Investigating the Diversity of Right Ventricular (RV) Macrophages and Their Relationship With the Incidence of Circulating Inflammatory Monocytes and RV Dysfunction: A Longitudinal Study in Rats With Monocrotaline Induced Pulmonary Hypertension
Bibliographic record
Abstract
Abstract Rationale: Right ventricular failure (RVF) is the leading cause of death in pulmonary arterial hypertension (PAH). In males with RVF, there is an increase in the number of blood-recruited macrophages in the RV which express C-C chemokine receptor 2 (CCR2). The timing of monocyte recruitment remains unclear. We hypothesized that recruitment of inflammatory monocytes to the RV contributes to the development of RVF. Methods: PAH was induced in male rats using monocrotaline (MCT; 60mg/kg). A longitudinal study was conducted at: 5, 10, 14, 20, and 24 days after MCT (n=4/group, control rats included). PA pressure (estimated from the pulmonary artery acceleration time, PAAT) and RV function (estimated from RV free wall thickness (%RVFWT) and tricuspid annular plane systolic excursion, TAPSE) were assessed via echocardiography. Circulating monocytes were identified using flow cytometry and distinguished as inflammatory (CD43LoHis48Hi) or anti-inflammatory (CD43HiHis48Lo). RV macrophages were identified as CD68+ cells using immunofluorescence, and CCR2 and myeloperoxidase (MPO) were used to distinguish macrophage subtypes. Results were statistically analyzed. Results: PAAT was reduced 14 days after MCT (PBS: 30.06±5.98 vs MCT: 24.07±1.50 ms; p<0.004), indicating the presence of pulmonary hypertension. TAPSE and RVFWT% were reduced within 14 days, while cardiac output (CO) was reduced by day 20 (PBS: 106.7±21.3 vs MCT: 44.2±1.7 ml/min; p=0.03). Inflammatory monocytes were 1.27 (p=0.04) and 1.54 (p=0.0002) times higher in MCT rats than controls at days 20 and 24, respectively. Total RV macrophages were significantly more abundant in MCT rats on day 14, reaching its highest at day 20 and 24 (p<0.003). Resident CCR2- macrophages were the most abundant subtype at the earlier time points (5 to 14 days), whereas blood-recruited CCR2+ macrophages peaked at the day 20 (p<0.0001; Fig1), suggesting that resident macrophages account for the rise in total RV macrophages at earlier time points, while the increase of recruited macrophages occurs later. The incidence of inflammatory monocytes correlated with RV CCR2+ macrophages (r2=0.49, p=0.03) and CO (r2=-0.50, p=0.03) at days 20 and 24. Macrophages expressing MPO, a marker for oxidative stress, were elevated only on day 24, implying its involvement in an acute response to RVF. Conclusion: Blood-recruited and resident RV macrophages are differentially regulated during PAH progression. The elevation of blood-recruited RV macrophages in later stages of the disease coincides with a critical reduction in CO, and increased circulating inflammatory monocytes. This association suggests a role for recruited macrophages as a pathogenic mechanism of RVF in PAH.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".