Dataset Information

Successful ablation of bifocal premature ventricular complexes from both left bundle branches triggering polymorphic ventricular tachycardia in long QT syndrome 2: a case report.

ABSTRACT:

Background

A 19-year-old woman with an established diagnosis of long QT syndrome (LQTS) 2 and underlying KCNH2-mutation was referred to our centre for recurrent polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) refractory to medical therapy and bilateral thoracic sympathectomy.

Case summary

Holter monitoring revealed a relevant premature ventricular complex (PVC) burden of two different morphologies. One PVC was originating from the left anterior fascicle, the other from the left posterior fascicle. Radiofrequency ablation resulted in complete suppression of both spontaneous PVC morphologies with a favourable clinical course over the next 2 years.

Discussion

This case presents two interesting insights: firstly, the consistent bigeminal pattern of the torsade de pointes triggering PVC. These were retrieved from the device interrogation and correlated with the pattern that was seen at the time of the procedure. Secondly, PVC morphologies suggested an origin from both the left ventricular (posterior and anterior) fascicles, which have not been described so far. This was confirmed by the preceding Purkinje potentials seen at the successful ablation sites in sinus rhythm and during PVC. Ablation of triggering PVCs causing recurrent VT/VF in LQTS 2 is feasible and effective over a mid-term follow-up.

SUBMITTER: Martinek M

PROVIDER: S-EPMC8715737 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.