Neuronal Nav1.8 Channels as a Novel Therapeutic Target of Acute Atrial Fibrillation Prevention.
Ganglionated plexus have been developed as additional ablation targets to improve the outcome of atrial fibrillation (AF) besides pulmonary vein isolation. Recent studies implicated an intimate relationship between neuronal sodium channel Nav1.8 (encoded by SCN10A) and AF. The underlying mechanism between Nav1.8 and AF remains unclear. This study aimed to determine the role of Nav1.8 in cardiac electrophysiology in an acute AF model and explore possible therapeutic targets.



Immunohistochemical study was used on canine cardiac ganglionated plexus. Both Nav1.5 and Nav1.8 were expressed in ganglionated plexus with canonical neuronal markers. Sixteen canines were randomly administered either saline or the Nav1.8 blocker A-803467. Electrophysiological study was compared between the 2 groups before and after 6-hour rapid atrial pacing. Compared with the control group, administration of A-803467 decreased the incidence of AF (87.5% versus 25.0%, P<0.05), shortened AF duration, and prolonged AF cycle length. A-803467 also significantly suppressed the decrease in the effective refractory period and the increase in effective refractory period dispersion and cumulative window of vulnerability caused by rapid atrial pacing in all recording sites. Patch clamp study was performed under 100 nmol/L A-803467 in TSA201 cells cotransfected with SCN10A-WT, SCN5A-WT, and SCN3B-WT. INa,Pwas reduced by 45.34% at -35 mV, and INa,Lby 68.57% at -20 mV. Evident fast inactivation, slow recovery, and use-dependent block were also discovered after applying the drug.



Our study demonstrates that Nav1.8 could exert its effect on electrophysiological characteristics through cardiac ganglionated plexus. It indicates that Nav1.8 is a novel target in understanding cardiac electrophysiology and SCN10A-related arrhythmias.
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
XiaoMeng
X
Chen
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China.
LiLei
L
Yu
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China.
ShaoBo
S
Shi
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China.
Hong
H
Jiang
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China.
CongXin
C
Huang
Masonic Medical Research Laboratory, Utica, NY.
Mayurika
M
Desai
Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
YiGang
Y
Li
Masonic Medical Research Laboratory, Utica, NY.
Hector
H
Barajas-Martinez
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, China dianah@mmrl.edu hudan0716@hotmail.com.|Masonic Medical Research Laboratory, Utica, NY.
Dan
D
Hu
D000208:Acute Disease; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000628:therapy; D004285:Dogs; D005663:Furans / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D007150:Immunohistochemistry; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D013997:Time Factors; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology; D062549:Voltage-Gated Sodium Channel beta-3 Subunit / Q000235:genetics
C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D061567:Voltage-Gated Sodium Channel Blockers; D062549:Voltage-Gated Sodium Channel beta-3 Subunit

SCN10A
; Nav1.8; atrial fibrillation; electrophysiology; ganglionated plexus