Late I Na activation of cardiac TTX-sensitive sodium channels by AaH-II induces an arrhythmogenic phenotype
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Aims
Late sodium current (I NaL ) is a key contributor to cardiac arrhythmias, but its precise origin and arrhythmogenic potential from tetrodotoxin-sensitive (TTX-S) sodium (Na v ) channels remain unclear. While the FDA-endorsed toxin ATX-II has been widely used to model I NaL -associated arrhythmogenesis, it lacks selectivity, limiting its utility in dissecting the roles of individual Na v channel subtypes. This study investigates the proarrhythmic impact of TTX-S Na v channel activation using AaH-II*, a scorpion venom-derived peptide with selective efficacy for TTX-S channels.
Methods and Results
Using automated patch-clamp recordings, we characterized AaH-II* selectivity across human Na v isoforms and demonstrated potent, preferential activation of I NaL in hNa v 1.1, 1.2, 1.3, and 1.6 over the TTX-resistant cardiac isoform hNa v 1.5. Calcium imaging in isolated adult rat cardiomyocytes showed that low nanomolar concentrations of AaH-II* induced spontaneous calcium release events and arrhythmogenic calcium transients, even in the absence of Na v 1.5 activation. Ex vivo multielectrode array recordings in Langendorff-perfused rat hearts confirmed dose-dependent ventricular conduction slowing, prolonged repolarization, and increased arrhythmia burden, all mitigated by TTX. In vivo , intravenous AaH-II* administration in rats elicited QTc prolongation, atrioventricular block, and ventricular tachyarrhythmias, which were significantly suppressed by TTX pretreatment.
Conclusion
We identify AaH-II* as a powerful and selective tool to study I NaL from TTX-S Na v channels in cardiac tissue. Our findings reveal that TTX-S channel-mediated I NaL alone is sufficient to induce arrhythmias and that pharmacological inhibition of these channels offers a promising antiarrhythmic strategy. These results advocate for broader consideration of TTX-S Na v channels as targets in arrhythmia research and drug safety screening.
