R01HL157261

Role of Inflammation in Intraplaque Hemorrhage Pathogenesis - Project Summary

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the US. Despite guidelines promoting aggressive anti-atherosclerotic therapies, there is a residual ASCVD risk of around 5% per year in patients who achieve profound LDL-C lowering (median 30 mg/dL) with combined statin and PCSK9 inhibitor therapy. New treatment strategies are needed to target the mechanisms beyond LDL to reduce this residual risk.

Histologic studies have demonstrated that plaque neovasculature constitutes the main entrance for inflammatory cells into plaques and provides a major source for the formation and progression of intraplaque hemorrhage (IPH). IPH, mainly resulting from plaque neovascularization, is a common feature of advanced atherosclerotic lesions and a critical element leading to accelerated plaque progression, plaque instability, and ischemic vascular events in humans.

We found that plaque neovessel permeability (measured as Ktrans, using dynamic contrast-enhanced magnetic resonance imaging) is strongly correlated with macrophage content and that greater adventitial Ktrans is associated with IPH. Recent studies have identified that CD163+ macrophages are associated with IPH and can further promote neovascularization leading to IPH progression. On the other hand, B1 cell-derived IgM can inhibit inflammation and reduce atherosclerosis, and circulating human B1 cells are inversely associated with coronary plaque volume and instability features. Our preliminary data showed that plasma IgM levels are reduced in patients with carotid IPH and B1 cells are inversely associated with IPH progression.

We, therefore, propose to study the role of B1 cell-derived IgM and B1 cells in IPH pathology. To test a novel hypothesis that B1 cell-derived IgM levels are reduced in patients with IPH and that the reduction in protective IgMs results in unobstructed IPH-promoted inflammation and neovessel permeability, thereby exacerbating plaque progression, we propose to conduct comprehensive studies including:

(1) Histological examination of CEA specimens to determine whether plaques with increased Ktrans and/or IPH have a lower density of IgM and a higher density of CD163+ macrophages;
(2) A longitudinal clinical follow-up study in 250 patients to determine whether lower IgM levels and B1 cells predict progression of Ktrans and IPH and whether IgM production and effect on macrophages are different in B1 cells in patients with and without IPH;
(3) In vitro mechanistic studies of endothelial sprouting and leakiness using 3D microvessels to determine the effects of IgM and B1 cells on RBC-induced changes in macrophages and vascular permeability.

This proposal utilizes state-of-the-art imaging techniques for quantification of vascular permeability and IPH and 3D microvessels to study how hemoglobin-stimulated macrophages and B1 cells and/or IgM influence endothelial function related vascular permeability. Our study will gain new knowledge to uncover inflammatory mechanisms in IPH pathogenesis and to discover potential therapeutic targets with a goal of reduced vascular permeability to prevent IPH and its progression, which will ultimately reduce residual ASCVD risk.

University Of Washington

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Seattle, Washington 981951016 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 295% from $820,050 to $3,239,521.