title: Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber.
abstract: Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Sampson
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D008955:Models, Cardiovascular; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D009928:Organ Specificity; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011690:Purkinje Fibers / Q000473:pathology* / Q000503:physiopathology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel