European Journal of Heart Failure

European Journal of Heart Failure 2002 4(4):411-417; doi:10.1016/S1388-9842(02)00010-7

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© 2002 European Society of Cardiology

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

Alida L.P. Caforio^a,*, Niall J. Mahon^b, Francesco Tona^a and William J. McKenna^b

^a Division of Cardiology, Department of Clinical and Experimental Medicine, University of Padua, Policlinico Universitario, Centro ‘V. Gallucci’ via N. Giustiniani, 2, 35128 Padua, Italy
^b Department of Cardiological Sciences St. George's Hospital Medical School, London, UK

^* Corresponding author. Tel.: +39-049-821-2348; fax: +39-049-875-4179 E-mail address: alida.caforio{at}unipd.it

	Abstract

Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 
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 - and the ventricular and skeletal muscle β-heavy chain isoform. The -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, -myosin is entirely cardiac-specific. Additional antigenic targets of heart-reactive autoantibodies include unknown sarcolemmal proteins, mitochondrial enzymes, β-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.

Key Words: Dilated cardiomyopathy • Familial • Autoimmunity • Autoantibodies • Myosin • Immunology

Received June 29, 2001; Revised September 21, 2001; Accepted December 14, 2001

	1. Introduction

Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 
According to the current WHO classification of cardiomyopathy, in a patient subset, myocarditis and dilated cardiomyopathy (DCM) represent the acute and chronic phases of an inflammatory disease of the myocardium, which can be viral, post-infectious immune or primarily organ-specific autoimmune [1–4]. Autoimmune features in human myocarditis/DCM include familial aggregation [5,6], a weak association with HLA-DR4 [2], abnormal expression of HLA class II on cardiac endothelium [7], and increased levels of circulating cytokines and cardiac autoantibodies [8–36]. Here, we mainly review the clinical and pathogenetic significance of the circulating cardiac autoantibodies in patients with myocarditis/DCM and their relatives.

	2. Circulating cardiac autoantibodies as clinical markers of organ-specific autoimmunity in human myocarditis and DCM

Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 
In organ-specific autoimmune disease, the destruction process is restricted to one organ, and the serum autoantibodies found in patients and relatives at risk, but not in normal and disease control subjects, react with autoantigens unique to that organ [4]. These organ- and disease-specific autoantibodies are not necessarily pathogenic, but represent markers of immune-mediated injury [2,4]. Several groups have found antibodies to various cardiac antigens in myocarditis and DCM [8–36], but the organ and disease specificity of these antibody types have not been always evaluated (Table 1). Using indirect immunofluorescence (IFL), earlier studies identified antibodies to sarcolemmal and myofibrillar antigens, but these were not strictly cardiac-specific, because they cross-reacted with skeletal muscle [25]. In addition, it remained unclear whether these antibodies were disease-specific for myocarditis/DCM, because control subjects with other cardiac diseases were not included [25].

View this table: [in this window] [in a new window]   Table 1 Frequency of heart autoantibodies in acute myocarditis and DCM

 
Antibodies against distinct mitochondrial antigens, the M7 [19,30], the adenine nucleotide translocator (ANT) [15] and the branched-chain -ketoacid dehydrogenase dihydrolipoyl transacylase (BCKD-E2) [26] and other respiratory chain enzymes [35] have also been detected. Mitochondrial antigens have generally been classified as non-organ-specific [2,4]. However, the heart specificity of the M7 antibodies was shown by absorption studies, whereas these were not performed with the ANT and the BCKD-E2 antibodies. Studies to rule out potential cross-reactivity with skeletal muscle are warranted. Experimentally induced affinity-purified anti-ANT antibodies cross-reacted with calcium-channel complex proteins of rat cardiac myocytes, induced enhancement of transmembrane calcium current, and produced calcium-dependent cell lysis in the absence of complement [15,36]. The authors suggested that such enhancing effect of the antibodies might lead to impaired function of the ANT, imbalance of energy delivery and demand within the myocyte, and subsequent cell death in vivo in patients. The presence of this mechanism of antibody-dependent cell lysis has not been shown using the antibodies present in patients’ sera.

Several groups have demonstrated antibodies against the β₁-adrenoceptor [10,16,27]. These antibodies induced sequestration and endocytosis of β₁-receptors predominantly dependent on the β₁-receptor kinase, and selectively inhibited isoproterenol-sensitive adenylate cyclase activity [27]. When analyzed in a functional test system of spontaneously beating neonatal rat myocytes, antibody-positive DCM sera [16] or the affinity-purified β₁-receptor antibodies [10] increased the beating frequency of isolated myocytes in vitro. β₁-blocking drugs inhibited the effect. These workers suggested that this antibody-mediated stimulation of the β₁-receptor observed in vitro could occur in vivo and account for the accelerated decline in ventricular systolic function in some myocarditis/DCM patients. The same group also showed that DCM sera contained antibodies directed against the second extracellular loop of human M2 muscarinic receptors [12]. A limitation of the work involving anti-receptor antibodies is that few disease controls have been studied. These receptors are not organ-specific cardiac autoantigens; in fact, their distribution is not restricted to the heart, and there are no cardiac-specific isoforms [37].

Using indirect IFL on human heart and absorption with relevant tissues, organ- and disease-specific antibodies of the IgG class were found in approximately one-third of myocarditis or DCM patients at presentation (Tables 1 and 2) [9,17]. The organ-specific antibodies produced a diffuse cytoplasmic staining of myocytes, but did not stain skeletal muscle. The organ-specific and cross-reactive patterns are illustrated in the original report [9]. Another group reported antibodies that gave a similar staining pattern on rat heart in 20% of DCM patients [18]. It is likely that the antibodies detected by IFL on human and on rat heart recognize the same organ-specific cardiac autoantigen(s). The frequency of the organ-specific cardiac antibodies found by IFL was higher in myocarditis or DCM than in control subjects with cardiac disease or in normal subjects (Table 2). Cardiac antibodies of the cross-reactive 1 type, which exhibited partial organ specificity for heart antigens by absorption, were also more frequently detected in DCM/myocarditis than in control subjects. Conversely, cardiac antibodies of the cross-reactive 2 type, which were entirely skeletal muscle cross-reactive by absorption, were found in similar proportions among groups (Table 2).

View this table: [in this window] [in a new window]   Table 2 Frequency of the cardiac antibodies detected by IFL in DCM, myocarditis, healthy relatives and control subjects

 
Two of the autoantigens recognized by the cardiac autoantibodies detected by IFL were identified as and β myosin heavy chain isoforms by Western blotting [11]. Several bands due to yet unknown antigens were also detected in DCM-positive sera [11]. The β chain is expressed in slow skeletal and ventricular myosin, and is therefore only partially cardiac-specific. The isoform is expressed solely within the atrial myocardium. Antibodies to this molecule represent truly organ-specific cardiac autoantibodies [11]. The identification of and β heavy chains of myosin as relevant autoantigens in DCM patients parallels what is observed in the experimental model of autoimmune myocarditis/DCM [38,39] and in human myocarditis [17,18,20]. The finding of anti- and -β myosin antibodies of the IgG class in DCM patients has been independently confirmed using Western blotting [13] or enzyme-linked immunosorbent assay (ELISA) [8,14,23,31]; a recent study has suggested that the disease-specific anti-myosin antibodies in DCM sera are mainly of the IgG3 subclass [31].

	3. Cardiac-specific antibodies as predictors of progression to myocarditis/DCM in symptom-free family members

Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 
Organ-specific autoimmune diseases occur as a result of genetic predisposition and environmental influence [4,40]. Genetic susceptibility to autoimmunity is responsible for the fact that autoantibodies are detected in family members even years before the development of disease [2,4]. DCM is familial in at least 25% of cases, and 9–21% of asymptomatic relatives have mild left ventricular enlargement associated with preserved systolic function, which may indicate early disease [5,6]. To identify symptom-free relatives at potential risk, the frequency of the organ-specific cardiac antibodies detected by IFL was assessed among DCM patients from both familial and non-familial pedigrees and their symptom-free relatives [24]. The frequency of cardiac antibodies was higher among DCM patients and their relatives than in normal subjects (Table 2). Antibody-positive relatives were younger and had larger mean echocardiographic left-ventricular end-systolic dimension and reduced % fractional shortening compared to antibody-negative relatives [24]. These findings suggested that the antibody could be associated with early disease. Short-term follow-up (median 33 months) has been reported in 108 symptom-free relatives who had a positive antibody test and/or mild echocardiographic abnormalities at baseline [41]. The finding of cardiac antibodies at baseline was more common among relatives who progressed compared to those who did not. These data suggested that cardiac antibodies might identify symptom-free relatives at risk of progression to DCM [41]. Extended follow-up is in keeping with this interpretation [42].

	4. Cardiac-specific antibodies in myocarditis/DCM: clinical correlates and potential functional role

Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 
The presence of organ- and disease-specific cardiac antibodies of the IgG class against myosin and other unknown antigens in myocarditis/DCM patients supports the involvement of autoimmunity in at least one-third of patients [2,9,13,18,22,23]. These antibodies were associated with shorter duration and minor severity of symptoms at diagnosis [9,29], as well as with greater exercise capacity [21]. In many patients who were antibody-positive at diagnosis, these markers became undetectable at follow-up [21]. These findings strongly suggest that cardiac-specific autoantibodies are early markers. The absence of antibodies at diagnosis in two-thirds of patients could indicate that cell-mediated mechanisms are predominant, and/or that autoimmunity is not involved; since the pre-clinical stage in DCM may be prolonged, it might also relate to reduction of antibody levels with disease progression [21]. These findings have been obtained using different techniques, all standardized and widely used for autoimmune serology studies, i.e. IFL [9,14,24], ELISA [14] and immunoblotting [11], and have been confirmed by several groups [8,13,18,23]. The low frequency of cardiac-specific antibodies in control patients with heart dysfunction not due to myocarditis/DCM [9,14,24] and the decrease in antibody titers in advanced DCM [21,29] also point out that these markers are not epiphenomena associated with tissue necrosis of various causes, but represent specific markers of immune pathogenesis. The role of inflammatory cytokines (e.g. the IL-2/sIL-2R system) as markers of T-lymphocyte activation in immune-mediated myocarditis/DCM and its relation to cardiac autoantibodies is a controversial issue [8,29]. In particular, some authors [8] found that high-titer anti-β₁-receptor antibodies were more common among DCM patients with abnormal sIL-2R serum levels. Others found no association between the cardiac-specific autoantibodies found by IFL and the anti--myosin antibodies detected by ELISA and sIL-2R levels [29]. sIL-2R may be related to distinct autoantibody specificity, e.g. in Graves’ disease, high sIL-2R was associated with anti-TSH receptor autoantibodies, but was unrelated to the autoantibodies to intracellular antigens (anti-microsomal and anti-thyroglobulin) [43]. The same may apply to DCM, high sIL-2R being present in association with antibodies to extracellular, e.g. the anti-β₁-receptor, rather than intracellular antigens, e.g. -myosin and the other cardiac-specific antigens involved in the IFL reaction [29]. The cardiac-specific autoantibodies found by IFL and the anti--myosin antibodies detected by ELISA were found in similar proportions of patients with DCM and with biopsy-proven myocarditis according to the Dallas criteria, included in the Myocarditis Treatment Trial, suggesting that conventional histology does not distinguish between patients with and without an ongoing immune-mediated process in myocarditis/DCM [17]. The Myocarditis Treatment Trial failed to show an improvement in survival in biopsy-proven myocarditis with immunosuppressive therapy [44]; however, no immunohistochemical or serological markers (e.g. increased HLA expression on endomyocardial biopsy and/or detection of cardiac-specific autoantibodies in serum in the absence of viral genome in myocardial tissue) were used to identify those patients with immune-mediated pathogenesis in whom immunosuppression could have been beneficial [44]. Interestingly, a recent randomized, placebo control study in DCM patients with HLA up-regulation on endomyocardial biopsy showed long-term benefit with immunosuppressive treatment [45]. Myocarditis/DCM patients with cardiac-specific autoantibodies should also be included in future trials of immunosuppressive therapy.

Myosin fulfilled the expected criteria for organ-specific autoimmunity, in that immunization with cardiac, but not skeletal myosin reproduced, in susceptible mouse strains, the human disease phenotype of DCM [38,39], whereas this requirement has not yet been met by other autoantigens proposed [10,12,15,19]. In addition, -myosin is entirely cardiac-specific and is only expressed in the myocardium; again, this does not apply to other antigens so far reported [10,12]. Altogether, the evidence available strongly indicates that myosin is a target autoantigen in myocarditis/DCM. However, autoimmune diseases are often polyclonal, with the production of autoantibodies to different autoantigens [4]. Some of these autoantigens are involved earlier in disease and are more closely related to primary pathogenetic events compared to those that play a role in secondary immunopathogenesis [4]. Both experimental [2,3] and clinical evidence [9–12,15,16,18,19] exists to indicate that this also applies to myocarditis/DCM. Myosin is an intracellular protein, and thus there are two major hypotheses, which may be not mutually exclusive, to explain the interruption of tolerance to this autoantigen. These include molecular mimicry, since cross-reactive epitopes between cardiac myosin and infectious agents have been found, and myocyte necrosis due to viral infection or other tissue insults [46–48]. Both mechanisms would explain the association of viral infection with autoimmune myocarditis/DCM [46–48]. Infection with Coxsackie B3 (CB3) virus triggers antimyosin reactivity and autoimmune myocarditis in many mouse strains, and immunization with cardiac myosin induces disease in the same susceptible strains [2,3,38,39]. In some strains, such as Balb/c mice, CB3 virus-induced or myosin-induced myocarditis is T-cell-mediated [39], whereas in other strains, such as DBA/2 mice, it is an antibody-mediated disease [49]. The same may apply to humans, so that the antimyosin antibodies may be directly pathogenic in some [20], but not all patients with myocarditis/DCM [21], according to different immunogenetic backgrounds, isotype and/or subclass specificity of these antibodies [49,31].

In relation to the proposed functional role of antibodies not against myosin, e.g. the anti-receptor [10,12,16,27] and anti-mitochondrial antibodies [15,19,26,30,35] in man, passive transfer of the myocarditis/DCM phenotype to genetically susceptible animals by antibody-positive patients’ sera would provide conclusive evidence for antibody-mediated pathogenesis. Non-antigen-specific IgG adsorption has recently been used in DCM patients with high-titer antibodies to the β₁-receptor, and it has been claimed that it has beneficial clinical effects, accompanied by undetectable antibody titers during follow-up [50]. This does not imply a direct pathogenic effect of the anti-β₁-receptor antibodies. The adsorption technique used was non-antigen-specific; in addition, in antibody-mediated disorders, the antibody titers rise again at the end of plasmapheresis. However, it may be that this technique has a favorable immunomodulatory/immunosuppressive effect; randomized studies are warranted. This does not undermine the possible role of any of the antibodies described (Table 2) as predictive markers. In keeping with this view, mid-term follow-up suggests that positive antibody status by IFL at baseline may identify relatives at risk of myocarditis/DCM [41,42]. Extended follow-up will better define predictive accuracy of the IFL test and a possible role for early preventative therapy, e.g. immunosuppression. It is unknown whether the antibodies not detected by IFL will be independent or additional predictors. Subjects classified as negative for one antibody may be positive for another, and combined testing may be advantageous. To this end, standardization of nomenclature and protocols for antibody detection and exchange of sera among laboratories currently assessing the individual antibodies will be useful.

In conclusion, several groups have shown that a subset of patients with myocarditis/idiopathic DCM and of their symptom-free relatives have circulating heart-reactive autoantibodies. These autoantibodies are directed against multiple antigens, some of which are strictly expressed in the myocardium (e.g. organ-specific for the heart), others are expressed in heart and skeletal muscle (e.g. muscle-specific). Distinct autoantibodies also have different prevalence in disease and normal control subjects (e.g. by IFL, the organ-specific antibodies are disease-specific for DCM, some of the muscle-specific antibodies are not). Different antibody techniques detect one (e.g. ELISA for myosin or for anti-receptor antibodies) or more antibody specificities (e.g. indirect IFL), thus they cannot be used interchangeably as screening tools. Antibody frequency in DCM vs. control subjects is expected to be different using distinct techniques; at present, it is unknown whether the same subset (30–40%) of patients produce more than one antibody or if different patient groups develop autoimmunity to different antigens. Antibodies of the IgG class which are shown to be cardiac and disease-specific for myocarditis/DCM can be used as reliable markers of autoimmune pathogenesis for identifying patients in whom immunosuppression and/or immunomodulation therapy may be beneficial and their relatives at risk. Some of these autoantibodies may also have a functional role in patients, as suggested by in vitro observations, but further work is needed to clarify this important issue.

	Acknowledgements

 
Dr Caforio is supported by the Veneto Region (Venice, Italy, years 2000–2002) and the MURST (Rome, Italy, years 2000–2001) Projects on Myocarditis.

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Top Abstract 1. Introduction 2. Circulating cardiac... 3. Cardiac-specific antibodies... 4. Cardiac-specific antibodies... References

 

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