title: Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils.
abstract: In the healthy heart, cardiac myocytes form an electrical syncytium embedded in a supportive fibroblast-rich extracellular matrix designed to optimize the electromechanical coupling for maximal contractile efficiency of the heart. In the injured heart, however, fibroblasts are activated and differentiate into myofibroblasts that proliferate and generate fibrosis as a component of the wound-healing response. This review discusses how fibroblasts and fibrosis, while essential for maintaining the structural integrity of the heart wall after injury, have undesirable electrophysiological effects by disrupting the normal electrical connectivity of cardiac tissue to increase the vulnerability to arrhythmias. We emphasize the dual contribution of fibrosis in altering source-sink relationships to create a vulnerable substrate while simultaneously facilitating the emergence of triggers such as afterdepolarization-induced premature ventricular complexes-both factors combining synergistically to promote initiation of reentry. We also discuss the potential role of fibroblasts and myofibroblasts in directly altering myocyte electrophysiology in a pro-arrhythmic fashion. Insight into these processes may open up novel therapeutic strategies for preventing and treating arrhythmias in the setting of heart disease as well as avoiding potential arrhythmogenic consequences of cell-based cardiac regeneration therapy. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signaling in Myocardium."
authors.affiliation: UCLA Cardiovascular Research Laboratory and the Departments of Medicine (Division of Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: tpnguyen@mednet.ucla.edu.
authors.forename: Thao P
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: UCLA Cardiovascular Research Laboratory and the Departments of Medicine (Division of Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: UCLA Cardiovascular Research Laboratory and the Departments of Medicine (Division of Cardiology) and Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation; D056966:Excitation Contraction Coupling / Q000502:physiology; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017629:Gap Junctions / Q000502:physiology; D006329:Heart Conduction System / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000502:physiology*
keywords: Cardiac arrhythmia; Dispersion of refractoriness; Fibrosis; Myofibroblast; Reentry; Source–sink mismatch