title: Antiproliferative treatment of myofibroblasts prevents arrhythmias in vitro by limiting myofibroblast-induced depolarization.
abstract: OBJECTIVE
  Cardiac fibrosis is associated with increased incidence of cardiac arrhythmias, but the underlying proarrhythmic mechanisms remain incompletely understood and antiarrhythmic therapies are still suboptimal. This study tests the hypothesis that myofibroblast (MFB) proliferation leads to tachyarrhythmias by altering the excitability of cardiomyocytes (CMCs) and that inhibition of MFB proliferation would thus lower the incidence of such arrhythmias.
  
  
  RESULTS
  Endogenous MFBs in neonatal rat CMC cultures proliferated freely or under control of different dosages of antiproliferative agents (mitomycin-C and paclitaxel). At Days 4 and 9, arrhythmogeneity of these cultures was studied by optical and multi-electrode mapping. Cultures were also studied for protein expression and electrophysiological properties. MFB proliferation slowed conduction from 15.3 ± 3.5 cm/s (Day 4) to 8.8 ± 0.3 cm/s (Day 9) (n = 75, P < 0.01), whereas MFB numbers increased to 37.4 ± 1.7 and 62.0 ± 2%. At Day 9, 81.3% of these cultures showed sustained spontaneous reentrant arrhythmias. However, only 2.6% of mitomycin-C-treated cultures (n = 76, P < 0.0001) showed tachyarrhythmias, and ectopic activity was decreased. Arrhythmia incidence was drug-dose dependent and strongly related to MFB proliferation. Paclitaxel treatment yielded similar results. CMCs were functionally coupled to MFBs and more depolarized in cultures with ongoing MFB proliferation in which only L-type Ca(2+)-channel blockade terminated 100% of reentrant arrhythmias, in contrast to Na(+) blockade (36%, n = 12).
  
  
  CONCLUSIONS
  Proliferation of MFBs in myocardial cultures gives rise to spontaneous, sustained reentrant tachyarrhythmias. Antiproliferative treatment of such cultures prevents the occurrence of arrhythmias by limiting MFB-induced depolarization, conduction slowing, and ectopic activity. This study could provide a rationale for a new treatment option for cardiac arrhythmias.
authors.affiliation: Department of Cardiology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Saïd F A
authors.initials: SF
authors.lastname: Askar
authors.forename: Arti A
authors.initials: AA
authors.lastname: Ramkisoensing
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schalij
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bingen
authors.forename: Jim
authors.initials: J
authors.lastname: Swildens
authors.forename: Arnoud
authors.initials: A
authors.lastname: van der Laarse
authors.forename: Douwe E
authors.initials: DE
authors.lastname: Atsma
authors.forename: Antoine A F
authors.initials: AA
authors.lastname: de Vries
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Ypey
authors.forename: Daniël A
authors.initials: DA
authors.lastname: Pijnappels
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D016685:Mitomycin / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D013610:Tachycardia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D017239:Paclitaxel