Complete Elimination of Cardiodepressant IgG3 Autoantibodies by Immunoadsorption in Patients With Severe Heart Failure

Baba, Akira; Amaki, Makoto; Shimada, Megumi; Monkawa, Toshiaki; Wakabayashi, Yasuhisa; Takahashi, Michiko; Nagatomo, Yuji; Yoshikawa, Tsutomu

doi:10.1253/circj.cj-09-0748

Cited by 37 publications

(27 citation statements)

References 21 publications

(11 reference statements)

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“…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.…”

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confidence: 58%

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

et al. 2012

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“…Often referred to as “cardio-depressant" AAbs, certain types of AAb purified from patients with DCM have been found to induce a negative inotropy in vitro (32) and ex vivo (27,33). Interestingly, patients with cardio-depressant AAbs demonstrated an acute increase in cardiac index and LVEF after IA therapy (27,32). Staudt and colleagues have reported that the cardio-depressant effects of these AAbs are unlikely to be induced by either the F(ab′) 2 or Fc fragment alone (34).…”

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confidence: 99%

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β 1 -Adrenergic Receptors

Nagatomo

McNamara

Alexis

et al. 2017

Journal of the American College of Cardiology

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BACKGROUND Among various cardiac autoantibodies (AAb), those recognizing the β1 adrenergic receptor (β1AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption. OBJECTIVES We investigated the role of β1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy. METHODS Peripheral blood was drawn at enrollment in subjects with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). Presence of IgG and IgG3-β1AR-AAb was determined and echocardiograms assessed at baseline and 6 months. Subjects were followed for up to 4 years. RESULTS Among the 353 enrolled subjects, 62 (18%) were positive for IgG3-β1AR-AAb (IgG3), 58 (16%) were positive for IgG but not IgG3 (non-IgG3), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. LV end-diastolic and end-systolic (LVEDD and LVESD, respectively) diameters were significantly larger in the non-IgG3 group compared to the other groups (LVEDD: p < 0.01; LVESD: p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis demonstrated IgG3-β1AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In the subjects with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint. CONCLUSIONS IgG3-β1AR-AAb was associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

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“…A therapeutic benefit also holds true for Immunsorba TR selective IgG3 columns, as recently investigated even under blinded measurement conditions. 11 Our previously selected aptamer using the Monolex technology 12 bound β1-AABs isolated from patients with DCM, Chagas' cardiomyopathy, or peripartum cardiomyopathy and neutralized their pathogenic functions, which we demonstrated in vitro by reducing β1-AAB-induced chronotropy and apoptosis. 1 However, as recently discussed, 13 the relationship between the selected aptamer and β1-AABs must be consolidated in vivo using animal models.…”

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The First Aptamer-Apheresis Column Specifically for Clearing Blood of β1-Receptor Autoantibodies

Wallukat

Haberland

Berg

et al. 2012

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp e present here for the first time in vitro and animal experiments demonstrating aptamer-based clearing from blood of pathogenic autoantibodies targeting the second extracellular loop of the β1-receptor using apheresis technology.We recently published the selection and identification of a novel ssDNA aptamer that targets autoantibodies directed against the second extracellular loop of the adrenergic β1-receptor (β1-AABs). 1 As recently summarized, 2,3 autoantibodies directed against the first or second extracellular loop of the adrenergic β1-receptor (ie, β1-AABs) have been found in patients with cardiomyopathies, with evidence that mainly β1-AABs directed at the second loop are related to disease pathogenesis. 4 Up to 80% of patients with dilated cardiomyopathy (DCM) are positive for either first-or second-loop β1-AABs; approximately one-half of the patients present with first-loop β1-AABs, the other half with second-loop β1-AABs. As demonstrated in a Bolivian cohort, nearly 100% of patients with Chagas' cardiomyopathy are positive for second-loop β1-AABs. 5 A first indication exists that exclusively second-loop β1-AABs were found also in patients with peripartum cardiomyopathy. 6 Consequently, technologies have been developed to clear β1-AABs from the blood of β1-AAB-positive DCM patients via immunoapheresis. In addition, β1-AAB immunoapheresis has been suggested for the treatment of Chagas' patients. Background: Application of immunoapheresis to eliminate pathogenic autoantibodies targeting the second extracellular loop of the β1-receptor (β1-AABs) is currently investigated in patients with cardiomyopathy. Aptamers (single short DNA or RNA strands) are a new class of molecules that bind to a specific target molecule. This property qualifies aptamers for potential use in the apheresis technique. We recently identified an aptamer that specifically binds to β1-AABs, so in the present study we tested whether this aptamer could be used as a binder to prepare an apheresis column suitable for clearing β1-AABs from rat's blood.

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Complete Elimination of Cardiodepressant IgG3 Autoantibodies by Immunoadsorption in Patients With Severe Heart Failure

Cited by 37 publications

References 21 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

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β 1 -Adrenergic Receptors

The First Aptamer-Apheresis Column Specifically for Clearing Blood of β1-Receptor Autoantibodies

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Complete Elimination of Cardiodepressant IgG3 Autoantibodies by Immunoadsorption in Patients With Severe Heart Failure

Cited by 37 publications

References 21 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

Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β 1 -Adrenergic Receptors

The First Aptamer-Apheresis Column Specifically for Clearing Blood of β1-Receptor Autoantibodies

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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