title: Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm.
abstract: BACKGROUND
  Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca(2+)-related protein alterations in ES.
  
  
  RESULTS
  We studied 37 rabbits with complete atrioventricular block for ≈80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (≥3 VF episodes per 24-hour period; 103±23 VF episodes per rabbit). Expression/phosphorylation of Ca(2+)-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca(2+)/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca(2+) channel α-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca(2+)/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction.
  
  
  CONCLUSIONS
  ES causes Ca(2+)/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. y-tsuji@hh.iij4u.or.jp
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hojo
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Inden
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017147:Defibrillators, Implantable; D004195:Disease Models, Animal; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006327:Heart Block / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D012008:Recurrence; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D000099211:Phospholamban
chemical_list: D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; D000099211:Phospholamban; C021042:protein phosphatase inhibitor-1; C017967:W 7