Arrhythmogenic Ca2+ release from cardiac myofilaments
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Bibliographic record
Abstract
We investigated the initiation of Ca(2+)waves underlying triggered propagated contractions (TPCs) occurring in rat cardiac trabeculae under conditions that simulate the functional non-uniformity caused by mechanical or ischemic local damage of the myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small constant flow jet of solution with a composition that reduces excitation-contraction coupling in myocytes within that segment. Force was measured and sarcomere length as well as [Ca(2+)](i) were measured regionally. When the jet-contained Caffeine, BDM or Low-[Ca(2+)], muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening of the normal regions outside the jet. During relaxation the sarcomeres in the exposed segment shortened rapidly. Short trains of stimulation at 2.5 Hz reproducibly caused Ca(2+)-waves to rise from the borders exposed to the jet. Ca(2+)-waves started during force relaxation of the last stimulated twitch and propagated into segments both inside and outside of the jet. Arrhythmias, in the form of non-driven rhythmic activity, were triggered when the amplitude of the Ca(2+)-wave increased by raising [Ca(2+)](o). The arrhythmias disappeared when the muscle uniformity was restored by turning the jet off. We have used the four state model of the cardiac cross bridge (Xb) with feedback of force development to Ca(2+) binding by Troponin-C (TnC) and observed that the force-Ca(2+) relationship as well as the force-sarcomere length relationship and the time course of the force and Ca(2+) transients in cardiac muscle can be reproduced faithfully by a single effect of force on deformation of the TnC.Ca complex and thereby on the dissociation rate of Ca(2+). Importantly, this feedback predicts that rapid decline of force in the activated sarcomere causes release of Ca(2+) from TnC.Ca(2+),which is sufficient to initiate arrhythmogenic Ca(2+) release from the sarcoplasmic reticulum. These results show that non-uniform contraction can cause Ca(2+)-waves underlying TPCs, and suggest that Ca(2+) dissociated from myofilaments plays an important role in the initiation of arrhythmogenic Ca(2+)-waves.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| 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) | 0.000 | 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 it