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Role of inflammation in intraplaque hemorrhage pathogenesis

Award Number: R01HL157261
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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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 »5%/year residual ASCVD risk 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 technique for quantification of vascular permeability and IPH and 3D microvessels for 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $731,649 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	4	4/3/2025	NON-COMPETING CONTINUATION	$731,649
														Subtotal = $731,649

Issue Date FY: 2024 ( Subtotal = $798,845 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	3	4/17/2024	NON-COMPETING CONTINUATION	$733,633
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	3	6/13/2024	NON-COMPETING CONTINUATION	$65,212
														Subtotal = $798,845

Issue Date FY: 2023 ( Subtotal = $807,682 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	2	5/2/2023	NON-COMPETING CONTINUATION	$807,682
														Subtotal = $807,682

Issue Date FY: 2022 ( Subtotal = $820,050 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	1	8/22/2022	NEW	$0
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	1	4/28/2022	NEW	$820,050
														Subtotal = $820,050

Grand Total All Awards = $3,158,226

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Role of inflammation in intraplaque hemorrhage pathogenesis

Award Number: R01HL157261

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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