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Background: Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood.Objective: The purpose of this study was to explore the electrophysiological substrate for experimental ES.Methods: A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes.Results: Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes in vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP.Conclusion: A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES. [ABSTRACT FROM AUTHOR]

Background: Although defective Ca2+ homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of sarcoplasmic reticulum (SR) Ca2+-release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6. Objective: The objective of the present study was to test the hypothesis that Ca2+ leak from the SR through RyR2 increases the propensity for AF in FKBP12.6-deficient (−/−) mice. Methods: Surface electrocardiogram and intracardiac electrograms were recorded simultaneously in FKBP12.6−/− mice and wild-type (WT) littermates. Right atrial programmed stimulation was performed before and after injection of RyR2 antagonist tetracaine (0.5 mg/kg). Intracellular Ca2+ transients were recorded in atrial myocytes from FKBP12.6−/− and WT mice. Results: FKBP12.6−/− mice had structurally normal atria and unaltered expression of key Ca2+-handling proteins. AF episodes were inducible in 81% of FKBP12.6−/−, but in only 7% of WT mice (P <.05), and were prevented by tetracaine in all FKBP12.6−/− mice. SR Ca2+ leak in FKBP12.6−/− myocytes was 53% larger than in WT myocytes, and FKBP12.6−/− myocytes showed increased incidence of spontaneous SR Ca2+ release events, which could be blocked by tetracaine. Conclusion: The increased vulnerability to AF in FKBP12.6−/− mice substantiates the notion that defective SR Ca2+ release caused by abnormal RyR2 and FKBP12.6 interactions may contribute to the initiation or maintenance of atrial fibrillation. [Copyright &y& Elsevier]