Anti-heart autoantibodies in familial dilated cardiomyopathy
ABSTRACT Familial aggregation is a feature of myocarditis and dilated cardiomyopathy (DCM). Myocarditis, a clinically polymorphic inflammatory disease of the myocardium, is diagnosed by endomyocardial biopsy (EMB) and may lead to DCM. Mutations in several genes encoding myocyte structural proteins are known monogenic DCM causes, but because of high etiologic and genetic heterogeneity, the gene defects identified so far account for a minority of cases. In the last decade, it has been discovered that autoimmunity plays a pivotal role in myocarditis and DCM that are thought to represent different stages of an organ-specific autoimmune disease in genetically predisposed individuals. None of the available genetic studies in familial DCM has taken into account the autoimmune phenotype markers in the characterization of index patients and relatives, thus it is not known whether or not the described gene defects are involved in the autoimmune form of the disease. In animal models autoimmune myocarditis/DCM can be induced by viral infection, immunization with heart-specific autoantigens, or develop spontaneously in genetically predisposed strains. It may be cell or antibody-mediated; susceptibility is based upon multiple MHC and non-MHC genes. In patients, the diagnosis of autoimmune myocarditis/DCM requires exclusion of viral genome on EMB and detection of serum heart-reactive autoantibodies. They are found in index patients and relatives from about 60% of both familial and non-familial pedigrees and predict DCM development among healthy relatives. Some antibodies have functional effects on cardiac myocytes in vitro, in animal models and possibly in a DCM subset without inflammation, responsive to extracorporeal immunoadsorption. Cardiac-specific autoantibodies, which are shown to be disease-specific for myocarditis/DCM, can be used as biomarkers for identifying patients in whom, in the absence of active infection of the myocardium, immunosuppression and/or immunomodulation may be beneficial and their relatives at risk. Future studies should clarify genetic basis of human autoimmune myocarditis/DCM as well as genotype/immune phenotype correlations.
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- "A DCM subgroup of about 30% is addressed as 'idiopathic' because its origin remains unclear despite efforts at reclassification (Maron et al., 2006). Data accumulated over the past three decades strongly suggest that at least a fraction of this DCM subgroup could represent a later stage of a heart-specific autoimmune disease triggered by viral (Yoshikawa et al., 2009) or protozoic (Cunha-Neto et al., 2006) infections or possibly induced by autoimmunization with heart-specific antigens in genetically predisposed individuals (Caforio et al., 2008b). Humoral autoimmunity seems to play a crucial role in DCM, as heart-reactive autoantibodies found in patients and relatives from familial and non-familial pedigrees predict disease development among healthy relatives (Caforio et al., 2008a). "
ABSTRACT: Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the β-adrenergic (β-adrenoceptor) and M2 muscarinic receptor. β(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of β(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human β(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies.British Journal of Pharmacology 01/2012; 166(3):847-57. DOI:10.1111/j.1476-5381.2012.01828.x · 4.99 Impact Factor
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ABSTRACT: Cardiomyopathy is a major cause of sudden unexpected death in young patients, it contributes significantly to the societal burden of heart failure. Now significant evidences from animal models and clinical studies suggests that viral myocarditis is important in the etiology of dilated cardiomyopathy. Enterovirus, and especially Coxsackieviruses of group B (CVB), is the most common infectious agent [1, 2]. Enteroviruses (family Picornaviridae) are nonenveloped icosahedral viruses that contain a single plus-strand RNA genome of about 7,500bp. The CVB are typical enteroviruses and 5' end of the genome is not capped but is linked covalently to the viral protein, VPg. The virus receptor, human coxsackievirus and adenovirus receptor (CAR), a protein of the immunoglobulin superfamily [3-5], most likely interacts with virus capsid in the depression that surrounds the 5-fold axes of symmetry.
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ABSTRACT: The objective of this study was to investigate functional effects of immunoadsorption (IA) in severely limited study patients with chronic nonfamilial dilated cardiomyopathy (DCM), and to analyze the prevalence of Troponin I (TNI) autoantibodies. Immunoadsorption (IA) has been shown to induce early hemodynamic improvement in patients with nonfamilial DCM. We performed IA using Immunosorba columns on five consecutive days in 27 patients with chronic DCM, congestive heart failure of NYHA class >or=II, left ventricular ejection fraction below 40%, and mean time since initial diagnosis of 7.2 +/- 6.8 years. Immediately after IA, IgG decreased by 87.7% and IgG3 by 58.5%. Median NT-pro BNP was reduced from 1740.0 ng/L at baseline to 1504.0 ng/L after 6 months (P = 0.004). Mean left ventricular ejection fraction (LVEF) was not significantly improved overall (24.1 +/- 7.8% to 25.4 +/- 10.4% after 6 months, P = 0.38), but LVEF improved >or=5% (absolute) in 9 of 27 (33%) patients. Bicycle spiroergometry showed a significant increase in exercise capacity from 73.7 +/- 29.4 Watts to 88.8 +/- 31.1 Watts (P = 0.003) after 6 months while VO2max rose from 13.7 +/- 3.8 to 14.9 +/- 3.0 mL/min kg after 6 months (P = 0.09). Subgroup analysis revealed a higher NT-pro BNP reduction in patients with shorter disease duration (P = 0.03) and without TNI autoantibodies at baseline (P = 0.05). All 9 patients with an absolute increase of LVEF of >or=5.0% were diabetic (P = 0.0001). In this study, on severely limited heart failure patients with nonfamilial DCM, IA therapy moderately improved markers of heart failure severity in a limited subgroup of patients. This may be due to the selected study population with end-stage heart failure patients and the lower reduction of IgG3 compared to previous studies. Future blinded multicenter studies are necessary to identify those patients that benefit most.Journal of Clinical Apheresis 01/2009; 24(4):141-9. DOI:10.1002/jca.20204 · 1.58 Impact Factor