LECTURE
Is cardiomyopathy an autoimmune disease?
Michael Fu and Shinobu Matsui1
Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden, 1Department of Cardiology
Kanazawa Medical University, Kanazawa, Japan(Received for publication on September 1, 2002)

Abstract. Idiopathic dilated cardiomyopathy (DCM) is one of the leading causes of severe heart
failure and the most common cause of heart transplantation due to its ventricular dilatations and contractile dysfuntions. Twenty percent of DCM is in the familiar form and the rest is sporadic. The clinicalimpact of DCM is far greater than its position in epidemiological terms. Despite recent improvementsin therapy, both incidence and mortality are still very high. The main problem is its heterogeneous
etiology. So far, three factors have been identiﬁed to be potentially important: enteroviral infection,
immune mechanism and genetic factors. During the last 10 years there have been many investigations
showing distinct autoantibodies or other immune factors in heterogeneous subsets of DCM which havecontributed supportive and confounding evidence to the hypothesis that multiple autoimmune mechanisms are involved in DCM. Accumulated evidence hitherto demonstrated a variety of circulating
autoantibodies in the sera of patients with DCM including antireceptor autoantibodies, myosin and
ADP/ATP translocator protein, etc. Data available from both in-vitro and in-vivo studies of antireceptor autoantibodies as well as from other autoantibodies and autoreactive lymphocytes demonstrated clearly that a subgroup of DCM is autoimmunity-mediated. This is understandable because
DCM is heterogeneous, implying that different subgroups of DCM may have different pathogeneses. It
may be practical in the future to separate ‘‘autoimmune cardiomyopathy’’ from other ‘‘idiopathic’’
DCM. (Keio J Med 51 (4): 208–212, December 2002)
Key words: autoimmunity, cardiomyopathy, receptors, antibody

Idiopathic dilated cardiomyopathy (DCM) is one of
the leading causes of severe heart failure and the mostcommon cause of heart transplantation due to its ventricular dilatations and contractile dysfuntions. Twenty
percent of DCM is in the familiar form and the rest is
sporadic. The clinical impact of DCM is far greater thanits position in epidemiological terms. Despite recent
improvements in therapy, both incidence and mortality
are still very high. The main problem is its heterogeneous etiology. So far, three factors have been identiﬁed to be potentially important: enteroviral infection,
immune mechanism and genetic factors. It is plausiblethat a subgroup of DCM is a post-infectious autoimmune disease, especially with individuals with genetic
susceptibility.

Do We Have Evidence Supporting Cardiomyopathy as
An Autoimmune Disease?
Evidence from clinical ﬁndings indicating existence ofautoimmunity
During last 10 years there have been many investigations showing distinct autoantibodies or other immune factors in heterogeneous subsets of DCM whichhave contributed supportive and confounding evidence
to a hypothesis that multiple autoimmune mechanisms
are involved in DCM. In DCM and myocarditis, abnormalities in cell-mediated immunity have been clinicallydemonstrated by the ﬁndings of an altered lymphocyte
function, altered relative proportions of lymphocyte
subsets, an activated immune cytokine system, the in-

Reprint requests to: Dr. Michael LX Fu, Wallenberg Laboratory, Sahlgrenska University Hospital, SE-413 45 Göteborg, SWEDEN, Fax: 46 31
823762, e-mail: Michael.Fu@wlab.wall.gu.se
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Keio J Med 2002; 51 (4): 208–212

appropriate expression of the major histocompatibility
complex on cardiac tissue and expression of adhesion
molecles on cardiac myocytes.1–9 The relative contribution of cellular and humoral immune disturbances tothe pathogenesis of myocyte injury in various heartdiseases has not been determined.
Accumulated evidence hitherto demonstrated a variety of circulating autoantibodies in the sera of patients with DCM. The list can be long, notably including autoantibodies directed against the myosin,6,10–14
mitochondrial adenine nucleotide translocator andM7,15–18 the branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase (BCKD-E2),19 laminin,20 b-adrenoceptors,21–26 M2 muscarinic receptors,25–27 sarcolemmal Na-K-ATPase28 and heat shockprotein29 respectively.
Since Venter et al. reported autoantibodes against
b2-adrenoceptors in allergic rhinitis and asthma in
1980,30 there is a great amount of evidence available
describing autoantibodies against b1-adrenoceptors inpatients with DCM. Wallukat and Wollenberger foundin 1987 that the IgG fraction of patients with DCM wasable to display positive chronotropic effect on cultured
neonatal rat myocytes.22 By using the ligand bindingsof DCM sera on rat cardiac membranes, Limas et al.
demonstrated autoantibodies against b-adrenergic receptors in 40% of patients with DCM.31 Magnusson
et al., by using synthetic peptides corresponding to
the second extracellular loops of human b1- and b2adrenergic receptors as coated antigens in an enzymelinked immunosorbent assay (ELISA), found autoantibodies against b1-adrenergic receptor peptide in 31%
of patients with DCM but no autoantibodies against b2adrenergic receptor peptide.24 We have demonstrated
for the ﬁrst time that the sera from patients with DCM
recognized the M2 muscarinic receptor peptide (36–37%).25–27 Further study demonstrated that anti-M2
muscarinic receptor and b1-adrenoceptor autoantibodies have an almost identical spectrum of frequenciesof occurrence in patients with DCM despite different
geographical origins from Japan, China and Sweden.25–27,32 Moreover, anti-b1-adrenoceptor autoantibodies are mainly present in DCM but not in hypertension25 and valvular heart disease.33 On the contrary,autoantibodies against the a1 -adrenoceptors and AT1
receptors were demonstrated mainly in hypertension(64% and 44% of cases, respectively).34,35
Although it has been shown that anti-muscarinic receptors and b1-adrenoceptor autoantibodies are morecommon in DCM compared with other antireceptor
autoantibodies, it does not mean that these antireceptor
autoantibodies are only speciﬁc for DCM since there
are only limited data available from antibody screenings from other cardiovascular diseases and/or by use ofother autoantigens. Recently we have shown that, in

209

aortic banding- and adriamycin-treated rats, the frequencies and titers of autoantibodies to the muscarinic
receptor and b1-adrenoceptor were increased when
myocardial remodeling occurred, suggesting that cardiac remodeling itself, in two disparate models of cardiomyopathy, was able to trigger the genesis of antireceptor autoantibodies.36 Therefore anti-muscarinic
receptor and b1-adrenoceptor autoantibodies are possibly triggered by myocardial remodeling in patientswith DCM. This may explain why there are also antimuscarinic receptor and b1-autoantibodies adrenoceptor in about 40% of patients with chronic Chagas’ infection.37 But this does not rule out that anti-muscarinic
receptor and b1-adrenoceptor autoantibodies can bepathogenic and play an important role in the progression, instead of initiation, of cardiomyopathy and heart
failure, and as long as they are functionally active invivo and persist over a certain period they may contribute to the pathophysiology of the disease. For example, viral infection can induce myocardial damage which
in turn triggers antibody production which can escalate
to aggravate myocardial damage. It is worthwhile topoint out that antibody production may be triggered
due to myocardial injury secondary to ischemia becauseof alteration of self-antigens that are normally sequestered from the immune system. Therefore, whether
autoantibodies play an important role in the development of disease depends on the availability of sustained
antigen exposure, properties of autoantibodies in
immunological, biochemical and kinetic aspects andother genetic factors as well as subclasses in serum of
autoantibodies. Recently, Jahns et al. showed that anti
b1-adrenoceptor antibodies from six of eight patientswith DCM act as receptor-sensitizing agents whereas
two of eight acts as partial agonists,38 and Warraich
et al. showed that IgG3 is probably more important
than other subclasses in mediating DCM.39
Evidence from in-vitro studies
Low titers of autoantibodies, which can be part of
the normal immunologic repertoire, are not necessarily
pathogenic.32 Functional characterization of an antibody is the ﬁrst step toward deﬁning the role of theantibody in the development of disease. Wallukat et al.
demonstrated that the IgG fractions of patients with
DCM were able to increase the beating rate of myocytes.22,40 Limas et al. found that positive sera from
DCM were able to immunoprecipitate b-adrenergic
receptors and to inhibit adenylyl cyclase activity.31
Magnusson et al. demonstrated that puriﬁed autoantibodies can not only decrease the the binding sites but
also recognize the target receptors by both immunobloting and immunocytochemistry.24,41 Krause et al.
demonstrated that autoantibodies against b1-adrenergic

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receptors from DCM were able to increase the activityof cAMP-dependent protein kinase (PKA).42 Likewise,
we have demonstrated speciﬁc localization of muscarinic receptors in the human myocardium from DCM
using anti-M2 muscarinic receptor autoantibodies, thus
suggesting that autoantibodies can interact with theirtarget receptors in failing heart tissue. In addition, anti
b1 adrenergic receptor and M2 muscarinic receptor
autoantibodies from DCM patients displayed positive
and negative chronotropic effects respectively, whichwere resistent to desensitization, being different fromthe classical b-adrenergic receptor agonist isoprenaline
and the muscarinic receptor agonist carbachol which
can induce desensitization after the short a period oftime.41,43,44
Evidence from in vivo studies
According to the deﬁnition of autoimmune diseaseas suggested by Rose and Bona (1993),45 it is notenough to deﬁne DCM as an autoimmune diseasealthough our and others’ previous data have shown
functional activities of autoantibodies in vitro. Direct
evidence is still needed in vivo to make sure that cardiomyopathy can be reproduced in animals by autoimmunity, either by passive transfering of immune
components from patients with DCM to SCID (Severely Combined Immunodeﬁcieny) mice or by chronic
active immunization of animals with autoantigens.
Schwimmbeck et al. successfully transfered peripheral
blood leukocytes of patients with chronic myocarditis
into SCID mice that developed human cellular inﬁltrates of the myocardium and an impairment of the left
ventricular function.46 Another study from our laboratory showed that transfer of lymphocytes from patientswith DCM to SCID mice demonstrated induced unfavourable remodeling and increased myocardial ﬁbrosis.47
By use of active immunization with receptor peptide(s) during 1 year, it was shown that both groups of
rabbits immunized with either the b1-adrenoceptor
peptide or the M2 muscarinic receptor peptide displayed signiﬁcantly enlarged ventricles and thinnerwalls, as compared with the control group. When
immunization was performed using combined b1 andM2 receptor peptides, cardiac hypertrophy was seen.
Moreover, microscopic examinations of the rabbit
hearts from both immunized groups demonstrated
mainly degenerative changes.48–50 Recently, Iwata et al.
used a similar protocol but in only 6 months demonstrated myocardial hypertroph, b1-adrenoceptor
receptor desensitization, increased Gi protein and Gprotein-coupled receptor kinase-5 expression in association with myocyte disorganization and interstitial ﬁbrosis.51,52

Fu M and Matsui S: Autoimmunity in cardiomyopathy

Evidence from therapeutical approaches
Theoretically, autoimmune therapy should be aimed
at modulating the immune system to inhibit antibody
production and at blocking the active autoantibodies
of pathogenic importance. In order to restore normal
immune function, it necessitates elucidation of mechanisms for initiation, development and regulation of
autoimmunity including genetic factors, cytokines, heatshock proteins etc. Unfortunately this mechanism has
not been fully understood yet. Therefore current autoimmune therapy is focused more upon inhibiting antibody activity and elimination of antibodies. For example, Matsui et al. has shown that the b1-receptor blocker
bisoprolol was able to prevent autoimmune injury by
b1-receptor antibody.52
Immunoadsorption has been and still is a heated
topic. Several studies have demonstrated that immunoadsorption can improve cardiac functions.53–56 The
underlying mechanisms for favourable effects on cardiac function remain unsolved. It has been postulated
that antireceptor autoantibodies play an importantrole.52,53,57,58 Our data from antibody analyses of
immunoadsorption, however, demonstrated that elimination of antireceptor autoantibodies may be importantbut not the only explanation. A recent study by Felix
et al. showed that removal of circulating negative inotropic autoantibodies may contribute to the early beneﬁcial hemodynamic effect of immunoadsorption.59
However, the speciﬁc antigen(s) to these negative inotropic autoantibodies have not been clariﬁed. Anotherstudy by Staudt et al. demonstrated that immunoadsorption can ameliorate myocardial inﬂammation.56
The above therapeutic approaches add further weightto the hypothesis that cardiomyopathy is autoimmunitymediated.
A Subgroup of Cardiomyopathy Is
Autoimmune Disease Related
To summarize the data available from both in-vitro
and in-vivo studies of antireceptor autoantibodies aswell as from other autoantibodies and autoreactive
lymphocytes, it is evident that a subgroup of DCM is
autoimmunity-mediated. This is understandable because DCM is heterogeneous, implying that different
subgroups of DCM may have different pathogeneses. It
may be practical in the future to separate ‘‘autoimmune
cardiomyopathy’’ from other ‘‘idiopathic’’ DCM.
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