title: Small conductance calcium-activated potassium current is important in transmural repolarization of failing human ventricles.
abstract: BACKGROUND
  The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear.
  
  
  RESULTS
  We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes.
  
  
  CONCLUSIONS
  SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Yu
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Corr
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Richard
authors.initials: R
authors.lastname: Shelton
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Mrinal
authors.initials: M
authors.lastname: Yadava
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Isaac B
authors.initials: IB
authors.lastname: Rhea
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Susan
authors.initials: S
authors.lastname: Straka
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.).
authors.forename: John C
authors.initials: JC
authors.lastname: Lopshire
authors.affiliation: From the Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology (C.-C.Y., C.C., R.S., M.Y., I.B.R., S.S., Z.C., S.-F.L., J.C.L., P.-S.C.) and Department of Biostatistics (C.S.), Indiana University School of Medicine, Indianapolis; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (C.-C.Y.); Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis (C.S.); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles (M.C.F.); Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan (S.-F.L.); and Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, IN (J.C.L.). chenpp@iu.edu.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D002304:Cardiac Pacing, Artificial; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010477:Perfusion; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C496897:KCNN2 protein, human; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D011188:Potassium
keywords: action potential; calcium; heart failure; ion channels; ventricular remodeling