Matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, B⁺ tenascin-C and ED-A⁺ fibronectin in dilated cardiomyopathy: potential impact on disease progression and patients' prognosis

Int J Cardiol. 2013 Oct 15;168(6):5344-51. doi: 10.1016/j.ijcard.2013.08.005. Epub 2013 Aug 15.


Background: Dilated cardiomyopathy (DCM) is associated with heart failure and increased mortality and there is no reliable biomarker to estimate patients' prognosis. During cardiac remodeling, an extensive reorganization of the extracellular matrix occurs. The study was aimed to investigate matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and fetal tenascin-C (B(+) Tn-C) and fibronectin (ED-A(+) Fn) variants known to be involved in that process.

Methods and results: In 187 patients with DCM, levels of MMP-9, TIMP-1 and B(+) Tn-C in serum as well as B(+) Tn-C and ED-A(+) Fn in tissue were quantified and subjected to univariate analysis. For all serum markers, concentrations above a calculated threshold were associated with decreased survival (MMP-9: p = 0.008, TIMP-1: p = 0.001, B(+) Tn-C: p < 0.001) and a significantly higher risk to die or undergo transplantation. In tissue, a reexpression of B(+) Tn-C and ED-A(+) Fn could be shown. Protein deposition levels of ≥4.5% for B(+) Tn-C and ≥2.1% for ED-A(+) Fn were associated with a significantly decreased survival (p = 0.001 for B(+) Tn-C, p = 0.031 for ED-A(+) Fn) and an increased risk to die or undergo transplantation. In a multivariate analysis, TIMP-1 is the superior parameter to predict transplantation free survival (p = 0.027).

Conclusions: Serum levels of MMP-9, TIMP-1 and B(+) Tn-C and tissue levels of B(+) Tn-C and ED-A(+) Fn are promising markers for risk assessment. The reoccurrence of ED-A(+) Fn and the availability of a human antibody usable as a vehicle for targeted drug delivery might be the basis for novel therapeutic strategies.

Keywords: Dilated cardiomyopathy; Fibronectin; MMP-9; Prognosis; TIMP-1; Tenascin-C.

MeSH terms

  • Adult
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Biopsy
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / mortality*
  • Cardiomyopathy, Dilated / pathology
  • Disease Progression
  • Extracellular Matrix / metabolism
  • Female
  • Fibronectins / blood*
  • Fibronectins / metabolism
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fluorescent Antibody Technique
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / blood*
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • Myocardium / metabolism
  • Myocardium / pathology
  • Prognosis
  • Risk Factors
  • Tenascin / blood*
  • Tenascin / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / blood*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / mortality
  • Ventricular Dysfunction, Left / pathology


  • Biomarkers
  • FN1 protein, human
  • Fibronectins
  • TIMP1 protein, human
  • Tenascin
  • Tissue Inhibitor of Metalloproteinase-1
  • MMP9 protein, human
  • Matrix Metalloproteinase 9