Origins and Burden of Multi-Organ Fibrosis in Patients with Single Ventricle Heart Disease

Elizabeth Goldmuntz, MD, FAAP, FACC and Jack Rychik, MD, Children’s Hospital of Philadelphia

Award Type: Innovation Fund

Abstract: Given medical and surgical advances, the majority of newborns presenting with single ventricle physiology now survive to early adulthood after staged surgical palliation to the Fontan circulation (FC).  However, time has shown that the ever-growing population with single ventricle disease (SVD) develops significant complications that impact morbidity and contribute to early mortality. Excessive cardiac and multi-organ fibrosis as a systemic process is likely an important contributor. The SVD population is exposed to multiple stimuli known to promote fibrogenesis including chronic hypoxia, and in the heart, pressure and volume loads. Additional mechanisms that promote fibrogenesis in other disease states, such as dysregulation of the renin-angiotensin-aldosterone (RAA) system and serotonin receptor signaling, may also contribute in the SVD population. Given notable variability in clinical outcomes, genetic variability that modifies individual response to clinical stressors likely plays an important role. Unfortunately, the underlying mechanisms of dysregulated fibrogenesis are poorly understood and we are unable to identify those at highest risk based on genetic or biochemical profiles.  Our goal is to identify genetic factors and biological mechanisms underlying this deleterious process so that the at-risk population can be identified and targeted therapeutics provided to prevent or reverse dysregulated fibrogenesis and preserve organ function. Specifically, we hypothesize that: (1) common and rare genetic variants within pathways regulating fibrogenesis contribute to individual risk, and (2) genotype and biomarker profiles will identify the SVD population at risk for mechanisms of dysregulated fibrogenesis, allowing for personalized, targeted therapeutics. To begin to identify the genetic and biological mechanisms underlying organ fibrogenesis, we will: (1) leverage a previously ascertained SVD cohort to test the association of genetic variants with myocardial fibrotic load as determined by cardiac MRI (CMR), and (2) prospectively enroll patients with SVD to better characterize multiorgan (heart, liver, kidney) fibrosis by MRI and serum biomarkers.

Shunt Audio Characteristics in Single Ventricle Infants as a Noninvasive Measure of Pulmonary Bloodflow

Saidie Rodriguez MD (other contributors: Camille Johnson, Goktug Ozmen, Omer Inan, PhD), Emory SOM and GaTech

Award Type: Innovation Fund

Abstract: Single ventricle infants with inadequate pulmonary blood flow require a systemic to pulmonary artery connection, (shunt) as initial palliation. When a patient is hypoxemic, shunt obstruction is among the differential diagnosis entertained with a high incidence of unplanned intervention. Current modalities to evaluate shunt function have limitations. There is a compelling need to innovate a noninvasive diagnostic tool to quantify the auditory characteristics of blood flow through shunts and could be done using a digital stethoscope combined with machine learning algorithms. We aim to 1) Establish audio characteristics of shunts correlating to a well-balanced circulation using various clinical parameters, and 2) Combine an acoustic signature with machine learning algorithms to improve detection of inadequate pulmonary bloodflow through the shunt.