ClinicalExperimentalRotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm
Graphical abstract
Introduction
Electrical storm (ES), characterized by repetitive episodes (generally defined as ≥3 within 24 hours) of ventricular tachycardia/ventricular fibrillation (VT/VF), is a life-threatening complication of implantable cardioverter-defibrillator (ICD) therapy. However, the pathophysiology and molecular basis of ES are poorly understood. We have created and initially characterized a model of ES by inducing chronic complete atrioventricular block (CAVB) in ICD-implanted rabbits, causing QT interval prolongation, repetitive torsades de pointes (TdP), and frequent VF episodes.1 Using this model, we showed that ES is associated with activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation changes in L-type Ca2+ channels and ryanodine receptor type 2 channels,1 contributing to the generation of afterdepolarization-related triggered activity.2 The cardiac Na+-channel subunit NaV1.5 (encoded by SCN5A) is another important target of CaMKII, phosphorylation of which is linked to arrhythmogenic late Na+ current (INa-L),2 but the role of this system in ES has not been evaluated.1 In the present study, the electrophysiological mechanisms of experimental ES were explored using high-resolution optical mapping. We report our findings here: drifting rotors in association with INa-L-mediated localized action potential duration (APD) prolongation acted as a driver of TdP and neural Na+-channel NaV1.8 upregulation, rather than CaMKII-mediated NaV1.5 hyperphosphorylation, was implicated in enhanced INa-L.
Section snippets
Methods
All animal handling protocols were approved by the animal ethics experimentation committees of Nagasaki University and Nagoya University. Details are provided in the Online Supplement.
Characteristics of rabbits used for optical mapping
The characteristics of 15 ES and 2 non-ES rabbits used for optical mapping experiments are summarized in Online Table SI. ES rabbits had 37 ± 6 VF episodes for 97 ± 8 days.
Localized regions with prominent APD prolongation in an ES heart
Figure 2 illustrates representative APD maps in an ES, a non-ES (ES #3 and non-ES #2, respectively, in Online Table SI), and a CTL heart at baseline and in the presence of 0.1 μM epinephrine, followed by 10 μM ranolazine application. The map for the ES heart at baseline was heterogeneous, showing regions with remarkably
Discussion
The electrophysiological substrate for ES associated with QT prolongation has been explored in animals. ES was associated with island-like long APD regions at the LV with increased spatial APD dispersion, which were exacerbated by epinephrine. We detected drifting rotational activity in the periphery of the refractory island during TdP and found the correlation of APD dispersion with the number of VF episodes. The localized APD prolongation was attributed to INa-L enhancement probably because
Conclusion
A tissue island with prolonged refractoriness created by increased INa-L contributes to the generation of drifting rotors that underlies ES associated with QT prolongation in this model. NaV1.8 likely underlies torsadogenic INa-L and is an interesting candidate for new drug targeting against ES.
Acknowledgments
We thank Peter Mohler, PhD (Ohio State University) for kindly gifting anti-phospho-Ser571-NaV1.5 antibody and Anna Nozza, MSc (Montreal Heart Institute Coordinating Center) for helping us with statistical analyses.
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2022, Canadian Journal of CardiologyCitation Excerpt :Furthermore, administration of W-7, a calmodulin antagonist that indirectly suppresses CaMKII function, to VF storm rabbits suppressed CaMKII hyperphosphorylation, prevented ventricular arrhythmia, and rescued contractile function,53 directly implicating the calmodulin/CaMKII system. In addition, a recent study using optical mapping showed that action potential duration-dispersion correlates with the number of VF episodes in vivo and that drifting rotors anchored by zones of enhanced refractoriness underlie electrical storm in this model,54 suggesting that the antiarrhythmic action of W-7 might be mediated by suppressing triggers that initiate rotors. Metabolic remodelling is one of the hallmarks of HF.55
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Funding Sources: This study was supported by the Japan Society for the Promotion of Science (18H02802, 15KK0341, 15K09078, 26461074, 17K09511, and 20K08450), Suzuken Memorial Foundation, SENSHIN Medical Research Foundation, and Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Drs Yamazaki, Honjo, and Tsuji); by the National Institutes of Health (R01-HL131517, R01-HL136389, and R01-HL089598) and German Research Foundation (DFG, Do 769/4–1) (to Dr Dobrev); and by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada (to Dr Nattel).
Disclosures: The authors have no conflicts of interest to disclose.