title: 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.
  
  
  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.
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University, 720 Rutland Ave, Baltimore, MD 21205, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Thompson
authors.forename: Craig R
authors.initials: CR
authors.lastname: Copeland
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Reich
authors.forename: Leslie
authors.initials: L
authors.lastname: Tung
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004553:Electric Conductivity; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005355:Fibrosis; D005682:Gadolinium / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D007365:Intercellular Junctions / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013307:Streptomycin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D016212:Transforming Growth Factor beta; C472645:blebbistatin; D005682:Gadolinium; D013307:Streptomycin