Repolarisation-relaxation dyscoupling and TRPA1 activation permit systolic mechano-arrhythmogenesis
Bibliographic record
Abstract
ABSTRACT Background The heart’s mechanical state feeds back to its electrical activity, potentially contributing to arrhythmias (mechano-arrhythmogenesis, MAR). MAR has been mechanistically explained during electrical diastole, when cardiomyocytes are at their resting membrane potential. Conversely, during electrical systole, cardiomyocytes appear to be protected from MAR, even as membrane potential and cytosolic calcium concentration ([Ca 2+ ] i ) are simultaneously restored to resting levels during repolarisation (repolarisation-relaxation coupling, RRC). Yet, systolic MAR has been reported in ischaemic myocardium, with unclear underlying mechanisms. Methods Rabbit left ventricular cardiomyocytes were electrically paced and exposed to a simulated ischaemia solution (including hyperkalaemia, acidosis, and block of oxidative phosphorylation) or pinacidil (to simulate ischaemia-induced opening of ATP-sensitive potassium [K ATP ] channels), with or without glibenclamide (to block K ATP channels). RRC was assessed by simultaneous measurement of membrane voltage and [Ca 2+ ] i dynamics with fluorescence imaging. Acute stretch at increasing magnitudes was applied using carbon fibres, with stretch timed to diastole or late systole. Stretch mechanics and the incidence of MAR was assessed by video-based measurement of sarcomere length. Mechanisms contributing to MAR were assessed by buffering [Ca 2+ ] i (BAPTA-AM), stabilising ryanodine receptors (dantrolene), non-specifically blocking mechano-sensitive channels (streptomycin), activating (AITC) or blocking (HC-030031) transient receptor potential kinase ankyrin 1 channels (TRPA1), or chelating (NAC) or blocking production of (DPI) reactive oxygen species (ROS). Results It was reconfirmed that MAR during physiological RRC is rare, while ischaemia- or pharmacologically-induced RRC dyscoupling generates a vulnerable period for systolic MAR. This systolic MAR depends on TRPA1, [Ca 2+ ] i , and ROS, which contribute to stretch-induced excitation and arrhythmia sustenance. An increase in systolic MAR can be prevented by mitigating RRC dyscoupling with K ATP channel block, or by blocking TRPA1, buffering [Ca 2+ ] i , or reducing ROS. Conclusion RRC dyscoupling may be arrhythmogenic in ischaemia and other pathologies associated with systolic MAR, and TRPA1 may be a novel anti-arrhythmic target.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".