Autoantibodies In Dilated Cardiomyopathy Research Articles

Anti-cardiac troponin antibodies in clinical human disease: a systematic review.

Anti-cardiac troponin antibodies have been studied in different types of clinical diseases and in healthy populations. A systematic review of published data on anti-troponin antibodies was carried out (search performed on PubMed, ISI Web of Knowledge and Scopus databases). From title and abstract analysis, thirty-three articles were included that met the pre-specified criteria; after full-text analysis, nine articles were excluded. Most studies assessed anti-troponin I antibodies. The prevalence of anti-cardiac troponin antibodies in healthy individuals ranged from 0.0% to 20.0%. The prevalence of anti-troponin I autoantibodies in dilated cardiomyopathy (DCM) ranged from 7.0% to 22.2%. Other conditions under study were myocardial infarction, ischemic cardiomyopathy (ICM), peripartum cardiomyopathy (PPCM), Chagas disease, Emery-Dreifuss muscular dystrophy (EDMD) and renal transplantation. In the different patient populations studied, anti-cardiac troponin antibodies have been shown to be either positively or negatively associated with prognostic and clinical features. In what concerns a possible value as biomarkers, these assays have not emerged up to the present moment as important aids for practical clinical decisions in cardiac or other types of patients. In what concerns pathophysiology, anti-cardiac troponin autoantibodies may play a role in different diseases. It can be speculated that these antibodies could be involved in perpetuating some degree of cardiac injury after an event, such as myocardial infarction or PPCM.

Impact of common β1-adrenergic receptor polymorphisms on the interaction with agonistic autoantibodies in dilated cardiomyopathy

Impact of common β1-adrenergic receptor polymorphisms on the interaction with agonistic autoantibodies in dilated cardiomyopathy

Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes

BackgroundAutoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. MethodsFive DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. ResultsElevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post–IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). ConclusionThe present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated.

National Heart, Lung, and Blood Institute state of the science symposium in therapeutic apheresis-Therapeutic apheresis in cardiovascular disease.

The National Heart, Lung, and Blood Institute in collaboration with the American Society for Apheresis, convened a State of the Science Symposium in November of 2012 due to the expanding application of therapeutic apheresis despite the lack of well-designed research to address its efficacy. This article reviews the opportunities that were presented at this meeting in the area of cardiovascular disease (CVD), specifically the use of columns to adsorb autoantibodies in dilated cardiomyopathy or damaging lipids in peripheral vascular disease. Understanding how absorption of these pathologic substances alters the inflammatory response in these disorders is important for the application of these technologies to the treatment of CVD.

Anti-KCNQ1 K+ channel autoantibodies increase IKs current and are associated with QT interval shortening in dilated cardiomyopathy

Autoimmune-associated proarrhythmia in dilated cardiomyopathy (DCM) is poorly understood. Given the significance of KCNQ1 potassium channels in heart rhythm disorders, we hypothesized that circulating anti-KCNQ1 autoantibodies directly modulate cardiac electrophysiology in DCM patients. The purpose of this pilot study was to characterize ion channel autoantibodies in DCM targeting the cardiac repolarizing K(+) current, IKs, and the underlying KCNQ1 potassium channel. One hundred and fifty DCM patients were screened for anti-KCNQ1 autoantibodies using an enzyme-linked immunosorbent assay. Autoantibodies targeting the extracellular pore domain of the KCNQ1 channel were detected in 6% of study patients. Seropositive individuals exhibited significantly shorter corrected QT intervals when compared with seronegative patients (371 ± 39.9 ms vs. 408 ± 47.9 ms; P = 0.036). There was no difference in clinical severity of heart failure between groups. The functional significance of anti-KCNQ1 antibodies was determined in human embryonic kidney 293 cells expressing KCNQ1/KCNE1 using the whole-cell patch clamp technique. IKs recordings demonstrated a 2.7-fold increase in mean current density on exposure to patients' sera containing anti-KCNQ1 antibodies in contrast to seronegative controls (8.74 ± 1.44 pA/pF vs. 3.26 ± 0.36 pA/pF; P = 0.003). IKs enhancement was not associated with increased KCNQ1 protein levels or altered cell surface expression of the channel. Anti-KCNQ1 autoantibodies found in a subgroup of DCM patients are associated with QT interval shortening and increased IKs current.

Editorial on the manuscript entitled “Impact of Troponin I-Autoantibodies in Chronic Dilated and Ischemic Cardiomyopathy” by Andreas O. Doesch and co-workers

Despite advances in medical treatment, the prognosis of heart failure due to left ventricular systolic dysfunction is poor. In many cases in which disease progression cannot be inhibited by pharmacotherapy, heart transplantation remains the only therapeutic option. The most common causes of heart failure due to myocardial diseases are coronary heart disease, valve diseases, and cardiomyopathies [4]. Dilated cardiomyopathy (DCM) is the third most common cause of heart failure and the most frequent reason for heart transplantation [18]. This myocardial disease is characterized by ventricular chamber enlargement and progressive systolic dysfunction. In approximately 20–35% of DCM cases, a genetic background has been reported [18]. In addition, both experimental and clinical data indicate that viral infection and inflammatory processes may be involved in the pathogenesis of DCM [3, 6, 11, 27]. Abnormalities of the cellular immune system are a common feature of myocarditis and DCM. For patients with DCM, immunohistological methods have been introduced for diagnosis of myocardial inflammation. The term ‘‘inflammatory cardiomyopathy’’ has therefore been coined to describe the etiology of acquired cardiomyopathy [18]. Infiltrations with lymphocytes and mononuclear cells, as well as increased expression of cell adhesion molecules, are frequent phenomena in DCM [14, 21, 26]. These findings support the hypothesis that the immune process is still active. Patients with myocarditis and DCM demonstrate abnormalities of the humoral immune system as well. Furthermore, various autoantibodies have been detected in DCM patients: these include antibodies against mitochondrial proteins [23], cardiac myosin [2], cardiac b1-adrenergic receptors [25], muscarinergic receptors [8], and the sarcolemmal Na-K-ATPase [1]. The functional role of cardiac autoantibodies in DCM is under debate. Antibodies may reflect an inflammatory response to myocyte necrosis, thereby representing an epiphenomenon or, alternatively, may play an active role in the disease process. In patients with chronic myocarditis and cardiomyopathy, the prevalence of antibodies against cardiac myosin is associated with the deterioration of cardiac function [15]. Experimental data indicate that certain cardiac autoantibodies may play a functional role in DCM: antibodies against the ADP/ATP carrier interact with the calcium channel and possess cardiotoxic properties [23]. In the plasma of patients with DCM, negative inotropic antibodies are detectable that decrease the calcium transients of isolated cardiomyocytes [7]. A recent study by Li et al. [17] demonstrated that anti-cardiac myosin antibodies induced by immunization of rats with cardiac myosin target the b-adrenergic receptor on the heart cell surface. Passive transfer of purified antibodies from cardiac myosinimmunized rats results in IgG deposition and apoptosis in the heart, leading to a cardiomyopathic heart disease phenotype in recipients. Immunization of rodents against peptides derived from cardiovascular G-protein receptors induces morphological changes of myocardial tissue resembling DCM [9, 19]. A recent study by Jahns et al. [12] investigated the pathogenic significance of autoantibodies that target cardiac b1-adrenoceptors in DCM: rats immunized against the second extracellular loop of cardiac b1-receptors developed progressive left-ventricular dilatation and dysfunction. Sera transferred from these immunized animals to unsensitized S. B. Felix (&) Klinik fur Innere Medizin B, Ernst-Moritz-Arndt-Universitat Greifswald, Friedrich-Loeffler Str. 23a, 17475 Greifswald, Germany e-mail: felix@uni-greifswald.de

Discovering novel targets for autoantibodies in dilated cardiomyopathy

There is increasing evidence that a large proportion of dilated cardiomyopathy (DCM) cases are mediated by autoimmune processes. Since DCM is a fatal disorder with rapid aggravation and is the leading cause of heart transplantation, further insights into disease pathogenesis are needed. Recent studies have separated the pathogenic capacity of autoantibodies and initial clinical trials removing such autoantibodies via immunoadsorption have been promising. In order to elucidate the full autoantibody repertoire involved in DCM, we applied an autoantibody screening test using ventricular and atrial proteomes as autoantigenic sources and subsequently tested the autoantibody-binding patterns of sera from dogs with spontaneous DCM. With this method, we detected five potentially DCM-related autoantigens which were identified by MS as being: myosin heavy chain cardiac muscle alpha isoform, alpha cardiac actin, mitochondrial aconitate hydratase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and brain glycogen phosphorylase (GPBB). The recovery of two known DCM autoantigens (myosin heavy chain and alpha cardiac actin) and the discovery of three novel autoantigens (mitochondrial aconitate hydratase, GADPH, and GPBB) underscore the efficacy of this experimental method and the significance of the spontaneous canine DCM model.

Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance.

Dilated cardiomyopathy (DCM) is a relevant cause of heart failure and a common indication for heart transplantation. It may be idiopathic, familial/genetic, viral, autoimmune or immune-mediated associated with a viral infection. Myocarditis is an inflammatory disease of the myocardium; it may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Thus, in a patient subset, myocarditis and DCM are thought to represent the acute and chronic stages of an organ-specific autoimmune disease of the myocardium. In keeping with this hypothesis, autoimmune features in patients with myocarditis/DCM include: familial aggregation; a weak association with HLA-DR4; abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy; and detection of organ- and disease-specific cardiac autoantibodies of the IgG class in the sera of affected patients and symptom-free relatives. The cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. Two of these, first identified using immunoblotting and confirmed by ELISA, are the atrial-specific alpha- and the ventricular and skeletal muscle beta-heavy chain isoform. The alpha-myosin isoform fulfils the expected criteria for organ-specific autoimmunity, in that immunization with cardiac, but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of myocarditis/DCM; in addition, alpha-myosin is entirely cardiac-specific. Additional antigenic targets of heart-reactive autoantibodies include unknown sarcolemmal proteins, mitochondrial enzymes, beta-adrenergic and muscarinic receptors. For some of these antibodies, there is in vitro evidence for a functional role. The organ-specific cardiac autoantibodies detected by immunofluorescence in symptom-free relatives were associated with echocardiographic features suggestive of early disease. Mid-term follow-up suggests that these antibodies are predictive markers of progression to DCM among symptom-free relatives with or without abnormal echocardiographic findings.

Screening of Serum Autoantibodies to Cardiac β1-adrenoceptors and M2-muscarinic Acetylcholine Receptors in 408 Healthy Subjects of Varying Ages

Autoantibodies to cardiac β1-adrenoceptors and M2-muscarinic receptors have mainly been found in the sera of patients with idiopathic dilated cardiomyopathy (DCM). In order to elucidate the pathological significance of these autoantibodies in DCM, it is necessary to understand their characteristic distribution in a healthy population of different genders and ages. The peptides corresponding to the sequences of the second extracellular loops of the human β1-adrenoceptor and M2-muscarinic receptors were therefore used as antigens to screen the sera of 408 healthy subjects of different ages (ranging from 0.5 to 85 years). Of 408 sera, 41 (10.0%) and 46 (11.3%) recognized the β1-adrenoceptor and M2-muscarinic receptor peptides respectively. Of the positive sera for β1-adrenoceptors and M2-muscarinic receptors, up to 63.4% and 56.5% had both anti-β1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies respectively. The antibody titres of the positive sera of healthy subjects were all of a low level, with a geometric mean titre of 1:42 ± 1.9 for anti-β1-adrenoceptor antibodies and 1:51 ± 1.7 for anti-M2-muscarinic receptor antibodies. The frequency of occurrence of autoantibodies to both receptors in the sera of healthy subjects increased significantly with age. In conclusion, the autoantibodies to β1-adrenoceptors and M2-muscarinic receptors in the sera of healthy subjects are characterized by a low frequency of occurrence and low titre, with the frequency of occurrence increasing with age.

Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression.

OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up....

Removal of autoantibodies in dilated cardiomyopathy by immunoadsorption

Immunoadsorption with Ig-Therasorb leads to a marked decrease in serum levels of immunoglobulins including of the agonist-like anti- β 1-adrenoceptor autoantibody found in the serum of patients with idiopathic dilated cardiomyopathy. The reduction in autoantibody levels was accompanied by an improvement of heart function and a shift to a lower NYHA state. In this disease, as in a variety of other autoimmune disorders, apheresis with Ig-Therasorb led to a rapid improvement of the clinical status and could be used in end-stage dilated cardiomyopathy (with autoantibodies) as a bridge for transplantation.

Frequency and clinical correlates of anti-intercalated disk autoantibodies in dilated cardiomyopathy

Frequency and clinical correlates of anti-intercalated disk autoantibodies in dilated cardiomyopathy

Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy

To determine whether organ-specific cardiac autoantibodies are present in dilated cardiomyopathy, indirect immunofluorescence on human heart and skeletal muscle was used to test sera from 200 normal subjects and from 65 patients with dilated cardiomyopathy, 41 with chronic heart failure due to myocardial infarction and 208 with other cardiac disease. Three immunofiuorescence patterns were observed: diffuse cytoplasmic on cardiac tissue only (organ-specific), fine striational on cardiac and, to a lesser extent, skeletal muscle (cross-reactive 1) and broad striational on both cardiac and skeletal muscle (cross-reactive 2). Cardiac specificity of the cytoplasmic pattern was confirmed by absorption studies with homogenates of human atrium, skeletal made and rat liver.Organ-specific cardiac antibodies (IgG; titer range 1/10 to 1/180) were more frequent in patients with dilated cardiomyopathy (17 [26%] of 65) than in those with other cardiac disease (2 [1%] of 208, p < 0.0001) or heart failure (0 [0%] of 41, p < 0.001) or in normal subjects (7 [3.5%] of 200, p < 0.0001). Organ-specific cardiac antibodies were more common in patients with dilated cardiomyopathy and in those with fewer symptoms (8 of 15 in New York Heart Association functional class I versus 9 of 50 in classes II to IV, p < 0.01) and more recent (<2 years) onset of disease (9 of 19 versus 8 of 46, p < 0.02). Conversely, cross-reactive antibodies 1 and 2 were detected in a similar proportion of patients with dilated cardiomyopathy (7 [11 %] of 65), other cardiac disease (15 [7%] of 208) or heart failure (1 [2%] of 41) and normal subjects (11 [5.5%] of 200, p = NS). The presence of organ-specific cardiac antibodies provides a novel serologic marker of cardiac autoimmunity in dilated cardiomyopathy.

Laminin distribution and autoantibodies to laminin in dilated cardiomyopathy and myocarditis

With the use of the enzyme-linked immunosorbent assay technique and indirect immunofluorescence, we determined the frequency of antibodies to laminin (a noncollagenous protein of basement membrane) and their influence on endomyocardial laminin distribution in 132 patients suffering from dilated cardiomyopathy and myocarditis. Seventy-eight percent of 91 patients with dilated cardiomyopathy and 73% of 41 patients with myocarditis exhibited significantly elevated anti-laminin antibody levels compared with 68 apparently healthy persons. A positive correlation was found between hemodynamic data and irregular myocardial immunofluorescence laminin staining patterns in dilated cardiomyopathy and myocarditis. With regard to recent studies, these data suggest that antibodies to laminin in dilated cardiomyopathy and myocarditis enhance clusters of cell-surface laminin, inducing an alteration of the cytoskeleton, which may account for functional abnormalities in dilated cardiomyopathy and myocarditis. Considering the fact that optical microscopy is unable to resolve sarcolemmal structures proper from the basement membranes, the high prevalence of laminin autoantibodies in dilated cardiomyopathy and myocarditis raises doubts as to the diagnostic value of direct immunofluorescence findings.