Effect of physical rehabilitation on molecular markers of frailty in heart failure

PROJECT SUMMARY/ABSTRACT Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by functional impairment, is highly prevalent in older persons, causes substantial morbidity, and has limited treatment options. An emerging view of HFpEF is that it represents a systemic geriatric condition resulting from accelerated biological aging of multiple

organ systems, underscoring the clinical and pathobiological overlap of HFpEF and frailty. The Rehabilitation Therapy in Older Acute Heart Failure Patients trial (REHAB-HF) randomized 349 hospitalized HF patients to usual care versus a dedicated physical rehabilitation intervention. At 3 months, the intervention was associated

with meaningful improvements in functional status, 6-minute walk distance, and quality of life and the effects were more pronounced in individuals with poorer baseline frailty. While these findings highlight the importance of addressing frailty in HF, current methods to assess frailty in individuals with cardiovascular disease (CVD) are

limited by lack of uniformity, overlap of frailty measures with CVD-related deficits, and lack of precision in assigning of frailty phenotypes to underlying biological pathways and mechanisms of frailty. In preliminary studies, we quantified >1000 circulating proteins in ≈800 older adults with aortic stenosis and developed

proteomic signatures of frailty phenotypes observing that: (1) age accounts for limited variance in frailty- associated proteins; (2) proteomic signatures of frailty are related to non-CVD mortality; and (3) proteins associated with frailty are involved in classic and novel pathways of metabolism, muscle physiology, fibrosis,

and cachexia. In this R21, we will evaluate how proteomic signatures of frailty respond to an effective intervention by measuring >700 circulating cardiometabolic/inflammatory proteins in REHAB-HF trial participants with HFpEF. We hypothesize that alterations in the circulating proteome during a randomized frailty-targeted

intervention will relate to changes in physical function and prioritize biomarkers of aging and frailty. We will test this hypothesis using 2 integrative Specific Aims (SAs). In SA1, we identify how the circulating proteome changes with physical rehabilitation in REHAB-HF and how these changes relate to improvements in frailty measures. In

SA2, we evaluate how proteins prioritized in our preliminary data and SA1 relate to multi-organ phenotypes of healthy aging and physical function in mostly middle-aged participants from the Framingham Heart Study (FHS) and Coronary Artery Risk Development in Young Adults (CARDA) Study with overlapping proteomic coverage.

Cohorts are diverse by race (CARDIA) and sex and capture a broad age range (FHS) and longitudinal follow-up in middle adulthood (with serial proteomics; CARDIA). Successful completion of this project will characterize the modifiability of proteomic signatures of frailty in response to a physical rehabilitation intervention in frail older

persons with a crucial age-related comorbidity (HFpEF) and pave the way to larger studies to define biomarkers of frailty that may be used for screening and predicting the clinical response to physical rehabilitation. Samples are immediately available for assay, and data will be made available per NIH Data Sharing Policies.