Mechanical Coupling Between Myofibroblasts and Cardiomyocytes Slows Electric Conduction in Fibrotic Cell Monolayers
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/dtmax) 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/dtmax 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.
- Received December 16, 2010.
- Accepted March 8, 2011.
- © 2011 American Heart Association, Inc.