Abstract: HomeCirculation ResearchVol. 93, No. 5Heterogeneous Cell Coupling in the Heart Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHeterogeneous Cell Coupling in the HeartAn Electrophysiological Role for Fibroblasts Peter Kohl Peter KohlPeter Kohl From the University Lab of Physiology, Oxford, UK. Originally published5 Sep 2003https://doi.org/10.1161/01.RES.0000091364.90121.0CCirculation Research. 2003;93:381–383The heart is a muscle. Muscles are made up of myocytes. These may differ in form and function, but—in essence—they are the cells in which we are interested when we consider the structural makeup of the heart. Likewise, when we assess electrical coupling of cardiac cells by connexins, we are often content to assume that gap junctions occur exclusively—or at least in the overwhelming majority of cases—between homologous cell types.It is sobering, in this context, to reflect on the fact that cardiac myocytes form a minority of cells in the heart, insofar as cell numbers are concerned (which, for cell coupling, is more relevant than total volume occupied by a cell population). A meticulous study by Adler et al1 demonstrated that myocyte and connective tissue cell numbers increase at a similar rate in early human development, from about 0.5×109 at 28 weeks of fetal development to 2 to 3×109 several weeks postpartum. Thereafter, myocyte cell numbers remain stable, while the connective tissue cell count increases with cardiac weight to ≈7×109 at 2 months of age.This mitotic potential of cardiac fibroblasts is maintained after cell isolation and is the key reason for which fibroblasts are omnipresent in primary cardiac cell cultures. This is not for lack of effort to eliminate nonmyocytes. Measures to enrich myocyte content in cardiac cell culture include addition of mitotic inhibitors, substrate restrictions, and, most prominently, preplating steps (occasionally in the presence of antibodies against muscle cell surface adhesion factors).2 Nonetheless, cardiac cell cultures are essentially always cocultures of myocytes and (proliferating) nonmyocytes. This insight is reflected in some of the earliest cardiac cell culture work from the 1950s, where mitosis was observed—but not in pulsating cells (ie, in cells other than myocytes).3A contribution of nonmyocytes to in vitro impulse conduction was first established in 1966 by Mark and Strasser4 who identified two main cell populations in trypsin-digested neonatal rat heart cell cultures: myocytes and "endothelioid" cells (whose detailed description and photographic presentation allows classification of them as what nowadays is referred to as fibroblasts). Using time-lapse and real-time video microscopy, they discovered that synchronization of spontaneous contractile activity in individual cardiomyocytes required cell contact, which could be either direct or indirect via nonmuscle cells (see Figures 6 through 8 in Reference 4). This line of investigation was followed by Goshima et al,5–7 who combined cinematographic, histological, and electrophysiological methods to confirm that a whole range of heterocellular constructs can conduct excitation between cultured cardiac myocytes. Goshima and Tonomura6 also described effective synchronization of distant myocytes (≥150 μm) via conduction pathways involving multiple nonmyocytes (see Figure). Download figureDownload PowerPointTwo myocardial cells (M) with three intermediate fibroblast-like cells (FL) beat synchronously after 1 day of cultivation. Phase contrast, ×450. (Original caption of Figure 4 in Reference 6). Reprinted from Goshima K, Tonomura Y. Synchronized beating of embryonic mouse myocardial cells mediated by FL cells in monolayer culture. Exp Cell Res. 1969;56:387–392, copyright 1969, with permission from Elsevier.The practical relevance of these observations was intensely debated in the late 1980s/early 1990s when, on the one hand, homogeneous and heterogeneous gap junctions between cardiac myocytes and fibroblasts in vitro were characterized in great detail (down to single-channel conductances),8–10 while, on the other hand, in vivo investigations largely drew blanks on the underlying histological substrate.11 This issue of Circulation Research contains a report by Gaudesius et al12 that, in all likelihood, will rekindle this debate on an elevated level.In their thorough study, Gaudesius et al12 describe a novel cardiac coculture system in which myocyte strands (80 μm wide) are interrupted by inserts of variable length (50 to 800 μm) that are filled with heterogeneous cell types, including cardiac fibroblasts, wild-type HeLa cells, and HeLa cells transfected with connexin43 (HeLa-Cx43). Using a combination of time-lapse and real-time video microscopy, immunocytochemistry, and optical measurement of impulse propagation, they show that cardiac fibroblasts can transmit electrical excitation, bridging gaps of up to ≈300 μm. They further show that heterotypic cell inserts can replace cardiac fibroblasts only if they express suitable connexins (here Cx43). This highlights the requirement for formation of gap junctional coupling between nonmyocytes, and between myocytes and nonmyocytes, for successful impulse transmission via the latter. It also begs the question as to whether highly sophisticated in vitro systems can become suitable models of in vivo cardiac structure and function, including gap junctional coupling patterns.Experimental models for the study of cardiovascular function must always be a compromise between relevance (the only true model here would be humans), reproducibility (where lower levels of functional integration with fewer degrees of freedom yield less variability), and cost, as expertly explained by Hearse and Sutherland.13 Cell culture models offer a very attractive compromise, as they are about midscale on all three parameters. Extensive efforts have been made to improve the properties of cardiac tissue culture. Microstructuring of the cell adhesion matrix, for example, allows one to predetermine areas for cell attachment,14 and this has been found to improve characteristic cell morphology and alignment, particularly if cells are grown on lines that ≤40 μm wide.15 Further improvements in cell culture quality can be achieved by application of controlled stretch to deformable cell culture substrates, which affects gene expression, protein synthesis, autocrine and paracrine signaling, and connexin expression in cocultures of cardiomyocytes and fibroblasts.16–19 Recently, the advantages of microstructuring and mechanical control have been combined in a single cell culture system.15The issue of mechanical effects on cellular interactions is relevant even for cultures grown on solid substrates, since the contractile activity of cardiomyocytes affects adjacent cells. Gaudesius et al12 neatly reconfirm the role of gap junctional coupling for impulse conduction via nonmyocytes by showing that replacement of HeLa-Cx43 with wild-type cells lacking the electrotonic conduction pathway afforded by Cx43 prevents impulse transmission. While this finding provides convincing evidence in favor of a role for gap junctional coupling, it should be reconfirmed in the absence of streptomycin in the cell culture medium, since this aminoglycoside is a potent blocker of cardiac stretch-activated ion channels20 and could cause false-negative findings insofar as possible stretch-mediated effects are concerned.A vital remaining question is that of the applicability of in vitro findings on (homogeneous and) heterogeneous cell coupling to the in vivo setting. Gaudesius et al12 report that myocytes and fibroblasts express Cx43—the main connexin to which cultured cells tend to revert—and Cx45, and that small punctate labeling for both connexins can be found at points of contact between both homogeneous and heterogeneous cell types. Cx40 label was not observed.How representative of the in vivo setting are in vitro model findings? As the authors point out, at present there is little hard evidence on fibroblast-myocyte coupling in native cardiac tissue. Functional studies are hampered by the fact that cardiac fibroblasts have a very high membrane resistance (GΩ range). This may be an advantage for electrotonic impulse transmission, but it means that—if fibroblasts are well-coupled to cardiac myocytes—they mimic the intracellular membrane potential dynamics of the latter (albeit with reduced upstroke velocities, as observed in rat atrium21 and isolated cell pairs9), which makes it difficult to identify them electrophysiologically in situ. If fibroblasts are not coupled to neighboring cardiac muscle cells, they display a resting membrane potential of between 0 and −50 mV and are of little interest in the given context.A painstaking transmission electron microscopy study by De Mazière et al11 revealed only "one tiny gap junction-like structure" in a sinoatrial node tissue volume containing an estimated ≥104 homologous nexus contacts. Instead, abundant heterogeneous cell approximations were reported, where fibroblast membranes anchor directly into the basal membrane of cardiomyocytes. Whether these membrane approximations accommodate dispersed gap junction channels that are not clustered densely enough to form a sufficiently electron-dense substrate for recognition by electron microscopy is not known. The present communication by Gaudesius et al12 reconfirms, however, that heterogeneous gap junctions between cardiac myocytes and fibroblasts are of much smaller dimension than those between myocyte pairs.More recently, sinoatrial node fibroblasts have been reported to express punctate Cx40 and Cx45 label (but not Cx43) in vivo, and Cx45 was found at the point of contact of cardiac fibroblasts and myocytes in native sinoatrial node tissue.22 There are also first indications of functional heterogeneous coupling, as witnessed by dye transfer studies in rabbit sinoatrial node.23 These findings highlight the desirability of cell-type identification in immunohistochemical studies of connexin distribution in cardiac tissue, as it is inappropriate to assume that all label will be located between homologous cells.What would be the functional relevance of electrical coupling between cardiac myocytes and fibroblasts? First of all, there can be no doubt that connective tissue can form barriers that interfere with the orderly conduction of excitation. The report by Gaudesius et al12 supports the possibility that fibroblasts may also act as a substrate for electrical coupling. This opens up a number of scenarios. Fibroblasts could act as a current sink, thereby contributing to the formation of unidirectional block of conduction.24 They could, via short-range interaction, contribute to the smoothing of propagation, in particular in the sinoatrial node (where pacemaker cells form islands embedded in connective tissue) and in the cross-sheet direction of ventricular tissue (which otherwise would give rise to fragmented conduction patterns).25 As long-distance communication lines, fibroblasts could bridge posttransplantation (or other) scar tissue with beneficial or detrimental effects on organ function, or explain the delay in atrioventricular conduction, as discussed by the authors.12 Furthermore, the inherent mechanosensitivity of cardiac fibroblasts could allow them to play a sensory role and affect cardiac electrophysiology in the context of mechano-electric feedback.26The dynamics of the development of the idea of cardiac heterogeneous cell coupling bears striking similarities to that of neuron-glia interaction: early reports on in vivo heterogeneous structural and functional coupling27,28 were reassessed in the 1990s, largely rejected,29 and are now being reconsidered as potentially of functional relevance.30 As in the case of the nervous system, further advancement of our insight into the issue of direct electrical coupling of "main" and "bystander" cells of the heart will be technically challenging, yet conceptually rewarding.The heart is a muscle, and muscles are structurally and functionally complex, highly integrated heterocellular constructs.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This work was supported by the British Heart Foundation and the Biotechnology and Biological Sciences Research Council. P.K. is a Royal Society Research Fellow. The author thanks Patricia J. Cooper for her help with this manuscript.FootnotesCorrespondence to Peter Kohl, MD, PhD, University Lab of Physiology, Parks Road, Oxford OX1 3PT, UK. E-mail [email protected] References 1 Adler CP, Ringlage WP, Böhm N. DNS-Gehalt und Zellzahl in Herz und Leber von Kindern. Pathol Res Pract. 1981; 172: 25–41.CrossrefMedlineGoogle Scholar2 McDonagh JC, Cebrat EK, Nathan RD. Highly enriched preparations of cultured myocardial cells for biochemical and physiological analyses. J Mol Cell Cardiol. 1987; 19: 785–793.CrossrefMedlineGoogle Scholar3 Cavanaugh MW. Pulsation, migration and division in dissociated chick embryo heart cells in vitro. J Exp Zool. 1955; 128: 573–589.CrossrefGoogle Scholar4 Mark GE, Strasser FF. Pacemaker activity and mitosis in cultures of newborn rat heart ventricle cells. Exp Cell Res. 1966; 44: 217–233.CrossrefMedlineGoogle Scholar5 Goshima K. Formation of nexuses and electrotonic transmission between myocardial and FL cells in monolayer culture. Exp Cell Res. 1970; 63: 124–130.CrossrefMedlineGoogle Scholar6 Goshima K, Tonomura Y. Synchronized beating of embryonic mouse myocardial cells mediated by FL cells in monolayer culture. Exp Cell Res. 1969; 56: 387–392.CrossrefMedlineGoogle Scholar7 Goshima K. Synchronized beating of and electrotonic transmission between myocardial cells mediated by heterotypic strain cells in monolayer culture. Exp Cell Res. 1969; 58: 420–426.CrossrefMedlineGoogle Scholar8 Rook MB, de Jonge B, Jongsma HJ, Masson-Pévet MA. Gap junction formation and functional interaction between neonatal rat cardiocytes in culture: a correlative physiological and ultrastructural study. J Membr Biol. 1990; 118: 179–192.CrossrefMedlineGoogle Scholar9 Rook MB, van Ginneken ACG, De Jonge B, El Aoumari A, Gros D, Jongsma HJ. Differences in gap junction channels between cardiac myocytes, fibroblasts, and heterologous pairs. Am J Physiol. 1992; 263: C959–C977.CrossrefMedlineGoogle Scholar10 Rook MB, Jongsma HJ, de Jonge B. Single channel currents of homo- and heterologous gap junctions between cardiac fibroblasts and myocytes. Pflügers Arch. 1989; 414: 95–98.CrossrefMedlineGoogle Scholar11 De Mazière AMGL, van Ginneken ACD, Wilders R, Jongsma HJ, Bouman LN. Spatial and functional relationship between myocytes and fibroblasts in the rabbit sinoatrial node. J Mol Cell Cardiol. 1992; 24: 567–578.CrossrefMedlineGoogle Scholar12 Gaudesius G, Miragoli M, Thomas SP, Rohr S. Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ Res. 2003; 93: 421–428.LinkGoogle Scholar13 Hearse DJ, Sutherland FJ. Experimental models for the study of cardiovascular function and disease. Pharmacol Res. 2000; 41: 597–603.CrossrefMedlineGoogle Scholar14 Rohr S, Scholly DM, Kléber AG. Patterned growth of neonatal rat heart cells in culture: morphological and electrophysiological characterization. Circ Res. 1991; 68: 114–130.CrossrefMedlineGoogle Scholar15 Gopalan SM, Flaim C, Bhatia SN, Hoshijima M, Knoell R, Chien KR, Omens JH, McCulloch AD. Anisotropic stretch-induced hypertrophy in neonatal ventricular myocytes micropatterned on deformable elastomers. Biotechnol Bioeng. 2003; 81: 578–587.CrossrefMedlineGoogle Scholar16 van Wamel JET, Ruwhof C, van der Valk-Kokshoorn EJM, Schrier PI, van der Laarse A. Rapid gene transcription induced by stretch in cardiac myocytes and fibroblasts and their paracrine influence on stationary myocytes and fibroblasts. Pflügers Arch. 2000; 439: 781–788.CrossrefMedlineGoogle Scholar17 Wang T-L, Tseng Y-Z, Chang H. Regulation of connexin 43 gene expression by cyclical mechanical stretch in neonatal rat cardiomyocytes. Biochem Biophys Res Commun. 2000; 267: 551–557.CrossrefMedlineGoogle Scholar18 Ruwhof C, van der Laarse A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. 2000; 47: 23–37.CrossrefMedlineGoogle Scholar19 Zhuang J, Yamada KA, Saffitz JE, Kléber AG. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ Res. 2000; 87: 316–322.CrossrefMedlineGoogle Scholar20 Belus A, White E. Streptomycin and intracellular calcium modulate the response of single guinea-pig ventricular myocytes to axial stretch. J Physiol. 2003; 546: 501–509.CrossrefMedlineGoogle Scholar21 Kohl P, Kamkin AG, Kiseleva IS, Noble D. Mechanosensitive fibroblasts in the sino-atrial node region of rat heart: interaction with cardiomyocytes and possible role. Exp Physiol. 1994; 79: 943–956.CrossrefMedlineGoogle Scholar22 Camelliti P, Kohl P, Green C. Gap junction coupling of cardiac fibroblasts in situ. Biophys J. 2002; 82: 3089.Abstract.CrossrefMedlineGoogle Scholar23 Camelliti P, Kohl P, Green C. Functional coupling of fibroblasts in rabbit sino-atrial node. Biophys J. 2003; 84: 96a.Abstract.Google Scholar24 Kohl P, Hunter P, Noble D. Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models. Prog Biophys Mol Biol. 1999; 71: 91–138.CrossrefMedlineGoogle Scholar25 Hooks DA, Tomlinson KA, Marsden SG, LeGrice IJ, Smaill BH, Pullan AJ, Hunter PJ. Cardiac microstructure: implications for electrical propagation and defibrillation in the heart. Circ Res. 2002; 91: 331–338.LinkGoogle Scholar26 Kohl P, Noble D. Mechanosensitive connective tissue: potential influence on heart rhythm. Cardiovasc Res. 1996; 32: 62–68.CrossrefMedlineGoogle Scholar27 Walker FD, Hild WJ. Neuroglia electrically coupled to neurons. Science. 1969; 165: 602–603.CrossrefMedlineGoogle Scholar28 Morales R, Duncan D. Specialized contacts of astrocytes with astrocytes and with other cell types in the spinal cord of the cat. Anat Rec. 1975; 182: 255–266.CrossrefMedlineGoogle Scholar29 Rash JE, Duffy HS, Dudek FE, Bilhartz BL, Whalen LR, Yasumura T. Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system, with evidence for a "panglial syncytium" that is not coupled to neurons. J Comp Neurol. 1997; 388: 265–292.CrossrefMedlineGoogle Scholar30 Fróes MM, Menezes JRL. Coupled heterologous arrays in the brain. Neurochem Int. 2002; 41: 367–375.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Renaud L, Waldrep K, da Silveira W, Pilewski J and Feghali-Bostwick C (2023) First Characterization of the Transcriptome of Lung Fibroblasts of SSc Patients and Healthy Donors of African Ancestry, International Journal of Molecular Sciences, 10.3390/ijms24043645, 24:4, (3645) Feil R, Lehners M, Stehle D and Feil S (2021) Visualising and understanding cGMP signals in the cardiovascular system, British Journal of Pharmacology, 10.1111/bph.15500, 179:11, (2394-2412), Online publication date: 1-Jun-2022. Bae H, Kim T and Lim I (2022) Carbon monoxide activation of delayed rectifier potassium currents of human cardiac fibroblasts through diverse pathways, The Korean Journal of Physiology & Pharmacology, 10.4196/kjpp.2022.26.1.25, 26:1, (25-36), Online publication date: 1-Jan-2022. Bae H, Kim T and Lim I (2021) Carbon monoxide activates large-conductance calcium-activated potassium channels of human cardiac fibroblasts through various mechanisms, The Korean Journal of Physiology & Pharmacology, 10.4196/kjpp.2021.25.3.227, 25:3, (227-237), Online publication date: 1-May-2021. Oliván-Viguera A, Pérez-Zabalza M, García-Mendívil L, Mountris K, Orós-Rodrigo S, Ramos-Marquès E, Vallejo-Gil J, Fresneda-Roldán P, Fañanás-Mastral J, Vázquez-Sancho M, Matamala-Adell M, Sorribas-Berjón F, Bellido-Morales J, Mancebón-Sierra F, Vaca-Núñez A, Ballester-Cuenca C, Marigil M, Pastor C, Ordovás L, Köhler R, Diez E and Pueyo E (2020) Minimally invasive system to reliably characterize ventricular electrophysiology from living donors, Scientific Reports, 10.1038/s41598-020-77076-0, 10:1 Perbellini F and Thum T (2019) Living myocardial slices: a novel multicellular model for cardiac translational research, European Heart Journal, 10.1093/eurheartj/ehz779, 41:25, (2405-2408), Online publication date: 1-Jul-2020. Rajan D, Maki A, Pekkanen-Mattila M, Kreutzer J, Ryynanen T, Valimaki H, Verho J, Koivumaki J, Ihalainen H, Aalto-Setala K, Kallio P and Lekkala J Cardiomyocytes: Analysis of Temperature Response and Signal Propagation Between Dissociated Clusters Using Novel Video-Based Movement Analysis Software, IEEE Access, 10.1109/ACCESS.2020.3001191, 8, (109275-109288) Menges L, Krawutschke C, Füchtbauer E, Füchtbauer A, Sandner P, Koesling D and Russwurm M (2019) Mind the gap (junction): cGMP induced by nitric oxide in cardiac myocytes originates from cardiac fibroblasts, British Journal of Pharmacology, 10.1111/bph.14835, 176:24, (4696-4707), Online publication date: 1-Dec-2019. Song J, Yang R, Yang J and Zhou L (2018) Mitochondrial Dysfunction-Associated Arrhythmogenic Substrates in Diabetes Mellitus, Frontiers in Physiology, 10.3389/fphys.2018.01670, 9 Maiullari F, Costantini M, Milan M, Pace V, Chirivì M, Maiullari S, Rainer A, Baci D, Marei H, Seliktar D, Gargioli C, Bearzi C and Rizzi R (2018) A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes, Scientific Reports, 10.1038/s41598-018-31848-x, 8:1 Bae H, Choi J, Kim Y, Lee D, Kim J, Ko J, Bang H, Kim T and Lim I (2018) Effects of Nitric Oxide on Voltage-Gated K+ Currents in Human Cardiac Fibroblasts through the Protein Kinase G and Protein Kinase A Pathways but Not through S-Nitrosylation, International Journal of Molecular Sciences, 10.3390/ijms19030814, 19:3, (814) Teh I (2018) Cardiac Diffusion MRI Protocols and Methodologies in Basic Science and Clinical Cardiac MRI, 10.1007/978-3-319-53001-7_3, (55-109), . Zimik S and Pandit R (2017) Reentry via high-frequency pacing in a mathematical model for human-ventricular cardiac tissue with a localized fibrotic region, Scientific Reports, 10.1038/s41598-017-15735-5, 7:1 Gentemann L, Kalies S, Coffee M, Meyer H, Ripken T, Heisterkamp A, Zweigerdt R and Heinemann D (2016) Modulation of cardiomyocyte activity using pulsed laser irradiated gold nanoparticles, Biomedical Optics Express, 10.1364/BOE.8.000177, 8:1, (177), Online publication date: 1-Jan-2017. Zimik S and Pandit R (2016) Instability of spiral and scroll waves in the presence of a gradient in the fibroblast density: the effects of fibroblast–myocyte coupling, New Journal of Physics, 10.1088/1367-2630/18/12/123014, 18:12, (123014) Gourdie R, Dimmeler S and Kohl P (2016) Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease, Nature Reviews Drug Discovery, 10.1038/nrd.2016.89, 15:9, (620-638), Online publication date: 1-Sep-2016. Teh I, Burton R, McClymont D, Capel R, Aston D, Kohl P and Schneider J (2016) Mapping cardiac microstructure of rabbit heart in different mechanical states by high resolution diffusion tensor imaging: A proof-of-principle study, Progress in Biophysics and Molecular Biology, 10.1016/j.pbiomolbio.2016.06.001, 121:2, (85-96), Online publication date: 1-Jul-2016. Kharaziha M, Memic A, Akbari M, Brafman D and Nikkhah M (2016) Nano-Enabled Approaches for Stem Cell-Based Cardiac Tissue Engineering, Advanced Healthcare Materials, 10.1002/adhm.201600088, 5:13, (1533-1553), Online publication date: 1-Jul-2016. Travers J, Kamal F, Robbins J, Yutzey K and Blaxall B (2016) Cardiac Fibrosis, Circulation Research, 118:6, (1021-1040), Online publication date: 18-Mar-2016. Navaei A, Truong D, Heffernan J, Cutts J, Brafman D, Sirianni R, Vernon B and Nikkhah M (2016) PNIPAAm-based biohybrid injectable hydrogel for cardiac tissue engineering, Acta Biomaterialia, 10.1016/j.actbio.2015.12.019, 32, (10-23), Online publication date: 1-Mar-2016. Valiente-Alandi I, Schafer A and Blaxall B (2016) Extracellular matrix-mediated cellular communication in the heart, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2016.01.011, 91, (228-237), Online publication date: 1-Feb-2016. Rog-Zielinska E, Norris R, Kohl P and Markwald R (2016) The Living Scar – Cardiac Fibroblasts and the Injured Heart, Trends in Molecular Medicine, 10.1016/j.molmed.2015.12.006, 22:2, (99-114), Online publication date: 1-Feb-2016. Moghtadaei M, Polina I and Rose R (2016) Electrophysiological effects of natriuretic peptides in the heart are mediated by multiple receptor subtypes, Progress in Biophysics and Molecular Biology, 10.1016/j.pbiomolbio.2015.12.001, 120:1-3, (37-49), Online publication date: 1-Jan-2016. Gomez J, Cardona K and Trenor B (2015) Lessons learned from multi-scale modeling of the failing heart, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2015.10.016, 89, (146-159), Online publication date: 1-Dec-2015. Saini H, Navaei A, Van Putten A and Nikkhah M (2015) 3D Cardiac Microtissues Encapsulated with the Co-Culture of Cardiomyocytes and Cardiac Fibroblasts, Advanced Healthcare Materials, 10.1002/adhm.201500331, 4:13, (1961-1971), Online publication date: 1-Sep-2015. Meens M, Kwak B and Duffy H (2015) Role of connexins and pannexins in cardiovascular physiology, Cellular and Molecular Life Sciences, 10.1007/s00018-015-1959-2, 72:15, (2779-2792), Online publication date: 1-Aug-2015. Sbaizero O, DelFavero G, Martinelli V, Long C and Mestroni L (2015) Analysis of long- and short-range contribution to adhesion work in cardiac fibroblasts: An atomic force microscopy study, Materials Science and Engineering: C, 10.1016/j.msec.2014.12.083, 49, (217-224), Online publication date: 1-Apr-2015. Dostal D, Glaser S and Baudino T (2015) Cardiac Fibroblast Physiology and Pathology Comprehensive Physiology, 10.1002/cphy.c140053, (887-909) Periasamy A, So P, König K, Corbett A, Burton R, Bub G and Wilson T (2015) Imaging cardiomyocytes in intact tissue with a remote focusing microscope SPIE BiOS, 10.1117/12.2087342, , (932936), Online publication date: 5-Mar-2015. Corbett A, Burton R, Bub G and Wilson T (2015) Uniquely identifying cell orientation and sarcomere length in the intact rodent heart with oblique plane remote focussing microscopy European Conference on Biomedical Optics, 10.1364/ECBO.2015.95360A, 9781628417012, (95360A) Müller A and Freed D (2015) Bone Marrow-Derived Progenitor Cells, micro-RNA, and Fibrosis Cardiac Fibrosis and Heart Failure: Cause or Effect?, 10.1007/978-3-319-17437-2_4, (55-69), . Koivumäki J, Clark R, Belke D, Kondo C, Fedak P, Maleckar M and Giles W (2014) Na+ current expression in human atrial myofibroblasts: identity and functional roles, Frontiers in Physiology, 10.3389/fphys.2014.00275, 5 Zhan H, Xia L, Shou G, Zang Y, Liu F and Crozier S (2014) Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study, Journal of Zhejiang University SCIENCE B, 10.1631/jzus.B1300156, 15:3, (225-242), Online publication date: 1-Mar-2014. Silvestri A, Boffito M, Sartori S and Ciardelli G (2013) Biomimetic Materials and Scaffolds for Myocardial Tissue Regeneration, Macromolecular Bioscience, 10.1002/mabi.201200483, 13:8, (984-1019), Online publication date: 1-Aug-2013. Fan D, Takawale A, Lee J and Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease, Fibrogenesis & Tissue Repair, 10.1186/1755-1536-5-15, 5:1, Online publication date: 1-Dec-2012. Rai R, Tallawi M, Grigore A and Boccaccini A (2012) Synthesis, properties and biomedical applications of poly(glycerol sebacate) (PGS): A review, Progress in Polymer Science, 10.1016/j.progpolymsci.2012.02.001, 37:8, (1051-1078), Online publication date: 1-Aug-2012. Arenal A, Hernandez J, Perez-David E, Rubio-Guivernau J, Ledesma-Carbayo M and Fernandez-Aviles F (2012) Do the spatial characteristics of myocardial scar tissue determine the risk of ventricular arrhythmias?, Cardiovascular Research, 10.1093/cvr/cvs113, 94:2, (324-332), Online publication date: 1-May-2012. Gondalia R, Rothermel B, Lavandero S, Gillette T and Hill J (2012) Cardiac Plasticity in Health and Disease Translational Cardiology, 10.1007/978-1-61779-891-7_7, (185-250), . Kaneko T, Nomura F and Yasuda K (2011) On-chip constructive cell-Network study (I): Contribution of cardiac fibroblasts to cardiomyocyte beating synchronization and community effect, Journal of Nanobiotechnology, 10.1186/1477-3155-9-21, 9:1, Online publication date: 1-Dec-2011. Vasquez C, Benamer N and Morley G (2011) The Cardiac Fibroblast: Functional and Electrophysiological Considerations in Healthy and Diseased Hearts, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0b013e31820cda19, 57:4, (380-388), Online publication date: 1-Apr-2011. Yuan L, Liu Z, Zhang H, Ding X, Yang M, Gu H and Ren W (2011) Noise-induced synchronous stochastic oscillations in small scale cultured heart-cell networks, Chinese Physics B, 10.1088/1674-1056/20/2/020508, 20:2, (020508), Online publication date: 1-Feb-2011. Krenning G, Zeisberg E and Kalluri R (2010) The origin of fibroblasts and mechanism of cardiac fibrosis, Journal of Cellular Physiology, 10.1002/jcp.22322, 225:3, (631-637), Online publication date: 1-Dec-2010. Vasquez C, Mohandas P, Louie K, Benamer N, Bapat A and Morley G (2010) Enhanced Fibroblast–Myocyte Interactions in Response to Cardiac Injur