Heart Failure Reviews

, Volume 20, Issue 6, pp 731–749 | Cite as

Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance

  • Andrea BarisonEmail author
  • Chrysanthos Grigoratos
  • Giancarlo Todiere
  • Giovanni Donato Aquaro


Myocardial remodelling involves not only the myocytes, but also non-myocyte cells and the extracellular matrix, which constitutes around 6 % of the normal heart and includes fluid, collagen and glycoproteins. In non-ischaemic dilated cardiomyopathy (DCM), the cardiac interstitium increases as a result of diffuse interstitial (microscopic) fibrosis, post-necrotic replacement (macroscopic) fibrosis or myocardial oedema. The activation of the renin–angiotensin–aldosterone system is a major determinant of fibroblasts activation and collagen deposition, with the transforming growth factor β as the downstream signal mediator. Endomyocardial biopsy still represents the current reference method for interstitial and replacement myocardial fibrosis assessment, but cardiovascular magnetic resonance (CMR) allows in vivo detection of macroscopic fibrosis with post-contrast late enhancement imaging. Moreover, recent pre- and post-contrast T1 mapping techniques provide a quantitative estimation of myocardial interstitial remodelling, with potential diagnostic and prognostic clinical utility. Here, we review the pathophysiological mechanisms of myocardial interstitial remodelling in DCM, its non-invasive characterization with biomarkers and with CMR, as well as the most recent studies about their clinical utility.


Dilated cardiomyopathy Fibrosis Interstitium Remodelling Magnetic resonance Late enhancement T1 mapping T2 mapping 



Cardiovascular magnetic resonance


Dilated cardiomyopathy


Extracellular volume


Late gadolinium enhancement


Left ventricular


Matrix metalloproteinase


Modified look-locker inversion recovery


N-terminal fragment of the pro-brain natriuretic peptide


Shortened modified look-locker inversion recovery


Transforming growth factor beta


Tumour necrosis factor alpha


Compliance with ethical standards

Conflict of interest

Drs. Barison A., Grigoratos C., Todiere G., Aquaro G. D. have no conflicts of interest or financial ties to disclose.


  1. 1.
    Felker GM, Thompson RE, Hare JM et al (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342:1077–1084PubMedCrossRefGoogle Scholar
  2. 2.
    Merlo M, Pyxaras SA, Pinamonti B et al (2011) Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 57:1468–1476. doi: 10.1016/j.jacc.2010.11.030 PubMedCrossRefGoogle Scholar
  3. 3.
    Steimle AE, Stevenson LW, Fonarow GC et al (1994) Prediction of improvement in recent onset cardiomyopathy after referral for heart transplantation. J Am Coll Cardiol 23:553–559PubMedCrossRefGoogle Scholar
  4. 4.
    Wilcox JE, Fonarow GC, Yancy CW et al (2012) Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from IMPROVE HF. Am Heart J 163(49–56):e2. doi: 10.1016/j.ahj.2011.10.001 PubMedGoogle Scholar
  5. 5.
    McMurray JJV, Adamopoulos S, Anker SD et al (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart. Eur J Heart Fail 14:803–869. doi: 10.1093/eurjhf/hfs105 PubMedCrossRefGoogle Scholar
  6. 6.
    Goldberger JJ, Buxton AE, Cain M et al (2011) Risk stratification for arrhythmic sudden cardiac death: identifying the roadblocks. Circulation 123:2423–2430. doi: 10.1161/CIRCULATIONAHA.110.959734 PubMedCrossRefGoogle Scholar
  7. 7.
    Swynghedauw B (2006) Phenotypic plasticity of adult myocardium: molecular mechanisms. J Exp Biol 209:2320–2327. doi: 10.1242/jeb.02084 PubMedCrossRefGoogle Scholar
  8. 8.
    Unverferth DV, Baker PB, Swift SE et al (1986) Extent of myocardial fibrosis and cellular hypertrophy in dilated cardiomyopathy. Am J Cardiol 57:816–820PubMedCrossRefGoogle Scholar
  9. 9.
    Weber KT, Brilla CG (1991) Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83:1849–1865PubMedCrossRefGoogle Scholar
  10. 10.
    Beltrami CA, Finato N, Rocco M et al (1995) The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol 27:291–305PubMedCrossRefGoogle Scholar
  11. 11.
    Neglia D, Parodi O, Gallopin M et al (1995) Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. Circulation 92:796–804PubMedCrossRefGoogle Scholar
  12. 12.
    Neglia D, Michelassi C, Trivieri MG et al (2002) Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation 105:186–193PubMedCrossRefGoogle Scholar
  13. 13.
    Lionetti V, Guiducci L, Simioniuc A et al (2007) Mismatch between uniform increase in cardiac glucose uptake and regional contractile dysfunction in pacing-induced heart failure. Am J Physiol Heart Circ Physiol 293:H2747–H2756. doi: 10.1152/ajpheart.00592.2007 PubMedCrossRefGoogle Scholar
  14. 14.
    Passino C, Barison A, Vergaro G et al (2015) Markers of fibrosis, inflammation, and remodeling pathways in heart failure. Clin Chim Acta 443:29–38. doi: 10.1016/j.cca.2014.09.006 PubMedCrossRefGoogle Scholar
  15. 15.
    Emdin M, Barison A, Passino C, Vergaro G (2013) Biomarkers in heart failure: an update. G Ital Cardiol (Rome) 14:809–816. doi: 10.1714/1371.15237 Google Scholar
  16. 16.
    Libby P, Lee RT (2000) Matrix matters. Circulation 102:1874–1876PubMedCrossRefGoogle Scholar
  17. 17.
    De Jong S, van Veen TAB, de Bakker JMT et al (2011) Biomarkers of myocardial fibrosis. J Cardiovasc Pharmacol 57:522–535. doi: 10.1097/FJC.0b013e31821823d9 PubMedCrossRefGoogle Scholar
  18. 18.
    Weber KT, Janicki JS, Shroff SG et al (1988) Collagen remodeling of the pressure-overloaded, hypertrophied nonhuman primate myocardium. Circ Res 62:757–765PubMedCrossRefGoogle Scholar
  19. 19.
    López B, González A, Varo N et al (2001) Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension 38:1222–1226PubMedCrossRefGoogle Scholar
  20. 20.
    Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573. doi: 10.1016/j.cardiores.2005.12.002 PubMedCrossRefGoogle Scholar
  21. 21.
    Risteli J, Risteli L (1995) Analysing connective tissue metabolites in human serum. Biochemical, physiological and methodological aspects. J Hepatol 22:77–81PubMedCrossRefGoogle Scholar
  22. 22.
    Pauschinger M, Knopf D, Petschauer S et al (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99:2750–2756PubMedCrossRefGoogle Scholar
  23. 23.
    Weber KT, Sun Y, Katwa LC et al (1995) Connective tissue and repair in the heart. Potential regulatory mechanisms. Ann N Y Acad Sci 752:286–299PubMedCrossRefGoogle Scholar
  24. 24.
    Mewton N, Liu CY, Croisille P et al (2011) Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 57:891–903. doi: 10.1016/j.jacc.2010.11.013 PubMedCrossRefGoogle Scholar
  25. 25.
    Díez J, Querejeta R, López B et al (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105:2512–2517PubMedCrossRefGoogle Scholar
  26. 26.
    Bernaba BN, Chan JB, Lai CK, Fishbein MC (2010) Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol Off J Soc Cardiovasc Pathol 19:308–311CrossRefGoogle Scholar
  27. 27.
    Meune C, Vignaux O, Kahan A, Allanore Y (2010) Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies. Arch Cardiovasc Dis 103:46–52PubMedCrossRefGoogle Scholar
  28. 28.
    Garzoni LR, Adesse D, Soares MJ et al (2008) Fibrosis and hypertrophy induced by Trypanosoma cruzi in a three-dimensional cardiomyocyte-culture system. J Infect Dis 197:906–915PubMedCrossRefGoogle Scholar
  29. 29.
    Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210. doi: 10.1002/path.2277 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255–278. doi: 10.1016/j.pharmthera.2009.05.002 PubMedCrossRefGoogle Scholar
  31. 31.
    Camelliti P, Borg TK, Kohl P (2005) Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65:40–51. doi: 10.1016/j.cardiores.2004.08.020 PubMedCrossRefGoogle Scholar
  32. 32.
    Seeland U, Schäffer A, Selejan S et al (2009) Effects of AT1- and beta-adrenergic receptor antagonists on TGF-beta1-induced fibrosis in transgenic mice. Eur J Clin Invest 39:851–859. doi: 10.1111/j.1365-2362.2009.02183.x PubMedCrossRefGoogle Scholar
  33. 33.
    Brilla CG (2000) Renin-angiotensin-aldosterone system and myocardial fibrosis. Cardiovasc Res 47:1–3PubMedCrossRefGoogle Scholar
  34. 34.
    Watanabe T, Barker TA, Berk BC (2005) Angiotensin II and the endothelium: diverse signals and effects. Hypertension 45:163–169. doi: 10.1161/01.HYP.0000153321.13792.b9 PubMedCrossRefGoogle Scholar
  35. 35.
    Parodi O, De Maria R, Oltrona L et al (1993) Myocardial blood flow distribution in patients with ischemic heart disease or dilated cardiomyopathy undergoing heart transplantation. Circulation 88:509–522PubMedCrossRefGoogle Scholar
  36. 36.
    Tsagalou EP, Anastasiou-Nana M, Agapitos E et al (2008) Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy. J Am Coll Cardiol 52:1391–1398. doi: 10.1016/j.jacc.2008.05.064 PubMedCrossRefGoogle Scholar
  37. 37.
    Masci PG, Marinelli M, Positano V, Aquaro GD, Landini L, Piacenti M, Pingitore A, Lombardi MND (2009) Regional matching between the extent of discoordinate contraction and myocardial metabolic activity in patients with dilated cardiomyopathy and left bundle branch block. Eur Heart J 30:746Google Scholar
  38. 38.
    Cicoira M, Rossi A, Bonapace S et al (2004) Independent and additional prognostic value of aminoterminal propeptide of type III procollagen circulating levels in patients with chronic heart failure. J Card Fail 10:403–411PubMedCrossRefGoogle Scholar
  39. 39.
    Zannad F, Alla F, Dousset B et al (2000) 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). Rales investigators. Circulation 102:2700–2706PubMedCrossRefGoogle Scholar
  40. 40.
    Lijnen PJ, Maharani T, Finahari N, Prihadi JS (2012) Serum collagen markers and heart failure. Cardiovasc Hematol Disord Drug Targets 12:51–55PubMedCrossRefGoogle Scholar
  41. 41.
    Kitahara T, Takeishi Y, Arimoto T et al (2007) Serum carboxy-terminal telopeptide of type I collagen (ICTP) predicts cardiac events in chronic heart failure patients with preserved left ventricular systolic function. Circ J 71:929–935PubMedCrossRefGoogle Scholar
  42. 42.
    Klappacher G, Franzen P, Haab D et al (1995) Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol 75:913–918PubMedCrossRefGoogle Scholar
  43. 43.
    Querejeta R, López B, González A et al (2004) Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 110:1263–1268. doi: 10.1161/01.CIR.0000140973.60992.9A PubMedCrossRefGoogle Scholar
  44. 44.
    Gullestad L, Ueland T, Vinge LE et al (2012) Inflammatory cytokines in heart failure: mediators and markers. Cardiology 122:23–35. doi: 10.1159/000338166 PubMedCrossRefGoogle Scholar
  45. 45.
    Lin Y-H, Lin L-Y, Wu Y-W et al (2009) The relationship between serum galectin-3 and serum markers of cardiac extracellular matrix turnover in heart failure patients. Clin Chim Acta 409:96–99. doi: 10.1016/j.cca.2009.09.001 PubMedCrossRefGoogle Scholar
  46. 46.
    Gopal DM, Kommineni M, Ayalon N et al (2012) Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure. J Am Heart Assoc 1:e000760. doi: 10.1161/JAHA.112.000760 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Tang WHW, Shrestha K, Shao Z et al (2011) Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol 108:385–390. doi: 10.1016/j.amjcard.2011.03.056 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    De Boer RA, Lok DJA, Jaarsma T et al (2011) Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 43:60–68. doi: 10.3109/07853890.2010.538080 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Lok DJ, Lok SI, Bruggink-André de la Porte PW et al (2013) Galectin-3 is an independent marker for ventricular remodeling and mortality in patients with chronic heart failure. Clin Res Cardiol 102:103–110. doi: 10.1007/s00392-012-0500-y PubMedCrossRefGoogle Scholar
  50. 50.
    Bayes-Genis A, de Antonio M, Vila J et al (2013) Head-to-head comparison of two myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 vs. Galectin-3. J Am Coll Cardiol. doi: 10.1016/j.jacc.2013.07.087 PubMedGoogle Scholar
  51. 51.
    Van der Velde AR, Gullestad L, Ueland T et al (2013) Prognostic value of changes in galectin-3 levels over time in patients with heart failure: data from CORONA and COACH. Circ Heart Fail 6:219–226. doi: 10.1161/CIRCHEARTFAILURE.112.000129 PubMedCrossRefGoogle Scholar
  52. 52.
    Juillière Y, Barbier G, Feldmann L et al (1997) Additional predictive value of both left and right ventricular ejection fractions on long-term survival in idiopathic dilated cardiomyopathy. Eur Heart J 18:276–280PubMedCrossRefGoogle Scholar
  53. 53.
    Gulati A, Ismail TF, Jabbour A et al (2013) The prevalence and prognostic significance of right ventricular systolic dysfunction in nonischemic dilated cardiomyopathy. Circulation 128:1623–1633. doi: 10.1161/CIRCULATIONAHA.113.002518 PubMedCrossRefGoogle Scholar
  54. 54.
    Shen WF, Tribouilloy C, Rey JL et al (1992) Prognostic significance of Doppler-derived left ventricular diastolic filling variables in dilated cardiomyopathy. Am Heart J 124:1524–1533PubMedCrossRefGoogle Scholar
  55. 55.
    Rihal CS, Nishimura RA, Hatle LK et al (1994) Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 90:2772–2779PubMedCrossRefGoogle Scholar
  56. 56.
    Rossi A, Cicoira M, Zanolla L et al (2002) Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 40:1425PubMedCrossRefGoogle Scholar
  57. 57.
    Gulati A, Ismail TF, Jabbour A et al (2013) Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy. Eur J Heart Fail 15:660–670. doi: 10.1093/eurjhf/hft019 PubMedCrossRefGoogle Scholar
  58. 58.
    Ridgway JP (2010) Cardiovascular magnetic resonance physics for clinicians: part I. J Cardiovasc Magn Reson Off J Soc Cardiovasc Magn Reson 12:71. doi: 10.1186/1532-429X-12-71 Google Scholar
  59. 59.
    Kellman P, Wilson JR, Xue H et al (2012) Extracellular volume fraction mapping in the myocardium, part 1: evaluation of an automated method. J Cardiovasc Magn Reson 14:63. doi: 10.1186/1532-429X-14-63 PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Messroghli DR, Plein S, Higgins DM et al (2006) Human myocardium: single-breath-hold MR T1 mapping with high spatial resolution—reproducibility study. Radiology 238:1004–1012. doi: 10.1148/radiol.2382041903 PubMedCrossRefGoogle Scholar
  61. 61.
    Perea RJ, Ortiz-Perez JT, Sole M et al (2014) T1 mapping: characterisation of myocardial interstitial space. Insights Imaging 6:189–202. doi: 10.1007/s13244-014-0366-9 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Goldfarb JW, Arnold S, Han J (2007) Recent myocardial infarction: assessment with unenhanced T1-weighted MR imaging. Radiology 245:245–250. doi: 10.1148/radiol.2451061590 PubMedCrossRefGoogle Scholar
  63. 63.
    Ferreira VM, Piechnik SK, Dall’Armellina E et al (2012) Non-contrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance. J Cardiovasc Magn Reson 14:42. doi: 10.1186/1532-429X-14-42 PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Dall’Armellina E, Ferreira VM, Kharbanda RK et al (2013) Diagnostic value of pre-contrast T1 mapping in acute and chronic myocardial infarction. JACC Cardiovasc Imaging 6:739–742. doi: 10.1016/j.jcmg.2012.11.020 PubMedCrossRefGoogle Scholar
  65. 65.
    Germain P, El Ghannudi S, Jeung M-Y et al (2014) Native T1 mapping of the heart—a pictorial review. Clin Med Insights Cardiol 8:1–11. doi: 10.4137/CMC.S19005 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Puntmann VO, Voigt T, Chen Z et al (2013) Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging 6:475–484. doi: 10.1016/j.jcmg.2012.08.019 PubMedCrossRefGoogle Scholar
  67. 67.
    Bull S, White SK, Piechnik SK et al (2013) Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart 99:932–937. doi: 10.1136/heartjnl-2012-303052 PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Karamitsos T, Banypersad SM, Sado D et al (2012) Pre-contrast ShMOLLI T1 mapping in cardiac AL amyloidosis. J Cardiovasc Magn Reson 14:O76. doi: 10.1186/1532-429X-14-S1-O76 PubMedCentralCrossRefGoogle Scholar
  69. 69.
    Sado DM, White SK, Piechnik SK et al (2013) Identification and assessment of Anderson-Fabry disease by cardiovascular magnetic resonance noncontrast myocardial T1 mapping. Circ Cardiovasc Imaging 6:392–398. doi: 10.1161/CIRCIMAGING.112.000070 PubMedCrossRefGoogle Scholar
  70. 70.
    Feng Y, He T, Carpenter J-P et al (2013) In vivo comparison of myocardial T1 with T2 and T2* in thalassaemia major. J Magn Reson Imaging 38:588–593. doi: 10.1002/jmri.24010 PubMedCrossRefGoogle Scholar
  71. 71.
    Sado DM, Maestrini V, Piechnik SK et al (2014) Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload. J Magn Reson Imaging. doi: 10.1002/jmri.24727 PubMedGoogle Scholar
  72. 72.
    Dass S, Suttie JJ, Piechnik SK et al (2012) Myocardial tissue characterization using magnetic resonance noncontrast t1 mapping in hypertrophic and dilated cardiomyopathy. Circ Cardiovasc Imaging 5:726–733. doi: 10.1161/CIRCIMAGING.112.976738 PubMedCrossRefGoogle Scholar
  73. 73.
    Puntmann VO, Arroyo Ucar E, Hinojar Baydes R et al (2014) Aortic stiffness and interstitial myocardial fibrosis by native T1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy. Hypertension 64:762–768. doi: 10.1161/HYPERTENSIONAHA.114.03928 PubMedCrossRefGoogle Scholar
  74. 74.
    Francone M, Carbone I, Agati L et al (2011) Utility of T2-weighted short-tau inversion recovery (STIR) sequences in cardiac MRI: an overview of clinical applications in ischaemic and non-ischaemic heart disease. Radiol Med 116:32–46. doi: 10.1007/s11547-010-0594-0 PubMedCrossRefGoogle Scholar
  75. 75.
    Mirakhur A, Anca N, Mikami Y, Merchant N (2013) T2-weighted imaging of the heart—a pictorial review. Eur J Radiol 82:1755–1762. doi: 10.1016/j.ejrad.2013.06.005 PubMedCrossRefGoogle Scholar
  76. 76.
    Abdel-Aty H, Simonetti O, Friedrich MG (2007) T2-weighted cardiovascular magnetic resonance imaging. J Magn Reson Imaging 26:452–459. doi: 10.1002/jmri.21028 PubMedCrossRefGoogle Scholar
  77. 77.
    Ferreira VM, Piechnik SK, Robson MD et al (2014) Myocardial tissue characterization by magnetic resonance imaging: novel applications of T1 and T2 mapping. J Thorac Imaging 29:147–154. doi: 10.1097/RTI.0000000000000077 PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Nishii T, Kono AK, Shigeru M et al (2014) Cardiovascular magnetic resonance T2 mapping can detect myocardial edema in idiopathic dilated cardiomyopathy. Int J Cardiovasc Imaging 30(Suppl 1):65–72. doi: 10.1007/s10554-014-0414-z PubMedCrossRefGoogle Scholar
  79. 79.
    Kim RJ, Chen EL, Lima JA, Judd RM (1996) Myocardial Gd-DTPA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation 94:3318–3326PubMedCrossRefGoogle Scholar
  80. 80.
    Vöhringer M, Mahrholdt H, Yilmaz A, Sechtem U (2007) Significance of late gadolinium enhancement in cardiovascular magnetic resonance imaging (CMR). Herz 32:129–137. doi: 10.1007/s00059-007-2972-5 PubMedCrossRefGoogle Scholar
  81. 81.
    Vermes E, Carbone I, Friedrich MG, Merchant N (2012) Patterns of myocardial late enhancement: typical and atypical features. Arch Cardiovasc Dis 105:300–308. doi: 10.1016/j.acvd.2011.12.006 PubMedCrossRefGoogle Scholar
  82. 82.
    McCrohon JA, Moon JCC, Prasad SK et al (2003) Differentiation of heart failure related to dilated cardiomyopathy and coronary artery disease using gadolinium-enhanced cardiovascular magnetic resonance. Circulation 108:54–59. doi: 10.1161/01.CIR.0000078641.19365.4C PubMedCrossRefGoogle Scholar
  83. 83.
    Moreo A, Ambrosio G, De Chiara B et al (2009) Influence of myocardial fibrosis on left ventricular diastolic function: noninvasive assessment by cardiac magnetic resonance and echo. Circ Cardiovasc Imaging 2:437–443. doi: 10.1161/CIRCIMAGING.108.838367 PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Choi E-Y, Choi BW, Kim S-A et al (2009) Patterns of late gadolinium enhancement are associated with ventricular stiffness in patients with advanced non-ischaemic dilated cardiomyopathy. Eur J Heart Fail 11:573–580. doi: 10.1093/eurjhf/hfp050 PubMedCrossRefGoogle Scholar
  85. 85.
    Karaahmet T, Tigen K, Dundar C et al (2010) The effect of cardiac fibrosis on left ventricular remodeling, diastolic function, and N-terminal pro-B-type natriuretic peptide levels in patients with nonischemic dilated cardiomyopathy. Echocardiography 27:954–960. doi: 10.1111/j.1540-8175.2010.01170.x PubMedCrossRefGoogle Scholar
  86. 86.
    Nazarian S, Bluemke DA, Lardo AC et al (2005) Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 112:2821–2825. doi: 10.1161/CIRCULATIONAHA.105.549659 PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Tachi M, Amano Y, Inui K et al (2015) 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. doi: 10.1177/0284185115580840 PubMedGoogle Scholar
  88. 88.
    Perazzolo Marra M, De Lazzari M, Zorzi A et al (2014) Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy. Heart Rhythm 11:856–863. doi: 10.1016/j.hrthm.2014.01.014 PubMedCrossRefGoogle Scholar
  89. 89.
    Vergaro G, Del Franco A, Giannoni A et al (2015) Galectin-3 and myocardial fibrosis in nonischemic dilated cardiomyopathy. Int J Cardiol 184C:96–100. doi: 10.1016/j.ijcard.2015.02.008 CrossRefGoogle Scholar
  90. 90.
    Lopez-Andrès N, Rossignol P, Iraqi W et al (2012) Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 14:74–81. doi: 10.1093/eurjhf/hfr151 PubMedCrossRefGoogle Scholar
  91. 91.
    Assomull RG, Prasad SK, Lyne J et al (2006) Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol 48:1977–1985. doi: 10.1016/j.jacc.2006.07.049 PubMedCrossRefGoogle Scholar
  92. 92.
    Wu KC, Weiss RG, Thiemann DR et al (2008) Late gadolinium enhancement by cardiovascular magnetic resonance heralds an adverse prognosis in nonischemic cardiomyopathy. J Am Coll Cardiol 51:2414–2421. doi: 10.1016/j.jacc.2008.03.018 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Masci PG, Barison A, Aquaro GD et al (2012) Myocardial delayed enhancement in paucisymptomatic nonischemic dilated cardiomyopathy. Int J Cardiol 157:43–47. doi: 10.1016/j.ijcard.2010.11.005 PubMedCrossRefGoogle Scholar
  94. 94.
    Shimizu I, Iguchi N, Watanabe H et al (2010) Delayed enhancement cardiovascular magnetic resonance as a novel technique to predict cardiac events in dilated cardiomyopathy patients. Int J Cardiol 142:224–229. doi: 10.1016/j.ijcard.2008.12.189 PubMedCrossRefGoogle Scholar
  95. 95.
    Hombach V, Merkle N, Torzewski J et al (2009) Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy. Eur Heart J 30:2011–2018. doi: 10.1093/eurheartj/ehp293 PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Lehrke S, Lossnitzer D, Schöb M et al (2011) Use of cardiovascular magnetic resonance for risk stratification in chronic heart failure: prognostic value of late gadolinium enhancement in patients with non-ischaemic dilated cardiomyopathy. Heart 97:727–732. doi: 10.1136/hrt.2010.205542 PubMedCrossRefGoogle Scholar
  97. 97.
    Leyva F, Taylor RJ, Foley PWX et al (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. doi: 10.1016/j.jacc.2012.05.054 PubMedCrossRefGoogle Scholar
  98. 98.
    Gulati A, Jabbour A, Ismail TF et al (2013) Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 309:896–908. doi: 10.1001/jama.2013.1363 PubMedCrossRefGoogle Scholar
  99. 99.
    Barison A, Masci PG, Emdin M (2013) Fibrosis and mortality in patients with dilated cardiomyopathy. JAMA 309:2547. doi: 10.1001/jama.2013.6453 PubMedCrossRefGoogle Scholar
  100. 100.
    Masci PG, Schuurman R, Andrea B et al (2013) Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study. Circ Cardiovasc Imaging 6:790–799. doi: 10.1161/CIRCIMAGING.113.000438 PubMedCrossRefGoogle Scholar
  101. 101.
    Cleland JGF, Daubert J-C, Erdmann E et al (2005) The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539–1549. doi: 10.1056/NEJMoa050496 PubMedCrossRefGoogle Scholar
  102. 102.
    Bristow MR, Saxon LA, Boehmer J et al (2004) Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:2140–2150. doi: 10.1056/NEJMoa032423 PubMedCrossRefGoogle Scholar
  103. 103.
    Kadish A, Dyer A, Daubert JP et al (2004) Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 350:2151–2158. doi: 10.1056/NEJMoa033088 PubMedCrossRefGoogle Scholar
  104. 104.
    Bardy GH, Lee KL, Mark DB et al (2005) Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 352:225–237. doi: 10.1056/NEJMoa043399 PubMedCrossRefGoogle Scholar
  105. 105.
    Kubanek M, Sramko M, Maluskova J et al (2013) Novel predictors of left ventricular reverse remodeling in individuals with recent-onset dilated cardiomyopathy. J Am Coll Cardiol 61:54–63. doi: 10.1016/j.jacc.2012.07.072 PubMedCrossRefGoogle Scholar
  106. 106.
    Leong DP, Chakrabarty A, Shipp N et al (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. doi: 10.1093/eurheartj/ehr391 PubMedCrossRefGoogle Scholar
  107. 107.
    Yan AT, Shayne AJ, Brown KA et al (2006) Characterization of the peri-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation 114:32–39. doi: 10.1161/CIRCULATIONAHA.106.613414 PubMedCrossRefGoogle Scholar
  108. 108.
    Aquaro GD, Masci P, Formisano F et al (2010) Usefulness of delayed enhancement by magnetic resonance imaging in hypertrophic cardiomyopathy as a marker of disease and its severity. Am J Cardiol 105:392–397PubMedCrossRefGoogle Scholar
  109. 109.
    Iles L, Pfluger H, Phrommintikul A et al (2008) Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol 52:1574–1580. doi: 10.1016/j.jacc.2008.06.049 PubMedCrossRefGoogle Scholar
  110. 110.
    Flett AS, Hayward MP, Ashworth MT et al (2010) Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation 122:138–144. doi: 10.1161/CIRCULATIONAHA.109.930636 PubMedCrossRefGoogle Scholar
  111. 111.
    White SK, Sado DM, Fontana M et al (2013) T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique. JACC Cardiovasc Imaging 6:955–962. doi: 10.1016/j.jcmg.2013.01.011 PubMedCrossRefGoogle Scholar
  112. 112.
    Kehr E, Sono M, Chugh SS, Jerosch-Herold M (2008) Gadolinium-enhanced magnetic resonance imaging for detection and quantification of fibrosis in human myocardium in vitro. Int J Cardiovasc Imaging 24:61–68. doi: 10.1007/s10554-007-9223-y PubMedCrossRefGoogle Scholar
  113. 113.
    Iles LM, Ellims AH, Llewellyn H et al (2015) Histological validation of cardiac magnetic resonance analysis of regional and diffuse interstitial myocardial fibrosis. Eur Heart J Cardiovasc Imaging 16:14–22. doi: 10.1093/ehjci/jeu182 PubMedCrossRefGoogle Scholar
  114. 114.
    Jerosch-Herold M, Sheridan DC, Kushner JD et al (2008) Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 295:H1234–H1242. doi: 10.1152/ajpheart.00429.2008 PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Kahler E, Waller C, Rommel E et al (1999) Perfusion-corrected mapping of cardiac regional blood volume in rats in vivo. Magn Reson Med 42:500–506PubMedCrossRefGoogle Scholar
  116. 116.
    Waller C, Kahler E, Hiller KH et al (2000) Myocardial perfusion and intracapillary blood volume in rats at rest and with coronary dilatation: MR imaging in vivo with use of a spin-labeling technique. Radiology 215:189–197PubMedCrossRefGoogle Scholar
  117. 117.
    Sado D, Flett A, Banypersad S et al (2012) Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart 98:1436–1441. doi: 10.1136/heartjnl-2012-302346 PubMedCrossRefGoogle Scholar
  118. 118.
    aus dem Siepen F, Buss SJ, Messroghli D et al (2015) T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy. Eur Heart J Cardiovasc Imaging 16:210–216. doi: 10.1093/ehjci/jeu183 PubMedCrossRefGoogle Scholar
  119. 119.
    Barison A, Del Torto A, Chiappino S et al (2015) Prognostic significance of myocardial extracellular volume fraction in nonischaemic dilated cardiomyopathy. J Cardiovasc Med 16:681. doi: 10.2459/JCM.0000000000000275 CrossRefGoogle Scholar
  120. 120.
    Wong TC, Piehler K, Meier CG et al (2012) Association between extracellular matrix expansion quantified by cardiovascular magnetic resonance and short-term mortality. Circulation 126:1206–1216. doi: 10.1161/CIRCULATIONAHA.111.089409 PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Hong YJ, Park CH, Kim YJ et al (2015) Extracellular volume fraction in dilated cardiomyopathy patients without obvious late gadolinium enhancement: comparison with healthy control subjects. Int J Cardiovasc Imaging. doi: 10.1007/s10554-015-0595-0 Google Scholar
  122. 122.
    Dabir D, Child N, Kalra A et al (2014) Reference values for healthy human myocardium using a T1 mapping methodology: results from the International T1 Multicenter cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 16:69. doi: 10.1186/s12968-014-0069-x PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Neilan TG, Coelho-Filho OR, Shah RV et al (2013) Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol 111:717–722. doi: 10.1016/j.amjcard.2012.11.022 PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Florian A, Ludwig A, Rösch S et al (2014) Myocardial fibrosis imaging based on T1-mapping and extracellular volume fraction (ECV) measurement in muscular dystrophy patients: diagnostic value compared with conventional late gadolinium enhancement (LGE) imaging. Eur Heart J Cardiovasc Imaging 15:1004–1012. doi: 10.1093/ehjci/jeu050 PubMedCrossRefGoogle Scholar
  125. 125.
    Fontana M, Barison A, Botto N et al (2013) CMR-verified interstitial myocardial fibrosis as a marker of subclinical cardiac involvement in LMNA mutation carriers. JACC Cardiovasc Imaging 6:124–126. doi: 10.1016/j.jcmg.2012.06.013 PubMedCrossRefGoogle Scholar
  126. 126.
    Roujol S, Weingärtner S, Foppa M et al (2014) Accuracy, precision, and reproducibility of four T1 mapping sequences: a head-to-head comparison of MOLLI, ShMOLLI, SASHA, and SAPPHIRE. Radiology. doi: 10.1148/radiol.14140296 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Caravan P, Das B, Dumas S et al (2007) Collagen-targeted MRI contrast agent for molecular imaging of fibrosis. Angew Chem Int Ed Engl 46:8171–8173. doi: 10.1002/anie.200700700 PubMedCrossRefGoogle Scholar
  128. 128.
    Helm PA, Caravan P, French BA et al (2008) Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent. Radiology 247:788–796. doi: 10.1148/radiol.2473070975 PubMedCrossRefGoogle Scholar
  129. 129.
    Burton RAB, Lee P, Casero R et al (2014) Three-dimensional histology: tools and application to quantitative assessment of cell-type distribution in rabbit heart. Europace 16(Suppl 4):iv86–iv95. doi: 10.1093/europace/euu234 PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Blondiaux E, Pidial L, Vilar J et al (2013) Evaluation of rat heart microvasculature with high-spatial-resolution susceptibility-weighted MR imaging. Radiology 269:277–282. doi: 10.1148/radiol.13122152 PubMedCrossRefGoogle Scholar
  131. 131.
    Ritter CO, Wilke A, Wichmann T et al (2011) Comparison of intravascular and extracellular contrast media for absolute quantification of myocardial rest-perfusion using high-resolution MRI. J Magn Reson Imaging 33:1047–1051. doi: 10.1002/jmri.22557 PubMedCrossRefGoogle Scholar
  132. 132.
    Niedermayer S, Prompona M, Cyran CC et al (2014) Dose response of the intravascular contrast agent gadofosveset trisodium in MR perfusion imaging of the myocardium using semiquantitative evaluation. J Magn Reson Imaging 39:203–210. doi: 10.1002/jmri.24091 PubMedCrossRefGoogle Scholar
  133. 133.
    Mahmod M, Piechnik SK, Levelt E et al (2014) Adenosine stress native T1 mapping in severe aortic stenosis: evidence for a role of the intravascular compartment on myocardial T1 values. J Cardiovasc Magn Reson 16:92. doi: 10.1186/s12968-014-0092-y PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Wassmuth R, Schulz-Menger J (2011) Cardiovascular magnetic resonance imaging of myocardial inflammation. Expert Rev Cardiovasc Ther 9:1193–1201. doi: 10.1586/erc.11.118 PubMedCrossRefGoogle Scholar
  135. 135.
    Ambale-Venkatesh B, Lima JAC (2015) Cardiac MRI: a central prognostic tool in myocardial fibrosis. Nat Rev Cardiol 12:18–29. doi: 10.1038/nrcardio.2014.159 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Andrea Barison
    • 1
    • 2
    Email author
  • Chrysanthos Grigoratos
    • 1
    • 3
  • Giancarlo Todiere
    • 1
    • 2
  • Giovanni Donato Aquaro
    • 1
  1. 1.Fondazione Toscana Gabriele MonasterioPisaItaly
  2. 2.Scuola Superiore Sant’AnnaPisaItaly
  3. 3.Cardiac, Thoracic and Vascular DepartmentUniversity of PisaPisaItaly

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