Effects of Empagliflozin on Left Atrial Function in Adults at Risk for Heart Failure - PROJECT SUMMARY/ABSTRACT Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of medications that reduce CVD events, particularly heart failure (HF) outcomes in patients with HF and reduced or normal left ventricular (LV) function. The mechanism for the effect of SGLT2i is not well understood, but they may beneficially alter LV structure and function through changes in plasma proteins. Atrial myopathy is a novel biomarker for increased cardiovascular disease (CVD) risk. Atrial myopathy is characterized by abnormalities in the structure, function, and electrical conduction of the left atrium (LA). LA function can be quantified using strain analysis with 2-dimensional echocardiography (2DE) allowing detection of LA dysfunction before overt structural changes and LA enlargement occur. LA dysfunction is associated with increased risk for atrial fibrillation, stroke, dementia, and heart failure. Despite this risk, there are no proven therapies to treat or prevent LA dysfunction. Untargeted proteomic analyses done in adults with LA dysfunction are suggestive of an association with plasma proteins involved in cardiomyocyte function and inflammatory pathways. The goal of this K23 Career Development Award is to conduct a 9-month double-blind placebo-controlled RCT of empagliflozin (an SGLT2i) in 80 individuals at risk for HF but no diagnosis of HF or diabetes. Individuals will be identified by screening patients who visit the Cardiology clinic at the University of Minnesota. The primary endpoints for the proposed RCT include changes in LA and LV function assessed by 2DE at baseline and 9 months; and change in 8 a priori identified plasma proteins. Aim 1 will test the hypothesis that change in LA function from baseline to 9 months will be more favorable in the empagliflozin group than placebo. Aim 2 will test the hypothesis that change in LV diastolic from baseline to 9 months will be more favorable in the empagliflozin group than placebo. Aim 3 will test the hypothesis that compared with placebo, empagliflozin will be associated with greater change in the selected proteins after 9 months. The proposed training and mentoring plan has the following goals: 1) acquire expertise in clinical trial design, implementation, and analysis; 2) develop expert knowledge in left atrial myopathy; 3) acquire necessary skills to design, execute, and interpret studies involving proteomic analysis; 4) develop enhanced collaborative skills, written and oral communication skills, and management skills necessary to lead a multidisciplinary team. The training plan includes attendance at educational seminars and scientific meetings, structured mentoring, formal coursework, and hands on experience on this mentored K23 project and other collaborative research with mentors. In summary, the requested K23 support will provide the training and mentoring necessary for the candidate to establish himself as a successful independent physician scientist in the field of preventive cardiology. The proposed research will also provide novel preliminary evidence regarding the effect of empagliflozin on LA and LV function in an understudied population, informing a future R01-funded RCT evaluating SGLT2i treatment effect on CVD outcomes in patients without diabetes or HF.
