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.