Flow Disturbances and the Development of Endocardial Fibroelastosis

先天性心脏缺陷是最常见的出生缺陷，发生率为8：1000活产婴儿，是出生缺陷相关死亡的主要原因。大多数先天性心脏病的基本共性是结构改变和血流动力学变化，影响胎儿和出生后期间一个或两个心室的正常生长和发育。血流对胎儿心脏的结构发育和出生后有重要影响。通过修复瓣膜和恢复血流的机械干预，可以解决几种结构缺陷，但还有治疗其他病理的可能性，例如存在厚层细胞纤维弹性组织，称为内膜弹力纤维增生症（EFE）。EFE的存在已被报道在一些心脏疾病，如心肌病，感染性疾病，免疫性疾病和最严重的左心发育不良综合征（HLHS）。在严重的情况下，整个左心室都衬有这层白色厚纤维化组织。在高达70%的HLHS患者中，EFE限制了左心室流出道（LVOT），手术切除EFE组织是有益的，可以进行治愈性修复，但复发是常见的。根据目前对EFE的理解和方法，有必要采用一种治疗EFE的新方法来改善受这种疾病影响的儿童的生活质量。由流动的血液产生的生物力学力可以影响内皮细胞的结构和功能，并诱导导致EFE形成的改变。最近发表的一份报告首次将机械力（如流动扰动）与EFE发展联系起来，并将内皮-间质转化（EndMT）确定为潜在机制。随着药理学干预的目标确定，这个建议的目标是建立血流动力学的力量，触发EndMT介导的EFE的形成和发展，并确定化合物的转录调控，编排的模式表达的病理生理相关的基因，以靶向EndMT。目的I：建立血流动力学改变与EFE进展的因果关系。目的II：通过4D-MRI将EFE患者的局部EFE形成与血流动力学改变相关联。

Congenital heart defects are the most common birth defects occurring in 8:1000 live births and are the leading cause of birth defect-related deaths. The underlying commonality of most congenital heart defects are structural alterations and hemodynamic changes which affect normal growth and development of one or both ventricles during the fetal and postnatal period. Blood flow has a major influence on the structural development of the fetal heart and postnatally. With mechanical interventions for repairing of valves and restoring blood flow, several structural defects can be addressed, but there is additional potential to treat other pathologies such as the presence of a thick layer of cellular fibro-elastic tissue, termed endocardial fibroelastosis (EFE). The presence of EFE has been reported in several cardiac diseases such as cardiomyopathies, infectious diseases, immunologic diseases and most severely in hypoplastic left heart syndrome (HLHS). In severe cases, the entire left ventricle is lined with this white layer of thick fibrotic tissue. In up to 70% of all HLHS patients, EFE restricts the left ventricular outflow tract (LVOT) and surgical removal of EFE tissue has been found to be beneficial, allowing for curative repairs, however, recurrence is common.Based on the current understanding and approach towards EFE, a novel approach in the treatment of EFE is warranted to improve the quality of life for children affected by this condition. Biomechanical forces generated by flowing blood can influence the structure and function of endocardial cells and induce alterations leading to EFE formation. For the first time, a recently published report associates mechanical forces such as flow disturbances with EFE development and identifies endothelial-to-mesenchymal transition (EndMT) as underlying mechanism. With a target amenable to pharmacological intervention identified, the goal of this proposal is now to establish the hemodynamic forces that trigger EndMT-mediated EFE formation and progression, and to identify compounds of transcriptional regulation that orchestrate the pattern of expression of pathophysiologically relevant genes, in order to target EndMT. AIM I: To establish the causative relationship of altered hemodynamic forces and EFE progression. AIM II: To correlate localized EFE formation with hemodynamic alterations in patients with EFE through 4D-MRI.