Abstract 5325: Electrical Storm: Role of Protein Phosphorylation Abnormalities and Ca2+-Calmodulin Related Signaling
Electrical storm (ES), characterized by recurrent ventricular fibrillation (VF), causes sudden death in patients with implantable cardioverter-defibrillators (ICDs) and adversely affects prognosis in survivors. Because VF may be associated with increased [Ca2+] i, Ca2+handling protein alteration by Ca2+-activated signals may be responsible for the poor outcome of ES. Here, we tested this hypothesis in an experimental model of ES. We studied 19 rabbits with complete atrioventricular block for 79±6 days (M±SEM), all with extracardiac ICD system implantation. All rabbits had corrected QT-interval (QTc) prolongation and ICD-detected VF and self-terminating ventricular tachyarrhythmia episodes. Expression and phosphorylation of Ca2+ handling proteins were evaluated in left ventricular (LV) tissues from: 12 rabbits with ES, defined as ≥3 VF episodes per 24-hour; 7 rabbits that had VF episodes but not ES (non-ES) and 5 control (CTL) rabbits. QTc prolongation at the end of the follow-up period was greater in ES than in non-ES rabbits (275±11 vs. 230±5 ms, p<0.01). The number of VF episodes/rabbit averaged 111±31 for ES and 2.1±0.7 for non-ES rabbits. Phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) expression was significantly increased in both ES and non-ES rabbits (261±36*, 151±27* vs. 100±12% in CTL, *p<0.05), while phosphorylated protein kinase C (PKC)-α was increased in ES rabbits only (250±78*, 110±19 vs. 100±15%, *p<0.05). Protein kinase A (PKA)-α catalytic subunit was unaltered. In ES rabbits, ryanodine receptor (RyR2) was hyperphosphorylated at Ser2809 (140±8*, 100±5 vs. 100±16%, *p<0.05) and phospholamban (PLB) was dephosphorylated at both PKA (3.5±1.0*, 72±37 vs. 100±15%) and CaMKII (14±3*, 73±19 vs. 100±22%) sites. Total RyR2, sarcoplasmic reticulum Ca2+-ATPase and PLB expression were not different among groups. LV fractional shortening was smaller in ES (24±2%) vs non-ES rabbits (34±2%). Calmodulin inhibition with IV W-7 suppressed ES. ES is associated with multiple protein phosphorylation abnormalities related to Ca2+ calmodulin signaling, which contribute to arrhythmias and cardiac dysfunction. This study for the first time provides a molecular basis for ES.