Proteoglycan-Rich Leaflet Thickening in Diet-Induced Early Aortic Valve Disease
Bibliographic record
Abstract
Abstract Aortic valve disease (AVD) is a cell-mediated pathology without effective pharmacotherapy, and the early pathogenesis of AVD is drastically understudied. Examining the early stages of disease development may identify biomarkers and novel treatment strategies for use before an untreatable burden of calcification develops. We investigated the effects of a mildly atherogenic diet on early AVD development in mice, and the involvement of proteoglycans (PG) and Sox9 in this process. Male wild-type (WT) C57Bl/6J mice were fed a control diet or BioServ F3282, a high-fat, high-carbohydrate diet (HF/HC) with 58.7% kcal from fat (cholesterol <0.1% w/w) for four months (n = 4-6 per group). Aortic valve function was examined by high-resolution ultrasound biomicroscopy (UBM). Longitudinal aortic valve sections from formalin-fixed and paraffin-embedded hearts were stained by Movat’s pentachrome (morphological changes and ECM composition) and Osteosense 680 (calcification), then immunostained for α-smooth muscle actin (αSMA) and Sox9. Mice on the HF/HC diet for four months became significantly obese (46.7 ± 4.7 vs. 32.3 ± 0.8 g, p < 0.05) but did not develop cardiac hypertrophy. They developed mild but statistically significant hypercholesterolemia (4.7 ± 1.0 vs. 3.1 ± 0.4 mmol/L total cholesterol, p < 0.05). UBM revealed moderate decreases in aortic valve opening area along with increased left ventricular ejection time in HF/HC mice, while no mice exhibited aortic regurgitation. Significant valve thickening was found in the distal third of HF/HC leaflets (84.4 ± 10.4 vs. 37.3 ± 2.7 µm, p < 0.05), while proximal and medial regions were unaltered. Valve thickening was primarily due to PG deposition in HF/HC leaflets (11435 ± 7681 vs. 5448 ± 2948 µm2, p < 0.01), not an increase in collagen content (1729 ± 815 vs. 1771 ± 663 µm2, p = 0.87). Sox9 expression was increased in thickened HF/HC leaflets, and was most highly expressed in PG-rich lesions. HF/HC leaflets did not stain positive for αSMA, implying that changes in leaflet structure and function were not the result of actively synthetic myofibroblasts. Osteosense 680 staining was negative, denoting that the HF/HC diet did not induce leaflet microcalcification. These studies reveal that a high-fat Western diet lacking cholesterol can induce changes in the ECM and functional properties of a WT mouse aortic valve. This early AVD is characterized by thickened leaflets with lesions that are PG-rich and have increased Sox9 expression. Although AVD is considered to be driven by pathological myofibroblast differentiation leading to fibrosis and calcification, the early changes observed herein occur independently of myofibroblast activation, and provide new insight into the initiation and pathogenesis of AVD.
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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 | 0.001 | 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 | 0.001 |
| 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".