European Heart Journal Advance Access published June 23, 2011

REVIEW

European Heart Journal

doi:10.1093/eurheartj/ehr165

Frontiers in cardiovascular medicine

The management of myocarditis

Heinz-Peter Schultheiss 1,2*, Uwe Kuhl 1,2, and Leslie T. Cooper 1,2
1

Charite Hospital, Berlin, Germany; and 2Mayo Clinic, Rochester, MN, USA

Received 2 January 2011; revised 25 March 2011; accepted 28 April 2011

Despite considerable advances in our understanding of myocarditis pathogenesis, the clinical management of myocarditis has changed
relatively little in the last few years. This review aims to help bridge the widening gap between recent mechanistic insights, which are
largely derived from animal models, and their potential impact on disease burden. We illustrate the pathogenenic mechanisms that are
prime targets for novel therapeutic interventions. Pathway and pathogen-specific molecular diagnostic tests have expanded the role for
endomyocardial biopsy. State of the art cardiac magnetic resonance imaging can now provide non-invasive tissue characterization and localize
inflammatory infiltrates but imaging techniques are misleading if infectious agents are involved. We emphasize the gaps in our current clinical
knowledge, particularly with respect to aetiology-based therapy, and suggest opportunities for high impact, translational investigations.

----------------------------------------------------------------------------------------------------------------------------------------------------------Myocarditis pathogenesis Clinical management

Aetiology of myocarditis
Aetiologies of myocarditis include a number of infectious and noninfectious agents such as viruses, bacteria, protozoa, fungi, toxins,
myocardial involvement in systemic diseases, or physical condition,
but often the underlying cause cannot be identified (Table 1).
Drugs can induce myocardial inflammation by either direct toxic
effects on heart tissue or by inducing hypersensitivity reactions,
which are often associated with an eosinophilic myocarditis.1 Eosinophils are also observed in myocardial inflammatory processes
which are associated with ChurgStrauss or hypereosinophilic
syndromes, vaccination against smallpox or caused by helminthic
and parasitic infections. Myocardial involvement may be caused
by granulomatous and systemic diseases or (auto)immune processes with often unknown pathogenetic mechanisms, but all
these aetiologies are far less common than virus-induced myocarditis or post-infectious inflammatory cardiomyopathy.2 4 Apart
from enteroviruses, which traditionally have been considered the
most common agent in myocarditis and dilated cardiomyopathy,
distinct RNA- and DNA viruses and virus subtypes have been
identified with varying degrees of frequency (Table 1).5 22
Although viral infections can cause serious human diseases, the
majority of viral infections are asymptomatic or oligosymptomatic
and therefore, such infections are frequently not recognized as
possible causes of delayed onset of heart disease.23 In the past,
viral myocarditis and chronic viral heart disease have therefore

more often been a clinically derived diagnosis of exclusion,

rather than a specifically proven diagnosis. Beside the temporary
changes of virus epidemics and the geographical differences in
the aetiological profiles of viruses, the presence of myocarditic
and non-myocarditic virus variants, the enormous variability of
clinical symptoms of viral heart disease, which may range from
asymptomatic presentation to manifest heart failure, and last but
not least the lack of consequent diagnostic efforts for complete
virus analysis have hampered an early identification of afflicted
patients and thus have prevented the generation of valid
epidemiological data.

Pathogenic mechanisms
For many viruses, the exact cardiac infection site and the underlying pathogenic mechanisms are unknown. Most information on
the pathophysiology of viral heart disease and post-infectious autoimmune myocarditis in both rodent models and humans is known
from enteroviral infections such as coxsackievirus B3. Enteroviruses enter the host through the gastrointestinal or respiratory
tract, reside in the reticuloendothelial system as an extracardiac
reservoir, and attack heart tissue as a secondary target organ.
After enterovirus internalization, the negative strand RNA is
reversely transcribed into a positive strand for subsequent virus
replication.22,24 A direct virus-related cytolysis of cardiomyocytes

* Corresponding author. Tel: +49 308 445 2344; Fax: +49 308 445 3565; Email: heinz-peter.schultheiss@charite.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com

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Keywords

Page 2 of 13

Table 1

H.-P. Schultheiss et al.

Causes of myocarditis

Infectious causes

Non-infectious causes

RNA viruses: picornaviruses (coxsackie A + B, echovirus, poliovirus,

hepatitis virus), orthomyxovirus (influenza), paramyxoviruses
(respiratory syncitial virus, mumps), togaviruses (rubella), flaviviruses
(dengue fever, yellow fever)

Autoimmune diseases: dematomyositis, inflammatory bowel disease,

rheumatoid arthritis, sjogren syndrome, systemic lupus erythematodes,
Wegeners granulomatosis, giant cell myocarditis

DNA viruses: adenovirus (A 1, 2 ,3, and 5), erythrovirus [1 (B19V) and 2],
herpesviruses (human herpes virus 6 A/B, cytomegalievirus, Epstein-Barr
virus, varicella-zoster virus), retrovirus (HIV)

Drugs: aminophyllin, amphetamine, anthracyclin, catecholamines,

chloramphenicol, cocain cyclophosphamid, doxorubicin, 5-fluoruracil,
mesylate, methylsergit, phenytoin, trastuzumab, zidovudine

Bacteria: chlamydia (C. pneumonia/psittacosis) haemophilus influence,

legionella, pneumophilia, brucella clostridium, francisella tularensis,
neisseria meningitis, mycobacterium (tuberculosis), salmonella,
staphylococcus, streptococcus A, S. pneumonia, tularemia, tetanus,
syphilis, Vibrio cholera
Spirocheta: Borrelia recurrentis, leptospira, Treponema pallidum

Hypersensitivity reactions (drugs): azitromycin, benzodiazepines, clozapine,

cephalosporins, dapsone, dobutamin, lithium, diuretics, thiazide,
methyldopa, mexiletine, Streptomycin, sulfonamides, non-steroidal
anti-inflammational drugs, tetanus toxoid, tetracycline, tricyclic
antidepressiva
Hypersensitivity reactions (venomes): bee, wasp, black widow spider,
scorpion, snakes
Systemic diseases: Churg-Strauss syndrome, collagen diseases, sarcoidosis,
Kawasaki disease, scleroderma
Others: heart stroke, hypothermia, transplant rejection, radiation injury

...............................................................................................................................................................................

Reckettsia: Coxiella burnetii, R. rickettsii/prowazekii

Fungi: actinomyces, aspergillus, candida, cryptococcus, histoplasma,
nocardia
Protozoa: Entamoeba histolytica, leishmania, Plasmodium falciparum,
Trypanosoma cruzi, Trypanosoma brucei, Toxoplasma gondii
Helmintic: ascaris, Echinococcus granulosus, Schistosoma, Trichinella spiralis,
Wuchereria bancrofti

unchanged in non-treated patients providing evidence that

B19-induced damage of ECs is at least partially mediated via
direct virus cell interaction.46
HHV-6 is a lymphotropic virus with tropism mainly for CD4+
and CD8+ T cells, B cells, and natural killer cells. Although
HHV-6 is thought of as a lymphotropic virus, it also can infect
vascular endothelium.47,48 Several studies have identified
HHV-6-specific DNA in the vascular endothelium in vivo, and
suggested EC damage by the virus.48 51 It has been suggested
that ECs and cardiac myocytes might be an important reservoir
for viral latency and reactivation.47
Similar to the other herpes viruses, HHV-6 becomes frequently
reactivated by infections or drugs with subacute clinical presentations, especially in acquired or drug-induced immunodeficiencies
(e.g. transplant recipients) or in patients with autoimmune disorders. It has been suggested that often HHV-6 rather enhances
the pathogenicity of other viruses than being a pathogen itself. In
a minority of patients (,1%), HHV-6 is integrated into the
chromosome of all nucleated cells resulting in lifelong persistence
of HHV-6 which is then passed to 50% of the progenies.
Since distinct cardiac target structures are affected by different
infectious agents and post-infectious mechanisms, viral myocarditis
(viral heart disease) and post-infectious immune myocarditis
present with heterogenic clinical phenotypes. If the contractile
apparatus (cardiomyocytes) or interstitial cells and matrix
structures (e.g. dystrophin) are preferentially involved, ventricular
dilatation and systolic heart failure with progression towards postmyocarditic dilated cardiomyopathy (DCM) is directly caused by
cytolytic viruses or viral proteases.52 Involvement of vascular
tissue (ECs) by other viruses may affect myocardial contractility
indirectly,
e.g.
as
a
consequence
of
endothelial

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is already detected before any inflammatory infiltrate develops and

appears to be decisive in fulminant cases of myocarditis.25,26
In contrast to enteroviruses, which primarily infect and injure
cardiomyocytes, other frequent cardiotropic viruses such as erythroviruses or human herpesvirus 6 A/B infect the vascular endothelial cells (ECs).27 30 Following primary infection in childhood,
erythroviruses, including its genotype 1 (parvovirus B19, B19V),
may reside asymptomatically in the bone marrow of a vast majority
of the adult population. The in vivo tropism of B19V infection is
regulated by a number of determinants and persistent infection
and replication is mainly restricted to erythroid progenitor cells,
but also EC, by the distribution of the primary erythroviral receptor, the P antigen, and reported co-receptors-like integrin a5b1
and the KU80 protein.31 33 With respect to the heart tissue, erythroviruses do not infect cardiomyocytes. In biopsy samples of
patients with fulminant myocarditis or sudden onset heart failure,
B19V genomes have been localized in EC of venuoles, small
arteries, or arterioles.27 In chronic inflammatory cardiomyopathy,
B19V infection is predominantly detected in ECs of small
capillaries.28,29
Endothelial cell infection is associated with endothelial dysfunction which predicts long-term disease progression in chronic heart
failure.34 39 The pathogenetic mechanisms by which B19 exerts
endothelial damage are complex and may involve cytotoxicity of
the non-structural protein 1, transactivation of interleukin-6
(IL-6), and tumour necrosis factor a, as well as induction of apoptosis as shown in vitro. 40 45. Recently, we could show that B19V is
released from the bone marrow by infected capillary precursor
cells and that interferon-b (IFN-b) improves viability of B19V
infected human ECs.46 Since endothelial dysfunction and respective
symptoms improved upon IFN-b treatment while both remained

The management of myocarditis

dysfunction-associated chronic ischaemia with less often early systolic ventricular dysfunction and possibly slower progression
towards systolic heart failure.36,46,53,54 Often patients with EC

Page 3 of 13
infection complain for symptoms associated with vasospasm and
EC-dysfunction despite normal or nearly normal left ventricular
function. The contribution of the virus loads and effects of different

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Figure 1 Distinct phases of myocardial injury in infectious and post-infectious myocarditis. Myocarditis is an inflammatory disease of the
cardiac muscle caused by myocardial infiltration of immunocompetent cells following any kind of cardiac injury. Acute myocarditis is often a
result of a viral infection that produces myocardial necrosis and triggers an immune response to eliminate the infectious agent (healed myocarditis and/or dilated cardiomyopathy). Chronic myocardial injury may be caused by post-infectious immune or autoimmune processes
[indlammatory cardiomyopathy (DCMi)], be associated with systemic autoimmune diseases or develop by a persisting virus infection (viral
heart disease), which, in the long run, are responsible for persistent or progressive ventricular dysfunction, arrhythmias, and cardiac complaints.
The disease often presents as an acute form of dilated cardiomyopathy but due to its broad spectrum of presentation the clinical diagnosis is
frequently misleading. If the underlying infectious or immune-mediated causes of the disease are carefully defined by clinical and biopsy-based
tools, specific immunosuppressive and antiviral treatment options in addition to basic symptomatic therapy may improve prognosis in a number
of patients with acute and chronic disease.

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H.-P. Schultheiss et al.

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Figure 2 Infection of cardiac endothelial cells or cardiac myocytes by virus causes direct cellular damage and subsequently an innate and
adaptive immune response, all of which contribute to cardiomyopathy. Cardiomyopathy from viral injury and the subsequent immune reaction
can include diastolic as well as systolic dysfunction.
virus subtypes are still poorly understood.55 Consequently, distinct
viruses with different infection sites in cardiac tissue do not only
explain the heterogenic and unpredictable course of viral heart
disease with respect to the expression of its phenotype and
early or late clinical presentation but also determine indication
and response to treatment, or prognosis.
Direct cytopathic injury, apoptosis, activation of the innate and
adaptive immune system, and cardiac remodelling have all been
implicated in the pathogenesis of viral myocarditis. It develops
with pathologically distinct phases which time depending determine both clinical presentation and indication for symptomatic
or specific treatment strategies (Figure 1).3,56
The early phase of viral myocarditis is initiated by infection of
cardiac myocytes, fibroblasts, or ECs through receptor-mediated
endocytosis.57 59 Acute myocardial injury can result from either
direct virus-mediated lytic processes or are caused by the emerging antiviral immune response (Figure 1).60,61 In fulminant cases
of myocarditis, resulting myocyte necrosis may cause a significant
loss of contractile tissue, which is accompanied by rapidly

developing cardiac failure and early death of the host (early

phase). Cytokines released by macrophages and activation of
natural killer cells that directly kill virus-infected heart cells
through perforin or granzyme-mediated lysis contribute to early
myocardial lesions and impaired myocardial function.
The activation of antigen-specific immunity mediated by T-cells,
B-cells, and antibody production (adaptive immune response)
initiates the second phase of virus clearance (Figure 2).62 64 The
recruitment of leucocytes to sites of infection is crucial to the
inflammatory clearance of pathogens. Various molecules may
control inflammatory cell trafficking including chemokines, a family
of low-molecular-weight proteins involved in adherence of inflammatory cells to activated endothelium and leucocyte chemotaxis
(Table 2). Chemokines are important for containment of the infectious agents but may extend tissue injury, if attracted inflammatory
cells produce pathological mediators that injure terminally differentiated cardiomyocytes or induce extensive fibrosis (e.g. TGF-b).65
T-regulatory cells are also important in inhibiting the pathogenesis of acute viral myocarditis and subsequent dilated

Page 5 of 13

The management of myocarditis

Table 2 Potential pathogenesis-directed therapies depend on the phase of myocarditis. At all phases, guideline based
treatments appropriate to the clinical scenario are indicated
Phase of disease

Proposed mechanism and infectious agents

Potential therapy

Direct cytopathic injury

Innate immune system activation (macrophages,
NK-cells, and cytokines)

Antiviral agents?
Antiviral agents? intravenous immune
globulin?

Post-infectious (auto)immunity

Adaptive immune response (T-cells, B-cells,

antibody production)

Immune modulation
Steroids
Immunoadsorption
Intravenous immune globulin
Muronomab-CD3

Chronic viral cardiomyopathy

Enterovirus
Adenovirus
Erythro-/parvovirus

Interferon-b
Interferon-b
Intravenous immune globulin (acute infection)
Type I interferons (chronic infection)

Human herpesvirus 6
Cytomegalovirus

Val-/Ganciclovir
Val-/ganciclovir
Foscanet
Cidovir

...............................................................................................................................................................................
Symptomatic heart failure medication
Acute myocarditis (early phase)

Ebstein-Barr virus

cardiomyopathy. Adoptive transfer of T-regulatory cells protects

mice from coxsackievirus B3 (CVB3)-induced myocarditis
through the transforming growth factor b-coxsackie-adenovirus
receptor pathway and thus suppresses the immune response to
cardiac tissue.66 Coxsackievirus B3 causes severe myocarditis in
BALB/c mice. BALB/c mice receiving CD4(+) CD25(+) T regulatory cells from gd(+) T-cell-depleted donors developed significantly less myocarditis and CD4(+) Th1 cell responses
compared with mice receiving equal numbers of CD4(+)
CD25(+) cells from infected gd (+) T-cell-sufficient animals.
This study showed that gd (+) cells promote CD4(+)
IFN-g(+) acute and memory responses by limiting FoxP3(+) T
regulatory cell activation.67 Finally, male BALB/c mice infected
with CVB3 develop more severe acute inflammation in the heart
compared with females due to fewer T regulatory cells and
Tim-3(+) M2 macrophages.68
Negative immune modulation, an important property of an
intact immune system to prevent excessive tissue damage by an
overwhelming immune response, normally occurs rapidly after
successful elimination of the infectious pathogens. Under certain
circumstances, chronic immune stimulation and autoimmunity
may result from incompletely cleared virus infection or in response
to the virus- and immune-mediated chronic tissue damage,
respectively. Both cellular and humeral inflammatory processes
may contribute to the progression of chronic myocardial
injury.69 The underlying pathological processes are not well

Aciclovir
Aciclovir
Ribavirin
Pegylated Interferon-a + ribavirin
Anti-retrovirals

understood but in chronic inflammatory cardiomyopathy, subgroups of patients may benefit from immunosuppression.
If viral infection and autoimmune processes have resolved, the
magnitude of the remaining tissue damage determines the further
course of the disease.70 This late phase of post-infectious disease
is distinguished by cardiac remodelling, progressive dilitation, and
chronic heart failure. Aetiology-specific treatment is probably not
useful but only standard heart failure medication and/or devices
may prevent or delay progression and improve prognosis.
Genetic predisposition is a likely factor in some cases of myocarditis, although direct evidence in human disease is lacking. In
murine models of myocarditis, genetic predisposition to Th1,
Th2, and Th17 cytokine responses influence the severity and
time course of viral infection (reviewed in Rose 2009).71 Similarly,
truncations in the 5 untranslated region of the Coxsackie B virus
genome can lower viral replication rate and lead to chronic infection.72 Few genomic studies in human disease have been performed in part due to relatively small patient cohorts and lack of
large multi-centre biobanks linked to well-characterized clinical
phenotypes with outcome data.
Autoimmune myocarditis, exemplified by giant cell myocarditis,
usually occurs without an identified trigger such as a viral infection;
although vial infection can amplify naturally occurring autoantibodies
and autoreactive T cells. The time course of cytokine and chemokine
expression following experimental autoimmune myocarditis in the
Lewis rat is similar to the pattern observed in models of severe

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Herpes simplex virus

Varicella
Respiratory syntitial virus
Hepatitis C virus
HIV

Val-/ganciclovir
Foscanet
Cidovovir

Page 6 of 13

H.-P. Schultheiss et al.

Figure 3 Adapted from Kodama M. et al. Animal Models of Autoimmune Myocarditis, in Cooper, LT, ed, Myocarditis from Bench to Bedside.
Humana Press, Towtowa, NJ 2003.

Select knowledge gaps and opportunities in the pathogenesis of

myocarditis
The heterogeneity of clinical presentations and incomplete
understanding of human immunopathology are obstacles to
current investigation.
The major long-term consequence of myocarditis is chronic
dilated cardiomyopathy, but the pathways that lead to myocardial fibrosis are poorly understood.
Investigation of the pathways that lead to fibrosis and DCM
after viral injury requires bidirectional collaboration between
investigators with small animal models that recapitulate late
cardiac fibrosis and clinicians who take a multi-centre,
programmatic approach to patient care.
The genetic factors contributing to human myocarditis are
poorly understood. Advances in the genetics of myocarditis
will require multi-centre, pathogen-specific registries with
linked biobanks, core facilities with next generation whole
genome sequencing and candidate driven transcriptomic and
metabolomic studies.

Diagnosis and prognosis

The clinical presentation of acute myocarditis ranges broadly from
subclinical disease to fulminant heart failure, and chest pain, palpitations, and syncope are not uncommon. Young children often
have a more fulminant presentation than adults.82 Men with presumed viral myocarditis may have more severe damage than
women.83 A viral prodrome including fever and respiratory or gastrointestinal symptoms frequently precedes the onset of myocarditis.84 Chest pain in acute myocarditis may resemble angina with
ischaemic electrocardiographic changes or be more typical for
pericarditis, when both the epicardium and adjacent pericardium
are inflamed. In a representative sample of the adult patients
screened in the European Study of the Epidemiology and Treatment of inflammatory Heart Disease, 72% had dyspnoea, 32%
had chest pain, and 18% had arrhythmias.85
The sensitivity of cardiac biomarkers of myocardial injury varies
depending on the time from symptom onset to testing and the
cut-off values used. For example, in acute paediatric myocarditis,
the sensitivity of specificity of Troponin T (TnT) were 75 and
75% when the cut-off was set at 0.026 ng/mL and 63 and 89%
with a cut-off value of 0.071 ng/mL.86 Elevations of Troponin I
(TnI) in patients with myocarditis were significantly correlated
with 1-month duration of heart failure symptoms.87 Troponin I
or TnT are more commonly elevated than creatinine kinase MB
in both adults and children with acute myocarditis.87 89 Nonspecific serum makers of inflammation, including erythrocyte
sedimentation rate, C-reactive protein, and leucocyte count may
be elevated.
The most common electrocardiogram (ECG) findings are
non-specific T-wave changes.90 Occasionally, the ECG changes
may mimic acute myocardial infarction or pericarditis with ST
segment elevation, ST segment depression, PR segment
depression, and pathological Q-waves.91,92 Tachyarrhythmias are

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enteroviral myocarditis (Figure 3)73 The early rise in pro-inflammatory

cytokines such as Il-2 and IFN-g, is followed by regulatory cytokines
such as IL-10 and profibrotic cytokines like TGF-b1.65,74 76
However, in other models of autoimmune and viral myocarditis
gender, hormone milieu, and the nature of the initial innate
immune response impact the severity and time course of subsequent
inflammation and cardiomyopathy.77,78 In nave BABL/c mice organspecific, IL-17-mediated autoimmunity and heart failure is induced
by self-antigen loaded activated dendritic cells (DCs) that prime
MYHC-a-specific CD4 T-cells if DCs are activated through toll-like
receptors and CD40 costimulation.79,80 In such a model, suppression
of activated autoreactive Th17-cells by IFN-g-producing monocytes
limits cardiac inflammation and prevents further tissue injury.81

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The management of myocarditis

Select knowledge gaps and opportunities in the diagnosis and prognosis of myocarditis
The incidence and prevalence of myocarditis are unknown.
There is an immediate need for inexpensive, sensitive, and
specific diagnostic tests that can be used in population-based
studies in regions without access to advanced imaging or
cardiac catheterization laboratories.
Gender issues: the protective effect of estrogens and the role
of viral myocarditis in peripartum cardiomyopathy are
incompletely understood.
Paediatric cases: the optimal strategy for diagnosing
myocarditis in children is controversial and based largely
on expert opinion.
Molecular inflammatory markers in peripheral blood combined with newer echocardiographic and CMR imaging techniques and EMB may lead to more accurate diagnosis and
aetiology-specific treatments.

Treatment
Cardiomyocytes can be destroyed by direct virus damage, the antiviral immune response, or a truly autoimmune injury. Since adult
cardiomyocytes rarely regenerate, recovery of myocardial function
depends on the residual myocardial tissue. The treatment response
of acute and chronic myocarditis therefore depends on the specific
causes of the disease, severity of irreversible tissue alterations at
the onset of treatment and consequently on the potential of the
myocardium to compensate for such processes. If the pretreatment damage is severe, aetiology-specific treatment options
at best can halt rapid progression of the disease but will not
achieve significant improvement in ventricular function.

Treatment for heart failure

The mainstay of treatment for myocarditis presenting as dilated cardiomyopathy is an optimal heart failure medical regimen. If the left ventricular ejection fraction (LVEF) is ,40%, we recommend that an
angiotensin-converting
enzyme-inhibitor/angiotensin
receptor
blocker and/or a b-adrenergic blocking agent be used according to
the current AHA/ACCF and ESC guidelines for the management of
heart failure.106 108 Supporting this strategy are experimental
studies that show captopril and candesartan improve myocarditis in
murine myocarditis models.109,110 Non-steroidal anti-inflammatory
agents such as indomethacin should be considered for patients with
a myopericarditis-like syndrome of chest pain and normal or nearnormal ventricular function because they can worsen cardiomyopathy
in experimental models.111 In addition to guideline-based medical
management, we recommend that patients with acute myocarditis
refrain from competitive athletics for a period of months after the
acute infection or until ventricular recovery has been documented
by non-invasive imaging.

Antiviral treatment
Treatment of early disease
Elimination of viral translation, transcription, and proliferation with
the use of antiviral medications that target viral attachment to
host-cell receptors, virus entry, or virus uncoating, e.g. Pleconaril,

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often non-sustained and rarely cause haemodynamic compromise

in adult viral myocarditis. The prognostic significance and optimal
management of non-sustained ventricular tachycardia in the
setting of acute myocarditis are not known. However, Q-waves
and a widened QRS complex, including left bundle branch block,
are associated with higher rates of death or cardiac
transplantation.90,93 95
Echocardiography is useful to exclude other causes of heart
failure and identify ventricular thrombi. There are no specific echocardiographic features of myocarditis.96,97 Indeed, segmental or
global wall motion abnormalities can mimic myocardial infarction.98
Patients with fulminant myocarditis tend to present with more
normal cardiac chamber dimensions and thickened walls, compared with patients with less acute myocarditis who have greater
left ventricular dilation and normal wall thickness.99 Right ventricular dysfunction is an uncommon but important predictor of death
or cardiac transplantation.100 Newer imaging techniques including
strain echocardiography may have better specificity and specificity
for myocarditis.
Cardiovascular magnetic resonance (CMR) in suspected myocarditis can localize and quantitate tissue injury, including
oedema, hyperaemia, and fibrosis.101 In a recent series of 82
patients with myocarditis all of whom had biopsy-proven disease,
CMR alone made the correct diagnosis in 80% (66 out of 82)
cases.102 However, both T2- and T1-weighted imaging are
needed to achieve optimal sensitivity and specificity, and in contrast to older reports, CMR abnormalities do not correlate
closely with endomyocardial biopsy (EMB) evidence of myocarditis.39 When two or more of the three Lake Louise criteria are
positive, myocardial inflammation can be predicted with a diagnostic accuracy of 78%; if only delayed, post-gadolinium enhancement
imaging is performed, the diagnostic accuracy drops to 68%.101
Prospective clinical studies of the prognostic value of CMR are
needed to identify whether tissue characterization adds to the
management or outcome of patients with myocarditis.
Confirmation of myocarditis still requires histological or immunohistological evidence of inflammation in heart tissue. Endomyocardial biopsy can be performed with a very low major
complication rate when performed by highly experienced operators.103 In experienced hands, left ventricular biopsy is as safe
as right ventricular biopsy.39 An AHA/ACCF/ESC joint scientific
statement recommended that EMB should be performed (Class I
indication) in patients with heart failure and (i) a normal sized
or dilated left ventricle, ,2 weeks of symptoms, and haemodynamic compromise and also in (ii) patents with a dilated ventricle, 2 weeks to 3 months of symptoms, new ventricular
arrhythmias or Mobitz type II second degree or third degree
heart block, or who fail to respond to usual care within 1 2
weeks.104 More recently, EMB-based criteria (inflammation
present by immunohistology and viral genomes absent by polymerase chain reaction) have been used to define a cohort of
patients with chronic DCM who respond to immunosuppression.105 In clinical practice, EMB should be used in those scenarios
in which the incremental prognostic and therapeutic information
gained from biopsy outweighs the risk and cost. This will vary by
medical centre, depending on availability of necessary facilities
and expertise.

Page 8 of 13
WIN 54954, or soluble CAR-Fc, would be effective in the early
stages, but, unfortunately, most adult patients present in the
chronic phases of disease (Figure 1).112 These agents, therefore,
are of limited use in virus-associated heart disease. The current
challenge of antiviral therapy in patients with chronic cardiac viral
infections therefore is the timing of treatment that prevents progressive myocardial injury by viral clearance before chronically
infected heart tissue has irreversible damage.

Treatment of chronic viral heart disease

uncommonly observed in infections such as parvovirus B19 or

human herpesvirus 6 which according to a distinct pathophysiology
do not directly affect contractile cells of the myocardium.
Parvovirus B19 and human herpes virus 6 respond less well upon
IFN-b treatment with respect to virus clearance and haemodynamic
changes, although affected patients too improve clinically despite
incomplete virus clearance following reduction of virus load and/or
improvement of endothelial dysfunction.114,115 Complete clearance
of those viruses may need longer treatment intervals, higher doses,
or even a complete change of the antiviral treatment regimens. Currently, effective treatment conditions for viruses other than enterovirus and adenovirus have not yet been tested consequently.
Information taken from uncontrolled cohorts of treated viruspositive patients may be, however, of limited value for general
treatment recommendations for a number of reasons. According
to animal and cell culture studies, different viruses and even different virus subtypes may respond in distinct and unpredictable ways
to immunomodulatory treatment. Furthermore, virus load and the
type of the infected cell, both of which influence course of the
disease and drug response, have to be taken into consideration.
Despite such comprehensible reservations, a recent randomized,
placebo controlled phase II trial (BICC-Study) has confirmed that
even patients with a long history who had not responded to conventional heart failure treatment can get clinical and haemodynamic benefit from an IFN therapy.115
Response to the IFN-b1a therapy may be influenced by the
virus-associated local inflammation and the extent of the myocardial
injury at the time when the specific therapy is started. The lack of
haemodynamic improvement in some of the patients is not unexpected, if the long history and the above-mentioned pathogenetic suggestions are taken into consideration. In view of the information
derived from other virus infections of the heart, one can expect that
the chronic enteroviral and adenoviral infections or the
virus-associated inflammatory process may already have caused considerable myocardial damage and consequently, ventricular dysfunction may be unable to recover completely in those patients who did
not improve despite virus clearance. Nevertheless, the complete
clearance of both viruses after treatment suggests that early biopsybased diagnosis and timely treatment may prevent disease progression
and thereby improve the outcome of chronic viral cardiomyopathy.
Select knowledge gaps and opportunities in the treatment of
myocarditis
Studies have not been done to determine when and how to
discontinue standard heart failure therapy in patients who
recovery LV function.
More work is needed to identify patient cohorts who will
benefit from tailored antiviral or immunosuppressive
therapy.
The optimal time frame to initiate immunosuppressive treatment improves cardiac function and health without impairment of a healing immune processes is unknown.
With respect to our limited knowledge of involved pathological processes and optimal treatment conditions, prevention of disease progression rather than curative treatment
may turn out to be the most realistic short-term goal.

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Interferon-beta
Interferons serve as a natural defense against many viral infections.
Their innate production is associated with clinical recovery from
viral infection and subsequent sequelae, while exogenous administration is protective. Type I interferons therefore constitute a
promising choice for treatment of chronic viral cardiomyopathy.
Currently, there is no approved treatment for chronic viral heart
disease, but data from uncontrolled open labelled phase II
studies have demonstrated that subgroups of patients, who had
not improved upon regular heart failure medication, may get significant benefit even years after onset of chronic disease.
In a first study, patients with persistent enterovirus and adenovirus
infections of the myocardium responded well to a 6-months
interferon-beta (IFN-b1a) course.113 Complete elimination of
enteroviral and adenoviral genome was proved by follow-up biopsies
taken 3 month after termination of the antiviral therapy. Virus clearance was paralleled by an improvement of mean left ventricular function, a decrease in ventricular size, an amelioration of heart failure
symptoms, and a decrease of infiltrating inflammatory cells. Of
note, no patient deteriorated and patients with severely affected
LV-dysfunction gained most benefit.113
The drug is usually administered subcutaneously every other day
in addition to constant heart failure medication for a 6months
period. In order to limit IFN-specific side effects, the patient
should enter a run-in period to improve tolerance following a
stepped regimen, during which the patient receives 2 106 IU
IFN-b per application every other day for 1 week. Within the following 2 weeks, the study medication can be elevated to 4 106
and 6 106 IU IFN-b, respectively, and continued for the following 21 weeks. The IFN-b1a medication was well tolerated with no
unexpected non-cardiologic or cardiologic side effects. Frequently
reported IFN-associated side effects were fatigue, influenza-like
symptoms, and injection site erythema but symptoms vanished regularly during the first 4 weeks of treatment. No major clinical
events occurred during the treatment phase or follow-up.
If patients with a severely depressed cardiac contractility (LVEF
,25%) are treated with an immunmodulatory drug such as IFN-b,
LV function should be close-mesh monitored by echocardiography.
Between Week 4 and 12, patients complain for a mild aggravation of
heart failure symptoms which is often associated with a wall
oedema, a slight increase of LV-dimensions and a minor deterioration
of LVEF. Complains regularly disappear within 1 or 2 weeks followed
by an direct and continuous improvement of heart failure in 40% of
patients. Improvement may start with a delay of for 24 months in
2530% of patients. This outlined course, which is probably caused
by an IFN-induced cellular immune response, preferentially concerns
viruses that infect cardiomyocytes (e.g. enteroviruses). It is

H.-P. Schultheiss et al.

The management of myocarditis

Immunosuppression

cardiomyopathy is an effective and safe option in addition to supportive treatment for recovery of cardiac failure. However, larger
studies powered to detect a difference in clinical endpoints such as
heart failure hospitalization, transplantation, and death are still
needed.

Intravenous immunoglobulin
and immunoadsorption
The first data of acute myocarditis treated with intravenous immunoglobulin (IVIG) suggested that use of high-dose IVIG for treatment of acute myocarditis is associated with improved recovery
of left ventricular function and with a tendency to better survival
during the first year after presentation.122 Later investigations
and randomized studies which compared IVIG and cortisone treatment revealed that the treatment with intravenous immune globulin in children was not effective.123 Freedom from death or
transplantation was 81% at 1 year, and 74% at 5 years, with no
difference between the modes of treatments. The median time
to recovery of function was also comparable between the
groups. Thus, treatment with intravenous immune globulin
appear to confer no advantage to steroid therapy alone.124
The rationale for immunoadsorption is to lower cardiotoxic
antibodies in the patients plasma, and with serial treatments
over 5 or more days, extract antibodies and immune complexes
from the heart as well. The plasma is separated from cellular components by a centrifuge or column and passed through an immunoadsorbtion column. IgG and to a lesser degree IgA and IgM
are non-specifically adsorbed during repetitive sessions. Plasma
IgG levels are partially restored by infusion of 0.5 g/kg polyclonal
IgG .18 h after the last apheresis treatment. The favourable
haemodynamic results of immunoadsorption in patients with
DCMi may be related to removal of functionally active cardiac
autoantibodies or other immunologically active compounds, since
immunoadsorption leads to biopsy-proven decrease in lymphocytic infiltration and CAM expression.

Summary and perspectives

Current
pharmacological
heart
failure
therapy
of
myocarditis-associated cardiomyopathy mainly focuses on decreasing the activity of the neuroendocrine system but does not directly
influence
virus-induced
inflammatory
cardiomyopathy.
Interferon-b suppresses erythrovirus replication while at the
same time it improves replication and viability of human ECs.46
Accumulating experimental and clinical data indicate that cellular
transplantation may improve myocardial function.26,125,126
Mesenchymal stem cells (MSCs) have anti-apoptotic, anti-fibrotic
properties, are non-immunogenic, and possess immunomodulatory
properties.127 129 They suppress T-cell responses, induce apoptosis of activated T cells and increase T regulatory cells.130 132
Interferon-g primes MSC-mediated immunoregulatory effects
and induces nitric oxide (NO) production in MSCs the latter of
which exerts anti-apoptotic effects on cardiomyocytes and has
antiviral properties in a NO-dependent manner.129,133 135 These
different strategies including pharmacological and gene therapeutic

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Myocardial inflammatory processes due to pathogenic autoimmunity may survive myocardial virus elimination and warrant immunosuppressive treatment in order to prevent later immune-mediated
myocardial injury.116 118 Immunosuppression demands biopsybased exclusion of virus from treated patients since virus-positive
patients do not improve upon anti-inflammatory treatment, while
virus-negative patients with post-infectious or auto-immune inflammatory processes respond well in early clinical trials.105,117,119,120
Frequently administered anti-inflammatory drugs are immunoglobulins, corticosteroids, azathioprine, and cyclosporine, which
are administered on top of regular heart failure medication.
a-Methylprednisolone is generally given at Charite Hospital, at a
dose of 1 mg/kg body weight, initially for 4 weeks. Depending on
the body weight, azathioprine is administered at a dose of 100
150 mg daily in addition to the corticosteroid. The steroid
dosage is titrated down every 2 weeks in increments of 10 mg
until a maintenance dose of 10 mg is reached. The treatment duration should last for 3 to 6 months. Actual data of first randomized
trials confirm efficacy of those treatment regimens in carefully
selected patients.105,118
Sustained beneficial effects of immunosuppression on heart
failure symptoms, left ventricular dimensions, and LVEF in immunohistologically biopsy-proven inflammatory cardiomyopathy have
been confirmed in a randomized trial with 41 patients at 2 years
follow-up after 3 months of treatment with corticosteroids
and azathioprine.118 This trial ultimately validates the diagnostic
sensitivity and accuracy of cell adhesion molecule (CAM) abundance for indlammatory cardiomyopathy (DCMi) even in the
absence of lymphocytic infiltration, possibly due to the close functional association between CAM induction and immunocompetent
infiltration and cytokine induction,121 and thus constitutes an
important criterion for selecting those patients who will likely
benefit from immunosuppression. Furthermore, this study
showed that a 3-month regimen may equally be effective as previous trials that used 6 months of immunosuppression, and that
beneficial effects last for an extended period of time (2 years). In
another recently published randomized trial (TIMIC study), the
authors confirmed a positive treatment response in patients with
chronic active myocarditis.105 Thirty-eight out of 43 patients on
immunosuppressive therapy (88%) showed a improvement of
cardiac function and dimensions, defined as an increase of .10
percentage points in the absolute EF and a reduction of LV enddiastolic volume (EDV) or LV end-diastolic diameter (EDD) 10%
(i.e. LVEF from 26.4 + 6.9 to 48.0 + 7.3%, LVEDV from 258.0 +
52.5 to 125.9 + 29.6, and LVEDD from 68.6 + 7.4 to 52.8 +
6.3 mm). None of the untreated patients show at 6 month
improvement of LVEF, that significantly worsened compared with
baseline. In particular, 35 out of 42 patients (83%) showed
further impairment of cardiac function (LVEF from 27.6 + 6.6 to
19.5 + 4.8, LVEDV from 244.7 + 48.0 to 287.3 + 48.0, and
LVEDD from 69.2 + 7.9 to 75.3 + 7.4), while the remaining 7
patients remained stationary. Finally, LVEF declined to baseline
(27.2 + 5.6%) or lower (19.7 + 4.4%) values.
Currently available data show that immunosuppressive therapy
in patients with biopsy-proven, virus-negative inflammatory

Page 9 of 13

Page 10 of 13
approaches directed at blocking viral replication or stimulating the
antiviral-directed immune response, are under investigation in
experimental and clinical studies.70,114,136,137 Because of the low
rate of diagnosis, multi-centre collaborations with standardized
evaluations and treatment protocols, mechanistically oriented
registries, and core molecular diagnostic facilities will be needed.

Funding
Basic experimental diagnostic and clinical works have been supported
by a grant from the German Research Foundation (DFG), Transregional Collaborative Research Centre Inflammatory Cardiomyopathy
Molecular Pathogenesis and Therapy (SFB TR 19 04) (HPS, UK,
Charite Berlin).
Conflict of interest: none declared.

References

17. Vare D, Vare B, Dauphin C, Lafeuille H, Gaulme J, Labbe A, Motreff P, Lusson JR.
[Acute myocarditis in children. Study of 11 clinical cases]. Arch Mal Coeur Vaiss
2000;93:571 579.
18. Camargo PR, Okay TS, Yamamoto L, Del Negro GM, Lopes AA. Myocarditis in
children and detection of viruses in myocardial tissue: implications for immunosuppressive therapy. Int J Cardiol 2011;148:204248.
19. Kuhl U, Lassner D, Pauschinger M, Gross UM, Seeberg B, Noutsias M, Poller W,
Schultheiss HP. Prevalence of erythrovirus genotypes in the myocardium of
patients with dilated cardiomyopathy. J Med Virol 2008;80:1243 1251.
20. Kuhl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W,
Kandolf R, Schultheiss HP. High prevalence of viral genomes and multiple viral
infections in the myocardium of adults with idiopathic left ventricular dysfunction. Circulation 2005;111:887 893.
21. Pauschinger M, Bowles NE, Fuentes-Garcia FJ, Pham V, Kuhl U,
Schwimmbeck PL, Schultheiss HP, Towbin JA. Detection of adenoviral
genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 1999;99:1348 1354.
22. Pauschinger M, Doerner A, Kuehl U, Schwimmbeck PL, Poller W, Kandolf R,
Schultheiss HP. Enteroviral RNA replication in the myocardium of patients
with left ventricular dysfunction and clinically suspected myocarditis. Circulation
1999;99:889 895.
23. Modlin FJ. Picornaviridae. In: Mandell GL, Douglas RG, Bennett JE Jr (eds), Principles and Practice of Infectious Diseases. New York: Chrchill Livingstone; 1990,
p721 732.
24. Fujioka S, Kitaura Y, Ukimura A, Deguchi H, Kawamura K, Isomura T, Suma H,
Shimizu A. Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2000;36:1920 1926.
25. Chow LH, Beisel KW, McManus BM. Enteroviral infection of mice with severe
combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab Invest 1992;66:24 31.
26. Yuan JP, Zhao W, Wang HT, Wu KY, Li T, Guo XK, Tong SQ. Coxsackievirus
B3-induced apoptosis and caspase-3. Cell Res 2003;13:203 209.
27. Bultmann BD, Klingel K, Sotlar K, Bock CT, Baba HA, Sauter M, Kandolf R. Fatal
parvovirus B19-associated myocarditis clinically mimicking ischemic heart
disease: an endothelial cell-mediated disease. Hum Pathol 2003;34:9295.
28. Bock CT, Klingel K, Aberle S, Duechting A, Lupescu A, Lang F, Kandolf R. Human
parvovirus B19: a new emerging pathogen of inflammatory cardiomyopathy. J Vet
Med 2005;52:340 343.
29. Klingel K, Sauter M, Bock CT, Szalay G, Schnorr JJ, Kandolf R. Molecular pathology of inflammatory cardiomyopathy. Med Microbiol Immunol (Berl) 2004;193:
101 107.
30. Krueger GRF, Rojo J, Buja LM, Lassner D, Kuehl U. Human herpesvirus-6
(HHV-6) is a possible cardiac pathogen: an immunihistological and ultrastructural study. Hosp Gen 2008;71:187 191.
31. Brown KE, Anderson SM, Young NS. Erythrocyte P antigen: cellular receptor for
B19 parvovirus. Science 1993;262:114 117.
32. Weigel-Kelley KA, Yoder MC, Srivastava A. Alpha5beta1 integrin as a cellular
coreceptor for human parvovirus B19: requirement of functional activation of
beta1 integrin for viral entry. Blood 2003;102:3927 3933.
33. Munakata Y, Saito-Ito T, Kumura-Ishii K, Huang J, Kodera T, Ishii T, Hirabayashi Y,
Koyanagi Y, Sasaki T. Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection. Blood 2005;106:3449 3456.
34. Vallbracht KB, Schwimmbeck PL, Kuhl U, Seeberg B, Schultheiss HP.
Endothelium-dependent flow-mediated vasodilation of systemic arteries is
impaired in patients with myocardial virus persistence. Circulation 2004;110:
2938 2945.
35. Tschope C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck PL,
Pauschinger M, Poller WC, Kuhl U, Kandolf R, Schultheiss HP. High prevalence
of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation 2005;111:879 886.
36. Vallbracht KB, Schwimmbeck PL, Kuhl U, Rauch U, Seeberg B, Schultheiss HP.
Differential aspects of endothelial function of the coronary microcirculation
considering myocardial virus persistence, endothelial activation, and myocardial
leukocyte infiltrates. Circulation 2005;111:1784 1791.
37. Lupescu A, Bock C-T, Lang PA, Aberle S, Kaiser H, Kandolf R, Lang F. Phospholipase A2 activity-dependent stimulation of Ca2+ entry by human parvovirus
B19 capsid protein VP1 J Virol 2006;80:11370 11380 doi:10.1128/JVI.01041-06.
38. Fischer D, Rossa S, Landmesser U, Spiekermann S, Engberding N, Hornig B,
Drexler H. Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J 2005;26:65 69.
39. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A,
Hill S, Mahrholdt H, Voehringer M, Schieber M, Klingel K, Kandolf R, Bohm M,
Sechtem U. Comparative evaluation of left and right ventricular endomyocardial

Downloaded from by guest on January 18, 2015

1. Taliercio CP, Olney BA, Lie JT. Myocarditis related to drug hypersensitivity. Mayo
Clin Proc 1985;60:463 468.
2. Guarner J, Paddock CD, Shieh WJ, Packard MM, Patel M, Montague JL,
Uyeki TM, Bhat N, Balish A, Lindstrom S, Klimov A, Zaki SR. Histopathologic
and immunohistochemical features of fatal influenza virus infection in children
during the 2003 2004 season. Clin Infect Dis 2006;43:132 140.
3. Liu PP, Schultheiss HP. Myocarditis. In: Baunwald, E. (ed), Heart Disease. 8th ed.
Philadelphia: W B Saunders Co; 2008, p1775 1792.
4. Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis 2010;52:274 288.
5. Calabrese F, Rigo E, Milanesi O, Boffa GM, Angelini A, Valente M, Thiene G. Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol 2002;11:
212 221.
6. Bowles NE, Kearney DL, Ni J, Perez-Atayde AR, Kline MW, Bricker JT,
Ayres NA, Lipshultz SE, Shearer WT, Towbin JA. The detection of viral
genomes by polymerase chain reaction in the myocardium of pediatric patients
with advanced HIV disease. J Am Coll Cardiol 1999;34:857 865.
7. Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss HP, McCarthy R,
Hare J, Bricker JT, Bowles KR, Towbin JA. Detection of viruses in myocardial
tissues by polymerase chain reaction. Evidence of adenovirus as a common
cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42:466 472.
8. Carturan E, Milanesi O, Kato Y, Giacometti C, Biffanti R, Thiene G, Calabrese F.
Viral detection and tumor necrosis factor alpha profile in tracheal aspirates from
children with suspicion of myocarditis. Diagn Mol Pathol 2008;17:21 27.
9. Comar M, DAgaro P, Campello C, Poli A, Breinholt JP III, Towbin JA, Vatta M.
Human herpes virus 6 in archival cardiac tissues from children with idiopathic
dilated cardiomyopathy or congenital heart disease. J Clin Pathol 2009;62:80 83.
10. Dettmeyer R, Baasner A, Schlamann M, Haag C, Madea B. Coxsackie B3 myocarditis in 4 cases of suspected sudden infant death syndrome: diagnosis by
immunohistochemical and molecular-pathologic investigations. Pathol Res Pract
2002;198:689 696.
11. Gouton M, Di Filippo S, Sassolas F, Stamm D, Bozio A, Floret D. [Acute infectious myocarditis in children. Apropos of 2 series from Lyon]. Arch Mal Coeur
Vaiss 1995;88:753759.
12. Martin AB, Webber S, Fricker FJ, Jaffe R, Demmler G, Kearney D, Zhang YH,
Bodurtha J, Gelb B, Ni J. Acute myocarditis. Rapid diagnosis by PCR in children.
Circulation 1994;90:330 339.
13. Munro K, Croxson MC, Thomas S, Wilson NJ. Three cases of myocarditis in
childhood associated with human parvovirus (B19 virus). Pediatr Cardiol 2003;
24:473 475.
14. Savon C, Acosta B, Valdes O, Goyenechea A, Gonzalez G, Pinon A, Mas P,
Rosario D, Capo V, Kouri V, Martinez PA, Marchena JJ, Rodriguez H,
Guzman MG. A myocarditis outbreak with fatal cases associated with adenovirus
subgenera C among children from Havana City in 2005. J Clin Virol 2008;43:
152 157.
15. Schowengerdt KO, Ni J, Denfield SW, Gajarski RJ, Bowles NE, Rosenthal G,
Kearney DL, Price JK, Rogers BB, Schauer GM, Chinnock RE, Towbin JA. Association of parvovirus B19 genome in children with myocarditis and cardiac allograft rejection: diagnosis using the polymerase chain reaction. Circulation 1997;
96:3549 3554.
16. Talsma MD, Kroos MA, Visser G, Kimpen JL, Niezen KE. A rare presentation of
childhood pompe disease: cardiac involvement provoked by Epstein-Barr virus
infection. Pediatrics 2002;109:e65.

H.-P. Schultheiss et al.

The management of myocarditis

40.

41.

42.

43.

44.
45.

46.

47.

48.
49.

51.

52.

53.

54.

55.
56.
57.

58.

59.
60.
61.
62.

63.

64.

65. Rutschow S, Leschka S, Westermann D, Puhl K, Weitz A, Ladyszenskij L,

Jaeger S, Zeichhardt H, Noutsias M, Schultheiss HP, Tschope C,
Pauschinger M. Left ventricular enlargement in coxsackievirus-B3 induced
chronic myocarditisongoing inflammation and an imbalance of the matrix
degrading system. Eur J Pharmacol 2009;630:145151.
66. Puglielli MT, Browning JL, Brewer AW, Schreiber RD, Shieh WJ, Altman JD,
Oldstone MB, Zaki SR, Ahmed R. Reversal of virus-induced systemic shock
and respiratory failure by blockade of the lymphotoxin pathway. Nat Med
1999;5:1370 1374.
67. Huber SA. Depletion of gammadelta+ T cells increases CD4+ FoxP3 (T regulatory) cell response in coxsackievirus B3-induced myocarditis. Immunology 2009;
127:567 576.
68. Frisancho-Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL,
Fairweather D. Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the
heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun
2009;23:649 657.
69. Rose NR. Autoimmunity in coxsackievirus infection. Curr Top Microbiol Immunol
2008;323:293 314.
70. Kuhl U, Schultheiss HP. Viral myocarditis: diagnosis, aetiology and management.
Drugs 2009;69:1287 1302.
71. Rose NR. Myocarditis: infection versus autoimmunity. J Clin Immunol 2009;29:
730 737.
72. Kim KS, Tracy S, Tapprich W, Bailey J, Lee CK, Kim K, Barry WH, Chapman NM.
5 -Terminal deletions occur in coxsackievirus B3 during replication in murine
hearts and cardiac myocyte cultures and correlate with encapsidation of
negative-strand viral RNA. J Virol 2005;79:7024 7041.
73. Okura Y, Yamamoto T, Goto S, Inomata T, Hirono S, Hanawa H, Feng L,
Wilson C, Kihara T, Izumi T, Shibata A, Aizawa Y, Seki S, Abo T. Characterization
of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats. J Mol Cell Cardiol 1997;29:491502.
74. Kania G, Blyszczuk P, Stein S, Valaperti A, Germano D, Dirnhofer S, Hunziker L,
Matter CM, Eriksson U. Heart-infiltrating prominin-1/CD133 progenitor cells
represent the cellular source of transforming growth factor b-mediated
cardiac fibrosis in experimental autoimmune myocarditis. Circ Res 2009;105:
462 470.
75. Riad A, Westermann D, Escher F, Becher PM, Savvatis K, Lettau O,
Heimesaat MM, Bereswill S, Volk HD, Schultheiss HP, Tschope C. Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo. Am J Physiol Heart Circ Physiol 2010;298:
H2024 H2031.
76. Rutschow S, Li J, Schultheiss HP, Pauschinger M. Myocardial proteases and
matrix remodeling in inflammatory heart disease. Cardiovasc Res 2006;69:
646 656.
77. Frisancho-Kiss S, Coronado M, Frisancho J, Lau V, Rose N, Klein S,
Fairweather D. Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the
heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun
2009;23:649 657.
78. Fairweather D, Frisancho-Kiss S, Yusung S, Barrett M, Davis S, Gatewood S,
Njoku D, Rose N. Interferon-gamma protects against chronic viral myocarditis
by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.
Am J Pathol 2004;165:1883 1894.
79. Eriksson U, Ricci R, Hunziker L, Kurrer MO, Oudit GY, Watts TH,
Sonderegger I, Bachmaier K, Kopf M, Penninger JM. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003;9:1484 1490.
80. Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO,
Komnenovic V, Penninger JM, Eriksson U. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp
Med 2006;205:2009 2019.
81. Valaperti A, Marty RR, Kania G, Germano D, Mauermann N, Dirnhofer S,
Leimenstoll B, Blyszczuk P, Dong C, Mueller C, Lukas Hunziker L, Eriksson U.
CD11b monocytes abrogate Th17 CD4 T cell-mediated experimental autoimmune myocarditis. J Immunol 2008;180:2686 2695.
82. Amabile N, Fraisse A, Bouvenot J, Chetaille P, Ovaert C. Outcome of acute fulminant myocarditis in children. Heart 2006;92:1269 1273.
83. Cocker MS, Abdel-Aty H, Strohm O, Friedrich MG. Age and gender effects on
the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart 2009;95:1925 1930.
84. Mason JW, OConnell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME,
Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The
Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269 275.

Downloaded from by guest on January 18, 2015

50.

biopsy: differences in complication rate and diagnostic performance. Circulation

2010;122:900909.
Moffat S, Yaegashi N, Tada K, Tanaka N, Sugamura K. Human parvovirus B19
nonstructural (NS1) protein induces apoptosis in erythroid lineage cells. J Virol
1998;72:3018 3028.
Hsu TC, Tzang BS, Huang CN, Lee YJ, Liu GY, Chen MC, Tsay G. Increased
expression and secretion of interleukin-6 in human parvovirus B19 nonstructural protein (NS1) transfected COS-7 epithelial cells. Clin Exp Immunol
2006;144:152157.
Fu Y, Ishii KK, Munakata Y, Saitoh T, Kaku M, Sasaki T. Regulation of tumor
necrosis factor alpha promotor by human parvovirus B19 NS1 through activation of AP-1 and AP-2. J Virol 2008;82:7942 7952.
Duechting A, Tschope C, Kaiser H, Lamkemeyer T, Tanaka N, Aberle S, Lang F,
Torresi J, Kandolf R, Bock C-T. Human parvovirus B19 NS1 protein modulates
inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells.
J Virol 2008;82:7942 7952.
Poole BD, Karetny YV, Naides S. Parvovirus B19-induced apoptosis of hepatocytes. J Virol 2004;78:7775 7783.
Poole BD, Zhou J, Grote A, Schiffenbauer A, Naides SJ. Apoptosis of liverderived cells induced by parvovirus B19 nonstructural protein. J Virol 2006;80:
41144121.
Schmidt-Lucke C, Spillmann F, Bock T, Kuhl U, Van Linthout S, Schultheiss HP,
Tschope C. Interferon beta modulates endothelial damage in patients with
cardiac persistence of human parvovirus B19 infection. J Infect Dis 2010;201:6.
Rotola A, Di Luca D, Cassai E, Ricotta D, Giulio A, Turano A, Caruso A,
Muneretto C. Human herpesvirus 6 infects and replicates in aortic endothelium.
J Clin Microbiol 2000;38:3135 3136.
Wu CA, Shanley JD. Chronic infection of human umbilical vein endothelial cells
by human herpesvirus-6. J Gen Virol 1998;79:1247 1256.
Aita K, Jin Y, Irie H, Takahashi I, Kobori K, Nakasato Y, Kodama H, Yanagawa Y,
Yoshikawa T, Shiga J. Are there histopathologic characteristics particular to fulminant hepatic failure caused by human herpesvirus-6 infection? A case report
and discussion. Hum Pathol 2001;32:887889.
Caruso A, Rotola A, Comar M, Favilli F, Galvan M, Tosetti M, Campello C,
Caselli E, Alessandri G, Grassi M, Garrafa E, Cassai E, Di Luca D. HHV-6
infects human aortic and heart microvascular endothelial cells, increasing their
ability to secrete proinflammatory chemokines. J Med Virol 2002;67:528 533.
Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T,
Kanamaru A, Kakishita E. Endothelial damage caused by cytomegalovirus and
human herpesvirus-6. Bone Marrow Transplant 2003;31:475 479.
Badorff C, Lee GH, Lamphear BJ, Martone ME, Campbell KP, Rhoads RE,
Knowlton KU. Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 1999;5:320 326.
Kuhl U, Pauschinger M, Bock T, Klingel K, Schwimmbeck CP, Seeberg B,
Krautwurm L, Poller W, Schultheiss HP, Kandolf R. Parvovirus B19 infection
mimicking acute myocardial infarction. Circulation 2003;108:945 950.
Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G,
Voehringer M, Kispert EM, Deluigi C, Baccouche H, Spodarev E, Klingel K,
Kandolf R, Sechtem U. Coronary vasospasm as the underlying cause for chest
pain in patients with PVB19 myocarditis. Heart 2008;94:1456 1463.
Bock CT, Klingel K, Kandolf R. Human parvovirus B19-associated myocarditis. N
Engl J Med 2010;362:1248 1249.
Mason JW. Myocarditis and dilated cardiomyopathy: an inflammatory link. Cardiovasc Res 2003;60:510.
Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS,
Horwitz MS, Crowell RL, Finberg RW. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997;275:1320 1323.
Martino TA, Petric M, Brown M, Aitken K, Gauntt CJ, Richardson CD, Chow LH,
Liu PP. Cardiovirulent coxsackieviruses and the decay-accelerating factor
(CD55) receptor. Virology 1998;244:302 314.
Liu PP, Opavsky MA. Viral myocarditis: receptors that bridge the cardiovascular
with the immune system?. Circ Res 2000;86:253 254.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell
2006;124:783801.
Kawai T, Akira S. TLR signaling. Cell Death Differ 2006;13:816825.
Yuan J, Cao AL, Yu M, Lin QW, Yu X, Zhang JH, Wang M, Guo HP, Liao YH.
Th17 cells facilitate the humoral immune response in patients with acute viral
myocarditis. J Clin Immunol 2010;30:226 234.
Yuan J, Yu M, Lin QW, Cao AL, Yu X, Dong JH, Wang JP, Zhang JH, Wang M,
Guo HP, Cheng X, Liao YH. Th17 cells contribute to viral replication in coxsackievirus B3-induced acute viral myocarditis. J Immunol 2010;185:4004 4010.
Yuan J, Yu M, Lin QW, Cao AL, Yu X, Dong JH, Wang JP, Zhang JH, Wang M,
Guo HP, Liao YH. Neutralization of IL-17 inhibits the production of anti-ANT
autoantibodies in CVB3-induced acute viral myocarditis. Int Immunopharmacol
2010;10:272276.

Page 11 of 13

Page 12 of 13

107.

108.

109.
110.

111.

112.

113.

114.

115.

116.

117.
118.

119.

120.

121.

122.

123.
124.

125.

AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in
Adults A Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am
Coll Cardiol 2009;53:e1 e90.
Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM,
Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG,
Tang WH, Teerlink JR, Walsh MN. HFSA 2010 Comprehensive Heart Failure
Practice Guideline. J Card Fail 16:e1 194.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P,
Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW,
Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, Vahanian A,
Camm J, De Caterina R, Dean V, Funck-Brentano C, Hellemans I,
Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P,
Zamorano JL. ESC Guidelines for the diagnosis and treatment of acute and
chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of
Acute and Chronic Heart Failure 2008 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association of the ESC
(HFA) and endorsed by the European Society of Intensive Care Medicine
(ESICM). Eur Heart J 2008;29:2388 2442.
Rezkalla SH, Raikar S, Kloner RA. Treatment of viral myocarditis with focus on
captopril. Am J Cardiol 1996;77:634 637.
Saegusa S, Fei Y, Takahashi T, Sumino H, Moriya J, Kawaura K, Yamakawa J,
Itoh T, Morimoto S, Nakahashi T, Iwai K, Matsumoto M, Kanda T. Oral administration of candesartan improves the survival of mice with viral myocarditis
through modification of cardiac adiponectin expression. Cardiovasc Drugs Ther
2007;21:155 160.
Costanzo-Nordin MR, Reap EA, JB OC, Robinson JA, Scanlon PJ. A nonsteroid
anti-inflammatory drug exacerbates Coxsackie B3 murine myocarditis. J Am Coll
Cardiol 1985;6:1078 1082.
Schultheiss HP, Kuehl U. Cardiovascular viral infections. In: Lennette EH (ed),
Lennettes Laboratory Diagnosis of Viral Infections, Chapter 18. 4th ed. New York:
Informa Healthcare USA Inc; 2010, p304 318.
Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M,
Poller W, Schultheiss HP. Interferon-beta treatment eliminates cardiotropic
viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003;107:
2793 2798.
Schmidt-Lucke C, Spillmann F, Bock T, Van Linthout S, Kuhl U, Schultheiss HP,
Tschoepe C. Interferon-beta modulates endothelial damage in patients with
cardiac persistance of parvovirus B19V. J Infect Dis 2010;201:936 945.
Schultheiss HP, Piper C, Sowade K, Karason JF, Kapp G, Groetzbach F,
Waagstein E, Arbustini E, Siedentop H, Kuehl U. The effect of subcutaneous
treatment with interferon-beta-1b over 24 weeks on safety, virus elimination
and clinical outcome in patients with chronic viral cardiomyopathy. Eur Heart J
2009;30:1995 2002.
Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J 2009;30:1995 2002.
Kuhl U, Strauer BE, Schultheiss HP. Methylprednisolone in chronic myocarditis.
Postgrad Med J 1994;70:S35 S42.
Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G,
Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J.
Randomized, placebo-controlled study for immunosuppressive treatment of
inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation
2001;104:3945.
Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic
profile of responders versus nonresponders. Circulation 2003;107:857 863.
Stanton C, Mookadam F, Cha S, McNamara D, Aukrust P, Wojnicz R, Bailey KR,
Cooper LT. Greater symptom duration predicts response to immunomodulatory therapy in dilated cardiomyopathy. Int J Cardiol 2008;128:38 41.
Noutsias M, Seeberg B, Schultheiss HP, Kuhl U. Expression of cell adhesion molecules in dilated cardiomyopathy: evidence for endothelial activation in inflammatory cardiomyopathy. Circulation 1999;99:2124 2131.
Drucker NA, Colan SD, Lewis AB, Beiser AS, Wessel DL, Takahashi M,
Baker AL, Perez-Atayde AR, Newburger JW. Gamma-globulin treatment of
acute myocarditis in the pediatric population. Circulation 1994;89:252 257.
English RF, Janosky JE, Ettedgui JA, Webber SA. Outcomes for children with
acute myocarditis. Cardiol Young 2004;14:488 493.
Klugman D, Berger JT, Sable CA, He J, Khandelwal SG, Slonim AD. Pediatric
patients hospitalized with myocarditis: a multi-institutional analysis. Pediatr
Cardiol 2009;31:222 228.
Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP,
Gerstenblith G, DeMaria AN, Denktas AE, Gammon RS, Hermiller JB Jr,

Downloaded from by guest on January 18, 2015

85. Grimm W, Glaveris C, Hoffmann J, Menz V, Muller HH, Hufnagel G, Maisch B.

Arrhythmia risk stratification in idiopathic dilated cardiomyopathy based on
echocardiography and 12-lead, signal-averaged, and 24-hour holter electrocardiography. Am Heart J 2000;140:4351.
86. Soongswang J, Durongpisitkul K, Nana A, Laohaprasittiporn D, Kangkagate C,
Punlee K, Limpimwong N. Cardiac troponin T: a marker in the diagnosis of
acute myocarditis in children. Pediatr Cardiol 2005;26:45 49.
87. Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations of cardiac troponin I
associated with myocarditis. Experimental and clinical correlates. Circulation
1997;95:163 168.
88. Franz WM, Remppis A, Kandolf R, Kubler W, Katus HA. Serum troponin T: diagnostic marker for acute myocarditis. Clin Chem 1996;42:340 341.
89. Lauer B, Niederau C, Kuhl U, Schannwell M, Pauschinger M, Strauer BE,
Schultheiss HP. Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol 1997;30:1354 1359.
90. Morgera T, Di Lenarda A, Dreas L, Pinamonti B, Humar F, Bussani R, Silvestri F,
Chersevani D, Camerini F. Electrocardiography of myocarditis revisited: clinical
and prognostic significance of electrocardiographic changes. Am Heart J 1992;
124:455 467.
91. Vignola PA, Aonuma K, Swaye PS, Rozanski JJ, Blankstein RL, Benson J,
Gosselin AJ, Lister JW. Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to
immunosuppression. J Am Coll Cardiol 1984;4:812 819.
92. Dec GW Jr, Waldman H, Southern J, Fallon JT, Hutter AM Jr, Palacios I. Viral
myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol 1992;20:
85 89.
93. Magnani JW, Danik HJ, Dec GW Jr, DiSalvo TG. Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathologic, clinical, and
hemodynamic predictors. Am Heart J 2006;151:463470.
94. Nakashima H, Katayama T, Ishizaki M, Takeno M, Honda Y, Yano K. Q wave and
non-Q wave myocarditis with special reference to clinical significance. Jpn Heart J
1998;39:763 774.
95. Greenwood RD, Nadas AS, Fyler DC. The clinical course of primary myocardial
disease in infants and children. Am Heart J 1976;92:549 560.
96. Pinamonti B, Alberti E, Cigalotto A, Dreas L, Salvi A, Silvestri F, Camerini F.
Echocardiographic findings in myocarditis. Am J Cardiol 1988;62:285291.
97. Escher F, Westermann D, Gaub R, Pronk J, Bock T, Al-Saadi N, Kuhl U,
Schultheiss HP, Tschope C. Development of diastolic heart failure in a 6-year
follow-up study in patients after acute myocarditis. Heart 2011;97:709714.
98. Angelini A, Calzolari V, Calabrese F, Boffa GM, Maddalena F, Chioin R, Thiene G.
Myocarditis mimicking acute myocardial infarction: role of endomyocardial
biopsy in the differential diagnosis. Heart 2000;84:245 250.
99. Felker GM, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Baughman KL,
Hare JM. Echocardiographic findings in fulminant and acute myocarditis. J Am
Coll Cardiol 2000;36:227232.
100. Mendes LA, Dec GW, Picard MH, Palacios IF, Newell J, Davidoff R. Right ventricular dysfunction: an independent predictor of adverse outcome in patients with
myocarditis. Am Heart J 1994;128:301 307.
101. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT,
White JA, Abdel-Aty H, Gutberlet M, Prasad S, Aletras A, Laissy JP, Paterson I,
Filipchuk NG, Kumar A, Pauschinger M, Liu P. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 2009;53:1475 1487.
102. Baccouche H, Mahrholdt H, Meinhardt G, Merher R, Voehringer M, Hill S,
Klingel K, Kandolf R, Sechtem U, Yilmaz A. Diagnostic synergy of non-invasive
cardiovascular magnetic resonance and invasive endomyocardial biopsy in
troponin-positive patients without coronary artery disease. Eur Heart J 2009;
30:2869 2879.
103. Holzmann M, Nicko A, Kuhl U, Noutsias M, Poller W, Hoffmann W, Morguet A,
Witzenbichler B, Tschoepe C, Schultheiss HP, Pauschinger M. Complication rate
in right ventricular endomyocardial biopsya retro- and prospective study over
a 11 year period analyzing 3048 diagnostic procedures. Circulation 2008;118:
667 671.
104. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U,
Levine GN, Narula J, Starling RC, Towbin J, Virmani R. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement
from the American Heart Association, the American College of Cardiology,
and the European Society of Cardiology. Endorsed by the Heart Failure
Society of America and the Heart Failure Association of the European Society
of Cardiology. J Am Coll Cardiol 2007;50:1914 1931.
105. Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Circulation 2008;118:667 671.
106. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG,
Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA,
Stevenson LW, Yancy CW. 2009 Focused update incorporated into the ACC/

H.-P. Schultheiss et al.

The management of myocarditis

126.

127.

128.

129.

130.

131.

Reisman MA, Schaer GL, Sherman W. A randomized, double-blind, placebocontrolled, dose-escalation study of intravenous adult human mesenchymal
stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol
2009;54:2277 2286.
Yerebakan C, Kaminski A, Liebold A, Steinhoff G. Safety of intramyocardial stem
cell therapy for the ischemic myocardium: results of the Rostock trial after
5-year follow-up. Cell Transplant 2007;16:935 940.
Li JH, Zhang N, Wang JA. Improved anti-apoptotic and anti-remodeling potency
of bone marrow mesenchymal stem cells by anoxic pre-conditioning in diabetic
cardiomyopathy. J Endocrinol Invest 2008;31:103110.
Ohnishi S, Sumiyoshi H, Kitamura S, Nagaya N. Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine
actions. FEBS Lett 2007;581:3961 3966.
Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of
chemokines and nitric oxide. Cell Stem Cell 2008;2:141 150.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P,
Grisanti S, Gianni AM. Human bone marrow stromal cells suppress Tlymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.
Blood 2002;99:3838 3843.
Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC. Mesenchymal
stem cells induce apoptosis of activated T cells. Leukemia 2005;19:1597 1604.

Page 13 of 13
132. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D,
Sportoletti P, Falzetti F, Tabilio A. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 2008;36:309 318.
133. Oh I, Ozaki K, Sato K, Meguro A, Tatara R, Hatanaka K, Nagai T, Muroi K,
Ozawa K. Interferon-gamma and NF-kappaB mediate nitric oxide production
by mesenchymal stromal cells. Biochem Biophys Res Commun 2007;355:956 962.
134. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L,
Li N. A critical role of IFNgamma in priming MSC-mediated suppression of T cell
proliferation through up-regulation of B7-H1. Cell Res 2008;18:846 857.
135. Zell R, Markgraf R, Schmidtke M, Gorlach M, Stelzner A, Henke A, Sigusch HH,
Gluck B. Nitric oxide donors inhibit the coxsackievirus B3 proteinases 2A and
3C in vitro, virus production in cells, and signs of myocarditis in virus-infected
mice. Med Microbiol Immunol 2004;193:91 100.
136. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M,
Poller W, Schultheiss HP. Interferon-beta treatment eliminates cardiotropic
viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003;107:
2793 2798.
137. Pinkert S, Westermann D, Wang X, Klingel K, Dorner A, Savvatis K, Grossl T,
Krohn S, Tschope C, Zeichhardt H, Kotsch K, Weitmann K, Hoffmann W,
Schultheiss HP, Spiller OB, Poller W, Fechner H. Prevention of cardiac dysfunction in acute coxsackievirus B3 cardiomyopathy by inducible expression of a
soluble coxsackievirus-adenovirus receptor. Circulation 2009;120:2358 2366.

Downloaded from by guest on January 18, 2015