Reducing Heart Failure Risk in Late-Life With Physical Activity: Impact on Cardiac Structure and Function and Proteomic Signatures

PROJECT SUMMARY This K23 application supports Dr. Sheila Hegde, a highly promising cardiac imager and early-stage investigator who is committed to investigating the underlying mechanisms by which physical activity (PA) favorably impacts the risk of heart failure (HF) in late-life. Her long-term goal is to be an independent investigator studying modifiable biomarkers of aging and HF risk that will ultimately inform therapeutic intervention. The overall scientific objective of this proposal is to identify biologic pathways underlying the beneficial effects of PA on cardiac function, functional capacity, and HF risk using high dimensional ‘-omic’ data. The main hypothesis is that PA delays age-related changes in cardiac structure and function and mitigates HF risk through biologic pathways that can be identified through high throughput circulating proteomic profiling. The specific aims are to: 1) Employ high-throughput plasma proteomics and genomic data to identify novel molecular pathways underlying longitudinal PA-related changes in cardiovascular structure and function and incident HF (NHLBI ARIC cohort); and 2) Identify molecular pathways underlying the beneficial effect of a structured PA intervention on functional capacity with the use of plasma proteomics in older sedentary adults at high risk of HF. (Brigham and Women’s Hospital-based cohort). These aims will also serve as a vehicle to achieve the following career and learning objectives: 1) Attain advanced skills in novel, data science driven methods for high-dimensional data, particularly in proteomics analysis; and 2) Develop the necessary skills to design, implement, and conduct a clinical trial in order to transition to an independent clinical investigator. These objectives will be accomplished through: 1) structured interactions with a committed and expert multidisciplinary panel of mentors and advisors; 2) focused didactic coursework in study design and statistical approaches relevant to ‘-omic’ data; and 3) progressive participation in multi-institutional working groups and committees for national multicenter studies, dedicated mini-courses and meetings relevant to PA and multi ‘-omic’ analyses, and national cardiovascular professional organizations. These activities will also act as a framework to grow her leadership skills and to develop external collaborations. The results of the proposed early career development award will provide further insight into the underlying cardiovascular mechanisms by which physical activity impacts age-related changes in cardiac structure and function, functional capacity, and heart failure (HF) risk and serve as the necessary foundation for Dr. Hegde to transition to an independent investigator.