Role of inflammation in intraplaque hemorrhage pathogenesis

项目总结 动脉粥样硬化性心血管疾病(ASCVD)仍然是美国主要的死亡原因。尽管 促进积极抗动脉粥样硬化治疗的指南，每年有5%的残留ASCVD风险 联合应用他汀类药物和PCSK9抑制剂可显著降低低密度脂蛋白胆固醇(中位数30 mg/dL)的患者 心理治疗。需要新的治疗策略来针对低密度脂蛋白以外的机制，以减少这种残留 风险。组织学研究表明，斑块新生血管构成了 炎症细胞进入斑块，是斑块形成和发展的主要来源 出血(IPH)。IPH主要由斑块新生血管引起，是晚期高血压的共同特征。 动脉粥样硬化病变和导致斑块加速进展、斑块不稳定性和 人类的缺血性血管事件。我们发现斑块Neovessel通透性(用Ktras测量，使用 动态增强磁共振成像)与巨噬细胞含量和 更大的外膜KTRANS与IPH有关。最近的研究发现CD163+巨噬细胞 与IPH相关，并可进一步促进新生血管，从而导致IPH的进展。另一方面 另一方面，B1细胞衍生的IgM可以抑制炎症和减轻动脉粥样硬化，并使人类B1细胞循环 与冠状动脉斑块体积和不稳定性特征呈负相关。我们的初步数据显示 颈动脉IPH患者血浆IgM水平降低且B1细胞与IPH呈负相关 进步。因此，我们建议研究B1细胞来源的IgM和B1细胞在IPH病理中的作用。 为了检验一种新的假设，即IPH患者B1细胞来源的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通畅 渗透性，从而加剧斑块的进展，我们建议进行全面的研究 包括：(1)对CEA标本进行组织学检查，以确定斑块是否伴有Ktras增加 和/或IPH的IgM密度较低，CD163+巨噬细胞密度较高；(2)纵向临床 250例患者的随访研究，以确定低IgM水平和B1细胞是否预示KTRANS的进展 与正常对照组比较，AND患者B1细胞中IgM的产生及对巨噬细胞的影响是否不同 无IPH；(3)血管内皮细胞体外发芽和渗漏的三维微血管机制研究 确定IgM和B1细胞在红细胞诱导的巨噬细胞和血管通透性变化中的作用。 这一建议利用最先进的成像技术来量化血管通透性和IPH 和3D微血管研究血红蛋白刺激的巨噬细胞和B1细胞和/或IgM如何影响 内皮功能与血管通透性相关。我们的研究将获得新的知识来揭示炎症性疾病 IPH发病机制及寻找减少血管的潜在治疗靶点 渗透性，以防止IPH及其进展，这将最终降低残留的ASCVD风险。

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.