Dataset Information

Late I_Na Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

ABSTRACT:

Background

Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I_NaL) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.

Methods

We tested the effects of the selective I_NaL blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca²⁺ imaging, and computer modeling.

Results

GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca²⁺-mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca²⁺ imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca²⁺ transient duration via accelerating Na⁺/Ca²⁺ exchanger (I_NCX)-mediated Ca²⁺ efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I_NaL potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na⁺ (Na_i) that decreases the depolarizing I_NCX thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K⁺ channels (I_Ks), suggesting important roles of I_NaL in regulating Na_i.

Conclusions

Selective I_NaL blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na_i. Graphic Abstract: A graphic abstract is available for this article.

SUBMITTER: Hwang J

PROVIDER: S-EPMC10626560 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Late I<sub>Na</sub> Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Hwang Jungmin J Kim Tae Yun TY Terentyev Dmitry D Zhong Mingwang M Kabakov Anatoli Y AY Bronk Peter P Arunachalam Karuppiah K Belardinelli Luiz L Rajamani Sridharan S Kunitomo Yukiko Y Pfeiffer Zachary Z Lu Yichun Y Peng Xuwen X Odening Katja E KE Qu Zhilin Z Karma Alain A Koren Gideon G Choi Bum-Rak BR

Circulation. Arrhythmia and electrophysiology 20200706 8

<h4>Background</h4>Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I<sub>NaL</sub>) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.<h4>Methods</h4>We tested the effects of the selective I<sub>NaL</sub> blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using ...[more]

PMID: 32628505

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Project description:RationaleAutosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia.ObjectiveTo determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+).Methods and resultsGuide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients.ConclusionsAAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.

Dataset Information

Late I_Na Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Background

Methods

Results

Conclusions

Publications

Late I<sub>Na</sub> Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Late INa Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Background

Methods

Results

Conclusions

Publications

Late I<sub>Na</sub> Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Late I_Na Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.