Graduate Research Fellow University of Michigan Ann Arbor, Michigan
This abstract has been invited to present during the Better Patient Outcomes through Diversity Platform poster session This abstract has been invited to present during the Investigators Workshop Platform poster session This abstract is recognized by Partners Against Mortality in Epilepsy for its contribution to improving the understanding of epilepsy-related mortality
Rationale: Sudden Unexpected Death in Epilepsy (SUDEP) is the most devastating consequence of epilepsy, yet little is understood about its causes and no biomarkers exist to identify at risk patients. To gain insight into these critical issues, we are focusing on epilepsy syndromes with a high SUDEP incidence. Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases that predispose patients to sudden death, including early infantile epileptic encephalopathy type 52 (EIEE52, OMIM 617350), Brugada Syndrome 5 (OMIM 612838), and Atrial Fibrillation Familial 13 (OMIM 615377). β1/β1B subunits are multifunctional proteins that play critical roles in regulating the excitability of brain neurons and cardiac rhythmicity. The Scn1b null mouse model phenocopies EIEE52, with severe seizures and mortality by the third week of life. Consistent with evidence linking SCN1B variants to cardiac disease in humans, Scn1b null mice also have ventricular cardiac arrhythmias. However, whether Scn1b also regulates atrial cardiac excitability is unknown. Here, we investigated the effects of Scn1b deletion on atrial structure, function, and electrophysiology in neonatal mice. Methods: We analyzed P16-P17 Scn1b null mice using immunofluorescence, RNA-Sequencing, and invivo and invitro cardiac electrophysiology techniques to model the effects of SCN1B LOF variants on atrial physiology in human patients. Results: We found that Scn1b deletion results in the differential expression of several genes that are associated with atrial dysfunction. Scn1b null hearts have a significant accumulation of atrial collagen, increased susceptibility to pacing induced atrial fibrillation (AF) in vivo, sinoatrial node dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the sinoatrial node. Administration of atropine significantly reduced the incidence of AF in the null animals. Finally, we found prolonged action potential duration and increased late sodium current density, with no change in transient sodium current density, in null atrial myocytes compared to wildtype littermates. Conclusions: Scn1b LOF results in atrial remodeling and AF, demonstrating the critical role played by Scn1b in atrial physiology during early postnatal mouse development. Our results suggest that SCN1B LOF variants may significantly impact the developing pediatric heart in addition to the brain. These results, together with our work in other mouse models of sodium channelopathies, have led us to propose a neuro-cardiac mechanism for SUDEP. Funding: Please list any funding that was received in support of this abstract.: This work was supported by NIH R37-NS076752 to LLI, R01-HL139842 to MSR, F31HL144047 to AAB, predoctoral fellowships from T32-GM00776737 and T32-HL125242 to NE, and a predoctoral fellowship from T32-GM008322 to AAB. We acknowledge support from the University of Michigan Bioinformatics Core for analysis of RNA Seq and DNA Sequencing Core for library preparation and sequencing of samples of the University of Michigan Medical School’s Biomedical Research Core Facilities.