Cardiovascular disease remains the leading cause of death and of health care expenditure in the U.S. Evidence from observational and mechanistic studies supports the protective role of HDL cholesterol in atherosclerosis, but recent negative findings from genetic studies and clinical trials targeted at raising HDL have raised doubt about the importance of HDL in human populations. We propose using a newly developed assay of cholesterol efflux from macrophages to examine the relationships of efflux to incident CVD and plaque progression in the MESA cohort and to 18-FDG PET uptake in carotid plaque as a measure of plaque inflammation and to MRI carotid plaque burden. We propose to conduct this research as an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), using previously collected data and blood samples as well as the planned MESA Exam 6 to recruit participants for 18-FDG PET/MRI scanning and additional data collection.
The specific aims are as follows. 1. To test the hypothesis that HDL-mediated cholesterol efflux using subjects' HDL from MESA Exam 1 samples assayed in THP-1 macrophages is inversely associated with (a) incidence of CVD (n=453 cases and n=453 age- and sex-matched controls); and (b) progression of carotid plaque, after adjustment for standard CVD risk factors (n=450 cases and n=450 age- and sex-matched controls). 2. To test the hypothesis that HDL-mediated cholesterol efflux using subjects' HDL assayed in THP-1 macrophages is inversely associated with FDG uptake in carotid plaque and with carotid plaque volume, using blood samples and PET-MRI data to be collected at MESA Exam 6 (n=350 subjects). Other MRI-derived variables, including plaque wall area, plaque wall thickness, plaque eccentricity, normalized [plaque] wall index, and plaque composition (presence or absence of a lipid rich necrotic core, calcification or intra-plaque hemorrhage) will be examined as secondary outcomes. Exploratory Aim. To test the hypothesis that HDL-mediated cholesterol efflux using subjects' monocytes and control HDL is inversely associated with FDG uptake in carotid plaque and with carotid plaque burden, in a subsample with >median FDG uptake and >median efflux based on the subjects' HDL and THP-1 macrophages. Findings have implications for understanding the role of HDL in the process of atherosclerosis, for the predictive importance of HDL, and for behavioral and drug targeting of HDL-raising as an athero-protective strategy.
Evidence from observational and mechanistic studies supports the protective role of HDL cholesterol in atherosclerosis, but recent negative findings from genetic studies and clinical trials targeted at raising HDL have raised doubt about the importance of HDL in human populations. We propose using a newly developed assay of cholesterol efflux from macrophages to examine the relationships of efflux to incident CVD and plaque progression in the MESA cohort and to 18-FDG PET uptake in carotid plaque as a measure of plaque inflammation and to MRI carotid plaque burden. Findings have implications for understanding the role of HDL in the process of atherosclerosis, for the predictive importance of HDL, and for behavioral and drug targeting of HDL-raising as an athero-protective strategy.
