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Open AccessArticle

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

Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, 3000 Leuven, Belgium
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Author to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 952; https://doi.org/10.3390/biom10060952
Received: 5 June 2020 / Revised: 19 June 2020 / Accepted: 21 June 2020 / Published: 24 June 2020
(This article belongs to the Special Issue Pharmacology of Medicinal Plants)
Type 3 long QT syndromes (LQT3) are associated with arrhythmogenic gain-of-function mutations in the cardiac voltage-gated Na+ channel (hNaV1.5). 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 hNaV1.5 channel mutant R1623Q. Here we investigated whether HSP also has potentially beneficial effects on another LQT3 hNaV1.5 channel variant, the ΔKPQ, which is associated to lethal ventricular arrhythmias. We used whole-cell patch-clamp to record Na+ currents (INa) in HEK293T cells transiently expressing hNaV1.5 wild type or ΔKPQ mutant channels. HSP blocked peak INa and the late INa 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. View Full-Text
Keywords: hesperetin; flavonoid; citrus; human cardiac Na+ channel; NaV1.5; genetic variant; mutant; long QT type 3 syndrome; ΔKPQ; precision medicine hesperetin; flavonoid; citrus; human cardiac Na+ channel; NaV1.5; genetic variant; mutant; long QT type 3 syndrome; ΔKPQ; precision medicine
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Alvarez-Collazo, J.; López-Requena, A.; Alvarez, J.L.; Talavera, K. The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaV1.5 Mutant of the Long QT Type 3 Syndrome. Biomolecules 2020, 10, 952.

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