title: Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing.
abstract: BACKGROUND
  Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is activated during hypokalemia and that IKAS blockade is proarrhythmic.
  
  
  RESULTS
  Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD80) by 26 milliseconds (95% confidence interval [CI], 14-37) during normokalemia and by 54 milliseconds (95% CI, 40-68) during hypokalemia (P=0.01) at a 1000-millisecond pacing cycle length. In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the pacing cycle length threshold of APD alternans, the pacing cycle length for wave-break induction, and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained ventricular fibrillation (from 3 of 9 hearts to 9 of 9 hearts; P=0.009). Short-term cardiac memory was assessed by the slope of APD80 versus activation time. The slope increased from 0.01 (95% CI, -0.09 to 0.12) at baseline to 0.34 (95% CI, 0.23-0.44) after apamin (P<0.001) during right ventricular pacing and from 0.07 (95% CI, -0.05 to 0.20) to 0.54 (95% CI, 0.06-1.03) after apamin infusion (P=0.045) during left ventricular pacing. Patch-clamp studies confirmed increased IKAS in isolated rabbit ventricular myocytes during hypokalemia (P=0.038).
  
  
  CONCLUSIONS
  Hypokalemia activates IKAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. IKAS blockade prominently lengthens the APD at late activation sites and facilitates ventricular fibrillation induction.
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Chan
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Jum-Suk
authors.initials: JS
authors.lastname: Ko
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Dechun
authors.initials: D
authors.lastname: Yin
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Everett
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.).
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: From Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (Y.-H.C., W.-C.T., P.-C.C., T.H.E., S.-F.L., P.-S.C.) and Wells Center for Pediatrics Research, Department of Pediatrics (M.R.), Indiana University School of Medicine, Indianapolis; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linkou, Taoyuan, Taiwan (Y.-H.C., P.-C.C.); Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung University College of Medicine, Taiwan (W.-C.T.); Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Jeonbuk, Republic of Korea (J.-S.K.); Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China (D.Y.); Departments of Medicine (Cardiology) and Physiology, University of California, Los Angeles (J.N.W.); and Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.). chenpp@iu.edu.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D004198:Disease Susceptibility; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D007008:Hypokalemia / Q000150:complications / Q000503:physiopathology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D001030:Apamin; D011188:Potassium
keywords: arrhythmias; cardiac; death; ion channels; sudden