Do age-associated changes of voltage-gated sodium channel isoforms expressed in the mammalian heart predispose the elderly to atrial fibrillation?

Table 1 Properties of voltage-gated sodium channel isoforms

Voltage-gated sodium channel isoform	Tissue	Gene	Amino acid length	Activated	Inactivated	Associated β-subunit
Nav1.1	Brain	SCN1A	2009aa (human and rat)	-33 mV	-72 mV	β1, β2, β3, β4
Nav1.2	Brain	SCN2A	2005aa (human); 2006aa (rat)	-24 mV	-53 mV	β1, β2, β3, β4
Nav1.3	Brain	SCN3A	1951aa (human and rat)	-23 to -26 mV	-65 to -69 mV	β1 and β3
Nav1.4	Skeletal muscle	SCN4A	1836aa (human); 1840aa (rat)	-26 to -30 mV	-56 mV	β1
Nav1.5	Heart	SCN5A	2016aa (human); 1951aa (rat)	-47 mV	-84 mV	β1, β2, β3, β4
Nav1.6	Brain	SCN8A	1980aa (human); 1976aa (rat)	-37.7 mV	-98 mV	β1 and β2
Nav1.7	PNS	SCN9A	1977aa (human); 1984aa (rat)	-31 mV	-61 to -78 mV	β1 and β2
Nav1.8	PNS	SCN10A	1957aa (human)	-16 to -21 mV	-30 mV	Not established
Nav1.9	PNS	SCN11A	1792aa (human); 1765aa (rat)	-47 to -54 mV	-44 to -54 mV	Not established

Illustrating the standardised nomenclature, regional tissue where the isoform predominantly located, gene, amino acid length, activation and inactivation membrane potentials and associated beta subunits. PNS: Peripheral nervous system; aa: Amino acids; mV: millivolts. Adapted from Catterall et al[23], 2005, with permission.

Table 2 Summary of sodium channel blockers (class I antiarrhythmics)

Drug	Subclass	Pharmacological targets	Electrophysiological effects	Corresponding therapeutic mechanisms	Major clinical applications
Quinidine; ajmaline; disopyramide	Ia	Nav1.5 open state; intermediate dissociation kinetics; often concomitant K+ channel block	Reduction in peak INa, AP generation, increased excitation threshold; slowing of AP conduction in the atria, ventricles, and specialized conduction pathways; concomitant IK block increasing AP duration and refractory period, increase in QT interval	(1) Reduction in ectopic ventricular/atrial automaticity; (2) Reduction in accessory pathway conduction; and (3) Increase in refractory period decreasing re-entrant tendency	SVTs, recurrent AF, VT, VF
Lidocaine; mexiletine	Ib	Nav1.5 open state; rapid dissociation; window current	Reduction in peak INa, AP generation with increased excitation threshold; slowed AP conduction in the atria, ventricles and specialised ventricular conduction pathways; shortening of AP duration and refractory period in normal ventricular and Purkinje myocytes; prolongation of ERP, reduced window current in ischaemic, partially repolarised cells. Little ECG effect, slight QTc shortening	(1) Reduction in ectopic ventricular automaticity; (2) Reduction in DAD-induced triggered activity; and (3) Reduced re-entrant tendency by converting unidirectional to bidirectional block particularly In ischaemic, partially depolarised myocardium	VT and VF particularly after myocardial infarction
Propafenone; flecainide	Ic	Nav1.5 inactivated state; slow dissociation	Reduction in peak INa, AP generation with increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialised ventricular conduction pathways; reduced overall excitability; prolongation of APD at higher heart rates; increase in QRS duration	(1) Reduction in ectopic ventricular/atrial automaticity; (2) Reduction in DAD- induced triggered activity; and (3) Reduced re-entry tendency slowed conduction and reduced excitability particularly at rapid heart rates blocking re-entrant pathways showing depressed conduction	SVTs (atrial tachycardia, atrial flutter, AF, tachycardias involving Accessory pathways). Ventricular tachyarrhythmias resistant to other treatment in the absence of structural heart disease, premature ventricular contraction, catecholaminergic polymorphic VT
Ranolazine	Id	Nav1.5 late current.	Reduction in the late Na+ current, affection AP recovery, refractoriness, repolarisation reserve and QT interval	(1) Decrease in AP recovery time; and (2) Reduction in EAD-induced triggered activity	Stable angina, VT. A new class of drug for the management of atrial tachyarrhythmias

Highlighting subclassification, pharmacological targets, electrophysiological effects, therapeutic mechanisms and clinical applications. AP: Action potential; SVT: Supraventricular tachycardia; DAD: Delayed afterdepolarizations; EAD: Early afterdepolarizations; ERP: Effective refractory period. Adapted from Lei et al[76], 2018, with permission.