Abstract 4366239: Rare Variants in Cardiomyopathy and Channelopathy Genes are Associated with Severe Ventricular Arrhythmias in Mitral Valve Prolapse
Bibliographic record
Abstract
Introduction: Mitral valve prolapse (MVP) is a common valvular disorder associated, in a minority of cases, with severe arrhythmic events including sudden cardiac arrest/death (SCA/SCD). Traditional imaging parameters of arrhythmic risk such as bileaflet prolapse, mitral annular disjunction (MAD), and late gadolinium enhancement by cardiac MRI are not found in all SCA survivors, suggesting an alternative arrhythmogenic mechanism. Recently, the presence of a genetic myopathy and/or channelopathy has been suggested in MVP, albeit only in case reports or cross-sectional investigations. Hence, the utility of genetic testing in MVP remains uncertain. Hypothesis: Testing for cardiomyopathy/channelopathy (CC) variants in a large MVP cohort will identify a subset with pathogenic/likely pathogenic (P/LP) variants associated with an increased risk of severe arrhythmic events longitudinally. Methods: We prospectively recruited MVPs at the University of California, San Francisco between 2017 and 2024. 196/220 patients underwent whole exome sequencing. Variants of interest were rare (<0.1% frequency), protein-coding, nonsynonymous variants in genes present on a selected clinical Arrhythmia and Cardiomyopathy panel. P/LP classification was assigned with an automated algorithm (Franklin). Severe arrhythmic events were defined as SCA/SCD or sustained ventricular arrhythmias requiring an implantable cardioverter defibrillator (ICD) or ablation. We assessed the risk of severe arrhythmic outcomes in MVPs with and without CC P/LP variants using both adjusted logistic regression and survival analyses. Results: We included 196 MVPs, of which 187 (95%) had CC variants and 20 (10%) were P/LP ( Figure 1 ). None of the MVPs in our study demonstrated channelopathy or overt cardiomyopathy. However, P/LP variants were significantly associated with severe arrhythmic events after adjusting for age, sex, bileaflet involvement, and MAD (Odds Ratio: 3.1, p=0.03). Time to event analysis confirmed that MVPs with P/LP variants were at significantly increased risk for severe arrhythmic events starting at birth ( Figure 2 ). Conclusions: Occult P/LP variants associated with cardiomyopathy or channelopathy independently increase the risk of severe arrhythmic events in MVP. Genetic testing should be investigated as a novel arrhythmic risk stratification tool for MVP, especially for cases that may not yet demonstrate an arrhythmic phenotype but may need closer clinical follow-up.
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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 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.004 | 0.001 |
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".