Mechanical coupling between myofibroblasts and cardiomyocytes slows electric conduction in fibrotic cell monolayers

Circulation. 2011 May 17;123(19):2083-93. doi: 10.1161/CIRCULATIONAHA.110.015057. Epub 2011 May 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomechanical Phenomena
  • Cell Communication / drug effects
  • Cell Communication / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Electric Conductivity*
  • Feedback, Physiological / drug effects
  • Feedback, Physiological / physiology
  • Fibrosis
  • Gadolinium / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / physiology*
  • Models, Animal
  • Myocardium / pathology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology*
  • Myofibroblasts / drug effects
  • Myofibroblasts / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Streptomycin / pharmacology
  • Transforming Growth Factor beta / pharmacology

Substances

  • Heterocyclic Compounds, 4 or More Rings
  • Transforming Growth Factor beta
  • blebbistatin
  • Gadolinium
  • Streptomycin