title: Atrial Fibrillation and Fibrosis: Beyond the Cardiomyocyte Centric View.
abstract: Atrial fibrillation (AF) associated with fibrosis is characterized by the appearance of interstitial myofibroblasts. These cells are responsible for the uncontrolled deposition of the extracellular matrix, which pathologically separate cardiomyocyte bundles. The enhanced fibrosis is thought to contribute to arrhythmias "indirectly" because a collagenous septum is a passive substrate for propagation, resulting in impulse conduction block and/or zigzag conduction. However, the emerging results demonstrate that myofibroblasts in vitro also promote arrhythmogenesis due to direct implications upon cardiomyocyte electrophysiology. This electrical interference may be considered beneficial as it resolves any conduction blocks; however, the passive properties of myofibroblasts might cause a delay in impulse propagation, thus promoting AF due to discontinuous slow conduction. Moreover, low-polarized myofibroblasts reduce, via cell-density dependence, the fast driving inward current for cardiac impulse conduction, therefore resulting in arrhythmogenic uniformly slow propagation. Critically, the subsequent reduction in cardiomyocytes resting membrane potential in vitro significantly increases the likelihood of ectopic activity. Myofibroblast densities and the degree of coupling at cellular border zones also impact upon this likelihood. By considering future in vivo studies, which identify myofibroblasts "per se" as a novel targets for cardiac arrhythmias, this review aims to describe the implications of noncardiomyocyte view in the context of AF.
authors.affiliation: Centre of Excellence for Toxicological Research, Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy ; Humanitas Clinical and Research Centre, Via Manzoni 56, Rozzano, 20090 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Miragoli
authors.affiliation: Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Glukhov
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology