpEF and controls.10 Chronotropic reserve is typically blunted in both HFrEF and HFpEF,2,8–10 and it remains unknown whether EDV reserve would be similar if heart rate during exercise were higher in HFpEF, as with rate-adaptive pacing. Although EDV reserve is preserved in HFpEF, the increase in LV filling pressures required to achieve adequate EDV is much greater than what is observed in healthy controls.11 This elevation in LV filling pressures causes secondary elevation in pulmonary artery pressure which may affect right ventricular performance, and acute LV filling pressures elevation during exercise is thought to play the dominant role in promoting symptoms of exertional dyspnea, although the underlying mechanisms remain poorly understood. Limitation in stroke volume reserve in both HFrEF and HFpEF is related to decreased ability to reduce LV end-systolic volume.8–11 There is an evidence that the latter finding is related to impairments in both contractile and vasodilatory reserve responses with exercise.In HFrEF exercise, training is generally associated with improved exercise CO and stroke volume, lower heart rate at submaximal workloads, reductions in resting LV volumes, and no changes in resting or exercise filling pressure or pulmonary artery pressures.12,13 Central effects of training in HFpEF have been minimal in the few studies to date.14,15The pathophysiology of HFpEF in many ways represents an exaggeration of normal cardiovascular aging. Even healthy aging leads to cardiac stiffening16,17 that can be prevented by lifelong exercise training.17 Aging also leads to slowing of relaxation, a seemingly inevitable consequence of senescence that is not modified even by prolonged and intensive training.18 Patients with HFpEF seem to have hearts that are less distensible than those of sedentary, age-matched controls, with increased wall stress, slower relaxation, and impaired ventriculo-arterial coupling.19 These changes lead to markedly increased filling pressures during exercise, which likely contributes to dyspnea and exercise intolerance.20,21 This slowed cardiac relaxation may be compounded by abnormalities in skeletal muscle oxygen use, which augment the CO response to exercise, increasing flow into a small, stiff, and slowly relaxing heart.10,11Although short-term exercise training studies in the healthy elderly22 or patients with HFpEF23 typically show significant improvements in functional capacity as estimated by VO2 max, the mechanism of this improvement is uncertain. Evidence is strongest for improvements in oxygen extraction by skeletal muscle (a-vO2 diff),14 with little evidence for altered cardiovascular structure even in long-term studies. For example, 1 year of training of sedentary seniors failed to improve ventricular compliance or estimated aortic age although it did increase VO2 max and facilitate ventriculo-arterial coupling.24 Similarly, a full year of training in 12 invasively studied patients with HFpEF failed to alter cardiac compliance or improve ventriculo-arterial coupling.15 One potential mechanism for the apparent limited plasticity of cardiac training responses in patients with HFpEF may be the presence of advanced glycation end products, which increase with normal aging but are present to a greater degree in patients with HF and diabetes mellitus.25 Recent data in rats suggest that breaking these end products, combined with exercise training, may reverse the consequences of sedentary aging,26 although this must be confirmed in human studies.Key Knowledge Gaps:Are there overarching, systemic processes in HFpEF or HFrEF that underlie the global impairments in cardiac and peripheral reserve that might be targeted therapeutically to improve overall exercise capacity and reduce morbidity/mortality?Would approaches to phenotype the predominant mechanism(s) of exercise intolerance (central versus peripheral) in the individual patient improve understanding of pathophysiology and optimize treatment approaches in HFpEF or HFrEF?What is the optimal dose (frequency, duration, intensity) and modality of exercise training that will be most effective in HFpEF?Are there pharmacological strategies that can be combined with exercise training in HFpEF to facilitate an improvement in cardiac and vascular compliance, blood flow delivery, or speed relaxation (cross-link breakers, nitrite donors, SERCA2a upregulators, and pericardial resection)?Peripheral Mechanisms of Exercise Intolerance in HFSubstantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and symptoms among patients with HF as recently reviewed.27 To help redirect available blood flow and maintain arterial pressure during exercise in patients with HF, locomotory muscles experience enhanced sympathetic vasoconstriction, downregulation of endothelial vasodilatory function, and elevated venous pressures that impair the muscle pumping action to facilitate blood flow. Compelling evidence supports the concept that there may be a peripheral block in patients with HF that limits the ability to translate changes in central hemodynamics into changes in functional capacity, potentially accounting for the failure of many therapies to improve exercise tolerance, such as low LVEF, increased pulmonary wedge pressure, and other hemodynamic indices measured at rest do not predict exercise capacity in HF.28,29 Furthermore, intrinsic abnormalities are present in skeletal muscles of patients with HF compared with aerobically matched sedentary normal controls,30,31 resulting in anaerobic metabolism (measured using 31P-MRI) in leg skeletal muscle of patients with HF, both under basal conditions and after occluding skeletal muscle blood flow.32,33 In addition, acute use of inotropes and vasodilators does not translate into increases in exercise tolerance or reduction of early anaerobic metabolism, despite improving leg blood flow and CO.34,35 Conversely, exercise training improves lactate threshold and aerobic capacity, but without significantly improving CO in both HFrEF12 and HFpEF.14 What is less clear is the temporal sequence of central and peripheral changes in HF, which has important implications for informing new therapeutic strategies. Figure 1 represents a model of how left ventricular systolic dysfunction, induced by a myocardial insult with decreased CO, can lead to impaired exercise tolerance and how exercise training may reverse such changes.Download figureDownload PowerPointFigure 1. The figure presents a model of how left ventricular systolic dysfunction, induced by a myocardial insult with decreased cardiac output (CO), can lead to impaired exercise tolerance and how exercise training may reverse such changes. Pathophysiological responses at each step are represented in large type and the corresponding mechanisms are represented in small type in brackets. Potential points at which exercise training has been shown to induce a physiological response that might block progression to symptomatic exercise intolerance are shown with flat-headed arrows. Reprinted from Kraus et al27 with permission of the publisher. Copyright ©2010, Elsevier. ACE indicates angiotensin-converting enzyme; Ang II, angiotensin II; EC, electrochemical; NO, nitric oxide; and SKM, skeletal muscle.Esposito et al36 have demonstrated that HF severely reduces muscle oxygen diffusion conductance (DO2m), helping to explain why increasing O2 delivery to skeletal muscle via vasodilators in HF might not yield expected increases in muscle O2 consumption during aerobic exercise (Figure 2). The impaired DO2m may also help to account for poor muscle function and exercise intolerance in both HFrEF and HFpEF.37 Determining the mechanistic bases for this reduced DO2m and developing strategies to correct it are crucial for increasing blood-muscle O2 flux in the face of limited O2 delivery, which may be relatively refractory to exercise training in many patients with HF.Download figureDownload PowerPointFigure 2. Schematic illustrating how the muscle perfusive (curved lines, Fick principle, VO2=Qm×[arterial-venous O2 content]) and diffusive O2 (straight lines from origin, Fick law, VO2=DO2m×[Pmicrovascular O2−Pintracellular O2]) conductances conflate to yield VO2 during exercise (eg, cycling). In chronic (C) HF (dashed lines), VO2 is reduced by both impaired perfusive and diffusive (D) O2 conductances and microvascular O2 partial pressures may be either the same or lower than that found in health notwithstanding the presence of marked diffusional derangements (ie, lower DO2m). Note that correction of DO2m deficits by improving capillary hemodynamics has the potential to increase VO2 even in the absence of improved muscle perfusion. Adapted from the study by Poole et al.37Peripheral Mechanisms to Improve Exercise Tolerance With TrainingIn part, because of limitations in O2 delivery, patients with HF have an extremely slow increase of VO2 after the onset of acute exercise and also prolonged recovery.38 These slow kinetics create a greater perturbation of intramuscular high-energy phosphates (ie, Δ [creatine phosphate], [ADPfree]) and pH, which exacerbate glycogenolysis and premature fatigue.37,38 Moreover, because these patients have a low lactate threshold, even at modest activity levels they incur the increased energetic costs associated with slow VO2 kinetics, which decreases muscle efficiency and raises the VO2 demands, thereby increasing the O2 deficit.37Effectively improving blood-muscle O2 flux via exercise training has the potential to speed VO2 kinetics and reduce the VO2 requirement of exercise, that is, improved muscle efficiency. In addition, emerging evidence suggests that enhancing nitric oxide bioavailability by beetroot juice or inorganic nitrate supplementation can effectively lower the mitochondrial O2 cost of ATP production, thereby lowering the exercising VO2 requirement.39 Using these strategies, a therapeutic program that improves skeletal muscle O2 delivery, while simultaneously improving mitochondrial and contractile efficiency might substantially improve metabolic function and exercise tolerance in patients with HF.Key Knowledge Gaps:Do pre-existing skeletal muscle characteristics determine responses to HF or is the converse true—skeletal muscle alterations are a consequence of the disease process?Does exercise training ameliorate skeletal muscle alterations induced in HF? If so, do such salutary changes in skeletal muscle morphology predict improved clinical outcomes?How quantitatively do events in the capillary decrease DO2m in HF, are they similar in HFrEF and HFpEF, and what are the most effective exercise training (duration, intensity, frequency: whole-body, small muscle mass) or alternative (↑nitric oxide, ↓cytokines) strategies to reverse this pathophysiology?Do exercise therapy–induced improvements in capillary hemodynamics (if they occur) effectively speed O2 uptake kinetics and lower the O2 cost of exercise?Effect of Aging, Frailty, and ComorbiditiesAging per se is associated with a progressive decline in exercise capacity and decreased physiological reserve in cardiovascular function as well as in most other organ systems, altered pharmacological responses, increased adverse effects of medical therapy, and prolonged and often incomplete recovery. The prevalence and incidence of HF increase