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      Fibroblast–myocyte electrotonic coupling: Does it occur in native cardiac tissue?

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          Abstract

          Heterocellular electrotonic coupling between cardiac myocytes and non-excitable connective tissue cells has been a long-established and well-researched fact in vitro. Whether or not such coupling exists in vivo has been a matter of considerable debate. This paper reviews the development of experimental insight and conceptual views on this topic, describes evidence in favour of and against the presence of such coupling in native myocardium, and identifies directions for further study needed to resolve the riddle, perhaps less so in terms of principal presence which has been demonstrated, but undoubtedly in terms of extent, regulation, patho-physiological context, and actual relevance of cardiac myocyte–non-myocyte coupling in vivo. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium."

          Highlights

          • Electrical coupling of cardiomyocytes and fibroblasts is well-established in vitro

          • Whether such hetero-cellular coupling exists in vivo has been a matter of debate

          • We review the development of experimental and conceptual insight into the topic

          • Conclusion 1: hetero-cellular coupling in heart tissue has been shown in principle

          • Conclusion 2: extent, regulation, context, and relevance remain to be established

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          Most cited references135

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          Myofibroblast-mediated mechanisms of pathological remodelling of the heart.

          The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
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            Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation.

            Cardiac fibroblasts account for about 75% of all cardiac cells, but because of their small size contribute only ∼10-15% of total cardiac cell volume. They play a crucial role in cardiac pathophysiology. For a long time, it has been recognized that fibroblasts and related cell types are the principal sources of extracellular matrix (ECM) proteins, which organize cardiac cellular architecture. In disease states, fibroblast production of increased quantities of ECM proteins leads to tissue fibrosis, which can impair both mechanical and electrical function of the heart, contributing to heart failure and arrhythmogenesis. Atrial fibrosis is known to play a particularly important role in atrial fibrillation (AF). This review article focuses on recent advances in understanding the molecular electrophysiology of cardiac fibroblasts. Cardiac fibroblasts express a variety of ion channels, in particular voltage-gated K(+) channels and non-selective cation channels of the transient receptor potential (TRP) family. Both K(+) and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca(2+)-entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes producing ECM proteins. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Co-cultured preparations of cardiomyocytes and fibroblasts generate arrhythmias by a variety of mechanisms, including spontaneous impulse formation and rotor-driven reentry. In addition, the excess ECM proteins produced by fibroblasts can interrupt cardiomyocyte-bundle continuity, leading to local conduction disturbances and reentrant arrhythmias. A better understanding of the electrical properties of fibroblasts should lead to an improved comprehension of AF pathophysiology and a variety of novel targets for antiarrhythmic intervention.
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              Molecular regulation of atrioventricular valvuloseptal morphogenesis.

              The majority of congenital heart defects arise from abnormal development of valvuloseptal tissue. The primordia of the valve leaflets and membranous septa of the heart are the cardiac cushions. Remodeling of the cushions is associated with a transitional extracellular matrix that includes sulfated proteoglycans and the microfibrillar proteins fibulin and fibrillin. Cushion formation is restricted to the AV canal and ventricular outflow tract regions of the primary heart tube. The proper placement of the cushions may be the result of the development of the primary heart tube as a segmented organ, as well as the subsequent looping of the heart. Segmentation of the heart tube may be demonstrated by the alternating molecular expression pattern along the longitudinal axis. In support of this hypothesis is the restricted expression of BMP-4 and msx-2 to the AV canal and ventricular outflow tract. The importance of looping for cushion positioning may imply that the iv and inv genes and retinoic acid are important for the proper patterning of the heart. The cells of the cushions evolve from endocardial cells that undergo an epithelial-to-mesenchymal transformation. This developmental event is regulated by the myocardium and is probably due to the production of protein complexes, present within the cardiac jelly of the cushion-forming regions, that consist of fibronectin and the ES proteins. Both the cushion mesenchyme and its endocardial cell antecedents express JB3, an ECM protein. JB3 expression is also featured within the heart-forming fields of the primary mesoderm, from which the endocardial progenitors of the cushion cells originate.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Contributors
                Journal
                J Mol Cell Cardiol
                J. Mol. Cell. Cardiol
                Journal of Molecular and Cellular Cardiology
                Academic Press
                0022-2828
                1095-8584
                1 May 2014
                May 2014
                : 70
                : 100
                : 37-46
                Affiliations
                [a ]Imperial College, National Heart and Lung Institute, Harefield Hospital, UB6 9JH, UK
                [b ]Virginia Tech, Carilion Research Institute, 2 Riverside Circle, Roanoke, VA 24015, USA
                Author notes
                [* ]Corresponding author. p.kohl@ 123456imperial.ac.uk
                Article
                S0022-2828(14)00002-9
                10.1016/j.yjmcc.2013.12.024
                4001130
                24412581
                86622aa3-b5b7-4702-9f9d-c95d31d5a072
                © 2013 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                Categories
                Review Article

                Cardiovascular Medicine
                heart,electrophysiology,connective tissue,gap junction,fibrosis,scar
                Cardiovascular Medicine
                heart, electrophysiology, connective tissue, gap junction, fibrosis, scar

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