14 Myocardial sheetlet abnormality as a marker of sarcomere dysfunction in carriers of rare HCM-causing sarcomere gene variants before phenotypic conversion
Bibliographic record
Abstract
Introduction Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac muscle disease and a major cause of sudden cardiac death in young adults.1 It is characterised by unexplained left ventricular hypertrophy (LVH), typically caused by rare gene variants affecting cardiac sarcomere.2 Genetic screening identifies asymptomatic sarcomere variant carriers before LVH develops, i.e. genotype-positive phenotype-negative G+P-(HCM) subjects who require regular surveillance. However, current phenotyping is limited to the macroscopic scale. Diffusion tensor cardiovascular magnetic resonance (DT-CMR) non-invasively probes the myocardial microstructurein vivo,3characterising cardiomyocytes and their functional units (sheetlets) and can provide new insights into the pathophysiology of HCM. We aimed to investigate if DT-CMR can detect abnormal myocardial microstructure in G+P-(HCM) subjects before phenotypic conversion. Materials and Methods In-vivo DT-CMR of mid-LV short axis slice was performed using stimulated echo acquisition mode sequence on a 3T Vida scanner3 in G+P-(HCM) patients and healthy volunteers (HVOL). G+P-(HCM) patients carried a HCM-causing sarcomere variant confirmed by Sanger sequencing and had maximal LV wall thickness (LVWT) <13 mm on CMR. This study was ethically approved (13/LO/1830). Results 25 G+P-(HCM) were matched with 20 HVOL for age and gender. There was no difference between the cohorts in the LVWT at the imaged by DT-CMR slice, LV volumes, mass, ejection fraction, systolic strain, native T1 and T2 values, ECV% and LGE%. G+P-(HCM) subjects had significantly elevated second eigenvector angle (E2A), i.e. sheetlet angle when compared to HVOL: diastolic E2A 18°(14–21) vs 15°(12–17) and systolic E2A 70°(±5) vs 64°(±5). There was no difference in sheetlet mobility, magnitude of diffusivity (mean diffusivity) or its anisotropy (fractional anisotropy). Discussion This is the first in human study demonstrating that in G+P-(HCM) patients myocardial sheetlet abnormality affects both diastole and systole and precedes irreversible changes (LVH and myocardial tissue alteration). This likely reflects primary sarcomere defect caused by rare gene variants, occurring early in the pathophysiological cascade of HCM development. E2A abnormality should be investigated further as a potential novel pre-phenotypic imaging biomarker of sarcomere dysfunction in G+P-(HCM) and a target for developing therapeutics aimed at mitigating phenotypic conversion before irreversible myocardial tissue changes occur. Conclusion DT-CMR detects myocardial sheetlet abnormality which precedes the development of irreversible phenotypic changes in G+P-(HCM) and may be an early and potentially modifiable marker of disease. Acknowledgements This study is supported by the British Heart Foundation (BHF programme grant RG 19/1/34160). We are also grateful to our collaborators Professor Sanjay Prasad, Dr Antonis Pantazis, Dr Tessa Homfray and Dr Deborah Morris-Rosendahl. References O’Mahony C, Jichi F, Pavlou M, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Gimeno JR, Limongelli G, McKenna WJ, Omar RZ, Elliott PM, Ortiz-Genga M, Fernandez X, Vlagouli V, Stefanadis C, Coccolo F, Sandoval MJO, Pacileo G, et al. A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk-SCD). Eur Heart J. 2014;35(30):2010–2020. Walsh R, Buchan R, Wilk A, John S, Felkin LE, Thomson KL, Chiaw TH, Loong CCW, Pua CJ, Raphael C, Prasad S, Barton PJ, Funke B, Watkins H, Ware JS, Cook SA. Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes. Eur Heart J. 2017;38(46):3461–3468. Nielles-Vallespin S, Khalique Z, Ferreira PF, de Silva R, Scott AD, Kilner P, McGill LA, Giannakidis A, Gatehouse PD, Ennis D, Aliotta E, Al-Khalil M, Kellman P, Mazilu D, Balaban RS, Firmin DN, Arai AE, Pennell DJ. Assessment of myocardial microstructural dynamics by in vivo diffusion tensor cardiac magnetic resonance. J Am Coll Cardiol. 2017;69(6):661–676.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".