JACC Basic to Translational Science · 2023 · 11 citations · 26 references
MedicineCardiologyPharmacologyCell SignalingElectrophysiologyGene ExpressionCalcium SignalingCardiac ArrhythmiasCardiac Ion ChannelsIntracellular Calcium SignalingIon Channel PharmacologyJunctional SignalingArrhythmogenic MechanismsCa2+ SignalingCalcium SparksCardiac Ion Channel RegulationIn Vivo StudiesRyanodine Receptor RegulationRyanodine Receptor SignalingRyanodine Receptors
Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)–mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a novel in vivo model of JET, Hcn4:shJph2 mice demonstrated rapid conversion of JET to sinus rhythm with infusion of EL20. Primary atrioventricular nodal cells demonstrated increased Ca2+ transient oscillation frequency and increased RyR2-mediated stored Ca2+ leak which was normalized by EL20. EL20 was found to be rapidly degraded in mouse and human plasma, making it a potential novel therapy for JET.
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