Abstract
Abstract 4142680: Functional Heterogeneity of Na V 1.5 in Mouse Heart
Circulation (New York, N.Y.), Vol.150(Suppl_1)
11/12/2024
DOI: 10.1161/circ.150.suppl_1.4142680
Abstract
Abstract only Introduction: The voltage-gated sodium channel Na V 1.5 controls cardiac excitability. The mechanisms by which loss of function Na V 1.5 mutations cause diverse pathogenic outcomes (Brugada syndrome, conduction disease, heart failure) are not fully resolved. The physiological significance of non-Na V 1.5 Na + channels in the heart is also uncertain. Methods: We engineered knock-in mice in which Na V 1.5 was modified to contain a high-affinity binding site for acylsulfonamide (GX) drugs, enabling a pharmacological strategy to drive nonconducting channel conformations. We used optical mapping (di-4 ANEPPS) of Langendorff-perfused WT (n=6) and homozygous GX/GX hearts (n=14) to investigate how selective Na V 1.5 blockade influences action potential (AP) propagation and arrhythmogenesis. Results: In the absence of the GX drug (GX-674) in sinus rhythm, action potential duration (APD; 71±7 vs. 68±10 ms), APD dispersion (13±5 vs. 12±3 ms), AP upstroke rise time (6±1 vs. 6±1 ms) and longitudinal (CVL, 0.71±0.16 vs. 0.85±0.16 m/s) and transverse conduction velocity (CVT, 0.43±0.11 vs. 0.49±0.1 m/s) were not statistically different between GX/GX and WT hearts. GX-674 application (0 ~ 300 nM) during optical mapping with S1S2 pacing resulted in loss of excitability (50% loss at 10 nM in GX/GX ; 0% loss up to 300 nM in WT) associated with an increase of AP upstroke rise time (10±3 vs. 5.4±0.5 ms) and conduction slowing mainly along the longitudinal direction (CVL=0.49±0.22 vs. 0.85±0.24 m/s); APD remained relatively stable (85±15 vs. 76±11 ms). The AP upstroke in GX/GX hearts often exhibited 2 steps (Fig-A), leading to frequent premature beats, reentry, and non-sustained ventricular tachycardia (Fig-B,C). The loss of excitability was heterogeneous, with sensitivity to GX-674 being higher in the right versus left ventricle (16% vs. 50% at 10 nM), Purkinje fibers and AV node (100% AV block at 100 nM), and atrial tissue (100% excitable at 100 nM but complete loss at 300 nM). Conclusion: Regional heterogeneities in Na V 1.5 function, along with Na + channels other than Na V 1.5, may contribute to cardiac conduction and arrhythmias in the mouse heart.
Details
- Title: Subtitle
- Abstract 4142680: Functional Heterogeneity of Na V 1.5 in Mouse Heart
- Creators
- Bum-rak Choi - Brown UniversityJason Dierdorff - University of Iowa, Internal MedicineColin Clark - University of IowaPeter Bronk - Brown UniversitySade Solola Nussbaum - Brown UniversityJin-Young Yoon - University of IowaHannah Choi - University of IowaHaider Mehdi - University of IowaChristopher Ahern - University of IowaBarry London - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.150(Suppl_1)
- DOI
- 10.1161/circ.150.suppl_1.4142680
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Language
- English
- Date published
- 11/12/2024
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984749558702771
Metrics
64 Record Views