Mechanical Coupling Between Myofibroblasts and Cardiomyocytes Slows Electric Conduction in Fibrotic Cell Monolayers

Abstract

Background— After cardiac injury, activated cardiac myofibroblasts can influence tissue electrophysiology. Because mechanical coupling through adherens junctions provides a route for intercellular communication, we tested the hypothesis that myofibroblasts exert tonic contractile forces on the cardiomyocytes and affect electric propagation via a process of mechanoelectric feedback. Methods and Results— The role of mechanoelectric feedback was examined in transforming growth factor-β–treated monolayers of cocultured myofibroblasts and neonatal rat ventricular cells by inhibiting myofibroblast contraction and blocking mechanosensitive channels. Untreated (control) and transforming growth factor-β–treated (fibrotic) anisotropic monolayers were optically mapped for electrophysiological comparison. Longitudinal conduction velocity, transverse conduction velocity, and normalized action potential upstroke velocity (dV/dt max ) significantly decreased in fibrotic monolayers (14.4±0.7 cm/s [mean±SEM], 4.1±0.3 cm/s [n=53], and 3.1±0.2% per ms [n=14], respectively) compared with control monolayers (27.2±0.8 cm/s, 8.5±0.4 cm/s [n=40], and 4.9±0.1% per ms [n=12], respectively). Application of the excitation-contraction uncoupler blebbistatin or the mechanosensitive channel blocker gadolinium or streptomycin dramatically increased longitudinal conduction velocity, transverse conduction velocity, and dV/dt max in fibrotic monolayers (35.9±1.5 cm/s, 10.3±0.6 cm/s [n=17], and 4.5±0.1% per ms [n=14], respectively). Similar results were observed with connexin43–silenced cardiac myofibroblasts. Spiral-wave induction in fibrotic monolayers also decreased after the aforementioned treatments. Finally, traction force measurements of individual myofibroblasts showed a significant increase with transforming growth factor-β, a decrease with blebbistatin, and no change with mechanosensitive channel blockers. Conclusions— These observations suggest that myofibroblast-myocyte mechanical interactions develop during cardiac injury, and that cardiac conduction may be impaired as a result of increased mechanosensitive channel activation owing to tension applied to the myocyte by the myofibroblast.