title: Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation.
abstract: Our laboratory previously demonstrated that perfusate sodium and potassium concentrations can modulate cardiac conduction velocity (CV) consistent with theoretical predictions of ephaptic coupling (EpC). EpC depends on the ionic currents and intercellular separation in sodium channel rich intercalated disk microdomains like the perinexus. We suggested that perinexal width (WP) correlates with changes in extracellular calcium ([Ca(2+)]o). Here, we test the hypothesis that increasing [Ca(2+)]o reduces WP and increases CV. Mathematical models of EpC also predict that reducing WP can reduce sodium driving force and CV by self-attenuation. Therefore, we further hypothesized that reducing WP and extracellular sodium ([Na(+)]o) will reduce CV consistent with ephaptic self-attenuation. Transmission electron microscopy revealed that increasing [Ca(2+)]o (1 to 3.4 mM) significantly decreased WP Optically mapping wild-type (WT) (100% Cx43) mouse hearts demonstrated that increasing [Ca(2+)]o increases transverse CV during normonatremia (147.3 mM), but slows transverse CV during hyponatremia (120 mM). Additionally, CV in heterozygous (∼50% Cx43) hearts was more sensitive to changes in [Ca(2+)]o relative to WT during normonatremia. During hyponatremia, CV slowed in both WT and heterozygous hearts to the same extent. Importantly, neither [Ca(2+)]o nor [Na(+)]o altered Cx43 expression or phosphorylation determined by Western blotting, or gap junctional resistance determined by electrical impedance spectroscopy. Narrowing WP, by increasing [Ca(2+)]o, increases CV consistent with enhanced EpC between myocytes. Interestingly, during hyponatremia, reducing WP slowed CV, consistent with theoretical predictions of ephaptic self-attenuation. This study suggests that serum ion concentrations may be an important determinant of cardiac disease expression.
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia;
authors.forename: Sharon A
authors.initials: SA
authors.lastname: George
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; and.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bonakdar
authors.affiliation: Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Roanoke, Virginia.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeitz
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; and.
authors.forename: Rafael V
authors.initials: RV
authors.lastname: Davalos
authors.affiliation: Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Roanoke, Virginia.
authors.forename: James W
authors.initials: JW
authors.lastname: Smyth
authors.affiliation: Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Virginia Tech Carilion Research Institute and Center for Heart and Regenerative Medicine, Roanoke, Virginia poelzing@vtc.vt.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002450:Cell Communication; D003198:Computer Simulation; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics; D058266:Dielectric Spectroscopy; D017097:Electric Impedance; D017629:Gap Junctions / Q000378:metabolism; D005838:Genotype; D007010:Hyponatremia / Q000097:blood / Q000503:physiopathology; D000067268:Isolated Heart Preparation; D007700:Kinetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D012964:Sodium / Q000378:metabolism*; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; D012964:Sodium; D002118:Calcium
keywords: calcium; conduction; ephaptic coupling; ion concentration; sodium