Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction

Chiale, Pablo A.; Ferrari, Inés; Mahler, Evelina; Vallazza, Marina A.; Elizari, Marcelo V.; Rosenbaum, Mauricio B.; Levìn, Mariano J.

doi:10.1161/01.cir.103.13.1765

Cited by 108 publications

(86 citation statements)

References 24 publications

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“…It will be important to elucidate in future studies the precise molecular mechanism how antibodies against these receptors induced a similar phenotypes. Nevertheless, anti-M 2 R antibodies have also been implicated in two additional human diseases, sinus node dysfunction [37] and atrial fibrillation [38,39]. It is thus possible that mechanisms similar to what we observe in our mouse model are operative in humans.…”

Section: Discussionsupporting

confidence: 68%

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: 68%

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

et al. 2012

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“…Prevalencia de autoanticuerpos contra receptores autonómicos y características generales de los pacientes en los grupos evaluados y en controles sanos. (4) 18/7 (5) 16/9 (6) Autoanticuerpos contra receptores autonómicos (%) 24,5 20,0 (7) 16,0 (8) 0 (9) (1) Grupo 1 (47,88 ± 6,6) Vs. grupo 2 (57,8±6,4); p=0,89 (2) Grupo 1 (47,88 ± 6,6) Vs. grupo 3 (56,0±6,9); p=0,77 (3) Grupo 1 (47,88 ± 6,6) Vs. grupo controles sanos (39,1±7,1); p=0,64 (4) Grupo CCC (57%) Vs. grupo IC (56%); p=0,84 (5) Grupo CCC (57%) Vs. grupo AC (72%); p=0,29 (6) Grupo CCC (57%) Vs. grupo CS (64%); p=0,71 (7) Grupo CCC (24,5%) Vs. grupo IC (20%); p=0,88 (8) Grupo CCC (24,5%) Vs. grupo AC (16%); p=0,57 (9) Grupo CCC (57%) Vs. grupo CS (0%); p=0,008*** CCC: cardiomiopatía chagásica crónica; IC: insuficiencia cardiaca; AC: arritmia cardiaca; CS: controles sanos Autoanticuerpos en pacientes chagásicos panameños infectados crónicamente con T. cruzi, 48 (90,6%) presentaron algún grado de alteración cardíaca.…”

Section: Resultsunclassified

“…Estos autooanticuerpos también se han observado con diferentes frecuencias en pacientes con cardiopatías de origen no chagásico, incluyendo cardiomiopatía idiopática dilatada, cardiomiopatías isquémicas, arritmias y trastornos de la conducción (7,14,15).…”

Section: Discussionunclassified

“…Los diversos efectos funcionales que pueden ejercer los anticuerpos contra los receptores β1 adrenérgicos y M2 colinérgicos en el tejido cardiaco, podrían explicar la variedad de alteraciones cardiacas observadas durante la enfermedad de Chagas (7,9,18). Sin embargo, no se han realizado estudios multicéntricos bien diseñados en distintas poblaciones endémicas que permitan establecer con claridad si estos autoanticuerpos están implicados directamente en la etiología de estas enfermedades o, si más bien, son la consecuencia de la propia enfermedad.…”

Section: Discussionunclassified

“…Al respecto, se ha detectado la presencia de anticuerpos circulantes dirigidos contra los receptores beta-adrenérgicos y colinérgicos muscarínicos del miocardio en pacientes chagásicos. Estas moléculas pueden desencadenar señales intracelulares y alterar la función cardiaca durante el curso de la infección (7,8). Se ha planteado que la detección de estos autoanticuerpos podría tener valor clínico como marcadores tempranos de alteraciones cardiacas en pacientes chagásicos afectados crónicamente (9).…”

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Prevalencia de autoanticuerpos contra receptores autonómicos en pacientes panameños con cardiopatía chagásica crónica y con otras formas de cardiopatía

et al. 2009

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Introducción. La enfermedad de Chagas es la principal causa de cardiomiopatía crónica en Centroamérica. Existe controversia sobre los mecanismos causantes de la patología cardiaca observada durante la fase crónica de esta parasitosis. Varios estudios han detectado la presencia de autoanticuerpos circulantes dirigidos contra receptores beta-adrenérgicos y colinérgicos muscarínicos del miocardio en pacientes chagásicos, que pueden desencadenar señales intracelulares y alterar la función cardiaca durante el curso de la enfermedad. Objetivo. Nuestro objetivo principal fue comparar la frecuencia sérica de estos autoanticuerpos en pacientes chagásicos crónicos con la observada en pacientes con otras formas de cardiopatía y en controles sanos. Materiales y métodos. Se determinó la prevalencia de autoanticuerpos contra receptores betaadrenérgicos y colinérgicos muscarínicos en cuatro grupos de pacientes panamelos: 53 pacientes chagásicos, 25 pacientes seronegativos con insuficiencia cardiaca, 25 pacientes con diferentes tipos de arritmia cardiaca y 25 controles sanos. Resultados. Los autoanticuerpos contra receptores autonómicos fueron más frecuentes en el grupo de pacientes con cardiopatía chagásica crónica (24,5%) comparados con el grupo de insuficiencia cardiaca (20,0%) y con el grupo con arritmias cardiacas (16,0%). Al comparar la proporción de autoanticuerpos entre el grupo de pacientes con cardiopatía chagásica crónica y los controles sanos, se detectaron diferencias muy significativas (24,5% versus 0%; p=0,0015). De los 53 pacientes con infección crónica, 48 (90,6%) presentaron algún grado de alteración cardiaca. Conclusiones. En comparación con el grupo de controles sanos, la frecuencia de los autoanticuerpos contra receptores autonómicos se encuentra significativamente aumentada en pacientes con enfermedad de Chagas crónica y con otras formas de cardiopatía.

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Autoimmune Myocarditis, Valvulitis, and Cardiomyopathy

et al. 2013

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Cardiac myosin-induced autoimmune myocarditis (EAM) is a model of inflammatory heart disease initiated by CD4+ T cells (Smith and Allen 1991; Li, Heuser et al. 2004). It is a paradigm of the immune-mediated cardiac damage believed to play a role in the pathogenesis of a subset of postinfectious human cardiomyopathies (Rose, Herskowitz et al. 1993). Myocarditis is induced in susceptible mice by immunization with purified cardiac myosin (Neu, Rose et al. 1987) or specific peptides derived from cardiac myosin (Donermeyer, Beisel et al. 1995; Pummerer, Luze et al. 1996) (see Basic Protocol 1), or by adoptive transfer of myosin-reactive T cells (Smith and Allen 1991) (see Alternate Protocol). Myocarditis has been induced in Lewis rats by immunization with purified rat or porcine cardiac myosin (Kodama, Matsumoto et al. 1990; Li, Heuser et al. 2004) (see Basic Protocol 2) or S2-16 peptide (Li, Heuser et al. 2004), or by adoptive transfer of T cells stimulated by specific peptides derived from cardiac myosin (Wegmann, Zhao et al. 1994). Myocarditis begins 12 to 14 days after the first immunization, and is maximal after 21 days. Other animal models commonly used to study myocarditis development include the pathogen-induced models in which disease is initiated by viral infection. The first murine model of acute viral myocarditis causes sudden death via viral damage to cardiomyocytes (Huber, Gauntt et al. 1998; Horwitz, La Cava et al. 2000; Fong 2003; Fuse, Chan et al. 2005; Fairweather and Rose 2007; Cihakova and Rose 2008) whereas the second model is based on inoculation with heart-passaged coxsackievirus B3 (CVB3) that includes damaged heart proteins (Fairweather, Frisancho-Kiss et al. 2004; Fairweather D 2004; Fairweather and Rose 2007; Cihakova and Rose 2008) In addition to the protocols used to induce EAM in mice and rats, support protocols are included for preparing purified cardiac myosin using mouse or rat heart tissue (see Support Protocol 1), preparing purified cardiac myosin for injection (see Support Protocol 2), and collecting and assessing hearts by histopathological means (see Support Protocol 3).

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Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction

Cited by 108 publications

References 24 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

Prevalencia de autoanticuerpos contra receptores autonómicos en pacientes panameños con cardiopatía chagásica crónica y con otras formas de cardiopatía

Autoimmune Myocarditis, Valvulitis, and Cardiomyopathy

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Differential Profile and Biochemical Effects of Antiautonomic Membrane Receptor Antibodies in Ventricular Arrhythmias and Sinus Node Dysfunction

Cited by 108 publications

References 24 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

Prevalencia de autoanticuerpos contra receptores autonómicos en pacientes panameños con cardiopatía chagásica crónica y con otras formas de cardiopatía

Autoimmune Myocarditis, Valvulitis, and Cardiomyopathy

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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