Improving exercise tolerance and quality of life in heart failure with preserved ejection fraction – time to think outside the heart

This article refers to ‘Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction’ by S.J. Shah et al., published in this issue on pages 1541–1551. Heart failure with preserved ejection fraction (HFpEF) is growing in prevalence and associated with a high burden of morbidity, mortality, and poor quality of life.1, 2 HFpEF is common in older adults and particularly among women, with more than 80% of new-onset heart failure among octogenarian women being due to HFpEF.3 Development of HFpEF involves a complex interplay of multiple pathophysiologic impairments, including adverse physiologic consequences of adiposity, increased comorbidity burden, accelerated decline in exercise capacity with aging, up-regulation of inflammatory pathways, and sarcopenia, that culminates in decreased aerobic physiologic reserve and symptoms of clinical heart failure.2, 4-7 Patients with HFpEF have a similar high burden of functional impairment, frailty, and poor quality of life as patients with heart failure with reduced ejection fraction.7-9 Exercise intolerance, characterized by reduced exercise capacity and symptoms of fatigue and dyspnoea with usual daily activities, is one the most common manifestations of HFpEF. Patients with HFpEF have 30–40% lower exercise capacity than healthy age- and sex-matched controls and often perform activities of daily living using near maximal aerobic effort.10-12 Exercise intolerance is associated with higher risk of hospitalization, death, and poor quality of life in HFpEF.12, 13 Thus, exercise intolerance and low aerobic capacity are meaningful endpoints that should be targeted for developing effective therapies to improve this patient-centred outcome. While the efforts to develop novel and effective therapies to reduce the risk of mortality and hospitalization in patients with HFpEF continue, there has been a recent focus toward patient-centred outcomes as well, including quality of life, symptom burden, and functional status. Consistent with this notion, the Food and Drug Administration has also issued guidance emphasizing the role of improvement in quality of life and exercise capacity as valid endpoints for heart failure therapies.14 The PARALLAX (Prospective Comparison of ARNI vs. Comorbidity-Associated Conventional Therapy on Quality of Life and Exercise Capacity) trial, the largest to date randomized trial focusing on exercise capacity as one of the primary endpoints among patients with HFpEF, represents a significant advancement in developing effective therapies to improve patient-centred outcomes in HFpEF.15 The PARALLAX trial enrolled 2572 patients with HFpEF with poor quality of life to evaluate the efficacy of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and 6-min walk distance as co-primary endpoints. The trial also assessed the effects of sacubitril/valsartan on symptom burden as assessed by New York Heart Association (NYHA) class and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 36-item Short Form (SF-36) questionnaire.15 As reported earlier,16 sacubitril/valsartan failed to improve exercise capacity and quality of life in the PARALLAX trial. However, the study nevertheless provides a rich resource from a large, contemporary cohort of patients to understand better the drivers of poor quality of life and exercise intolerance in patients with HFpEF, as reported by Shah et al.17 in this issue of the Journal. Several aspects of the study population make the PARALLAX trial cohort unique compared with prior HFpEF trials. The patients enrolled in the PARALLAX trial had less severe disease than other HFpEF trials, as highlighted by a high proportion of patients with NYHA class II symptoms, prior heart failure hospitalization in only 30% of the cohort, and lower baseline NT-proBNP levels. However, despite lower disease severity, participants had a high burden of symptoms, including dyspnoea on exertion in >90% and fatigue in >70% of patients, and worse quality of life scores and exercise capacity compared with prior HFpEF trials.18-20 These observations suggest that exercise intolerance and poor quality of life among participants of the PARALLAX trial may more be driven by functional impairment that span multiple physiologic systems. To this end, prior studies have implicated frailty, a biologic phenomenon characterized by accelerated decline in global physiologic reserve and increased vulnerability to physiologic stressors, as one of the key drivers of exercise intolerance and poor functional status in patients with heart failure, particularly HFpEF. Thus, an important consideration for developing effective therapies to improve exercise intolerance and quality of life in HFpEF is to target mechanisms underlying the impairment in global physiologic reserve in these patients.8 Several prior studies have evaluated the contribution of cardiac and extra-cardiac mechanisms toward exercise intolerance and functional impairment in HFpEF.10, 21-23 Besides reduced stroke volume reserve and chronotropic incompetence, impairment in peripheral oxygen extraction at peak exercise is one of the key determinants of reduced exercise capacity in HFpEF.10, 21, 23 Frailty, dysfunctional adiposity, sarcopenia, capillary rarefaction, endothelial dysfunction, and mitochondrial dysfunction in skeletal muscles have been implicated as drivers of exercise intolerance in HFpEF.4, 7, 8, 21, 22, 24-26 Exercise training and intentional weight loss have consistently improved peak exercise peripheral oxygen extraction, aerobic capacity, and quality of life in HFpEF through pleiotropic favourable effects on these extra-cardiac factors.27-29 Future studies are needed to develop and test the effects of specific pharmacotherapies such on these extra-cardiac drivers of exercise tolerance in HFpEF. While the favourable effects of sacubitril/valsartan on cardiovascular haemodynamics and remodelling are well established,30-32 little is known about its effects on frailty, sarcopenia, and skeletal muscle endothelial and mitochondrial dysfunction. A better understanding of the biological effects of sacubitril/valsartan on these extra-cardiac drivers of exercise intolerance will help understand the mechanisms underlying the observed lack of improvement in exercise capacity and quality of life with sacubitril/valsartan in HFpEF. An important observation noted by Shah et al.17 in this study is the correlation between quality of life, exercise capacity, and NT-proBNP levels among patients with HFpEF. The authors observed a modest correlation between the measures of quality of life, exercise capacity, and NT-proBNP levels, indicating that these measures may provide orthogonal and complementary prognostic information in HFpEF. The biological drivers of heart failure severity and congestion, as assessed by NT-proBNP levels, are largely different for those of quality of life and functional capacity. These observations suggest that each of these parameters should be considered to assess prognosis, overall disease burden, and optimal management strategies for patients with HFpEF. In conclusion, the PARALLAX trial has laid down the platform for conducting large, adequately powered trials evaluating exercise capacity and patient-centred outcomes in the contemporary HFpEF population. Its contribution to our understanding of HFpEF goes beyond the therapeutic effects of sacubitril/valsartan on the study endpoints. Future analyses from this trial will hopefully inform us about the determinants of the decline in exercise capacity and quality of life, and may help us find potentially modifiable targets to improve these patient-centred outcomes. Conflict of interest: A.P. has served on the advisory board of Roche Diagnostics, has received non-financial support from Pfizer and Merck, and has received research support from the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics. J.B. is a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol-Myers Squib, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Limited, and Vifor.