Abstract 16016: Role For Macitentan in Angiogenesis of Right Ventricle, Peripheral Muscle and Lungs in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by remodeling of distal pulmonary arteries (PA) leading to increased mean PA pressure, subsequent right ventricular (RV) failure and ultimately death of patients. Impaired angiogenesis is now recognized as a major factor in PAH etiology. It contributes not only to the decrease in lung perfusion but also to a rarefaction of the capillary network within the skeletal muscle and RV leading to exercise intolerance and RV failure. Several studies have suggested that endothelin-1 (ET-1) contributes to decrease angiogenesis in PAH. In light of these observations, we hypothesized that macitentan, an ET-1 receptors blocker, improves PAH by promoting angiogenesis in lungs, RV and skeletal muscles. Methods/Results: In the Sugen/hypoxia rat model of PAH, we demonstrated by right catheterization in closed chest rats that compared to vehicle treated animals, daily treatment during two weeks with macitentan (30 mg/kg) decreases significantly mean PA pressure (n=8-20; p<0.01) and total pulmonary resistance (n=8-20; p<0.05) and improves cardiac output, stroke volume (n=7-17; p<0.05) and RV hypertrophy measured by echo (n=6-10; p<0.05). These effects were associated with an increase of 2.9 fold in lung blood perfusion (n=6), 4.1 fold in quadriceps perfusion (n=5-7) and 1.5 fold in right ventricle perfusion (n=5-6) measured in vivo by micro CT angiogram (p<0.05). Both in vivo lectin perfusion (n=4-10; p<0.05) and immunologic CD31 staining (n=4-5; p<0.05) confirmed these findings. In the lungs, the hemodynamic and perfusion improvements were associated with decreased vascular remodeling (H&E) (n=6-17; p<0.01). In vitro, using primary cultured human endothelial cells isolated from distal PA (PAEC) and RV (RVEC), we showed that macitentan decreases PAH-PAEC proliferation (Ki67 assay) and resistance to apoptosis (TUNEL assay), while increasing angiogenesis capacity of healthy PAEC and RVEC (matrigel assay). Conclusion: Our data provide structural and functional evidence that ET-1 receptor inhibition with macitentan may improve PAH by promoting angiogenesis.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".