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Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.

ABSTRACT: Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT).The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1.Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive dye and CMOS cameras.Bolus injection of isoproterenol (140 nM) induced pVT initiated by focal excitations from the right ventricle (RV; n = 16 of 18 pVTs). After the pVT was initiated, complex focal excitations occurred in both the RV and the left ventricle, which caused oscillations of the QRS complexes on ECG, consistent with the recent proposal of multiple shifting foci caused by EAD chaos. Moreover, the action potential upstroke in pVT showed a bimodal distribution, demonstrating the coexistence of 2 types of excitation that interacted to produce complex pVT: Na(+) current (INa)-mediated fast conduction and L-type Ca(2+) current (ICa)-mediated slow conduction coexist, manifesting as pVT. Addition of 2 ?M tetrodotoxin to reduce INa converted pVT into monomorphic VT. Reducing late INa in computer simulation converted pVT into a single dominant reentry, agreeing with experimental results.Our study demonstrates that pVT in LQT1 rabbits is initiated by focal excitations from the RV and is maintained by multiple shifting foci in both ventricles. Moreover, wave conduction in pVT exhibits bi-excitability, that is, fast wavefronts driven by INa and slow wavefronts driven by ICa co-exist during pVT.

SUBMITTER: Kim TY

PROVIDER: S-EPMC4277941 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.

Kim Tae Yun TY Kunitomo Yukiko Y Pfeiffer Zachary Z Patel Divyang D Hwang Jungmin J Harrison Kathryn K Patel Brijesh B Jeng Paul P Ziv Ohad O Lu Yichun Y Peng Xuwen X Qu Zhilin Z Koren Gideon G Choi Bum-Rak BR

Heart rhythm 20141005 1

<h4>Background</h4>Long QT syndrome type 1 (LQT1) is a congenital disease arising from a loss of function in the slowly activating delayed potassium current IKs, which causes early afterdepolarizations (EADs) and polymorphic ventricular tachycardia (pVT).<h4>Objective</h4>The purpose of this study was to investigate the mechanisms underlying pVT using a transgenic rabbit model of LQT1.<h4>Methods</h4>Hearts were perfused retrogradely, and action potentials were recorded using a voltage-sensitive ...[more]

PMID: 25285647

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Project description:RATIONALE:Autosomal-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. OBJECTIVE:To 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 RESULTS:Guide 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. CONCLUSIONS:AAV 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

Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.

Publications

Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1.

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