Abstract
BackgroundInflammatory 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.MethodsPatients 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.ResultsThe 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.ConclusionsData 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.
Highlights
Inflammatory dilated cardiomyopathy is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation
In the present study, we have investigated the level of inflammation and subsequent induction of apoptosis, necrosis and fibrosis in sera and biopsies of chronic Inflammatory dilated cardiomyopathy (iDCM) patients with purpose to estimate which of previously mentioned processes are mostly and firstly activated
In addition to clinical severity of heart failure according to the New York Heart Association classification, heart failure was identified by determination of concentration of brain natriuretic peptide (BNP) in sera
Summary
Inflammatory dilated cardiomyopathy (iDCM) is a common debilitating disease with poor prognosis that often leads to heart failure and may require heart transplantation. Inflammatory cytokines activate members of the matrix metalloproteinase (MMP) family, zinc-depended endopeptidases, which participate in remodeling of ECM and fibrotic processes [12]. It is agreed, that likewise to heart failure, the main processes characterizing DCM are hypertrophy or loss/death of myocytes and interstitial fibrosis [13]. In the present study, we have investigated the level of inflammation and subsequent induction of apoptosis, necrosis and fibrosis in sera and biopsies of chronic iDCM patients with purpose to estimate which of previously mentioned processes are mostly and firstly activated. A more detailed estimation of molecular mechanisms will allow more efficient use of therapeutic means to treat chronic iDCM and thereby prevent further myocardium destruction
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