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

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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.