ReviewRole of β1-adrenoceptor autoantibodies in the pathogenesis of dilated cardiomyopathy
Introduction
Dilated cardiomyopathy (DCM), a chronic myocardial disease characterized by progressive impairment of myocardial contractile function and associated with dilation of the heart, is a common cause of heart failure (HF) and one of the principal reasons for heart transplantation (Mestroni et al. 2004). Despite the immense clinical impact of this disease due to its unacceptably high mortality, little is known concerning its etiopathogenesis. Up to 80% of cases are idiopathic in nature and therapy is usually focused on restoration of neurohumoral balance and symptomatic treatment of HF rather than targeting the primary cause (Mestroni et al., 2004, Maron et al., 2006, Lappé et al., 2008).
After the identification of several immune regulatory abnormalities in DCM, including humoral and cellular autoimmune reactivity against myocytes, decreased natural killer cell activity and abnormal suppressor cell activity, increasing attention has been focused on autoimmune mechanisms as potential key elements in the pathogenesis of the disease (Kawai et al., 1975, Fowles et al., 1979, Anderson et al., 1982, Limas et al., 1995). DCM has appeared to be often related to elevated levels of autoantibodies against cardiac structural or functional proteins, especially mitochondrial proteins, M2 muscarinic receptors, β1-adrenoreceptors, and myosin heavy chains (Gerli et al., 1986, Limas et al., 1989, Schulze et al., 1990, Fu et al., 1993, Magnusson et al., 1994, Wallukat et al., 1995, Caforio et al., 2002). Among the several autoantibodies which react against cardiac cellular proteins that have been detected in sera from DCM patients, those against β1-adrenoreceptors (β1-AABs) appeared particularly relevant from a pathophysiological point of view (Dörfel et al., 1997, Matsui et al., 1997, Müller et al., 2000, Felix et al., 2000, Knebel et al., 2004). This article aims to summarize the present knowledge about β1-AABs, their role in DCM etiopathogenesis and the potential therapeutic benefits of β1-AAB removal.
Section snippets
Infection, inflammation and autoimmune response in the pathogenesis of DCM
Although the majority of DCM cases are designated as idiopathic (IDCM), the inflammatory nature of IDCM was recognized a long time ago and the hypothesis that it may originate from an extended process of myocarditis has been increasingly accepted (Lappé et al. 2008). Because IDCM shares many inflammatory and infectious characteristics with myocarditis (association with systemic and organ-specific inflammation, correlation with chronic myocardial viral infection, evidence of cardiac-specific
β1-Adrenoceptor autoantibodies
Functional auto-antibodies with β-adrenergic effects were isolated for the first time from sera of patients with IDCM nearly 25 years ago (Wallukat and Wollenberger 1987). Shortly afterwards the presence of a gamma globulin fraction with stimulatory effect on beta-1-adrenoceptors (“autoantibodies against beta-1-adrenoceptors”) in sera of IDCM patients was confirmed by another group (Limas et al. 1989).
Conclusion and future directions
Autoimmune mechanisms are possibly key elements in the pathogenesis of DCM and in many patients with idiopathic DCM the β1-AABs appear to be involved in the initiation and progression of the disease. Functional β1-AABs are detectable in the majority of DCM patients with end-stage HF and the available experimental and clinical data suggest that in β1-AAB-positive patients with DCM the cardiomyopathy might be considered a β1-AR-targeted autoimmune disease.
The binding sites for the β1-AABs are
Acknowledgement
The authors thank Anne M. Gale for editorial assistance.
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2017, Journal of CardiologyCitation Excerpt :Dilated cardiomyopathy (DCM) and inflammatory DCM (DCMi) refer to a heterogeneous group of conditions in which autoimmunity plays a major role and progressive cardiac chamber dilatation and remodeling finally leads to congestive heart failure [1]. Numerous autoantibodies against myocyte structural and functional proteins, muscarinic and β1-adrenergic receptors have been detected in patients affected from DCM/DCMi [1,2], and animal models have proved the pathogenic roles of autoantibodies [3,4]. In addition, plasmapheresis of cardiac autoantibodies in patients with DCM/DCMi and subsequent immunoglobulin (Ig) G substitution resulted in significant increase in cardiac index, left ventricular ejection fraction (LVEF), improvement in endothelial function [5], and symptom relief [6–9].