Key result
Chronic exposure (2-48 hours) to certain IKr blockers like dofetilide generated arrhythmogenic afterdepolarizations and ≥15-fold increases in late sodium current via the PI3K pathway.
Some IKr blockers induce arrhythmias by augmenting late sodium current via the PI3K pathway after chronic exposure, indicating that acute IKr block screening is insufficient for detecting Torsades de Pointes liability.
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May warrant caution in relying solely on acute IKr screening; hypothesis-generating for chronic PI3K-mediated proarrhythmia in humans.
Yang et al. (2014) studied Torsades de Pointes Liability. IKr blockers (e.g., dofetilide) vs. Acute exposure was evaluated on Late sodium current (INa-L) and arrhythmogenic afterdepolarizations. Chronic exposure (2-48 hours) to certain IKr blockers like dofetilide generated arrhythmogenic afterdepolarizations and ≥15-fold increases in late sodium current via the PI3K pathway.
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