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  1. Article ; Online: Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice.

    Caforio, Alida L P / Angelini, Annalisa / Blank, Miri / Shani, Alice / Kivity, Shaye / Goddard, Gisele / Doria, Andrea / Schiavo, Alessandro / Testolina, Martina / Bottaro, Stefania / Marcolongo, Renzo / Thiene, Gaetano / Iliceto, Sabino / Shoenfeld, Yehuda

    International journal of cardiology

    2015  Volume 179, Page(s) 166–177

    Abstract: Background: Human autoimmune myocarditis is characterized by an increased frequency of serum organ and disease-specific anti-heart autoantibodies (AHA) in affected patients. To assess whether AHA are directly pathogenic, we used the passive transfer ... ...

    Abstract Background: Human autoimmune myocarditis is characterized by an increased frequency of serum organ and disease-specific anti-heart autoantibodies (AHA) in affected patients. To assess whether AHA are directly pathogenic, we used the passive transfer technique of AHA from patients to normal Balb/c mice to induce an experimental myocarditis.
    Methods: In keeping with a classical passive transfer experiment, sera from 5 AHA positive myocarditis patients (3 male, mean age 30 ± 11 years, 3 with giant cell and 2 with lymphocytic myocarditis) were affinity purified and injected into 25 Balb/c mice. As controls, affinity purified sera from 5 healthy donors were passively transferred to 25 Balb/c mice. Further 15 control mice were injected with phosphate-buffered saline and 9 mice did not receive any injection. In all patients cardiac-specific AHA of IgG class had been previously detected by an indirect immunofluorescence (IFL) technique on cryostat sections of O blood group human heart. The animals were sacrificed after 4 weeks and the hearts were blindly examined for histological evidence of myocarditis by an expert cardiac pathologist.
    Results: Myocarditis was present in 13/25 (52%) of the mice which received affinity-purified IgG from patients. The findings of severe, moderate or mild myocarditis were more common in the mice which received affinity-purified IgG from patients (20%; 20% and 12%) than in control animals (2%, p=0.01; 0%, p=0.003; and 0%, p=0.04 respectively).
    Conclusions: These findings provide a new evidence for AHA-mediated pathogenicity in human myocarditis, according to Rose-Witebsky criteria.
    MeSH term(s) Adolescent ; Adult ; Animals ; Autoantibodies/blood ; Autoantibodies/immunology ; Female ; Humans ; Immunization, Passive/methods ; Male ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Myocarditis/blood ; Myocarditis/immunology ; Myocarditis/pathology ; Myocardium/immunology ; Myocardium/pathology ; Prospective Studies ; Species Specificity ; Young Adult
    Chemical Substances Autoantibodies
    Language English
    Publishing date 2015-01-20
    Publishing country Netherlands
    Document type Journal Article ; Randomized Controlled Trial
    ZDB-ID 779519-1
    ISSN 1874-1754 ; 0167-5273
    ISSN (online) 1874-1754
    ISSN 0167-5273
    DOI 10.1016/j.ijcard.2014.10.165
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy.

    Caforio, Alida L P / Tona, Francesco / Bottaro, Stefania / Vinci, Annalisa / Dequal, Greta / Daliento, Luciano / Thiene, Gaetano / Iliceto, Sabino

    Autoimmunity

    2008  Volume 41, Issue 1, Page(s) 35–45

    Abstract: Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20-30%), viral, ... ...

    Abstract Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20-30%), viral, and/or immune. On endomyocardial biopsy there is chronic inflammation in 30-40% of cases. Mutations in genes encoding myocyte structural proteins, cardiotoxic noxae and infectious agents are known causes; due to high aetiologic and genetic heterogeneity, the gene defects identified so far account for a tiny proportion of the familial cases. In at least two thirds of patients, DCM remains idiopathic. Myocarditis may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Circulating heart-reactive autoantibodies are found in myocarditis/DCM patients and symptom-free relatives at higher frequency than in normal or noninflammatory heart disease control groups. These autoantibodies are directed against multiple antigens, some of which are expressed only in the heart (organ-specific); some autoantibodies have functional effects on cardiac myocytes in vitro as well as in animal models. Depletion of nonantigen-specific antibodies by extracorporeal immunoadsorption is associated with improved ventricular function and reduced cardiac symptoms in some DCM patients, suggesting that autoantibodies may also have a functional role in humans. Immunosuppression seems beneficial in patients who are virus-negative and cardiac autoantibody positive. Prospective family studies have shown that cardiac-specific autoantibodies are present in at least 60% of both familial and non familial pedigrees and predict DCM development among asymptomatic relatives, years before clinical and echocardiographic evidence of disease. Animal models have shown that autoimmune myocarditis/DCM can be induced by virus as well as reproduced by immunization with a well-characterized autoantigen, cardiac myosin. Thus, in a substantial proportion of patients, myocarditis and DCM represent different stages of an organ-specific autoimmune disease, that represents the final common pathogenetic pathway of infectious and noninfectious myocardial injuries in genetically predisposed individuals.
    MeSH term(s) Antibody Specificity ; Autoantibodies/blood ; Autoantibodies/immunology ; Autoantigens/immunology ; Autoimmune Diseases/immunology ; Autoimmune Diseases/physiopathology ; Cardiac Myosins/immunology ; Cardiomyopathy, Dilated/immunology ; Cardiomyopathy, Dilated/physiopathology ; Humans ; Myocarditis/immunology ; Myocarditis/physiopathology ; Myocardium/immunology
    Chemical Substances Autoantibodies ; Autoantigens ; Cardiac Myosins (EC 3.6.1.-)
    Language English
    Publishing date 2008-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1025450-x
    ISSN 1607-842X ; 0891-6934
    ISSN (online) 1607-842X
    ISSN 0891-6934
    DOI 10.1080/08916930701619235
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis.

    Caforio, Alida L P / Calabrese, Fiorella / Angelini, Annalisa / Tona, Francesco / Vinci, Annalisa / Bottaro, Stefania / Ramondo, Angelo / Carturan, Elisa / Iliceto, Sabino / Thiene, Gaetano / Daliento, Luciano

    European heart journal

    2007  Volume 28, Issue 11, Page(s) 1326–1333

    Abstract: Aims: Myocarditis may be idiopathic, viral, and/or immune; frequency of these forms and prognosis are ill-defined. We aimed at identifying aetiopathogenetic and prognostic markers in myocarditis, including viral genome on endomyocardial biopsy (EMB) by ... ...

    Abstract Aims: Myocarditis may be idiopathic, viral, and/or immune; frequency of these forms and prognosis are ill-defined. We aimed at identifying aetiopathogenetic and prognostic markers in myocarditis, including viral genome on endomyocardial biopsy (EMB) by polymerase chain reaction (PCR) and serum anti-heart autoantibodies (AHA).
    Methods and results: We studied 174 patients, 110 males, aged 36 +/- 18 years, median follow-up 23.5 months, range 10-54; 85 patients had active myocarditis and 89 borderline myocarditis (no diffuse or severe inflammation) (Dallas criteria). Serum AHA were detected by indirect immunofluorescence. PCR was used to detect virus. Six-year actuarial survival was 73%. AHA were found in 56% of patients and positive PCR in 26%. Univariate predictors of death/transplantation were young age, longer symptom duration, giant cell myocarditis, NYHA II-IV, positive PCR, presentation with LV dysfunction, clinical signs/symptoms of heart failure, and echocardiographic and haemodynamic indexes of cardiac dysfunction. By Cox univariate analysis, highest risk was conferred by clinical signs/symptoms of left (HR = 4.3, CI 1.7-10.8, P = 0.002) and right heart failure (HR 3.4, CI 1.5-7.3, P = 0.002).
    Conclusion: In myocarditis, biventricular dysfunction at diagnosis was the main predictor of death/transplantation. AHA identified immune-mediated myocarditis in the majority of cases. Viral genome was a univariate predictor of adverse prognosis. Our approach of using AHA and positive PCR as aetiopathogenetic markers should help patient selection and recruitment in future studies on aetiological therapy.
    MeSH term(s) Adult ; Autoantibodies/analysis ; Biopsy/methods ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Male ; Myocarditis/etiology ; Myocarditis/immunology ; Myocarditis/pathology ; Myocardium/pathology ; Necrosis ; Polymerase Chain Reaction ; Prospective Studies
    Chemical Substances Autoantibodies
    Language English
    Publishing date 2007-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603098-1
    ISSN 1522-9645 ; 0195-668X
    ISSN (online) 1522-9645
    ISSN 0195-668X
    DOI 10.1093/eurheartj/ehm076
    Database MEDical Literature Analysis and Retrieval System OnLINE

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