Flow Disturbances and the Development of Endocardial Fibroelastosis

先天性心脏病是发生在8：1000活产中最常见的出生缺陷，也是与出生缺陷相关的死亡的主要原因。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改变，这些改变影响胎儿和出生后单侧或双侧脑室的正常生长和发育。血流对胎儿心脏和出生后心脏的结构发育有重要影响。通过机械干预修复瓣膜和恢复血流，一些结构性缺陷可以解决，但还有其他潜在的治疗其他病理，如存在厚厚的细胞纤维弹性组织，称为心内膜纤维弹力纤维增生症(EFE)。据报道，EFE存在于几种心脏疾病中，如心肌病、感染性疾病、免疫学疾病，尤其是左心发育不良综合征(HLHS)。严重的情况下，整个左心室被这层白色的厚厚的纤维组织覆盖。在所有HLHS患者中，多达70%的患者EFE限制了左心室流出道(LVOT)，手术切除EFE组织被发现是有益的，可以进行根治性修复，但复发很常见。根据目前对EFE的认识和方法，有必要采用一种新的方法来治疗EFE，以改善受这种情况影响的儿童的生活质量。血液流动产生的生物力能影响心内膜细胞的结构和功能，并导致EFE的形成。最近发表的一份报告首次将血流扰动等机械力与EFE的发生联系起来，并确定内皮细胞到间充质细胞的转变(EndMT)是潜在的机制。随着药物干预靶点的确定，这项提议的目标现在是建立触发EndMT介导的EFE形成和进展的血流动力学力量，并识别协调病理生理相关基因表达模式的转录调控化合物，以便靶向EndMT。目的I：建立血流动力改变与EFE进展之间的因果关系。目的：通过4D-MRI研究EFE患者局部EFE形态与血流动力学改变之间的关系。

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.