Characterisation of familial idiopathic ventricular fibrillation linked to DPP6
Bibliographic record
Abstract
Purpose: Idiopathic ventricular fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p<0.01 vs non-carriers), with events starting from age 16 with a worse phenotype in males (median survival 59 vs 82 years, p<0.01 vs females). Biopsy studies uncovered DPP6 mRNA overexpression in carriers (p<0.01 vs controls). Studies in non-diseased explanted human hearts revealed higher DPP6 mRNA expression in Purkinje fibers than in other regions (p<0.01 vs ventricular myocardium) while DPP6-overexpression significantly increased Ito density in canine Purkinje cells (∼52%, p<0.05 vs control) but not in cardiomyocytes, further underpinning the importance of the Purkinje network in the DPP6 risk haplotype. Conclusions: A new arrhythmia gene DPP6 is linked to familial IVF and shows a malignant phenotype. Our results point to a pivotal role of DPP6 overexression in Purkinje fibers eliciting short-coupled extrasystoles which trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".