Complement and 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.

Increased circulating IgG levels, myocardial immune cells and IgG deposits support a role for an immune response in pre‐ and end‐stage heart failure

“…29,[35][36][37] In DCM, it has also been described that immunoglobulins can directly bind to antigens expressed by the cardiomyocytes, and then crosslink to the Fc gamma receptor IIa on the cardiomyocyte, resulting in reduced calcium transients, cell shortening and initiating cellular apoptosis. [37][38][39] The direct binding of immunoglobulins can also lead to complement-dependent cytotoxicity (CDC). Using immunofluorescence, we observed an increased deposition of both IgG3 and C3c in the myocardial tissue of DCM and IHD patients.…”

“…Binding of immunoglobulins to cardiac‐specific antigens on cardiomyocytes can initiate the process of complement activation and antibody‐dependent cellular cytotoxicity (ADCC), resulting in lysis of cardiomyocytes . In DCM, it has also been described that immunoglobulins can directly bind to antigens expressed by the cardiomyocytes, and then crosslink to the Fc gamma receptor IIa on the cardiomyocyte, resulting in reduced calcium transients, cell shortening and initiating cellular apoptosis . The direct binding of immunoglobulins can also lead to complement‐dependent cytotoxicity (CDC).…”

The Emerging Role of Innate Immunity in the Heart and Vascular System

“…1 Moreover, recent studies have also indentified an important role for the complement system an essential component of the innate immune system in the heart. 2 As will be discussed in the following focused review, recent insights into the role of TLRs have provided important new insights with respect to our understanding of the role inflammation in health and disease.…”

Association of Ficolin-3 with Severity and Outcome of Chronic Heart Failure

“…Complement activation occurs in CHF [4] and has been associated with adverse clinical events in patients with symptomatic heart failure [5], [6]. Deposition of the terminal complement complex (TCC) has been observed in myocardial biopsies from patients with dilated cardiomyopathy [7], but its relation to disease severity in cardiomyopathy is debated [8].…”