Abstract
Abstract 4371509: Long-term Flecainide Exposure Triggers Expression of Neuronal Sodium Channels in the Murine Heart
Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4371509-A4371509
11/04/2025
DOI: 10.1161/circ.152.suppl_3.4371509
Abstract
Introduction: Class IC antiarrhythmic agents are widely used to treat arrhythmias. However, in the CAST trial these drugs increased arrhythmic mortality in patients with recent myocardial infarction/systolic heart failure. Some of the underlying molecular mechanisms remain poorly understood.
Research Question: Does chronic exposure to flecainide promote electrical remodeling that is reflected in the sodium channel composition of the murine heart?
Methods: C57BL/6 mice, with or without engineered NaV1.5 sensitivity to acyl/arylsulfonamides (GX drugs) by knock-in (KI) of a chimeric SCN5A construct incorporating a GX drug binding site into VSD IV (GX mice), were treated with flecainide via drug pellets (20 mg/kg/day) for 21-28 days. Surface ECGs were recorded on days 0, 1, 3, 7, 14, and 21 in flecainide-treated (n > 11) and placebo (n = 2) mice. After 21 days, ventricular cardiomyocytes (CMs) were isolated via Langendorff perfusion and manually patch-clamped under voltage-clamp to measure sodium currents (INa). Isoform-specific toxins and small-molecule inhibitors were sequentially applied to identify different isoforms contributions to INa. GX-674 assessed NaV1.5 in GX mice and NaV1.2/1.6/1.7 in wild-type mice. μ-conotoxin GIIIB (NaV1.4), low-dose TTX (NaV1.1/1.3), and voltage sensitive toxin 3 (NaV1.8) probed other isoforms (n>8 all isoforms). Control data were obtained from untreated cardiomyocytes using the same protocols (n > 7).
Results: Flecainide treatment caused bradycardia and prolongation of the PR interval and QRS duration at day 1 compared to untreated mice (HR 483.0±60.7 vs. 598±33.9 BPM p<.05, PR 62.1±10.7 vs. 43.5±0.7 ms p<.01; QRS 28.2±6.4 vs 14.9±0.8 ms p<.0001). There were no EKG differences at day 3. Patch-clamp (Fig. 2) showed reduced NaV1.5 contributions in CMs from flecainide treated mice (75.9±10.4% vs 92.6±4.9%, p<.0001) with increased NaV1.1/1.3 (11.8±4.8% vs 0.4±0.2%, p<.0001) and NaV1.2/1.6/1.7 (9.0±6.3% vs 0.7±0.9%, P<.0005) contributions. There was no difference in NaV1.4 or NaV1.8/1.9 contributions.
Conclusions: Flecainide effectively treats arrhythmias but increases arrhythmic deaths in patients with structural heart disease/ischemia. We show that flecainide treatment increases the contributions of neuronal sodium channel isoforms to INa. These isoforms have distinct biophysical properties which may promote arrhythmogenesis, potentially explaining the adverse outcomes in the CAST trial and offering potential therapeutic strategies.
Details
- Title: Subtitle
- Abstract 4371509: Long-term Flecainide Exposure Triggers Expression of Neuronal Sodium Channels in the Murine Heart
- Creators
- Christian Anderson - University of IowaColin Clark - University of IowaJason Dierdorff - University of IowaAlex Dou - University of IowaHannah Choi - University of IowaChris Ahern - University of IowaBarry London - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.152(Suppl_3), pp.A4371509-A4371509
- DOI
- 10.1161/circ.152.suppl_3.4371509
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 11/04/2025
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9985024143702771
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