Abstract 10530: Stretch-Induced Arrhythmias Are Increased by Microtubule Detyrosination in a TRPA1 Dependent Manner in the Rabbit Heart

Abstract

Introduction: Clinical evidence indicates that in hypertension, acute fluctuations in blood pressure can trigger ventricular arrhythmias. Single cell rabbit studies suggest that these stretch-induced arrhythmias (SIA) are related to increased microtubule (MT) density or detyrosination and depend on transient receptor potential ankyrin 1 channels (TRPA1). However, whether these mechanisms of SIA apply to the whole heart is unknown. Hypothesis: An increase in MT density or detyrosination will reduce the threshold for SIA in the whole heart and be dependent on TRPA1. Methods: Isolated rabbit hearts were instrumented with surface electrodes to monitor electrical activity and an intraventricular balloon to alter LV load. Transient changes in LV volume were applied to induce SIA (50-500μL, 10mL/s, 20 repetitions of each volume separated by 30s). SIA incidence vs volume was used to calculate the volume that resulted in a 50% SIA incidence (V 50 ). Paclitaxel (5μM) was applied alone to increase MT density and detyrosination or in combination with parthenolide (10μM) to prevent the increase in detyrosination or HC-030031 (10μM) to block TRPA1. Voltage optical mapping was used to determine the nature of SIA. MT density was assessed by immunofluorescence in isolated LV myocytes. Results: Paclitaxel reduced the threshold for SIA (decreased V 50 versus control: 133±16 vs 173±11μL; n =8 , p =0.02 by paired t-test) and resulted in the conversion of some stretch-induced ectopy to sustained activity. These effects were prevented by reduced detyrosination with parthenolide (262±27 vs 256±26μL; n =8 , p =0.75). Paclitaxel also increased MT density versus control, however this was not prevented by parthenolide (63±3 and 60±3 vs 50±4%; n =15, p =0.04 by one-way ANOVA). The decreased V 50 and occurrence of sustained arrhythmias with paclitaxel was also prevented by TRPA1 block with HC-030031 (249±26 vs 237±27μL; n =8, p =0.60). Optical mapping revealed stretch-induced ectopic excitation originating from the LV freewall, which resulted in re-entrant activity with paclitaxel. Conclusions: An increase in MT detyrosination leads to a reduced threshold for SIA and the triggering of sustained arrhythmias in the whole heart in a TRPA1 dependent manner.