Pathogenesis of Heart Failure with Preserved Ejection Fraction in Chronic Kidney Disease

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Project Summary Rupal Mehta, MD is an Assistant Professor of Medicine in the Division of Nephrology and Hypertension at the Northwestern University (NU) Feinberg School of Medicine. Dr. Mehta has assembled a cross-disciplinary mentorship team to advance her independent research program focused on studying heart failure (HF) pathogenesis in patients with chronic kidney disease (CKD). Heart failure with preserved ejection fraction (HFpEF) is a common manifestation of cardiovascular disease (CVD) in patients with CKD, and patients with CKD represent a distinct and highly prevalent sub-phenotype within the heterogeneous syndrome of HFpEF. Targeting of traditional mechanisms for CVD has not relieved the burden of HFpEF in CKD, suggesting that CKD-specific mechanisms may exist. Given the kidney’s impact on small molecule clearance and metabolism, Dr. Mehta proposes to investigate the central hypothesis that an altered metabolome in CKD contributes to HFpEF pathogenesis. The scientific premise is based on the emergence of distinct metabolic signatures of HFpEF, which suggests that CKD-induced metabolic changes may contribute to HFpEF pathogenesis. In Aim 1, Dr. Mehta will use the Chronic Renal Insufficiency Cohort Study, a population-based epidemiologic study, to investigate the associations between circulating metabolites and subclinical and clinical HFpEF in patients with CKD. In a patient-oriented (POR) study in Aim 2, Dr. Mehta will examine the dose-response relationship between circulating metabolites and subclinical HFpEF, phenotyped using 2D-speckle tracking echocardiography and cardiopulmonary exercise testing, in patients with and without CKD. In an interventional POR study in Aim 3, Dr. Mehta will use sodium glucose cotransporter 2 inhibition as a therapeutic probe to investigate whether modification of the metabolome in patients with CKD and subclinical HFpEF is associated with improved cardiac structure and function over 6 months. The results will provide critical data to inform future studies. Dr. Mehta’s career development goals are: 1) to expand knowledge of metabolomics testing and interpretation of metabolomics data; 2) to strengthen skills in identifying HFpEF phenotypes and interpreting cardiac testing in patients with CKD; 3) to develop expertise in conducting mechanistic POR studies; and 4) to enrich research portfolio, master scientific management skills and build cross-disciplinary collaborations. Dr. Mehta’s cross-disciplinary mentorship team includes experts in POR and CKD clinical trials (Primary mentor - Dr. Tamara Isakova), cardiac phenotyping and HFpEF trials (Co-Mentor - Dr. Sanjiv Shah) and biostatistics and metabolomics (Dr. Denise Scholtens). Two external advisory committee members will also provide mentorship in metabolomics in HF (Dr. Ravi V Shah) and CKD (Dr. Morgan Grams). By completing the proposed studies and attaining career development goals with guidance from experienced mentors and support from the dynamic scientific environment at NU, Dr. Mehta will transition to research independence and thrive as a physician-scientist committed to advancing the care of patients with CKD and HF.