Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary artery smooth muscle cell proliferation and impaired apoptosis leading to obstruction of resistance pulmonary arteries. We hypothesized that antiproliferative (rapamycin) and proapoptotic (statins) agents, already used clinically for other indications, would decrease experimental PAH, facilitating translation to human therapies. Prior studies in the rat monocrotaline-PAH model have indicated that simvastatin regresses and rapamycin prevents, but cannot reverse, PAH. Two PAH regression strategies (rapamycin monotherapy vs. rapamycin + atorvastatin) and one prevention strategy (simvastatin) were tested in a rat monocrotaline-PAH model. Adult male Sprague-Dawley rats were randomized to saline (n = 6) or monocrotaline (60 mg/kg ip, n = 36) treatment groups. Monocrotaline rats were randomized to gavage with vehicle, rapamycin (2.5 mgxkg(-1)xday(-1)), or rapamycin + atorvastatin (10 mgxkg(-1)xday(-1)) treatment groups, beginning 12 days post-monocrotaline. Echocardiographic and hemodynamic end points were assessed 2 wk later. Additional monocrotaline-PAH rats (n = 20) were randomized to vehicle or simvastatin (2 mgxkg(-1)xday(-1)) treatment groups and followed echocardiographically for 4 wk. Monocrotaline-PAH increased lung p70 S6 kinase phosphorylation, and this was reversed by rapamycin, confirming the biological activity of rapamycin. Despite the use of high doses, neither rapamcyin nor rapamycin + atorvastatin improved survival nor reduced PAH, vascular remodeling, and right ventricular hypertrophy. Although prophylactic simvastatin slowed PAH progression, by 4 wk PAH severity and mortality were not different from placebo. Apart from the new finding of p70 S6 kinase phosphorylation in monocrotaline-PAH, this is a negative therapeutic trial (none of these promising therapies improved monocrotaline-PAH). These negative results should be considered as human trials with these agents are underway (simvastatin) or proposed (rapamycin).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".