Epidemiology and mechanisms linking ectopic FAT with inflammation and atherosclerosis

The National Heart Lung and Blood Institute awarded Northwestern University $2,139,171 under Project Grant R01HL184083 on September 1, 2026, to conduct epidemiological and mechanistic research linking ectopic fat with inflammation and atherosclerosis.

The research addresses gaps in understanding how distinct fat depots—hepatic, visceral, epicardial, and pericoronary—drive local vascular inflammation and coronary plaque formation across populations. Northwestern will leverage two well-phenotyped cohorts: the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study and the Miami Heart Study, obtaining harmonized coronary CT angiography to quantify hepatic fat, epicardial adipose tissue, pericoronary fat attenuation index as a measure of perivascular inflammation, and coronary plaque. The research framework posits that dysregulated peripheral blood mononuclear cell inflammatory programs mediate the effect of specific ectopic fat depots on vascular inflammation and atherosclerosis. The project operates under the Cardiovascular Diseases Research program (CFDA 93.837), which supports heart and vascular research in basic, translational, clinical, and population sciences.

Work is performed in Chicago, Illinois, with a period of performance extending from September 1, 2026, through May 31, 2031. The award is a Project Grant, a type of assistance funding.

Abstract

Although atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, stroke, and coronary revascularization, is a leading cause of death, its incidence varies across populations in ways not explained by traditional cardiovascular risk factors, clinical care, lifestyle, or environment. Our prior work in the mediators of atherosclerosis in south asians living in america (MASALA) study cohort showed that south asian americans accumulate excess hepatic and visceral FAT at modest BMI, and that this "ectopic" FAT contributes to ASCVD risk. Although inflammation is a key mediator linking ectopic FAT to ASCVD, major knowledge gaps remain: (1) adipose depot-specific effects: how distinct FAT depots drive local vascular inflammation and coronary plaque is unclear; (2) population specificity: whether the ectopic FAT-immune- plaque relationships are shared or differ across populations is unknown; (3) cell-specific mechanisms: large human studies linking ectopic FAT to PBMC transcriptional and functional states are lacking, and IT is unknown which circulating immune signatures track with perivascular inflammation or plaque; (4) causality: whether adipose depots directly program immune cells toward pro-atherogenic states has not been tested. We will address these gaps using complementary epidemiologic and mechanistic approaches. Our framework posits that dysregulated peripheral blood mononuclear cell (PBMC) inflammatory programs mediate the effect of specific ectopic FAT depots on vascular inflammation and atherosclerosis. We will leverage two well-phenotyped cohorts, MASALA and the miami heart study (MIHEART), and obtain harmonized coronary CT angiography (CCTA) to quantify hepatic FAT, epicardial adipose tissue, pericoronary FAT attenuation index (PFAI) as a measure of perivascular inflammation, and coronary plaque. These data will be used in aim 1 to: define associations between ectopic FAT, PFAI, and coronary plaque across MASALA and MIHEART. Next, we will link CCTA imaging measures to PBMC transcriptional and functional profiles in aim 2: determine PBMC transcriptional signatures associated with ectopic FAT, perivascular inflammation, and plaque in MASALA participants. Finally, we will directly test whether human adipose tissue depots induce pro-inflammatory activation in immune cells in aim 3: experimentally test the effects of specific human FAT depots on the transcriptional state of circulating immune cells using fresh surgical FAT specimens to create adipose conditioned media and exposing pbmcs from healthy donors to the media. These aims will establish a causal chain from FAT depots to immune dysregulation to plaque. Our team brings expertise in cardiovascular epidemiology, CT imaging, immunology, adipose biology, and bioinformatics. This study addresses critical gaps in how depot-specific ectopic FAT drives immune activation and vascular inflammation and will inform new prevention and therapeutic targets for ASCVD.