title: Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.
abstract: BACKGROUND
  Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT).
  
  
  OBJECTIVE
  The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1.
  
  
  METHODS
  Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras.
  
  
  RESULTS
  Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n = 16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na(+) current (INa)-mediated fast conduction and L-type Ca(2+) current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 μM tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results.
  
  
  CONCLUSIONS
  Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT.
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Tae Yun
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kunitomo
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Pfeiffer
authors.affiliation: Cardiovascular Institutes, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Divyang
authors.initials: D
authors.lastname: Patel
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Department of Pharmacology, University of Rhode Island, Kingston, Rhode Island.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Harrison
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Patel
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Paul
authors.initials: P
authors.lastname: Jeng
authors.affiliation: Case Western Reserve University, School of Medicine, Cleveland, Ohio.
authors.forename: Ohad
authors.initials: O
authors.lastname: Ziv
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Xuwen
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Medicine, University of California, Los Angeles, California.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address: Bum-Rak_Choi@brown.edu.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D003198:Computer Simulation; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology; D008297:Male; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D011817:Rabbits; D029597:Romano-Ward Syndrome / Q000150:complications* / Q000503:physiopathology*; D017180:Tachycardia, Ventricular / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D024642:Potassium Channels, Voltage-Gated
keywords: Action potential duration dispersion; Bi-excitability; Early afterdepolarization; Long QT syndrome; Optical mapping; Polymorphic ventricular tachycardia; Ventricular tachycardia