Elsevier

Heart Rhythm

Volume 19, Issue 2, February 2022, Pages 318-329
Heart Rhythm

Clinical
Experimental
Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm

https://doi.org/10.1016/j.hrthm.2021.10.012Get rights and content

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.

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.

References (19)

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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.

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