Abstract 4139461: Proteomic and Phosphoproteomic Profiling in an Experimental Model of Electrical Storm
Bibliographic record
Abstract
Background: Electrical storm (ES), characterized by clustered ventricular tachycardia/fibrillation (VT/VF) episodes, is a major problem with substantial mortality in patients with implantable cardioverter-defibrillators (ICDs) and ischemic/non-ischemic cardiomyopathy, but available therapeutic approach is suboptimal, likely due to incomplete understanding of the pathophysiology. Objective: To identify the cardiac-specific features of protein/phosphoprotein changes in experimental ES. Methods: The model was created by inducing chronic complete atrioventricular-block in ICD-implanted rabbits, causing hypertrophy, QT prolongation, and frequent VT/VF-episodes. Relative protein/phosphoprotein abundances in hearts from 4 rabbits with ES (defined as ≥3 VF-episodes/24-hr period) experiencing 97±27 VF-episodes and 4 controls (CTL) were assessed by iTRAQ LC-MS/MS and key regulatory pathways were examined by Ingenuity-Pathway-Analysis. Results: Proteomic analysis identified 1938 proteins, 106 of which were differentially expressed between ES and CTL (False Discovery Rate (FDR)<0.1). ES was profoundly associated with mitochondrial dysfunction, oxidative phosphorylation inactivation and ATP depletion along with decreased measurement of electron transport chain and ATP synthase proteins and inner membrane-localized transporters and enzymes. Reductions in mitochondrial matrix-enzymes inferred downregulation of fatty acid β-oxidation and TCA cycle. Phosphoproteome detected 641 phosphorylated proteins, 82 of which have changes in phosphorylation state in ES versus CTL (FDR<0.1). Hyperphosphorylation of Z-disc proteins/associated proteins of sarcomeres, especially N-terminals of titin, and actin and protein kinase A subunits predicted striated muscle contraction and integrin signaling activation, which in part explain cardiac dilation with enhanced contractility due to sustained bradycardia in this model. Nuclear integrators for mitochondrial biogenesis and function, including cyclic AMP-response element binding, peroxisome proliferative activated receptor gamma, coactivator 1 alpha and nuclear respiratory factor 1, were activated, the prediction opposite to proteomic data. The activation status of other pathways linked to heart failure was undeterminable. Conclusion: ES is associated with evidence of mitochondrial dysfunction, known to contribute to ventricular dysfunction and arrhythmogenesis. Mitochondria-targeted agents merit further investigations as therapeutic targets in ES.
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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".