title: Molecular mechanisms behind progressing chronic inflammatory dilated cardiomyopathy.
abstract: BACKGROUND
  Inflammatory dilated cardiomyopathy (iDCM) is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation. The aim of this study was to evaluate sera and biopsy samples from chronic iDCM patients, and to investigate molecular mechanism associated with left ventricular remodeling and disease progression in order to improve therapeutic intervention.
  
  
  METHODS
  Patients were divided into inflammatory and non-inflammatory DCM groups according to the immunohistochemical expression of inflammatory infiltrates markers: T-lymphocytes (CD3), active-memory T lymphocyte (CD45Ro) and macrophages (CD68). The inflammation, apoptosis, necrosis and fibrosis were investigated by ELISA, chemiluminescent, immunohistochemical and histological assays.
  
  
  RESULTS
  The pro-inflammatory cytokine IL-6 was significantly elevated in iDCM sera (3.3 vs. 10.98 μg/ml; P < 0.05). Sera levels of caspase-9, -8 and -3 had increased 6.24-, 3.1- and 3.62-fold, (P < 0.05) and only slightly (1.3-, 1.22- and 1.03-fold) in biopsies. Significant release of Hsp60 in sera (0.0419 vs. 0.36 ng/mg protein; P < 0.05) suggested a mechanistic involvement of mitochondria in cardiomyocyte apoptosis. The significant MMP9/TIMP1 upregulation in biopsies (0.1931 - 0.476, P < 0.05) and correlation with apoptosis markers show its involvement in initiation of cell death and ECM degradation. A slight activation of the extrinsic apoptotic pathway and the release of hsTnT might support the progression of chronic iDCM.
  
  
  CONCLUSIONS
  Data of this study show that significant increase of IL-6, MMP9/TIMP1 and caspases-9, -8, -3 in sera corresponds to molecular mechanisms dominating in chronic iDCM myocardium. The initial apoptotic pathway was more activated by the intramyocardial inflammation and might be associated with extrinsic apoptotic pathway through the pro-apoptotic Bax. The activated intrinsic form of myocardial apoptosis, absence of necrosis and decreased fibrosis are most typical characteristics of chronic iDCM. Clinical use of anti-inflammatory drugs together with specific anti-apoptotic treatment might improve the efficiency of therapies against chronic iDCM before heart failure occurs.
authors.affiliation: Dept. of Stem Cell Biology, State Research Institute, Center for Innovative Medicine, Zygimantu 9, LT01102, Vilnius, Lithuania. d.bironaite@imcentras.lt.
authors.forename: Daiva
authors.initials: D
authors.lastname: Bironaite
authors.affiliation: Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Dainius.Daunoravicius@mf.vu.lt.
authors.forename: Dainius
authors.initials: D
authors.lastname: Daunoravicius
authors.affiliation: Department of Integrative Pathophysiology, Universitätsmedizin Mannheim, Mannheim, Germany. Julius.Bogomolovas@medma.uni-heidelberg.de.
authors.forename: Julius
authors.initials: J
authors.lastname: Bogomolovas
authors.affiliation: Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Sigitas.Cibiras@santa.lt.|Vilnius University, Faculty of Medicine, Clinic of Cardiovascular Diseases, Vilnius, Lithuania. Sigitas.Cibiras@santa.lt.
authors.forename: Sigitas
authors.initials: S
authors.lastname: Cibiras
authors.affiliation: Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Dalius.Vitkus@santa.lt.
authors.forename: Dalius
authors.initials: D
authors.lastname: Vitkus
authors.affiliation: Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Edvardas.Zurauskas@vpc.lt.
authors.forename: Edvardas
authors.initials: E
authors.lastname: Zurauskas
authors.affiliation: Vilnius University, Faculty of Medicine, Clinic of Cardiovascular Diseases, Vilnius, Lithuania. Ieva.Zasytyte@gmail.com.
authors.forename: Ieva
authors.initials: I
authors.lastname: Zasytyte
authors.affiliation: Vilnius University, Faculty of Medicine, Clinic of Cardiovascular Diseases, Vilnius, Lithuania. Kestutis.Rucinskas@santa.lt.
authors.forename: Kestutis
authors.initials: K
authors.lastname: Rucinskas
authors.affiliation: Department of Integrative Pathophysiology, Universitätsmedizin Mannheim, Mannheim, Germany. Labeit@medma.de.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.affiliation: Dept. of Stem Cell Biology, State Research Institute, Center for Innovative Medicine, Zygimantu 9, LT01102, Vilnius, Lithuania. A.Venalis@imcentras.lt.
authors.forename: Algirdas
authors.initials: A
authors.lastname: Venalis
authors.affiliation: Department of Pathology, Forensic Medicine and Pharmacology, Vilnius University, Faculty of Medicine, Vilnius, Lithuania. Virginija.Grabauskiene@santa.lt.|Vilnius University, Faculty of Medicine, Clinic of Cardiovascular Diseases, Vilnius, Lithuania. Virginija.Grabauskiene@santa.lt.
authors.forename: Virginija
authors.initials: V
authors.lastname: Grabauskiene
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology; D053453:Caspase 9 / Q000276:immunology; D018834:Chaperonin 60 / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000276:immunology; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000276:immunology; D020107:Troponin T / Q000378:metabolism; D020257:Ventricular Remodeling / Q000276:immunology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D018834:Chaperonin 60; D016207:Cytokines; D017493:Leukocyte Common Antigens; D020780:Matrix Metalloproteinase 9; D024101:Mitochondrial Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020107:Troponin T; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C060293:HSPD1 protein, human; C560822:TIMP1 protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C579270:MMP9 protein, human