title: Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits.
abstract: OBJECTIVE
  We sought to define the electrophysiologic property of the rabbit heart associated with autoimmunity against the second extracellular loop of the beta(1)-adrenergic receptor.
  
  
  BACKGROUND
  Sudden death of patients with cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted by the presence of autoantibodies against the second extracellular loop of the beta(1)-adrenergic receptor.
  
  
  METHODS
  Rabbits were immunized by repetitive subcutaneous administration of a synthetic peptide corresponding to the second extracellular loop of beta(1)-adrenergic receptors (beta group; n = 30) for a mean of 4.2 months. Control rabbits received only vehicle (control group; n = 30).
  
  
  RESULTS
  One of the rabbits in the beta group died suddenly during the observation period, but none of the control animals died. The prevalence of sustained ventricular tachycardia was significantly higher in the beta group (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment revealed prolongation of the action potential duration (APD) in the right ventricular papillary muscle (beta: 156 +/- 5 ms vs. control: 131 +/- 4 ms; p < 0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta group (1 of 26), but not in any animals in the control group (0 of 17). A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp experiment on left ventricular M cells showed significant decreases in transient outward current (I(to1)) (-43%) and slowly activated delayed rectifier current (I(Ks)) densities (-33%), whereas the inward-rectifying K current (I(K1)) and rapidly activated delayed rectifier current (I(Kr)) densities remained unchanged.
  
  
  CONCLUSIONS
  Long-term immunization against the second extracellular loop of the beta(1)-adrenergic receptor caused EAD and APD prolongation and decreased the K-channel density, suggesting that an arrhythmic substrate via autoimmune mechanisms is present in cardiomyopathic patients who have autoantibodies directed against the receptors.
authors.affiliation: Cardiopulmonary Division of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan. yukikof@cpnet.med.keio.ac.jp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Kojiro
authors.initials: K
authors.lastname: Tanimoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Oota
authors.forename: Kana
authors.initials: K
authors.lastname: Fujikura
authors.forename: Michikado
authors.initials: M
authors.lastname: Iwata
authors.forename: Akiyasu
authors.initials: A
authors.lastname: Baba
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Mitamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000200:Action Potentials; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D009202:Cardiomyopathies / Q000276:immunology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D008297:Male; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000008:administration & dosage* / Q000276:immunology; D017180:Tachycardia, Ventricular / Q000276:immunology*
chemical_list: D010446:Peptide Fragments; D015221:Potassium Channels; D018342:Receptors, Adrenergic, beta-1