title: Paradoxical effects of KB-R7943 on arrhythmogenicity in a chronic myocardial infarction rabbit model.
abstract: BACKGROUND
  Na(+)/Ca(2+) exchanger blockade has been reported to be anti-arrhythmic in different models. The effects of KB-R7943, a Na(+)/Ca(2+) exchanger blocker, on arrhythmogenesis in hearts with chronic myocardial infarction (MI) remain unclear.
  
  
  METHODS
  Dual voltage and intracellular Ca(2+) (Cai) optical mapping was performed in nine rabbit hearts with chronic MI and four control hearts. Electrophysiology studies including inducibility of ventricular tachyarrhythmias, ventricular fibrillation dominant frequency, action potential, Cai alternans, Cai decay, and conduction velocity were performed. The same protocol was repeated in the presence of KB-R7943 (0.5, 1, and 5μM) after the baseline studies.
  
  
  RESULTS
  KB-R7943 was effective in suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias in hearts with chronic MI. Surprisingly, KB-R7943 increased the inducibility of ventricular tachyarrhythmias in a dose-dependent manner (11%, 11%, 22%, and 56% at baseline and with 0.5, 1, and 5μM KB-R7943, respectively, p=0.02). Optical mapping analysis revealed that the underlying mechanisms of the induced ventricular tachyarrhythmias were probably spatially discordant alternans with wave breaks and rotors. Further analysis showed that KB-R7943 significantly enhanced both action potential (p=0.033) and Cai (p=0.001) alternans, prolonged Cai decay (tau value) in a dose-dependent manner (p=0.004), and caused heterogeneous conduction delay especially at peri-infarct zones during rapid burst pacing. In contrast, KB-R7943 had insignificant effects in control hearts.
  
  
  CONCLUSIONS
  In this chronic MI rabbit model, KB-R7943 has contrasting effects on arrhythmogenesis, suppressing afterdepolarizations and spontaneous ventricular tachyarrhythmias, but enhancing the inducibility of tachyarrhythmias. The mechanism is probably the enhanced spatially discordant alternans because of prolonged Cai decay and heterogeneous conduction delay.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Linko, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Linko, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Hung-Ta
authors.initials: HT
authors.lastname: Wo
authors.affiliation: Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Anesthesia, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Linko, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Linko, Chang Gung Memorial Hospital, Taipei, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: 2867@adm.cgmh.org.tw.
authors.forename: Chung-Chuan
authors.initials: CC
authors.lastname: Chou
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D013890:Thiourea
keywords: Myocardial infarction; Sodium–calcium exchanger; Ventricular tachyarrhythmias