Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade

• DOI: 10.1016/j.jacbts.2023.07.008
• Publication Date: 2023-09-27T18:05:41Z
• Authors: Qixin Yang; Hanna J. Tadros; Bo Sun; Minu-Tshyeto Bidz...; Jordan E. Ezekian; Feng Li; Andreas Ludwig; Xander H.T. Wehrens; Andrew P. Landstrom

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.