Dr Amil Shah is an Associate Professor of Medicine at Harvard Medical School and an active clinical cardiologist and cardiovascular imager at Brigham and Women's Hospital (BWH). His overall career goal is to make substantial contributions to the diagnosis, treatment, and prevention of heart failure (HF) – and HF with preserved ejection fraction (HFpEF) in particular – through impactful research and effective mentoring of the next generation of investigators. He has developed a successful, independent patient oriented research (POR) program aiming to define the cardiac perturbations responsible for HFpEF by integrating cardiac imaging into prospective hospital-based physiologic studies, multicenter epidemiologic cohorts, and randomized clinical trials. He has led impactful publications informing HFpEF pathophysiology, diagnosis, and management, and has secured continuous NIH funding (PI on 2 active R01 grants). He has been primary mentor to 22 trainees to-date, and his program provides a unique platform for training in POR which is amplified by integration with the Harvard CTSA, BWH cardiovascular imaging T32 program, and degree-granting programs in clinical investigation at Harvard Medical School and School of Public Health. His objectives for this K24 proposal are (1) to improve the quality and scope of his mentoring by engaging in didactic and peer-led workshops; (2) to expand his research program to include `-omic' science; and (3) to develop expertise in analysis of high- dimensional `-omic' data to relate to imaging phenotypes and clinical outcomes. Protected time from the K24 will enable Dr Shah to pursue didactic and peer-led training in mentoring, to expand his mentoring activities, and to engage in coursework and `hands-on' training in `-omic' science. Funds from the K24 will support expansion of his research program into translational proteomics and genomics, including computational biology support. HFpEF is common, morbid, and increasing in prevalence, but no efficacious disease-specific therapy currently exists. While LV dysfunction underlying HFpEF is an intense focus of investigation, little is known regarding biological pathways promoting the preservation of cardiac function in the face of detrimental co-morbidities (cardiac resilience). This is a critical missed opportunity to develop interventions promoting normal cardiac function to prevent HF. The specific scientific aims of this proposal are to define circulating individual proteins and protein networks that (1) positively and negatively correlate with exercise- hemodynamic perturbations characteristic of HFpEF; (2) associate with cardiac resilience in late life; and (3) are most likely to be mediators of cardiac resilience based on studies using genomic data. Aim 1 will occur in patients prospectively enrolled at BWH to undergo invasive exercise testing. Aims 2 and 3 will be performed in the Atherosclerosis Risk in Communities cohort, with replication in the Jackson Heart Stu...