The Relationship between Ephaptic Coupling and Excitability in Ventricular Myocardium

Introduction: Excitability in cardiomyocytes is dependent on the subthreshold current required to raise transmembrane potential to the activation threshold and subsequent recruitment of voltage gated sodium channels to trigger an action potential. Conduction in cardiomyocytes is dependent on the robustness and speed of action potential propagating through tissue. Both are equally important for normal heart function and claim to be linear correlated (i.e if conduction decreases, excitability decreases) Cardiac sodium channels are densely expressed in the intercalated disc within the perinexus, which is two orders of magnitude narrower than bulk extracellular interstitium. The biphasic relationship between conduction and perinexus is well-researched and consistent between computations models. We hypothesized a biphasic relationship between Excitability and perinexal width (Wp). In addition, we hypothesize that the relationship between excitability and conduction is not linear but dependent on the original width of the perinexus. Methods/and Results: Ex vivo guinea pig hearts were epicardially paced and optically mapped to assess ventricular conduction and excitability. Strength-duration curves were constructed for pacing stimuli to measure rheobase (inversely correlated to excitability). Computation models incorporating ephaptic coupling and sodium channel localization to cleft widths between cardiomyocytes demonstrate these findings. Conclusion: Models and experiments reveal that the excitability and perinexus relationship is biphasic where narrowing and widening perinexus decreases conduction and excitability thus showing a linear relationship between excitability and conduction. However, the excitability and conduction become overly complex in the transition phase from release of self-attenuation to reduced self-activation. Therefore, targeting ephaptic coupling and monitoring plasma ions may be a novel strategy for increasing the efficacy and efficiency of cardiac pacemakers.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biomedical Engineering

Department dc:contributor.department

Department of Biomedical Engineering and Mechanics

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2022

Author dc:creator

• Colucci-Chang, Katrina

Chair dc:contributor.committeechair

• Poelzing, Steven

Committee members dc:contributor.committeemember

• Gourdie, Robert G.
• Campbell, Susan
• Chappell, John Christopher
• Huckle, William R.

• Cardiac
• Conduction
• Excitability
• Ephaptic Coupling

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:34904

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/110372