# Integrated epidemiology of systemic and plaque-specific immunologic features of human atherosclerosis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $796,083

## Abstract

SUMMARY - Subclinical atherosclerotic cardiovascular disease (ASCVD) occurs in more than half of adults over
50 and progresses in many to clinical ASCVD events such as myocardial infarction (MI), stroke, and limb
ischemia. A key contributor to ASCVD progression is excess inflammation, which persists in 1/3rd of people on
otherwise optimal therapy for ASCVD and confers twice the risk for recurrent ASCVD and death. Yet, although
therapies bluntly targeting inflammation can modestly reduce ASCVD events, off-target effects resulting from
broad and sustained systemic inflammation reduction, such as infection, limit use. These results highlight the
therapeutic potential of inflammation modulation in ASCVD, but also the need for more precise, nuanced
immunologic targets. Experimental findings from our group and others revealed dynamic ways in which immune
cells polarize to favor inflammatory versus inflammation-resolving functions, including via metabolic and
epigenetic rewiring to alter gene expression. Yet, these have largely been limited to experimental models and
small cross-sectional human studies utilizing convenience samples. Meanwhile, studies by our group and others
in large population-based cohorts indicated associations of broad immune cell phenotypes in the blood with
ASCVD, but lacked granular data on cell-level functional heterogeneity within these broad cell subsets. Thus,
there is a critical gap in human data, particularly longitudinal data, on relationships between immune cell
functional polarization and ASCVD; this limits precise insights into immune cell-level features that could be
targeted to modulate inflammation and reduce ASCVD. We propose a translational epidemiologic study
investigating single-cell transcriptomic and gene-regulatory profiles of immune cells in human peripheral blood
mononuclear cells (PBMCs) and plaque associated with coronary, carotid, and lower extremity manifestations
of ASCVD. Based on our pilot and prior data, we hypothesize that inflammatory monocyte polarization, as well
as linked epigenetic regulatory elements and glycolytic metabolic preference: (1) precede clinical ASCVD onset
and (2) associate with high-risk plaque morphology and clinical presentation. We investigate this in Aim 1 with
single-cell sequencing and functional metabolic analyses of PBMCs viably preserved from Multi-Ethnic Study of
Atherosclerosis (MESA) participants with subclinical ASCVD at baseline who progressed to (cases) versus
remained free from (controls) clinical ASCVD over follow-up. In Aim 2, we analyze immune cells isolated from
the blood and plaque of patients with prevalent clinical ASCVD undergoing carotid or femoral endarterectomy;
we will determine single-cell gene expression, epigenetic regulation, and metabolic polarization associated with
high-risk plaque morphology and clinical presentation, as well as whether these features in plaque are imprinted
in blood. Our pilot data in human PBMCs and plaque inform our approach...

## Key facts

- **NIH application ID:** 10995816
- **Project number:** 1R01HL175893-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Matthew Joel Feinstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $796,083
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995816

## Citation

> US National Institutes of Health, RePORTER application 10995816, Integrated epidemiology of systemic and plaque-specific immunologic features of human atherosclerosis (1R01HL175893-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10995816. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*