Facing ethical concerns in the age of precise gene therapy:Outlook on inherited arrhythmias

This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.

Trigger elimination of polymorphic ventricular tachycardia and ventricular fibrillation by catheter ablation:trigger and substrate modification

Ventricular fibrillation （VF） is a malignant arrhythmia, usually initiated by a ventricular premature contraction （VPC） during the vulnerable period of cardiac repolarization. Ablation therapy for VF has been described and increasingly reported. Targets for VF triggers are VPCs preceded by Purkinje potentials or from the right ventricular outflow tract （RVOT） in structurally normal hearts, and VPC triggers preceded by Purkinje potentials in ischemic cardiomyopathy. During the session, mapping should be focused on the earliest activation and determining the earliest potential is the key to a successful ablation. However, suppression of VF can be achieved by not only the elimination of triggering VPCs, but also by substrate modification of possible reentry circuits in the Purkinje network, or between the PA and RVOT. The most important issue before the ablation session is the recording of the 12-lead ECG of the triggering event, which can prove invaluable in regionalizing the origin of the triggering VPC for more detailed mapping. In cases where the VPC is not spontaneous or inducible, ablation may be performed by pace mapping. Further studies are needed to evaluate the precise mechanisms of this arrhythmia.

A novel deletion-frameshift mutation in the S1 region of HERG gene in a Chinese family with long QT syndrome

Background The congenital Long QT syndrome （LQTS） is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type 2 congenital LQTS （LQT2） is caused by gene mutations in the human ether-a-go-go-related gene （HERG）.Methods A Chinese family diagnosed with LQTS were screened for KCNQ1,HERG and SCN5A,using polymerase chain reaction （PCR）,direct sequencing,and clong sequencing.We also investigated the mRNA expression of the HERG gene.Results We identified a novel i414fs＋98X mutation in the HERG gene.The deletion mutation of 14-bp in the first transmembrane segment （S1） introduced premature termination codons （PTCs） at the end of exon 6.This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels.But only the proband was symptomatic.Conclusions We found that the mRNA level of the HERG gene was significantly lower in 1414fs＋98X carriers than in noncarriers.We found a novel 1414fs＋98X mutation.The mRNA level supports that NMD mechanism might regulate the novel mutation.