Mechanisms of Congenital Heart Valve Disease

先天性心脏瓣膜病的发病机制 项目摘要 由形态或细胞外基质(ECM)缺陷引起的先天性心脏瓣膜异常 随着时间的推移，发展为粘液瘤性瓣膜病(MVD)，需要手术瓣膜置换。MVD 影响多达2%的美国人口，超过10%的75岁以上的人患有二尖瓣 反胃。目前，还没有药物治疗，如果不治疗，MVD可能会导致左半部受损 心功能，心力衰竭，最终死亡。目前的护理标准是瓣膜修复或 替换，这是高度侵入性的，并不总是成功的，耐用性有限，并且禁止 年龄和许多常见的合并症。先天性瓣膜异常，包括与 马凡综合征(MF)可发展为以胶原纤维断裂为特征的进展性MVD 并被粘多糖和蛋白多糖取代，导致小叶增厚和功能不全。 然而，促进瓣叶进行性退变的机制尚不清楚，而且 目前还没有可用的治疗方法来预防或逆转MVD的进展。我们最近对小鼠的研究 MVD模型，包括马凡综合征的Fbn1C1039G模型，涉及Wnt信号和髓系 进展性MVD中的细胞浸润。Fbn1基因编辑突变的猪也证明了 MFS的特征，包括二尖瓣叶增厚。我们假设先天性ECM 异常导致瓣膜间质细胞Wnt信号增加S，导致细胞因子增加 表达和巨噬细胞浸润，有助于病理性胶原重构和瓣膜 MVD进展的特征是功能障碍。目的是：1)鉴定VIC亚类、巨噬细胞 MVD在小鼠、猪和人MFS瓣膜中的基因表达变化。2)确定是否 Fbn1C1039G瓣膜中的WNT信号是细胞外基质调节失调和粘液瘤进展所必需的 疾病。3)确定浸润性巨噬细胞是否参与ECM的发病过程 MFS的重塑和粘液瘤性瓣膜病。这些研究的长期目标是定义 微血管病变进展的调控途径，包括先天性瓣膜缺陷引起的微血管病变，以及 微血管疾病非手术治疗新方法的确定。

Mechanisms of Congenital Heart Valve Disease Project Summary Congenital heart valve abnormalities due to morphological or extracellular matrix (ECM) defects can progress over time to myxomatous valve disease (MVD), necessitating surgical valve replacement. MVD affects up to 2% of the US population and more than 10% of individuals over 75 have mitral valve regurgitation. Currently, there is no medical therapy, and, if left untreated, MVD can lead to impaired left ventricular function, heart failure, and ultimately death. The current standard of care is valve repair or replacement, which is highly invasive, not always successful, of limited durability, and contraindicated by age and many common comorbidities. Congenital valve abnormalities, including those associated with Marfan Syndrome (MF) can develop into progressive MVD characterized by collagen fiber fragmentation and replacement by mucopolysaccharides and proteoglycans, leading to leaflet thickening and insufficiency. However, the mechanisms that promote progressive valve leaflet degeneration are not known, and there are currently no therapies available to prevent or reverse MVD progression. Our recent studies in mouse models of MVD, including the Fbn1C1039G model of Marfan syndrome, implicate Wnt signaling and myeloid cell infiltration in progressive MVD. Pigs with gene-edited mutations in Fbn1 also demonstrate characteristics of MFS, including thickening of mitral valve leaflets. We hypothesize that congenital ECM abnormalities lead to increased Wnt signaling in valve interstitial cells (VIC)s, resulting in increased cytokine expression and macrophage infiltration, that contribute to pathologic collagen remodeling and valve dysfunction characteristic of MVD progression. The Aims are: 1) Identify VIC sublineages, macrophage populations, and gene expression changes of MVD in mouse, pig and human MFS valves. 2) Determine if Wnt signaling in Fbn1C1039G valves is required for ECM dysregulation and progression of myxomatous disease. 3) Determine if infiltrating macrophages contribute to the pathogenic progression of ECM remodeling and myxomatous valve disease in MFS. The long-term goals of these studies are definition of regulatory pathways in MVD progression, including MVD resulting from congenital valve defects, and identification of new nonsurgical therapeutic approaches for MVD.