TRPA1 is a source of calcium-mediated cardiac mechano-arrhythmogenesis

Abstract

SUMMARY PARAGRAPHMaintenance of cardiac function involves an important intrinsic regulatory loop, in which electrical excitation causes the heart to mechanically contract,1 and the cardiac mechanical state directly affects its electrical activity.2 In diseases that affect myocardial mechanical properties and function, it is thought that this feedback of mechanics to electrics may contribute to arrhythmias (‘mechano-arrhythmogenesis’).3 However, the molecular identity of the specific factor(s) underlying mechano-arrhythmogenesis are unknown.4 We show in rabbit ventricular myocytes that mechano-sensitive5–11 transient receptor potential kinase ankyrin 1 (TRPA1) channels12 are a source of cardiac mechano-arrhythmogenesis through a calcium (Ca2+)-mediated mechanism. Using a cell-level approach involving rapid stretch of single ventricular myocytes, we found that increased TRPA1 activity results in stretch-induced arrhythmias, with trans-sarcolemmal depolarising arrhythmic triggers mediated by increased diastolic levels of cytosolic Ca2+ and sustained arrhythmic activity driven by cytosolic Ca2+ oscillations. This mechano-arrhythmogenesis increased with application of a microtubule stabilising agent and was prevented by pharmacological TRPA1 channel block or buffering of cytosolic Ca2+. Our results demonstrate that TRPA1 channels can act as a trigger for stretch-induced excitation and create a substrate for sustained arrhythmias. TRPA1 channels may thus represent a novel anti-arrhythmic target in cardiac diseases in which their activity is augmented.13–17