Physical Frailty in Older Patients with Acute Heart Failure: From Risk Marker to Modifiable Treatment Target

Acute decompensated heart failure (ADHF) is the most frequent hospital discharge diagnosis in older persons in the US. It is associated with poor quality-of-life, high rehospitalization rates, and increased mortality.^{1, 2} Furthermore, little progress has been made in the therapeutic management of older patients with ADHF, particularly for reducing mortality and hospitalization rates.²

Over the past two decades, there has been an evolution in the epidemiology of ADHF such that the hospitalized patients with HF are older, have a higher burden of cardiac and non-cardiac comorbidities.³ Furthermore, the phenotype of HF more commonly encountered among older hospitalized patients with ADHF is heart failure with preserved ejection fraction (HFpEF), about which much less is known than HF with reduced EF.⁴ A recent insight is that a key determinant of functional and clinical outcomes in older patients with HF, particularly HFpEF, is physical frailty.⁵ Frailty is defined as a state of decreased reserve and resistance to stressors resulting in increased vulnerability to adverse outcomes. Two distinct approaches have been proposed for assessment of frailty among older adults: The Fried phenotype method and the Rockwood frailty index or deficit index model. The Fried phenotype captures decline in physiologic reserve across different domains of physical function.⁶ The Fried model has limitations to its routine use in evaluation of patients with HF including lower discriminatory power of the proposed thresholds to define frailty, overlap in clinical symptom burden from HF and the frailty measures, and the time and resource intensive nature of Fried phenotype assessment. The Rockwood model of Deficit index quantifies the frailty burden as accumulation of deficits across multiple domains.⁷ The deficit index model of frailty assessment provides a continuous assessment of frailty that can be performed retrospectively using existing data. The search for an optimal model for assessment of frailty in patients with HF continue to be a subject of ongoing research.⁸ Prior studies have used both Fried phenotype and Rockwood deficit index and reported a high prevalence of frailty among older patients with chronic HF around ~30 −50% with higher prevalence among those with HFpEF and those hospitalized with ADHF.^8-12 As patients with chronic HF transition to hospitalized ADHF, there is a decline in physical function from HF decompensation and then accelerated physical deconditioning from hospitalization-related bed rest and myopathy, all of which contribute to the worsening frailty burden. Frailty burden is associated with worse quality-of-life, frequent rehospitalization, and worse functional status.^8-12

While prior studies have established frailty as a risk marker for adverse outcomes in HF, its role as a risk factor—a trait that can be modulated by an intervention leading to a parallel change in the downstream risk—is less well-established. This is particularly relevant because frailty burden and functional impairment in patients with HF has been suggested as markers for high-risk, potentially non-modifiable, disease substrate leading to lesser use of guideline-recommended therapies and lesser enrollment in clinical trials. Taken together, there is a need for novel studies to identify and evaluate the efficacy of innovative treatments targeting improvement in frailty burden as a strategy to improve clinical and patient-reported outcomes in patients hospitalized with HF.

The study reported by Mudge, et al, in this issue of the Journal,¹³ advances our understanding of frailty as a modifiable treatment target among older, recently hospitalized patients with ADHF. The authors performed a secondary analysis of the EJECTION-HF trial, a randomized controlled trial evaluating the efficacy of 6-months of supervised exercise training (SET) on top of a home-based exercise program (SET + home-based exercise vs. home-based exercise only) among patients recently hospitalized for ADHF with background home-based exercise program in both the arms.¹⁴ The primary study findings did not show any significant differences in the rates of the primary outcome (12-month mortality or readmission) across the two arms. In the present analysis, the authors stratified the study participants based on their frailty status —determined using the deficit model as frailty index (FI)—and evaluated the attendance of SET sessions, changes in frailty burden, and changes in exercise capacity across the baseline frailty strata (not frail vs. frail vs. very frail) from baseline to 12-month follow up.

The authors observed that 57% of study participants were frail or very frail at baseline, comparable to that reported from other studies of hospitalized patients with HF.⁸ At baseline, a higher burden of frailty was associated with lower exercise capacity measured by 6-minute walk distance. On follow up, there was a substantial improvement in exercise capacity across all frailty groups. Among participants with repeat FI assessment at 6-month follow-up (66% of the cohort), there was a significant improvement in the frailty burden across all frailty groups. The improvements in exercise capacity and frailty burden were similar across both study arms (SET + home-based exercise vs. home-based exercise only). Due to the lack of a control group without any exercise interventions, the study cannot determine the therapeutic efficacy of home-based or supervised exercise in improving frailty burden.

The low rates of adherence to SET in the intervention arm could have contributed to the overall lack of additional therapeutic benefits in the SET treatment arm. Suboptimal adherence is a frequent limitation in exercise training and cardiac rehabiliation studies and the present study further highlights the need for novel strategies to enhance long-term adherence to exercise-based interventions.¹⁵

Despite the suboptimal adherence to the treatment intervention, the consistent improvement in frailty burden and exercise capacity among recently hospitalized HF patients across all strata of baseline frailty in the overall cohort, is encouraging. These findings highlight the potential modifiable nature of frailty and associated functional impairment among hospitalized HF patients. The authors observed a much greater improvement in frailty burden on follow-up in the very frail vs. less frail patients at baseline, suggesting the potential for greater benefit of physical function interventions in those most frail. This observation also allays potential concerns regarding physical function interventions in frail older heart failure patients

There are several mechanisms that may underlie improvement in frailty burden with exercise in patients with HF. As we recently reviewed, the pathophysiology of frailty and HF are intertwined.⁵ Aging, high comorbidity burden, and physical inactivity lead to systemic inflammation, sarcopenia, endothelial dysfunction, impairment in mitochondrial function, capillary loss, skeletal muscle myopathy, and cardiac function abnormalities. These physiologic abnormalities lead to markedly reduced global reserve and the development of frailty as well as HF.⁵ Improvement in frailty in patients with HF could entail favorable changes across multiple domains of physiologic impairments (Figure).

Figure:

Effects of physical function interventions on contributors to frailty and associated functional outcomes in older patients with heart failure

Exercise training and physical function interventions may improve frailty by favorable effects on the aforementioned physiologic impairments, particularly skeletal muscle structure and function. Compared with myocardial tissue, which is terminally differentiated with limited capacity for repair and regeneration, skeletal muscle tissue has satellite cells, which are stem cells residing in the muscle that can promote robust tissue regeneration and repair.¹⁶ Exercise training has been shown to upregulate satellite cell proliferation and regenerative potential, increase muscle mass, muscle perfusion, and mitochondrial function.^{16, 17} Consistent with this notion, prior exercise training trials among patients with HFpEF have demonstrated that improvements in functional capacity with exercise are largely driven by improvements in skeletal muscle oxygen delivery and utilization.^{16, 18}

Besides impairment in endurance, older patients recently hospitalized for HF have impairments in all domains of physical function including balance, gait, and strength as well as endurance which contribute to frailty.⁸ This suggests the need for physical function intervention that address all domains of physical dysfunction. Indeed, studies in other older patient populations suggest it is imperative to address balance, mobility, and strength deficits before addressing endurance in order to prevent falls and injuries and to enhance ability to improve endurance^{10, 19}. The use of primarily traditional endurance exercise training in the present study, with the high rates of frailty, could have contributed to the lack of a treatment effect from SET on frailty. Other potential strategies to improve frailty burden in patients with HF include dietary interventions aimed at improving nutritional status.²⁰

Mudge, et al are congratulated for an important study that begins to address a key largely overlooked aspect of pathophysiology in older patients recently hospitalized for ADHF physical function impairment and frailty as target intervention targets. The study facilitates future randomized controlled trials evaluating the efficacy of a novel interventions aimed at modifiable geroscience therapeutic targets to improve frailty and associated impairments in functional status. Such interventions could target hospitalized patients, who have higher burden of frailty and functional impairments, and focus on improving functional impairments across multiple domains including endurance capacity, gait, strength, balance and perhaps cognition. To this end, the recently concluded multicenter REHAB-HF trial, which evaluated the efficacy of an innovative, early, transitional, tailored multi-domain physical rehabilitation intervention in hospitalized patients with HF may answer some of these pertinent questions. If positive, the REHAB-HF trial will build on the observations by Mudge et al,¹³ and help solidify frailty as a therapeutic target in older HF patients, and potentially improve physical function as well as the associated persistently high rate of adverse clinical outcomes.