PROJECT SUMMARY Virginia Shalkey Hahn, MD is an Assistant Professor of Medicine and heart failure cardiologist in the Division of Cardiology at Johns Hopkins University. Her long-term goal is to become an independent investigator harnessing bioinformatics to answer clinically relevant questions in the fields of heart failure and cardiometabolic disease. She focuses on the intersection of cardiometabolic disease and heart failure due to the rising prevalence of obesity and its prominent role in Heart Failure with Preserved Ejection Fraction (HFpEF). HFpEF is a common disease with limited effective therapies due to its heterogeneity and limited analysis of human tissue. Her prior work used myocardial transcriptomics to create HFpEF subgroups that had distinct clinical profiles, one of which was composed of women with normal natriuretic peptides, a group that was excluded from most all prior and even recent positive clinical trials for HFpEF. The Specific Aims of the current proposal are to 1) determine differences in myocardial cell composition and cell cluster-specific transcriptomics in HFpEF using single nuclei RNA sequencing, 2) define the myocardial metabolic profiles of HFpEF using multi-omic analysis of endomyocardial biopsy tissue, and 3) measure differences in metabolite uptake/secretion by the heart in HFpEF using coronary sinus sampling. The significance of the proposal stems from the use of human tissue with strong clinical phenotyping, and its likelihood to spawn precision therapies for HFpEF that target unique abnormalities in distinct subgroups, particularly subsets of female patients who are traditionally excluded from clinical trials. Dr. Hahn has assembled a world-class mentoring team well- poised to complete the research and training aims of the proposal. The primary mentor, Dr. David A. Kass, is an internationally renowned cardiovascular scientist with >36 years of experience training several generations of physician-scientists. He has extensive experience serving as primary mentor for NIH career development awards. Co-mentors Dr. Patrick Ellinor and Dr. Kavita Sharma have expertise in cardiovascular bioinformatics, translational research, and HFpEF. Collaborators add expertise in proteomics, metabolism, and bioinformatics. The work is performed in the fertile academic environment at the Johns Hopkins University School of Medicine, where the Division of Cardiology demonstrates a clear commitment and investment in Dr. Hahn's research career. The career development plan focuses on development of a formal bioinformatics skillset through hands-on analysis and a Master of Science degree in Bioinformatics. These skills will distinguish Dr. Hahn from her mentors as an independent investigator with a unique niche in bioinformatics and heart failure. Dr. Hahn and her mentoring team are well poised to address the most pressing knowledge gaps in HFpEF and make major breakthroughs toward better care for our patients.