Disturbed Repolarization-Relaxation Coupling During Acute Myocardial Ischemia Permits Systolic Mechano-Arrhythmogenesis
Bibliographic record
Abstract
BACKGROUND: The heart’s mechanical state feeds back to its electrical activity, potentially contributing to arrhythmias. Mechano-arrhythmogenesis has been mechanistically explained during electrical diastole, when cardiomyocytes are at their resting membrane potential. During electrical systole, cardiomyocytes are refractory right after the onset of depolarization, while during repolarization in physiological conditions, they seem to be protected from systolic mechano-arrhythmogenesis by near-simultaneous restoration of resting membrane potential and cytosolic calcium concentration ([Ca 2+ ] i ): repolarization-relaxation coupling (RRC). Yet, late-systolic mechano-arrhythmogenesis has been reported in ischemic myocardium, with unclear underlying mechanisms. We hypothesize that ischemia-induced alteration of RRC gives rise to a vulnerable period for mechano-arrhythmogenesis. METHODS: Acute left ventricular regional ischemia was induced by coronary artery ligation in Langendorff-perfused rabbit hearts, with mechanical load controlled by an intraventricular balloon. Mechanical activity was assessed by echocardiography and arrhythmia incidence by ECG. Single left ventricular cardiomyocytes were exposed to simulated ischemia or pinacidil (ATP-sensitive potassium channel opener). Stretch was applied in diastole or late systole using carbon fibers. Stretch characteristics and arrhythmia incidence were assessed by sarcomere length measurement. In both models, RRC was assessed by simultaneous voltage-[Ca 2+ ] i fluorescence imaging and mechano-arrhythmogenesis mechanisms were pharmacologically tested. RESULTS: In whole hearts, acute regional ischemia leads to systolic stretch and disturbed RRC at the ischemic border. These electro-mechanical changes were associated with waves of arrhythmias, which could be reduced by mechanical unloading, electro-mechanical uncoupling, or buffering of [Ca 2+ ] i . In left ventricular cardiomyocytes, physiological RRC is associated with a low incidence of systolic mechano-arrhythmogenesis, while a vulnerable period emerged by prolonged RRC during ischemia. The increase in systolic mechano-arrhythmogenesis was reduced by restoring RRC, chelating [Ca 2+ ] i , blocking mechano-sensitive TRPA1 (transient receptor potential ankyrin 1) channels, or buffering reactive oxygen species levels. CONCLUSIONS: Prolonged RRC allows for late-systolic mechano-arrhythmogenesis in acute ischemia, involving contributions of elevated [Ca 2+ ] i , TRPA1 activity, and reactive oxygen species, which represent potential antiarrhythmic targets.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.000 | 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".