Mouse models of hypoplastic left heart syndrome (HLHS) reveal new targets for potential intervention
Authors: Lo Cecilia , Gabriel George 
Published: June 2021

Hypoplastic left heart syndrome (HLHS) is one of the most lethal congenital heart disease (CHD), with a 30% 5‐year mortality rate after surgical palliation. Patients can succumb to heart failure and among surviving patients, neurodevelopmental delay and neurobehavioral and neurocognitive disabilities are observed at a high prevalence. While hypoxia and hemodynamic disturbance related to the structural heart defect and from cardiopulmonary bypass surgical intervention are suggested as factors driving these poor outcomes, studies over the past decade indicate they are largely attributable to as yet unidentified patient intrinsic factors. The recent recovery of mouse models of HLHS has provided some insights into the nature of such intrinsic factors. Analysis of the HLHS mutant mice have revealed HLHS has a complex genetic architecture and is profoundly genetically heterogeneous. Detailed investigation of the Ohia HLHS mutant mouse line showed HLHS arises combinatorially from mutations in two genes, Sap130 – a chromatin modifying protein in the Sin3A HDAC repressor complex, and PchdhA9 ‐ a protocadherin mediating cell‐cell adhesion. While Sap130 drives the LV hypoplasia, Pcdha9 drives the aortic valve defects and can cause bicuspid aortic valve. These findings have been validated with the production and analysis of CRISPR gene targeted mice and zebrafish models.Analyses of CHD defects in Ohia mutant mice and the emergence of HLHS during embryonic/fetal development indicated the LV hypoplasia is not hemodynamically driven, but instead is associated with cell intrinsic defects involving mitotic cell cycle arrest. Interestingly, the Ohia mutant mice also showed forebrain abnormalities involving hypoplasia of the cerebral cortex, and dysplasia of the hippocampus, corpus callosum and cerebellum, brain structures also observed to be impacted in HLHS patients. Further analysis of a floxed Sap130 allele with Emx1‐Cre targeted forebrain‐specific deletion of Sap130 yielded viable adult mice with normal heart structure but with brain abnormalities that included microcephaly, similar to findings in the Ohia mutant fetuses. This was associated with cell intrinsic defects involving loss of neural progenitors. Brain MRI and neuronal fiber tractography with diffusion tensor imaging revealed extensive alterations in neural network connectivity. Behavioral assessments further showed learning and memory deficits. Together these findings suggest a shared genetic etiology for the heart and brain defects in HLHS. This likely is mediated by cell intrinsic defects, suggesting the need to shift the focus of therapeutic intervention from hemodynamic modulation to targeting the cell intrinsic deficits associated with HLHS. Only then will it be possible to achieve substantive improvement in cardiac and neurodevelopmental outcome for HLHS.Support or Funding InformationFunded by NIH Grants HL142788 and HL132024This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.