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Archives of cardiovascular diseases
Volume 102, n° 6-7
pages 559-568 (juin 2009)
Doi : 10.1016/j.acvd.2009.04.010
Received : 3 Mars 2009 ;  accepted : 21 April 2009
Viral causes of human myocarditis
Étiologies virales des myocardites
 

Laurent Andréoletti a, b, , Nicolas Lévêque a, b, Camille Boulagnon c, Camille Brasselet d, Paul Fornes c
a Laboratoire de virologie médicale et moléculaire, hôpital Robert-Debré, CHU de Reims, avenue du Général-Koenig, 51092 Reims cedex, France 
b EA4303/IFR53, faculté de médecine, Reims, France 
c Laboratoire d’anatomopathologie, hôpital Robert-Debré, CHU de Reims, Reims, France 
d Service de cardiologie, hôpital Robert-Debré, CHU de Reims, Reims, France 

Corresponding author. Fax: +33 3 26 78 41 34.
Summary

The diagnosis of acute myocarditis is complex and challenging. The use of the Dallas criteria in the diagnosis of myocarditis is associated with poor sensitivity and specificity because of the sampling error related to the often focal distribution of the specific histological lesions in cardiac tissue and the variability in pathological interpretation. To improve histological diagnosis, additional virological evaluation of cardiac tissues is required, with immunohistochemical and polymerase chain reaction (PCR) techniques allowing identification and quantification of viral infection markers. The diagnostic gold standard is endomyocardial biopsy (EMB) with the histological Dallas criteria, in association with new immunohistochemical and PCR analyses of cardiac tissues. Using real-time PCR and reverse transcription PCR assays, parvovirus B19, Coxsackie B virus, human herpesvirus 6 (HHV-6) type B and adenovirus have been detected in 37, 33, 11 and 8% of EMB, respectively, from young adults (aged<35 years) with histologically proven acute myocarditis. Viral co-infections have also been found in 12% of acute myocarditis cases, generally parvovirus B19 plus HHV-6. Moreover, herpesviruses such as the Epstein-Barr virus or cytomegalovirus can also be associated with myocarditis after heart transplantation. During the clinical course of myocarditis, the immunohistochemical detection of enterovirus, adenovirus or parvovirus B19 capsid proteins or herpesvirus late proteins is necessary to differentiate a viral cardiac infection with replication activities from a persistent or latent cardiac infection. These new viral diagnostic approaches can lead to better identification of the aetiology of myocarditis and may therefore enable the development and evaluation of specific aetiology-directed treatment strategies.

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Résumé

La myocardite aiguë reste actuellement un diagnostic complexe et un défi en cardiologie. La seule utilisation des critères de la classification histologique de Dallas ne permet pas un diagnostic sensible et spécifique de myocardite à cause de la distribution focale des lésions endomyocardiques ainsi que de la variabilité de l’interprétation anatomopathologique des résultats. Afin d’améliorer le diagnostic histologique de myocardite virale, l’analyse virologique des échantillons de tissus cardiaques par des approches immunohistochimiques et de biologie moléculaire (techniques de polymerase chain reaction [PCR]) est nécessaire car elle autorise l’identification et la quantification des marqueurs d’infection virale endomyocardique. Le diagnostic de certitude d’une myocardite virale ne peut être réalisé que grâce à l’analyse de différents fragments de tissus cardiaques ventriculaires qui seront obtenus par « biospie endomyocardique » permettant ainsi d’effectuer des analyses histologiques (critères de Dallas) qui seront associées à des tests immunohistochimiques et de biologie moléculaire. En utilisant des techniques de PCR et de reverse transcription polymerase chain reaction (RT-PCR) en temps réel, le parvovirus B19, le virus Coxsackie B , le virus human herpesvirus 6 (HHV6) type B et l’Adénovirus ont été respectivement détectés dans 37, 33, 11 et 8 % des biopsies endoymocardiques réalisées dans des cohortes de patients âgés de moins de 35 ans et qui présentaient une myocardite histologiquement documentée. Des co-infections virales ont été également détectées dans 12 % de ces cas de myocardites aiguës avec dans 60 % de ces cas une association entre le parvovirus B19 et le virus HHV6. De plus, des herpesvirus comme le CMVH et l’EBV peuvent aussi être responsables de myocardites post-transplantation atteignant le greffon cardiaque et cela plus particulièrement au cours de la première année suivant la greffe cardiaque. Au cours du processus physiopathologique et du diagnostic de myocardite virale, la détection immunohistochimique des protéines de capside virale ou des antigènes tardifs des enterovirus, herpesvirus , adenovirus et parvovirus B19 est nécessaire afin de différentier une infection cardiaque virale active d’une infection virale cardiaque persistante ou latente. Ces nouvelles approches diagnostiques combinant des techniques immunohistochimiques et de biologie moléculaire peuvent conduire à une meilleure identification et à une caractérisation des infections cardiaques virales responsables de myocardites ainsi qu’au développement et à l’évaluation de futures stratégies thérapeutiques antivirales spécifiques.

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Keywords : Cardiotropic virus, Myocarditis, Dilated cardiomyopathy, Sudden cardiac death, Diagnosis, Virology, Immunohistochemistry

Mots clés : Virus cardiotropes, Myocardite virale, Classification de Dallas, PCR, Immunohistochimie


Abbreviations

DCM : dilated cardiomyopathy
EMB : endomyocardial biopsy
HHV-6 : human herpesvirus 6
LVEF : left ventricular ejection fraction
PCR : polymerase chain reaction
RT-PCR : reverse transcription polymerase chain reaction

Background

Acute myocarditis remains a complex and challenging diagnosis in cardiology [1]. This cardiomyopathy is defined histologically by the Dallas criteria as an “inflammation of the myocardium” associated with necrosis and an absence of ischaemia [2, 3, 4, 5]. The use of the Dallas criteria in the diagnosis of myocarditis is associated with poor sensitivity and specificity, mainly because of the sampling error related to the often focal distribution of the specific histological lesions in cardiac tissue and because of the variability in pathological interpretation [6, 7]. Moreover, the Dallas classification does not consider local quantification and differentiation of inflammatory cells and does not take into account viral infection and autoimmune regulation in cardiac tissues [4]. To improve the histological diagnosis, additional virological and immunological evaluation of cardiac tissues is required using immunohistochemical and PCR techniques, which allow identification and quantification of inflammatory cells and viral infection markers [4]. The diagnostic gold standard is EMB with the histological Dallas criteria in association with new immunohistochemical and viral PCR analyses of cardiac tissues [8]. This new diagnostic approach can lead to better identification of the aetiological cause of the myocarditis and can therefore enable the development and evaluation of aetiology-directed treatment strategies.

Here, we present an overview of the pathogenesis of human myocarditis, focusing on the viral aetiology. We also examine the contribution and importance of the virological techniques used for the analysis of EMB samples and their potential impact on the clinical management and treatment of acute and chronic viral myocarditis cases.

Pathogenesis

Acute myocarditis can be caused by a toxic or allergic heart injury or can be associated with a systemic or infectious disease (Table 1) [5]. Current understanding of the pathogenesis of myocarditis is derived largely from virus-induced myocarditis in murine models [9, 10, 11]. The pathophysiological progression of virus-induced myocarditis is composed of three distinct phases [5]. During the first phase, direct destruction of the cardiomyocytes occurs by direct virus-mediated lysis associated with indirect myocyte destruction linked to the innate immune response that includes natural killer cells and macrophages, with subsequent expression of proinflammatory cytokines [5, 12, 13]. This innate immune response enhances cardiac cell injury and can also result in efficient viral clearance, which can correspond clinically to a non-symptomatic or subclinical myocarditis.

The second phase is characterized by an immune shift towards a specific immune response. The viral particles are captured by antigen-presenting cells and are degraded within the Golgi apparatus before being presented at the cell surface by the major histocompatibility complex class I to the CD8+ lymphocytes [14]. These primed T-cells are capable of detecting the viral antigen and destroy the infected cardiac cells through cytokine or perforine secretion [15]. The amplification of this phenomenon can lead to the destruction of cardiomyocytes. In addition, some host myocardial cellular antigens can share epitopic similarities (molecular mimicry) with viral antigens, and can therefore induce an autoimmune trait that can sustain the inflammatory response and hence the chronic inflammation phase (Figure 1) [5]. During the third phase, the pathological signs of myocarditis generally disappear and the destroyed myocytes are replaced by diffuse fibrosis (Figure 1) [16]. At this stage, evolutive biventricular dilatation with cardiac failure can be observed, which has been linked to a persistent virus or latent endomyocardial replication [17].



Figure 1


Figure 1. 

Pathophysiological process of viral myocarditis.

IL: interleukin; NO: nitric oxide; TNF: tumour necrosis factor; IFNs: interferons; NK: natural killer; CTL: cytotoxic T-lymphocyte.

Processus physiopathologique développé au cours d’une myocardite virale.

IL : interleukine ; NO : oxyde nitrique ; TNF : tumor necrosis factor ; IFNs : interférons ; NK : natural killer ; CTL : cytotoxic T lymphocyte.

Zoom

Natural history of viral myocarditis

Clinical manifestations of acute myocarditis range from non-specific systemic symptoms (fever, myalgia, palpitations or exertional dyspnoea) to fulminant haemodynamic collapse (five to 10 cases per million inhabitants per year) [4, 5]. Moreover, 10–20% of viral acute myocarditis cases evolve towards a chronic active phase characterized by an inflammatory infiltrate of mononuclear cells with evidence of myocyte necrosis and fibrosis, and then in 9% of cases towards a stage of DCM that at end-stage is a leading cause of cardiac transplantation [4, 5, 16]. In a series of human cases, viral persistence was seen in the myocardium of patients with histologically proven active chronic myocarditis associated with left ventricular systolic dysfunction related to a reduction in the contractile function of the myocytes [18]. Longitudinal studies showed that the immune clearance of the virus during or after the acute phase correlated with an improvement in LVEF [19]. Altogether, these clinical, histological and virological data have demonstrated the pathophysiological role of several human viruses in the genesis and evolution of myocarditis and DCM (Figure 2).



Figure 2


Figure 2. 

Acute myocarditis: evolution and clinical outcomes.

ARVD: arrhythmogenic right ventricular dysplasia.

Incidence and prevalence rates: refs [1, 3, 5].

a Undetermined.

Myocardite aiguë : évolution et issues cliniques ; ARVD : dysplasie arythmogénique droite ventriculaire.

Taux d’incidence et de prévalence : références [1, 3, 5].

Zoom

Recent prospective post-mortem data have implicated myocarditis in the sudden cardiac death of young adults at rates of 8.6–42% [20, 21, 22]. The reason for susceptibility to viral-induced myocarditis remains unclear (Figure 2). The cardiotropic viruses that cause myocarditis are common viral agents in human infectious diseases (Table 1) and one or more of them will infect more than 90% of subjects in their lifetime. Because less than 10% of these infected subjects develop histologically proven myocarditis, a specific genetic background, related or not to specific immune responses, may be a prerequisite for developing clinical acute or chronic myocarditis and/or progression to DCM after active viral infection of the heart [23]. In addition, dystrophin mutations may facilitate myocarditis and cardiac failure during human Coxsackie B3 virus infection, whereas dystrophin and/or sarcoglycan disruption by viral protease 2A accounts for myocardial injury in mice models and human cases [18]. Further experimental and clinical investigations are needed to investigate the underlying genetic susceptibility traits for acute or chronic symptomatic viral myocarditis.

Imaging tools in the diagnosis of myocarditis

Cardiac magnetic resonance imaging has emerged as an important tool in the diagnosis of human myocarditis [3]. Gadolinium late enhancement and T2-weighted image sequences can be used to distinguish between ischaemic and non-ischaemic cardiomyopathy [3]. Visual assessment of T2 images relating the signal intensity of the myocardium to that of skeletal muscle (if not affected) allows an estimation of global oedema and enables highly accurate identification of myocarditis (sensitivity 100%; specificity 90%) [4]. The combination of the cardiac magnetic resonance approach of T2-weighted imaging with early and late gadolinium enhancement can provide an accurate diagnosis and should be considered as a standard imaging procedure in patients in whom myocarditis is suspected [4].

Recently, the diagnostic contribution and the therapeutic and prognostic implications of three-dimensional electroanatomical mapping-guided EMB were evaluated in patients with arrhythmogenic right ventricular cardiomyopathy [24, 25]. Three-dimensional electroanatomical mapping-guided EMB appeared to be a safe and effective tool in the differential diagnosis of arrhythmogenic right ventricular cardiomyopathy and in the selection of the most appropriate therapeutic strategy [24, 25]. These recent findings suggested that the use of three-dimensional electroanatomical mapping-guided EMB might also be of major interest in patients with suspected myocarditis.

Viral aetiological cause of myocarditis

In Europe and the USA, viral aetiologies largely prevail over other causes of myocarditis (Table 1). Coxsackie virus, parvovirus B19, HHV-6 type B and the adenovirus are the most frequent aetiological viral agents implicated in acute myocarditis in children or young adults (aged<35 years) (Table 2) [19, 26, 27]. Human immunodeficiency virus and hepatitis C virus can be also aetiological agents of myocarditis [28, 29]. Recent data showed that it was possible to detect viruses in 67% of idiopathic left ventricular dysfunction cases using molecular techniques for the virological analysis of cardiac biopsy samples [27]. Co-infections were found in more than 12% of cases, generally HHV-6 plus parvovirus B19; HHV-6 seems to be an important cofactor in myocarditis caused by parvovirus B19 [27]. Other viruses, such as the Epstein-Barr virus or cytomegalovirus, are also associated with this pathology after heart transplantation [30].

With regard to chronic myocarditis, there are no data from transverse or longitudinal studies indicating the incidence of various viral causes of cardiac infection. However, viral persistence in the myocardium was associated with ventricular dysfunction whereas viral genome clearance was related to haemodynamic improvement [19]. DCM occurs after the chronic phase of myocarditis [3, 19]. The data published by our group and other teams show that enteroviral genomic RNA can be detected in 35% of cases [17]. In addition, the presence of the VP1 viral capsid protein can be highlighted by immunohistochemistry in myocardial samples fixed in 10% neutral buffered formalin and embedded in paraffin [31, 32]. The detection of VP1 is complementary and correlates with the detection of the viral genomic RNA in 60% of myocarditis cases [32]. As in the case of acute myocarditis, recent studies have tested a broad panel of cardiotropic viruses at the DCM stage; in a case series of 245 patients with clinically suggested DCM, one or more viruses were detected in 67.4% of patients (Table 2) [27]. In cases of herpesvirus, adenovirus or parvovirus B19 infections, a latent phase occurred after the acute phase, during which it was not possible to detect viral structural proteins (late proteins) but only viral enzymatic proteins (early proteins) related to the regulation of viral replication or associated with viral DNA replication [19, 30, 33]. However, the sites and mechanisms of persistence of herpesviruses and parvoviruses in heart tissues remain to be assessed.

Diagnosis of viral causes of myocarditis

The aetiological diagnosis of viral myocarditis, specifically during the acute phase, is based on the detection of viruses or viral components (proteins or genomes) in peripheral blood samples in the viraemia phase (characterized clinically by fever) and also at the entry and excretion sites (throat, urine and stool samples) and, of course, in heart tissue samples, which are the organ site of viral replication in myocarditis. EMB therefore remains the gold standard for establishing unequivocally the histopathological and virological diagnosis of unexplained cardiomyopathies as acute or chronic myocarditis [8, 34]. The clinical impact on prognosis and treatment depends largely on establishing a rapid and standardized set of diagnostic methods including histopathological and virological analyses of endomyocardial tissue taken by EMB [4, 8].

Endomyocardial biopsy

As recommended by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology, the implementation of a right or left ventricular EMB is indicated in cases of acute symptoms of heart failure refractory to standard management, a substantial worsening of ejection fraction despite optimized pharmacological therapy, the development of haemodynamically significant arrhythmia, heart failure with concurrent rash, fever or peripheral eosinophilia, a history of collagen vascular disease (such as systemic lupus, erythematosus, scleroderma or polyarteritis nodosum) and new-onset cardiomyopathy in the presence of known amyloidosis, sarcoidosis or haemochromatosis, when no obvious cause (particularly ischaemic) can be established [8]. EMB remains the gold standard for establishing unequivocally the diagnosis of unexplained cardiomyopathy [8]. However, its sensitivity and specificity are limited by the often focal distribution of the specific histological lesions [6, 7].

Biopsy samples should be obtained in more than one area of the right ventricular septum and the number of samples should range from five to 10, with a volume of 1–2mm3. Five of these samples should be fixed in neutralized 10% formalin or 10% paraformaldehyde; the other five should be flash-frozen or placed immediately in a newly commercially-available fixative agent (RNAlater, Ambion, Austin, TX, USA) for further examination using classical or molecular virology-based techniques [8].

Histopathological evaluation of cardiac biopsy samples

The histological evaluation of cardiac biopsies from patients with clinically suspected myocarditis is done routinely in accordance with the Dallas criteria [2]. As myocarditis is a focal disease, four to five biopsy samples obtained in more than one area of the right ventricular septum should be analysed using light microscopic examination and immunohistochemical assays [8]. For routine light microscopy examination, EMB tissue is embedded in paraffin and serial sections are obtained and stained with haematoxylin and eosin. Masson’s trichrome or Sirius red can be useful for better evaluation of fibrosis [2]. Additional slides have to be made for subsequent immunohistochemical assays [4, 8].

To improve the histological diagnosis, additional immunological evaluation of cardiac tissues is required, using immunohistochemical techniques that allow quantification, identification and differentiation of inflammatory cells [4]. The criterion for the immunohistological diagnosis of inflammatory cardiomyopathy in the EMB is specified quantitatively as greater than 14 infiltrating leukocytes/mm2, preferably T-lymphocytes or activated T-cells. If the foci of T-lymphocytes are present, active myocarditis can be diagnosed due to the nature of the infiltrate, even when the critical level of 14leukocytes/mm2 is not reached [4]. Subsequent biopsies allow reliable follow-up of the myocarditis with a semiquantitative evaluation of myocardial inflammation, necrosis and healing. If the levels of inflammation appear unchanged from the most recent previous cardiac biopsies, the term ongoing (or persistent) myocarditis is used [2].

Finally, in cases of clinically suspected viral myocarditis or unexplained cardiomyopathy, the Dallas criteria have to be associated with classical immunohistological assays for the identification of inflammatory cells and also for the detection of viral capsid or early or late antigens in EMB. Moreover, these histological and immunohistological assays have to be combined with new, reliable PCR and RT-PCR assays for viral genomic RNA or DNA detection in EMB (Figure 3) [4].



Figure 3


Figure 3. 

Combination of histological, immunohistological and virological assays for the analysis of endomyocardial tissues of patients with suspected viral myocarditis.

PCR: polymerase chain reaction; RT-PCR: reverse transcription polymerase chain reaction.

a Viral genomes of enteroviruses, herpesviruses, parvovirus B19 and adenoviruses.

Combinaison de tests virologiques, histologiques et immunohistochimiques pour l’analyse de tissus cardiaques de patients suspects de myocardite virale.

a Génomes viraux des enterovirus, herpesvirus, parvovirus B19 et adenovirus .

Zoom

Virological analyses of samples taken from patients with myocarditis

The aetiological diagnosis of viral myocarditis, specifically during the acute phase corresponding to the acute viral infection, is based on the detection of the viruses or viral components (proteins or genomes) in peripheral blood samples, throat, urine and stool samples and in heart biopsy tissues samples. The direct virological techniques are based on classical virus isolation in cell cultures for peripheral blood, throat, urine and stool samples and molecular biology-based assays (PCR, RT-PCR) for EMB. By comparison, the contribution of viral serological assays to the clinical diagnosis of acute or chronic myocarditis is relatively poor and the serological assays are of interest only for a late and retrospective diagnosis of viral myocarditis. However, hepatitis B, hepatitis C and human immunodeficiency virus serologies should be done systematically in patients with acute or chronic myocarditis [4].

Using molecular biology-based techniques, the genomes of enteroviruses, adenoviruses, human hepatitis viruses or herpesviruses were detected in 40–70% of the cardiac tissues of patients with histologically proven acute myocarditis (Table 1) [19, 26, 29]. These molecular techniques must be performed on a pool of several EMB taken from different heart tissue areas, which should be extracted together to optimize the efficiency of viral nucleic acid recovery rates. The molecular techniques used are highly sensitive, real-time PCR assays that have to be standardized by the use of European quality controls (Quality Control for Molecular Diagnostics) and therefore can only be performed by some specialized laboratories [8]. At the moment, specialized laboratories use real-time PCR assays that allow a quantitative approach to the estimation of the viral loads of most cardiotropic viruses. However, no published data exist on the clinical value of real-time PCR viral loads or the determination of clinical thresholds that could differentiate a viral cardiac replicative infection from a persistent or latent viral endomyocardial infection. Only the strategy of using combined RT-PCR and PCR assays or PCR microarrays for the detection of all the most common cardiotropic viruses can provide an accurate diagnosis of viral myocarditis. However, sampling errors in this focal cardiac disease and the frequent late timing of EMB can also hamper the clinical application of these molecular assays after disease onset. Finally, while a positive RT-PCR or PCR result can provide an aetiological diagnosis that can be evaluated in the clinical context, negative PCR results do not exclude a viral-related cardiac disease. Moreover, the molecular techniques cannot distinguish an active from a persistent viral cardiac infection (Figure 3) [8]. Therefore, during the clinical course of myocarditis, the immunohistochemical detection of enterovirus, adenovirus or parvovirus B19 capsid proteins or herpesviruses late proteins is necessary to differentiate a viral cardiac infection with replication activities from a persistent or latent cardiac infection (Figure 4) [32]. Currently, the combination of molecular and immunohistochemical assays of cardiac tissue samples provides a reliable diagnostic strategy for a complete diagnosis of a potential viral-induced acute or latent/persistent cardiac infection. The direct detection of viral genomes in association with the immunohistochemical detection of viral capsid or late proteins in cardiac tissues is crucial for the characterization of the phase of the viral infection (acute or persistent/chronic) and enables the therapeutic strategies to be adapted specifically (Figure 4) [17, 19, 31, 32].



Figure 4


Figure 4. 

Proposed treatment algorithm based on endomyocardial biopsy results.

AHA: anti-heart autoantibodies; HF: heart failure; IAV: immunohistochemistry assay for viral late or capsid antigen detection; Inf.: immunohistological inflammation; PCR: polymerase chain reaction; pos: positive; neg: negative.

Proposition d’un algorithme de traitement basé sur l’utilisation des résultats obtenus à partir de l’analyse des biopsies endomyocardiques.

AHA : autoanticorps anticardiaques ; HF : défaillance cardiaque ; IAV : immunohistochimie pour la détection des antigènes viraux tardifs ou de capside virale ; PCR : polymerase chain reaction ; Neg : négatif.

Zoom

Detection of cardiac autoantibodies in peripheral whole blood of patients with histologically proven myocarditis

Molecular mimicry of viral antigens with self-determinants has been proposed as one of the pathogenic mechanisms in autoimmune myocarditis. Coxsackie virus and cytomegalovirus have been found to mimic important host cardiac proteins physiologically [35]. Autoantibodies against contractile structures, proteins involved in energy metabolism/transfer, ion channels and transporters and sarcolemmal receptors have been identified in human myocarditis [4]. Circulating cardiac autoantibodies against cardiac myosin heavy chain are present in up to 50% of patients with active-to-borderline biopsy-proven myocarditis; these antibodies may play a key role as clinical and pathogenetic markers and may also have some prognostic value [36]. These autoantibodies could be used to determine an autoimmune myocarditis [37, 38]. The detection of these autoantibodies in viral-induced and non-viral-induced myocarditis is of major interest for the identification of the aetiological causes of the myocarditis and for the prescription of specific aetiology-directed treatment strategies (Figure 4).

Treatment of viral myocarditis
First line: symptomatic treatment

The initial treatment of patients with acute myocarditis and demonstrating signs of advanced heart failure due to severe left ventricular failure will involve intensive levels of haemodynamic support, aggressive pharmacological intervention (including the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers and beta-adrenergic blockers) and sometimes extracorporeal membrane oxygenation implantation [3]. In some acute or fulminant cases where the LVEF remains less than 35%, heart transplantation can be required urgently [4].

Specific treatment strategies
Immunosuppression

Different clinical evaluations of immunosuppressive therapy in acute myocarditis have failed to prove their efficiency. The benefits of using a treatment combining corticoids and azathioprine or ciclosporin compared with a traditional treatment have not been demonstrated [39, 40]. Moreover, there are strong experimental arguments against the use of corticoids in viral myocarditis, particularly in the early acute phase of the disease and when viral endomyocardial replication activity is detected by a positive immunohistochemical assay for enterovirus, adenovirus or parvovirus B19 capsid proteins or herpesviruses late proteins [39, 41]. In addition, non-steroidal anti-inflammatory drugs have shown a possible deleterious effect in viral myocarditis [42]. However, aggressive immunosuppressive protocols can benefit patients with myocarditis due to systemic autoimmune diseases, particularly lupus erythematosus, scleroderma and polymyositis and also patients with idiopathic giant cell myocarditis [4, 8] (Figure 4).

Use of immunoglobulins

Immunoglobulins have been shown to have both an antiviral and an anti-inflammatory effect. They may suppress proinflammatory cytokines and reduce oxidative stress. A prospective placebo-controlled trial was designed to determine whether intravenous immunoglobulin improves LVEF in adults with recent-onset idiopathic dilated cardiomyopathy or myocarditis. Sixty-two patients (37 men, 25 women) with recent onset (<6 months of symptoms) dilated cardiomyopathy and LVEF less than 0.40 were randomized to 2g/kg intravenous immunoglobulin or placebo. All underwent an EMB before randomization, which revealed cellular inflammation in 16% of cases. These results suggest that for patients with recent-onset dilated cardiomyopathy, intravenous immunoglobulin does not augment the improvement in LVEF. However, in the overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favourable [43]. However, a trial is still lacking that takes into account the different aetiologies (different viruses assessed separately vs non-viral/autoreactive vs placebo) [44].

Other therapeutic strategies currently under evaluation

Therapeutic strategies adapted specifically to the phase of the disease are currently under evaluation and may improve prognosis and clinical outcomes significantly. It might be more efficient to use positive immunomodulators (interleukins, interferon alpha, interferon gamma) alone or in combination with specific antiviral components such as ribavirin in the initial phase of the disease when viral replication activity can be detected in the cardiomyocytes [45]. By contrast, immunosuppressive drugs would be more appropriate in the chronic phase of myocarditis, when no or low viral replication activities are detectable in cardiac tissues by immunohistochemistry assays (Figure 4). Moreover, an immunosuppressive treatment combining corticoids and azathioprine has shown effectiveness in myocarditis related to the presence of self-antibodies without detection of viral infection (negative PCR and RT-PCR assays) in the myocardial cells [36]. Future clinical studies including corticoids or immunosuppressive drugs and/or antiviral treatments according to the algorithm proposed in Figure 4 should be based only on results of histological and virological assays of EMB tissues, and on the immunological detection of autoantibodies in the peripheral whole blood of patients with suspected myocarditis or unexplained DCM. Currently, these virological, immunological and histological analyses of EMB tissues can only be performed in specialized reference centres.

Conclusion

Acute myocarditis remains a complex and challenging diagnosis in cardiology. To improve the histological diagnosis, additional virological evaluation of cardiac tissues is required, with immunohistochemical and PCR techniques allowing identification and quantification of viral infection markers. In acute and chronic myocarditis or unexplained DCM cases, the analysis of EMB is the gold standard for establishing the diagnosis unequivocally by the combination of histological and new immunohistochemical and PCR analyses of cardiac tissues. The immunohistochemical detection of enterovirus, adenovirus or parvovirus B19 capsid proteins or herpesvirus late proteins is needed to distinguish between viral replicative and non-viral replicative forms of the viral myocarditis. These new insights into the viral diagnostic approach can lead to a better identification of the aetiological causes of the myocarditis and will therefore enable the development and evaluation of specific aetiology-directed treatment strategies.

Conflicts of interests

We declare that no conflict of interests exists.


Acknowledgments

In memory of Professor C. Stankowiak, cardiovascular surgeon to the University Hospital Centre of Lille (North of France), who died suddenly in 1998, for his constant encouragement and clinical support of our research programmes into the viral causes of human myocarditis and dilated cardiomyopathy.

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