| Autor: |
Ramos-Mondragon R; Department of Pharmacology and., Edokobi N; Department of Pharmacology and., Hodges SL; Department of Pharmacology and., Wang S; Department of Pharmacology and., Bouza AA; Department of Pharmacology and., Canugovi C; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Scheuing C; Department of Pharmacology and., Juratli L; Department of Pharmacology and., Abel WR; Department of Pharmacology and., Noujaim SF; Department of Molecular Pharmacology & Physiology, University of South Florida College of Medicine, Tampa, Florida, USA., Madamanchi NR; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Runge MS; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Lopez-Santiago LF; Department of Pharmacology and., Isom LL; Department of Pharmacology and.; Department of Neurology and.; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA. |
| Abstrakt: |
Loss-of-function (LOF) variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases. Scn1b-null mice have spontaneous seizures and ventricular arrhythmias and die by approximately 21 days after birth. β1/β1B Subunits play critical roles in regulating the excitability of ventricular cardiomyocytes and maintaining ventricular rhythmicity. However, whether they also regulate atrial excitability is unknown. We used neonatal Scn1b-null mice to model the effects of SCN1B LOF on atrial physiology in pediatric patients. Scn1b deletion resulted in altered expression of genes associated with atrial dysfunction. Scn1b-null hearts had a significant accumulation of atrial collagen, increased susceptibility to pacing induced atrial fibrillation (AF), sinoatrial node (SAN) dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the SAN. Atropine reduced the incidence of AF in null animals. Action potential duration was prolonged in null atrial myocytes, with increased late sodium current density and reduced L-type calcium current density. Scn1b LOF results in altered atrial structure 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. |
