Diabetes, which leads to greater atherosclerotic cardiovascular disease and disproportionately affects women, involves periods of greater vascular lesion development and times of repair. Repair--defined as a reduction in plaque lipid and macrophages, and an increase in collagen--occurs in the majority of patients with marked reduction in circulating cholesterol levels. Diabetes leads to a striking defect in regression. This SFRN application will use animal studies and human samples to determine why arterial repair is defective in women and men with diabetes. In addition, we will utilize data from a large international study of patients with stable ischemic heart disease to determine factors associated with recurrent vascular events. We will determine what changes in circulating WBCs and platelets prevent normal arterial repair after cholesterol reduction with diabetes. We predict that our studies will explain why defective regression is more deleterious in women and help us identify the biomarkers and targets from which we can predict and treat patients for whom cholesterol reduction alone is insufficient to allow vascular repair. To do this, we propose three projects: 1) A basic project to define how insulin resistance and obesity affect circulating cells and atherosclerosis regression. 2) A population project that will use currently available and continued collections of human atherosclerotic vascular tissue to determine the pathological differences in lesional pathology after cholesterol reduction in patients with diabetes, coupled to clinical data obtained in the ISCHEMIA trial. 3) A clinical project to acutely treat subjects whose LDL is not at goal with statin and PCSK9 inhibitors to determine how dramatic cholesterol reduction changes the function and transcriptome of circulating platelets and WBCs in woman and men with diabetes. These synergistic projects will link animal experiments, human pathology and circulating cells with disease outcome. All projects will specifically study health disparity due to sex. The investigative team is from two major research medical centers and two low research activity sites. In addition, we will provide AHA fellows with clinical and basic science research training, required and elective didactic work, and career and research guidance via a structured mentoring program. Our studies focusing on atherosclerosis repair should lead to a number of collaborative projects with other AHA SFRN sites.
|Program type||Strategically Focused Research Network|
|Effective start/end date||01/01/2020 → 12/31/2023|