Acute Imposition of Fontan Physiology in The Single Ventricle Patient: Effects on Fibrosis, Function and Drug Intervention

项目总结/摘要 先天性心脏病（CHD）使0.8-1%的活产并发症，并且是2010年死亡的主要原因之一。 孩子那些出生时只有一个泵室，一个单一的心室（SV），是最容易发病， 死亡率，消耗大量和不成比例的医疗资源。这些婴儿存活下来， 成年后，一系列姑息性心脏手术，最终在丰唐手术。近85%的 那些接受Fontan手术的人在手术后活了30年，估计有60，000人 患者生活在今天不幸的是，他们遭受多种并发症，如肝纤维化，淋巴结转移， 充血和蛋白质丢失性肠病等等。此外，该疾病的独特病理生理学 Fontan循环本身可能因多种原因（如一个泵室）而导致心脏纤维化和衰竭 做两个人的工作）。虽然描述临床状态的研究正在年龄较大的儿童中进行， 对于年轻人来说，这些并发症的发生仍不清楚。这一建议试图填补的知识空白 是了解肝脏和心脏纤维化的起点以及淋巴异常沿着 它们之间的相互作用，通过评估这些之前，以及相对较早后，实施丰唐 流通此外，将进行抗纤维化药物螺内酯的试点试验，以确定是否 这种方法可以减少纤维化，如果磁共振成像（MRI）可以辨别这种差异。 本研究的目的是通过非侵入性手段表征急性肝纤维化的后果， Fontan血流动力学的施加，并研究肝脏和心脏纤维化之间的相互关系， 血液动力学异常和淋巴充血。安体舒通的试点试验将决定 是否可以减轻SV患者的纤维化以及MRI是否可以辨别这种差异。的 血清生物标志物和MRI的组合形成了一个强大的非侵入性工具， 复杂的器官功能障碍在Fontan手术之前，一年，两年，可能三年后， 儿童将接受MRI检查，以评估肝脏和心脏纤维化、心室功能和流量以及淋巴 考核将探讨所有这些指标之间的相互关系。 现在，Fontan死亡率在过去20年中显著下降， 调查纤维化损伤，以改善终身福祉。这项研究意义重大，因为它 旨在了解如何减轻发病率，因为这些儿童进入他们的成年年， Fontan血流动力学的施加如何在其最早阶段发挥作用，以及 螺内酯给药对这种生理学的影响，确定MRI是否可以辨别这种差异。

Project Summary/Abstract Congenital heart disease (CHD) complicates 0.8–1% of live births and is one of leading causes of death in children. Those born with only one pumping chamber, a single ventricle (SV), are most prone to morbidity and mortality, consuming a significant and disproportionate amount of medical resources. These infants survive to adulthood following a series of palliative heart operations culminating in the Fontan operation. Nearly 85% of those undergoing the Fontan operation are alive up to 30 years after surgery with an estimated 60,000 such patients living today. Unfortunately, they suffer multiple complications such as liver fibrosis, lymphatic congestion and protein loosing enteropathy to name a few. In addition, the unique pathophysiology of the Fontan circulation may itself cause cardiac fibrosis and failure for many reasons (eg one pumping chamber performing the work of two). While studies describing the clinical state are taking place in older children and young adults, the onset of these complications remains unclear. The knowledge gap this proposal seeks to fill is understanding the starting point of liver and cardiac fibrosis as well as lymphatic abnormalities along with the interplay between them by assessing these before as well as relatively early after imposition of the Fontan circulation. In addition, a pilot trial of the antifibrotic agent spironolactone will be undertaken to determine if this approach could decrease fibrosis and if magnetic resonance imaging (MRI) can discern this difference. The purpose of this study is to characterize by non-invasive means the fibrotic consequences of the acute imposition of Fontan hemodynamics, and to investigate the interrelationship between liver and cardiac fibrosis, abnormal hemodynamics and lymphatic congestion. The pilot trial of spironolactone will determine mechanistically whether it can mitigate fibrosis in SV patients and if MRI can discern this difference. The combination of serum biomarkers and MRI form a powerful non-invasive tool in putting together the complicated web of organ dysfunction. Prior to, one, two and possibly three years after Fontan operation, children will undergo MRI to assess liver and cardiac fibrosis, ventricular function and flows and lymphatic assessment. The interrelationship between all these metrics will be explored. Now that Fontan mortality has markedly decreased over the past 20 years, it’s imperative to investigate fibrotic insults in order to improve lifelong well-being. This study is significant because it aims to understand how to alleviate morbidity as these children enter their adult years by appreciating how the imposition of Fontan hemodynamics plays a role in its earliest stage and the effects of spironolactone administration on this physiology, determining if MRI can discern this difference.