The relevance of genetic testing in 20 patients with recurrent unexplained ventricular fibrillation

Background: Idiopathic ventricular fibrillation (VF) is diagnosed in patients who are survivors of a VF episode without any identifiable structural or electrical cause. Implantable cardioverter defibrillator is usually recommended in this population. Catheter ablation of VF triggers is associated with high rates of long-term freedom from VF recurrence in individual patients. Genetic testing can be useful in idiopathic VF but its diagnostic yield has been reported to be relatively low.

Aims: The purpose of this study was to describe the results of genetic testing in 20 consecutive patients with recurrent unexplained VF referred for ablation of triggering ventricular extrasystoles (VES) or other individual therapy.
Patients and methods: 20 patients (10 male, 41 +-18 years) with recurrent unexplained (documented) VF underwent genetic testing using comprehensive panels for primary arrhythmia syndromes (long QT, Brugada, catecholaminergic polymorphic ventricular tachycardia (CPVT)) and arrhythmogenic cardiomyopathy. Genetic variants were classified as pathogenic, likely pathogenic, variants of unknown significance (VUS), likely benign and benign following the current ACMG guidelines. All patients had cardiac examination including ECG, exercise test, Holter ECG, echocardiography, coronary angiography and cardiac magnetic resonance imaging. Family history of sudden unexplained cardiac death or maternal miscarriages were found in 5 patients. 17 patients had more than 1000 VES/24 hours in Holter ECG.

Results: Pathogenic or likely pathogenic genetic variants (RYR2, n=2; PKP2, n=2; SCN5A, n=1; FLNC, n = 1) were found in 6 patients. VUS were found in 3 patients (CAV3, n =1; HCN4, n=1; ABCC9, n =1) and a benign variant in homocygous form (SCN5A) in one patient. 7 patients underwent catheter ablation of triggering VES or inducible high frequent ventricular tachycardia which was successful in 6. Each 2 patients were treated with chinidine or flecainide and 3 patients received amiodarone. During the follow-up, the clinical phenotype of arrhythmogenic right ventricular cardiomyopathy and of long QT syndrome, respectively, became obvious in each one patient. In a reference group of 20 patients without the history of VF undergoing VES ablation, one patient had a VUS (SCN5A) and two patients had benign variants.

Conclusion: Genetic testing allowed the detection of CPVT-causative pathogenic RYR2 mutations in 2 patients. In 4 patients, the detection of a pathogenic or likely pathogenic variant prompted to probe deeper for clinical evidence of an underlying concealed channelopathy or arrhythmogenic cardiomyopathy in an unrecognized or pre-cardiomyopathic electrical state. Thus, genetic testing helps to improve patient selection for catheter ablation or individual drug therapy in a substantial part of patients with unexplained VF.