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European Heart Journal Supplements (2002) 4 (Supplement I), I73–I80
Diagnosis and treatment of patients with virus
induced inflammatory cardiomyopathy
U. Kühl1, M. Pauschinger1, M. Noutsias1, J.-F. Kapp2 and H.-P. Schultheiss1
1Department
of Cardiology and Pneumonology, Medical Clinic II, Department of Cardiology, University Hospital
Benjamin Franklin, Free University of Berlin, and 2Schering AG, Spezial Therapeutika, Berlin, Germany
cardiomyo-pathy by differentiating the disease entity in
subgroups of virus positive and virus negative patients with or
without cardiac inflammation. This may not only contribute
toward improving our understanding of underlying
pathological mechanisms, but ultimately may also assist in
developing
specific
immunomodulatory
treatments.
Preliminary results from ongoing treatment trials suggest that
specific antiviral or anti-inflammatory treatment strategies are
successful in patients who have been carefully selected and
characterized according to biopsy-based diagnostic criteria.
(Eur Heart J Supplements 2002; 4 (Suppl I): I73–I80)
© 2002 The European Society of Cardiology
Introduction
initial infection, and than finally to progressive dilatation
after resolution or amelioration of the immune injury[7].
Chronic viral infection of the myocardium has been
detected in patients clinically presenting with myocarditis
and DCM. Thus, although viruses are classically regarded
as agents of self-limiting infections, a considerable body of
evidence implicates them in the aetiology of chronic
diseases, including DCM[8–10].
The diagnosis or exclusion of virus-induced inflammatory cardiomyopathy depends on accurate analysis of
endomyocardial biopsies, and confusion in diagnosis and
subsequent errors in therapy are particularly likely if
inadequate diagnostic tools are employed. Even with the use
of adequate diagnostic methods, it is difficult to make
decisions regarding specific therapeutic strategies because
of overlapping phases of the disease. Nevertheless, and in
spite of some as yet unresolved shortcomings of the
diagnostic procedures (e.g. sampling error), a rational
decision regarding specific therapy requires the use of all
currently available diagnostic tools.
Idiopathic dilated cardiomyopathy (DCM) is a serious
disorder and is the most common cause of heart failure in
young patients. Its prevalence in the U.S.A. is 36 cases per
1 million, being responsible for 25% of the more than
750,000 cases of heart failure reported and for
approximately 250,000 deaths. The long-term outcome of
approximately 50% of patients is terminal heart failure
requiring cardiac transplantation[1,2]. A genetic origin for
DCM has been reported in up to 25% of cases but the
majority are sporadic, and a viral or immune pathogenesis
is suspected in approximately 20–30% of idiopathic
DCM[3–6]. Virus-induced myocarditis may progress to an
autoimmune phase after resolution or amelioration of the
Correspondence: Uwe Kühl, PhD, University Hospital Benjamin
Franklin, Department of Cardiology and Pneumonology, Free
University of Berlin, Hindenburgdamm 30, D-12200 Berlin,
Germany.
1520-765X/02/0I0073 + 08 $35.00/0
Key Words: Inflammatory cardiomyopathy, viral heart
disease, diagnosis, treatment, immunosuppression, interferon
© 2002 The European Society of Cardiology
Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 9, 2014
Chronic viral induced inflammatory cardiomyopathy causes
progression of left ventricular dysfunction and is an important
cause of dilated cardiomyopathy. Despite of the progress made
in heart failure therapy, mortality of dilated cardiomyopathy is
still 10% per year. Current heart failure therapy is symptomatic
and does not impact on the specific underlying pathogenic
mechanisms. Thus, specific treatment strategies that are
directed against the underlying pathogenetic causes are
required if myocarditis and its sequela, namely inflammatory
cardiomyopathy, are to be successfully treated. Because
histological and, especially, clinical diagnosis is fraught with
numerous problems, an aetiological classification based on
histology, immunohistochemistry and molecular biology is
favourable, particularly in view of the improvements in
methods made in recent years. The combination of these
diagnostic techni-ques allows a new classification of dilated
I74
U. Kühl et al.
Current heart failure therapy is symptomatic and does not
impact on the specific underlying pathogenic mechanisms.
Progression of left ventricular dysfunction therefore cannot
be halted by conventional heart failure therapies. Thus,
specific treatment strategies that are directed against the
underlying pathogenetic causes are required if myocarditis
and its sequela, namely inflammatory cardiomyopathy, are
to be successfully treated.
Pathogenetic mechanisms in
inflammatory cardiomyopathy
Diagnosis of inflammatory
cardiomyopathy
Histological analysis
Myocardial inflammation is defined by the presence of
infiltrating lymphocytes, either with (active myocarditis) or
without (borderline myocarditis) myocyte necrosis.
Direct viral infection
Myocardial cell death
(Auto-) Immune response
Inflammation and cell dysfunction
Cellular
immunity
Humoral
immunity
Immune
modulation
Viral
persistence
T-lymphocytes
Macrophages
NK-cells
Heart reactive
antibodies
Cytokines
TNF-α, IFN,
Il-1, Il-2, Il-6
Coxsackie virus
Adenovirus
Viral replication
Immunosuppression
Immunoadsorption
Immunomodulatory therapy
Figure 1 Pathogenesis of virus-induced inflammatory cardiomyopathy.
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
Anti-viral treatment
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Myocardial damage may occur during several stages of
virus-induced cardiomyopathy (Fig. 1). The acute phase
begins with myocardial cell infection and viral replication,
culminating in cell lysis caused by virus. Early defence
mechanisms include a cellular immune response that
prevents further virus spreading and results in virus
clearance. This is achieved by production of antiviral
cytokines and elimination of virus-infected myocardial cells
through cytokine-activated macrophages and natural killer
cells, perforin mediated cell cytolysis (cytotoxic T lymphocytes) and induction of apoptosis[11,12]. Thus, both the viral
pathogen itself and the protective antiviral immune response
may produce irreversible loss of infected myocardial cells,
thereby contributing to irreversible damage of the
myocardium, long-term remodelling and progression of
heart failure. Successful virus clearance and resolution of
the inflammatory process therefore results in persistent
sequelae.
If there is no history of virus-induced disease, then the
observed clinical outcome is referred to as DCM. Persistent
T-cell activation, induced by intrinsic myocardial antigens
that cross-react with viral peptides (molecular mimicry),
may induce an inflammatory process that is not terminated
and escapes regular control mechanisms[12] (see the review
by Afanasyeva and Rose, in the present supplement).
Resulting immune-mediated injury may further increase
ventricular dysfunction. The pathogenetic mechanisms that
are involved are poorly understood, but the first encounter
with antigens may set the stage for later harmful
autoimmune processes, when antigen-specific and antigen
non-specific signals are presented to the immune system.
For example, these signalling molecules include
costimulatory cell surface markers such as CD28 or CD40,
their ligands (i.e. B7 or CD154), and soluble mediators such
as interleukin (IL)-1, tumour necrosis factor-alpha, IL-12,
interferon (IFN)-gamma, IL-4 and IL-13, all of which may
play important roles in orchestrating the later adaptive
immune response.
Diagnosis and treatment of virus-induced inflammatory cardiomyopathy
I75
Clinical diagnosis
Myocarditis/dilated cardiomyopathy
(n=658)
Immunohistology
Histology
Lympocytic
infiltration
(n=37)
No cellular
infiltration
(n=605)
Positive
(n=327)
Negative
(n=331)
Active
myocarditis
(2·4%)
Borderline
myocarditis
(5·6%)
No
myocarditis
(92%)
Inflammatory
cardiomyopathy
(49·7%)
No myocarditis
DCM
(50·3%)
Figure 2 Histological and immunohistological analysis of inflammatory cardiomyopathy.
Histologically, the diagnosis of a chronic inflammatory
process is difficult to establish by light microscopy because
of the often sparse or focally distributed cellular infiltrates,
which may easily be missed by sampling error. Moreover, in
haematoxilin and eosin stained sections, it is difficult if not
impossible to differentiate unequivocally non-inflammatory
cells (e.g. fibroblasts or pericytes) from infiltrating immune
effector cells. Thus, misinterpretation of interstitial cells
may lead to an overestimation or underestimation of the
degree of the inflammatory process within the myocardium,
in the absence of knowledge of the activity and cellular type
of infiltration. As a result of low histological sensitivity, no
myocardial inflammatory process is seen in the majority of
biopsies from patients with DCM (Fig. 2). Thus, it is
generally accepted that histological analysis does not
contribute important information to the diagnosis of
inflammatory cardiomyopathy.
is whether the relative low cell number (which is often seen in
the myocardium of DCM patients) can be considered a marker
for ongoing immunological processes that cause progression
of the disease. Because long-term clinical complaints and
outcome of patients usually do not correlate with the number
of infiltrating cells, both subtype of infiltrating cells and
detection of an even low-grade inflammatory processes spread
within the entire myocardium are of more importance than the
number of infiltrating lymphocytes. Using subtype-specific
antibodies, immunohistochemical analysis revealed the
presence of cytotoxic lymphocytes and natural killer cells in
chronic inflamed myocardium (see the review by Noutsias et
al., in the present supplement)[11,13].
Immunohistochemical analysis
of inflammatory cells
In order to gain additional information on the myocardial
immune process, we introduced an expanded panel of
diagnostic immune markers (i.e. cellular adhesion
molecules) into the immunohistological diagnosis of
myocarditis[14–16]. The expression patterns of cellular
adhesion molecules differ substantially both in terms of
quantity and quality. CD29 expression is not confined to
endothelial and interstitial cells, but is also expressed within
the extracellular matrix, exhibiting the greatest immunoreactivity of the spectrum of investigated adhesion
receptors. Furthermore, whereas HLA, intercellular
adhesion molecule-1, CD58 and CD29 are distributed
homogenously within DCM biopsies, vascular cell adhesion
molecule-1 and the selectins are confined to single postcapillary venules (Fig. 3)[17].
In order to obtain more specific diagnostic and prognostic
information, immunohistological techniques have been
introduced to identify and characterize mononuclear cellular
infiltrates in myocardial biopsies of patients with DCM.
Although myocarditis is detected in fewer than 2% of
endomyocardial biopsies from patients with DCM on
histological analysis (4·5% of biopsies are consistent with the
diagnosis of borderline myocarditis), a myocardial
inflammatory process is detected in 43% of endomyocardial
biopsies when immunohistochemical staining procedures are
employed (Fig. 2). One of the key questions still under debate
Immunohistochemical analysis
of adhesion molecules
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
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Myocytolysis
(n=16)
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U. Kühl et al.
Table 1 Immunohistological definition of inflammatory cardiomyopathy
Parameter
Details
Infiltrating lymphocytes (CD2+, CD3+, CD4+,CD8+)
Adhesion molecules (HLA I/II, CD54, CD59, VCAM-1)
>7·0 cells . mm – 2
Enhanced expression on interstitial cells and vascular endothelium
HLA = human leucocyte antigen; VCAM = vascular cell adhesion molecule.
Myocardial expressions of most adhesion molecules
correlate with the number of inflammatory infiltrates and are
enhanced within the entire myocardium if the mean
lymphocyte number exceeds 2·0 CD3+ cells per high-power
microscopic field (at magnification ×400), even in cases with
focal lymphocytic infiltration. Combining enhanced
expression of adhesion molecules on interstitial cells and the
vascular endothelium with identification, quantification and
subtyping of cellular infiltration improves diagnostic yield
and reduces sampling error when compared with histological
analysis (Fig. 2)[5,17]. Therefore, using immunohistochemical
analysis, we defined myocardial inflammation as the
presence of more than 2·0 infiltrating T lymphocytes per
high-power field (corresponding to 7·0 cells/mm2) in addition
to an enhanced expression of adhesion molecules on
interstitial cells or the vascular endothelium (Table 1)[5,17,18].
Using digital imaging analysis, an observer-independent,
standardized quantification of immunohistochemically
marked infiltrates and adhesion molecules in endomyocardial biopsies is possible[19,20]. Moreover, digital
imaging analysis enables the objective and quantitative
evaluation of parameters that are not accessible via visual
assessment (e.g. heart area, and quantitative muscle
evaluation of cellular adhesion molecule immunoreactivity). This may ultimately permit us to overcome the
differences reported in evaluation of endomyocardial
biopsies between different laboratories[19,20].
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
Virus analysis: detection of viral
genome by nested PCR
Even positive serological tests cannot prove virus infection
of the myocardium. A positive diagnosis of virus infection
of the myocardium is only confirmed by analysis of
endomyocardial biopsies using molecular biology methods
such as in situ hybridization and polymerase chain reaction
(PCR). Among 900 consecutive patients who underwent
endomyocardial biopsy in our department in order to
elucidate the origin of their persistent left ventricular
dysfunction in the absence of apparent causes, enteroviral
and adenoviral genomes were detected in 15% and 7%,
respectively. For the virus analysis, primer pairs were
designed to amplify the genomic sequence of adenoviruses
that encodes the hexon protein region (5′-untranslated
region). The adenovirus-specific primers were designed to
detect all adenovirus serotypes while the enterovirus
primers detect most enterovirus types[10,21]. Total RNA and
genomic/viral DNA were isolated simultaneously from
biopsy specimens (Fig. 4). Beta-actin primers were used as
internal controls for the isolation of intact DNA and RNA.
Adenovirus type 5 DNA isolated from infected cells and a
cloned cDCA of coxsackievirus B3 83, were used as
positive viral controls for PCR analysis, as was recently
reported[10,21].
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Figure 3 Immunohistochemical staining for adhesion molecules in endomyocardial biopsies.
Diagnosis and treatment of virus-induced inflammatory cardiomyopathy
I77
Treatment of patients with virusinduced inflammatory cardiomyopathy
Immunosuppressive and
immunomodulatory therapy
Biopsy derived diagnosis and
classification of viral heart disease
Because pathological/anatomical and, especially, clinical
diagnosis is fraught with numerous problems, an aetiological
classification based on histology, immunohistochemistry
and molecular biology is favourable, particularly in view of
the improvements in methods made in recent years. Such a
classification may not only contribute toward improving our
understanding of underlying pathological mechanisms, but
ultimately may also assist in developing specific
immunomodulatory treatments.
Current standards for diagnostic procedures require
routine histological staining, which allows analysis of
histomorphological changes and may depict myocytolysis
(active myocarditis). For analysis of chronic inflammatory
processes, however, immunohistological methods are
recommended. Detection of viral genome and replication
requires molecular biological techniques such as
polymerase chain reaction (PCR) and in situ hybridization.
According to the data obtained using these methods,
clinically suspected DCM can be subclassified to different
disease entities (Fig. 2)[22,23]. Further information is derived
from cytokine analysis of patients. Preliminary data suggest
that dysregulation of the host defence mechanisms against
viral infections, associated with an inappropriate T-helper2-like immune response that lacks antiviral IFN-gamma,
favours enteroviral RNA persistence and subsequent
progression of left ventricular dysfunction (Kühl et al.,
unpublished data). A rise in pro-inflammatory antiviral
T-helper-1 cytokines such as IFN-gamma appears to be
necessary to control and eliminate viral RNA, thereby
limiting progression of the disease.
Potential therapeutic efficacy of immunosuppressive
therapy was suggested by previous uncontrolled
studies[27–32]. However, it has not proved efficacious in
previous randomized trials in patients with recent-onset
cardiomyopathy because spontaneous recovery occurred
both in patients treated with conventional therapy and in
those treated with anti-inflammatory (methylprednisolone,
cyclosporine A, intravenous immune globulin)
therapy[33–35]. Selection of patients on histological rather
than immunohistological and molecular biological
diagnostic criteria, and failure to account for the high
spontaneous healing rate of recent-onset myocarditis may
therefore account for those findings[36–38]. Moreover,
Frustaci et al. reported that most patients who did not
respond to immunosuppressive therapy were enteroviruspositive in a retrospective PCR analysis, demonstrating
virus-induced myocyte damage during immunosuppressive
treatment (see the review by Frustaci et al., in the present
supplement). In order to avoid such diagnostic
shortcomings future trials must focus on reliable diagnostic
criteria, which should include histological and
immunohistological evaluation of myocardial inflammatory
processes, as well as molecular biological analysis of
myocardial virus infection (Fig. 5).
Immunosuppressive treatment regimens include
corticosteroids, azathioprine or cyclosporin A. Alphamethylprednisolone is generally initially given at a rate of
1 mg . kg – 1 body weight (for children 1–2 mg . kg – 1) for
4 weeks, after which the dosage is tapered biweekly in
increments of 8–12 mg until a maintenance dose of 12 mg
is reached. The treatment should last for 6 months. In cases
of persistent inflammation (35–40% of patients are affected
by this), azathioprine may be administered in addition to
low-dose corticosteroid. However, this appears to be
effective only if a sufficient level of immunosuppression is
achieved, which is signalled by a reduction in peripheral
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
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Figure 4 Molecular biological analysis (polymerase
chain reaction [PCR]) of enteroviral RNA in
endomyocardial biopsies. Lanes 1 and 7, molecular
weight markers; lane 2, positive control; lanes 3 and 4,
negative biopsy; lanes 5 and 6, enterovirus RNA-positive
biopsies.
In spite of progress made in heart failure therapy since the
introduction of angiotensin-converting enzyme inhibitors,
beta-blockers, spironolactone and amiodarone/implantable
cardiovertor–defibrillator treatment, mortality associated
with DCM is still 10%/year[24–26]. Current heart failure
therapy is symptomatic and does not impact on specific
underlying pathogenic mechanisms. Progression of left
ventricular dysfunction therefore cannot be halted by
therapy with digitalis, diuretics, angiotensin-converting
enzyme inhibitors and beta-blocking agents. Thus, specific
treatment strategies that are directed against the underlying
pathogenetic causes are required if myocarditis and its
sequela, namely inflammatory cardiomyopathy, are to be
successfully treated.
I78
U. Kühl et al.
Acute viral myocarditis
Cardiomyopathy
Non-inflammatory
cardiomyopathy
No viral persistence
Inflammatory
cardiomyopathy
No viral persistence
Viral persistence
Immunosuppression
Antiviral therapy
Figure 5 Biopsy-derived diagnosis and classification of inflammatory cardiomyopathy.
lymphocytes levels to around 1000/µl. Provided that
adequate molecular biology and immunohistochemical
characterization of patients is conducted, both clinical and
haemodynamic improvement can be achieved in 65% of
cases with immunosuppressive treatment (Fig. 6).
Antiviral therapy with interferon-beta
Three types of IFNs have been identified, which differ both
in structure and in antigenic properties; IFN-alpha is
derived from leucocytes, IFN-beta from fibroblasts and
IFN-gamma from lymphocytes. The important role played
by the IFNs as a natural defence mechanism against viruses
is documented by three lines of experimental and clinical
evidence: in many viral infections a strong correlation has
been established between IFN production and natural
recovery; inhibition of production or action of IFN
enhances the severity of infection; and treatment with IFN
protects against viral infection. The antiviral effect is
independent of virus type and results in an intracellular
block of the viral replication cycle. IFNs increase resistance
toward viral replication, even in cells that neighbour
infected cells but have not yet been infected. Because
effective concentrations of IFN-beta can be attained in vivo,
IFN-beta may become useful in the treatment of patients
with viral cardiomyopathy.
Analyzing virus positive patients in a phase II pilot study,
we demonstrated that patients with persistence of viral
genomes and left ventricular dysfunction benefit from
antiviral treatment with IFN-beta (manuscript submitted).
Before IFN-beta treatment, clinical complaints and
haemodynamic course did not improve and left ventricular
diameters slowly increased, in spite of constant heart failure
medication before IFN-beta treatment and during therapy.
After 6 months of IFN-beta treatment, viral genomes were
Eur Heart J Supplements, Vol. 4 (Suppl I) December 2002
no longer detectable in the biopsies of all treated patients,
indicating that this treatment had led to a complete
elimination of both adenoviral and enteroviral genomes.
Virus clearance was accompanied by a reduction in clinical
complaints such as angina pectoris, dyspnoea, palpitations
and fatigue, resulting in improvement in New York Heart
Association functional class. This clinical improvement was
associated with a significant increase in left ventricular
ejection fraction and a decrease in left ventricular diameters.
Because viral genomes were no longer detectable in any
patient after completion of IFN-beta treatment, our data
suggest that the beneficial clinical effect of IFN-beta is
based on elimination of cardiotropic viral genomes, which
occurred even in DCM patients with a long history of
disease.
Conclusion
Myocarditis is caused by a wide variety of pathological
conditions, in particular viral infections, and often precedes
the development of DCM. The infecting virus initiates the
disease process and then may persist as an insidious
molecular pathogen, causing ongoing cardiac damage (viral
heart disease). If the host immune system can effectively
clear the viral infection, then cardiac inflammation often
resolves. Dysregulation of the immune response, however,
may result in a persisting pathological (auto)immune
process (chronic myocarditis/inflammatory cardiomyopathy), causing progression of left ventricular dysfunction. Cytokines play a critical role in the development
of viral persistence and chronic inflammation. Because
pathological/anatomical and, especially, clinical diagnosis
is fraught with numerous problems, the current standard of
biopsy-based diagnostic procedures means that routine
histological staining, which allows analysis of histo-
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Symptomatic therapy
Diagnosis and treatment of virus-induced inflammatory cardiomyopathy
I79
(a)
EF>55%
EF(%)
30%>EF<55%
EF(%)
90
EF(%)
EF<30%
60
70
80
50
60
70
40
30
50
20
40
60
10
Before
Treatment
P < 0·001
After
Before
After
Treatment
0
P < 0·05
Before
After
Treatment
(b)
NYHA
I
n=2
11
II
n=13
14
III
n=16
15
IV
n=10
1
Before
After
Treatment
morphologic changes and may demonstrate myocytolysis
(active myocarditis), is quite appropriate. For the analysis of
chronic inflammatory processes, immunohistological
methods are recommended. Detection of viral genome and
replication requires molecular biology techniques such as
PCR and in situ hybridization. The aetiological classification thus obtained may not only contribute toward
improving our understanding of underlying pathological
mechanisms, but ultimately may also assist in developing
specific immunomodulatory treatments.
Preliminary results from ongoing treatment trials suggest
that specific antiviral or anti-inflammatory treatment
strategies are successful in patients who have been carefully
selected and characterized according to biopsy-based
diagnostic criteria. At present, the optimal timeframe for
starting antiviral or immunosuppressive therapy is
speculative because of lack of data. However, treatment
should certainly begin as early as possible and before the
emergence of serious ventricular dysfunction, because
complete normalization of ventricular function is unlikely
to be achieved once serious myocardial damage has
occurred.
Figure 6 (a) Haemodynamic improvement in patients with mild (left
ventricular ejection fraction [EF] >55%),
moderate (EF 30–55%) and severe (EF
<30%) left ventricular dysfunction during
immunosuppressive treatment (n = 41).
(b) Clinical improvement (in terms of
New York Heart Association [NYHA]
classification) of patients during immunosuppressive treatment (n = 41).
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