During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27–51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001). Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.

Previously, we demonstrated that inferolateral mitral annular disjunction (MAD) is more prevalent in patients with idiopathic ventricular fibrillation (IVF) than in healthy controls. In the present study, we advanced the insights into the prevalence and ventricular arrhythmogenicity by inferolateral MAD in an even larger IVF cohort. This retrospective multi-centre study included 185 IVF patients [median age 39 (27, 52) years, 40% female]. Cardiac magnetic resonance images were analyzed for mitral valve and annular abnormalities and late gadolinium enhancement. Clinical characteristics were compared between patients with and without MAD. MAD in any of the 4 locations was present in 112 (61%) IVF patients and inferolateral MAD was identified in 24 (13%) IVF patients. Mitral valve prolapse (MVP) was found in 13 (7%) IVF patients. MVP was more prevalent in patients with inferolateral MAD compared with patients without inferolateral MAD (42 vs. 2%, P < 0.001). Pro-arrhythmic characteristics in terms of a high burden of premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (VT) were more prevalent in patients with inferolateral MAD compared to patients without inferolateral MAD (67 vs. 23%, P < 0.001 and 63 vs. 41%, P = 0.046, respectively). Appropriate implantable cardioverter defibrillator therapy during follow-up was comparable for IVF patients with or without inferolateral MAD (13 vs. 18%, P = 0.579). A high prevalence of inferolateral MAD and MVP is a consistent finding in this large IVF cohort. The presence of inferolateral MAD is associated with a higher PVC burden and non-sustained VTs. Further research is needed to explain this potential interplay. ICD, implantable cardioverter defibrillator; ilMAD, inferolateral mitral annular disjunction; PVC, premature ventricular complex; NSVT, non-sustained ventricular tachycardia.

Background: Idiopathic ventricular fibrillation (iVF) is a rare cause of sudden cardiac arrest and, by definition, a diagnosis of exclusion. Due to the rarity of the disease, previous and current studies are limited by their retrospective design and small patient numbers. Even though the incidence of iVF has declined owing to the identification of new disease entities, an important subgroup of patients remains. Aim: To expand the existing Dutch iVF Registry into a large nationwide cohort of patients initially diagnosed with iVF, to reveal the underlying cause of iVF in these patients, and to improve arrhythmia management. Methods: The Dutch iVF Registry includes sudden cardiac arrest survivors with an initial diagnosis of iVF. Clinical data and outcomes are collected. Outcomes include subsequent detection of a diagnosis other than ‘idiopathic’, arrhythmia recurrence and death. Non-invasive electrocardiographic imaging is used to investigate electropathological substrates and triggers of VF. Results: To date, 432 patients have been included in the registry (median age at event 40 years (interquartile range 28–52)), 61% male. During a median follow-up of 6 (2–12) years, 38 patients (9%) received a diagnosis other than ‘idiopathic’. Eleven iVF patients were characterised with electrocardiographic imaging. Conclusion: The Dutch iVF Registry is currently the largest of its kind worldwide. In this heterogeneous population of index patients, we aim to identify common functional denominators associated with iVF. With the implementation of non-invasive electrocardiographic imaging and other diagnostic modalities (e.g. echocardiographic deformation, cardiac magnetic resonance), we advance the possibilities to reveal pro-fibrillatory substrates.

Idiopathic ventricular fibrillation is a rare cause of sudden cardiac arrest and a diagnosis by exclusion. Unraveling the mechanism of ventricular fibrillation is important for targeted management, and potentially for initiating family screening. Sudden cardiac arrest survivors undergo extensive clinical testing, with a growing role for multimodality imaging, before diagnosing “idiopathic” ventricular fibrillation. Multimodality imaging, considered as using multiple imaging modalities as diagnostics, is important for revealing structural myocardial abnormalities in patients with cardiac arrest. This review focuses on combining imaging modalities (echocardiography, cardiac magnetic resonance and computed tomography) and the electrocardiographic characterization of sudden cardiac arrest survivors and discusses the surplus value of multimodality imaging in the diagnostic routing of these patients. We focus on novel insights obtained through electrostructural and/or electromechanical imaging in apparently idiopathic ventricular fibrillation patients, with special attention to non-invasive electrocardiographic imaging.

Deterioration of atrial fibrillation into ventricular fibrillation has frequently been described in patients with pre -excitation of the ventricles. We report two cases of atrial fibrillation without pre-excitation leading to rapid ventricular tachycardias and recurrent implantable cardioverter defibrillator therapy in young idiopathic ven-tricular fibrillation patients.

Current cohorts of idiopathic ventricular fibrillation (IVF) patients primarily include adult-onset patients. Underlying causes of a sudden cardiac arrest vary with age, therefore underlying causes and disease course may differ for adolescent-onset versus adult-onset patients. To compare adolescent-onset with adult-onset patients with an initially unexplained cause for VF. This study includes 39 patients with an index event ≤19 years (adolescent-onset) and 417 adult-onset patients from the Dutch Idiopathic VF registry. Event circumstances, clinical characteristics, a change in diagnosis, and arrhythmia recurrences were collected and compared between the two groups. In total, 42 patients received an underlying diagnosis during follow-up (median of 7 [2 - 12] years), with a similar yield (15% for adolescent-onset vs. 9% for adult-onset, p=0.16). Among the remaining unexplained patients, adolescent-onset patients (n=33) had their index event at a median age of 17 [16 - 18] years, 72% were male. The youngest patient was 13 years. In comparison with adults (n=381), adolescent-onset patients more often had their index event during exercise (p<0.01). Adolescent-onset patients experienced more appropriate implantable cardioverter defibrillator (ICD) therapy (44% vs. 26%, p=0.03) during follow-up compared with adults. Inappropriate ICD therapy (26% vs. 17%, p=0.19), ICD complications (19% vs. 14%, p=0.41) and deaths (3% vs. 4%, p=1.00) did not significantly differ between adolescent-onset and adult-onset patients. IVF may occur in adolescence. Adolescent-onset patients more often present during exercise compared with adults. Furthermore, they are more vulnerable for ventricular arrhythmias reflected by a higher incidence of appropriate ICD therapy.