title: Re-entrant cardiac arrhythmias in computational models of long QT myocardium.
abstract: The long QT syndrome (LQTS) is an inherited disorder in which repolarization of cardiac ventricular cells is prolonged. Patients with the LQTS are at an increased risk of ventricular cardiac arrhythmias. Two phenotypes of the inherited LQTS are caused by defects in K(+)channels (LQT1 and LQT2) and one by defects in Na(+)channels (LQT3). Patients with LQT1 are more likely to have self-terminating arrhythmias than those with LQT3. The aim of this computational study was to propose an explanation for this finding by comparing the vulnerability of normal and LQT tissue to re-entry, and estimating the likelihood of self-termination by motion of re-entrant waves to an inexcitable boundary in simulated LQT1, LQT2 and LQT3 tissue. We modified a model of mammalian cardiac cells to simulate LQT1 by reducing maximal I(K(s))conductance, LQT2 by reducing maximal I(K(r))conductance, and LQT3 by preventing complete inactivation of I(Na)channels. Each simulated phenotype was incorporated into a computational model of action potential propagation in one- and two-dimensional homogeneous tissue. Simulated LQT tissue was no more vulnerable to re-entry than simulated normal tissue, but the motion of re-entrant waves in simulated LQT1 tissue was between 2 and 5 times greater than the motion of re-entrant waves in simulated LQT2 and LQT3 tissue. These findings suggest that LQT arrhythmias do not result from increased vulnerability to re-entry, and that re-entry once initiated is more likely to self-terminate by moving to an inexcitable tissue boundary in LQT1 than in LQT2 and LQT3. This finding is consistent with clinical observations.
authors.affiliation: School of Biomedical Sciences, Worsley Building, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK. richard@cbiol.leeds.ac.uk
authors.forename: R H
authors.initials: RH
authors.lastname: Clayton
authors.forename: A
authors.initials: A
authors.lastname: Bailey
authors.forename: V N
authors.initials: VN
authors.lastname: Biktashev
authors.forename: A V
authors.initials: AV
authors.lastname: Holden
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D003198:Computer Simulation; D004562:Electrocardiography; D006168:Guinea Pigs; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000503:physiopathology*; D008955:Models, Cardiovascular