The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ Na_V1.5 Mutant of the Long QT Type 3 Syndrome

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Genetics of Cardiac Arrhythmias

Background:

• Type 3 Long QT Syndrome (LQT3) arises from gain-of-function mutations in the cardiac sodium channel (hNa_V1.5).
• Hesperetin (HSP), a citrus flavanone, was previously identified as a potential anti-arrhythmic agent for the LQT3-associated R1623Q mutation.
• The efficacy of HSP on other LQT3 variants, such as ΔKPQ, remains to be elucidated.

Purpose of the Study:

• To investigate the effects of hesperetin (HSP) on the ΔKPQ LQT3 hNa_V1.5 channel variant.
• To determine if HSP can mitigate the arrhythmogenic late sodium current (I_Na) in the ΔKPQ mutation.
• To assess the potential of HSP as a precision medicine therapeutic for specific LQT3 genotypes.

Main Methods:

• Whole-cell patch-clamp electrophysiology was employed to record sodium currents (I_Na).
• HEK293T cells expressing either wild-type or ΔKPQ mutant hNa_V1.5 channels were utilized.
• The effects of varying concentrations of HSP on peak and late I_Na were analyzed.

Main Results:

• Hesperetin (HSP) inhibited both peak and late sodium currents (I_Na) in ΔKPQ mutant channels with an IC50 of approximately 300 μM.
• HSP's inhibition was largely voltage-independent and tonic, decreasing the inactivation rate of ΔKPQ channels.
• HSP demonstrated limited efficacy in reducing intracellular sodium load for the ΔKPQ mutation.

Conclusions:

• Hesperetin (HSP) is not an adequate therapeutic agent for LQT3 associated with the ΔKPQ genetic variant.
• While HSP shows promise for the R1623Q LQT3 variant, its mechanism differs for the ΔKPQ mutation.
• These findings underscore the necessity of genotype-specific understanding for personalized treatment strategies in Long QT Syndrome.