Background
Pathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the
case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies
as well as bilateral stellate ganglionectomy. The patient’s novel variant, p.F1760C-SCN5A,
involves a critical residue of the Nav1.5’s local anesthetic binding domain.
Objective
The purpose of this study was to characterize functionally the p.F1760C-SCN5A variant
using TSA-201 and patient-specific induced pluripotent stem cell–derived cardiomyocytes
(iPSC-CMs).
Methods
Whole-cell patch clamp was used to assess p.F1760C-SCN5A associated sodium currents
with/without lidocaine (Lido), flecainide, and phenytoin (PHT) in TSA-201 cells. p.F1760C-SCN5A
and CRISPR-Cas9 variant-corrected isogenic control (IC) iPSC-CMs were generated. FluoVolt
voltage dye was used to measure the action potential duration (APD) with/without mexiletine
or PHT.
Results
V1/2 of inactivation was right-shifted significantly in F1760C cells (–72.2 ± 0.7 mV)
compared to wild-type (WT) cells (–86.3 ± 0.9 mV; P <.0001) resulting in a marked increase in window current. F1760C increased sodium
late current 2-fold from 0.18% ± 0.04% of peak in WT to 0.49% ± 0.07% of peak in F1760C
(P = .0005). Baseline APD to 90% repolarization (APD90) was increased markedly in F1760C iPSC-CMs (601 ± 4 ms) compared to IC iPSC-CMs (423
± 15 ms; P <.0001). However, 4-hour treatment with 10 μM mexiletine failed to shorten APD90, and treatment with 5μM PHT significantly decreased APD90 of F1760C iPSC-CMs (453 ± 6 ms; P <.0001).
Conclusion
PHT rescued electrophysiological phenotype and APD of a novel p.F1760C-SCN5A variant.
The antiepileptic drug PHT may be an effective alternative therapeutic for the treatment
of LQT3, especially for variants that disrupt the Lido/mexiletine binding site.
Keywords
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Article info
Publication history
Published online: January 30, 2023
Publication stage
In Press Journal Pre-ProofFootnotes
Funding Sources: This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
Disclosures: Dr Ackerman is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics; however, none of these entities have contributed to this study in any manner. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- Variant-specific therapy for long QT syndrome type 3Heart Rhythm
- PreviewCongenital long QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome characterized by a prolonged QT interval on the electrocardiogram.1 Long QT syndrome type 3 (LQT3) is caused by gain-of-function variants in the SCN5A-encoded α-subunit of the voltage-gated cardiac sodium (Na+) channel Nav1.5. LQT3-linked SCN5A variants typically interfere with fast inactivation of the channel, which causes increased sustained inward Na+ current (INa) and prolongation of the cardiac action potential.2 In addition, some variants such as p.D1790G can prolong the ventricular action potential in the absence of an LQT3 variant-induced sustained Na+ current.
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