Abstract P3138: Potentiation Mechanism Of SR-Ca2+ Uptake During Myocardial Infarction; A Molecular Explanation Of Ca2+ Arrhythmogenicity Of Purkinje Fibers In The Ischemic Heart.
Bibliographic record
Abstract
Experimental and clinical evidence attributes lethal VTs and VFs associated with ischemic myocardial infarctions ( MI ) to abnormal electric signaling in the Purkinje network. In cardiac Purkinje cells ( Pcells ), spontaneous Ca 2+ releases from the sarcoplasmic reticulum ( SR-CaR ) generate depolarizing Ca 2+ waves which, in turn, can mediate DADs and non-driven APs. Increase of SR-CaR was reported in Pcells of dog heart with 48Hrs MI. An augmentation of SR-Ca 2+ uptake ( SR-CaU ) accelerates SR-Ca 2+ recycling and is a possible cause of larger (pro-arrhythmic) SR-CaR in Pcells of ischemic heart. We tested this hypothesis in canine and porcine models of acute MI.Pcells and heart tissues were prepared 48Hrs after LAD coronary artery ligation. Intracellular Ca 2+ activity was captured by confocal microscopy. SR-CaU was studied by analyzing Purkinje-typical Ca 2+ events, namely Ca 2+ -sparks, peripheral Ca 2+ -wavelets and cell-wide Ca 2+ -waves ( CWW s). Relevance of our analysis was tested with a Purkinje-specific model of Ca 2+ mobilization. Protein/gene expressions of SR-Ca 2+ pump isoforms were studied by immunofluorescence, WBs, and qPCR in dog and pig infarcted tissues.We found that (1) individual Ca 2+ release sites in MI Pcells fired sparks at 61% larger frequency, (2) the duration of wavelet Ca 2+ decay was reduced by 25% due to 37% acceleration of cytosolic Ca 2+ removal (time constant: 156±21ms (Normal; n=10) vs 98±9ms (MI; n=16; P<0.01)), (3) wavelet amplitude was increased by 50%, and (4) larger waves (CWWs) showed similar alterations. Numerical replication of MI wavelets succeeded with 52% increase of Ca 2+ uptake rate in the model of normal wavelets. Our results are consistent with an augmentation of SR-CaU taking place in Pcells shortly after the onset of MI. Molecular analyses done in the same MI model in pig showed that post-MI increase of SR-CaU results from the substitution of cardiac isoform SERCA2a by the ubiquitous and more potent SERCA2b in the infarcted cardiac tissues including Purkinje fibers. Our study reveals, for the first time, the molecular foundation of Purkinje arrhythmogenicity in ischemic heart and highlights novel targets for diagnosis, prevention, and treatment of risk of sudden cardiac death associated with ischemic MIs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".