title: Heterogeneous upregulation of apamin-sensitive potassium currents in failing human ventricles.
abstract: BACKGROUND
  We previously reported that IKAS are heterogeneously upregulated in failing rabbit ventricles and play an important role in arrhythmogenesis. This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca(2+) activated K(+) (SK2) channel and apamin-sensitive K(+) currents (IKAS) are upregulated in failing human ventricles.
  
  
  RESULTS
  We studied 12 native hearts from transplant recipients (heart failure [HF] group) and 11 ventricular core biopsies from patients with aortic stenosis and normal systolic function (non-HF group). IKAS and action potential were recorded with patch-clamp techniques, and SK2 protein expression was studied by Western blotting. When measured at 1 μmol/L Ca(2+) concentration, IKAS was 4.22 (median) (25th and 75th percentiles, 2.86 and 6.96) pA/pF for the HF group (n=11) and 0.98 (0.54 and 1.72) pA/pF for the non-HF group (n=8, P=0.008). IKAS was lower in the midmyocardial cells than in the epicardial and the endocardial cells. The Ca(2+) dependency of IKAS in HF myocytes was shifted leftward compared to non-HF myocytes (Kd 314 versus 605 nmol/L). Apamin (100 nmol/L) increased the action potential durations by 1.77% (-0.9% and 7.3%) in non-HF myocytes and by 11.8% (5.7% and 13.9%) in HF myocytes (P=0.02). SK2 protein expression was 3-fold higher in HF than in non-HF.
  
  
  CONCLUSIONS
  There is heterogeneous upregulation of IKAS densities in failing human ventricles. The midmyocardial layer shows lower IKAS densities than epicardial and endocardial layers of cells. Increase in both Ca(2+) sensitivity and SK2 protein expression contributes to the IKAS upregulation.
authors.affiliation: Division of Cardiology, Krannert Institute of Cardiology, Indianapolis, IN.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Isik
authors.initials: I
authors.lastname: Turker
authors.forename: John C
authors.initials: JC
authors.lastname: Lopshire
authors.forename: Saqib
authors.initials: S
authors.lastname: Masroor
authors.forename: Bich-Lien
authors.initials: BL
authors.lastname: Nguyen
authors.forename: Wen
authors.initials: W
authors.lastname: Tao
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
mesh_terms: D000200:Action Potentials; D000328:Adult; D000368:Aged; D001030:Apamin / Q000494:pharmacology*; D001706:Biopsy; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left
chemical_list: C496897:KCNN2 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D011188:Potassium; D002118:Calcium