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Mechanisms of Cardiac Fibrosis and Heart Failure

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Cardiac Fibrosis and Heart Failure: Cause or Effect?

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 13))

Abstract

The cardiac extracellular matrix (ECM) is the dynamic interstitial scaffolding environment that plays an important role in optimal cardiac function. The strength of the cardiac ECM is known to confer significant protection against myocardial rupture, and the elasticity supports cardiomyocyte contractile function. Upon haemodynamic or ischemic stress, ECM remodeling occurs and is now well established to play a role in the progression of heart disease. Increased turnover of ECM is promoted when resident fibroblasts differentiate into the active myofibroblast phenotype. Although ECM remodeling can be initially beneficial under some circumstances, prolonged and extensive fibrosis is typically associated with decreased contractility, diastolic dysfunction and poor clinical outcome. In this chapter we review the structure and function of the cardiac ECM from development to various pathological states. We will also discuss the role of fibroblasts and the activation of myofibroblasts as well as highlight new findings in the study of reverse cardiac remodelling following unloading of the left ventricle.

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References

  1. Weber KT (1989) Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol 13(7):1637–1652

    CAS  PubMed  Google Scholar 

  2. Weber KT et al (2013) Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol 10(1):15–26

    CAS  PubMed  Google Scholar 

  3. Fedak PW et al (2005) Cardiac remodeling and failure from molecules to man (part II). Cardiovasc Pathol 14(2):49–60

    CAS  PubMed  Google Scholar 

  4. Bishop JE et al (1995) The regulation of collagen deposition in the hypertrophying heart. Ann N Y Acad Sci 752:236–239

    CAS  PubMed  Google Scholar 

  5. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87(4):1285–1342

    CAS  PubMed  Google Scholar 

  6. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102(4):470–479

    CAS  PubMed  Google Scholar 

  7. Segura AM, Frazier OH, Buja LM (2012) Fibrosis and heart failure. Heart Fail Rev 19(2):173–185

    Google Scholar 

  8. Harston RK, Kuppuswamy D (2011) Integrins are the necessary links to hypertrophic growth in cardiomyocytes. J Signal Transduct 2011:521742

    PubMed Central  PubMed  Google Scholar 

  9. Ross RS, Borg TK (2001) Integrins and the myocardium. Circ Res 88(11):1112–1119

    CAS  PubMed  Google Scholar 

  10. Miner EC, Miller WL (2006) A look between the cardiomyocytes: the extracellular matrix in heart failure. Mayo Clin Proc 81(1):71–76

    CAS  PubMed  Google Scholar 

  11. Graham HK, Horn M, Trafford AW (2008) Extracellular matrix profiles in the progression to heart failure. European young physiologists symposium keynote lecture-Bratislava 2007. Acta Physiol (Oxf) 194(1):3–21

    Google Scholar 

  12. Banerjee I et al (2007) Determination of cell types and numbers during cardiac development in the neonatal and adult rat and mouse. Am J Physiol Heart Circ Physiol 293(3):H1883–H1891

    CAS  PubMed  Google Scholar 

  13. Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123(2):255–278

    CAS  PubMed  Google Scholar 

  14. Lajiness JD, Conway SJ (2013) Origin, development, and differentiation of cardiac fibroblasts. J Mol Cell Cardiol 70:2–8

    PubMed  Google Scholar 

  15. de Lange FJ et al (2004) Lineage and morphogenetic analysis of the cardiac valves. Circ Res 95(6):645–654

    PubMed  Google Scholar 

  16. Goldsmith EC et al (2004) Organization of fibroblasts in the heart. Dev Dyn 230(4):787–794

    CAS  PubMed  Google Scholar 

  17. Ieda M et al (2009) Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 16(2):233–244

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Burstein B et al (2008) Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation 117(13):1630–1641

    PubMed  Google Scholar 

  19. Zhang Y, Kanter EM, Yamada KA (2010) Remodeling of cardiac fibroblasts following myocardial infarction results in increased gap junction intercellular communication. Cardiovasc Pathol 19(6):e233–e240

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Ikeda K et al (2008) Cellular physiology of rat cardiac myocytes in cardiac fibrosis: in vitro simulation using the cardiac myocyte/cardiac non-myocyte co-culture system. Hypertens Res 31(4):693–706

    CAS  PubMed  Google Scholar 

  21. LaFramboise WA et al (2007) Cardiac fibroblasts influence cardiomyocyte phenotype in vitro. Am J Physiol Cell Physiol 292(5):C1799–C1808

    CAS  PubMed  Google Scholar 

  22. Zhang P, Su J, Mende U (2012) Cross talk between cardiac myocytes and fibroblasts: from multiscale investigative approaches to mechanisms and functional consequences. Am J Physiol Heart Circ Physiol 303(12):H1385–H1396

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Kakkar R, Lee RT (2010) Intramyocardial fibroblast myocyte communication. Circ Res 106(1):47–57

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Takeda N et al (2010) Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest 120(1):254–265

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Nagai R et al (2005) Significance of the transcription factor KLF5 in cardiovascular remodeling. J Thromb Haemost 3(8):1569–1576

    CAS  PubMed  Google Scholar 

  26. Fan D et al (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5(1):15

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Turner NA, Porter KE (2013) Function and fate of myofibroblasts after myocardial infarction. Fibrogenesis Tissue Repair 6(1):5

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Vasquez C, Benamer N, Morley GE (2011) The cardiac fibroblast: functional and electrophysiological considerations in healthy and diseased hearts. J Cardiovasc Pharmacol 57(4):380–388

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Stewart JA Jr et al (2010) Temporal alterations in cardiac fibroblast function following induction of pressure overload. Cell Tissue Res 340(1):117–126

    PubMed Central  PubMed  Google Scholar 

  30. Davis J, Molkentin JD (2013) Myofibroblasts: Trust your heart and let fate decide. J Mol Cell Cardiol

    Google Scholar 

  31. Zhang X et al (2001) Differential vulnerability to oxidative stress in rat cardiac myocytes versus fibroblasts. J Am Coll Cardiol 38(7):2055–2062

    CAS  PubMed  Google Scholar 

  32. Gao X et al (2009) Angiotensin II increases collagen I expression via transforming growth factor-beta1 and extracellular signal-regulated kinase in cardiac fibroblasts. Eur J Pharmacol 606(1–3):115–120

    CAS  PubMed  Google Scholar 

  33. Huang D et al (2009) Angiotensin II promotes poly(ADP-ribosyl)ation of c-Jun/c-Fos in cardiac fibroblasts. J Mol Cell Cardiol 46(1):25–32

    CAS  PubMed  Google Scholar 

  34. Davis J et al (2012) A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell 23(4):705–715

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Campbell SE, Katwa LC (1997) Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 29(7):1947–1958

    CAS  PubMed  Google Scholar 

  36. Lee AA et al (1995) Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol 27(10):2347–2357

    CAS  PubMed  Google Scholar 

  37. Lal H et al (2008) Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: opposing roles of JNK1/2 and p38alpha MAP kinases. J Mol Cell Cardiol 45(6):770–778

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Blaauboer ME et al (2011) Cyclic mechanical stretch reduces myofibroblast differentiation of primary lung fibroblasts. Biochem Biophys Res Commun 404(1):23–27

    CAS  PubMed  Google Scholar 

  39. Lee AA et al (1999) Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns. J Mol Cell Cardiol 31(10):1833–1843

    CAS  PubMed  Google Scholar 

  40. van Wamel AJ et al (2001) The role of angiotensin II, endothelin-1 and transforming growth factor-beta as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Mol Cell Biochem 218(1–2):113–124

    PubMed  Google Scholar 

  41. Bishop JE, Laurent GJ, (1995) Collagen turnover and its regulation in the normal and hypertrophying heart. Eur Heart J 16(Suppl C):38–44

    CAS  PubMed  Google Scholar 

  42. Trackman PC (2005) Diverse biological functions of extracellular collagen processing enzymes. J Cell Biochem 96(5):927–937

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Gonzalez A et al (2011) New targets to treat the structural remodeling of the myocardium. J Am Coll Cardiol 58(18):1833–1843

    CAS  PubMed  Google Scholar 

  44. Robinson TF et al (1988) Coiled perimysial fibers of papillary muscle in rat heart: morphology, distribution, and changes in configuration. Circ Res 63(3):577–592

    CAS  PubMed  Google Scholar 

  45. Whittaker P et al (1994) Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol 89(5):397–410

    CAS  PubMed  Google Scholar 

  46. Pauschinger M et al (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99(21):2750–2756

    CAS  PubMed  Google Scholar 

  47. Marijianowski MM et al (1995) Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: a quantitative assessment. J Am Coll Cardiol 25(6):1263–1272

    CAS  PubMed  Google Scholar 

  48. Diez J et al (1995) Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 91(5):1450–1456

    CAS  PubMed  Google Scholar 

  49. Shamhart PE, Meszaros JG (2010) Non-fibrillar collagens: key mediators of post-infarction cardiac remodeling? J Mol Cell Cardiol 48(3):530–537

    CAS  PubMed  Google Scholar 

  50. Naugle JE et al (2006) Type VI collagen induces cardiac myofibroblast differentiation: implications for postinfarction remodeling. Am J Physiol Heart Circ Physiol 290(1):H323–H330

    CAS  PubMed  Google Scholar 

  51. Kielty CM (2006) Elastic fibres in health and disease. Expert Rev Mol Med 8(19):1–23

    PubMed  Google Scholar 

  52. Nguyen TP, Qu Z, Weiss JN (2013) Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils. J Mol Cell Cardiol

    Google Scholar 

  53. Spinale FG (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90(5):520–530

    CAS  PubMed  Google Scholar 

  54. Galis ZS, Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90(3):251–262

    CAS  PubMed  Google Scholar 

  55. Spinale FG et al (2000) A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102(16):1944–1949

    CAS  PubMed  Google Scholar 

  56. Peterson JT et al (2001) Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure. Circulation 103(18):2303–2309

    CAS  PubMed  Google Scholar 

  57. Matsumura S et al (2005) Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J Clin Invest 115(3):599–609

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Ducharme A et al (2000) Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106(1):55–62

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Mujumdar VS, Smiley LM, Tyagi SC (2001) Activation of matrix metalloproteinase dilates and decreases cardiac tensile strength. Int J Cardiol 79(2–3):277–286

    CAS  PubMed  Google Scholar 

  60. Lalu MM et al (2005) Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart. Eur Heart J 26(1):27–35

    CAS  PubMed  Google Scholar 

  61. Itoh Y (2006) MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58(10):589–596

    CAS  PubMed  Google Scholar 

  62. Golubkov VS et al (2007) Proteolysis of the membrane type-1 matrix metalloproteinase prodomain: implications for a two-step proteolytic processing and activation. J Biol Chem 282(50):36283–36291

    CAS  PubMed  Google Scholar 

  63. Eisenach PA et al (2012) Membrane type 1 matrix metalloproteinase (MT1-MMP) ubiquitination at Lys581 increases cellular invasion through type I collagen. J Biol Chem 287(14):11533–11545

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Morgunova E et al (2002) Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci U S A 99(11):7414–7419

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Strongin AY et al (1995) Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 270(10):5331–5338

    CAS  PubMed  Google Scholar 

  66. Dadson K et al. (2013) Adiponectin mediated APPL1-AMPK signaling induces cell migration, MMP activation, and collagen remodeling in cardiac fibroblasts. J Cell Biochem

    Google Scholar 

  67. Schram K et al (2008) Increased expression and cell surface localization of MT1-MMP plays a role in stimulation of MMP-2 activity by leptin in neonatal rat cardiac myofibroblasts. J Mol Cell Cardiol 44(5):874–881

    CAS  PubMed  Google Scholar 

  68. Deschamps AM, Spinale FG (2006) Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res 69(3):666–676

    CAS  PubMed  Google Scholar 

  69. Vianello A et al (2009) Role of matrix metalloproteinases and their tissue inhibitors as potential biomarkers of left ventricular remodelling in the athlete’s heart. Clin Sci (Lond) 117(4):157–164

    CAS  Google Scholar 

  70. Spinale FG, Janicki JS, Zile MR (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112(1):195–208

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Miragoli M, Salvarani N, Rohr S (2007) Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 101(8):755–758

    CAS  PubMed  Google Scholar 

  72. Sun Y, Weber KT (2000) Infarct scar: a dynamic tissue. Cardiovasc Res 46(2):250–256

    CAS  PubMed  Google Scholar 

  73. Willems IE et al (1994) The alpha-smooth muscle actin-positive cells in healing human myocardial scars. Am J Pathol 145(4):868–875

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Czubryt MP (2012) Common threads in cardiac fibrosis, infarct scar formation, and wound healing. Fibrogenesis Tissue Repair 5(1):19

    PubMed Central  PubMed  Google Scholar 

  75. Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81(4):1161–1172

    CAS  PubMed  Google Scholar 

  76. Al Darazi F et al. (2014) Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery. J Cardiovasc Pharmacol

    Google Scholar 

  77. Takeuchi T (2014) Regulation of cardiomyocyte proliferation during development and regeneration. Dev Growth Differ 56(5):402–409

    CAS  PubMed  Google Scholar 

  78. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG (2010) The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48(3):504–511

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Wang H et al (2012) Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus. PLoS ONE 7(7):e39969

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Li Y et al (2004) Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure. Circ Res 95(6):627–636

    CAS  PubMed  Google Scholar 

  81. Rosenkranz S (2004) TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63(3):423–432

    CAS  PubMed  Google Scholar 

  82. Lindsey ML et al (2006) Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113(25):2919–2928

    CAS  PubMed  Google Scholar 

  83. Zavadzkas JA et al (2011) Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling. Am J Physiol Heart Circ Physiol 301(4):H1656–H1666

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Eleftheriades EG et al (1993) Regulation of procollagen metabolism in the pressure-overloaded rat heart. J Clin Invest 91(3):1113–1122

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Matsusaka H et al (2006) Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47(4):711–717

    CAS  PubMed  Google Scholar 

  86. Heymans S et al (2005) Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Am J Pathol 166(1):15–25

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Kandalam V et al (2011) Lack of tissue inhibitor of metalloproteinases 2 leads to exacerbated left ventricular dysfunction and adverse extracellular matrix remodeling in response to biomechanical stress. Circulation 124(19):2094–2105

    CAS  PubMed  Google Scholar 

  88. Kassiri Z et al (2005) Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circ Res 97(4):380–390

    CAS  PubMed  Google Scholar 

  89. Kassiri Z et al (2009) Simultaneous transforming growth factor beta-tumor necrosis factor activation and cross-talk cause aberrant remodeling response and myocardial fibrosis in Timp3-deficient heart. J Biol Chem 284(43):29893–29904

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Suryakumar G et al (2010) Lack of beta3 integrin signaling contributes to calpain-mediated myocardial cell loss in pressure-overloaded myocardium. J Cardiovasc Pharmacol 55(6):567–573

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Willey CD et al (2008) STAT3 activation in pressure-overloaded feline myocardium: role for integrins and the tyrosine kinase BMX. Int J Biol Sci 4(3):184–199

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Stewart JA Jr et al. (2013) Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats. Am J Physiol Heart Circ Physiol

    Google Scholar 

  93. Levy D et al (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322(22):1561–1566

    CAS  PubMed  Google Scholar 

  94. Hellawell JL, Margulies KB (2012) Myocardial reverse remodeling. Cardiovasc Ther 30(3):172–181

    CAS  PubMed  Google Scholar 

  95. Kirkpatrick JN, John Sutton MS (2012) Assessment of ventricular remodeling in heart failure clinical trials. Curr Heart Fail Rep 9(4):328–336

    CAS  PubMed  Google Scholar 

  96. Baba HA, Wohlschlaeger J (2008) Morphological and molecular changes of the myocardium after left ventricular mechanical support. Curr Cardiol Rev 4(3):157–169

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Zerkowski HR et al. (2000) Reverse remodeling by surgery–fact or fiction? Z Kardiol 89(Suppl 7):76–84

    PubMed  Google Scholar 

  98. Bjornstad JL et al (2012) A mouse model of reverse cardiac remodelling following banding-debanding of the ascending aorta. Acta Physiol (Oxf) 205(1):92–102

    CAS  Google Scholar 

  99. Stansfield WE et al (2007) Characterization of a model to independently study regression of ventricular hypertrophy. J Surg Res 142(2):387–393

    PubMed  Google Scholar 

  100. Gao XM et al (2005) Regression of pressure overload-induced left ventricular hypertrophy in mice. Am J Physiol Heart Circ Physiol 288(6):H2702–H2707

    CAS  PubMed  Google Scholar 

  101. Stansfield WE et al. (2009) Regression of pressure-induced left ventricular hypertrophy is characterized by a distinct gene expression profile. J Thorac Cardiovasc Surg 137(1):232–238, 238e1–238e8

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Hariharan N et al (2013) Autophagy plays an essential role in mediating regression of hypertrophy during unloading of the heart. PLoS ONE 8(1):e51632

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Andersen NM et al (2012) Recovery from decompensated heart failure is associated with a distinct, phase-dependent gene expression profile. J Surg Res 178(1):72–80

    PubMed Central  PubMed  Google Scholar 

  104. Sharma S et al (2006) Atrophic remodeling of the transplanted rat heart. Cardiology 105(2):128–136

    PubMed  Google Scholar 

  105. Molina EJ et al. (2008) Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy. J Thorac Cardiovasc Surg 135(2):292–299, 299e1

    PubMed  Google Scholar 

  106. Arsalan M et al. (2013) The reverse remodeling effect of mesenchymal stem cells is independent from the site of epimyocardial cell transplantation. Innovations (Phila) 8(6):433–439

    Google Scholar 

  107. Bjornstad JL et al (2011) Collagen isoform shift during the early phase of reverse left ventricular remodelling after relief of pressure overload. Eur Heart J 32(2):236–245

    PubMed  Google Scholar 

  108. Grundy SM et al (1999) Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100(10):1134–1146

    CAS  PubMed  Google Scholar 

  109. Grundy SM et al (1998) Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA task force on risk reduction. American Heart Association. Circulation 97(18):1876–1887

    CAS  PubMed  Google Scholar 

  110. Abel ED, Litwin SE, Sweeney G (2008) Cardiac remodeling in obesity. Physiol Rev 88(2):389–419

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Taegtmeyer H et al (2004) Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann N Y Acad Sci 1015:202–213

    CAS  PubMed  Google Scholar 

  112. Battiprolu PK et al (2010) Diabetic cardiomyopathy: mechanisms and therapeutic targets. Drug Discov Today Dis Mech 7(2):e135–e143

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Siwik DA, Pagano PJ, Colucci WS (2001) Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280(1):C53–C60

    CAS  PubMed  Google Scholar 

  115. Tang M et al (2007) High glucose promotes the production of collagen types I and III by cardiac fibroblasts through a pathway dependent on extracellular-signal-regulated kinase 1/2. Mol Cell Biochem 301(1–2):109–114

    CAS  PubMed  Google Scholar 

  116. Aragno M et al (2008) Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats. Endocrinology 149(1):380–388

    CAS  PubMed  Google Scholar 

  117. Hutchinson KR et al (2013) Cardiac fibroblast-dependent extracellular matrix accumulation is associated with diastolic stiffness in type 2 diabetes. PLoS ONE 8(8):e72080

    CAS  PubMed Central  PubMed  Google Scholar 

  118. van Heerebeek L, Somsen A, Paulus WJ (2009) The failing diabetic heart: focus on diastolic left ventricular dysfunction. Curr Diab Rep 9(1):79–86

    PubMed  Google Scholar 

  119. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115(25):3213–3223

    PubMed  Google Scholar 

  120. Frustaci A et al (2000) Myocardial cell death in human diabetes. Circ Res 87(12):1123–1132

    CAS  PubMed  Google Scholar 

  121. Fang ZY, Prins JB, Marwick TH (2004) Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25(4):543–567

    CAS  PubMed  Google Scholar 

  122. Mori J et al (2013) ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4. Am J Physiol Heart Circ Physiol 304(8):H1103–H1113

    CAS  PubMed  Google Scholar 

  123. Li P et al (2010) Evidence for the importance of adiponectin in the cardioprotective effects of pioglitazone. Hypertension 55(1):69–75

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biology, York University, 4700 Keele Street, M3J1P3, Toronto, ON, Canada

    Keith Dadson, Vera Kovacevic & Dr. Gary Sweeney

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  1. Keith Dadson
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  2. Vera Kovacevic
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  3. Dr. Gary Sweeney
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Correspondence to Gary Sweeney .

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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada

    Ian M.C. Dixon

  2. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

    Jeffrey T. Wigle

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Dadson, K., Kovacevic, V., Sweeney, G. (2015). Mechanisms of Cardiac Fibrosis and Heart Failure. In: Dixon, I., Wigle, J. (eds) Cardiac Fibrosis and Heart Failure: Cause or Effect?. Advances in Biochemistry in Health and Disease, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-17437-2_15

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