title: Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density.
abstract: Fibroblasts are electrophysiologically quiescent in the healthy heart. Evidence suggests that remodeling following myocardial infarction may include coupling of myofibroblasts (Mfbs) among themselves and with myocytes via gap junctions. We use a magnetic resonance imaging-based, three-dimensional computational model of the chronically infarcted rabbit ventricles to characterize the arrhythmogenic substrate resulting from Mfb infiltration as a function of Mfb density. Mfbs forming gap junctions were incorporated into both infarct regions, the periinfarct zone (PZ) and the scar; six scenarios were modeled: 0%, 10%, and 30% Mfbs in the PZ, with either 80% or 0% Mfbs in the scar. Ionic current remodeling in PZ was also included. All preparations exhibited elevated resting membrane potential within and near the PZ and action potential duration shortening throughout the ventricles. The unique combination of PZ ionic current remodeling and different degrees of Mfb infiltration in the infarcted ventricles determines susceptibility to arrhythmia. At low densities, Mfbs do not alter arrhythmia propensity; the latter arises predominantly from ionic current remodeling in PZ. At intermediate densities, Mfbs cause additional action potential shortening and exacerbate arrhythmia propensity. At high densities, Mfbs protect against arrhythmia by causing resting depolarization and blocking propagation, thus overcoming the arrhythmogenic effects of PZ ionic current remodeling.
authors.affiliation: The Johns Hopkins University, Department of Biomedical Engineering and Institute for Computational Medicine, Baltimore, Maryland, USA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: McDowell
authors.forename: Hermenegild J
authors.initials: HJ
authors.lastname: Arevalo
authors.forename: Mary M
authors.initials: MM
authors.lastname: Maleckar
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Trayanova
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications*; D002452:Cell Count; D002921:Cicatrix / Q000473:pathology; D004198:Disease Susceptibility; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008953:Models, Anatomic; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology; D058628:Myofibroblasts / Q000473:pathology*; D011817:Rabbits; D059547:Stereocilia / Q000473:pathology