Disturbed repolarisation-relaxation coupling during acute ischaemia permits 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’ has been mechanistically explained during electrical diastole, when cardiomyocytes are at their resting membrane potential. During electrical systole, cardiomyocytes are refractory right from the onset of depolarisation, while during repolarisation they appear to be protected from mechano-arrhythmogenesis by near-simultaneous restoration of resting membrane potential and cytosolic calcium concentration ([Ca 2+ ] i ): repolarisation-relaxation coupling (RRC). Yet, systolic mechano-arrhythmogenesis has been reported in ischaemic myocardium, with unclear underlying mechanisms. We hypothesise that ischaemia-induced alteration of RRC gives rise to a vulnerable period for mechano-arrhythmogenesis. Methods Acute left-ventricular (LV) regional ischaemia 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 electrocardiogram. Single LV cardiomyocytes were exposed to simulated ischaemia or pinacidil (ATP-sensitive potassium channel opener). Stretch was applied in diastole or late systole using carbon fibres. 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 heart, acute regional ischaemia leads to systolic stretch and disturbed RRC at the ischaemic border. These electro-mechanical changes were associated with waves of arrhythmias, which were reduced by mechanical unloading, electro-mechanical uncoupling, or buffering of [Ca 2+ ] i . In LV cardiomyocytes, physiological RRC is associated with a low incidence of systolic mechano-arrhythmogenesis, while a vulnerable period emerged by prolonged RRC during ischaemia. The increase in systolic mechano-arrhythmogenesis was reduced by restoring RRC, chelating [Ca 2+ ] i , blocking mechano-sensitive transient receptor potential kinase ankyrin 1 channels (TRPA1), or buffering reactive oxygen species (ROS) levels. Conclusion Prolonged RRC allows for systolic mechano-arrhythmogenesis in acute ischaemia, involving contributions of elevated [Ca 2+ ] i , TRPA1 activity, and ROS, which represent potential anti-arrhythmic targets. GRAPHICAL ABSTRACT LEGEND Role of disturbed repolarisation-relaxation coupling (RRC), transient receptor potential kinase ankyrin 1 (TRPA1) channels, cytosolic calcium concentration ([Ca 2+ ] i ), and reactive oxygen species (ROS) in ventricular systolic mechano-arrhythmogenesis. Schematic of the proposed mechanisms underlying the TRPA1- and Ca 2+ -mediated increase in systolic mechano-arrhythmogenesis with disturbed RRC. AITC, Allyl isothiocyanate (TRPA1 channel activator); AP, action potential; BAPTA ([Ca 2+ ] i buffer); CaT, Ca 2+ transient; DNT, dantrolene (ryanodine receptor stabiliser); DPI, diphenyleneiodonium (ROS production blocker); GLIB, glibenclamide (K ATP channel blocker); HC-300031 (TRPA1 channel blocker); K ATP , ATP-sensitive potassium channel; NAC, N-acetyl-L-cysteine (ROS chelator); NCX, sodium-Ca 2+ exchanger; PIN, pinacidil (K ATP channel activator); ROS, reactive oxygen species; SI, simulated ischaemia; STP, streptomycin (non-specific mechano-sensitive ion channel blocker).
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".