Background: Electrical storm (ES) is a serious complication of defibrillator (ICD)-treated arrhythmic syndromes, including long QT syndrome (LQTS).
Objective: The hypothesis that ICD-shocks for recurrent ventricular tachyarrhythmias may cause accentuated action potential duration (APD) heterogeneities was tested in a model of ES, which was created by inducing chronic complete atrioventricular block in ICD-implanted rabbits, causing LQTS and Torsades de Pointes (TdP) and ventricular fibrillation (VF) episodes.
Methods: We studied 42 rabbits with ES (defined as ≥3 VF episodes/24 h), 8 rabbits with TdP or VF episodes but not ES (non-ES) and 20 control rabbits.
Results: Optical mapping revealed island-like long-APD regions at the left ventricular (LV) base, leading to increased spatial APD-dispersion, in ES rabbits, in contrast to homogeneous APD prolongation in non-ES rabbits. TdP was initiated by an ectopic beat that failed to enter the refractory island and formed a reentrant wave, and perpetuated by rotors swirling in the periphery of the island. The APD and its dispersion ex vivo correlated with the number of VF episodes in vivo. Epinephrine exacerbated the island by prolonging APD and producing striking APD-dispersion, which disappeared in response to 10 μM ranolazine. Epinephrine infusion effectively evoked TdP in vivo; lidocaine (2 mg/kg i.v.) ameliorated QT-U abnormalities and completely suppressed TdP in 4/4 epinephrine-loaded rabbits. Patch-clamp experiments showed late Na⁺-current (I_Na-L) enhancement in ES rabbit LV myocytes. Immunoblotting revealed that, in addition to cardiac Na⁺-channel Na_V1.5 (Ser571) hyperphosphorylation and upregulation of phosphorylated and oxidized Ca²⁺/calmodulin-dependent protein kinase II, the neuronal Na⁺-channel Na_V1.8 was strongly upregulated in ES rabbit LV tissues. Immunohistochemistry showed intense Na_V1.8 labeling within myocardium corresponding to the island detected in optically mapped ES hearts.
Conclusion: A tissue-island with enhanced refractoriness created by increased I_Na-L contributes to the generation of drifting rotors in a unique manner that underlies LQTS-associated ES. Na_V1.8 likely underlies torsadogenic I_Na-L and is an interesting candidate for new-drug targeting.