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

Maintenance of cardiac function involves an important intrinsic regulatory loop, in which electrical excitation causes the heart to mechanically contract,[1][1] and the cardiac mechanical state directly affects its electrical activity.[2][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][3] However, the molecular identity of the specific factor(s) underlying mechano-arrhythmogenesis are unknown.[4][4] We show in rabbit ventricular myocytes that mechano-sensitive[5][5]–[11][6] transient receptor potential kinase ankyrin 1 (TRPA1) channels[12][7] 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][8]–[17][9] ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-11 [7]: #ref-12 [8]: #ref-13 [9]: #ref-17