Myocyte Stretch Slows Cardiac Conduction by a Caveolae-Dependent Increase in Sarcolemmal Capacitance

Abstract

Alterations in cardiac electrophysiology by mechanical perturbations have been long observed, however the cellular basis for these changes remains poorly understood. Most studies have focused on pro-arrhythmic consequences of stretch-activated currents (SAC). However, alterations in cardiac conduction that can create an arrhythmogenic substrate have also been observed even in the presence of SAC blockade. We tested the hypotheses that stretch slows conduction by increasing cell membrane capacitance via recruitment and sarcolemmal integration of caveolae and found that: (1) Conduction slowing occurred with stretch in both (a) pressure-loaded mouse hearts and (b) biaxially-stretched micropatterned murine cardiomyocyte monolayers, (2) Inhibition of stretch-activated currents had no effect on this slowing in both models, (3) Slowing was abrogated by caveolae depletion in both models, using cav3-knockout mice or incubation with 1 mM MβCD, (4) Stretch significantly increased cell membrane capacitance and time constant in single wild-type, but not caveolae-depleted cells, and (5) These effects on cell membrane capacitance and conduction slowing concide with recruitment and integration of caveolae by stretch. Together, these data suggest that myocyte stretch promotes recruitment and integration of caveolae and causes slowing of cardiac conduction by increasing cell membrane capacitance.