Background: Recently we have shown that neuronal Na+ channel (nNav) are an integral part of catecholaminergic polymorphic ventricular tachycardia (CPVT). With the advent of disorders manifesting combined CPVT and long QT (LQT) phenotypes, there is an increased interest in the cross-talk between aberrant Na+ and Ca2+ handling. However, the contribution of nNav to the LQT-promoted arrhythmias in CPVT is unknown.
Methods: To address this we used a mouse model with cardiac calsequestrin-associated CPVT where the Ca2+ influx was augmented with BayK8644 (BayK). We performed confocal microscopy to assess Ca2+ handling and simultaneously recorded action potentials (APs) during various pharmacological interventions.
Results: BayK (500nM) promoted aberrant Ca2+ release and AP prolongation on the cellular level and precipitated QT prolongation and ventricular tachycardias (VT) upon catecholamine challenge in vivo. Selective nNav inhibition with 4,9-anhydro-tetrodotoxin (4,9-ah-TTX; 300nM) had a negligible effect on BayK-promoted AP as well as QT prolongation in vivo. Despite this, 4,9-ah-TTX reduced arrhythmia burden both on the cellular level as well as in CPVT mice exposed to BayK and a catecholamine challenge.
Conclusion: These data suggest that aberrant Ca2+ handling evidenced during exposure to BayK promotes aberrant Na+/Ca2+ signaling through nNav. Furthermore, arrhythmia frequency in BayK-exposed CPVT animals treated with 4,9-ah-TTX was strikingly reduced, providing strong support for nNav inhibition is a viable antiarrhythmic strategy.