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  • In silico prediction software SIFT PolyPhen

    2019-05-08

    In silico prediction software, SIFT [51], PolyPhen2 [52], CADD [53], and other prediction systems are useful to evaluate a specific mutation which is detected in a patient. However, even if the in silico software predicts a mutation as pathogenic, we need to examine whether the genetic result is compatible with the phenotype.
    Conclusion
    Conflict of interest
    Introduction A channelopathy (also termed a primary electrical disorder) is defined as an inherited syndrome caused by mutations in dcb encoding for ion channels, their subunits, or their associated proteins [1]. Drug therapy and implantable cardioverter defibrillator (ICD) implantation are generally used as first-line therapies for the treatment and prevention of sudden cardiac death (SCD) in channelopathy patients [1]. However, recent advances in mapping techniques and ablation technology allow us to perform ablation therapy more safely and effectively for the treatment of ventricular tachycardia (VT) and ventricular fibrillation (VF), even in channelopathies. A recent consensus report recommended that catheter ablation of VT or a triggering focus of VF should be considered as a class IIa indication in patients with VT/VF storm when adequate operator experience is available, although, presumably, this recommendation also includes VT/VF in patients with structural heart disease [1]. According to the European Heart Rhythm Association Survey, catheter ablation for tachyarrhythmia is currently undertaken in 5–10% of recurrent cases with channelopathies such as Brugada syndrome (BrS) and long QT syndrome (LQTS) [2]. However, the long-term effectiveness of catheter ablation for VT/VF remains to be precisely elucidated as no randomized data on the effect of catheter ablation on arrhythmic events has been collected. In this article, we summarize the clinical reports on catheter ablation for the treatment of VT/VF in channelopathic patients in Table 1 and describe the current understanding of this field.
    Brugada syndrome BrS is characterized by coved-type or saddleback-type ST-segment elevation in the right precordial leads of the standard electrocardiogram (ECG) or high intercostal ECG. It is associated with an increased risk of SCD due to VF [3]. Approximately 15–30% of BrS cases are attributed to mutations in SCN5A, and a further 10–20% of BrS cases are attributed to mutations in other genes [4,5]. ICD implantation is recommended in patients with a diagnosis of BrS who are survivors of a cardiac arrest and/or have documented VF or spontaneous sustained VT with or without syncope. Isoproterenol and quinidine are also useful for the treatment of electrical storm in BrS patients. Experimental studies have shown that heterogeneous loss of the action potential dome occurs at the right ventricular (RV) epicardial sites, resulting in a marked dispersion of repolarization which underlies the development of local re-excitation via a mechanism termed phase 2 reentry in BrS [6]. Phase 2 reentrant ventricular extrasystole can trigger polymorphic VT/VF. Therefore, the elimination of trigger ventricular premature contractions (VPCs) might suppress VT/VF. Haïssaguerre et al. reported the electrophysiological properties and effects of catheter ablation in three symptomatic patients with BrS [7], with one patient exhibiting a familial SCN5A deletion mutation (2850delT). Monomorphic VPCs originating from the RV outflow tract (RVOT) were observed in all patients, with monomorphic VPCs with left bundle-branch block (LBBB) and superior axis in one patient. RVOT triggers were eliminated by radiofrequency (RF) energy applications at the earliest site (25 and 40ms before QRS onset), and VF inducibility was modified after ablation in two patients. In the third patient, RF energy application could ablate the VPCs originating from the anterior RV Purkinje network, thus rendered the VF non-inducible. During a mean follow-up period of 7±6 months, there was no evidence of recurrence of syncope, VF, or SCD in any of the patients.