Mechanisms of Congenital Heart Valve Disease

先天性心脏瓣膜病的发病机制 项目摘要 由于形态学或细胞外基质（ECM）缺陷导致的先天性心脏瓣膜异常可 随着时间的推移进展为粘液瘤性瓣膜病（MVD），需要进行外科瓣膜置换术。MVD 影响高达2%的美国人口，超过10%的75岁以上的个体患有二尖瓣 返流程度目前，没有药物治疗，如果不治疗，MVD可导致左心室功能受损。 心室功能心力衰竭最终死亡目前的护理标准是瓣膜修复或 置换，具有高度侵入性，并非总是成功，耐久性有限， 年龄和许多常见的合并症。先天性瓣膜畸形，包括与 马凡氏综合征（MF）可发展为进行性MVD，其特征为胶原纤维断裂 并被粘多糖和蛋白聚糖替代，导致小叶增厚和功能不全。 然而，促进进行性瓣叶退化的机制尚不清楚， 目前尚无可用于预防或逆转MVD进展的疗法。我们最近在小鼠 MVD模型，包括马凡氏综合征的Fbn1C1039G模型，涉及Wnt信号传导和髓样细胞凋亡。 进行性MVD中细胞浸润。在Fbn1中具有基因编辑突变的猪也表明 MFS的特征，包括二尖瓣瓣叶增厚。我们假设先天性ECM 异常导致瓣膜间质细胞（维克）中Wnt信号传导增加，导致细胞因子 表达和巨噬细胞浸润，这有助于病理性胶原重塑和瓣膜 MVD进展特征性功能障碍。目的：1）鉴定维克细胞亚系、巨噬细胞 群体，以及小鼠、猪和人MFS瓣膜中MVD的基因表达变化。2)确定是否 Fbn1C1039G瓣膜中的Wnt信号传导是ECM失调和粘液瘤性疾病进展所必需的 疾病3)确定浸润性巨噬细胞是否有助于ECM的致病进展 MFS中的重塑和粘液瘤性瓣膜病。这些研究的长期目标是定义 MVD进展中的调节途径，包括先天性瓣膜缺陷导致的MVD，以及 确定新的MVD非手术治疗方法。

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.