Myocarditis

Myocarditis

Arthur M. Feldman, M.D., Ph.D., and Dennis McNamara, M.D.

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Myocarditis is defined clinically as inflammation of the heart muscle. First introduced into the medical literature at the beginning of the 19th century, the term "myocarditis" was initially used to describe diseases of the heart muscle not associated with valvular abnormalities.¹ With the recognition of the importance of coronary-artery occlusion as a cause of heart-muscle disease at the beginning of the 20th century, the term was largely discarded. In the second half of the 20th century, a constellation of clinical observations renewed interest in inflammation of the heart muscle: myocarditis was recognized in a surprisingly large number of postmortem studies²; virus was isolated from the hearts of both adults and infants with acute cardiac disease^3,4,5; the endomyocardial biopsy provided an opportunity to assess the premorbid presence of myocardial inflammation in patients^6,7; and increased attention by clinicians led to the recognition of cardiac involvement in a large number of systemic diseases.⁸ More recent studies in animals have enhanced our understanding of the complex interactions between direct viral injury and the host's immune response,⁹ and sensitive molecular techniques have detected viral genome in patients with suspected myocarditis.¹⁰ Taken together, this new information has led to the recognition of a causal link between viral myocarditis and the development of dilated cardiomyopathy.¹¹

Epidemiology

Myocarditis is an insidious disease that is usually asymptomatic; thus, important clues to its epidemiology come from postmortem studies.¹² Such studies suggest that myocarditis is a major cause of sudden, unexpected death (accounting for approximately 20 percent of cases) in adults less than 40 years of age,¹³ young athletes,¹⁴ U.S. Air Force recruits,¹⁵ and elite Swedish orienteers.¹⁶ In addition, prospective and retrospective studies have identified myocardial inflammation in 1 to 9 percent of routine postmortem examinations.^2,17,18 Introduced in the early 1980s, the endomyocardial biopsy provided a method for assessing the presence of myocarditis in living patients.¹⁹ However, biopsy studies had highly variable results, with the incidence of myocarditis ranging from 0 to 80 percent.²⁰ These disparities may be due, at least in part, to differences between studies in patient selection (myocarditis appears to be far more common in children than in adults),²¹ differences between studies in diagnostic criteria, and the inherent insensitivity of the biopsy in the detection of inflammatory disease.^8,22

To resolve the problem of differences in methods of diagnostic evaluation, the Dallas criteria for the histologic diagnosis of myocarditis were introduced in 1986 (Figure 1).²³ Endomyocardial-biopsy specimens were considered diagnostic of active myocarditis if routine light microscopy revealed infiltrating lymphocytes and myocytolysis. The specimens indicated borderline or ongoing myocarditis if myocytolysis was not present, despite lymphocytic infiltration. The biopsy was considered negative if both myocytolysis and lymphocytes were absent. The Dallas criteria probably underestimate the true incidence of myocarditis, since the degree of intraobserver variability is large.²⁴ Indeed, fewer than 10 percent of patients in whom myocarditis was already suspected on clinical grounds had positive biopsies, as assessed by the Dallas criteria.⁶ A second clinicopathological classification system was proposed in 1991,²⁵ but it has received only limited acceptance.

View larger version (379K): [in this window] [in a new window] Figure 1. Histopathological Appearance of Normal Myocardium (Panel A, x100), Borderline Myocarditis (Panel B, x100; Panel C, x350), and Active Myocarditis (Panel D, x100; Panel E, x300), According to the Dallas Criteria,23 on Staining with Hematoxylin and Eosin.

Causation

Although the cause of myocarditis in any given patient often remains unknown, a large variety of infections, systemic diseases, drugs, and toxins have been associated with the development of this disease (Table 1). Viruses, bacteria, protozoa, and even worms have been implicated as infectious agents. There is a consensus that viruses are an important cause of myocarditis in North America and Europe. Initially, selected viruses were implicated by serologic demonstration of rising antibody titers in the serum of patients during acute myocarditis and convalescence.²⁸ Recently, however, the enterovirus genome has been identified in the myocardium of patients with myocarditis and patients with dilated cardiomyopathy.²⁹ Enterovirus and enterovirus-like RNA sequences have also been identified in endomyocardial-biopsy specimens from patients with clinically suspected myocarditis and from those with idiopathic dilated cardiomyopathy by the polymerase chain reaction (PCR) or by PCR–single-strand conformation polymorphism analysis.^10,30

View this table: [in this window] [in a new window] Table 1. Causes of Myocarditis.

The frequency of detection of viral genome by these techniques has not been as high as in earlier studies, undoubtedly because of the insensitivity of a test on a single endomyocardial-biopsy sample. Viral genome has been identified in less than 20 percent of patients with presumed myocarditis³¹ and in 10 to 34 percent of patients with dilated cardiomyopathy.^31,32,33 The marked differences in these rates are probably due to differences in the number of biopsy samples obtained from each patient. The specific viruses associated with the pathogenesis of myocarditis in adults remain controversial. For example, it has been generally assumed that the majority of cases of viral myocarditis are due to enterovirus infection,³⁴ but a recent report suggests that adenoviruses may also be important.³⁵

Cardiac disease has also been associated with human immunodeficiency virus type 1 (HIV-1),^36,37 and HIV-1 RNA has been detected in heart tissue from patients with the acquired immunodeficiency syndrome (AIDS).³⁸ Dilated cardiomyopathy was evident in 80 percent of a large group of asymptomatic HIV-positive patients, 83 percent of whom had myocarditis and 6 percent of whom had detectable HIV in the myocardium.³⁹ However, recent studies have failed to identify HIV proviral DNA in myocardial samples obtained post mortem from HIV-infected children, despite the presence of histologically defined myocarditis and immunohistochemical evidence of adenoviruses and cytomegalovirus.⁴⁰ Furthermore, in studies in vitro, HIV-1 did not infect fetal cardiomyocytes.⁴¹

Thus, it is unclear whether it is HIV itself or the appearance of secondary viruses in an immunocompromised host that accounts for the high incidence of myocarditis in HIV-positive patients. Recent studies have suggested that hepatitis C virus may also be involved in the development of dilated cardiomyopathy,⁴² and the presence of both positive- and negative-strand RNA in the myocardium of patients with dilated cardiomyopathy suggests that hepatitis C virus is able to replicate in the human myocardium.⁴³ These results have aroused controversy, and large-scale studies are needed to confirm the relation between hepatitis C virus and myocarditis.^44,45

Bacterial diseases are less commonly associated with myocarditis in immunocompetent hosts. The most common myocarditis worldwide is Chagas' disease, an inflammatory disease caused by the parasitic protozoan Trypanosoma cruzi. This form of myocarditis is endemic in rural Central and South America. Although most patients survive the acute phase of the disease and remain asymptomatic for many years, approximately 20 percent of patients eventually have chronic heart failure,⁴⁶ which is probably caused by immune activation.⁴⁷ Drugs also cause myocardial inflammation, either by a direct toxic effect on the myocyte or through immune-mediated mechanisms.^48,49 A relatively common form of drug-induced toxicity occurs after therapy with the antitumor agent doxorubicin.⁵⁰ An inordinately high incidence of heart failure has been reported when anthracyclines are combined with the anti–HER-2 receptor antibody trastuzumab.⁵¹ Another drug that is increasingly associated with the acute onset of cardiac dysfunction is cocaine, owing largely to its potent vasoconstrictor properties. In rare cases, idiopathic giant-cell myocarditis can occur in young, previously healthy adults. These patients often die unless cardiac transplantation is performed.^52,53 Finally, the possibility of drug-induced allergic myocarditis should be considered in any patient taking either prescription or over-the-counter medications. Patients with such an allergic reaction may have eosinophilia or an eosinophilic infiltrate in the myocardium, although the diagnosis is often unsuspected.^54,55

Lessons from Animal Models of Myocarditis

Our understanding of the pathophysiology of myocarditis comes largely from studies in animals, in which susceptible strains of mice or immunocompromised animals are infected with a cardiotropic virus, such as encephalomyocarditis virus or coxsackievirus B. These RNA viruses are taken into cells by receptor-mediated endocytosis and are directly translated inside the cells to produce viral protein.⁵⁶ The virus then replicates in the cytoplasm of the myocytes, but over time it can also be released into the interstitium, where it undergoes phagocytosis by macrophages.¹¹ In susceptible mice, viral infection results in death within four days even when there is no histologically apparent myocarditis,⁵⁷ although necrotic myofibers can be identified that are consistent with virus-induced cytotoxic effects.⁵⁸ In some strains of mice the initial noninflammatory phase is not immediately lethal and is followed by marked myocarditis between 4 and 14 days after infection.⁵⁹ This second phase of viral infection is characterized by infiltration by inflammatory cells, including natural killer cells and macrophages, with the subsequent expression of proinflammatory cytokines.¹¹ The series of events that unfolds after viral infection is illustrated in Figure 2.

View larger version (51K): [in this window] [in a new window] Figure 2. Time Course of Experimental Viral Myocarditis in Mice. Adapted from Kawai11 with the permission of the publisher. The timeline is not drawn to scale.

Macrophage activation probably results from the release of viral particles into the interstitium and the release of interferon- by natural killer cells and other activated white cells. After activation by interleukin-2, the natural killer cells protect against viral invasion by eliminating virally infected cells and thus inhibiting virus replication.⁶⁰ The beneficial role of natural killer cells is evidenced by the finding that increased viral titers and severe myocarditis are found in natural killer cell–deficient mice.⁶¹ Although natural killer cells can release perforin as well as granzymes, and in so doing can exacerbate disease by injuring the cardiomyocytes,⁶² natural killer cells interact only with virus-infected myocytes, sparing uninfected cells.⁶¹

The proinflammatory cytokines also have important roles in the development of chronic inflammatory disease. Tumor necrosis factor activates endothelial cells, recruits inflammatory cells, enhances the production of inflammatory cytokines, and has significant negative inotropic effects. In contrast to these disease-producing effects, it also appears to be necessary for the rapid clearance of viral particles. Interferons have potent antiviral properties when administered exogenously,⁶³ and endogenous interferons have a critical role in attenuating viral proliferation.⁶⁴ The cytokines are also able to activate inducible nitric oxide synthase in cardiac myocytes, an action that affords cardioprotection after experimentally induced myocarditis in some strains of mice.⁶⁵ However, the role of nitric oxide in the development of myocarditis is complex, since inhibition of nitric oxide synthesis has also been shown to have salutary effects.⁶⁶

Cell-mediated immunity also has an important role in viral clearing. Within seven days of infection, antigen-specific T cells infiltrate the mouse myocardium.¹¹ These circulating T cells, which express the and chains of the T-cell receptor and either CD4 or CD8 coreceptor molecules,⁶⁷ include T helper (Th or TCR+CD4+) cells and cytotoxic T lymphocytes (TCR+CD8+).¹¹ The cytotoxic T cells recognize degraded fragments of viral proteins that are presented by the major-histocompatibility-complex class I antigens on the surface of the myocyte membrane.⁶⁸ Cytokines, notably interferon-, induce up-regulation of the major-histocompatibility-complex antigens on the surface of the myocytes.

To become fully activated, T cells must also receive a second signal (e.g., B7), termed the costimulatory signal, from costimulatory molecules on the antigen-presenting cells.⁶⁹ In the presence of appropriate cofactors and antigens, cytotoxic T lymphocytes become activated and are able to lyse virus-infected cardiocytes. In addition, the cell-to-cell contact that is necessary to allow effective lysis is also mediated by up-regulation of intercellular adhesion molecules on the surface of the infected myocyte, which is induced by tumor necrosis factor , interferon-, or both.⁷⁰ Viral clearing is also enhanced by the development of neutralizing antiviral antibodies.⁷¹ Indeed, inhibition of the development of such neutralizing antibodies by treatment with prednisone delays viral clearing.⁷¹ Thus, a variety of host defense mechanisms are able to limit cardiac injury after a viral infection.

Although the immune response normally functions to clear virus and allow healing in many instances of myocardial infection, the exquisite balance between viral clearing and damage to myocytes and the temporal relation between viral clearing and continued immunologic surveillance can tip toward either inefficient viral clearing or overaggressive immunologic activation (Figure 2).^9,72 For example, in some strains of mice, normal host defense mechanisms are inadequate, and persistent viral replication occurs in the myocytes, resulting in chronic viral disease with cardiac dilatation and failure.⁷³ Alternatively, persistent activation of infiltrating T cells during viral infection can cause long-term tissue destruction, leading to dilated cardiomyopathy.^11,74,75

The finding that immunization with cardiac myosin (but not skeletal-muscle myosin) in susceptible strains of mice induced myocarditis led to the hypothesis that humoral immunity is also important in the development of postinfectious myocarditis.⁷⁶ This finding was further supported by subsequent studies showing that a T-cell–dependent myocarditis could be demonstrated in mice after immunization with cardiac C protein or streptococcal M protein peptide,^77,78 adoptive transfer of myosin-reactive cells⁷⁹ or splenocytes after myocardial infarction,⁸⁰ or transplantation of a normal heart into a virus-treated host after documentation of viral clearance.⁸¹

Although the presentation of myosin fragments by the major-histocompatibility-complex antigens or the presence of myosin in the extracellular spaces after cellular necrosis may explain the presentation of myosin to the immune system, recent studies suggest that molecular mimicry may also be involved in the pathogenesis of autoimmune myocarditis. This concept is supported by the finding of cross-reactive epitopes between cardiac myosin and infectious agents.^82,83,84 Although studies in murine models have clearly demonstrated a relation between virus and the subsequent development of cardiomyopathy, it is important to note that the virulence of the infection is dependent on a variety of factors, including physical-activity level, sex, age, and genetic background. In addition, the murine model has been useful in demonstrating the salutary effects of a variety of pharmacologic agents in the treatment of viral myocarditis.^85,86,87,88 However, the clinical relevance of these findings remains obscure.

Pathobiology in Humans

Recent studies have identified several important features in patients with idiopathic dilated cardiomyopathy that support the infectious–immune hypothesis derived from studies in murine models. These include the following findings in patients with myocarditis: an imbalance exists between helper and cytotoxic T cells⁸⁹; an inappropriate expression of the major histocompatibility complex can be found on cardiac tissues⁹⁰; and circulating organ-specific autoantibodies are present in the serum.⁹¹ In patients with dilated cardiomyopathy, autoantibodies have been identified that react with heart mitochondria,⁹² the adenine nucleotide translocator,⁹³ the muscarinic receptor,⁹⁴ myosin heavy chain,⁹⁵ or laminin.⁹⁶ Autoantibodies raised against the second extracellular loop of the ₁-adrenergic receptor have also been identified.^97,98 These antiadrenergic antibodies function as agonists and cause abnormalities in -adrenergic–receptor coupling in vitro. The abnormalities mimic those seen in patients with dilated cardiomyopathy,^98,99 and they are not associated with other forms of heart failure, including hypertrophic or valvular heart disease.¹⁰⁰

The majority of studies measuring autoantibody levels were performed in patients with idiopathic dilated cardiomyopathy, not in patients with myocarditis. Furthermore, the percentage of patients with histologically proved myocarditis and serum autoantibodies is highly variable, ranging from 25 percent to 73 percent.^91,101 Five percent of patients with ischemic heart disease and heart failure have autoantibodies to cardiac tissue. Thus, the role of autoantibodies in the pathophysiology of myocarditis and the relation between autoantibodies and the subsequent development of cardiac dilatation and failure remain intriguing questions.

In a finding consistent with those in murine models, the development of idiopathic dilated cardiomyopathy appears to be influenced by the genetic background. In a prospective study, nearly one third of asymptomatic relatives of patients with dilated cardiomyopathy had echocardiographic evidence of left ventricular dysfunction.¹⁰² Furthermore, although the incidence of autoantibodies is as high in familial as in sporadic cases of cardiomyopathy,¹⁰³ autoantibodies are found more frequently in first-degree relatives than in the normal population.^104,105 These findings led investigators to speculate that dilated cardiomyopathy develops as a result of myocarditis in a subgroup of patients with the appropriate genetic background. This hypothesis remains to be confirmed.

Diagnosis

The clinical features of myocarditis are varied. The spectrum includes asymptomatic patients who may have electrocardiographic abnormalities; patients with signs and symptoms of clinical heart failure and ventricular dilatation; and patients with symptoms of fulminant heart failure and severe left ventricular dysfunction, with or without cardiac dilatation.¹⁰⁶ Patients may present with a history of a recent flulike syndrome accompanied by fever, arthralgias, and malaise. Laboratory tests may show leukocytosis, an elevated sedimentation rate, eosinophilia, or an elevation in the cardiac fraction of creatine kinase. The electrocardiogram may show ventricular arrhythmias or heart block, or it may mimic the findings in acute myocardial infarction or pericarditis.^107,108 The relations between these clinical and laboratory findings and the presence of myocarditis are obscure (Table 2).⁶ Thus, the endomyocardial biopsy remains the gold standard for the diagnosis of myocarditis, despite its limited sensitivity and specificity. However, the lack of association between biopsy evidence of myocarditis and the presence of autoantibodies in patients with clinical myocarditis,⁹¹ the paucity of positive biopsy findings in large cohorts of patients with suspected myocarditis,^115,116 the potential discordance between clinical and histologic features of myocarditis,¹¹⁷ and the inherent limitation of histologic diagnosis^6,24,118 suggest that the diagnosis of myocarditis should not be based on histologic findings alone. Rather, it is important to include other diagnostic tests, including assays for autoimmune serum markers⁹¹ or the induction of the major histocompatibility and intercellular adhesion molecules on cardiac myocytes, to identify patients with autoimmune myocarditis.¹¹⁹

View this table: [in this window] [in a new window] Table 2. Prevalence of Myocarditis in Published Series.

Creatine kinase levels are often elevated in myocarditis. In addition, recent studies demonstrate that measurement of serum levels of cardiac troponin T, troponin I, or both in patients in whom myocarditis is suspected on clinical grounds can provide evidence of myocardial-cell damage with a level of sensitivity that exceeds that of other enzymatic measurements^118,120 and can be correlated with the results of immunohistologic assessments.¹²⁰ Therefore, although the time window of detectability of creatine kinase, troponin I, and troponin T in patients with chronic heart failure remains to be defined, we recommend that these measurements be obtained in all patients with suspected myocarditis.

Because patients with systemic autoimmune diseases (e.g., scleroderma, lupus erythematosus, and polymyositis) can present with myocarditis, we measure the erythrocyte sedimentation rate and perform rheumatologic screening in patients with unexplained heart failure and signs and symptoms of connective tissue disease. These patients often present with a hypofunctional but relatively normal-sized ventricle and with hypoxia and exertional dyspnea that are disproportional to the degree of cardiac dysfunction. Recent studies also suggest that testing for the presence of viral genome in endomyocardial-biopsy specimens by PCR may provide diagnostic and prognostic information, as well as discriminating between autoimmune and viral myocarditis. For example, the persistence of enterovirus RNA in patients with dilated cardiomyopathy is a strong predictor of a poor prognosis.¹²¹ Furthermore, the presence of viral capsid protein in some patients with dilated cardiomyopathy may be a marker of persistent enterovirus infection.¹²² Not all investigators have been able to identify microbial persistence.¹²³ Thus, assessment of the presence of viral genome remains largely investigational. However, we conduct serologic tests for HIV in all patients with suspected myocarditis, because early and effective therapy may improve overall survival and cardiac function.

Several noninvasive strategies have also been used to identify myocarditis. Antimyosin scintigraphy can identify myocardial inflammation in the absence of histologic evidence.^{124,125,126,127} It has a higher specificity but a lower sensitivity than immunohistologic analysis.¹²⁷ Contrast–enhanced magnetic resonance imaging¹²⁸ and echocardiographic digital image processing¹²⁹ may also be useful for the noninvasive localization and assessment of the extent of inflammation in patients with presumed myocarditis. Additional clinical studies will be required to confirm the usefulness of these procedures. The diagnosis of myocarditis is dependent in large part on clinical suspicion rather than definitive diagnostic tests.

Recent studies have described patients with acute myocarditis masquerading as acute myocardial infarction. The clinical features of these patients include a young age and an absence of risk factors for coronary disease, together with the presence of signs, symptoms, and electrocardiographic findings consistent with the presence of myocardial ischemia or infarction. Obtaining the correct diagnosis in these patients usually requires cardiac catheterization. We have a low threshold for obtaining a coronary angiogram in patients with new-onset heart failure for which a cause is not readily identified.

Treatment

Supportive care is the first line of therapy for patients with myocarditis. In patients with symptoms of heart failure, therapy should include diuretics to lower ventricular filling pressures, an angiotensin-converting–enzyme inhibitor to decrease vascular resistance, and a beta-blocker once clinical stability has been achieved. In some patients, effective amelioration of high filling pressures may require the intravenous administration of potent vasodilators, including nitroglycerin or sodium nitroprusside. Aggressive therapy to lower vascular filling pressures might minimize immune activation by preventing the release of endotoxin in the gut.¹³⁰ Patients presenting with suspected myocarditis and signs and symptoms of heart failure should be hospitalized and cared for in a cardiac unit that has telemetric monitoring. Physicians have commonly recommended the use of digoxin in patients with myocarditis. However, digoxin increased both the expression of proinflammatory cytokines and mortality in a murine model of viral myocarditis, leading the investigators to conclude that digoxin should be used with caution and only at low doses.¹³¹

In patients with severe symptoms, supportive care may include the use of intravenous inotropic therapy or implantation of a ventricular assist device. The presence of either atrial or ventricular arrhythmias may require appropriate pharmacologic therapy or possibly the implantation of a defibrillator. Bed rest should be strongly considered during viremia, in contrast with noninflammatory dilated cardiomyopathy, although this recommendation is based on studies in animals and the recognition that myocarditis is often lethal in young athletes. Physicians should also eliminate any unnecessary medications to reduce the chances of allergic myocarditis, particularly in patients with eosinophilia.

Because the long-term consequences of myocarditis appear to be related to the activation of cellular and humoral autoimmunity, many clinicians believe that immunosuppression should be beneficial in patients with myocarditis. This hypothesis has been supported by a large number of uncontrolled clinical studies in which a variety of immunosuppressive agents caused rapid resolution of the inflammatory components of cardiac disease.²³ In addition, intravenous immune globulin caused marked improvements in left ventricular performance in children¹¹⁰ and adults¹³² with recent onset of symptoms of heart failure and in women with postpartum cardiomyopathy.¹¹⁴ However, histologic resolution of myocardial inflammation does not correlate with improvement in ventricular function.¹³³ Moreover, the incidence of spontaneous improvement in left ventricular performance is substantial, and the long-term survival of patients with myocarditis does not differ substantially from that of patients with idiopathic cardiomyopathy.^133,134 Furthermore, the results of recent randomized, placebo-controlled trials (including a study of the use of intravenous immune globulin) have failed to demonstrate beneficial effects of immunosuppression (Table 3).^109,111,135 Taken together, these studies suggest that immunosuppression should not be used in the routine treatment of patients with myocarditis.¹³⁶

View this table: [in this window] [in a new window] Table 3. Randomized Clinical Trials of Immune Modulation in Myocarditis and Dilated Cardiomyopathy.

Although immunosuppressive therapy is not recommended in patients with infectious or postinfectious myocarditis, immunosuppression may have an important role in the treatment of patients with cardiac dysfunction due to a systemic autoimmune disease. For example, patients with myocarditis due to scleroderma, lupus erythematosus, polymyositis, or sarcoidosis often benefit from immunosuppressive therapy. In addition, patients with idiopathic giant-cell myocarditis were recently found to benefit from trials of immunosuppressive therapy.^52,137

Several recent reports suggest that patients with acute fulminant myocarditis may benefit from short-term circulatory support with left ventricular assist devices^138,139,140 or from extracorporeal membrane oxygenation.¹⁴¹ Left ventricular support in patients with chronic heart failure causes favorable alterations in cellular and organ geometry, reduces wall stress, and improves myocyte function.^142,143 Patients presenting with signs and symptoms consistent with a diagnosis of acute myocarditis, including fever, leukocytosis or lymphocytosis, flulike symptoms, hemodynamic compromise, and elevated levels of creatine kinase, troponin I, or troponin T, should be rapidly transferred to a clinical site with the capability of ventricular support.

There should be a low threshold for instituting ventricular support in these patients, because they can have precipitous decompensation. The patients are frequently young and characteristically have a normal-sized but hypocontractile ventricle and a fulminant course. A substantial number of anecdotal reports suggest that many patients with fulminant myocarditis can be successfully weaned from ventricular support once any virus has been cleared. However, prudence suggests that these patients should continue to receive therapy, including angiotensin-converting–enzyme inhibition and beta-blockade, after being weaned from left ventricular support. In a recent observational study, fulminant myocarditis was actually associated with a better prognosis than acute nonfulminant myocarditis; however, the study population was small, and follow-up was incomplete.¹¹⁰

Intuitively, the association between myocarditis and viral infection suggests that antiviral strategies, antiviral vaccines, or both might have benefits. Several recent case reports have documented successful treatment of myocarditis with antiviral agents.^144,145 Furthermore, antiviral agents can reduce the number of infected cells and virus identified in human myocardial fibroblasts.^145,146 The clinical value of antiviral therapy is now being assessed in the European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease, in which enterovirus-positive patients are randomly assigned to treatment with the antiviral agent interferon alfa or placebo.¹⁴⁷

An alternative approach to the treatment of viral myocarditis has been the development of virus-specific vaccines. Attenuated vaccines have successfully prevented the development of myocarditis after viral challenge in mice, pigs, and elephants.^148,149 The usefulness of vaccines in humans remains unclear. Although viruses may be responsible for some forms of acute myocarditis, studies in animals suggest that persistent inflammation may instead be mediated by autoimmune mechanisms. Thus, it is not surprising that beneficial effects have also been reported from the use of immunoabsorption to modify the levels of circulating antibodies. Further studies are needed to confirm these initial reports.

Conclusions

Although myocarditis has been recognized for nearly two centuries, its insidious course, the insensitivity of traditional diagnostic tests, and the complex relation between adaptive and maladaptive immune responses have precluded the development of rational treatment strategies. Recent information from studies in animals has led to efforts to delineate the major cellular processes that are responsible for myocardial dysfunction in individual patients: viral replication, humoral immunity, or cellular immunity. Such efforts should provide new opportunities for the development of specific therapeutic algorithms. Ongoing evaluations of antiviral therapies, virus-specific vaccines, and mechanical support devices may provide new treatment options. The recent recognition of the genetic basis of immune-mediated heart disease should also provide valuable clues to the understanding and treatment of this enigmatic disease.

Supported in part by a grant (NIH 1RO1 HL60032-1) from the National Institutes of Health.

We are indebted to Dr. Chau-Ching Liu and Dr. Theresa Whiteside for their helpful comments and to Tracey Barry for assistance in the preparation of the manuscript.

Source Information

From the Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh.

Address reprint requests to Dr. Feldman at the Cardiovascular Institute, UPMC Health System, 200 Lothrop St., S-572 Scaife Hall, Pittsburgh, PA 15213, or at feldmanam@msx.upmc.edu.

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