title: Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling.
abstract: BACKGROUND
  Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome.
  
  
  RESULTS
  LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26±0.04, post: 0.52±0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16±4 vs. 38±6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53±0.12 vs. 1.17±0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15±1 Hz in LQT1-TICM vs. 13±1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of IKs.
  
  
  CONCLUSIONS
  Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the downregulation of IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: Lau
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kossidas
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Tae Yun
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kunitomo
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Ohad
authors.initials: O
authors.lastname: Ziv
authors.forename: Zhen
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Song
authors.initials: S
authors.lastname: Zhen
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Chantel
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Schofield
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Joe
authors.initials: J
authors.lastname: Yammine
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Gongxin
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Xuwen
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D053840:Brugada Syndrome; D002118:Calcium / Q000378:metabolism*; D000075224:Cardiac Conduction System Disease; D004452:Echocardiography; D006329:Heart Conduction System / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D017136:Ion Transport; D008297:Male; D009135:Muscular Diseases / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011817:Rabbits; D029597:Romano-Ward Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D024642:Potassium Channels, Voltage-Gated; D002118:Calcium