What is the clinical evidence from this study?

Study design: RCT. Population: Heart failure with preserved ejection fraction (HFpEF) (n=214). Intervention: Physical rehabilitation intervention (REHAB-HF) and aerobic plus resistance training with caloric restriction (SECRET-II) vs. Usual care in REHAB-HF; aerobic exercise plus caloric restriction without resistance training in SECRET-II. Primary outcome: Physical function measured by short physical performance battery (SPPB) and 6-minute walk distance (6MW).

What does this research mean for the field?

Physical rehabilitation improves physical function in HFpEF patients, and specific circulating proteomic signatures correlate with these functional changes following intervention. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

March 3, 2026Open Access

A multi-layered approach to elucidate mechanisms of physical function in response to rehabilitation in heart failure with preserved ejection fraction

Key Result

Physical rehabilitation improved physical function in HFpEF patients, with proteomic signatures correlating with functional changes after intervention in two RCTs totaling 214 patients.

Key Points

Physical rehabilitation improves functional capacity and correlates with specific protein changes in heart failure.
Key findings highlight over 5,000 proteins with prognostic relevance to physical function within two trials.
Analysis utilizes artificial intelligence-enabled multiplex network analysis to elucidate protein interactions.
These insights may offer potential therapeutic targets and help personalize rehabilitation approaches for heart failure.

Study Design

Type

RCT (n=214)

Blinding

Not explicitly stated, likely open-label or single-blind

Randomization

Yes, participants were randomized to intervention or control groups

Multicenter

Yes

Structured PICO

What are the molecular mechanisms and proteomic signatures underlying physical function impairment and response to rehabilitation in patients with HFpEF?

Population

Older adults with heart failure with preserved ejection fraction (HFpEF) from two randomized clinical trials (REHAB-HF, SECRET-II) and a validation cohort of >26,000 individuals.

Intervention

Physical rehabilitation

Outcome

Circulating proteins associated with prognostic measures of physical function (short physical performance battery, 6-minute walk distance) and protein changes after rehabilitationsurrogate

Multi-omics and AI network analysis identified a multi-system molecular program underlying physical function impairment and rehabilitation response in HFpEF, providing potential therapeutic targets and risk estimators.

Limitations

Small sample size (214 participants) limits power for detecting clinical endpoint effect sizes.
Details on blinding procedures were not provided, increasing risk of bias.
The study focused on biomarker identification rather than reporting clinical endpoint effect sizes such as change in SPPB or 6MW distance with exact numeric values.
Proteomic data from a subset of participants only; blood samples were not mandatory in REHAB-HF.
Lack of explicit numerical data on changes in physical function endpoints limits quantification of clinical effects.

Abstract

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common cause of morbidity and mortality in older adults that is driven by cardiac and non-cardiac mechanisms. Physical rehabilitation improves frailty and functional capacity in HFpEF, though underlying mechanisms remain less clear. We quantified >5,000 circulating proteins across two randomized clinical trials of rehabilitation in HFpEF (REHAB-HF, SECRET-II), identifying proteins associated with prognostic measures of physical function (short physical performance battery, 6-minute walk distance) and protein changes after rehabilitation. Using an artificial intelligence (AI)-enabled multiplex network analysis (MENTOR-IA), we identified biologically plausible networks central to this "physical function proteome," including endothelial remodeling, mitochondrial metabolism, calcium handling, and immune modulation. Expression of prioritized proteins at the transcriptional level localized to heart, skeletal muscle, and brain tissue, with several cognate transcripts implicated in frailty via tissue-specific transcriptome-wide genetic association studies. In addition, using novel human genetic approaches, we implicated select proteins as mediating tissue-specific genetic effects on frailty. These findings motivated us to construct multi-protein signatures of physical function, which correlated with functional changes observed with rehabilitation in REHAB-HF and SECRET-II and that were associated with heart failure and multi-dimensional clinical outcomes in >26,000 individuals. These findings collectively delineate a multi-system molecular program underlying physical function impairment and rehabilitation response in HFpEF, offering insights into potential precision risk estimators and therapeutic targets for surveillance and promotion of physiologic resilience.

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