Role of inflammation in intraplaque hemorrhage pathogenesis

炎症在斑块内出血发病机制中的作用

• 批准号: 10615058
• 负责人: Jenny E. Kanter
• 金额: $ 80.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615058
• 关键词: 3-Dimensional; Acceleration; Achievement; Address; Affect; Antibodies; Arterial Fatty Streak; Atherosclerosis; B-Lymphocytes; Blood Vessels; Cardiovascular system; Carotid Artery Plaques; Carotid Endarterectomy; Cause of Death; Cell Separation; Cells; Cholesterol; Clinical; Coculture Techniques; Collaborations; Complement; Data; Development; Elements; Endothelial Cells; Endothelium; Erythrocytes; Event; Excision; Follow-Up Studies; Goals; Growth; Guidelines; Health Care Costs; Hemoglobin; Hemorrhage; Histologic; Histology; Human; Hypoxia; Image; Imaging Techniques; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Investigation; Ischemia; Knowledge; Lipids; Low-Density Lipoproteins; Macrophage; Magnetic Resonance Imaging; Measures; Myocardial Infarction; Necrosis; Oxygen; Pathogenesis; Pathology; Patients; Permeability; Persons; Plasma; Production; Quality of life; Residual state; Risk; Role; Scanning; Source; Specimen; Stroke; Testing; Tissues; Tunica Adventitia; United States; Vascular Diseases; Vascular Permeabilities; atheroprotective; blood pressure control; cardiovascular disorder risk; contrast enhanced; coronary plaque; density; driving force; follow-up; histological studies; in vivo; inhibitor therapy; neovascularization; neovasculature; novel; novel therapeutic intervention; prevent; response; therapeutic target; treatment response; vasa vasorum

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.

项目概要 动脉粥样硬化性心血管疾病（ASCVD）仍然是美国的首要死因。 指南提倡积极的抗动脉粥样硬化治疗，每年有 5% 的残余 ASCVD 风险 使用他汀类药物和 PCSK9 抑制剂联合治疗实现深度 LDL-C 降低（中位 30 mg/dL）的患者 需要新的治疗策略来针对 LDL 以外的机制，以减少这种残留。 组织学研究表明，斑块新生血管构成了风险的主要入口。 炎症细胞进入斑块并为斑块内形成和进展提供主要来源 出血（IPH），主要由斑块新生血管形成引起，是晚期的常见特征。 动脉粥样硬化病变是导致斑块加速进展、斑块不稳定和 我们发现斑块新生血管通透性（使用 Ktrans 测量）。 动态对比增强磁共振成像）与巨噬细胞含量密切相关， 最近的研究发现，更大的外膜 Ktrans 与 IPH 相关。 另一方面，它们与 IPH 相关，并可进一步促进新生血管形成，导致 IPH 进展。 另一方面，B1细胞衍生的IgM可以抑制炎症并减少动脉粥样硬化，并且循环人类B1细胞 我们的初步数据显示，与冠状动脉斑块体积和不稳定特征呈负相关。 颈动脉 IPH 患者血浆 IgM 水平降低，B1 细胞与 IPH 呈负相关 因此，我们建议研究 B1 细胞来源的 IgM 和 B1 细胞在 IPH 病理学中的作用。 检验一项新假设，即 IPH 患者中 B1 细胞衍生的 IgM 水平降低，并且 保护性 IgM 的减少导致 IPH 促进的炎症和新生血管畅通无阻 渗透性，从而检查斑块进展，我们建议进行全面的研究 包括：（1）CEA标本的组织学检查以确定是否有Ktrans增加的斑块 和/或 IPH 具有较低的 IgM 密度和较高的 CD163+ 巨噬细胞密度 (2) 临床纵向； 对 250 名患者进行的后续研究，以确定较低的 IgM 水平和 B1 细胞是否可以预测 Ktrans 的进展 和 IPH 以及 IgM 产生和对巨噬细胞的影响是否在 IPH 和 IPH 患者的 B1 细胞中不同 无 IPH；(3) 使用 3D 微血管进行内皮出芽和渗漏的体外机制研究 确定 IgM 和 B1 细胞对红细胞诱导的巨噬细胞和血管通透性变化的影响。 该提案利用最先进的成像技术来量化血管通透性和 IPH 和 3D 微血管，用于研究血红蛋白刺激的巨噬细胞和 B1 细胞和/或 IgM 如何影响 我们的研究将获得揭示炎症的新知识。 IPH 发病机制，并发现潜在的治疗靶点，以减少血管 渗透性以预防 IPH 及其进展，最终降低残余 ASCVD 风险。