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

单心室患者急性 Fontan 生理学治疗：对纤维化、功能和药物干预的影响

• 批准号: 10456136
• 负责人: Mark A Fogel
• 金额: $ 72.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456136
• 关键词: Acute; Adult; Affect; Aldosterone Antagonists; Biological Markers; Blood Circulation; Bronchitis; Cardiac; Cardiovascular system; Cause of Death; Child; Chronic; Clinical; Common Ventricle; Complex; Computer Models; Congestive; Consumption; Cyanosis; Dose; Evaluation; Evolution; Fibrosis; Fontan Procedure; Functional disorder; Growth; Heart; Heart failure; Hypertension; Infant; Internet; Intervention; Investigation; Knowledge; Lead; Life; Live Birth; Liver; Liver Fibrosis; Lung; Lymphatic; Lymphatic System; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Medical; Morbidity - disease rate; Names; Operative Surgical Procedures; Organ; Patients; Perfusion; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Pilot Projects; Play; Proteins; Pulmonary Circulation; Pump; Reporting; Resources; Role; Series; Serum; Spironolactone; Survivors; Venous; Ventricular Function; Work; antifibrotic treatment; body system; congenital heart disorder; coronary fibrosis; heart function; hemodynamics; improved; insight; liver function; lymphatic malformations; mortality; operation; palliative; pilot trial; prevent; repaired; response; tool; young adult

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.

项目概要/摘要 先天性心脏病 (CHD) 使 0.8-1% 的活产儿复杂化，是导致死亡的主要原因之一 孩子们。那些出生时只有一个泵室、单心室 (SV) 的人最容易发病，并且 死亡率，消耗大量且不成比例的医疗资源。这些婴儿存活下来 成年后接受了一系列姑息性心脏手术，最终进行了丰坦手术。近85%的 接受 Fontan 手术的患者在手术后可存活长达 30 年，估计有 60,000 名此类患者 活在今天的病人。不幸的是，他们患有多种并发症，如肝纤维化、淋巴管 充血和蛋白质丢失性肠病等等。此外，其独特的病理生理学 Fontan 循环本身可能会因多种原因导致心脏纤维化和衰竭（例如，一个泵室 执行两人的工作）。虽然描述临床状态的研究正在大龄儿童中进行， 对于年轻人来说，这些并发症的发病情况仍不清楚。该提案试图填补的知识空白 正在了解肝脏和心脏纤维化以及淋巴异常以及 通过在实施 Fontan 之前和之后相对较早的时间评估它们之间的相互作用 循环。此外，还将进行抗纤维化药物螺内酯的试点试验，以确定是否 如果磁共振成像 (MRI) 能够辨别这种差异，这种方法可以减少纤维化。 本研究的目的是通过非侵入性手段表征急性纤维化后果 施加 Fontan 血流动力学，并研究肝脏和心脏纤维化之间的相互关系， 血流动力学异常和淋巴充血。螺内酯的试点试验将确定 从机制上讲，它是否可以减轻 SV 患者的纤维化，以及 MRI 是否可以辨别这种差异。这 血清生物标志物和 MRI 的结合形成了一种强大的非侵入性工具，可以将 器官功能障碍的复杂网络。在 Fontan 手术后一年、两年甚至可能三年之前， 儿童将接受 MRI 评估肝脏和心脏纤维化、心室功能以及流量和淋巴管 评估。将探讨所有这些指标之间的相互关系。 既然过去 20 年来 Fontan 死亡率已显着下降，那么当务之急是 研究纤维化损伤以改善终生福祉。这项研究意义重大，因为它 旨在了解当这些儿童进入成年时如何通过欣赏来减轻发病率 Fontan 血流动力学的施加在其早期阶段如何发挥作用以及其效果 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。