Exercise Training Can Improve Symptoms and Quality of Life Among Patients with Chronic Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) is a significant contributor to patient morbidity and mortality.^{1, 2} While acute HFpEF exacerbation due to congestion can cause an abrupt worsening in symptoms and quality-of-life, exercise intolerance is the cardinal symptom of chronic, stable, HFpEF. ^{3, 4} Importantly, these symptoms may persist despite treatment with diuretics to a compensated state and can severely limit quality-of-life. Peak aerobic exercise capacity (peak V̇O₂) is a reliable quantitative measure of exercise capacity which estimates the transportation and utilization of oxygen across the body using a cardiopulmonary exercise test. Patients with HFpEF have substantially lower peak V̇O₂ than healthy patients, with some patients not meeting a peak V̇O₂ threshold to conduct intended activities of daily living.⁵ In addition to clinical endpoints of mortality and hospitalization, quality of life and functional capacity are important, meaningful endpoints among patients with HFpEF. In recent guidance, the FDA emphasized that improvement in physical function and symptoms, even in the absence of a favorable effect of mortality or hospitalization, can be a basis for approval of therapies for HF. Thus, there is growing interest in developing therapeutic approaches to improve exercise capacity and quality of life among patients with HFpEF.

Supervised exercise training (SET) is one such approach that has been demonstrated to improve quality-of-life and functional capacity among patients with HFpEF.^{6, 7} However, SET or cardiac rehabilitation is not currently approved for coverage by the Center for Medicare and Medicaid Services as a therapeutic option for HFpEF, highlighting the existing gaps in its implementation in the real-world management of these patients. The AHA Scientific Statement entitled "Supervised Exercise Training for Chronic Heart Failure with Preserved Ejection Fraction (HFpEF)" represents an important step to bridge this gap and provides a timely summary of the literature supporting exercise training in HFpEF and highlighting the potential mechanisms for improvement in symptoms and future areas for study and implementation.

The Scientific Statement includes an up-to-date meta-analysis of 8 randomized controlled trials (RCT) of SET vs. usual care among patients with HFpEF. In the pooled analysis, SET was associated with a 12% increase in peak V̇O₂ vs. a 2% decrease in the usual care arm with an absolute treatment effect of 2.4 mL/kg/min. The improvement in peak V̇O₂ with SET among patients with HFpEF represents a substantial improvement. Prior studies have shown that a change in peak V̇O2 > 6-7% is a meaningful improvement among patients with HFpEF.⁸ A limitation to the pooled analysis is that a variety of SET was prescribed, including walking, cycling, strength training, or high-intensity interval training with varying durations (1-8 months), and this variation in prescribed exercise leads to some challenges in the interpretation of change in aerobic capacity. The Scientific Statement also highlights improvements in the quality of life associated with SET. However, the magnitude of improvement is heterogenous across trials. Finally, the safety profile of SET is excellent without increased risk of acute cardiovascular events.

The physiologic effects of exercise training can favorably modify both cardiac and extracardiac drivers of exercise intolerance among patients with chronic stable HFpEF.⁹ HFpEF represents a multiorgan, systemic syndrome of aging, and a substantial portion of patients with HFpEF suffer from obesity, comorbid disease, and impairments in skeletal muscle function.¹⁰ Studies investigating the mechanism of improvement have shed light on the effects of exercise training. Notably, the observed improvements in peak V̇O2 after SET may, in part, be more due to peripheral adaptions in vascular function and skeletal muscle than central adaptions in stroke volume.¹¹ Specifically, improved skeletal muscle oxygen extraction through improved mitochondrial and capillary functions appears to drive improvements.¹²

Compared to HF with reduced ejection fraction (HFrEF), patients with HFpEF appear to derive more significant improvements in peak V̇O2 change after SET. In the HF-ACTION trial of patients with chronic stable HFrEF, peak V̇O2 increased modestly by 4% (0.6 mL/kg/min). In a study comparing the response to SET among patients with HFpEF (n = 24) vs. HFrEF (n = 24), In a head-to-head comparison of patients with HFpEF than HFrEF who underwent identical exercise training protocols, Pandey et al. demonstrated a significantly greater increase in peak V̇O₂ with exercise among patients with HFpEF than HFrEF (18.7% vs. -0.3%).¹³ The greater improvement in peak V̇O₂ with exercise training in HFpEF vs. HFrEF may be related to a greater burden of functional impairment in HFpEF.

Despite the evidence supporting the use of SET in HFpEF, several substantial barriers exist to its implementation and uptake in clinical practice. Physician prescription of SET is low nationwide.¹⁴ There is a lack of data investigating the effects of SET on clinical endpoints of hospitalization and mortality that may impact physician interest in prescription. Furthermore, the optimal timing to start SET or physical rehabilitation intervention – in-hospital vs. soon after discharge vs. during chronic stable phase— is not well established. Finally, the optimal mode of exercise or physical function intervention is also not well-established. In a recent clinical trial, moderate continuous exercise training was associated with comparable improvement in exercise capacity as high-intensity training.¹⁵ Patients with HFpEF have functional deficits across multiple domains, including balance, mobility, strength, and endurance, and may benefit from a progressive physical function intervention that targets improvements across multiple domains.^{4, 16} The ongoing REHAB-HFpEF trial (NCT#05525663), which investigates the effects of a 6-month multi-domain physical rehabilitation intervention on all-cause mortality and hospitalization among older patients with decompensated HFpEF, may provide important data to address this knowledge gaps.

Several patient-specific challenges to participation in SET are noteworthy. Traditional center-based exercise training requires a patient to visit a healthcare center to perform the exercise as prescribed by a physician while being monitored. However, there are substantial barriers to participation, including cost, need for transportation, and poor adherence.^{17, 18} Completion rates within RCTs have been excellent, with many reporting adherence rates of over 80%. However, outside of the controlled environment of a clinical trial, these barriers pose considerable limitations. Many patients in rural or non-urban centers may not have available specialty centers which offer SET. To address these challenges, the Scientific Statement highlights recent trials of home-based or hybrid exercise training.¹⁹ These exercise strategies incorporate remote coaching with or without remote patient monitoring at home or in combination (hybrid approach) with a few facility-based exercise sessions.¹⁹ While all trials reported improved exercise capacity and quality of life, the evidence is limited by short-duration trials with small numbers of participants. Innovation in wearable monitors and remote monitoring systems hold substantial promise in alternative exercise training models, although investigation into patient outcomes and long-term adherence is needed.²⁰ Finally, the role of home-based, self-directed unsupervised exercise among patients with severe exercise intolerance in HFpEF is unknown with regards to safety and efficacy.

In summary, the AHA Scientific Statement on HFpEF and SET is a robust review on the symptom burden and exercise limitations in patients with HFpEF, the mechanistic underpinnings of both exercise intolerance and response to exercise, and an updated meta-analysis to provide concrete quantitative estimations of the observed improvements in aerobic function after SET. This Scientific Statement is timely and will help both bedside clinicians improve the care of patients with HFpEF and provide a roadmap for future research to improve exercise intolerance in HFpEF.