Skip to main content

Advertisement

Log in

Non-ischemic dilated cardiomyopathy and cardiac fibrosis

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Cardiac fibrosis is associated with non-ischemic dilated cardiomyopathy, increasing its morbidity and mortality. Cardiac fibroblast is the keystone of fibrogenesis, being activated by numerous cellular and humoral factors. Macrophages, CD4+ and CD8+ T cells, mast cells, and endothelial cells stimulate fibrogenesis directly by activating cardiac fibroblasts and indirectly by synthetizing various profibrotic molecules. The synthesis of type 1 and type 3 collagen, fibronectin, and α-smooth muscle actin is rendered by various mechanisms like transforming growth factor-beta/small mothers against decapentaplegic pathway, renin angiotensin system, and estrogens, which in turn alter the extracellular matrix. Investigating the underlying mechanisms will allow the development of diagnostic and prognostic tools and discover novel specific therapies. Serum biomarkers aid in the diagnosis and tracking of cardiac fibrosis progression. The diagnostic gold standard is cardiac magnetic resonance with gadolinium administration that allows quantification of cardiac fibrosis either by late gadolinium enhancement assessment or by T1 mapping. Therefore, the goal is to stop and even reverse cardiac fibrosis by developing specific therapies that directly target fibrogenesis, in addition to the drugs used to treat heart failure. Cardiac resynchronization therapy had shown to revert myocardial remodeling and to reduce cardiac fibrosis. The purpose of this review is to provide an overview of currently available data.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. McKenna WJ, Maron BJ, Thiene G (2017) Classification, epidemiology, and global burden of cardiomyopathies. Circ Res 121:722–730. https://doi.org/10.1161/CIRCRESAHA.117.309711

    Article  CAS  PubMed  Google Scholar 

  2. Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Böhm M, Duboc D, Gimeno J, de Groote P, Imazio M, Heymans S, Klingel K, Komajda M, Limongelli G, Linhart A, Mogensen J, Moon J, Pieper PG, Seferovic PM, Schueler S, Zamorano JL, Caforio ALP, Charron P (2016) Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J 37:1850–1858. https://doi.org/10.1093/eurheartj/ehv727

    Article  PubMed  Google Scholar 

  3. Cecchi F, Tomberli B, Olivotto I (2012) Clinical and molecular classification of cardiomyopathies. Glob Cardiol Sci Pract 2012:4. https://doi.org/10.5339/gcsp.2012.4

    Article  PubMed  PubMed Central  Google Scholar 

  4. Morita H, Seidman J, Seidman CE (2005) Genetic causes of human heart failure. J Clin Invest 115:518–526. https://doi.org/10.1172/JCI200524351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Venero JV, Doyle M, Shah M, Rathi VK, Yamrozik JA, Williams RB, Vido DA, Rayarao G, Benza R, Murali S, Glass J, Olson P, Sokos G, Biederman RWW (2015) Mid wall fibrosis on CMR with late gadolinium enhancement may predict prognosis for LVAD and transplantation risk in patients with newly diagnosed dilated cardiomyopathy-preliminary observations from a high-volume transplant centre. ESC Hear Fail 2:150–159. https://doi.org/10.1002/ehf2.12041

    Article  Google Scholar 

  6. Kong P, Christia P, Frangogiannis NG (2014) The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71:549–574. https://doi.org/10.1007/s00018-013-1349-6

    Article  CAS  PubMed  Google Scholar 

  7. Ivey MJ, Tallquist MD (2016) Defining the cardiac fibroblast. Circ J 80:2269–2276. https://doi.org/10.1253/circj.CJ-16-1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Legere SA, Haidl ID, Légaré J-F, Marshall JS (2019) Mast cells in cardiac fibrosis: new insights suggest opportunities for intervention. Front Immunol 10. https://doi.org/10.3389/fimmu.2019.00580

  9. Nevers T, Salvador AM, Velazquez F, Ngwenyama N, Carrillo-Salinas FJ, Aronovitz M, Blanton RM, Alcaide P (2017) Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J Exp Med 214:3311–3329. https://doi.org/10.1084/jem.20161791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T, Vagnozzi RJ, Liu R, Huynh T, Lee S-J, Karch J, Molkentin JD (2017) Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest 127:3770–3783. https://doi.org/10.1172/JCI94753

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ma Z-G, Yuan Y-P, Wu H-M, Zhang X, Tang Q-Z (2018) Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci 14:1645–1657. https://doi.org/10.7150/ijbs.28103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jia G, Aroor AR, Hill MA, Sowers JR (2018) Role of renin-angiotensin-aldosterone system activation in promoting cardiovascular fibrosis and stiffness. Hypertension 72:537–548. https://doi.org/10.1161/HYPERTENSIONAHA.118.11065

    Article  CAS  PubMed  Google Scholar 

  13. Ma F, Li Y, Jia L, Han Y, Cheng J, Li H, Qi Y, Du J (2012) Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS One 7:e35144. https://doi.org/10.1371/journal.pone.0035144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Medzikovic L, Aryan L, Eghbali M (2019) Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis. J Mol Med. https://doi.org/10.1007/s00109-019-01833-6

  15. Richards AM (2017) Circulating biomarkers of cardiac fibrosis. Circ Heart Fail 10. https://doi.org/10.1161/CIRCHEARTFAILURE.117.003936

  16. Michalska-Kasiczak M, Bielecka-Dabrowa A, von Haehling S, Anker SD, Rysz J, Banach M (2018) Biomarkers, myocardial fibrosis and co-morbidities in heart failure with preserved ejection fraction: an overview. Arch Med Sci 14:890–909. https://doi.org/10.5114/aoms.2018.76279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Becker MAJ, Cornel JH, van de Ven PM, van Rossum AC, Allaart CP, Germans T (2018) The prognostic value of late gadolinium-enhanced cardiac magnetic resonance imaging in nonischemic dilated cardiomyopathy. JACC Cardiovasc Imaging 11:1274–1284. https://doi.org/10.1016/j.jcmg.2018.03.006

    Article  PubMed  Google Scholar 

  18. Valbuena-López S, Hinojar R, Puntmann VO (2016) Cardiovascular magnetic resonance in cardiology practice: a concise guide to image acquisition and clinical interpretation. Rev Española Cardiol English Ed 69:202–210. https://doi.org/10.1016/j.rec.2015.11.011

    Article  Google Scholar 

  19. Croisille P, Revel D, Saeed M (2006) Contrast agents and cardiac MR imaging of myocardial ischemia: from bench to bedside. Eur Radiol 16:1951–1963. https://doi.org/10.1007/s00330-006-0244-z

    Article  PubMed  Google Scholar 

  20. Hinderer S, Schenke-Layland K (2019) Cardiac fibrosis – a short review of causes and therapeutic strategies. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2019.05.011

  21. Fan Z, Guan J (2016) Antifibrotic therapies to control cardiac fibrosis. Biomater Res 20:13. https://doi.org/10.1186/s40824-016-0060-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, Stack C, Latimer PA, Olson EN, van Rooij E (2011) Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124:1537–1547. https://doi.org/10.1161/CIRCULATIONAHA.111.030932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jaffe LM, Morin DP (2014) Cardiac resynchronization therapy: history, present status, and future directions. Ochsner J 14:596–607

    PubMed  PubMed Central  Google Scholar 

  24. Zusterzeel R, Curtis JP, Caños DA, Sanders WE, Selzman KA, Piña IL, Spatz ES, Bao H, Ponirakis A, Varosy PD, Masoudi FA, Strauss DG (2014) Sex-specific mortality risk by QRS morphology and duration in patients receiving CRT. J Am Coll Cardiol 64:887–894. https://doi.org/10.1016/j.jacc.2014.06.1162

    Article  PubMed  Google Scholar 

  25. Landry NM, Cohen S, Dixon IMC (2018) Periostin in cardiovascular disease and development: a tale of two distinct roles. Basic Res Cardiol 113:1. https://doi.org/10.1007/s00395-017-0659-5

    Article  CAS  PubMed  Google Scholar 

  26. Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC (2016) Cardiac fibrosis. Circ Res 118:1021–1040. https://doi.org/10.1161/CIRCRESAHA.115.306565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shinde AV, Humeres C, Frangogiannis NG (2017) The role of α-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta Mol basis Dis 1863:298–309. https://doi.org/10.1016/j.bbadis.2016.11.006

    Article  CAS  PubMed  Google Scholar 

  28. DeLeon-Pennell KY (2016) May the fibrosis be with you: is discoidin domain receptor 2 the receptor we have been looking for? J Mol Cell Cardiol 91:201–203. https://doi.org/10.1016/j.yjmcc.2016.01.006

    Article  CAS  PubMed  Google Scholar 

  29. Kong P, Christia P, Saxena A, Su Y, Frangogiannis NG (2013) Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am J Physiol Circ Physiol 305:H1363–H1372. https://doi.org/10.1152/ajpheart.00395.2013

    Article  CAS  Google Scholar 

  30. Wang L, Yue Y, Yang X, Fan T, Mei B, Hou J, Liang M, Chen G, Wu Z (2017) Platelet derived growth factor alpha (PDGFRα) induces the activation of cardiac fibroblasts by activating c-kit. Med Sci Monit 23:3808–3816. https://doi.org/10.12659/MSM.906038

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chu P-Y, Mariani J, Finch S, McMullen JR, Sadoshima J, Marshall T, Kaye DM (2010) Bone marrow-derived cells contribute to fibrosis in the chronically failing heart. Am J Pathol 176:1735–1742. https://doi.org/10.2353/ajpath.2010.090574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao X-H, Laschinger C, Arora P, Szaszi K, Kapus A, McCulloch CA (2007) Force activates smooth muscle -actin promoter activity through the Rho signaling pathway. J Cell Sci 120:1801–1809. https://doi.org/10.1242/jcs.001586

    Article  CAS  PubMed  Google Scholar 

  33. Bansal SS, Ismahil MA, Goel M, Patel B, Hamid T, Rokosh G, Prabhu SD (2017) Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ Hear Fail:10. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003688

  34. Abdullah CS, Li Z, Wang X, Jin Z-Q (2016) Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy. Int Immunopharmacol 39:251–264. https://doi.org/10.1016/j.intimp.2016.07.027

    Article  CAS  PubMed  Google Scholar 

  35. Koitabashi N, Danner T, Zaiman AL, Pinto YM, Rowell J, Mankowski J, Zhang D, Nakamura T, Takimoto E, Kass DA (2011) Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest 121:2301–2312. https://doi.org/10.1172/JCI44824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yue Y, Meng K, Pu Y, Zhang X (2017) Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract 133:124–130. https://doi.org/10.1016/j.diabres.2017.08.018

    Article  CAS  PubMed  Google Scholar 

  37. Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B, Simonson MS (2008) AMP-activated protein kinase inhibits transforming growth factor-β-induced Smad3-dependent transcription and Myofibroblast Transdifferentiation. J Biol Chem 283:10461–10469. https://doi.org/10.1074/jbc.M800902200

    Article  CAS  PubMed  Google Scholar 

  38. Wei C, Kim I-K, Kumar S, Jayasinghe S, Hong N, Castoldi G, Catalucci D, Jones WK, Gupta S (2013) NF-κB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol 228:1433–1442. https://doi.org/10.1002/jcp.24296

    Article  CAS  PubMed  Google Scholar 

  39. Duerrschmid C, Trial J, Wang Y, Entman ML, Haudek SB (2015) Tumor necrosis factor. Circ Heart Fail 8:352–361. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001893

    Article  CAS  PubMed  Google Scholar 

  40. Szekely Y, Arbel Y (2018) A review of interleukin-1 in heart disease: where do we stand today? Cardiol Ther 7:25–44. https://doi.org/10.1007/s40119-018-0104-3

    Article  PubMed  PubMed Central  Google Scholar 

  41. Lluri G, Deb A (2019) WNT signaling and cardiac fibrosis. Pp 319–334

  42. Xiang F-L, Fang M, Yutzey KE (2017) Loss of β-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice. Nat Commun 8:712. https://doi.org/10.1038/s41467-017-00840-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Menazza S, Murphy E (2016) The expanding complexity of estrogen receptor signaling in the cardiovascular system. Circ Res 118:994–1007. https://doi.org/10.1161/CIRCRESAHA.115.305376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kang S, Liu Y, Sun D, Zhou C, Liu A, Xu C, Hao Y, Li D, Yan C, Sun H (2012) Chronic activation of the G protein-coupled receptor 30 with agonist G-1 attenuates heart failure. PLoS One 7:e48185. https://doi.org/10.1371/journal.pone.0048185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang H, Jessup JA, Lin MS, Chagas C, Lindsey SH, Groban L (2012) Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats. Cardiovasc Res 94:96–104. https://doi.org/10.1093/cvr/cvs090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pedram A, Razandi M, Narayanan R, Levin ER (2016) Estrogen receptor beta signals to inhibition of cardiac fibrosis. Mol Cell Endocrinol 434:57–68. https://doi.org/10.1016/j.mce.2016.06.018

    Article  CAS  PubMed  Google Scholar 

  47. Dworatzek E, Mahmoodzadeh S, Schriever C, Kusumoto K, Kramer L, Santos G, Fliegner D, Leung Y-K, Ho S-M, Zimmermann W-H, Lutz S, Regitz-Zagrosek V (2019) Sex-specific regulation of collagen I and III expression by 17β-estradiol in cardiac fibroblasts: role of estrogen receptors. Cardiovasc Res 115:315–327. https://doi.org/10.1093/cvr/cvy185

    Article  CAS  PubMed  Google Scholar 

  48. Wang H, Zhao Z, Lin M, Groban L (2015) Activation of GPR30 inhibits cardiac fibroblast proliferation. Mol Cell Biochem 405:135–148. https://doi.org/10.1007/s11010-015-2405-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Verdonschot JAJ, Hazebroek MR, Derks KWJ, Barandiarán Aizpurua A, Merken JJ, Wang P, Bierau J, van den Wijngaard A, Schalla SM, Abdul Hamid MA, van Bilsen M, van Empel VPM, Knackstedt C, Brunner-La Rocca H-P, Brunner HG, Krapels IPC, Heymans SRB (2018) Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias. Eur Heart J 39:864–873. https://doi.org/10.1093/eurheartj/ehx808

    Article  CAS  PubMed  Google Scholar 

  50. Chatzifrangkeskou M, Le Dour C, Wu W, Morrow JP, Joseph LC, Beuvin M, Sera F, Homma S, Vignier N, Mougenot N, Bonne G, Lipson KE, Worman HJ, Muchir A (2016) ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene. Hum Mol Genet 25:2220–2233. https://doi.org/10.1093/hmg/ddw090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li W, Yin L, Shen C, Hu K, Ge J, Sun A (2018) SCN5A variants: association with cardiac disorders. Front Physiol 9. https://doi.org/10.3389/fphys.2018.01372

  52. Levick SP, Soto-Pantoja DR, Bi J, Hundley WG, Widiapradja A, Manteufel EJ, Bradshaw TW, Meléndez GC (2018) Doxorubicin-induced myocardial fibrosis involves the neurokinin-1 receptor and direct effects on cardiac fibroblasts. Hear Lung Circ. https://doi.org/10.1016/j.hlc.2018.08.003

  53. Robinson P, Kasembeli M, Bharadwaj U, Engineer N, Eckols KT, Tweardy DJ (2016) Substance P receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance. Biomed Res Int 2016:1–9. https://doi.org/10.1155/2016/1959270

    Article  CAS  Google Scholar 

  54. El-Agamy DS, El-Harbi KM, Khoshhal S, Ahmed N, Elkablawy MA, Shaaban AA, Abo-Haded HM (2018) Pristimerin protects against doxorubicin-induced cardiotoxicity and fibrosis through modulation of Nrf2 and MAPK/NF-kB signaling pathways. Cancer Manag Res Volume 11:47–61. https://doi.org/10.2147/CMAR.S186696

    Article  Google Scholar 

  55. Chu W, Li C, Qu X, Zhao D, Wang X, Yu X, Cai F, Liang H, Zhang Y, Zhao X, Li B, Qiao G, Dong D, Lu Y, Du Z, Yang B (2012) Arsenic-induced interstitial myocardial fibrosis reveals a new insight into drug-induced long QT syndrome. Cardiovasc Res 96:90–98. https://doi.org/10.1093/cvr/cvs230

    Article  CAS  PubMed  Google Scholar 

  56. Zhang Y, Wu X, Li Y, Zhang H, Li Z, Zhang Y, Zhang L, Ju J, Liu X, Chen X, Glybochko PV, Nikolenko V, Kopylov P, Xu C, Yang B (2016) Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis. Sci Rep 6:33787. https://doi.org/10.1038/srep33787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, Pauschinger M, Gajewski TF, Lipson EJ, Luke JJ (2016) Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer 4:50. https://doi.org/10.1186/s40425-016-0152-y

    Article  PubMed  PubMed Central  Google Scholar 

  58. Geng Y, Liu X, Liang J, Habiel DM, Vrishika K, Coelho AL, Deng N, Xie T, Wang Y, Liu N, Huang G, Kurkciyan A, Liu Z, Tang J, Hogaboam CM, Jiang D, Noble PW (2019) PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis. JCI Insight. https://doi.org/10.1172/jci.insight.125326

  59. Delgobo M, Frantz S (2018) Heart failure in cancer: role of checkpoint inhibitors. J Thorac Dis 10:S4323–S4334. https://doi.org/10.21037/jtd.2018.10.07

    Article  PubMed  PubMed Central  Google Scholar 

  60. Maisch B (2016) Alcoholic cardiomyopathy. Herz 41:484–493. https://doi.org/10.1007/s00059-016-4469-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fernández-Solà J, Planavila Porta A (2016) New treatment strategies for alcohol-induced heart damage. Int J Mol Sci 17:1651. https://doi.org/10.3390/ijms17101651

    Article  CAS  PubMed Central  Google Scholar 

  62. Havakuk O, Rezkalla SH, Kloner RA (2017) The cardiovascular effects of cocaine. J Am Coll Cardiol 70:101–113. https://doi.org/10.1016/j.jacc.2017.05.014

    Article  CAS  PubMed  Google Scholar 

  63. Paratz ED, Cunningham NJ, MacIsaac AI (2016) The cardiac complications of methamphetamines. Hear Lung Circ 25:325–332. https://doi.org/10.1016/j.hlc.2015.10.019

    Article  Google Scholar 

  64. Tschöpe C, Müller I, Xia Y, Savvatis K, Pappritz K, Pinkert S, Lassner D, Heimesaat MM, Spillmann F, Miteva K, Bereswill S, Schultheiss H-P, Fechner H, Pieske B, Kühl U, Van Linthout S (2017) NOD2 (nucleotide-binding oligomerization domain 2) is a major pathogenic mediator of coxsackievirus B3-induced myocarditis. Circ hear fail 10. https://doi.org/10.1161/CIRCHEARTFAILURE.117.003870

  65. Cao Y, Xu W, Xiong S (2013) Adoptive transfer of regulatory T cells protects against coxsackievirus B3-induced cardiac fibrosis. PLoS One 8:e74955. https://doi.org/10.1371/journal.pone.0074955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen P, Xie Y, Shen E, Li GG, Yu Y, Zhang CB, Yang Y, Zou Y, Ge J, Chen R, Chen H (2011) Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-β1 signaling in coxsackievirus B3-induced cardiomyopathy. Eur J Pharmacol 658:168–174. https://doi.org/10.1016/j.ejphar.2011.02.040

    Article  CAS  PubMed  Google Scholar 

  67. Hsue PY, Tawakol A (2016) Inflammation and fibrosis in HIV. Circ Cardiovasc Imaging 9. https://doi.org/10.1161/CIRCIMAGING.116.004427

  68. Laurence J, Elhadad S, Robison T, Terry H, Varshney R, Woolington S, Ghafoory S, Choi ME, Ahamed J (2017) HIV protease inhibitor-induced cardiac dysfunction and fibrosis is mediated by platelet-derived TGF-β1 and can be suppressed by exogenous carbon monoxide. PLoS One 12:e0187185. https://doi.org/10.1371/journal.pone.0187185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fowlkes V, Clark J, Fix C, Law BA, Morales MO, Qiao X, Ako-Asare K, Goldsmith JG, Carver W, Murray DB, Goldsmith EC (2013) Type II diabetes promotes a myofibroblast phenotype in cardiac fibroblasts. Life Sci 92:669–676. https://doi.org/10.1016/j.lfs.2013.01.003

    Article  CAS  PubMed  Google Scholar 

  70. Russo I, Frangogiannis NG (2016) Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 90:84–93. https://doi.org/10.1016/j.yjmcc.2015.12.011

    Article  CAS  PubMed  Google Scholar 

  71. Yuan H, Fan Y, Wang Y, Gao T, Shao Y, Zhao B, Li H, Xu C, Wei C (2019) Calcium-sensing receptor promotes high glucose-induced myocardial fibrosis via upregulation of the TGF-β1/Smads pathway in cardiac fibroblasts. Mol Med Rep. https://doi.org/10.3892/mmr.2019.10330

  72. Mitrut R, Stepan AE, Pirici D Histopathological aspects of the myocardium in dilated cardiomyopathy. Curr Heal Sci J 44:243–249. https://doi.org/10.12865/CHSJ.44.03.07

  73. Cunningham KS (2006) An approach to endomyocardial biopsy interpretation. J Clin Pathol 59:121–129. https://doi.org/10.1136/jcp.2005.026443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu T, Song D, Dong J, Zhu P, Liu J, Liu W, Ma X, Zhao L, Ling S (2017) Current understanding of the pathophysiology of myocardial fibrosis and its quantitative assessment in heart failure. Front Physiol 8. https://doi.org/10.3389/fphys.2017.00238

  75. López B, González A, Ravassa S, Beaumont J, Moreno MU, San José G, Querejeta R, Díez J (2015) Circulating biomarkers of myocardial fibrosis. J Am Coll Cardiol 65:2449–2456. https://doi.org/10.1016/j.jacc.2015.04.026

    Article  CAS  PubMed  Google Scholar 

  76. Aoki T, Fukumoto Y, Sugimura K, Oikawa M, Satoh K, Nakano M, Nakayama M, Shimokawa H (2011) Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. Circ J 75:2605–2613. https://doi.org/10.1253/circj.CJ-11-0568

    Article  CAS  PubMed  Google Scholar 

  77. Strimbu K, Tavel JA (2010) What are biomarkers? Curr Opin HIV AIDS 5:463–466. https://doi.org/10.1097/COH.0b013e32833ed177

    Article  PubMed  PubMed Central  Google Scholar 

  78. Seo W-Y, Kim J-H, Baek D-S, Kim S-J, Kang S, Yang WS, Song J-A, Lee M-S, Kim S, Kim Y-S (2017) Production of recombinant human procollagen type I C-terminal propeptide and establishment of a sandwich ELISA for quantification. Sci Rep 7:15946. https://doi.org/10.1038/s41598-017-16290-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. López B, Querejeta R, González A, Larman M, Díez J (2012) Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure. Hypertension 60:677–683. https://doi.org/10.1161/HYPERTENSIONAHA.112.196113

    Article  CAS  PubMed  Google Scholar 

  80. Izawa H, Murohara T, Nagata K, Isobe S, Asano H, Amano T, Ichihara S, Kato T, Ohshima S, Murase Y, Iino S, Obata K, Noda A, Okumura K, Yokota M (2005) Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy. Circulation 112:2940–2945. https://doi.org/10.1161/CIRCULATIONAHA.105.571653

    Article  CAS  PubMed  Google Scholar 

  81. Kaufman BD, Videon N, Zhang X, Harris MA, Shaddy RE, Goldmuntz E (2015) Procollagen type III amino-terminal propeptide: a serum biomarker of left ventricular remodelling in paediatric dilated cardiomyopathy. Cardiol Young 25:228–236. https://doi.org/10.1017/S1047951113001820

    Article  PubMed  Google Scholar 

  82. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco G, Bellotti C, Salehi L, Ricci A (2018) Galectin-3: one molecule for an alphabet of diseases, from A to Z. Int J Mol Sci 19:379. https://doi.org/10.3390/ijms19020379

    Article  CAS  PubMed Central  Google Scholar 

  83. Calvier L, Martinez-Martinez E, Miana M, Cachofeiro V, Rousseau E, Sádaba JR, Zannad F, Rossignol P, López-Andrés N (2015) The impact of Galectin-3 inhibition on aldosterone-induced cardiac and renal injuries. JACC Hear Fail 3:59–67. https://doi.org/10.1016/j.jchf.2014.08.002

    Article  Google Scholar 

  84. MacKinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T (2012) Regulation of transforming growth factor-β1–driven lung fibrosis by galectin-3. Am J Respir Crit Care Med 185:537–546. https://doi.org/10.1164/rccm.201106-0965OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wu C-K, Su M-Y, Lee J-K, Chiang F-T, Hwang J-J, Lin J-L, Chen J-J, Liu F-T, Tsai C-T (2015) Galectin-3 level and the severity of cardiac diastolic dysfunction using cellular and animal models and clinical indices. Sci Rep 5:17007. https://doi.org/10.1038/srep17007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Song X, Qian X, Shen M, Jiang R, Wagner MB, Ding G, Chen G, Shen B (2015) Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression. Biochim Biophys Acta, Mol Cell Res 1853:513–521. https://doi.org/10.1016/j.bbamcr.2014.12.001

    Article  CAS  PubMed  Google Scholar 

  87. Suthahar N, Meijers WC, Silljé HHW, Ho JE, Liu F-T, de Boer RA (2018) Galectin-3 activation and inhibition in heart failure and cardiovascular disease: an update. Theranostics 8:593–609. https://doi.org/10.7150/thno.22196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu Y-H, D’Ambrosio M, Liao T, Peng H, Rhaleb N-E, Sharma U, André S, Gabius H-J, Carretero OA (2009) N -acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin. Am J Physiol Circ Physiol 296:H404–H412. https://doi.org/10.1152/ajpheart.00747.2008

    Article  CAS  Google Scholar 

  89. Martínez-Martínez E, Brugnolaro C, Ibarrola J, Ravassa S, Buonafine M, López B, Fernández-Celis A, Querejeta R, Santamaria E, Fernández-Irigoyen J, Rábago G, Moreno MU, Jaisser F, Díez J, González A, López-Andrés N (2019) CT-1 (cardiotrophin-1)-Gal-3 (galectin-3) axis in cardiac fibrosis and inflammation. Hypertension 73:602–611. https://doi.org/10.1161/HYPERTENSIONAHA.118.11874

    Article  CAS  PubMed  Google Scholar 

  90. Agoston-Coldea L, Bheecarry K, Petra C, Strambu L, Ober C, Revnic R, Lupu S, Mocan T, Fodor D (2018) The value of global longitudinal strain and galectin-3 for predicting cardiovascular events in patients with severe aortic stenosis. Med Ultrason 20:205. https://doi.org/10.11152/mu-1456

    Article  PubMed  Google Scholar 

  91. Ho JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS, Larson MG, Levy D (2012) Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol 60:1249–1256. https://doi.org/10.1016/j.jacc.2012.04.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. de Boer RA, Lok DJA, Jaarsma T, van der Meer P, Voors AA, Hillege HL, van Veldhuisen DJ (2011) Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 43:60–68. https://doi.org/10.3109/07853890.2010.538080

    Article  CAS  PubMed  Google Scholar 

  93. Vergaro G, Del Franco A, Giannoni A, Prontera C, Ripoli A, Barison A, Masci PG, Aquaro GD, Cohen Solal A, Padeletti L, Passino C, Emdin M (2015) Galectin-3 and myocardial fibrosis in nonischemic dilated cardiomyopathy. Int J Cardiol 184:96–100. https://doi.org/10.1016/j.ijcard.2015.02.008

    Article  PubMed  Google Scholar 

  94. Villacorta H, Maisel AS (2015) Soluble ST2 testing: a promising biomarker in the management of heart failure. Arq Bras Cardiol. https://doi.org/10.5935/abc.20150151

  95. Lupu S, Agoston-Coldea L (2015) Soluble ST2 in ventricular dysfunction. Pp 139–159

  96. Bayes-Genis A, de Antonio M, Vila J, Peñafiel J, Galán A, Barallat J, Zamora E, Urrutia A, Lupón J (2014) Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification. J Am Coll Cardiol 63:158–166. https://doi.org/10.1016/j.jacc.2013.07.087

    Article  CAS  PubMed  Google Scholar 

  97. Santhanakrishnan R, Chong JPC, Ng TP, Ling LH, Sim D, Leong KT, Yeo PS, Ong HY, Jaufeerally F, Wong R, Chai P, Low AF, Richards AM, Lam CSP (2012) Growth differentiation factor 15, ST2, high-sensitivity troponin T, and N-terminal pro brain natriuretic peptide in heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail 14:1338–1347. https://doi.org/10.1093/eurjhf/hfs130

    Article  CAS  PubMed  Google Scholar 

  98. Wang Y-C, Yu C-C, Chiu F-C, Tsai C-T, Lai L-P, Hwang J-J, Lin J-L (2013) Soluble ST2 as a biomarker for detecting stable heart failure with a Normal ejection fraction in hypertensive patients. J Card Fail 19:163–168. https://doi.org/10.1016/j.cardfail.2013.01.010

    Article  CAS  PubMed  Google Scholar 

  99. Agoston-Coldea L, Lupu S, Hicea S, Paradis A, Mocan T (2014) Serum levels of the soluble IL-1 receptor family member ST2 and right ventricular dysfunction. Biomark Med 8:95–106. https://doi.org/10.2217/bmm.13.116

    Article  PubMed  Google Scholar 

  100. Wojciechowska C, Romuk E, Nowalany-Kozielska E, Jacheć W (2017) Serum galectin-3 and ST2 as predictors of unfavorable outcome in stable dilated cardiomyopathy patients. Hell J Cardiol 58:350–359. https://doi.org/10.1016/j.hjc.2017.03.006

    Article  Google Scholar 

  101. You H, Jiang W, Jiao M, Wang X, Jia L, You S, Li Y, Wen H, Jiang H, Yuan H, Huang J, Qiao B, Yang Y, Jin M, Wang Y, Du J (2019) Association of soluble ST2 serum levels with outcomes in pediatric dilated cardiomyopathy. Can J Cardiol 35:727–735. https://doi.org/10.1016/j.cjca.2019.02.016

    Article  PubMed  Google Scholar 

  102. Desmedt S, Desmedt V, De Vos L, Delanghe JR, Speeckaert R, Speeckaert MM (2019) Growth differentiation factor 15: a novel biomarker with high clinical potential. Crit Rev Clin Lab Sci 56:333–350. https://doi.org/10.1080/10408363.2019.1615034

    Article  PubMed  Google Scholar 

  103. Wang F, Guo Y, Yu H, Zheng L, Mi L, Gao W (2010) Growth differentiation factor 15 in different stages of heart failure: potential screening implications. Biomarkers 15:671–676. https://doi.org/10.3109/1354750X.2010.510580

    Article  CAS  PubMed  Google Scholar 

  104. Nair N, Gongora E (2018) Correlations of GDF-15 with sST2, MMPs, and worsening functional capacity in idiopathic dilated cardiomyopathy. J Circ Biomarkers 7:184945441775173. https://doi.org/10.1177/1849454417751735

    Article  CAS  Google Scholar 

  105. Wang F-F, Chen B-X, Yu H-Y, Mi L, Li Z-J, Gao W (2016) Correlation between growth differentiation factor-15 and collagen metabolism indicators in patients with myocardial infarction and heart failure. J Geriatr Cardiol 13:88–93. https://doi.org/10.11909/j.issn.1671-5411.2016.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cui J, Zhou B, Ross SA, Zempleni J (2017) Nutrition, microRNAs, and human health. Adv Nutr An Int Rev J 8:105–112. https://doi.org/10.3945/an.116.013839

    Article  CAS  Google Scholar 

  107. Huang W (2017) MicroRNAs: biomarkers, diagnostics, and therapeutics. Pp 57–67

  108. Cao W, Shi P, Ge J-J (2017) miR-21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway. BMC Cardiovasc Disord 17:88. https://doi.org/10.1186/s12872-017-0520-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yuan J, Chen H, Ge D, Xu Y, Xu H, Yang Y, Gu M, Zhou Y, Zhu J, Ge T, Chen Q, Gao Y, Wang Y, Li X, Zhao Y (2017) Mir-21 promotes cardiac fibrosis after myocardial infarction via targeting Smad7. Cell Physiol Biochem 42:2207–2219. https://doi.org/10.1159/000479995

    Article  CAS  PubMed  Google Scholar 

  110. Brønnum H, Andersen DC, Schneider M, Sandberg MB, Eskildsen T, Nielsen SB, Kalluri R, Sheikh SP (2013) miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving programmed cell death 4 and sprouty-1. PLoS one 8:e56280. https://doi.org/10.1371/journal.pone.0056280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Li X, Liu CY, Li YS, Xu J, Li DG, Han D (2016) Deep RNA sequencing elucidates microRNA-regulated molecular pathways in ischemic cardiomyopathy and nonischemic cardiomyopathy. Genet Mol Res:15. https://doi.org/10.4238/gmr.15027465

  112. Dai Y, Dai D, Mehta JL (2014) MicroRNA-29, a mysterious regulator in myocardial fibrosis and circulating miR-29a as a biomarker. J Am Coll Cardiol 64:2181. https://doi.org/10.1016/j.jacc.2014.03.064

    Article  CAS  PubMed  Google Scholar 

  113. Sassi Y, Avramopoulos P, Ramanujam D, Grüter L, Werfel S, Giosele S, Brunner A-D, Esfandyari D, Papadopoulou AS, De Strooper B, Hübner N, Kumarswamy R, Thum T, Yin X, Mayr M, Laggerbauer B, Engelhardt S (2017) Cardiac myocyte miR-29 promotes pathological remodeling of the heart by activating Wnt signaling. Nat Commun 8:1614. https://doi.org/10.1038/s41467-017-01737-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Yamada Y, Takanashi M, Sudo K, Ueda S, Ohno S, Kuroda M (2017) Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis. PLoS One 12:e0171957. https://doi.org/10.1371/journal.pone.0171957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Drummond CA, Fan X, Haller ST, Kennedy DJ, Liu J, Tian J (2018) Na/K-ATPase signaling mediates miR-29b-3p regulation and cardiac fibrosis formation in mice with chronic kidney disease. PLoS One 13:e0197688. https://doi.org/10.1371/journal.pone.0197688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Liang J, Zou X, Fang X, Xu J, Xiao Z, Zhu J, Li H, Yang J, Zeng N, Yuan S, Pan R, Fu Y, Zhang M, Luo J, Wang S, Shan Z (2019) The Smad3-miR-29b/miR-29c axis mediates the protective effect of macrophage migration inhibitory factor against cardiac fibrosis. Biochim Biophys Acta Mol basis Dis 1865:2441–2450. https://doi.org/10.1016/j.bbadis.2019.06.004

    Article  CAS  PubMed  Google Scholar 

  117. Jiang X, Tsitsiou E, Herrick SE, Lindsay MA (2010) MicroRNAs and the regulation of fibrosis. FEBS J 277:2015–2021. https://doi.org/10.1111/j.1742-4658.2010.07632.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen L, Ji Q, Zhu H, Ren Y, Fan Z, Tian N (2018) miR-30a attenuates cardiac fibrosis in rats with myocardial infarction by inhibiting CTGF. Exp Ther Med. https://doi.org/10.3892/etm.2018.5952

  119. Angelini A, Li Z, Mericskay M, Decaux J-F (2015) Regulation of connective tissue growth factor and cardiac fibrosis by an SRF/MicroRNA-133a axis. PLoS One 10:e0139858. https://doi.org/10.1371/journal.pone.0139858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Li N, Zhou H, Tang Q (2018) miR-133: a suppressor of cardiac remodeling? Front Pharmacol 9. https://doi.org/10.3389/fphar.2018.00903

  121. Wang DS, Zhang HQ, Zhang B, Yuan ZB, Yu ZK, Yang T, Zhang SQ, Liu Y, Jia XX (2016) miR-133 inhibits pituitary tumor cell migration and invasion via down-regulating FOXC1 expression. Genet Mol res 15. https://doi.org/10.4238/gmr.15017453

  122. Chen S, Puthanveetil P, Feng B, Matkovich SJ, Dorn GW, Chakrabarti S (2014) Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J Cell Mol Med 18:415–421. https://doi.org/10.1111/jcmm.12218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Nair N, Kumar S, Gongora E, Gupta S (2013) Circulating miRNA as novel markers for diastolic dysfunction. Mol Cell Biochem 376:33–40. https://doi.org/10.1007/s11010-012-1546-x

    Article  CAS  PubMed  Google Scholar 

  124. Wong LL, Armugam A, Sepramaniam S, Karolina DS, Lim KY, Lim JY, Chong JPC, Ng JYX, Chen Y-T, Chan MMY, Chen Z, Yeo PSD, Ng TP, Ling LH, Sim D, Leong KTG, Ong HY, Jaufeerally F, Wong R, Chai P, Low AF, Lam CSP, Jeyaseelan K, Richards AM (2015) Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail 17:393–404. https://doi.org/10.1002/ejhf.223

    Article  CAS  PubMed  Google Scholar 

  125. Watson CJ, Gupta SK, O’Connell E, Thum S, Glezeva N, Fendrich J, Gallagher J, Ledwidge M, Grote-Levi L, McDonald K, Thum T (2015) MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail 17:405–415. https://doi.org/10.1002/ejhf.244

    Article  CAS  PubMed  Google Scholar 

  126. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JAC (2011) Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 57:891–903. https://doi.org/10.1016/j.jacc.2010.11.013

    Article  PubMed  Google Scholar 

  127. Iles LM, Ellims AH, Llewellyn H, Hare JL, Kaye DM, McLean CA, Taylor AJ (2015) Histological validation of cardiac magnetic resonance analysis of regional and diffuse interstitial myocardial fibrosis. Eur Heart J Cardiovasc Imaging 16:14–22. https://doi.org/10.1093/ehjci/jeu182

    Article  PubMed  Google Scholar 

  128. Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway JP (2004) Modified Look-Locker inversion recovery (MOLLI) for high-resolutionT1 mapping of the heart. Magn Reson Med 52:141–146. https://doi.org/10.1002/mrm.20110

    Article  PubMed  Google Scholar 

  129. McCrohon JA, Moon JCC, Prasad SK, McKenna WJ, Lorenz CH, Coats AJS, Pennell DJ (2003) Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 108:54–59. https://doi.org/10.1161/01.CIR.0000078641.19365.4C

    Article  CAS  PubMed  Google Scholar 

  130. Assomull RG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M, Sheppard MN, Poole-Wilson PA, Pennell DJ (2006) Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 48:1977–1985. https://doi.org/10.1016/j.jacc.2006.07.049

    Article  PubMed  Google Scholar 

  131. Duan X, Li J, Zhang Q, Zeng Z, Luo Y, Jiang J, Chen Y (2015) Prognostic value of late gadolinium enhancement in dilated cardiomyopathy patients: a meta-analysis. Clin Radiol 70:999–1008. https://doi.org/10.1016/j.crad.2015.05.007

    Article  CAS  PubMed  Google Scholar 

  132. Machii M, Satoh H, Shiraki K, Saotome M, Urushida T, Katoh H, Takehara Y, Sakahara H, Ohtani H, Wakabayashi Y, Ukigai H, Tawarahara K, Hayashi H (2014) Distribution of late gadolinium enhancement in end-stage hypertrophic cardiomyopathy and dilated cardiomyopathy: differential diagnosis and prediction of cardiac outcome. Magn Reson Imaging 32:118–124. https://doi.org/10.1016/j.mri.2013.10.011

    Article  CAS  PubMed  Google Scholar 

  133. Tachi M, Amano Y, Inui K, Takeda M, Yamada F, Asai K, Kumita S (2016) Relationship of postcontrast myocardial T1 value and delayed enhancement to reduced cardiac function and serious arrhythmia in dilated cardiomyopathy with left ventricular ejection fraction less than 35%. Acta Radiol 57:430–436. https://doi.org/10.1177/0284185115580840

    Article  PubMed  Google Scholar 

  134. Patel AR, Kramer CM (2017) Role of cardiac magnetic resonance in the diagnosis and prognosis of nonischemic cardiomyopathy. JACC Cardiovasc Imaging 10:1180–1193. https://doi.org/10.1016/j.jcmg.2017.08.005

    Article  PubMed  PubMed Central  Google Scholar 

  135. Taylor RJ, Umar F, Lin ELS, Ahmed A, Moody WE, Mazur W, Stegemann B, Townend JN, Steeds RP, Leyva F (2015) Mechanical effects of left ventricular midwall fibrosis in non-ischemic cardiomyopathy. J Cardiovasc Magn Reson 18:1. https://doi.org/10.1186/s12968-015-0221-2

    Article  Google Scholar 

  136. Jellis CL, Kwon DH (2014) Myocardial T1 mapping: modalities and clinical applications. Cardiovasc Diagn Ther 4:126–137. https://doi.org/10.3978/j.issn.2223-3652.2013.09.03

    Article  PubMed  PubMed Central  Google Scholar 

  137. Burt JR, Zimmerman SL, Kamel IR, Halushka M, Bluemke DA (2014) Myocardial T1 mapping: techniques and potential applications. RadioGraphics 34:377–395. https://doi.org/10.1148/rg.342125121

    Article  PubMed  Google Scholar 

  138. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, McGregor C, Moon JC (2010) Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis. Circulation 122:138–144. https://doi.org/10.1161/CIRCULATIONAHA.109.930636

    Article  PubMed  Google Scholar 

  139. Halliday BP, Gulati A, Ali A, Guha K, Newsome S, Arzanauskaite M, Vassiliou VS, Lota A, Izgi C, Tayal U, Khalique Z, Stirrat C, Auger D, Pareek N, Ismail TF, Rosen SD, Vazir A, Alpendurada F, Gregson J, Frenneaux MP, Cowie MR, Cleland JGF, Cook SA, Pennell DJ, Prasad SK (2017) Association between midwall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction. Circulation 135:2106–2115. https://doi.org/10.1161/CIRCULATIONAHA.116.026910

    Article  PubMed  PubMed Central  Google Scholar 

  140. Klem I, Weinsaft JW, Bahnson TD, Hegland D, Kim HW, Hayes B, Parker MA, Judd RM, Kim RJ (2012) Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. J Am Coll Cardiol 60:408–420. https://doi.org/10.1016/j.jacc.2012.02.070

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ota S (2019) The pattern of myocardial fibrosis detected by cardiovascular magnetic resonance imaging provides prognostic information in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 73:1551. https://doi.org/10.1016/S0735-1097(19)32157-6

    Article  Google Scholar 

  142. Kono AK, Ishii K, Kumagai H, Taniguchi Y, Kajiya T, Sugimura K (2010) Late gadolinium enhancement on cardiac magnetic resonance imaging: is it associated with a higher incidence of nonsustained ventricular tachycardia in patients with idiopathic dilated cardiomyopathy? Jpn J Radiol 28:355–361. https://doi.org/10.1007/s11604-010-0433-1

    Article  PubMed  Google Scholar 

  143. Leyva F, Foley PW, Chalil S, Ratib K, Smith RE, Prinzen F, Auricchio A (2011) Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 13:29. https://doi.org/10.1186/1532-429X-13-29

    Article  PubMed  PubMed Central  Google Scholar 

  144. Leong DP, Chakrabarty A, Shipp N, Molaee P, Madsen PL, Joerg L, Sullivan T, Worthley SG, De Pasquale CG, Sanders P, Selvanayagam JB (2012) Effects of myocardial fibrosis and ventricular dyssynchrony on response to therapy in new-presentation idiopathic dilated cardiomyopathy: insights from cardiovascular magnetic resonance and echocardiography. Eur Heart J 33:640–648. https://doi.org/10.1093/eurheartj/ehr391

    Article  CAS  PubMed  Google Scholar 

  145. Leyva F, Taylor RJ, Foley PWX, Umar F, Mulligan LJ, Patel K, Stegemann B, Haddad T, Smith REA, Prasad SK (2012) Left ventricular midwall fibrosis as a predictor of mortality and morbidity after cardiac resynchronization therapy in patients with nonischemic cardiomyopathy. J Am Coll Cardiol 60:1659–1667. https://doi.org/10.1016/j.jacc.2012.05.054

    Article  PubMed  Google Scholar 

  146. Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TDH, Ismail NA, Dweck MR, Di Pietro E, Roughton M, Wage R, Daryani Y, O’Hanlon R, Sheppard MN, Alpendurada F, Lyon AR, Cook SA, Cowie MR, Assomull RG, Pennell DJ, Prasad SK (2013) Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 309:896. https://doi.org/10.1001/jama.2013.1363

    Article  CAS  PubMed  Google Scholar 

  147. Puntmann VO, Carr-White G, Jabbour A, Yu C-Y, Gebker R, Kelle S, Hinojar R, Doltra A, Varma N, Child N, Rogers T, Suna G, Arroyo Ucar E, Goodman B, Khan S, Dabir D, Herrmann E, Zeiher AM, Nagel E (2016) T1-mapping and outcome in nonischemic cardiomyopathy. JACC Cardiovasc Imaging 9:40–50. https://doi.org/10.1016/j.jcmg.2015.12.001

    Article  PubMed  Google Scholar 

  148. Pi S-H, Kim SM, Choi J-O, Kim EK, Chang S-A, Choe YH, Lee S-C, Jeon E-S (2018) Prognostic value of myocardial strain and late gadolinium enhancement on cardiovascular magnetic resonance imaging in patients with idiopathic dilated cardiomyopathy with moderate to severely reduced ejection fraction. J Cardiovasc Magn Reson 20:36. https://doi.org/10.1186/s12968-018-0466-7

    Article  PubMed  PubMed Central  Google Scholar 

  149. Oh J, Hong YJ, Ha J, Chun KH, Kim H, Lee CJ, Kim YJ, Choi BW, Kang SM (2019) P3555Lower native T1, extracellular volume and T2 on cardiac magnetic resonance imaging is related to more left ventricular reverse remodeling in nonischemic dilated cardiomyopathy. Eur heart J 40. https://doi.org/10.1093/eurheartj/ehz745.0418

  150. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol 62:e147–e239. https://doi.org/10.1016/j.jacc.2013.05.019

    Article  PubMed  Google Scholar 

  151. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola V-P, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 37:2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  152. Russo V, Papa AA, Williams EA, Rago A, Palladino A, Politano L, Nigro G (2018) ACE inhibition to slow progression of myocardial fibrosis in muscular dystrophies. Trends Cardiovasc Med 28:330–337. https://doi.org/10.1016/j.tcm.2017.12.006

    Article  PubMed  Google Scholar 

  153. Leask A (2015) Getting to the heart of the matter. Circ Res 116:1269–1276. https://doi.org/10.1161/CIRCRESAHA.116.305381

    Article  CAS  PubMed  Google Scholar 

  154. Rog-Zielinska EA, Norris RA, Kohl P, Markwald R (2016) The living scar – cardiac fibroblasts and the injured heart. Trends Mol Med 22:99–114. https://doi.org/10.1016/j.molmed.2015.12.006

    Article  PubMed  PubMed Central  Google Scholar 

  155. Tietjens J, Teerlink JR (2016) Serelaxin and acute heart failure. Heart 102:95–99. https://doi.org/10.1136/heartjnl-2014-306786

    Article  CAS  PubMed  Google Scholar 

  156. Wu X, Wang H, Wang Y, Shen H, Tan Y (2018) Serelaxin inhibits differentiation and fibrotic behaviors of cardiac fibroblasts by suppressing ALK-5/Smad2/3 signaling pathway. Exp Cell Res 362:17–27. https://doi.org/10.1016/j.yexcr.2017.10.004

    Article  CAS  PubMed  Google Scholar 

  157. Zhang N, Wei W-Y, Li L-L, Hu C, Tang Q-Z (2018) Therapeutic potential of polyphenols in cardiac fibrosis. Front Pharmacol 9. https://doi.org/10.3389/fphar.2018.00122

  158. Xu C, Hu Y, Hou L, Ju J, Li X, Du N, Guan X, Liu Z, Zhang T, Qin W, Shen N, Bilal MU, Lu Y, Zhang Y, Shan H (2014) β-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression. J Mol Cell Cardiol 75:111–121. https://doi.org/10.1016/j.yjmcc.2014.07.009

    Article  CAS  PubMed  Google Scholar 

  159. Ihm S-H, Chang K, Kim H-Y, Baek SH, Youn H-J, Seung K-B, Kim J-H (2010) Peroxisome proliferator-activated receptor-γ activation attenuates cardiac fibrosis in type 2 diabetic rats: the effect of rosiglitazone on myocardial expression of receptor for advanced glycation end products and of connective tissue growth factor. Basic Res Cardiol 105:399–407. https://doi.org/10.1007/s00395-009-0071-x

    Article  CAS  PubMed  Google Scholar 

  160. Shim CY, Song B-W, Cha M-J, Hwang K-C, Park S, Hong G-R, Kang S-M, Lee JE, Ha J-W, Chung N (2014) Combination of a peroxisome proliferator-activated receptor-gamma agonist and an angiotensin II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats. J Diabetes Investig 5:362–371. https://doi.org/10.1111/jdi.12153

    Article  CAS  PubMed  Google Scholar 

  161. Wang L-X, Yang X, Yue Y, Fan T, Hou J, Chen G-X, Liang M-Y, Wu Z-K (2017) Imatinib attenuates cardiac fibrosis by inhibiting platelet-derived growth factor receptors activation in isoproterenol induced model. PLoS One 12:e0178619. https://doi.org/10.1371/journal.pone.0178619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chaudhry PA, Mishima T, Sharov VG, Hawkins J, Alferness C, Paone G, Sabbah HN (2000) Passive epicardial containment prevents ventricular remodeling in heart failure. Ann Thorac Surg 70:1275–1280. https://doi.org/10.1016/S0003-4975(00)01755-0

    Article  CAS  PubMed  Google Scholar 

  163. Doenst T, Ahn-Veelken L, Schlensak C, Berchtold-Herz M, Sarai K, Schaefer M, van de Loo A, Beyersdorf F (2001) Left ventricular reduction for idiopathic dilated cardiomyopathy as alternative to transplant - truth or dare?*. Thorac Cardiovasc Surg 49:70–74. https://doi.org/10.1055/s-2001-11709

    Article  CAS  PubMed  Google Scholar 

  164. Calafiore A (1999) Surgical treatment of dilated cardiomyopathy with conventional techniques*1. Eur J Cardio-Thoracic Surg 16:S73–S78. https://doi.org/10.1016/S1010-7940(99)00193-1

    Article  Google Scholar 

  165. Isomura T, Suma H, Horii T, Sato T, Kikuchi N (2000) Partial left ventriculectomy, ventriculoplasty or valvular surgery for idiopathic dilated cardiomyopathy – the role of intra-operative echocardiography. Eur J Cardio-Thoracic Surg 17:239–245. https://doi.org/10.1016/S1010-7940(00)00322-5

    Article  CAS  Google Scholar 

  166. Suma H, Isomura T, Horii T, Nomura F (2006) Septal anterior ventricular exclusion procedure for idiopathic dilated cardiomyopathy. Ann Thorac Surg 82:1344–1348. https://doi.org/10.1016/j.athoracsur.2006.04.096

    Article  PubMed  Google Scholar 

  167. WANG J, GONG X, CHEN H, QIN S, ZHOU N, SU Y, GE J (2017) Effect of cardiac resynchronization therapy on myocardial fibrosis and relevant cytokines in a canine model with experimental heart failure. J Cardiovasc Electrophysiol 28:438–445. https://doi.org/10.1111/jce.13171

    Article  PubMed  Google Scholar 

  168. Broch K, Murbræch K, Andreassen AK, Hopp E, Aakhus S, Gullestad L (2015) Contemporary outcome in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 116:952–959. https://doi.org/10.1016/j.amjcard.2015.06.022

    Article  PubMed  Google Scholar 

  169. Keeling PJ, Goldman JH, Slade AKB, Elliott PM, Caforio ALP, Poloniecki J, McKenna WJ (1995) Prognosis of idiopathic dilated cardiomyopathy. J Card Fail 1:337–345. https://doi.org/10.1016/S1071-9164(05)80002-8

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

B.C.M., A.Z., and L.A.C. researched data for the article. B.C.M. and A.Z. wrote the article. L.A.C. discussed the content of the article, and B.C.M., A.Z., and L.A.C. reviewed and edited before submission.

Corresponding author

Correspondence to Lucia Agoston-Coldea.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cojan-Minzat, B.O., Zlibut, A. & Agoston-Coldea, L. Non-ischemic dilated cardiomyopathy and cardiac fibrosis. Heart Fail Rev 26, 1081–1101 (2021). https://doi.org/10.1007/s10741-020-09940-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-020-09940-0

Keywords

Navigation