Unexpected impairment of I_Na underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome.

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_V1.2 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 assess

SUBMITTER: Porta-Sanchez A 

PROVIDER: S-EPMC11041658 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature