In hypertension, there is an increased risk of sudden cardiac death, which is associated with acute hemodynamic fluctuations in the presence of ventricular structural remodelling. Increased microtubule network (MTN) density (via polymerisation) or stability (via post-translational modifications, such as detyrosination or acetylation) may enhance mechano-transduction in this setting and increase the incidence of mechanically-triggered arrhythmias (‘mechano-arrhythmogenicity’) mediated by TRPA1.
Determine the impact of alterations in the MTN on mechano-arrhythmogenicity.
Rabbit LV myocytes paced at 1Hz were rapidly stretched at increasing magnitudes (8-19% increase in sarcomere length over ∼112ms) during diastole with carbon fibres. Cells were exposed to paclitaxel to hyperpolymerise and stabilise (via increased detyrosination and acetylation) the MTN. Drugs were used in paclitaxel-treated cells to reduce microtubule density (colchicine) or detyrosination (parthenolide), or to block mechano-sensitive TRPA1 channels (HC-030031), and in control cells to increase acetylation (tubacin). Diastolic cell stiffness was measured from stepwise generated force-length curves. MTN density was assessed by immunofluorescence.
In paclitaxel-treated cells, there was a stretch magnitude-dependent threshold (≥13±1% increase in sarcomere length) over which mechano-arrhythmogenicity was greater than in control (13 vs 4% of stretches resulted in an arrhythmia; n=41 cells, N=5 rabbits; p<0.005). Arrhythmia incidence in paclitaxel-treated cells was reduced by colchicine (4%; p<0.005), parthenolide (6%; p<0.05), and HC-030031 (2%; p<0.0005), while tubacin applied to control cells did not increase arrhythmia incidence (n=41, N=5). Paclitaxel increased cell stiffness (45±6 vs 30±3nN/μm, n=25, N=5; p<0.05) and MTN density (64±2 vs 74±3%, n=7, N=2; p<0.05) compared to control, which was not prevented by colchicine or parthenolide. In control cells, tubacin also increased stiffness (43±5nN/μm, N=5, n=25; p<0.05).
An increase in MTN detyrosination, rather than cell stiffness, MTN density, or MTN acetylation, results in increased mechano-arrhythmogenicity mediated by TRPA1.
© 2021 Published by Elsevier Inc.