PROJECT SUMMARY/ABSTRACT Though implicated in half of all incident heart failure presentations, heart failure with preserved ejection fraction (HFpEF) is a poorly understood disease process with limited available therapies. Indeed, no medications were definitively shown to improve clinical outcomes in HFpEF until the recent serendipitous discovery of the benefit of sodium-glucose cotrasporter-2 inhibitors (SGLT2i) in heart failure. Unfortunately, the mechanisms of SGLT2i in HFpEF remain largely undefined. Elucidating these mechanisms will facilitate expansion of the HFpEF therapeutic armamentarium. While prior studies have suggested a positive anatomic cardiac remodeling benefit of SGLT2i in HFpEF, the molecular mechanisms driving this process are not understood. Recent animal data linking the anatomic remodeling benefits of SGTL2i in systolic heart failure to favorable shifts in cardiac energy metabolism have motivated strong speculation that SGLT2i afford benefit in HFpEF via similar mechanistic pathways. This study will investigate if SGLT2i therapy is associated with both positive anatomic and metabolic cardiac remodeling benefits in HFpEF. To achieve this, multiple novel cardiac imaging methods will be employed in service of two specific aims: (1) Evaluate the impact of SGLT2i therapy on cardiac remodeling in patients with HFpEF via retrospective analysis of serial echocardiograms and (2) explore the impact of SGLT2i therapy on metabolic cardiac remodeling in patients with HFpEF via Cr-CEST MRI. Application of novel echocardiographic artificial intelligence platforms will facilitate a standardized, high throughput retrospective analysis of select echocardiographic parameters derived from a large clinical cohort to detect changes in anatomic cardiac remodeling following initiation of SGLT2i. Additionally, creatine chemical exchange saturation transfer magnetic resonance imaging (Cr-CEST MRI) will be utilized to detect relative levels of intracellular creatine, a surrogate marker for cardiac metabolic activity, following SGLT2i therapy in HFpEF. Beyond facilitating these specific aims, the application of emerging advanced cardiac imaging techniques as outlined above will (1) demonstrate the utility of AI platforms in standardizing retrospective echocardiographic data and (2) outline the feasibility of Cr-CEST MRI in detecting shifts in HFpEF cardiac metabolism. This work will advance the field’s collective understanding of novel HFpEF therapeutics, operationalize innovative cardiac imaging techniques, and provide training in cardiac imaging research methodologies central to the applicant’s long-term goal of becoming a physician-scientist with expertise in heart failure and advanced cardiac imaging.