Abstract 2353: Molecular Mechanisms of Left Ventricular Function Deterioration Associated With Electrical Storm
Background: Electrical storm (ES), characterized by recurrent ventricular fibrillation (VF), adversely affects prognosis in implantable cardioverter-defibrillator (ICD) patients. ES patients often die of progressive heart failure (HF), but the underlying molecular basis is poorly understood. Here, we studied ES effects on Ca2+ handling protein expression/phosphorylation in an experimental model of ES.
Methods and Results: We studied 32 rabbits with complete AV block for 81±7 days (M±SEM), all with ICD implantation. All rabbits showed cardiac hypertrophy, long QT and ICD-detected VF episodes. ES (>3 VF episodes per 24 hr) was documented in 16/32 rabbits. Expression and phosphorylation of Ca2+ handling and myofibrillar proteins were assessed in LV tissues from: 8 rabbits with ES; 7 rabbits that had VF episodes but not ES (non-ES) and 8 control (CTL) rabbits (table⇓). LV end-diastolic diameter increased comparably, but the fractional shortening was smaller in ES (24±1%) vs. non-ES rabbits (32±1%). ES rabbits showed striking hyperphosphorylation of Ca2+ calmodulin kinase II (p-CaMKII), prominent phospholamban (PLB) dephosphorylation and increases of phosphatases 1 and 2A vs. CTL and non-ES. Ryanodine receptor (RyR2) was hyperphosphorylated at Ser2815 in both ES and non-ES, but at Ser2809 in ES rabbits only. Protein kinase A (PKA)-α catalytic subunit was decreased similarly. PKA-dependent phosphorylation of myosin-binding protein-C and troponin-I were reduced, but not different between ES and non-ES rabbits. To examine direct effects of ES, VF was induced 10 times at the 1st day (baseline) in 4 rabbits. Acute-ES tissues showed changes like chronic ES-rabbit hearts: p-CaMKII upregulation (276±41* vs. 100±29% in CTL, *p<0.05) and PLB dephosphorylation (eg, PKA site 11±4* vs. 100±23%).
Conclusions: ES causes marked CaMKII hyperphosphorylation and PLB dephosphorylation, which can explain progressive mechanical dysfunction and adverse HF-related outcomes.