ObjectiveTo determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF).MethodsA primary cohort (N=12) with HFpEF and obesity underwent echocardiography, magnetic resonance spectroscopy before, and 3- and 6-mos after bariatric surgery. Plasma lipidomics were performed on pre- and 3-mo post-surgery in the primary cohort and confirmed in a validation cohort (N=22).ResultsAfter surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, < 0.001, = 0.007); echo-derived e′ increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate.ConclusionsSurgery-induced weight loss in women with HFpEF and obesity is associated with improved symptoms, reverse cardiac remodeling and improved relaxation. While weight loss associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. Our study results suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis.