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

SUMMARY PARAGRAPH

Maintenance 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-sensitive^5–11 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