The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

SUMMARY PARAGRAPH Maintenance of cardiac function involves a regulatory loop in which electrical excitation causes the heart to contract through excitation-contraction coupling (ECC), 1 and the mechanical state of the heart directly affects its electrical activity through mechano-electric coupling (MEC). 2 However, in pathological states such as acute ischaemia that alter early or late electro-mechanical coordination ( i.e. , disturbances in ECC or repolarisation-relaxation coupling, RRC), MEC may contribute to the initiation and / or sustenance of arrhythmias (mechano-arrhythmogenesis). 3 The molecular identity of specific factor(s) underlying mechano-arrhythmogenesis in acute ischaemia, however, remain undefined. 4 By rapid stretch of rabbit single left ventricular cardiomyocytes, we show that upon ATP-sensitive potassium channel-induced alterations of RRC, overall vulnerability to mechano-arrhythmogenesis is increased, with mechano-sensitive 5–11 transient receptor potential kinase ankyrin 1 (TRPA1) channels 12 acting as the molecular driver through a Ca 2+ -mediated mechanism. Specifically, TRPA1 activation drives stretch-induced excitation and creates a substrate for self-sustained arrhythmias, which are maintained by increased cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) and spontaneous [Ca 2+ ] i oscillations. This TRPA1-dependent mechano-arrhythmogenesis involves microtubules, and can be prevented by block of TRPA1 or buffering of [Ca 2+ ] i . Thus, in cardiac pathologies with disturbed RRC dynamics and / or augmented TRPA1 activity, TRPA1 may represent an anti-arrhythmic target with untapped therapeutic potential. 13–17