Abstract 18559: Double or Compound Sarcomere Mutations in Hypertrophic Cardiomyopathy is Not Associated With Worsened Outcomes: A Single Center Cohort Study
Bibliographic record
Abstract
Background: The presence of two or more pathogenic sarcomere mutations in patients with hypertrophic cardiomyopathy (HCM) has been reported to be associated with early disease onset, particularly marked left ventricular (LV) hypertrophy, and advanced heart failure. Objective: The aim of the study was to clarify the relationship between multiple disease-causing sarcomere mutations and major cardiovascular outcomes in a large HCM cohort. Methods and Results: Between June 1, 1995, and January 2015, 1104 probands with a diagnosis of HCM were routinely referred for systematic sarcomeric mutational screening at a single HCM center. Pathogenic mutations were identified in 273 (25%). Of these patients, 10 (3.6%) were identified with double/compound sarcomere mutations. They were mostly male (70%), presented at an average age of 33±13 years (range, 21-58), with an average maximal wall thickness of 17 mm (range, 13-26). Of the 9 patients who had a cardiac MRI, 8 (88%) had late gadolinium enhancement (LGE), none of which were considered to be extensive (>20% of LV myocardium). Over a mean follow up of 17.4 ±14 years (range, 3-48 years) there were no sudden cardiac death events. Adverse cardiovascular events or severe disease progression occurred in 4 (40%) patients, with an event rate of 3.4 per 100 patient-years follow up including: 2 (20%) with stroke, 3 (30%) with progression to end-stage HCM (EF<50%), and 1 (10%) with progression to New York Heart Association III/IV symptoms. One patient had myectomy for obstructive symptoms, while none required cardiac transplantation. Three (30%) patients had implantable cardioverter-defibrillator (ICD) for primary prevention. However, over a mean follow-up of 6 years (range 1-14 years), no ICD discharges were documented. Conclusion: These observations do not support the hypothesis that double (or compound) mutations confer a gene dosage effect in HCM, nor is it associated with an adverse prognosis. Mutation analysis has proven imprecise in predicting the phenotype or prognosis for patients with HCM, suggesting that genome-wide association studies and gene expression profiling may be needed for better understanding of its utility in the management of HCM patients.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".