Abstract 4147522: Myofibroblast transition and loss of UCP2 in a rat model and a human pulmonary hypertension cohort underline right ventricular decompensation: potential value of a loss-of-function UCP2 SNP
Bibliographic record
Abstract
Backgrounds: The mechanism driving the transition from compensated (cRVH) to decompensated right ventricular hypertrophy (dRVH) in pulmonary hypertension (PHT) is unknown. We hypothesized that a transition from cardiac fibroblasts (cFB) to cardiac myofibroblasts (cMFB) underlies this mechanism. Decreased mitochondrial calcium (mCa ++ ) promotes cMFB differentiation (from cFB). Methylation of mCa ++ uptake 1 (MICU1) and lack of UCP2 (uncoupling protein 2, a component of the mCa ++ uniporter complex) decrease mCa ++ . Methods/Results: In the monocrotaline-rat PHT model, we separated cRVH from dRVH based on strict catheterization and echo criteria: dRVH had decreased cardiac output, increased right atrial pressure, decreased tricuspid annular plane systolic excursion (TAPSE) and increased RV end-diastolic diameter compared to cRVH. In isolated hearts, RV systolic pressure was lower in dRVH but in isolated cardiomyocytes (CM), contractility (sarcomere shortening) was not, pointing to a non-cardiomyocyte cause. The number of cMFB was not different between cRVH and Control, but dramatically increased in dRVH. Mitochondrial respiration was lower in dRVH cMFB than cRVH cFB. mCa ++ was progressively decreased from Control to cRVH to dRVH c(M)FB, while it was not different in CM. The MICU1 methyltransferase (PRMT1) levels and MICU1 methylation were increased but the expression of UCP2 was decreased from Control to cRVH to dRVH c(M)FB (but not CM). In a cohort of 60 patients with human RV tissues, dRVH (based on clinical criteria) had increased cMFBs compared to Control and cRVH. Cytoplasmic PRMT1 was increased and UCP2 was decreased from Control to cRVH to dRVH c(M)FB. UCP2 protein level correlated negatively with the presence of a loss-of-function SNP (rs659366) and positively with TAPSE. In a subgroup that had Echo and right heart catheterization data within 2 days, carriers of the UCP2 SNP had decreased TAPSE compared to non-carriers with similar mean PA pressure. Conclusion: Our data point to a change of cell identity (cFB to cMFB) in the RV as the basis of RV decompensation. UCP2 SNPs may be promising biomarkers for RV failure in PHT patients.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".