title: A Parsimonious Model of the Rabbit Action Potential Elucidates the Minimal Physiological Requirements for Alternans and Spiral Wave Breakup.
abstract: Elucidating the underlying mechanisms of fatal cardiac arrhythmias requires a tight integration of electrophysiological experiments, models, and theory. Existing models of transmembrane action potential (AP) are complex (resulting in over parameterization) and varied (leading to dissimilar predictions). Thus, simpler models are needed to elucidate the "minimal physiological requirements" to reproduce significant observable phenomena using as few parameters as possible. Moreover, models have been derived from experimental studies from a variety of species under a range of environmental conditions (for example, all existing rabbit AP models incorporate a formulation of the rapid sodium current, INa, based on 30 year old data from chick embryo cell aggregates). Here we develop a simple "parsimonious" rabbit AP model that is mathematically identifiable (i.e., not over parameterized) by combining a novel Hodgkin-Huxley formulation of INa with a phenomenological model of repolarization similar to the voltage dependent, time-independent rectifying outward potassium current (IK). The model was calibrated using the following experimental data sets measured from the same species (rabbit) under physiological conditions: dynamic current-voltage (I-V) relationships during the AP upstroke; rapid recovery of AP excitability during the relative refractory period; and steady-state INa inactivation via voltage clamp. Simulations reproduced several important "emergent" phenomena including cellular alternans at rates > 250 bpm as observed in rabbit myocytes, reentrant spiral waves as observed on the surface of the rabbit heart, and spiral wave breakup. Model variants were studied which elucidated the minimal requirements for alternans and spiral wave break up, namely the kinetics of INa inactivation and the non-linear rectification of IK.The simplicity of the model, and the fact that its parameters have physiological meaning, make it ideal for engendering generalizable mechanistic insight and should provide a solid "building-block" to generate more detailed ionic models to represent complex rabbit electrophysiology.
authors.affiliation: Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Richard A
authors.identifier: http://orcid.org/0000-0003-2798-6378
authors.initials: RA
authors.lastname: Gray
authors.affiliation: Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Pras
authors.identifier: http://orcid.org/0000-0003-2111-6689
authors.initials: P
authors.lastname: Pathmanathan
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001683:Biological Clocks / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D003198:Computer Simulation; D006329:Heart Conduction System / Q000503:physiopathology; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008955:Models, Cardiovascular; D008959:Models, Neurological; D032342:Muscle Cells / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology; D011817:Rabbits
chemical_list: D015221:Potassium Channels; D011188:Potassium