Left atrial remodeling in hypertrophic cardiomyopathy: morphological and transcriptional insights
Bibliographic record
Abstract
Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder. Left atrial (LA) myopathy, as a key feature of HCM, significantly increases the risk of atrial fibrillation (AF), hospitalization rates, and thromboembolism. Evidence suggests that AF in HCM arises from progressive LA remodeling, characterized by early structural and functional alterations preceding the onset of atrial arrhythmia. However, the cellular and molecular mechanisms driving this process remain poorly understood. Purpose This study aimed to enhance our understanding of structural and transcriptional changes in the remodeling LA during disease progression in HCM. Methods We conducted a longitudinal analysis of a non-obstructive MYH7 R403Q Yucatan minipig model. LA tissue was collected from 16 WT and 15 R403Q swine at early, mid and late disease stages from 2-13 month. Additionally, we analyzed explanted human LA tissue from 9 end-stage HCM patients (MYH7: n=4, MYBPC3: n=5) and 16 non-failing donors. Confocal microscopy and deep learning-based 3D image analysis were used to quantify cardiomyocyte (CM) volume, eccentricity (length-to-width ratio), and nuclei count. Single-nucleus RNA sequencing (snRNAseq) was performed on LA tissue from both pigs and humans to assess transcriptional changes. Results At 6 months, echocardiography revealed a significantly increased LA area in R403Q pigs (1457.0 ± 203.5 mm² vs. 801.9 ± 44.6 mm²; p = 4.3e-2). Moreover, Masson’s trichrome staining showed significant more fibrosis in mutant animals. Volumetric analysis of >22,500 CMs identified a ~4.5-fold and ~13-fold increase of cell volume over time in WT and R403Q (2-way ANOVA, genotype effect: p = 6.4e-41), respectively (Fig. 1 and 2). This cellular hypertrophy was driven by increases in both cell length and width. Quantification of nuclei count revealed a significantly higher number of bi- and multi-nucleated CMs in R403Q across all disease stages, with a strong correlation to cell volume (r = 0.81, p = 2.0e-8). SnRNAseq identified a progressive shift in CM states from a default atrial to a disease-related gene expression profile in R403Q pigs, specifically driven by transition from the atrial paralog MYH6 to the ventricular MYH7 (Fig. 1). Consequently, this resulted in a significant atrial expression of the mutant allele in R403Q pigs. We observed similar trends in humans with higher CM volume in end-stage HCM and a corresponding shift from MYH6 to MYH7 expression. Conclusion Our findings demonstrate that LA remodeling in R403Q pigs is characterized by progressive CM hypertrophy, fibrosis, and transcriptional reprogramming at the CM level. Similar trends in human end-stage HCM suggest a shared pathological mechanism. The increased atrial expression of the mutant MYH7 allele may contribute to atrial myopathy and the previously reported highest AF incidence in MYH7 HCM.Left Atrial Remodeling in Yucatan Pigs Cardiomyocyte Segmentations (Pig)
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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 | 0.000 | 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".