Future of Single Ventricle: Computational, Cellular, and Animal Models


The Congenital Heart Disease Cardiac Atlas Project

Andrew D. McCulloch, PhD, Shu Chien Chancellor’s Endowed Chair in Engineering and Medicine at the University of California San Diego and Director of the Institute for Engineering in Medicine

Abstract: The Cardiac Atlas Project uses computational modeling and machine learning to quantify and understand the wealth of structural and functional information available in cardiac magnetic resonance (CMR) imaging exams. By building statistical atlases that characterize the variation across populations and patient cohorts we are discovering new anatomical and functional features in CMR exams from adults and children with congenital heart diseases including tricuspid atresia and hypertrophic left heart syndrome with Fontan physiology and tetralogy of Fallot. By using mechanistic multiscale computational models, we can predict how structural defects contribute to functional impairment and arrhythmia risk. 

Mechanoregulation of fetal ventricular growth and maturation: emergence & complexity

Jonathan T. Butcher, PhD, Professor and Associate Director of the Nancy E. and Peter C. Meinig School of Biomedical Engineering at Cornell University

Abstract: Proper ventricular morphogenesis in humans requires the creation of bilaterally symmetric muscular pumping chambers, with trabeculated and compact domains, the latter with embedded conduction and vascular networks. Precise location and sizing of these domains is critical for gestational progression as each contributes vitally to the mechanical performance of the ensemble while sustaining further growth and maturation. While much is understood about mechanisms of early cardiogenesis, it is defects in later stages of growth and maturation that result in clinically serious malformations. While genetic manipulation has generated considerable insight into the contributions of individual cell lineages into cardiac formation, recent evidence elevates the potential that conditional signaling drives later growth and maturation events, in particular through sensation and response to their local hemodynamic environment. Our research group has developed novel experimental, imaging, and computational simulation technology to quantitatively monitor and perturb the environment of the fetal heart, using the chick animal model system. We have identified novel mechanically operated molecular switches that potentiate between growth and maturation motifs. Further, employing high resolution single cell and spatial RNA sequencing, we have further uncovered marked spatiotemporal differences in local cellular phenotype composition and signaling programs, which support local cellular composition as a previously unrecognized regulatory strategy for achieving structural heterogeneity. We here present some evidence towards this hypothesis as it relates to our efforts to understand and counteract mechanisms of ventricular malformation. 


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