Modeling ventricular hypoplasia in pulmonary atresia with intact ventricular septum (PA-IVS) using patient-specific induced pluripotent stem cells (iPSCs)

Mingtao Zhao, DVM, PhD and Vidu Garg, MD, Nationwide Children’s Hospital

Award Type: Innovation Fund

Abstract: Pulmonary atresia (PA) is a rare congenital heart defect (CHD) where the pulmonary valve that controls blood flow from the heart to the lungs does not properly develop. It is considered a critical CHD because surgical or catheter-based intervention is required soon after birth. In pulmonary atresia with intact ventricular septum (PA-IVS), the right ventricle (RV) does not fully develop because very little blood flows into or out of RV. PA-IVS is characterized by various degrees of RV hypoplasia and PA-IVS patients have long-term outcomes of single ventricle palliation (1v), 1 ½ ventricle palliation (1.5v), or bi-ventricular repair (2v). Mechanisms for the spectrum of RV hypoplasia in PA-IVS are unknown and difficult to fully ascribe to the absence of pulmonary valve. Currently, there are no reliable animal models to study the disease mechanisms of PA-IVS, further hindering the discovery of novel therapeutic treatments. In this study, we aim to elucidate the developmental mechanisms by which reduced biomechanical stretch suppresses cardiomyocyte proliferation and contributes to the RV hypoplasia found in PA-IVS patients. Our hypothesis is that reduced ventricular filling due to increased myocardial stiffness prevents embryonic cardiomyocyte proliferation and leads to the under development of RVs in PA-IVS patients. As human iPSC-derived cardiomyocytes (iPSC-CMs) are immature and resemble fetal-stage cardiomyocytes, we will employ PA-IVS patient-specific iPSC-CMs and engineered cyclic stretch to study how biomechanical forces alter the myocardial stiffness which further impacts early cardiomyocyte proliferation in PA-IVS.

The Genetics of Causes and Outcomes in SV CHD

Dr. Kim McBride, MD, Nationwide Children’s Hospital

Award Type: Innovation Fund

Abstract: The cause of  most SV CHD is not known, nor do we understand what influences the outcome. When there is an underlying genetic diagnosis, it is frequently made after many months, sometimes when complications or additional problems have surfaced. Making a diagnosis early can affect outcome and may give insight into the prognosis.  We will present how deep phenotyping and genome sequencing shortly after birth may impact care by early diagnosis.