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Complement and dilated cardiomyopathy: a role of sublytic terminal complement complex-induced tumor necrosis
Thomas P Zwaka1, Dimitar Manolov, Cüneyt Ozdemir
1Department of Internal Medicine II-Cardiology, University of Ulm, Ulm, Germany.
Insights
Complement activation, marked by C5b-9, is linked to dilated cardiomyopathy progression. This process drives Tumor Necrosis Factor-alpha expression in heart cells, suggesting a role for innate immunity in the disease.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Dilated cardiomyopathy involves heart enlargement and impaired systolic function.
- Tumor Necrosis Factor-alpha (TNF-alpha) is implicated in disease progression.
- The role of innate immunity, specifically complement activation, in dilated cardiomyopathy is under-investigated.
Purpose of the Study:
- To investigate the role of complement system activation in dilated cardiomyopathy.
- To examine the presence of C5b-9, the terminal complement complex, in human myocardial tissue.
- To explore the relationship between C5b-9, immunoglobulin deposition, and TNF-alpha expression.
Main Methods:
- Analysis of myocardial biopsies from 28 patients with dilated cardiomyopathy.
- Immunohistochemical detection of C5b-9 and immunoglobulin deposition.
- Assessment of myocardial TNF-alpha expression.
- In vitro experiments on cardiac myocytes exposed to C5b-9.
Main Results:
- C5b-9 accumulates in the myocardium of patients with dilated cardiomyopathy.
- C5b-9 levels significantly correlate with immunoglobulin deposition and myocardial TNF-alpha expression.
- In vitro, C5b-9 induces nuclear factor-kappaB (NF-kappaB) activation and TNF-alpha production in cardiac myocytes.
Conclusions:
- Chronic immunoglobulin-mediated complement activation contributes to dilated cardiomyopathy progression.
- The terminal complement complex C5b-9 induces TNF-alpha expression in cardiac myocytes, highlighting a role for innate immunity.
- Targeting complement activation may offer a therapeutic strategy for dilated cardiomyopathy.
Abstract:
Dilated cardiomyopathy is a syndrome characterized by cardiac enlargement and impaired systolic function of the heart. Tumor necrosis factor (TNF)-alpha, a pleiotropic cytokine, seems to play a central role in the progression of dilated cardiomyopathy. Recent data suggest that ongoing inflammation in the myocardium may, in many cases, contribute to the development of disease. Chronic generation of autoantibodies to myocardial antigens or, in some cases, viral infection are pathobiologically involved. Although both antibodies and some viruses activate the complement system, the role of innate immunity in dilated cardiomyopathy has as yet not been investigated systematically. In this study we demonstrate by analysis of myocardial biopsies from 28 patients that C5b-9, the terminal membrane attack complex of complement, accumulates in human myocardium in dilated cardiomyopathy. C5b-9 significantly correlates with immunoglobulin deposition and myocardial expression of TNF-alpha. In vitro, C5b-9 attack on cardiac myocytes induces nuclear factor (NF)-kappaB activation as well as transcription, synthesis, and secretion of TNF-alpha. We conclude that chronic immunoglobulin-mediated complement activation in the myocardium may contribute in part to the progression of dilated cardiomyopathy via C5b-9-induced TNF-alpha expression in cardiac myocytes.