Review article: Medical intelligence | Published 2 October 2014, doi:10.4414/smw.2014.14010
Cite this as: Swiss Med Wkly. 2014;144:w14010
Viral myocarditis
Uwe Kühl, Heinz-Peter Schultheiss
Medizinische Klinik für Kardiologie und Pulmologie , Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Germany
Summary
The term myocarditis describes
inflammatory disorders of the heart muscle of varied infectious and
non-infectious origins. It can be caused by any kind of infection,
drugs, toxic substances, or be associated with autoimmune conditions.
Viruses are the main causes at least in developed countries. Acute
myocarditis most commonly results from an external inflammatory trigger
inducing the host immune response, which may range from minimally
transient response to fulminant overwhelming cellular infiltration. If
the immune system does not eliminate the infectious pathogen early on,
chronic infection develops with or without accompanying inflammation.
Post-infectious autoimmunity may persist despite effective virus
clearance.
Since the pathological conditions take
place at the cellular level, viral myocarditis and postinfectious
autoimmunity can be suggested but not diagnosed clinically. All clinical
methods including imaging techniques are misleading if infectious
agents are involved. Accurate diagnosis demands simultaneous histologic,
immunohistochemical and molecular biological workup of the tissue. If
the primary infectious or immune-mediated causes of the disease are
carefully defined by clinical and biopsy based tools, specific antiviral
treatment options in addition to basic symptomatic therapy are
available under certain conditions. These may allow a tailored
cause-specific treatment that improves symptoms and prognosis of
patients with acute and chronic disease.
Key words: myocarditis; virus; viral cardiomyopathy; heart failure; endothelial infection
Clinical presentation and diagnosis
In acute disease, sudden onset of
chest pain, dyspnoea, congestive heart failure with normal or enlarged
ventricular chambers, ventricular arrhythmias and abnormal ST-T segments
changes in the presence of elevated cardiac enzymes (CK/CKMB or TnT)
are highly suspicious for an acute viral myocarditis, if other acute
cardiac diseases with similar clinical presentation have been excluded.
Without angiography accompanying acute viral myocarditis cannot be
clinically distinguished from an acute coronary syndrome.
In the subacute and chronic phase
after two to four weeks most clinical characteristics suggestive of
acute myocarditis have been resolved. Patients present with
uncharacteristic complaints such as persisting angina, dyspnoea,
fatigue, reduced physical ability, or arrhythmias in the presence of a
preserved or impaired systolic or diastolic ventricular function, or
with idiopathic dilated cardiomyopathy. A virus-specific phenotype of
myocarditis or inflammatory cardiomyopathy does not exist. The majority
of non-acute viral infections are asymptomatic or oligosymptomatic and
therefore, such infections are frequently not recognised prematurely as a
possible cause of a delayed onset of heart disease. The clinical
diagnostic challenge becomes even more complicated by the complex virus
profiles of the myocardium with a number of distinct virus species and
virus subtypes, different virus loads, or reactivated pathogens, all of
which may be present in the presence or absence of inflammatory
processes.
Since the pathological conditions in
viral myocarditis take place at the cellular level, tissue analysis
(endomyocardial biopsy) and not clinical tests are necessary to
elucidate the true nature of the underlying acquired disease. Despite
well-known limitations giving rise to false-negative results (sampling
error) if only low numbers (<8 a="" allow="" and="" are="" biopsy="" by="" cell="" complemented="" currently="" diagnosis="" diagnostic="" endomyocardial="" establishing="" for="" gold="" histology="" href="http://www.smw.ch/content/smw-2014-14010/#REF01" identification="" if="" immunohistochemical="" inflammatory="" is="" methods="" of="" particularly="" procedure="" quantification="" safe="" samples="" sensitive="" standard="" subtypes="" taken="" the="" unequivocally="" which="">1
–
4].
For the molecular biological virus
analysis, at least three to four biopsy specimens should be analysed for
DNA and RNA viruses, respectively, both in acute myocarditis and
idiopathic dilated cardiomyopathy. With these biopsy numbers, the
frequency of detectable viruses in right and left ventricular biopsies
are not significantly different in chronic disease. In the acute stage
of myocarditis with a history of less than two months, sampling error
may become a concern due to focal infection but respective data for
molecular analyses are still lacking.
Since immunosuppression may impair the
outcome of virus-associated inflammatory cardiomyopathy, biopsies of
all patients should undergo molecular analysis in addition to
histological and immunohistochemical evaluations in order to allow
optimal patient management [
5,
6].
Early biopsy is recommended in
clinically suspected acute disease in order to tailor personalised
management of patients. Due to the lack of prognostic information, this
also holds true for subacute myocarditis with its often uncharacteristic
complaints and all patients with idiopathic dilated cardiomyopathy at
first presentation or in cases of unexplained progression of heart
failure. Since an incomplete diagnostic does not allow a safe specific
treatment (see below), a complete diagnostic workup including molecular,
histological and immunohistochemical analysis is mandatory.
Modern molecular virus diagnostics are
not restricted to the solely PCR proof of viral RNA or DNA but also
include quantification of the viral loads and of molecular markers of
virus reactivation. Sequencing; furthermore confirms the involved virus
subtypes (table 1) [
7].
No other clinical diagnostic tool can recognise and quantify loads and
types of different viruses or non-viral infectious pathogens, elucidate
and quantify inflammatory cell subtypes, detect minor myocardial
necroses, newly developing fibrosis, or circumscribed early scar
formation characteristic of active infectious or postinfectious disease.
Of note, neither a positive virus serology nor a positive virus-PCR in
the peripheral blood can prove any organ involvement in acute or chronic
disease and virus copy numbers in myocardial biopsies may be
overestimated in the presence of high systemic virus loads by
contamination with virus infected blood cells (e.g., in chronic HCV
infection). Blood diagnostics may, however, allow the discrimination of
an acute viral infection from endogeneous B19V or HHV6 reactivation,
especially in cases with high virus loads as occasionally detected in
patients with HHV6 and ciHHV6 reactivation.
The histological, immunohistological
and molecular biological information are prerequisites to establish an
accurate diagnosis of viral myocarditis and successful management of
patients. They cannot be substituted by any non-invasive clinical
analysis. Although imaging techniques including MRI can provide
noninvasive tissue characterisation and may localise larger inflammatory
infiltrates they are misleading if infectious agents are involved,
since they neither detect nor quantify different virus types and loads
or inflammatory cell numbers nor differentiate between cell subtypes of
the immune response. On the other hand, MRI can provide prognostic
information on outcome. If extended fibroses and scars have developed
early, full recovery is less likely than in patients with an
inconspicuous MRI.
| Table 1: Frequent viruses causing infectious and post-infectious myocarditis. |
| Viral (most common) |
| Picornavirus (coxsackie A/B, echo) |
| Adenovirus (A1, 2, 3, 5) |
| Erythrovirus (Parvovirus B19, B19V) |
| Herpes virus (HSV 1, 2 ,6A/B, ciHHV6 A,B, EBV) |
| Cytomegalovirus |
| Influenza (1, 2) |
| Human immunodeficiency virus |
| Mixed infections |
| Autoimmune activation |
| Post-infectious immunity/autoimmunity |
The causes
Infectious agents are the major causes
of myocarditis and inflammatory cardiomyopathy (DCMI) in acquired
“idiopathic” diseases of the heart muscle [
4,
8,
9].
Although virtually any microbial agent can cause myocardial
inflammation and dysfunction, non-viral infections are rare in these
conditions, at least in western countries. Viral forms are considered
the most common cause of acquired inflammatory cardiomyopathies nowadays
[
4,
10].
For decades coxsackieviruses [
11,
12] and, to a lesser extent adenoviruses [
12,
13],
are well established in paediatric and adult myocarditis and chronic
heart muscle disease (table 1). Furthermore, distinct genotypes of
erythroviruses including parvovirus B19 (B19V), human herpesvirus type 6
(HHV6A/B and ciHHV6), human immune deficiency virus (HIV),
cytomegalovirus (CMV), herpes simplex type 2 virus and hepatitis C
virus, among many others have been identified with varying degrees of
frequency in cardiac tissues.
In a comprehensive study by Bowles et
al., nested PCR amplified a viral product in 40% of samples of 773
mostly younger American patients under 18 years of age with clinically
suspected myocarditis (n = 624) or DCM (n = 149), with adenoviruses and
enteroviruses predominating in the PCR analysis and only one percent was
tested positive for parvovirus [
13].
The frequency of myocardial virus species, however, changes with
geographical differences and over time. In different European studies,
viral genomes have been documented in 30% to 73% of EMB of patients with
left ventricular dysfunction and a similar epidemiological shift with
more frequent detection of B19V has recently been reported from the US [
14–
17].
Generally, erythrovirus and herpes
virus genomes are detected much more frequently than the other viral
species. Regarding such high numbers, it has to be kept in mind that in
contrast to “classical” acquired enterovirus and adenovirus infections,
erythroviruses and herpesviruses comprise life-long persistence after
childhood infection [
18,
19].
Particularly in adults, their detection in different tissues normally
does not represent recently acquired but rather latent infections.
Symptomatic diseases associated with such viruses are generally caused
by reactivation of those lifelong persisting pathogens (see below) [
4,
6].
Epidemiology and pathogenesis of viral myocarditis
Figure 1
Histological, immunohistochemical and molecular biological findings at distinct phases of viral myocarditis.
The overall incidence of myocardial involvement in any viral infections is estimated at 3–6% [
20].
The actual incidence of virus induced myocarditis or cardiomyopathy is
less well established. The majority of viral infections is asymptomatic
or oligosymptomatic and due to the infrequent use of biopsy based
diagnoses, such infections are frequently not recognised as possible
causes of acute or delayed onset heart failure. As far as human viral
myocarditis and inflammatory cardiomyopathy are concerned, the
underlying pathogenetic mechanisms are unknown for most of the
infectious agents. A limited conception is available for enteroviruses
and, to some extent, for erythroviruses and herpesviruses.
Newly acquired viral myocarditis develops with three pathologically distinct phases (
fig. 1 and
2) [
9,
21].
The early phase of viral myocarditis is initiated by an infection of
the cardiac myocytes, fibroblasts, or endothelial cells via
receptor-mediated endocytosis [
4,
22–
24].
The resulting kind and extent of myocardial compromise and hence the
prognosis of the disease depends on the nature of the offending
infectious agent, the affected cardiac structures, and the degree of
irreversible myocardial lesions caused by cytolytic viruses.
The activation of antigen-specific cell-mediated immunity initiates the second phase of virus clearance [
25,
26].
Because virus-infected cells are destroyed by immune effector cells of
the emerging cellular antiviral inflammatory response, virus clearance
will occur at the expense of further loss of infected myocytes. The
ensuing myocardial damage depends on the scale of the cellular virus
infection and increases with growing virus dispersion which, in addition
to the early virus- and immune-mediated injury of phase 1, contributes
to tissue remodelling and progression of the disease. Hence, the
resolving tissue infection occurs at the expense of a partial
destruction of myocardial tissue that is not capable of regeneration.
In patients with a regularly
controlled immune system the cellular inflammatory process fades away
within the following weeks or months after successful elimination or
substantial reduction of the infectious pathogen and thus prevents
ongoing tissue damage by an extended immune response. Whether resolving
inflammation contributes to myocardial injury and whether tissue
alteration could be avoided by a more rapid decline of inflammation,
e.g., supported by an early immunosuppressive treatment, is currently
unknown. The mildly improved outcome reported for early
immunosuppressive treatment in active myocarditis, however, would
suppose such an assumption [
27].
Chronic immune stimulation or
autoimmunity in chronic viral myocarditis results from incompletely
cleared virus infection or in response to the preceded virus- or
immune-mediated chronic tissue damage, respectively. Both the ongoing
antigenic trigger from continuously synthesised viral proteins and the
release of intracellular proteins from necrotic or apoptotic myocardial
cells may stimulate chronic inflammation which initially damages some
individual cells but ultimately can affect the whole myocardium [
28–
30].
In the third remodelling phase, the
virus infection has been cleared completely and antiviral immune
responses have been resolved. Nevertheless, the extent of the initially
caused tissue damage determines the further clinical course of the
disease. Biopsy-based diagnostics started so late can no longer
elucidate the initial causes of the disease and will postulate an
“idiopathic” disease. In those cases, a post-infectious or
postmyocarditis disease can only be suspected but no longer proven by
any diagnostic procedure. The clinical picture is consistent with an
often irreversible dilated cardiomyopathy which develops in about 25% to
30% of concerned patients with biopsy proven myocarditis [
31,
32].
| Table 2: Biopsy-based specific treatment options in patients with virus associated myocarditis. |
| Clinical diagnosis |
Virus PCR (myocardium) |
Histology/IHS |
Anti-viral treatment |
Immuno-suppression |
Comments |
| Acute myocarditis |
Any virus |
inflammation |
No |
No |
Optimal heart failure medication (HFM) |
| Chronic inflammation |
EV, ADV |
IFN-β |
No |
HFM, 8x106 IU IFN-β sc for 6 months [45, 47] |
| Latent B19V |
No |
Yes |
HFM, no specific antiviral treatment
Immunosuppression possible (see below), if acute infection has been excluded clinically and serologically |
| Reactivated B19V |
IN-β |
± |
HFM+ 8x106 IU IFN-β sc for 6 months [6, 48] |
| HHV6A/B |
No |
No |
Immunosuppression possible (see below), if acute infection has been excluded clinically and serologically |
| ciHHV6A/B |
Valganciclovir |
No |
HFM, 900–1800 mg valganciclovir [19] |
| Other viruses |
No |
No |
HFM, no specific recommendations |
| Chronic virus persistence |
EV, ADV |
no inflammation |
IFN-β |
No |
HFM, 8x106 IU IFN-β for 6 months [45, 47] |
| Latent B19V |
No |
No |
HFM, no specific antiviral treatment |
| Reactivated B19V |
IN-β |
No |
HFM+ 8x106 IU IFN-β sc for 6 months [6, 48] |
| HHV6A/B |
No |
No |
Often spontaneous improvement |
| ciHHV6A/B |
Valganciclovir |
No |
HFM, 900–1800 mg valganciclovir [6] |
| Other viruses |
No |
No |
HFM, no specific recommendations |
| Post-infectious immunity |
No virus |
inflammation |
No |
Yes |
Prednisolon 1 mg/kg bw +
azathioprin 100 mg, daily. The steroid is tapered every 2 weeks by 10
mg. Maintainance dose 10 mg/day, treatment for 3–10 months [6] |
Frequent infectious causes of viral myocarditis
Figure 2
Three phase model of
cardiovascular infection: A genetic predisposition is supposed (?) for
some viruses but currently not proven. During the viral phase, infected
cardiomyocytes become injured and the virus may persist due to an
inadequate immune response. A regularly mounted immune response (phase
2) eliminates the viral infection and may further damage the myocardium
if it declines improperly. Post-infectious, post-inflammatory immunity
and preceding myocardial damage may stimulate ongoing tissue remodelling
(phase 3) which affects cardiac function in the long run despite
clearance of the initial causes.
Figure 3
Clinical impact of viruses on the
myocardium. Distinct cardiac dysfunctions are caused by the different
cell tropisms of frequent cardiotropic viruses and post-infectious
(auto)immunity. Optimal heart failure treatment according to guidelines
have to be administered to all patients. The mode of treatment of
persisting cardiac infections is virus type specific. Reliable treatment
data for acute cardiac infections do not exist. Proposed treatment
strategies differ from the management of acute systemic viral
infections. Post-infectious autoimmunity is treated by
immunosuppression.
Newly acquired infections
Enteroviruses and adenoviruses are
established causes of acute myocarditis but are also detected in chronic
heart failure presenting as DCM [
12,
14,
33].
Both viruses infect cardiomyocytes in animal models and human disease
after binding to the coxsackie-adenoviral receptor (CAR) and the decay
accelerating factor (DAF, CD55) which serves as a co-receptor for
enterovirus internalisation [
23,
34].
After internalisation the enterovirus negative strand RNA is reversely
transcribed into a positive strand for subsequent virus replication and
spreading [
12,
35] Myocardial injury is directly caused by the lytic viral infections (phase 1) or the antiviral immunity (phases 1 and 2,
fig. 2).
Endogenous virus infection and reactivation
Acute parvovirus B19 (erythrovirus
genotype 1, B19V) infection is a common acute childhood disease
infrequently observed in adults [
36].
Erythrovirus infection and replication are primarily restricted to
erythroid progenitor cells in the bone marrow, but consistent with the
presence of the primary erythrovirus receptor P antigen as well as its
co-receptors (Integrins, KU80) on vascular endothelial cells, persistent
latent infection is detected in the vascular endothelium (EC) of
different organs, including the heart in which the virus has been
localised in endothelial cells of venuoles, small arteries or arterioles
of children and adults with fulminant myocarditis or sudden onset heart
failure [
36–
38].
In the majority of cases, latent
infection is asymptomatic. If the virus becomes reactivated,
transcriptional active erythrovirus is often associated with symptomatic
endothelial dysfunction [
7].
Cardiovascular impairment caused by erythrovirus infected endothelial
cells may also explain the earlier graft loss and the premature
development of advanced transplant coronary artery disease in paediatric
cardiac transplant recipients [
15,
16].
Human herpesvirus type 6 is another widespread latent virus infection frequently detected in endomyocarial tissue specimens (
fig. 2) [
14].
Clinical isolates form two genetically related but biologically
distinct groups (HHV-6A and HHV-6B) which, similar to B19V, persists in
>70% of the adult population after primary infection in childhood [
39].
HHV6 is a lymphotropic virus which also infects various other cell
types including cardiomyocytes and the vascular endothelium even though
infectious virus cannot be isolated from the peripheral blood and the
virus genome remains below the detection limit in these patients [
40–
42].
Intriguingly, HHV-6 is able to integrate its genomes into telomeres of
human chromosomes (ciHHV6), which allows transmission of ciHHV-6 via the
germ line in about 0.4–0.8% of the US and European populations [
19,
43].
Similar to the other herpes viruses,
HHV-6 and ciHHV6 become frequently reactivated with subacute clinical
presentations. Recently, HHV-6 has been detected in the myocardium of
patients with myocarditis and clinically suspected dilated
cardiomyopathy (DCM) by PCR. Short-term follow-ups have revealed an
association with the clinical course of the disease [
14,
42].
Clinical course of acute and chronic viral heart disease
If the antiviral immunity has
elaborated fast and efficiently with subsequent rapid resolution of
cellular processes, residual damage of the myocardium may be minor and
the remaining myocardium can compensate sufficiently for the partial loss
of contractile tissue (
fig. 1 and
3).
Consequently, 60% to 70% of patients recover completely within 2 to 12
months with no or only minor residual clinical signs of heart injury.
During or after recovery, follow-up biopsy will be consistent with
healed myocarditis. Even complete recovery and inconspicuous histology,
however, do not prove optimal long-term outcome, since a group of those
patients will develop slowly progressive heart failure or compromising
arrhythmias even after years of asymptomatic intervals [
33].
Depending on the severity of initial
cardiac damage, other patients may retain residual myocardial
impairment. Moderate loss of contractile tissue with more pronounced
remodelling of the myocardial matrix accounts for the course of those
25% to 30% of patients who only partially recover (
fig. 1 and
3).
In the longer run many of these patients experience progressive heart
failure despite regular heart failure medication. At this time point,
idiopathic DCM is diagnosed, histologically.
The resulting clinical presentation
is, however, not only influenced by the severity of irreversible matrix
alterations and the potential of the myocardium to compensate for these
processes. It may also depend on the effects which are exerted on the
cardiac tissue by a persisting lytic virus infection, virus-associated
low grade inflammatory processes or autoimmune mechanisms. Under these
circumstances, biopsy derived findings will be compatible with
inflammatory cardiomyopathy or chronic viral heart disease, respectively
(
fig. 1).
The transition of myocarditis into DCM
following direct virus- or immune-mediated myocardial damage is
generally accepted and supported by literature [
31,
32].
Continuous myocardial damage caused by persisting virus infection
and/or ongoing immune processes, however, has not been proven
unambiguously in human disease. A great deal of scepticism stems from
the inconsistency of currently available data. This inconsistency is
mostly derived from insufficiently diagnosed and inconsequently followed
cohorts of patients. There are, however, a number of sound clinical
reports which demonstrate that persistent viral infections directly
contribute to the progression of heart failure and adverse prognosis in
human disease [
14,
44,
45].
Effect of virus persistence on outcome
The clinical importance of persistent
enteroviral genomes in the myocardium was investigated by Why and
colleagues who demonstrated a higher mortality at 25 months (25% versus
4%) in the 41 patients with persistent enteroviral infection [
44].
The data reported by Frustaci et al.
from a retrospective analysis of immune suppressively treated patients
with inflammatory cardiomyopathy point to a similar direction [
5].
In this study patients with persistent viruses did not improve or even
deteriorated upon immunosuppression while virus-negative patients
improved significantly. Within a short period of 9 months, 7 out of 44
treated virus-positive patients died or were transplanted. In another
recent paper, Caforio and co-workers reported on a two year follow-up of
patients with active (n = 85) and borderline myocarditis (n = 89) in
which virus persistence was an univariate predictor of adverse
prognosis, in addition to anti-heart autoantibodies and clinical signs
or symptoms of left and right heart failure [
30].
These data are in accordance with our
own observations. When we initially followed 172 consecutive patients
with left ventricular dysfunction and biopsy-proven viral infection by
re-analysis of biopsies and haemodynamic measurements after a median
period of seven months, viral genomes persisted in 64% of patients with
single virus infections [
14].
50% of the enteroviral genomes were cleared spontaneously. Respective
data for adenovirus, parvovirus B19 and herpesvirus 6 were 36%, 22% and
44%. These data on spontaneous clearance of the virus infection
demonstrate that a single biopsy analysis can never prove virus
persistence unambiguously.
Clearance of virus was associated with
a significant decrease in left ventricular dimensions and improvement
in left ventricular ejection fraction. In contrast, LV function
decreased mildly during this short follow-up in patients with persistent
viral genomes [
46].
About five years later, 41% of the patients with enterovirus
persistence had died (10 year mortality rate: 52.5%), whereas 92% of
patients who spontaneously had cleared the infection where still alive
after 10 years [
45].
Respective data on other viruses are
not available because most published data do not refer to biopsy-based
virus controls and attempts to definitely prove virus persistence for
the whole study period by follow-up PCR analysis have predominantly not
been carried out in most studies. Since a high percentage of viral
infections are cleared at early stages of myocarditis by the antiviral
immune response, it is still unknown whether reported adverse prognoses
have to be attributed to early and more pronounced tissue damage in
initially virus-positive patients (phase 1) or whether it is caused by
latent viral infections with smoldering immune processes (phases 2 and
3).
Effect of antiviral treatment on outcome
In an attempt to gain more information
on this important issue, virus-positive patients with chronic
cardiomyopathy (median history: 44 months) were treated with
interferon-β in a non-randomised study. Upon treatment enterovirus and
adenovirus clearance was successful in all treated patients [
47].
Virus clearance was paralleled by a significant decrease of ventricular
dimensions and clinical complaints. LV ejection fraction improved
significantly in both patients with moderately and severely suppressed
ventricular function. Ten year follow-up documented, in contrast to
untreated patients, a significantly reduced mortality of treated
patients [
47].
Erythroviruses including parvovirus B19 and HHV6 are neither cleared by IFN-α nor IFN-β ([
48]
and unpublished data). Despite this fact, symptomatic B19V-positive
patients but not untreated controls benefit from suppression of virus
transcriptional activity. We recently have reported that endothelial
dysfunction and respective symptoms improve upon antiviral treatment
with interferon-beta (IFN-β) although the B19V virus load is barely
affected [
48].
The underlying mechanisms of how IFN-β delivers such beneficial
clinical effects without clearing the virus substantially are unknown
but cell culture analyses using infected immortalised human
microvascular EC cells (HMEC-1) have shown, that IFN-β inhibits B19V
reactivation and improves endothelial cell viability [
48]. In B19V infected patients IFN-β reduces endothelial cell apoptosis and improves endothelial dysfunction [
48].
In a recent preliminary study, the onset of advanced transplant
vasculopathy was delayed in parvovirus positive children who received
IVIG in addition to standard immune suppression [
16,
49].
Less information is available for HHV6
and ciHHV6. Similar to B19V, HHV6 is not cleared by interferons or
ganciclovir. CiHHV6 cannot be cleared due to its chromosomal integration
in every cell of the body. Again, symptomatic patients with reactivated
HHV6 and ciHHV6 improve symptomatically upon ganciclovir treatment [
51].
The above follow-up data and treatment
observations indicate that the course of the virus infection
predetermines the clinical course of the disease. The data furthermore
implicate that ventricular dysfunction in chronic enteroviral heart
disease should not be put on a level with irreversibly damaged
myocardium even in patients with a chronic history of cardiomyopathy,
since haemodynamic improvement occurs in 67% of treated patients with
chronic cardiomyopathy [
45,
50].
With respect to the clinical
management of the patients, data outlined argues for the necessity to
identify patients at an early and still reversible stage of
virus-associated heart disease (table 2). Depending on the infectious
agent, biopsy-guided, tailored antiviral treatment may clear the
infection and improve outcome, or be of symptomatic benefit if the virus
is not cleared completely. Post-infectious autoimmunity should be
treated by immunosuppression (table 2). One has to keep in mind,
however, that only patients with still minor or moderate irreversible
alterations of the heart tissue will benefit from early and specific
treatment and progression of heart failure can only be prevented by in
time therapy. Therefore, viral diagnostics and antiviral treatment
should be started before irreversible myocardial damage has developed.
Conclusions
Myocarditis is an inflammatory disease
of the cardiac muscle tissue caused by myocardial infiltration with
immunocompetent cells following any kind of cardiac injury. Infectious
aetiologies include a vast number of viruses, bacteria, protozoa or
fungi, but most frequently the myocardial inflammatory process is
directed against viral pathogens. In the early stage of the disease both
the infectious trigger and the resulting immune response may already
cause irreversible myocardial injuries that influence acute and
long-term outcome. If the infectious agent is rapidly eliminated and the
inflammatory process is resolved in a timely manner, the disease will
resolve with only minor alterations of the myocardium. At this phase,
the true underlying causes of the disease can no longer be identified.
Chronic myocardial injury in viral
myocarditis develops if the antiviral immune response fails to eliminate
the infectious agent completely or, if the inflammatory process does
not resolve properly despite virus clearance. In such conditions,
long-term outcome depends on the nature and extent of the virus-affected
tissue compartments which varies considerably with the amount and kind
of the infectious agent or the number and subtype of the smoldering
cellular inflammatory infiltrates. In addition to the initial
irreversible tissue alterations, persisting viruses, and post-infectious
immune or autoimmune processes may induce persisting or progressive
ventricular dysfunction, arrhythmias and symptomatic cardiac complaints.
Viral heart disease often presents as
an acute or chronic dilated cardiomyopathy (DCM) but due to its broad
spectrum of presentation a solely clinical diagnosis is frequently
misleading. Since the pathological conditions in viral myocarditis take
place at the cellular level, tissue analysis but not clinical tests are
necessary to elucidate the true nature of the underlying acquired
disease. If the primary infectious or immune-mediated causes of the
disease are carefully defined by clinical and biopsy based tools,
specific antiviral treatment options in addition to basic symptomatic
therapy are available under certain conditions. This may allow a
tailored cause-specific treatment that improves prognosis of patients
with acute and chronic disease.
Funding / potential competing interests:
Part of this work was supported by grants of the German Research
Foundation (DFG), Transregional Collaborative Research Centre
“Inflammatory Cardiomyopathy – Molecular Pathogenesis and Therapy” (SFB
TR 19 04, Project Z1) and the Federal Ministry of Education and Research
(BMBF, Germany) for KMU innovative program (No. 616 0315296). For their
excellent technical assistance, we thank Mrs. K. Winter, S. Ochmann, C.
Seifert, M. Willner and E. Hertel, Berlin, Germany.
Corrspondence:
Professor Heinz-Peter Schultheiss, Medizinische Klinik II, Cardiology
und Pneumonology, Charité – Universitätsmedizin Berlin, Campus Benjamin
Franklin, Hindenburgdamm 30, DE-12200 Berlin, Germany,
heinz-peter.schultheiss[at]charite.de
industrially it was necessary to rid the country of endemic diseases.
Many European ships refused to dock in Brazilian ports because of the
risk of contracting yellow fever, smallpox, bubonic plague, and
syphilis.
