Metabolism and Bioenergetics in the Right Ventricle and Pulmonary Vasculature in Pulmonary Hypertension
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary vascular cross sectional area and compliance are reduced by vasoconstriction, vascular remodeling, and inflammation. Vascular remodeling results in part from increased proliferation and impaired apoptosis of vascular cells. The resulting increase in afterload promotes right ventricular hypertrophy (RVH) and RV failure. Recently identified mitochondrial-metabolic abnormalities in PAH, notably pyruvate dehydrogenase kinase-mediated inhibition of pyruvate dehydrogenase (PDH), result in aerobic glycolysis in both the lung vasculature and RV. This glycolytic shift has diagnostic importance since it is detectable early in experimental PAH by increased lung and RV uptake of (18)F-fluorodeoxyglucose on positron emission tomography. The metabolic shift also has pathophysiologic and therapeutic relevance. In RV myocytes, the glycolytic switch reduces contractility while in the vasculature it renders cells hyperproliferative and apoptosis-resistant. Reactivation of PDH can be achieved directly by PDK inhibition (using dichloroacetate), or indirectly via activating the Randle cycle, using inhibitors of fatty acid oxidation (FAO), trimetazidine and ranolazine. In experimental PAH and RVH, PDK inhibition increases glucose oxidation, enhances RV function, regresses pulmonary vascular disease by reducing proliferation and enhancing apoptosis, and restores cardiac repolarization. FAO inhibition increases RV glucose oxidation and RV function in experimental RVH. The trigger for metabolic remodeling in the RV and lung differ. In the RV, metabolic remodeling is likely triggered by ischemia (due to microvascular rarefaction and/or reduced coronary perfusion pressure). In the vasculature, metabolic changes result from redox-mediated activation of transcription factors, including hypoxia-inducible factor 1α, as a consequence of epigenetic silencing of SOD2 and/or changes in mitochondrial fission/fusion. Randomized controlled trials are required to assess whether the benefits of enhancing glucose oxidation are realized in patients with 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".