Innovative Therapy to Treat Women with Angina with Nonobstructive CAD (ANOCA) and Coronary Microvascular Disease

PROJECT SUMMARY/ABSTRACT Innovative therapy to treat Women with Angina with Nonobstructive CAD (ANOCA) and Coronary Microvascular Disease(CMD). Heart disease is the leading cause of death among women and men. The scientific community has strived for a "one size fits all" approach to reduce our understanding of atherosclerosis to a single unifying model. Sex-

specific mechanisms warrant attention, considering the alarming trend of increasing coronary artery disease (CAD) in young women. Ischemic heart disease in women is different from that of men. Women have a unique phenotype with fewer calcified lesions and more nonobstructive disease. Recent studies also identified

differences between sexes in coronary endothelial and/or microvascular dysfunction, with women demonstrating a higher prevalence of coronary microvascular disease (CMD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a drug class approved for the treatment of diabetes, has been shown to significantly

reduce atherosclerotic events, hospitalization from heart failure (HF), cardiovascular and total mortality, and progression of chronic kidney disease. New recommendations suggest using SGLT2i in symptomatic patients with chronic HF with reduced ejection fraction to reduce hospitalization and cardiovascular mortality,

regardless of type 2 diabetes. In preclinical mouse models of myocardial infarction, SGLT2i improved coronary microvascular function and increased cardiac output. Recent studies show that SGLT2 inhibition has possible mechanisms of benefit that are unlikely to be related to improved glycemic control. There is evidence that SGLT2i targets several pathways. We hypothesize that

SGLT2i treatment will improve CMD in women with ANOCA by different pathways, including reducing markers of systemic inflammation and improving coronary blood flow, leading to a reduction of the functional impact of this disease process. In Aim 1, we will test the efficacy of SGLT2i in improving coronary blood flow (CFR) in

women with ANOCA and CMD. CFR will be assessed using stress Cardiac Magnetic Resonance (CMR) before and after 12 weeks of SGLT2i or placebo treatment. In Aim 2, we will determine whether SGLT2i treatment improves patients’ quality of life and how this relates to improvement of CMD. We will measure the

quality of life in women treated with SGLT2i or placebo using clinically validated questionnaires at baseline, 6 weeks, and 12 weeks post-treatment. Lastly, Aim 3 will study the impact of SGLT2i treatment on markers of systemic inflammation and inflammatory pathways in study participants. The proposed investigation will

significantly advance our understanding of the potential benefits of SGLT2 inhibition in CMD in women with non-obstructive CAD. Since there is a lack of evidence for treatment in this population, this proposal will fill an unmet need in managing women with ANOCA and CMD and significantly advance our

understanding of SGLT2 inhibitor's potential benefits in microvascular disease.