PROJECT SUMMARY (30 lines) Dr. Jarett Berry is a Professor of Medicine in the Division of Cardiology at UT Southwestern Medical Center. Over the last 13+ years, he has led a successful program of research that has been supported through sustained funding from the NIH and/or the American Heart Assocation. He has established a successful research program characterizing the impact of exercise on the risk for heart failure with preserved ejection fraction. He has held leadership roles at UT Southwestern and nationally. Furthermore, he has mentored numerous trainees at all levels, facilitating their transition to indepdnence as evidenced by their own independent research careers. Beginning in 2019, he was named the new PI of the Dallas Heart Study, where he is leading a multidisciplinary effort to characterize the biology of healthy aging in a large, multiethnic cohort. He also developed and serves as the director of the DHS Exercise Testing Laboratory where his lab performs comprehensive exercise testing on DHS participants. His current research is funded by a large institional commitment that supports the 3rd examination of the DHS. His research is also supported by additional funding from the NIH. Therefore he is well positioned to lead an expansion of his mentoring program that will be supported by this K24 mechanism and support his long-term career goals: (1) Lead a major research program focused on the prevention of heart failure with preserved ejection fraction (HFpEF); (2) Improve the understanding of the mechanisms contributing to low exercise capacity in middle age and identify targeted strategies for treatment; and (3) Develop a new generation of clinical investigators equipped with knowledge and skill set to conduct high-quality, patient oriented cardiovascular research. During this award period, the PI will acquire additional leadership training and gain exposure to advanced imaging techniques using high-field, 7T MRI through attending focused training experiences and hands-on work with his advanced imaging colleagues. Based on prior research established by the PI, the central hypothesis of this application is that exercise intolerance in older HFpEF patients reflects the natural history of low exercise capacity in midlife. The Specific Aims of the proposal are the following: Specific Aim #1: Characterize peripheral mechanisms of reduced exercise capacity in otherwise healthy middle-aged and older adults at increased risk for HFpEF. DHS participants will complete (1) functional measurements [VO2 kinetics and oxygen extraction (AVO2 difference) at submax exercise]; and (2) structural measurements (skeletal muscle volume, muscle fat infiltration). A subset DHS participants will also undergo additional functional in vivo measurements of mitochondrial function using our established 7T MRI/MRS platform. Specific Aim #2: Compare the peripheral mechanisms of EI in patients with established HFpEF with otherwise healthy adults with similar/matched...