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  • Review Article
  • Published:

Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease

Nature Reviews Drug Discovery volume 15, pages 620–638 (2016)Cite this article

Subjects

Key Points

  • Fibroblasts have central roles in cardiac homeostasis and in the pathogenic remodelling that occurs during myocardial ischaemia, hypertension and heart failure

  • Progress has been made towards rational approaches and mechanisms for targeting fibroblasts and fibrosis in cardiac disease, including cell therapies and micro RNA-, peptide- and drug-based interventions

  • Nature's own repair mechanisms, which include fibroblast-mediated remodelling, could be exploited to re-engineer cardiac scar tissue for patient benefit

  • Pharmaceutically tractable compositions and delivery systems are among the hurdles that must be overcome before fibroblast-based therapies will contribute to improved cardiac health

Abstract

Our understanding of the functions of cardiac fibroblasts has moved beyond their roles in heart structure and extracellular matrix generation and now includes their contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts also have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.

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Figure 1: The changing focus of cardiac fibroblast research in the past 50 years.
Figure 2: Cardiac fibroblasts and myofibroblasts in health and disease.

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References

  1. Porter, K. E. & Turner, N. A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol. Ther. 123, 255–278 (2009).

    CAS  PubMed  Google Scholar 

  2. Kohl, P. & Gourdie, R. G. Fibroblast–myocyte electrotonic coupling: does it occur in native cardiac tissue? J. Mol. Cell. Cardiol. 70, 37–46 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kong, P., Christia, P. & Frangogiannis, N. G. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 71, 549–574 (2014).

    CAS  PubMed  Google Scholar 

  4. Moore-Morris, T., Guimaraes-Camboa, N., Yutzey, K. E., Puceat, M. & Evans, S. M. Cardiac fibroblasts: from development to heart failure. J. Mol. Med. (Berl.) 93, 823–830 (2015).

    CAS  Google Scholar 

  5. Davis, J. & Molkentin, J. D. Myofibroblasts: trust your heart and let fate decide. J. Mol. Cell. Cardiol. 70, 9–18 (2014).

    CAS  PubMed  Google Scholar 

  6. Leask, A. Getting to the heart of the matter: new insights into cardiac fibrosis. Circ. Res. 116, 1269–1276 (2015).

    CAS  PubMed  Google Scholar 

  7. Vasquez, C. & Morley, G. E. The origin and arrhythmogenic potential of fibroblasts in cardiac disease. J. Cardiovasc. Transl. Res. 5, 760–767 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. Ongstad, E. L. & Gourdie, R. G. Myocyte–fibroblast electrical coupling: the basis of a stable relationship? Cardiovascular Res. 93, 215–217 (2012).

    CAS  Google Scholar 

  9. Mozaffarian, D. et al. Heart disease and stroke statistics — 2015 update: a report from the American Heart Association. Circulation 131, e29–e322 (2015).

    PubMed  Google Scholar 

  10. Spinale, F. G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285–1342 (2007).

    CAS  PubMed  Google Scholar 

  11. Caulfield, J. B. & Borg, T. K. The collagen network of the heart. Lab. Invest. 40, 364–371 (1979).

    CAS  PubMed  Google Scholar 

  12. Hales, P. W. et al. Histo-anatomical structure of the living isolated rat heart in two contraction states assessed by diffusion tensor MRI. Prog. Biophys. Mol. Biol. 110, 319–330 (2012).

    PubMed  PubMed Central  Google Scholar 

  13. Ott, H. C. et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).

    CAS  PubMed  Google Scholar 

  14. Sanchez, P. L. et al. Acellular human heart matrix: a critical step toward whole heart grafts. Biomaterials 61, 279–289 (2015).

    CAS  PubMed  Google Scholar 

  15. Lu, T. Y. et al. Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells. Nat. Commun. 4, 2307 (2013).

    PubMed  Google Scholar 

  16. Tedder, M. E. et al. Stabilized collagen scaffolds for heart valve tissue engineering. Tissue Eng. Part A 15, 1257–1268 (2009).

    CAS  PubMed  Google Scholar 

  17. Yacoub, M. H. In search of living valve substitutes. J. Am. Coll. Cardiol. 66, 889–891 (2015).

    PubMed  Google Scholar 

  18. Mohamed, T. M. A. et al. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy. Nat. Commun. 7, 11074 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. De Maziere, A. M., van Ginneken, A. C., Wilders, R., Jongsma, H. J. & Bouman, L. N. Spatial and functional relationship between myocytes and fibroblasts in the rabbit sinoatrial node. J. Mol. Cell. Cardiol. 24, 567–578 (1992).

    CAS  PubMed  Google Scholar 

  20. Camelliti, P., Green, C. R., LeGrice, I. & Kohl, P. Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogeneous and heterogeneous cell coupling. Circ. Res. 94, 828–835 (2004). This paper presents proof of in situ fibroblast–myocyte coupling in native rabbit sinoatrial node tissue.

    CAS  PubMed  Google Scholar 

  21. Vasquez, C. et al. Enhanced fibroblast–myocyte interactions in response to cardiac injury. Circ. Res. 107, 1011–1020 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Nguyen, T. P., Xie, Y., Garfinkel, A., Qu, Z. & Weiss, J. N. Arrhythmogenic consequences of myofibroblast–myocyte coupling. Cardiovasc. Res. 93, 242–251 (2012).

    CAS  PubMed  Google Scholar 

  23. Nisbet, A. M. et al. Prolongation of atrio-ventricular node conduction in a rabbit model of ischaemic cardiomyopathy: role of fibrosis and connexin remodelling. J. Mol. Cell. Cardiol. 94, 54–64 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hiruma, T. & Hirakow, R. Epicardial formation in embryonic chick heart: computer-aided reconstruction, scanning, and transmission electron microscopic studies. Am. J. Anat. 184, 129–138 (1989).

    CAS  PubMed  Google Scholar 

  25. Mikawa, T. & Gourdie, R. G. Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev. Biol. 174, 221–232 (1996). This cell lineage study identified an epicardial origin for cardiac fibroblasts and smooth muscle cells.

    CAS  PubMed  Google Scholar 

  26. Manasek, F. J. Embryonic development of the heart. II. Formation of the epicardium. J. Embryol. Exp. Morphol. 22, 333–348 (1969). This histological study of epicardial differentiation indicated that epicardium has an extracardiac origin.

    CAS  PubMed  Google Scholar 

  27. Dettman, R. W., Denetclaw, W. Jr, Ordahl, C. P. & Bristow, J. Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev. Biol. 193, 169–181 (1998).

    CAS  PubMed  Google Scholar 

  28. Gittenberger-de Groot, A. C., Vrancken Peeters, M. P., Mentink, M. M., Gourdie, R. G. & Poelmann, R. E. Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circul. Res. 82, 1043–1052 (1998).

    CAS  Google Scholar 

  29. Mizutani, M., Wu, J. C. & Nusse, R. Fibrosis of the neonatal mouse heart after cryoinjury is accompanied by Wnt signaling activation and epicardial-to-mesenchymal transition. J. Am. Heart Assoc. 4, e002457 (2016).

    Google Scholar 

  30. Cano, E., Carmona, R., Velecela, V., Martinez-Estrada, O. & Munoz-Chapuli, R. The proepicardium keeps a potential for glomerular marker expression which supports its evolutionary origin from the pronephros. Evol. Dev. 17, 224–230 (2015).

    CAS  PubMed  Google Scholar 

  31. Schlueter, J., Manner, J. & Brand, T. BMP is an important regulator of proepicardial identity in the chick embryo. Dev. Biol. 295, 546–558 (2006).

    CAS  PubMed  Google Scholar 

  32. Merki, E. et al. Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation. Proc. Natl Acad. Sci. USA 102, 18455–18460 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Compton, L. A., Potash, D. A., Mundell, N. A. & Barnett, J. V. Transforming growth factor-β induces loss of epithelial character and smooth muscle cell differentiation in epicardial cells. Dev. Dyn. 235, 82–93 (2006).

    CAS  PubMed  Google Scholar 

  34. Martinez-Estrada, O. M. et al. Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nat. Genet. 42, 89–93 (2010).

    CAS  PubMed  Google Scholar 

  35. Wu, S. P., Dong, X. R., Regan, J. N., Su, C. & Majesky, M. W. Tbx18 regulates development of the epicardium and coronary vessels. Dev. Biol. 383, 307–320 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Furtado, M. B. et al. Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair. Circ. Res. 114, 1422–1434 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sanchez, N. S. & Barnett, J. V. TGFβ and BMP-2 regulate epicardial cell invasion via TGFβR3 activation of the Par6/Smurf1/RhoA pathway. Cell Signal. 24, 539–548 (2012).

    CAS  PubMed  Google Scholar 

  38. Allison, P., Espiritu, D., Barnett, J. V. & Camenisch, T. D. Type III TGFβ receptor and Src direct hyaluronan-mediated invasive cell motility. Cell Signal. 27, 453–459 (2015).

    CAS  PubMed  Google Scholar 

  39. Vega-Hernandez, M., Kovacs, A., De Langhe, S. & Ornitz, D. M. FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium. Development 138, 3331–3340 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith, C. L., Baek, S. T., Sung, C. Y. & Tallquist, M. D. Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ. Res. 108, e15–e26 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Artamonov, M. V. et al. Signaling pathways that control rho kinase activity maintain the embryonic epicardial progenitor state. J. Biol. Chem. 290, 10353–10367 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dettman, R. W., Pae, S. H., Morabito, C. & Bristow, J. Inhibition of α4-integrin stimulates epicardial–mesenchymal transformation and alters migration and cell fate of epicardially derived mesenchyme. Dev. Biol. 257, 315–328 (2003).

    CAS  PubMed  Google Scholar 

  43. Benesh, E. C. et al. Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition. Mol. Biol. Cell 24, 3496–3510 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Brand, T., Simrick, S. L., Poon, K. L. & Schindler, R. F. The cAMP-binding Popdc proteins have a redundant function in the heart. Biochem. Soc. Trans. 42, 295–301 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Landerholm, T. E. et al. A role for serum response factor in coronary smooth muscle differentiation from proepicardial cells. Development 126, 2053–2062 (1999).

    CAS  PubMed  Google Scholar 

  46. Acharya, A. et al. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139, 2139–2149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Tandon, P., Miteva, Y. V., Kuchenbrod, L. M., Cristea, I. M. & Conlon, F. L. Tcf21 regulates the specification and maturation of proepicardial cells. Development 140, 2409–2421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Trembley, M. A., Velasquez, L. S., de Mesy Bentley, K. L. & Small, E. M. Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels. Development 142, 21–30 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bouacida, A. et al. Pericyte-like progenitors show high immaturity and engraftment potential as compared with mesenchymal stem cells. PLoS ONE 7, e48648 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Volz, K. S. et al. Pericytes are progenitors for coronary artery smooth muscle. eLife 4, e10036 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. Birbrair, A. et al. Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Res. Ther. 5, 122 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Eisenberg, L. M. & Markwald, R. R. Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circul. Res. 77, 1–6 (1995).

    CAS  Google Scholar 

  53. Hutson, M. R. & Kirby, M. L. Neural crest and cardiovascular development: a 20-year perspective. Birth Defects Res. C Embryo Today 69, 2–13 (2003).

    CAS  PubMed  Google Scholar 

  54. Rentschler, S., Jain, R. & Epstein, J. A. Tissue–tissue interactions during morphogenesis of the outflow tract. Pediatr. Cardiol. 31, 408–413 (2010).

    PubMed  Google Scholar 

  55. Ali, S. R. et al. Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ. Res. 115, 625–635 (2014).

    CAS  PubMed  Google Scholar 

  56. Cheng, G. et al. Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage. Development 126, 5041–5049 (1999).

    CAS  PubMed  Google Scholar 

  57. Nakajima, Y., Mironov, V., Yamagishi, T., Nakamura, H. & Markwald, R. R. Expression of smooth muscle alpha-actin in mesenchymal cells during formation of avian endocardial cushion tissue: a role for transforming growth factor β3. Dev. Dyn. 209, 296–309 (1997).

    CAS  PubMed  Google Scholar 

  58. Martin, P., Tzanidis, A., Stein-Oakley, A. & Krum, H. Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction. J. Cardiovasc. Pharmacol. 36, S367–S370 (2000).

    CAS  PubMed  Google Scholar 

  59. Campbell, S. E. & Katwa, L. C. Angiotensin II stimulated expression of transforming growth factor-β1 in cardiac fibroblasts and myofibroblasts. J. Mol. Cell. Cardiol. 29, 1947–1958 (1997).

    CAS  PubMed  Google Scholar 

  60. Dai, P., Nakagami, T., Tanaka, H., Hitomi, T. & Takamatsu, T. Cx43 mediates TGF-β signaling through competitive Smads binding to microtubules. Mol. Biol. Cell 18, 2264–2273 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Asazuma-Nakamura, Y. et al. Cx43 contributes to TGF-β signaling to regulate differentiation of cardiac fibroblasts into myofibroblasts. Exp. Cell Res. 315, 1190–1199 (2009).

    CAS  PubMed  Google Scholar 

  62. Sanders, Y. Y. et al. SMAD-independent down-regulation of caveolin-1 by TGF-β: effects on proliferation and survival of myofibroblasts. PLoS ONE 10, e0116995 (2015).

    PubMed  PubMed Central  Google Scholar 

  63. Xia, Y. et al. Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension 58, 902–911 (2011).

    CAS  PubMed  Google Scholar 

  64. McCurdy, S., Baicu, C. F., Heymans, S. & Bradshaw, A. D. Cardiac extracellular matrix remodeling: fibrillar collagens and secreted protein acidic and rich in cysteine (SPARC). J. Mol. Cell. Cardiol. 48, 544–549 (2010).

    CAS  PubMed  Google Scholar 

  65. Oka, T. et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ. Res. 101, 313–321 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Nishioka, T. et al. Eplerenone attenuates myocardial fibrosis in the angiotensin II-induced hypertensive mouse: involvement of tenascin-C induced by aldosterone-mediated inflammation. J. Cardiovasc. Pharmacol. 49, 261–268 (2007).

    CAS  PubMed  Google Scholar 

  67. Grotendorst, G. R. & Duncan, M. R. Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J. 19, 729–738 (2005).

    CAS  PubMed  Google Scholar 

  68. Dubash, A. D. et al. Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J. Cell Biol. 212, 425–438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Jeong, D. et al. Matricellular protein CCN5 reverses established cardiac fibrosis. J. Am. Coll. Cardiol. 67, 1556–1568 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kaur, H. et al. Targeted ablation of periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ. Res. http://dx.doi.org/10.1161/CIRCRESAHA.116.308643 (2016).

  71. Blaauw, E. et al. Stretch-induced upregulation of connective tissue growth factor in rabbit cardiomyocytes. J. Cardiovasc. Transl. Res. 6, 861–869 (2013).

    PubMed  Google Scholar 

  72. Fomovsky, G. M., Rouillard, A. D. & Holmes, J. W. Regional mechanics determine collagen fiber structure in healing myocardial infarcts. J. Mol. Cell. Cardiol. 52, 1083–1090 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Dalla Costa, A. P. et al. FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex. Cardiovasc. Res. 86, 421–431 (2010).

    CAS  PubMed  Google Scholar 

  74. Kamkin, A., Kiseleva, I. & Isenberg, G. Activation and inactivation of a non-selective cation conductance by local mechanical deformation of acutely isolated cardiac fibroblasts. Cardiovasc. Res. 57, 793–803 (2003).

    CAS  PubMed  Google Scholar 

  75. Kiseleva, I., Kamkin, A., Kohl, P. & Lab, M. J. Calcium and mechanically induced potentials in fibroblasts of rat atrium. Cardiovasc. Res. 32, 98–111 (1996).

    CAS  PubMed  Google Scholar 

  76. Peyronnet, R., Nerbonne, J. M. & Kohl, P. Cardiac mechano-gated ion channels and arrhythmias. Circ. Res. 118, 311–329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. van den Borne, S. W. et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nat. Rev. Cardiol. 7, 30–37 (2010).

    PubMed  Google Scholar 

  78. Roche, P. L., Filomeno, K. L., Bagchi, R. A. & Czubryt, M. P. Intracellular signaling of cardiac fibroblasts. Compr. Physiol. 5, 721–760 (2015).

    PubMed  Google Scholar 

  79. Nakatsuji, S., Yamate, J., Kuwamura, M., Kotani, T. & Sakuma, S. In vivo responses of macrophages and myofibroblasts in the healing following isoproterenol-induced myocardial injury in rats. Virchows Arch. 430, 63–69 (1997).

    CAS  PubMed  Google Scholar 

  80. Shiraishi, M. et al. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J. Clin. Invest. http://dx.doi.org/10.1172/JCI85782 (2016).

  81. Willems, I. E., Havenith, M. G., De Mey, J. G. & Daemen, M. J. The alpha-smooth muscle actin-positive cells in healing human myocardial scars. Am. J. Pathol. 145, 868–875 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hulsmans, M., Sam, F. & Nahrendorf, M. Monocyte and macrophage contributions to cardiac remodeling. J. Mol. Cell. Cardiol. 93, 149–155 (2016).

    CAS  PubMed  Google Scholar 

  83. van den Borne, S. W. et al. Mouse strain determines the outcome of wound healing after myocardial infarction. Cardiovasc. Res. 84, 273–282 (2009).

    CAS  PubMed  Google Scholar 

  84. Kong, P., Christia, P., Saxena, A., Su, Y. & Frangogiannis, N. G. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am. J. Physiol. Heart Circ. Physiol. 305, H1363–H1372 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou, B., von Gise, A., Ma, Q., Hu, Y. W. & Pu, W. T. Genetic fate mapping demonstrates contribution of epicardium-derived cells to the annulus fibrosis of the mammalian heart. Dev. Biol. 338, 251–261 (2010).

    CAS  PubMed  Google Scholar 

  86. Moore-Morris, T. et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J. Clin. Invest. 124, 2921–2934 (2014). A cell lineage study demonstrating the primary contribution of resident cardiac fibroblasts to pressure-overload-induced fibrosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruiz-Villalba, A. et al. Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar. J. Am. Coll. Cardiol. 65, 2057–2066 (2015).

    PubMed  Google Scholar 

  88. Mollmann, H. et al. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc. Res. 71, 661–671 (2006). This is a cell lineage study demonstrating that bone marrow-derived cells contribute to fibroblasts and myofibroblasts at myocardial infarcts.

    PubMed  Google Scholar 

  89. Visconti, R. P. & Markwald, R. R. Recruitment of new cells into the postnatal heart: potential modification of phenotype by periostin. Ann. NY Acad. Sci. 1080, 19–33 (2006).

    CAS  PubMed  Google Scholar 

  90. Crawford, J. R., Haudek, S. B., Cieslik, K. A., Trial, J. & Entman, M. L. Origin of developmental precursors dictates the pathophysiologic role of cardiac fibroblasts. J. Cardiovasc. Transl. Res. 5, 749–759 (2012).

    PubMed  PubMed Central  Google Scholar 

  91. Cieslik, K. A., Trial, J., Crawford, J. R., Taffet, G. E. & Entman, M. L. Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J. Mol. Cell. Cardiol. 70, 56–63 (2014).

    CAS  PubMed  Google Scholar 

  92. Duerrschmid, C., Trial, J., Wang, Y., Entman, M. L. & Haudek, S. B. Tumor necrosis factor: a mechanistic link between angiotensin-II-induced cardiac inflammation and fibrosis. Circ. Heart Fail. 8, 352–361 (2015).

    CAS  PubMed  Google Scholar 

  93. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    CAS  PubMed  Google Scholar 

  94. Deb, A. & Ubil, E. Cardiac fibroblast in development and wound healing. J. Mol. Cell. Cardiol. 70, 47–55 (2014).

    CAS  PubMed  Google Scholar 

  95. Ongstad, E. & Kohl, P. Fibroblast–myocyte coupling in the heart: potential relevance for therapeutic interventions. J. Mol. Cell. Cardiol. 91, 238–246 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kikuchi, K. & Poss, K. D. Cardiac regenerative capacity and mechanisms. Annu. Rev. Cell Dev. Biol. 28, 719–741 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Gerbin, K. A. & Murry, C. E. The winding road to regenerating the human heart. Cardiovasc. Pathol. 24, 133–140 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Nakada, Y., Kimura, W. & Sadek, H. A. Defining the limit of embryonic heart regeneration. Circulation 132, 77–78 (2015).

    PubMed  Google Scholar 

  100. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This paper presents the Nobel prize-winning discovery that pluripotent stem cells can be induced from mouse embryonic and adult fibroblast cultures by four defined transcription factors.

    CAS  PubMed  Google Scholar 

  101. Sadahiro, T., Yamanaka, S. & Ieda, M. Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications. Circ. Res. 116, 1378–1391 (2015).

    CAS  PubMed  Google Scholar 

  102. Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010). This study confirms that fibroblasts can be transdifferentiated into myocytes by defined transcription factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Qian, L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Song, K. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jayawardena, T. M. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ. Res. 110, 1465–1473 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640–644 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Gajzer, D. C., Balbin, J. & Chaudhry, H. W. Thymosin β4 and cardiac regeneration: are we missing a beat? Stem Cell Rev. 9, 303–312 (2013).

    CAS  Google Scholar 

  108. Chen, J. X. et al. Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5. Circ. Res. 111, 50–55 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang, L. et al. Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circ. Res. 116, 237–244 (2015).

    PubMed  Google Scholar 

  110. Nam, Y. J. et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc. Natl Acad. Sci. USA 110, 5588–5593 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Muraoka, N. et al. MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J. 33, 1565–1581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Pratico, E. D. et al. RNA-mediated reprogramming of primary adult human dermal fibroblasts into c-kit+ cardiac progenitor cells. Stem Cells Dev. 24, 2622–2633 (2015).

    CAS  PubMed  Google Scholar 

  113. Nam, Y. J. et al. Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development 141, 4267–4278 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ifkovits, J. L., Addis, R. C., Epstein, J. A. & Gearhart, J. D. Inhibition of TGFβ signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS ONE 9, e89678 (2014).

    PubMed  PubMed Central  Google Scholar 

  115. Zhou, H., Dickson, M. E., Kim, M. S., Bassel-Duby, R. & Olson, E. N. Akt1/protein kinase B enhances transcriptional reprogramming of fibroblasts to functional cardiomyocytes. Proc. Natl Acad. Sci. USA 112, 11864–11869 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Towbin, J. A. Scarring in the heart — a reversible phenomenon? N. Engl. J. Med. 357, 1767–1768 (2007).

    CAS  PubMed  Google Scholar 

  117. Gulati, A. et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 309, 896–908 (2013).

    CAS  PubMed  Google Scholar 

  118. Klem, I. et al. Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. J. Am. Coll. Cardiol. 60, 408–420 (2012).

    PubMed  PubMed Central  Google Scholar 

  119. Esposito, G., Dellegrottaglie, S. & Chiariello, M. The extent of irreversible myocardial damage and the potential for left ventricular repair after primary percutaneous coronary intervention. Am. Heart J. 160, S4–S10 (2010).

    PubMed  Google Scholar 

  120. Vander Heide, R. S. & Steenbergen, C. Cardioprotection and myocardial reperfusion: pitfalls to clinical application. Circ. Res. 113, 464–477 (2013).

    CAS  PubMed  Google Scholar 

  121. Murry, C. E., Jennings, R. B. & Reimer, K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136 (1986).

    CAS  PubMed  Google Scholar 

  122. Fordyce, C. B., Gersh, B. J., Stone, G. W. & Granger, C. B. Novel therapeutics in myocardial infarction: targeting microvascular dysfunction and reperfusion injury. Trends Pharmacol. Sci. 36, 605–615 (2015).

    CAS  PubMed  Google Scholar 

  123. Jones, S. P. et al. The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ. Res. 116, 572–586 (2015).

    CAS  PubMed  Google Scholar 

  124. Heusch, G., Botker, H. E., Przyklenk, K., Redington, A. & Yellon, D. Remote ischemic conditioning. J. Am. Coll. Cardiol. 65, 177–195 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hausenloy, D. J. & Yellon, D. M. Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis 204, 334–341 (2009).

    CAS  PubMed  Google Scholar 

  126. Duncker, D. J. & Verdouw, P. D. Role of K+ATP channels in ischemic preconditioning and cardioprotection. Cardiovasc. Drugs Ther. 14, 7–16 (2000).

    CAS  PubMed  Google Scholar 

  127. Chen, C. H. et al. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321, 1493–1495 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kornfeld, O. S. et al. Mitochondrial reactive oxygen species at the heart of the matter: new therapeutic approaches for cardiovascular diseases. Circ. Res. 116, 1783–1799 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Monassier, L., Ayme-Dietrich, E., Aubertin-Kirch, G. & Pathak, A. Targeting myocardial reperfusion injuries with cyclosporine in the CIRCUS Trial — pharmacological reasons for failure. Fundam. Clin. Pharmacol. 30, 191–193 (2015).

    Google Scholar 

  130. Das, A., Durrant, D., Salloum, F. N., Xi, L. & Kukreja, R. C. PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol. Ther. 147, 12–21 (2015).

    CAS  PubMed  Google Scholar 

  131. Adkins, G. B. & Curtis, M. J. Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol. Ther. 145, 67–75 (2015).

    CAS  PubMed  Google Scholar 

  132. Shen, Y., Shen, Z., Luo, S., Guo, W. & Zhu, Y. Z. The cardioprotective effects of hydrogen sulfide in heart diseases: from molecular mechanisms to therapeutic potential. Oxid. Med. Cell. Longev. 2015, 925167 (2015).

    PubMed  PubMed Central  Google Scholar 

  133. Das, A. et al. Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. Bas. Res. Cardiol. 110, 31 (2015).

    Google Scholar 

  134. Sun, J. & Murphy, E. Protein S-nitrosylation and cardioprotection. Circ. Res. 106, 285–296 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Luo, J., Obal, D., Dimova, N., Tang, X. L. & Rokosh, G. Cardiac myocyte-specific transgenic ecSOD targets mitochondria to protect against Ca2+ induced permeability transition. Front. Physiol. 4, 295 (2013).

  136. Hawat, G., Helie, P. & Baroudi, G. Single intravenous low-dose injections of connexin 43 mimetic peptides protect ischemic heart in vivo against myocardial infarction. J. Mol. Cell. Cardiol. 53, 559–566 (2012).

    CAS  PubMed  Google Scholar 

  137. Wang, N. et al. Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Bas. Res. Cardiol. 108, 309 (2013).

    Google Scholar 

  138. Rhett, J. M., Jourdan, J. & Gourdie, R. G. Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol. Biol. Cell 22, 1516–1528 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Sluijter, J. P. et al. Novel therapeutic strategies for cardioprotection. Pharmacol. Ther. 144, 60–70 (2014).

    CAS  PubMed  Google Scholar 

  140. Desplantez, T., Verma, V., Leybaert, L., Evans, W. H. & Weingart, R. Gap26, a connexin mimetic peptide, inhibits currents carried by connexin43 hemichannels and gap junction channels. Pharmacol. Res. 65, 546–552 (2012).

    CAS  PubMed  Google Scholar 

  141. Davidson, J. O., Green, C. R., Bennet, L. & Gunn, A. J. Battle of the hemichannels — connexins and pannexins in ischemic brain injury. Int. J. Dev. Neurosci. 45, 66–74 (2014).

    PubMed  Google Scholar 

  142. Afzal, M. R. et al. Adult bone marrow cell therapy for ischemic heart disease: evidence and insights from randomized controlled trials. Circ. Res. 117, 558–575 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Karantalis, V. & Hare, J. M. Use of mesenchymal stem cells for therapy of cardiac disease. Circ. Res. 116, 1413–1430 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Delewi, R. et al. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur. Heart J. 35, 989–998 (2014).

    PubMed  Google Scholar 

  145. Assmus, B., Dimmeler, S. & Zeiher, A. M. Cardiac cell therapy: lost in meta-analyses. Circ. Res. 116, 1291–1292 (2015).

    CAS  PubMed  Google Scholar 

  146. Gyongyosi, M. et al. Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ. Res. 116, 1346–1360 (2015).

    PubMed  PubMed Central  Google Scholar 

  147. Leri, A., Rota, M., Pasqualini, F. S., Goichberg, P. & Anversa, P. Origin of cardiomyocytes in the adult heart. Circ. Res. 116, 150–166 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bolli, R. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378, 1847–1857 (2011).

    PubMed  PubMed Central  Google Scholar 

  149. Makkar, R. R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised Phase 1 trial. Lancet 379, 895–904 (2012).

    PubMed  PubMed Central  Google Scholar 

  150. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ellison, G. M. et al. Adult c-kitpos cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154, 827–842 (2013).

    CAS  PubMed  Google Scholar 

  152. van Berlo, J. H. et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337–341 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Zaruba, M. M., Soonpaa, M., Reuter, S. & Field, L. J. Cardiomyogenic potential of c-kit+-expressing cells derived from neonatal and adult mouse hearts. Circulation 121, 1992–2000 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Sultana, N. et al. Resident c-kit+ cells in the heart are not cardiac stem cells. Nat. Commun. 6, 8701 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Liu, Q. et al. Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. Cell Res. 26, 119–130 (2016).

    CAS  PubMed  Google Scholar 

  156. Uchida, S. et al. Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Rep. 1, 397–410 (2013).

    CAS  Google Scholar 

  157. Abbott, A. Doubts over heart stem-cell therapy. Nature 509, 15–16 (2014).

    CAS  PubMed  Google Scholar 

  158. Burchfield, J. S. & Dimmeler, S. Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis. Fibrogen. Tissue Repair 1, 4 (2008).

    Google Scholar 

  159. Kinnaird, T. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94, 678–685 (2004).

    CAS  PubMed  Google Scholar 

  160. Pak, H. N. et al. Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a Swine model of myocardial infarction. J. Cardiovasc. Electrophysiol. 14, 841–848 (2003).

    PubMed  Google Scholar 

  161. Seeger, F. H. et al. CXCR4 expression determines functional activity of bone marrow-derived mononuclear cells for therapeutic neovascularization in acute ischemia. Arterioscler. Thromb. Vasc. Biol. 29, 1802–1809 (2009).

    CAS  PubMed  Google Scholar 

  162. Li, L. et al. Paracrine action mediate the antifibrotic effect of transplanted mesenchymal stem cells in a rat model of global heart failure. Mol. Biol. Rep. 36, 725–731 (2009).

    CAS  PubMed  Google Scholar 

  163. Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).

    CAS  PubMed  Google Scholar 

  164. Li, Z., Wei, H., Deng, L., Cong, X. & Chen, X. Expression and secretion of interleukin-1β, tumour necrosis factor-α and interleukin-10 by hypoxia- and serum-deprivation-stimulated mesenchymal stem cells. FEBS J. 277, 3688–3698 (2010).

    CAS  PubMed  Google Scholar 

  165. Chen, P. et al. Hypoxia preconditioned mesenchymal stem cells prevent cardiac fibroblast activation and collagen production via leptin. PLoS ONE 9, e103587 (2014).

    PubMed  PubMed Central  Google Scholar 

  166. Korf-Klingebiel, M. et al. Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat. Med. 21, 140–149 (2015).

    CAS  PubMed  Google Scholar 

  167. Sahoo, S. & Losordo, D. W. Exosomes and cardiac repair after myocardial infarction. Circ. Res. 114, 333–344 (2014).

    CAS  PubMed  Google Scholar 

  168. Malliaras, K. et al. Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol. Med. 6, 760–777 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Dimmeler, S., Ding, S., Rando, T. A. & Trounson, A. Translational strategies and challenges in regenerative medicine. Nat. Med. 20, 814–821 (2014).

    CAS  PubMed  Google Scholar 

  170. Marban, E., Cho, H. C. & Cingolani, E. Taking the cells out of cell therapy. J. Am. Coll. Cardiol. 60, 1707–1708 (2012).

    PubMed  Google Scholar 

  171. Goldstein, J. L. & Brown, M. S. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161, 161–172 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Patel, R. et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation 104, 317–324 (2001). This study demonstrates that statins can reduce cardiac fibrosis in an animal model.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Bauersachs, J., Galuppo, P., Fraccarollo, D., Christ, M. & Ertl, G. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme A reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation 104, 982–985 (2001).

    CAS  PubMed  Google Scholar 

  174. Abulhul, E. et al. Long-term statin therapy in patients with systolic heart failure and normal cholesterol: effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide. Clin. Ther. 34, 91–100 (2012).

    CAS  PubMed  Google Scholar 

  175. Shiroshita-Takeshita, A. et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc. Res. 74, 75–84 (2007).

    CAS  PubMed  Google Scholar 

  176. Raghu, G., Johnson, W. C., Lockhart, D. & Mageto, Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am. J. Respir. Crit. Care Med. 159, 1061–1069 (1999).

    CAS  PubMed  Google Scholar 

  177. Tank, J. et al. Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts. J. Mol. Cell. Cardiol. 66, 141–156 (2014).

    CAS  PubMed  Google Scholar 

  178. Szabo, Z. et al. Connective tissue growth factor inhibition attenuates left ventricular remodeling and dysfunction in pressure overload-induced heart failure. Hypertension 63, 1235–1240 (2014).

    CAS  PubMed  Google Scholar 

  179. Mirkovic, S. et al. Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats. Br. J. Pharmacol. 135, 961–968 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Kagitani, S. et al. Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/salt hypertensive rats. J. Hypertens. 22, 1007–1015 (2004).

    CAS  PubMed  Google Scholar 

  181. Koitabashi, N. et al. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J. Clin. Invest. 121, 2301–2312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Oyamada, S., Bianchi, C., Takai, S., Chu, L. M. & Sellke, F. W. Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion. J. Pharmacol. Exp. Ther. 339, 143–151 (2011).

    CAS  PubMed  Google Scholar 

  183. Kim, J. et al. Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J. Am. Coll. Cardiol. 48, 1378–1384 (2006).

    CAS  PubMed  Google Scholar 

  184. Hayashidani, S. et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 108, 2134–2140 (2003).

    CAS  PubMed  Google Scholar 

  185. Bujak, M. et al. Induction of the CXC chemokine interferon-γ-inducible protein 10 regulates the reparative response following myocardial infarction. Circ. Res. 105, 973–983 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Rodriguez-Pascual, F., Busnadiego, O. & Gonzalez-Santamaria, J. The profibrotic role of endothelin-1: is the door still open for the treatment of fibrotic diseases? Life Sci. 118, 156–164 (2014).

    CAS  PubMed  Google Scholar 

  187. De Mello, W. C. & Specht, P. Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart. J. Renin Angiotensin Aldosterone Syst. 7, 201–205 (2006).

    CAS  PubMed  Google Scholar 

  188. Shibasaki, Y. et al. Impact of the angiotensin II receptor antagonist, losartan, on myocardial fibrosis in patients with end-stage renal disease: assessment by ultrasonic integrated backscatter and biochemical markers. Hypertens. Res. 28, 787–795 (2005).

    CAS  PubMed  Google Scholar 

  189. Daskalopoulos, E. P., Hermans, K. C., Janssen, B. J. & Matthijs Blankesteijn, W. Targeting the Wnt/frizzled signaling pathway after myocardial infarction: a new tool in the therapeutic toolbox? Trends Cardiovasc. Med. 23, 121–127 (2013).

    CAS  PubMed  Google Scholar 

  190. He, W. et al. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc. Natl Acad. Sci. USA 107, 21110–21115 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Luo, K. et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev. 13, 2196–2206 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Cunnington, R. H. et al. Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility. Am. J. Physiol. Cell Physiol. 300, C176–C186 (2011).

    CAS  PubMed  Google Scholar 

  193. Espira, L. et al. The basic helix–loop–helix transcription factor scleraxis regulates fibroblast collagen synthesis. J. Mol. Cell. Cardiol. 47, 188–195 (2009).

    CAS  PubMed  Google Scholar 

  194. Balasubramanian, S. et al. β3 integrin in cardiac fibroblast is critical for extracellular matrix accumulation during pressure overload hypertrophy in mouse. PLoS ONE 7, e45076 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Shivshankar, P. et al. Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation in mice after myocardial infarction. J. Mol. Cell. Cardiol. 76, 84–93 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Yi, S. L., Liu, X. J., Zhong, J. Q. & Zhang, Y. Role of caveolin-1 in atrial fibrillation as an anti-fibrotic signaling molecule in human atrial fibroblasts. PLoS ONE 9, e85144 (2014).

    PubMed  PubMed Central  Google Scholar 

  197. Cunnington, R. H., Nazari, M. & Dixon, I. M. c-Ski, Smurf2, and Arkadia as regulators of TGF-β signaling: new targets for managing myofibroblast function and cardiac fibrosis. Can. J. Physiol. Pharmacol. 87, 764–772 (2009).

    CAS  PubMed  Google Scholar 

  198. Czubryt, M. P. Common threads in cardiac fibrosis, infarct scar formation, and wound healing. Fibrogen. Tissue Repair 5, 19 (2012).

    Google Scholar 

  199. Tourkina, E. et al. Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 294, L843–L861 (2008).

    CAS  PubMed  Google Scholar 

  200. Varr, B. C. & Maurer, M. S. Emerging role of serelaxin in the therapeutic armamentarium for heart failure. Curr. Atheroscler. Rep. 16, 447 (2014).

    PubMed  Google Scholar 

  201. Neverova, N. & Teerlink, J. R. Serelaxin: a potential new drug for the treatment of acute heart failure. Expert Opin. Investig. Drugs 23, 1017–1026 (2014).

    CAS  PubMed  Google Scholar 

  202. Tietjens, J. & Teerlink, J. R. Serelaxin and acute heart failure. Heart 102, 95–99 (2016).

    CAS  PubMed  Google Scholar 

  203. Squecco, R. et al. Inhibitory effects of relaxin on cardiac fibroblast-to-myofibroblast transition: an electrophysiological study. Exp. Physiol. 100, 652–666 (2015).

    CAS  PubMed  Google Scholar 

  204. Sassoli, C. et al. Relaxin prevents cardiac fibroblast-myofibroblast transition via notch-1-mediated inhibition of TGF-β/Smad3 signaling. PLoS ONE 8, e63896 (2013).

    PubMed  PubMed Central  Google Scholar 

  205. Small, E. M., Frost, R. J. & Olson, E. N. MicroRNAs add a new dimension to cardiovascular disease. Circulation 121, 1022–1032 (2010).

    PubMed  PubMed Central  Google Scholar 

  206. Thum, T. MicroRNA therapeutics in cardiovascular medicine. EMBO Mol. Med. 4, 3–14 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA 105, 13027–13032 (2008). This work established miR-29 as a regulator of cardiac fibrosis and potential therapeutic target for the management of tissue fibrosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    CAS  PubMed  Google Scholar 

  209. Cardin, S. et al. Role for microRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure. Circ. Arrhythm. Electrophysiol. 5, 1027–1035 (2012).

    CAS  PubMed  Google Scholar 

  210. Patrick, D. M. et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J. Clin. Invest. 120, 3912–3916 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02136862 (2016).

  212. Boon, R. A. & Dimmeler, S. MicroRNAs in myocardial infarction. Nat. Rev. Cardiol. 12, 135–142 (2015).

    CAS  PubMed  Google Scholar 

  213. Boon, R. A. et al. MicroRNA-34a regulates cardiac ageing and function. Nature 495, 107–110 (2013).

    CAS  PubMed  Google Scholar 

  214. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Takeda, N. et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J. Clin. Invest. 120, 254–265 (2010). This article demonstrated that fibroblasts are essential for the adaptive response of the heart to pressure overload.

    CAS  PubMed  Google Scholar 

  216. Burstein, B., Libby, E., Calderone, A. & Nattel, S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation 117, 1630–1641 (2008).

    PubMed  Google Scholar 

  217. Chatelier, A. et al. A distinct de novo expression of Nav1.5 sodium channels in human atrial fibroblasts differentiated into myofibroblasts. J. Physiol. 590, 4307–4319 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Nakajima, H. et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-β1 transgene in the heart. Circ. Res. 86, 571–579 (2000).

    CAS  PubMed  Google Scholar 

  219. Verheule, S. et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-β1. Circ. Res. 94, 1458–1465 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Wright, M. & Narayan, S. M. Ablation of atrial fibrillation. Trends Cardiovasc. Med. 25, 409–419 (2015).

    PubMed  Google Scholar 

  221. Moore, J. P. Arrhythmia management for the adult patient with congenital heart disease: an update and analytical review. Minerva Pediatr. 66, 415–439 (2014).

    CAS  PubMed  Google Scholar 

  222. Rog-Zielinska, E. A., Norris, R. A., Kohl, P. & Markwald, R. The living scar — cardiac fibroblasts and the injured heart. Trends Mol. Med. 22, 99–114 (2016).

    PubMed  PubMed Central  Google Scholar 

  223. Rouillard, A. D. & Holmes, J. W. Coupled agent-based and finite-element models for predicting scar structure following myocardial infarction. Prog. Biophys. Mol. Biol. 115, 235–243 (2014).

    PubMed  Google Scholar 

  224. Koomalsingh, K. J. et al. Optimized local infarct restraint improves left ventricular function and limits remodeling. Ann. Thorac. Surg. 95, 155–162 (2013).

    PubMed  Google Scholar 

  225. Fomovsky, G. M., Clark, S. A., Parker, K. M., Ailawadi, G. & Holmes, J. W. Anisotropic reinforcement of acute anteroapical infarcts improves pump function. Circ. Heart Fail. 5, 515–522 (2012).

    PubMed  PubMed Central  Google Scholar 

  226. Christman, K. L., Fok, H. H., Sievers, R. E., Fang, Q. & Lee, R. J. Fibrin glue alone and skeletal myoblasts in a fibrin scaffold preserve cardiac function after myocardial infarction. Tissue Eng. 10, 403–409 (2004).

    CAS  PubMed  Google Scholar 

  227. Ifkovits, J. L. et al. Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model. Proc. Natl Acad. Sci. USA 107, 11507–11512 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Rane, A. A. & Christman, K. L. Biomaterials for the treatment of myocardial infarction: a 5-year update. J. Am. Coll. Cardiol. 58, 2615–2629 (2011).

    CAS  PubMed  Google Scholar 

  229. Voorhees, A. P. et al. Building a better infarct: modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction. J. Mol. Cell. Cardiol. 85, 229–239 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Purcell, B. P. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat. Mater. 13, 653–661 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Eckhouse, S. R. et al. Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction. Sci. Transl. Med. 6, 223ra21 (2014).

    PubMed  PubMed Central  Google Scholar 

  232. Chung, E. S. et al. Effect of peri-infarct pacing early after myocardial infarction: results of the prevention of myocardial enlargement and dilatation post myocardial infarction study. Circ. Heart Fail. 3, 650–658 (2010).

    PubMed  Google Scholar 

  233. Hu, N., Yost, H. J. & Clark, E. B. Cardiac morphology and blood pressure in the adult zebrafish. Anat. Rec. 264, 1–12 (2001).

    CAS  PubMed  Google Scholar 

  234. Shimazaki, M. et al. Periostin is essential for cardiac healing after acute myocardial infarction. J. Exp. Med. 205, 295–303 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Moldovan, N. I. et al. Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction. J. Am. Heart Assoc. 3, e000471 (2014).

    PubMed  PubMed Central  Google Scholar 

  236. Norris, R. A., Gourdie, R. G., O'Quinn, M. P. & Markwald, R. R. Periostin inhibitory compositions for myocardial regeneration, methods of delivery, and methods of using same. US Patent US20100291188 A1 (2008).

  237. Bramwell, B. A. Case of heart-block, with fibrous degeneration and partial obliteration of the bundle of His. Br. Med. J. 1, 995–996 (1909).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Kohl, P. Structural and functional recoupling of atrial and ventricular myocardium: new conduits for electrical flow. J. Am. Coll. Cardiol. 64, 2586–2588 (2014).

    PubMed  Google Scholar 

  239. Goshima, K. Synchronized beating of and electrotonic transmission between myocardial cells mediated by heterotypic strain cells in monolayer culture. Exp. Cell Res. 58, 420–426 (1969). This electrophysiological demonstration in vitro of fibroblast-mediated synchronization of distant cardiac myocytes illustrates heterocellular electrotonic cell coupling.

    CAS  PubMed  Google Scholar 

  240. Gaudesius, G., Miragoli, M., Thomas, S. P. & Rohr, S. Coupling of cardiac electrical activity over extended distances by fibroblasts of cardiac origin. Circ. Res. 93, 421–428 (2003). This study quantitatively characterizes fibroblast-mediated passive conduction of excitation between otherwise separated groups of cardiomyocytes in structured cell culture.

    CAS  PubMed  Google Scholar 

  241. Lefroy, D. C. et al. Recipient-to-donor atrioatrial conduction after orthotopic heart transplantation: surface electrocardiographic features and estimated prevalence. Am. J. Cardiol. 82, 444–450 (1998).

    CAS  PubMed  Google Scholar 

  242. Hager, A. et al. Congenital and surgically acquired Wolff–Parkinson–White syndrome in patients with tricuspid atresia. J. Thorac. Cardiovasc. Surg. 130, 48–53 (2005).

    PubMed  Google Scholar 

  243. Camelliti, P., Borg, T. K. & Kohl, P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc. Res. 65, 40–51 (2005).

    CAS  PubMed  Google Scholar 

  244. Goldsmith, E. C. et al. Organization of fibroblasts in the heart. Dev. Dyn. 230, 787–794 (2004).

    CAS  PubMed  Google Scholar 

  245. Rother, J. et al. Crosstalk of cardiomyocytes and fibroblasts in co-cultures. Open Biol. 5, 150038 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Kohl, P. & Camelliti, P. Fibroblast-myocyte connections in the heart. Heart Rhythm 9, 461–464 (2012).

    PubMed  Google Scholar 

  247. He, K. et al. Long-distance intercellular connectivity between cardiomyocytes and cardiofibroblasts mediated by membrane nanotubes. Cardiovasc. Res. 92, 39–47 (2011).

    CAS  PubMed  Google Scholar 

  248. Veeraraghavan, R. et al. Sodium channels in the Cx43 gap junction perinexus may constitute a cardiac ephapse: an experimental and modeling study. Pflugers Arch. 467, 2093–2105 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Rhett, J. M., Veeraraghavan, R., Poelzing, S. & Gourdie, R. G. The perinexus: sign-post on the path to a new model of cardiac conduction? Trends Cardiovasc. Med. 23, 222–228 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Kohl, P. Heterogeneous cell coupling in the heart: an electrophysiological role for fibroblasts. Circ. Res. 93, 381–383 (2003).

    CAS  PubMed  Google Scholar 

  251. Kohl, P. & Noble, D. Mechanosensitive connective tissue: potential influence on heart rhythm. Cardiovasc. Res. 32, 62–68 (1996).

    CAS  PubMed  Google Scholar 

  252. MacCannell, K. A. et al. A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts. Biophys. J. 92, 4121–4132 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Nguyen, T. P., Qu, Z. & Weiss, J. N. Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J. Mol. Cell. Cardiol. 70, 83–91 (2014).

    CAS  PubMed  Google Scholar 

  254. Camelliti, P., Devlin, G. P., Matthews, K. G., Kohl, P. & Green, C. R. Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction. Cardiovasc. Res. 62, 415–425 (2004).

    CAS  PubMed  Google Scholar 

  255. Thodeti, C. K., Paruchuri, S. & Meszaros, J. G. A TRP to cardiac fibroblast differentiation. Channels (Austin) 7, 211–214 (2013).

    CAS  Google Scholar 

  256. Benamer, N. et al. Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts. Am. J. Physiol. Heart Circ. Physiol. 304, H1231–H1239 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Jacquemet, V. & Henriquez, C. S. Loading effect of fibroblast–myocyte coupling on resting potential, impulse propagation, and repolarization: insights from a microstructure model. Am. J. Physiol. Heart Circ. Physiol. 294, H2040–H2052 (2008).

    CAS  PubMed  Google Scholar 

  258. Sachse, F. B., Moreno, A. P. & Abildskov, J. A. Electrophysiological modeling of fibroblasts and their interaction with myocytes. Ann. Biomed. Eng. 36, 41–56 (2008).

    PubMed  Google Scholar 

  259. Maleckar, M. M., Greenstein, J. L., Giles, W. R. & Trayanova, N. A. Electrotonic coupling between human atrial myocytes and fibroblasts alters myocyte excitability and repolarization. Biophys. J. 97, 2179–2190 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Xie, Y. et al. Effects of fibroblast–myocyte coupling on cardiac conduction and vulnerability to reentry: a computational study. Heart Rhythm 6, 1641–1649 (2009).

    PubMed  PubMed Central  Google Scholar 

  261. Rutherford, S. L., Trew, M. L., Sands, G. B., LeGrice, I. J. & Smaill, B. H. High-resolution 3-dimensional reconstruction of the infarct border zone: impact of structural remodeling on electrical activation. Circ. Res. 111, 301–311 (2012).

    CAS  PubMed  Google Scholar 

  262. Ashihara, T. et al. The role of fibroblasts in complex fractionated electrograms during persistent/permanent atrial fibrillation: implications for electrogram-based catheter ablation. Circ. Res. 110, 275–284 (2012).

    CAS  PubMed  Google Scholar 

  263. Gonzales, M. J., Vincent, K. P., Rappel, W. J., Narayan, S. M. & McCulloch, A. D. Structural contributions to fibrillatory rotors in a patient-derived computational model of the atria. Europace 16 (Suppl 4.), iv3–iv10 (2014).

    PubMed  PubMed Central  Google Scholar 

  264. McDowell, K. S. et al. Virtual electrophysiological study of atrial fibrillation in fibrotic remodeling. PLoS ONE 10, e0117110 (2015).

    PubMed  PubMed Central  Google Scholar 

  265. Walker, N. L., Burton, F. L., Kettlewell, S., Smith, G. L. & Cobbe, S. M. Mapping of epicardial activation in a rabbit model of chronic myocardial infarction. J. Cardiovasc. Electrophysiol. 18, 862–868 (2007). The trans-scar electrotonic action potential propagation in rabbit left ventricular infarct tissue is shown in this paper.

    PubMed  Google Scholar 

  266. Ripplinger, C. M., Lou, Q., Li, W., Hadley, J. & Efimov, I. R. Panoramic imaging reveals basic mechanisms of induction and termination of ventricular tachycardia in rabbit heart with chronic infarction: implications for low-voltage cardioversion. Heart Rhythm 6, 87–97 (2009).

    PubMed  Google Scholar 

  267. Saba, S. et al. Prevention of adverse electrical and mechanical remodeling with biventricular pacing in a rabbit model of myocardial infarction. Heart Rhythm 5, 124–130 (2008).

    PubMed  Google Scholar 

  268. Mahoney, V. Connexin 43 Mediates Electrotonic Conduction Across Non-Myocyte Lesions in the Intact Heart. Thesis, New York Univ. (2015).

  269. Quinn, T. A. et al. Cell-specific expression of voltage-sensitive protein confirms cardiac myocyte to non-myocyte electrotonic coupling in healed murine infarct border tissue. Circulation 130, A11749 (2014).

    Google Scholar 

  270. Roell, W. et al. Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450, 819–824 (2007). This article demonstrated that the engraftment of Cx43-expressing non-excitable cells into murine scar tissue can prevent post-MI arrhythmogenesis.

    CAS  PubMed  Google Scholar 

  271. O'Quinn, M. P., Palatinus, J. A., Harris, B. S. & Hewett, K. W. & Gourdie, R. G. A peptide mimetic of the connexin43 carboxyl-terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. Circ. Res. 108, 704–715 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Choi, Y. H. et al. Cardiac conduction through engineered tissue. Am. J. Pathol. 169, 72–85 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. Pratola, C., Baldo, E., Notarstefano, P., Toselli, T. & Ferrari, R. Radiofrequency ablation of atrial fibrillation: is the persistence of all intraprocedural targets necessary for long-term maintenance of sinus rhythm? Circulation 117, 136–143 (2008).

    PubMed  Google Scholar 

  274. Yankelson, L. et al. Cell therapy for modification of the myocardial electrophysiological substrate. Circulation 117, 720–731 (2008).

    PubMed  Google Scholar 

  275. Anderson, D. M. et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160, 595–606 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Smyth, J., W. & Shaw, R. M. Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Rep. 5, 611–618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Ul-Hussain, M. et al. Internal ribosomal entry site (IRES) activity generates endogenous carboxyl-terminal domains of Cx43 and is responsive to hypoxic conditions. J. Biol. Chem. 289, 20979–20990 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Lindsey, M. L. et al. Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113, 2919–2928 (2006).

    CAS  PubMed  Google Scholar 

  279. Soares, A. R. et al. Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci. Rep. 5, 13243 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Lindsey, M. L. et al. Transformative impact of proteomics on cardiovascular health and disease: a scientific statement from the American Heart Association. Circulation 132, 852–872 (2015).

    CAS  PubMed  Google Scholar 

  281. Markwald, R. R., Fitzharris, T. P. & Smith, W. N. Sturctural analysis of endocardial cytodifferentiation. Dev. Biol. 42, 160–180 (1975). This histological and ultrastructural study demonstrated how endocardial endothelium generates cardiac cushion mesenchymal cells.

    CAS  PubMed  Google Scholar 

  282. Rook, M. B., Jongsma, H. J. & de Jonge, B. Single channel currents of homo- and heterologous gap junctions between cardiac fibroblasts and myocytes. Pflugers Arch. 414, 95–98 (1989). This stucy characterized homo- and heterocellular gap junctional channels between isolated cardiac myocyctes and fibroblasts.

    CAS  PubMed  Google Scholar 

  283. Potts, J. D. & Runyan, R. B. Epithelial–mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor β. Dev. Biol. 134, 392–401 (1989). In this paper, a role for TGFβ in EMT in atrioventricular cushion tissue was identified.

    CAS  PubMed  Google Scholar 

  284. Long, C. S., Henrich, C. J. & Simpson, P. C. A growth factor for cardiac myocytes is produced by cardiac nonmyocytes. Cell Regul. 2, 1081–1095 (1991). In this paper, paracrine signalling by fibroblasts was confirmed to represent a novel growth mechanism for myocardium.

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Kohl, P., Kamkin, A. G., Kiseleva, I. S. & Noble, D. Mechanosensitive fibroblasts in the sino-atrial node region of rat heart: interaction with cardiomyocytes and possible role. Exp. Physiol. 79, 943–956 (1994). In this study, mechanosensitive fibroblasts in the sinoatrial node region of rat heart were identified, and their potential influence on cardiomyocyte electrophysiology was quantitatively modelled for the first time.

    CAS  PubMed  Google Scholar 

  286. Morabito, C. J., Dettman, R. W., Kattan, J., Collier, J. M. & Bristow, J. Positive and negative regulation of epicardial–mesenchymal transformation during avian heart development. Dev. Biol. 234, 204–215 (2001). This paper illustrated that epicardial EMT and EndoMT are regulated by different signalling pathways.

    CAS  PubMed  Google Scholar 

  287. Assmus, B. et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 106, 3009–3017 (2002). This is an early report of a clinical trial involving intracoronary infusion of bone marrow-derived mesenchymal cells to treat acute MI.

    PubMed  Google Scholar 

  288. Perin, E. C. et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107, 2294–2302 (2003). This paper reports the safety results from a clinical trial studying effects of intramyocardial infusion of bone marrow-derived mesenchymal cells on severe heart failure.

    PubMed  Google Scholar 

  289. Visconti, R. P. et al. An in vivo analysis of hematopoietic stem cell potential: hematopoietic origin of cardiac valve interstitial cells. Circ. Res. 98, 690–696 (2006). This is a cell lineage study demonstrating haematopoietic stem cell contribution to valve fibroblast populations.

    CAS  PubMed  Google Scholar 

  290. Van de Werf, F. The history of coronary reperfusion. Eur. Heart J. 35, 2510–2515 (2014).

    PubMed  Google Scholar 

  291. Zannad, F., Alla, F., Dousset, B., Perez, A. & Pitt, B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Circulation 102, 2700–2706 (2000).

    CAS  PubMed  Google Scholar 

  292. Singh, A. D., Amit, S., Kumar, O. S., Rajan, M. & Mukesh, N. Cardioprotective effects of bosentan, a mixed endothelin type A and B receptor antagonist, during myocardial ischaemia and reperfusion in rats. Basic Clin. Pharmacol. Toxicol. 98, 604–610 (2006).

    CAS  PubMed  Google Scholar 

  293. Klapholz, M. β-blocker use for the stages of heart failure. Mayo Clin. Proc. 84, 718–729 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  294. Siddesha, J. M. et al. Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. J. Cell. Physiol. 229, 845–855 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Mughal, R. S. et al. Peroxisome proliferator-activated receptor γ-independent effects of thiazolidinediones on human cardiac myofibroblast function. Clin. Exp. Pharmacol. Physiol. 36, 478–486 (2009).

    CAS  PubMed  Google Scholar 

  296. Peterson, J. T. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc. Res. 69, 677–687 (2006).

    CAS  PubMed  Google Scholar 

  297. Liao, C. H. et al. Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. J. Clin. Invest. 120, 242–253 (2010).

    CAS  PubMed  Google Scholar 

  298. Levick, S. P. et al. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension 53, 1041–1047 (2009).

    CAS  PubMed  Google Scholar 

  299. Braunwald, E. The ten advances that have defined modern cardiology. Trends Cardiovasc. Med. 24, 179–183 (2014).

    PubMed  Google Scholar 

  300. Jaquet, K. et al. Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats: what is the mechanism? Stem Cells Dev. 14, 299–309 (2005).

    PubMed  Google Scholar 

  301. Chen, L., Qin, F., Ge, M., Shu, Q. & Xu, J. Application of adipose-derived stem cells in heart disease. J. Cardiovasc. Transl Res. 7, 651–663 (2014).

    PubMed  Google Scholar 

  302. Heusch, G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 116, 674–699 (2015).

    CAS  PubMed  Google Scholar 

  303. Qian, L. & Srivastava, D. Direct cardiac reprogramming: from developmental biology to cardiac regeneration. Circ. Res. 113, 915–921 (2013).

    CAS  PubMed  Google Scholar 

  304. Ye, L., Zimmermann, W. H., Garry, D. J. & Zhang, J. Patching the heart: cardiac repair from within and outside. Circ. Res. 113, 922–932 (2013).

    CAS  PubMed  Google Scholar 

  305. Bonauer, A. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324, 1710–1713 (2009).

    CAS  PubMed  Google Scholar 

  306. Gurman, P. et al. Recombinant tissue plasminogen activators (rtPA): a review. Clin. Pharmacol. Ther. 97, 274–285 (2015).

    CAS  PubMed  Google Scholar 

  307. Shuros, A. C. et al. Ventricular preexcitation modulates strain and attenuates cardiac remodeling in a swine model of myocardial infarction. Circulation 116, 1162–1169 (2007).

    PubMed  Google Scholar 

  308. Bugyei-Twum, A. et al. High glucose induces Smad activation via the transcriptional coregulator p300 and contributes to cardiac fibrosis and hypertrophy. Cardiovasc. Diabetol. 13, 89 (2014).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

R.G.G. acknowledges support by the US National Institutes of Health, the Center for Innovative Technology and the Virginia Biosciences Health Research Corporation. S.D. is supported by the LOEWE Center for Cell and Gene Therapy (State of Hesse), the Excellence Cluster Cardio-Pulmonary System (ECCPS; project Exc147-2, Deutsche Forschungsgemeinschaft) and the Leducq Network Minimal Invasive Right Ventricular Assist Device (MIRVAD) project. P.K. thanks the European Research Council (Advanced Grant CardioNECT), the British Heart Foundation (Senior Research Fellowship, New Horizon support), the Biotechnology and Biological Sciences Research Council (BBSRC) and the Magdi Yacoub Institute. The authors express deep gratitude to their colleagues R. R. Markwald, R. W. Dettman, R. A. Norris, G. E. Morley, S. Poelzing, T. K. Borg and J. W. Holmes for productive discussions and thoughtful suggestions. This review was inspired by a Keystone Symposium — 'Cell Biology of the Heart: Beyond the Myocyte-Centric View (X2)' organized by the authors in 2015 (http://www.keystonesymposia.org/15X2).

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Authors and Affiliations

  1. Center for Heart and Regenerative Medicine Research, Virginia Tech Carilion Research Institute, Roanoke, 2 Riverside Circle, 24016, Virginia, USA

    Robert G. Gourdie

  2. Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Kelly Hall, 325 Stanger Street, Blacksburg, 24061, Virginia, USA

    Robert G. Gourdie

  3. Department of Emergency Medicine, Carilion Clinic, 1906 Belleview Avenue, 24016, Virginia, USA

    Robert G. Gourdie

  4. Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, University Frankfurt, Theodor Stern Kai 7, Frankfurt, 60590, Germany

    Stefanie Dimmeler

  5. German Center of Cardiovascular Research (DZHK), RheinMain, Theodor Stern Kai 7, Frankfurt, 60590, Germany

    Stefanie Dimmeler

  6. Institute for Experimental Cardiovascular Medicine, University Heart Centre Freiburg · Bad Krozingen, Elsässer Strasse 2q, Freiburg, 79110, Germany

    Peter Kohl

  7. Faculty of Medicine, Albert-Ludwigs University, Freiburg, 79110, Germany

    Peter Kohl

  8. Cardiac Biophysics and Systems Biology, National Heart and Lung Institute, Imperial College London, London, SW3 6NP, UK

    Peter Kohl

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Correspondence to Robert G. Gourdie, Stefanie Dimmeler or Peter Kohl.

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The authors declare competing interests. R.G.G. is a member of the scientific advisory board of FirstString Research Inc. and holds modest ownership in this company (<5%). S.D. is founder of t2Cure GmbH and scientific adviser of miRagen.

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Gourdie, R., Dimmeler, S. & Kohl, P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov 15, 620–638 (2016). https://doi.org/10.1038/nrd.2016.89

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