title: Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles.
abstract: BACKGROUND
  Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that late phase 3 early afterdepolarization (EAD) induced by IKATP activation underlies the mechanisms of ES during isoproterenol infusion and hypokalemia.
  
  
  METHODS
  Intracellular calcium (Cai) and membrane voltage were optically mapped in 32 Langendorff-perfused normal rabbit hearts.
  
  
  RESULTS
  Repeated episodes of electrically induced ventricular fibrillation (VF) at baseline did not result in spontaneous VF (SVF). During isoproterenol infusion, SVF occurred in 1 of 15 hearts (7%) studied in normal extracellular potassium ([K(+)]o, 4.5 mmol/L), 3 of 8 hearts (38%) in 2.0 mmol/L [K(+)]o, 9 of 10 hearts (90%) in 1.5 mmol/L [K(+)]o, and 7 of 7 hearts (100%) in 1.0 mmol/L [K(+)]o (P <.001). Optical mapping showed that isoproterenol and hypokalemia enhanced Cai transient duration (CaiTD) and heterogeneously shortened action potential duration (APD) after defibrillation, leading to late phase 3 EAD and SVF. IKATP blocker (glibenclamide, 5 μmol/L) reversed the post-defibrillation APD shortening and suppressed recurrent SVF in all hearts studied despite no evidence of ischemia. Nifedipine reliably prevented recurrent VF when given before, but not after, the development of VF. IKr blocker (E-4031) and small-conductance calcium-activated potassium channel blocker (apamin) failed to prevent recurrent SVF.
  
  
  CONCLUSIONS
  Beta-adrenergic stimulation and concomitant hypokalemia could cause nonischemic activation of IKATP, heterogeneous APD shortening, and prolongation of CaiTD to provoke late phase 3 EAD, triggered activity, and recurrent SVF. IKATP inhibition may be useful in managing ES during resistant hypokalemia.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Cardiovascular Center, Chiba-Hokusoh Hospital, Nippon Medical School, Chiba, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Su-Kiat
authors.initials: SK
authors.lastname: Chua
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Hyung-Wook
authors.initials: HW
authors.lastname: Park
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shen
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: chenpp@iupui.edu.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006352:Heart Ventricles; D007008:Hypokalemia / Q000150:complications*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage*; D011817:Rabbits; D012008:Recurrence; D014693:Ventricular Fibrillation / Q000503:physiopathology*
chemical_list: D007545:Isoproterenol; D002118:Calcium
keywords: ATP-sensitive potassium channels; Afterdepolarization; Electrical storm; Hypokalemia; Intracellular calcium; Ventricular fibrillation