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Type 3 long QT syndromes (LQT3) are associated with arrhythmogenic gain-of-function mutations in the cardiac voltage-gated Na + channel (hNa V 1.5). The citrus flavanone hesperetin (HSP) was previously suggested as a template molecule to develop new anti-arrhythmic drugs, as it blocks slowly-inactivating currents carried by the LQT3-associated hNa V 1.5 channel mutant R1623Q. Here we investigated whether HSP also has potentially beneficial effects on another LQT3 hNa V 1.5 channel variant, the ΔKPQ, which is associated to lethal ventricular arrhythmias. We used whole-cell patch-clamp to record Na + currents (I Na ) in HEK293T cells transiently expressing hNa V 1.5 wild type or ΔKPQ mutant channels. HSP blocked peak I Na and the late I Na carried by ΔKPQ mutant channels with an effective concentration of ≈300 μM. This inhibition was largely voltage-independent and tonic. HSP decreased the rate of inactivation of ΔKPQ channels and, consequently, was relatively weak in reducing the intracellular Na + load in this mutation. We conclude that, although HSP has potential value for the treatment of the R1623Q LQT3 variant, this compound is inadequate to treat the LQT3 associated to the ΔKPQ genetic variant. Our results underscore the precision medicine rationale of better understanding the basic pathophysiological and pharmacological mechanisms to provide phenotype- genotype-directed individualization of treatment.

The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome