Overexpression of SCN5A in mouse heart mimics human syndrome of enhanced atrioventricular nodal conduction

Gong Xin Liu; Carol Ann Remme; Bastiaan J Boukens; Luiz Belardinelli; Sridharan Rajamani

doi:10.1016/j.hrthm.2015.01.029

Overexpression of SCN5A in mouse heart mimics human syndrome of enhanced atrioventricular nodal conduction

Heart Rhythm. 2015 May;12(5):1036-45. doi: 10.1016/j.hrthm.2015.01.029. Epub 2015 Jan 23.

Authors

Gong Xin Liu¹, Carol Ann Remme², Bastiaan J Boukens³, Luiz Belardinelli¹, Sridharan Rajamani⁴

Affiliations

¹ Department of Biology, Gilead Sciences, Fremont, California.
² Department of Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
³ Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
⁴ Department of Biology, Gilead Sciences, Fremont, California. Electronic address: Sridharan.Rajamani@gilead.com.

PMID: 25623181
DOI: 10.1016/j.hrthm.2015.01.029

Abstract

Background: In enhanced atrioventricular (A-V) nodal conduction (EAVNC) syndrome, patients have short A-V conduction times. Multiple mechanisms have been proposed to explain EAVNC; however, the electrophysiological or molecular substrate responsible for it remains unclear.

Objective: The purpose of this study was to test the hypothesis that overexpression of SCN5A in the mouse heart may provide an animal model mimicking EAVNC.

Methods: Electrocardiogram, atrial, His bundle, and ventricular electrograms were recorded from wild-type (WT) and transgenic (TG) mice overexpressing human SCN5A. The sodium current and NaV1.5 expression were measured using patch-clamp and immunohistochemistry techniques.

Results: The P-R interval in TG mice (13.6 ± 1.2 ms) was much shorter than that in WT mice (40.2 ± 0.59 ms). In TG isolated hearts, the A-V conduction time (14.4 ± 0.81 ms) during right atrial pacing was also shorter than that in WT hearts (39.5 ± 0.62 ms). Records of His bundle electrograms revealed that atrial-to-His and His-to-ventricular intervals were shorter in TG than in WT hearts. In addition, TG hearts had a shorter Wenckebach cycle length and A-V effective refractory period. The sodium current was 2-fold greater in TG ventricular myocytes than in WT ventricular myocytes. Flecainide prolonged the A-V conduction time in TG hearts to a value close to that in WT hearts. Nifedipine prolonged the atrial-to-His interval in WT hearts but not in TG hearts. Immunohistochemistry studies revealed increased NaV1.5 labeling in TG atrial and ventricular tissues, and NaV1.5 expression in A-V junction and A-V ring regions in TG hearts.

Conclusion: Enhanced A-V conduction in mice overexpressing SCN5A in the heart mimics the human syndrome of EAVNC. Thus, variants in sodium channel expression in the A-V nodal region may be an electrophysiological substrate responsible for EAVNC.

Keywords: Animal model; Enhanced atrioventricular nodal conduction; SCN5A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Animals
Anti-Arrhythmia Agents / pharmacology*
Arrhythmias, Cardiac / genetics
Atrioventricular Node* / drug effects
Atrioventricular Node* / physiopathology
Brugada Syndrome
Cardiac Conduction System Disease
Electrocardiography / methods
Heart Atria / physiopathology*
Heart Conduction System / abnormalities
Heart Ventricles / physiopathology
Mice
Mice, Transgenic
NAV1.5 Voltage-Gated Sodium Channel / genetics*

Substances

Anti-Arrhythmia Agents
NAV1.5 Voltage-Gated Sodium Channel
Scn5a protein, mouse