title: Increased phosphorylation of Ca(2+) handling proteins as a proarrhythmic mechanism in myocarditis.
abstract: BACKGROUND
  Because fatal arrhythmia is an important cause of death in patients with myocarditis, we investigated the proarrhythmic mechanisms of experimental autoimmune myocarditis. METHODS AND RESULTS: Myocarditis was induced by injection of 2 mg porcine cardiac myosin into the footpads of adult Lewis rats on days 1 and 8 (Myo, n=15) and the results compared with Control rats (Control, n=15). In an additional 15 rats, 6 mg/kg prednisolone was injected into the gluteus muscle before the injection of porcine cardiac myosin on days 1 and 8 (MyoS, n=15). Hearts with myocarditis had longer action potential duration (APD), slower conduction velocity (CV; P<0.01 vs. Control), higher CV heterogeneity, greater fibrosis, higher levels of immunoblotting of high-mobility group protein B1, interleukin 6 and tumor necrosis factor-α proteins. Steroid treatment partially reversed the translations for myocarditis, CV heterogeneity, reduced APD at 90% recovery to baseline, increased CV (P<0.01), and reversed fibrosis (P<0.05). Programmed stimulation triggered sustained ventricular tachycardia in Myo rats (n=4/5), but not in controls (n=0/5) or Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor (KN93) treated Myo rats (n=0/5, P=0.01). CaMKII autophosphorylation at Thr287 (201%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 126%) and Ser2814 (CaMKII site, 21%) were increased in rats with myocarditis and reversed by steroid.
  
  
  CONCLUSIONS
  The myocarditis group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca(2+)handling proteins. These changes were partially reversed by an antiinflammatory treatment and CaMKII inhibition.
authors: Cardiology Division, Yonsei University College of Medicine.
authors: Hyelim
authors: H
authors: Park
authors: Hyewon
authors: H
authors: Park
authors: Dajeong
authors: D
authors: Lee
authors: Sujung
authors: S
authors: Oh
authors: Jisoo
authors: J
authors: Lim
authors: Hye Jin
authors: HJ
authors: Hwang
authors: Sungha
authors: S
authors: Park
authors: Hui-Nam
authors: HN
authors: Pak
authors: Moon-Hyoung
authors: MH
authors: Lee
authors: Boyoung
authors: B
authors: Joung
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D008297:Male; D009205:Myocarditis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009218:Myosins / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D011239:Prednisolone / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D000893:Anti-Inflammatory Agents; D011239:Prednisolone; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009218:Myosins; D002118:Calcium