Repolarisation-relaxation dyscoupling and TRPA1 activation permit systolic mechano-arrhythmogenesis

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.