Molecular characterization of frailty and functional limitations in HFpEF
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PROJECT SUMMARY/ABSTRACT Nearly 1 in 4 Americans will experience heart failure (HF) during their lifetime, with at least 50% classified as HF with preserved ejection fraction (HFpEF). Exertional intolerance is a key clinical feature of HFpEF. While cardiac dysfunction is one aspect of this condition, limitations to exertion have increasingly been ascribed to age-related pathobiological processes in multiple organs outside the heart (e.g., muscle, vascular, adipose). Indeed, ≈60-90% of people with HFpEF are considered “frail”—a systemic condition defined as “impaired metabolic resilience to physiologic stress”—and frailty itself strongly and independently predicts both cardiac and non-cardiac morbidity in HFpEF. Efforts to combat frailty and restore multi-organ “resilience” in HFpEF through physical activity, rehabilitation, and metabolic interventions (e.g., SGLT2 inhibition) have shown promise, but the mechanisms by which rehabilitation alter outcomes in HFpEF remains unclear. The central hypothesis of this K23 application is that proteins linked to quantitative, multi-organ frailty phenotypes in HFpEF will specify prognostic pathways of disease to inform future targeted surveillance or therapeutic studies. In this application, the PI (Dr. Andrew Perry) will measure associations between the human proteome and detailed hemodynamic and physiologic measures of multi-organ function in HFpEF in a hospital-based referral sample with invasive hemodynamic cardiopulmonary exercise measures (Aim 1). Dr. Perry will then identify and prioritize reversible pathways of multi-organ system impairment in HFpEF by measuring a circulating proteome before and after an already conducted, NIH funded randomized clinical trial intervention in HFpEF (REHAB-HF; Aim 2). He will finally conduct a pilot prospective study of home-based rehabilitation using a mobile application in HFpEF, supported by a larger NIH-funded effort (Aim 3). Dr. Perry has assembled a comprehensive mentoring team to aid his career development and scientific aims, including NIH funded investigators in exercise physiology in HFpEF using prospective studies (Shah, Lewis, Nayor), frailty and HFpEF (Kitzman), and high-dimensional molecular characterization and statistics (Shah, Below). The scientific aims are embedded within a synergistic training/research program focused around exercise physiology, multi- omics, advanced statistical techniques, and human patient-oriented studies, including completion of a Master of Science in Clinical Investigation. He is also supported by a rich institutional environment within Department of Medicine and Cardiovascular Medicine, including Vanderbilt’s VICTR CTSA. Successful completion of the scientific and training objectives in this K23 will provide Dr. Perry with the requisite skills to take the next, formative independent step in his long-term goal of leading a patient-oriented translational research program studying mechanisms of functional improvement in patients with advanced cardiovascular disease.
