Abstract 9973: Combined Inhibition of Transforming-Growth Factorβ1 and Platelet-Derived Growth Factor Receptor Improves Right Ventricular Fibrosis and Diastolic Function in Experimental Right Ventricular Pressure-Loading
Bibliographic record
Abstract
Background: Residual lesions in repaired tetralogy of Fallot and other congenital heart diseases induce chronic right ventricular (RV) pressure and/or volume loading. These activate cardiac fibroblasts (CFs) resulting in pathological myocardial remodelling, including fibrosis, contributing to eventual RV diastolic dysfunction, failure, and mortality. Transforming growth factor (TGF)β1 and platelet-derived growth factor (PDGF) are implicated in generating a hyper-fibrotic response to ventricular pressure-loading through synergistic activation and proliferation of CFs. Hypothesis: Dual TGFβ1 and PDGF inhibition will effectively reduce fibrosis in response to RV pressure-loading and thereby improve RV function. Methods: Sprague-Dawley rats underwent pulmonary artery banding (PAB) to induce RV pressure-loading or sham surgery (n=10-12/group). One-week post-PAB, rats were randomized to Tranilast (TRN), a dual TGFβ1/ PDGF inhibitor treatment, (300mg/kg/day, p.o.) or vehicle (n=10-12/group) for 5-weeks. Catheter hemodynamics were measured prior to tissue collection. Results: Preliminary hemodynamic measurements (n=8-10/group) showed similar mean RV/LV pressure ratio (PAB Vehicle 0.8±0.22 vs. PAB TRN 0.81±0.23), +dP/dT, and -dP/dT in PAB groups. PAB TRN rats demonstrated improved end-diastolic pressure (7.0±1.7mmHg vs. 8.59±3.0mmHg), tau (24.15±9ms vs. 31.26±16.5ms), and end-systolic elastance (0.084±0.038mmHg/μL vs. 0.1139±0.057mmHg/μL) compared to PAB vehicle. These were associated with reduced RV collagen deposition (6.5±2.3% vs. 10±5.1%, p<0.05), hypertrophy (Fulton ratio 0.46±0.11 vs. 0.61±0.14, p=0.001), and cardiomyocyte area (921.4±131.7μm 2 vs. 1141±168.7μm 2 , p=0.003), when compared to PAB vehicle-treated controls. Immunoblotting (n=5-6/group) demonstrated reduced RV PDGFRβ expression and SMAD2/3 activation (phosphorylation), despite similar TGFβ1 levels in TRN-treated PAB rats vs. controls. Conclusion: Attenuation of TGFβR1 signalling and reduced PDGFRβ expression were associated with reduced fibrosis and hypertrophy and improved RV diastolic function. Combined inhibition of TGFβ1 and PDGF may be a relevant therapeutic target to improve RV diastolic function in RV pressure-loading.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".