Abstract 1080: Calmodulin Plays an Important Role in Electrical Storm: Insights from a New Experimental Model

Abstract

Background: Electrical storm (ES), characterized by recurrent episodes of ventricular fibrillation (VF), is a serious clinical condition, importantly complicating implantable cardioverter-defibrillator (ICD) therapy. The pathophysiology and molecular basis of ES are poorly understood because of a lack of suitable animal models. Here, we report a new experimental model that features repetitive episodes of ICD firing for recurrent VF, in which we assessed the potential involvement of calmodulin in ES. Methods and Results: The incidence of ES was assessed in 8 rabbits that had been in chronic complete atrioventricular block (CAVB) for 90±12 days (M±SEM; range 50 –129 days), all of whom had undergone extracardiac ICD system implantation. The maximal number of intervals to detect VF (NID: 105/140) was programmed to avoid inappropriate shocks for incessant ventricular tachyarrhythmias (VTs). Shock intensities were set >twice the defibrillation threshold (1.5±0.2 J). All rabbits had ICD-detected self-terminating VTs and corrected QT-interval (QTc) prolongation (226±12 versus 185±11 ms at baseline, P<0.05) before the first VF episode, and 7/8 rabbits subsequently developed ES, defined as ≥3 VF episodes per 24-hour. The ES appeared on day 30±7 and occurred for 19±5 days follow-up. The QTc was remarkably increased on the day of ES compared with the value on the day without ES (271±12 versus 219±10 ms, P<0.01). Analysis of 1006 VF episodes obtained from 8 rabbits showed no circadian variation of VF incidence. One-week infusion of W-7, a calmodulin antagonist, to 3 rabbits by osmotic pump caused dose-dependent reductions in days of VF (from 5.3±1.2 to 3.0±1.1 and 0.6±0.3*), VF episodes (from 20±3 to 19±7 and 1.7±1.2*) and self-terminating VT episodes (from 2572±854 to 997±197* and 178±24* for 1 week; all results are shown as before infusion to data during infusion of W-7 at doses of 297 and 744 μg/hr respectively; *P<0.05 versus before W-7) without shortening the QTc. Conclusions: This model shows a high incidence of ES, allowing for study of mechanisms and treatment of ES, as well as consequences of multiple high-energy shocks. The positive response of ES to W-7 suggests that the calmodulin/calmodulin kinase system may be crucial to the generation of ES in this model.