Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption

Felix, Stephan B.; Staudt, Alexander; Landsberger, Martin; Grosse, Yvonne; Stangl, Verena; Spielhagen, Thomas; Wallukat, Gerd; Wernecke, Klaus D.; Baumann, Gert; Stangl, Karl

doi:10.1016/s0735-1097(01)01794-6

Cited by 173 publications

(139 citation statements)

References 26 publications

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“…Rather than these antibodies, anti-M 2 R antibodies are likely involved in the disease process. Anti-M 2 R IgG decreased the amplitude of transient (Ca 2+ ) i in neonatal rat ventricular cardiomyocytes, which is consistent with the results obtained with the IgGs purified by IA columns from DCM patients' sera [26] and the effects of anti-M 2 R antibodies on guinea pig cardiomyocytes [35]. The antibodies had specificity for M 2 R because a selective M 2 R antagonist AF-DX 116 as well as a synthetic M 2 R peptide blocked the activity.…”

Section: Discussionsupporting

confidence: 90%

“…Whereas the thinning of the left ventricle wall, a common finding in DCM patients, was not observed in this model, echocardiograms showed contractile dysfunction along with chamber dilatation, which may represent an early stage of DCM. It has been unclear whether the production of autoantibodies against M 2 R in DCM patients is a result of inflammatory responses or whether such antibodies are pathogenic and actively participate in the disease progression [26][27][28][29]. Our present findings strongly suggest that the anti-M 2 R antibodies participate in the electrical remodeling of left ventricular muscles and subsequently lead to DCM-like cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 57%

“…Acute hemodynamic improvement including increased cardiac index and decreased systemic vascular resistance was observed following repeated IAs in DCM patients [25]. Interestingly, however, the eluant from IA columns, which contained the adsorbed IgG antibodies, caused an immediate decrease rather than increase of (Ca 2+ ) i as well as cell shortening when added to cultured cardiomyocytes [26]. Consistent with these results, a study using a patch-clump technique showed that antibodies from DCM patients negatively modulated the L-type calcium current in isolated cardiomyocytes [27].…”

Section: Introductionmentioning

confidence: 99%

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Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

et al. 2012

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Patients with dilated cardiomyopathy (DCM) often have autoantibodies against cardiac antigens including the M 2 muscarinic acetylcholine receptor (M 2 R). To elucidate the role of autoimmunity against M 2 R in disease development, we induced an immune response against M 2 R by adoptive transfer into Rag2 -/-mice of splenocytes from M 2 R -/-mice immunized with a recombinant M 2 R protein. T lymphocytes transiently infiltrated the heart in recipient mice followed by morphological changes in cardiomyocytes. These mice produced IgG antibodies against M 2 R, which bound to cardiomyocytes in vivo and decreased the amplitude of calcium signals in isolated rat cardiomyocytes in vitro. Recipient mice showed increased heart weights associated with increased intraventricular diameter, decreased systolic function, and increased action potential duration, which are characteristics of DCM. Our results suggest that myocarditis and DCM associated with the presence of anti-M 2 R antibodies are autoimmune diseases with a risk of progressing to the terminal stage. Our mouse model will be useful in the analysis of the molecular mechanisms of disease progression and the development of new therapies for DCM. Keywords IntroductionDilated cardiomyopathy (DCM) causes severe heart failure in young adults including occasional sudden cardiac death. Mutations in genes encoding myocyte structural proteins are found in about 30-40% of DCM, but the etiology of the remaining 60-70% of cases is poorly understood [1][2][3]. Advances in the field of immunology have shed light on the close relationship between immunological disturbances and the progression of heart failure [4][5][6][7]. Adenovirus or enterovirus-specific RNA sequences are often detected in the myocardium of patients with DCM and myocarditis [7][8][9]. Myocardial-reactive antibodies such as those against β 1 adrenergic receptor (β 1 AR), M 2 muscarinic acetylcholine receptor (M 2 R), and cardiac myosin have also been observed in the sera of these patients [10][11][12][13][14]. As a result, it has been hypothesized that prolonged immunological abnormalities after myocarditis, presumably induced by a subclinical viral infection or autoimmunity, could lead to DCM [5,6]. Evidence supporting this hypothesis has accumulated through clinical and experimental studies [15][16][17].For example, immunization of animals with peptides derived from proteins expressed in cardiomyocytes such as β 1 AR [16,17] or cardiac myosin [15] or the transfer of antibodies against cardiac antigens mimics the prolonged immune abnormalities observed after acute myocarditis [18,19]. However, the progression from myocarditis to DCM has not been investigated in detail. The causes of the initial myocardial damage and subsequent cardiac dysfunction along with the subsequent role of autoimmunity in DCM are still unclear.The pathophysiological role of autoantibodies in disease progression has been established in only some autoimmune diseases such as pemphigus vulgaris (PV), involving anti-desmoglein 3 (Dsg3) antibodi...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

et al. 2012

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“…These antibodies induce a negative inotropic effect in isolated rat cardiomyocytes through depression of calcium transients; they are furthermore detectable in the majority of DCM patients [15,17]. Recent in vitro data indicate that these antibodies belong to the IgG-3 subclass [16].…”

Section: Discussionmentioning

confidence: 99%

“…Animal models have shown that DCM can be triggered by autoantibodies [8][9][10][11]. Recent clinical studies indicate that cardiac antibodies may play an active role in the pathogenesis and progression of the disease in humans: removal of antibodies by immunoadsorption (IA) induces hemodynamic improvement and ameliorates myocardial inflammation in patients with DCM [12][13][14][15][16][17]. Elimination of cardiodepressant antibodies may be one explanation for the beneficial hemodynamic effects of IA in patients with DCM [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

et al. 2007

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Cardiac autoantibodies play a pathogenic role in dilated cardiomyopathy (DCM). Removal of antibodies by immunoadsorption (IA) induces hemodynamic improvement in DCM patients. The present study investigated the effects of IA on myocardial gene expression of the intermediate cytoskeletal filament desmin, which is upregulated in heart failure. RNA was isolated from five explanted nonfailing hearts and five explanted failing hearts of DCM patients, and myocardial gene expression of desmin was estimated by real-time polymerase chain reaction (PCR). In a case-control study in six DCM patients (LVEF < 40%,

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The D&T Report

2008

Dialysis & Transplantation

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Objective Development of functional limitation is thought to be unrelated to changes in severity of radiographic osteoarthritis (OA) of the knee. We evaluated the relationship of change in radiographic OA to the incidence of severe functional limitation. Methods Participants of the Multicenter Osteoarthritis Study, a cohort study of persons with or at high risk of knee OA, were evaluated at 0 and 30 months. Subjects were classified as having no, incident, stable, or worsening radiographic OA. Incidence of severe functional limitation was defined by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function scores (≥36.1/68) and walking speed (≤1.0 meter/second) at 30 months. The relationship of the change in radiographic OA to the incidence of severe functional limitation was evaluated by calculating risk ratios adjusted for potential confounders. Results Of the 2,210 subjects included (mean age 62 years, mean body mass index 30 kg/m2, 60% women), 53% had no, 6% had incident, 14% had stable, and 27% had worsening radiographic OA. Persons with incident radiographic OA had 1.9 and 1.8 times the risk by WOMAC physical function score and walking speed, respectively, to have incident severe functional limitation compared with those with no radiographic OA over 30 months. Compared with those with stable radiographic OA, persons with worsening radiographic OA had 2.2 and 2.3 times the risk of incident severe functional limitation, respectively. Conclusion Changes in structural disease are associated with the development of severe functional limitations in persons with or even at high risk of knee OA.

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Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption

Abstract: Cardiac autoantibodies play a functional role in DCM, and their removal may induce early hemodynamic improvement.

Cited by 173 publications

References 26 publications

Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

The D&T Report

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Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption

Abstract: Cardiac autoantibodies play a functional role in DCM, and their removal may induce early hemodynamic improvement.

Cited by 173 publications

References 26 publications

Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

The D&T Report

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Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

Autoimmunity against M₂ muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype