Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome
Andreu Porta‐Sánchez, Andrea Mazzanti, Carmen Tarifa, Deni Kukavica, Alessandro Trancuccio, Muhammad Mohsin, Elisa Zanfrini, Andrea Perota, Roberto Duchi, Kevin Hernández-López, Miguel E. Jáuregui-Abularach, Valerio Pergola, Eugenio Fernández, Rossana Bongianino, Elisa Tavazzani, Patrick Gambelli, Mirella Memmi, Simone Scacchi, Luca F. Pavarino, Piero Colli Franzone, Giovanni Lentini, David Filgueiras‐Rama, Cesare Galli, Demetrio J. Santiago, Silvia G. Priori
Abstract
Abstract Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C , known to impair Ca V 1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca 2+ overload and decreased peak I Na current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.