Abstract 976: Hyperpolarized Mitochondria in Right Ventricular Hypertrophy: a Target for Ventricular-Specific Therapies
Bibliographic record
Abstract
Objectives : The right ventricle (RV) fails quickly after increases in its afterload (pulmonary hypertension) compared to the LV (systemic hypertension). We hypothesized that the suboptimal performance of the hypertrophied RV (RVH) is caused by metabolic adaptation during hypertrophy. Mitochondria regulate metabolism, and mitochondrial membrane potential (ΔΨm) is a surrogate for mitochondrial function. Methods/Results : We measured ΔΨm in normal and hypertrophied myocardial specimens from 11 patients and in a rat model of RVH, using Tetramethylrhodamine methyl ester, a positively-charged dye that selectively localizes within the negatively charged mitochondria. ΔΨm was significantly higher in the normal LV compared to normal RV, and was the highest in RVH, both at the myocardium and isolated cardiomyocyte levels (p<0.01 for both). The increase in ΔΨm was recapitulated in an in vitro model of hypertrophy, where isolated neonatal cardiomyocytes were exposed to phenylephrine. This increase in ΔΨm was reversed by both a direct inhibitor of NFAT (Nuclear-Factor-of-Activated-T-lymphocytes, a transcription factor that regulates cardiac metabolism in development and hypertrophy) and Dichloroacetate (DCA, a metabolic modulator that has been shown to depolarize mitochondria and inhibit NFAT, reversing the phenotype of disease in both cancer and pulmonary hypertension) (p<0.01 for both). In ex-vivo Langendorff perfusions DCA acutely increased RV inotropy in rats with RVH (p<0.01) but not normal RVs, suggesting that the increased ΔΨm in RVH might be associated with its suboptimal performance in patients with pulmonary hypertension. Conclusions : The significant differences in ΔΨm between RV, LV, and RVH, can be targeted metabolically by DCA to improve contractility in RVH and provide a framework for development of novel RV-specific therapies.
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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 | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".