Sodium Channel Loss of Function Sensitizes Conduction to Changes in Extracellular Sodium Concentration

Sudden cardiac death is largely attributable to sudden onset ventricular arrhythmias. Alterations in cardiac conduction, particularly the slowing of conduction velocity is one major factor in arrhythmogenesis. By understanding the mechanisms and factors that modulate cardiac conduction velocity, we can assess and perhaps mitigate the risk of arrhythmia in patients for whom slowed conduction is a arrhythmogenic substrate. Cardiac conduction has traditionally been described by cable theory, which predicts an inverse relationship between extracellular resistance and conduction velocity (CV). However, in studies that reduce extracellular resistance by inducing interstitial edema, there are conflicting results, with some labs showing increased CV when edema is induced with one agent, and others showing reduced CV when edema is induced with a different agent. In the first part of this dissertation, we present experimental data in support of ephaptic coupling (EpC), a theorized mechanism of conduction that resolves these apparent contradictions. In the later part of this dissertation, we address how changes in sodium concentration can alter conduction, despite conventional wisdom suggesting that it should not. We show that when sodium channels are impaired, such as by genetic mutation or pharmacologic blockade, that conduction is sensitized to changes in sodium concentrations that would not otherwise induce changes in CV. We go on to explore the mechanisms that modulate this sensitivity and present data that show it is a function of both EpC and outward potassium currents. Taken together, these data expand our understanding of the mechanics behind cardiac conduction and demonstrate that EpC has a clinically relevant impact on conduction and represents a new pathway to explore in regard to the treatment and management of arrhythmogenic and conduction disorders.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Translational Biology, Medicine and Health

Department dc:contributor.department

Graduate School

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2024

Author dc:creator

• Adams, William Patrick

Chair dc:contributor.committeechair

• Poelzing, Steven

Committee members dc:contributor.committeemember

• Gourdie, Robert G.
• Lahmers, Sunshine M.
• Swanger, Sharon Ann

• Perinexus
• Intercalated Disc
• Cardiac Conduction
• Electrophysiology
• Ephaptic Coupling
• Flecainide
• Channel Loss of Function

Statement dc:rights

• Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc-sa/4.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:41005

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/119281