The Dutch Idiopathic Ventricular Fibrillation Registry: progress report on the quest to identify the unidentifiable.

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.

Comparing adolescent- and adult-onset unexplained cardiac arrest: Results from the Dutch Idiopathic VF Registry.

BACKGROUND: Current cohorts of patients with idiopathic ventricular fibrillation (IVF) primarily include adult-onset patients. Underlying causes of sudden cardiac arrest vary with age; therefore, underlying causes and disease course may differ for adolescent-onset vs adult-onset patients. OBJECTIVE: The purpose of this study was to compare adolescent-onset with adult-onset patients having an initially unexplained cause of VF. METHODS: The study included 39 patients with an index event aged ≤19 years (adolescent-onset) and 417 adult-onset patients from the Dutch Idiopathic VF Registry. Data on event circumstances, clinical characteristics, change in diagnosis, and arrhythmia recurrences were collected and compared between the 2 groups. RESULTS: In total, 42 patients received an underlying diagnosis during follow-up (median 7 [2-12] years), with similar yields (15% adolescent-onset vs 9% adult-onset; P = .16). Among the remaining unexplained patients, adolescent-onset patients (n = 33) had their index event at a median age of 17 [16-18] years, and 72% were male. The youngest patient was aged 13 years. In comparison with adults (n = 381), adolescent-onset patients more often had their index event during exercise (P <.01). Adolescent-onset patients experienced more appropriate implantable cardioverter-defibrillator (ICD) therapy during follow-up compared with adults (44% vs 26%; P = .03). Inappropriate ICD therapy (26% vs 17%; P = .19), ICD complications (19% vs 14%; P = .41), and deaths (3% vs 4%; P = 1) did not significantly differ between adolescent-onset and adult-onset patients. CONCLUSION: IVF may occur during adolescence. Adolescent-onset patients more often present during exercise compared with adults. Furthermore, they are more vulnerable to ventricular arrhythmias as reflected by a higher incidence of appropriate ICD therapy.

The genetic basis of apparently idiopathic ventricular fibrillation: a retrospective overview.

AIMS: 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. METHODS AND RESULTS: 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). CONCLUSION: 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.

Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation: a focused update.

BACKGROUND: The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. METHODS: DPP6 risk haplotype-positive family members (DPP6 cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. RESULTS: We included 327 DPP6 cases and 315 DPP6 controls. Median follow-up time was 9 years (interquartile range: 4-12). Of the DPP6 cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at a median age of 45 years (range: 15-97). Median overall survival was 83 years and 87 years for DPP6 cases and DPP6 controls, respectively (p < 0.001). In DPP6 cases, median overall survival was shorter for males (74 years) than females (85 years) (p < 0.001). Of the DPP6 cases, 97 (30%) died, at a median age of 50 years. With a prophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6 cases received an ICD, for primary prevention (n = 109) or secondary prevention (n = 28). In the primary prevention subgroup, 10 patients experienced a total of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6 cases with a secondary prevention ICD experienced a total of 231 appropriate ICD shocks. CONCLUSION: Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using a risk stratification approach based on risk haplotype, sex and age, a substantial proportion of patients with a primary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.

Importance of Systematic Diagnostic Testing in Idiopathic Ventricular Fibrillation: Results From the Dutch iVF Registry.

BACKGROUND: Idiopathic ventricular fibrillation (iVF) is a diagnosis of exclusion. Systematic diagnostic testing is important to exclude alternative causes for VF. The early use of "high yield" testing, including cardiac magnetic resonance (CMR), exercise testing, and sodium channel blocker provocation, has been increasingly recognized. OBJECTIVES: The purpose of this study was to investigate the importance and consistency of systematic diagnostic testing in iVF. METHODS: This study included 423 iVF patients from 11 large secondary and tertiary hospitals in the Netherlands. Clinical characteristics and diagnostic testing data were ascertained. RESULTS: IVF patients experienced the index event at a median age of 40 years (IQR: 28-52 years), and 61% were men. The median follow-up time was 6 years (IQR: 2-12 years). Over the years, "high yield" diagnostic tests were increasingly performed (mean 68% in 2000-2010 vs 75% in 2011-2021; P < 0.001). During follow-up, 38 patients (9%) originally labeled as iVF received an alternative diagnosis. Patients in whom "high-yield" diagnostic tests were consistently performed during the initial work-up received an alternative diagnosis less frequently during follow-up (HR: 0.439; 95% CI: 0.219-0.878; P = 0.020). Patients who received an alternative diagnosis during follow-up had a worse prognosis in terms of cardiac death (P = 0.012) with a trend toward more implantable cardioverter-defibrillator therapy (P = 0.055). CONCLUSIONS: Although adherence to (near) complete diagnostic testing in this population of iVF patients increased over the years, patients with iVF still undergo varying levels of diagnostic evaluation. The latter leads to initial underdiagnosis of alternative conditions and is associated with a worse prognosis. Our results underscore the importance of early systematic diagnostic assessment in patients with apparent iVF.

Atrial fibrillation begets ventricular fibrillation when the AV node fails.

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 ventricular fibrillation patients.

State-of-the-Art Multimodality Imaging in Sudden Cardiac Arrest with Focus on Idiopathic Ventricular Fibrillation: A Review.

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.

[A woman with shortness of breath and a rash]. / Een vrouw met dyspneu en een huidafwijking.

A 74-year-old woman presented with progressive dyspnoea which started a few days after developing a unilateral dermatomal rash characteristic for herpes zoster at dermatome C4-C5. X-ray of the thorax showed an elevated hemidiaphragm ipsilateral of the skin abnormalities. Cervical herpes zoster is a rare cause of a unilateral elevated hemidiaphragm.