Abstract 15760: A Critical Contribution of Cardiac Myofibroblasts and a Predictive Role of UCP2 SNPs in the RV Decompensation in Pulmonary Hypertension
Bibliographic record
Abstract
Introduction/hypothesis: 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 ++ , and therefore, activity of Krebs enzymes that produce diffusible metabolites, regulating epigenetic mechanisms that drive change in cell identity. Methods/Results: In the monocrotaline-rat PHT model, we separated cRVH from dRVH based on strict hemodynamics (canulating the main pulmonary artery through the jugular vein) and Echo: dRVH had decreased cardiac output, increased right atrium pressure, decreased 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 difference. 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 methylation of immunoprecipitated MICU1 were increased but the expression of UCP2 was decreased from Control to cRVH to dRVH c(M)FB (but not CM). In human RV tissues (from autopsy or biopsy, n=15), dRVH had increased number of cMFB compared to Control and cRVH. Cytoplasmic PRMT1 was increased and UCP2 was decreased from Control to cRVH to dRVH c(M)FB. In a cohort of 25 patients with PHT that had Echo and right heart Cath within 48 hours, carriers of the loss-of-function UCP2 SNP (rs659366) had decreased TAPSE compared to non-carriers that had similar mean PA pressure. Conclusion: A change of cell identity (cFB to cMFB) in the RV may be the basis of cRVH to dRVH transition, rather than contractile failure of CM. UCP2 SNP may predict early dRVH, if confirmed in larger cohorts.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 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) | 0.006 | 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".