title: The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts.
abstract: The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K(+)) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 muM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD(90)), ventricular effective refractory period (VERP), and transmural conduction time (Deltalatency), where appropriate, were applied to normokalemic (5.2 mM K(+)) and hypokalemic hearts. Hypokalemia increased epicardial APD(90) from 46.6 +/- 1.2 to 53.1 +/- 0.7 ms yet decreased epicardial VERP from 41 +/- 4 to 29 +/- 1 ms, left endocardial APD(90) unchanged (58.2 +/- 3.7 to 56.9 +/- 4.0 ms) yet decreased endocardial VERP from 48 +/- 4 to 29 +/- 2 ms, and left Deltalatency unchanged (1.6 +/- 1.4 to 1.1 +/- 1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD(90) (54.8 +/- 2.7 to 60.6 +/- 2.7 ms), epicardial VERP (84 +/- 5 to 81 +/- 7 ms), endocardial APD(90) (56.6 +/- 4.2 to 63.7 +/- 6.4 ms), endocardial VERP (80 +/- 2 to 84 +/- 4 ms), and Deltalatency (12.5 +/- 6.2 to 7.6 +/- 3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD(90) might diverge sharply from VERP.
authors.affiliation: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, UK.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Sabir
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Killeen
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001919:Bradycardia / Q000503:physiopathology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007008:Hypokalemia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010477:Perfusion; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology; D011188:Potassium / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects / Q000502:physiology*
chemical_list: D000889:Anti-Arrhythmia Agents; D008012:Lidocaine; D011188:Potassium