Correspondence *University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, NB10.228, Dallas, TX 75390-8573, USA

Email pradeep.mammen@utsouthwestern.edu

Introduction

Myocarditis is an inflammation of the myocardium that results in ventricular systolic dysfunction and may be the causative factor in up to 10% of patients with acute-onset heart failure.^{1, 2, 3} In most patients with myocarditis the clinical course is self-limiting. The disease can have a fulminant or nonfulminant presentation. In patients with acute, nonfulminant myocarditis, the initial course can be insidious and followed by acute onset of heart failure with subsequent development of chronic myocarditis. These patients either develop chronic, stable, dilated cardiomyopathy or progress to advanced, end-stage heart failure. By comparison, patients with fulminant myocarditis present with acute, severe heart failure and are often in cardiogenic shock. If fulminant myocarditis is quickly recognized and patients are given aggressive treatment, more than 90% will make a full recovery with minimal long-term sequelae.⁴

Currently, the factors that determine whether a patient presents with fulminant or nonfulminant myocarditis are not known. In this Review, we focus on the epidemiology, pathophysiology, clinical presentation, methods of diagnosis, management, and prognosis of fulminant myocarditis and highlight the importance of early recognition of this disease entity. When appropriate, certain features of fulminant myocarditis are contrasted with those of nonfulminant myocarditis. To our knowledge, this article is the first comprehensive review of fulminant myocarditis.

Epidemiology

Approximately 6–10% of cases of recent-onset, dilated cardiomyopathy are secondary to myocarditis.^{3, 4, 5, 6} In addition, nearly 20% of sudden deaths among young adults and athletes are the consequence of myocarditis.^{7, 8} As a result of its rarity, however, the incidence and prevalence of fulminant myocarditis is not well characterized. A single-center study reported the incidence in the US to be approximately one case per year.⁴ The observed prevalence was 10% among patients with biopsy-proven myocarditis and 0.9% among patients with new-onset heart failure.

Pathophysiology

Myocarditis is an inflammatory process that involves the myocardium and is caused by a variety of factors including infection, systemic disease and/or exposure to various drugs and toxins (Box 1). The underlying etiology and pathogenesis of fulminant and acute, nonfulminant myocarditis are thought to be similar. Viral infections are thought to be responsible for the majority of myocarditis cases in North America and Europe, although a viral genome is identified in the myocardium of only 10–20% of patients with active myocarditis.^{9, 10} Coxsackievirus and adenovirus are the most common viral causes. Mechanistic studies on the cause of myocarditis in the rest of the world have not been reported. The pathophysiology of myocarditis involves both direct, virally mediated myocyte dysfunction and immune-mediated tissue injury. Activation of the immune system is a host response that attenuates viral replication and so protects against virally mediated myocyte injury; however, some components of the immune response also contribute to the development of myocardial inflammation, necrosis and ventricular dysfunction.¹¹

The phases of viral myocarditis

The evolution of myocarditis can be divided into four phases, which are illustrated in Figure 1.

Figure 1 Pathogenesis of viral myocarditis can be divided into four phases.

Abbreviations: CHF, congestive heart failure; IFN, interferon; IL-1, interleukin 1; TNF, tumor necrosis factor.

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Phase 1

The initial phase involves viremia, during which a cardiotropic RNA virus (such as a coxsackie B virus) binds to its receptors on cardiomyocytes. The CD55 antigen (also termed decay-accelerating factor), a membrane protein that regulates the complement system, has been identified as the receptor for coxsackie B viruses.¹² Receptor-mediated endocytosis of the virus is followed by replication and translation of viral proteins within the cardiomyocyte. Proto-oncogene tyrosine-protein kinase LCK (p56-LCK) is known to be an essential host factor required for efficient viral replication; mice that lack the homologous Lck gene are completely protected from myocarditis induced by coxsackie B3 virus infection.¹³

Viral replication contributes to cellular dysfunction and promotes apoptosis.¹⁰ Similarly to hereditary forms of cardiomyopathy, abnormalities in cytoskeletal proteins have been observed in animal models of enteroviral myocarditis.^{14, 15} In cells infected with a coxsackie B virus, two specific viral proteases (2A and 3C) are expressed that cleave the viral polypeptide into mature peptides. In cultured myocytes and in mice, enteroviral protease 2A also cleaves dystrophin, which results in separation of its actin-binding N-terminal and rod domains from its b-dystroglycan-binding domain.¹⁶ This event disrupts myocyte integrity by disconnecting actin-based cytoskeletal and sarcomeric structures from membrane-bound dystrophin-associated glycoproteins and from the external basement membrane. Dysfunction of dystrophin decreases myocyte contractility, and loss of cell-membrane integrity results in increased cell permeability and thereby promotes cell death. Microvascular spasm also develops during acute viremia, which contributes to myocardial necrosis and dysfunction.¹⁷

Phase 2

After replication, viral proteins are expressed on the cell surface of cardiomyocytes, which leads to the second phase of myocarditis. Inflammatory cells infiltrate the myocardium and result in the release of various cytokines (e.g. interferon-, interleukins 1 and 2, tumor necrosis factor and elastases). Tumor necrosis factor and the interleukins activate macrophages, lymphocytes and endothelial cells, which stimulates viral clearing. At the same time, however, these inflammatory mediators contribute to the development of myocarditis.¹⁸ Elastases destroy the vascular endothelium by disrupting the integrity of the endothelial basement membrane.¹⁹ An in vitro assay to assess neutrophil-mediated endothelial injury demonstrated that activated neutrophils cause dose-dependent detachment of endothelial cells without concomitant cell lysis.²⁰ Endothelial dysfunction, in turn, contributes to vasoconstriction and increased permeability, which leads to further extravasation of neutrophils, release of elastases and necrosis of surrounding myocardial tissues.^{19, 20} A study that used an encephalomyocarditis-virus-induced murine model of myocarditis demonstrated that administration of ZD0892, a serine elastase inhibitor, decreased the inflammatory response associated with microvascular perfusion injury and myocardial necrosis.²¹ Subsequent fibrosis and myocardial dysfunction were also reduced.

In addition to cytokines, nitric oxide (NO) also has an important role in the pathogenesis of myocarditis, especially if the host is immunocompromised. In severe combined immunodeficient mice inoculated with coxsackie B3 virus, viral replication is unrestricted and myocarditis is severe and associated with high mortality.²² Similarly, mice deficient in inducible NO synthase (iNOS) are more susceptible to severe myocarditis than wild-type mice are.²³ NOS catalyzes the conversion of L-arginine to NO, a well-known, ubiquitous, intracellular chemical messenger involved in signal transduction. During infection, interferon- and lipopolysaccharide (in the case of bacterial infections) induce iNOS expression and thereby stimulate production of NO. To assess the importance of iNOS-generated NO in myocarditis, mice deficient in the gene for interferon regulatory factor 1 (Irf1) were engineered using homologous recombinant technology. Isolated macrophages from these mice produced lower levels of interferon in response to stimulation and had almost complete absence of iNOS expression compared with wild-type mice.²³ Furthermore, the Irf1-null mice developed severe heart failure after infection with coxsackie B3 virus. Hearts from these mice had extensive virus-mediated damage with inflammatory cellular infiltrates. Thus, in addition to the immune system, iNOS-generated NO has an essential role in limiting early viral infection. Activation of iNOS could, therefore, be beneficial during the initial viremic stage of myocarditis.²⁴

Phase 3

The third phase is marked by further activation of cell-mediated immunity and recruitment of immune cells. Antigen-specific T cells (T helper cells and cytotoxic T cells) are recruited into the infected myocardium to clear the virally infected cells.¹⁸ T cells recognize degraded viral protein fragments presented by antigen-presenting cells and become activated.²⁵ Activated cytotoxic T lymphocytes promote further lysis of virus-infected cardiomyocytes. Viral clearing is further enhanced by neutralizing antiviral antibodies and autoantibodies (directed against mitochondrial and contractile proteins) generated by activated B cells; however, these same antibodies, particularly the autoantibodies, have detrimental effects on myocyte signal transduction, calcium homeostasis and cardiac bioenergetics.²⁶

Phase 4

The final phase—resolution of inflammation—occurs when the host defense mechanisms outlined here have cleared the virus effectively, although no coordinated cellular program of inflammation resolution has been recognized. The myocardium can then heal. When genetically susceptible individuals are infected with highly virulent viral strains, however, maladaptive immunologic activity can occur. As a consequence viral clearance is ineffective, which leads to persistent activation of T cells and/or continued antibody-mediated myocyte destruction. This maladaptive activity, in turn, results in progressive ventricular dysfunction.^{1, 16, 18, 21, 27} It has been postulated that these susceptible individuals develop either fulminant myocarditis or chronic persistent myocarditis characterized by fibrosis, ventricular dilatation and progressive, end-stage heart failure.

Clinical presentation

Patients with fulminant myocarditis commonly present with sudden-onset heart failure. Over a 7-year period, Felker et al. compared the respective clinical presentations of individuals with fulminant and nonfulminant myocarditis (Table 1).²⁸ In contrast to patients with acute nonfulminant myocarditis, in whom NYHA class III symptoms are often seen, patients with fulminant myocarditis commonly present with NYHA class IV symptoms. Often, patients have flu-like symptoms (e.g. fevers, arthalgias and malaise) in the 2–4 weeks before presentation.^{28, 29} On physical examination, signs of cardiogenic shock are evident along with tachycardia, hypotension, cool and clammy extremities, marked hemodynamic compromise and, occasionally, respiratory failure.

Table 1 Baseline clinical characteristics of patients with acute fulminant and nonfulminant myocarditis.²⁸

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The initial laboratory tests in patients with myocarditis can show leukocytosis, eosinophilia, elevated erythrocyte sedimentation rate, and increased levels of cardiac troponins or of the creatinine kinase MB isoenzyme.^{30, 31, 32} Laboratory evidence of multiorgan failure is more commonly present in patients with fulminant as compared with nonfulminant myocarditis, with elevated levels of blood urea nitrogen (10.0 5.7 mmol/l vs 6.4 3.6 mmol/l), creatinine (97.2 44.2 mol/l vs 79.6 26.5 mol/l), transaminases (1158 595 U/l vs 189 59 U/l), creatinine kinase (1708 1217 U/l vs 617 447 U/l) and C-reactive protein (590 350 mg/l vs 340 260 mg/l). Furthermore, intraventricular conduction delays (73% vs 25%), ventricular arrhythmias (27% vs 4%), and depressed left ventricular ejection fraction (41% vs 57%) are more common in patients with fulminant than in those with nonfulminant myocarditis, respectively. In a multivariate analysis, prolonged QRS complex and depressed left ventricular ejection fraction were both independently associated with fulminant myocarditis.

Differential diagnosis

An important point is that patients with other diseases can present with acute cardiogenic shock and symptoms that mimic fulminant myocarditis.^{33, 34, 35, 36, 37, 38} The differential diagnosis includes giant cell myocarditis (GCM), necrotizing eosinophilic myocarditis (NEM), sarcoidosis, peripartum cardiomyopathy (PPCM) and acute myocardial infarction. As definitive, effective therapy is available for some of these disorders, patients with these conditions must be distinguished from those with fulminant myocarditis (Table 2).

Table 2 Differential diagnosis of fulminant myocarditis.

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GCM is commonly associated with autoimmune disorders, thymomas and drug hypersensitivity. The presence of multinucleated giant cells on hematoxylin and eosin staining of endomyocardial biopsy samples is a pathologic hallmark of this disease entity (Figure 2). Patients with GCM often develop malignant ventricular arrhythmias.^{34, 39, 40, 41} Reports have indicated that treatment with high-dose steroids combined with ciclosporin or azathioprine could be beneficial, although mortality remains very high (approximately 80% at 1 year).³⁴ The addition of muromonab-CD3 to the above immunosuppressive regimen could further improve transplant-free survival.⁴² At present, cardiac transplantation is the treatment of choice for those who do not respond to a trial of immunosuppressive therapy. In up to 25% of transplant recipients, however, GCM can recur in the transplanted heart.³⁴

Figure 2 Histologic image of an endomyocardial biopsy from a patient with giant cell myocarditis.

Hematoxylin and eosin staining of the biopsy sample reveals extensive myocyte necrosis, cellular inflammation and the formation of multinucleated giant cells (arrows). Scale bar 40 m.

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NEM, a very rare disorder, is characterized by a diffuse infiltration of eosinophils in the endomyocardium and extensive myocyte necrosis. Although rare, it is a deadly disorder with mortality approaching 100%. Unfortunately, treatment options are few, but high-dose steroids have been used with limited success.^{35, 36}

Patients with cardiac sarcoidosis, an immune-system disorder, can also occasionally present with acute heart failure. The pathological hallmark of this disease is the presence of noncaseating granulomas on endomyocardial biopsy (Figure 3).⁴³ Some patients respond to high-dose steroids although the optimum treatment has not been defined.⁴³ Recurrence of sarcoidosis in the allograft has been a concern should the patient undergo cardiac transplantation, but data published in 2007 indicate a favorable outcome following transplantation.³⁸

Figure 3 Histologic image of an endomyocardial biopsy from a patient with cardiac sarcoidosis.

Hematoxylin and eosin staining of the biopsy sample reveals non-necrotizing granulomatous inflammation with patchy interstitial fibrosis (arrow). Scale bar 40 m.

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The onset of unexplained dilated cardiomyopathy during the last month of pregnancy or occurring within 5 months after delivery is referred to as PPCM. The pathophysiology of PPCM is unclear, although research published in 2007 implicated a biologically active derivative of prolactin in its development and observed a beneficial effect with the prolactin inhibitor, bromocriptine.⁴⁴ Patients with persistent left ventricular dysfunction or evidence of myocarditis can benefit from immunosuppressive therapy and implantation of a left ventricular assist device (LVAD), in some cases followed by cardiac transplantation.³⁷

Acute myocardial infarction accompanied by cardiogenic shock is characterized by chest pain, ST-segment elevation on electrocardiography, and elevated levels of cardiac biomarkers. Urgent left heart catheterization is indicated in these patients, which usually reveals the presence of thrombosis in the epicardial coronary arteries. Emergent revascularization has been shown to improve outcomes.⁴⁵

Diagnostic studies

Histology

Differential diagnosis

Endomyocardial biopsy has a critical role in the evaluation of a patient with unexplained acute heart failure and has an ACC/AHA class I indication in the assessment of hemodynamically compromised patients with recent-onset heart failure of less than 2 weeks duration.⁵⁶ Biopsy is essential to differentiate GCM and NEM from lymphocytic myocarditis quickly and accurately. This differentiation is very important, as although immunosuppressive therapy is recommended for patients with GCM and NEM, the role of immunosuppressive agents in lymphocytic myocarditis is still under investigation. While individuals with lymphocytic myocarditis have an excellent long-term prognosis, both GCM and NEM are associated with very high mortality.^{34, 35, 36} Although endomyocardial biopsy is a highly sensitive (80–85%) and specific technique for diagnosing GCM, its sensitivity for diagnosing lymphocytic myocarditis is very low (10–22%). Endomyocardial biopsy has optimal sensitivity when performed soon after the onset of symptoms.⁵⁶

Safety

Endomyocardial biopsy can be performed safely either under fluoroscopic or echocardiographic guidance by experienced operators. The right internal jugular vein or the femoral vein is accessed percutaneously and four to six biopsy samples are obtained from the right ventricle using a flexible bioptome. The risk of serious complications such as cardiac perforation and tamponade, pneumothorax, arrhythmia or death, is less than 1%, although less serious complications (e.g. arterial puncture and prolonged bleeding) occur in 2–3% of cases.^{56, 57, 58}

Fulminant myocarditis

Intense myocardial inflammation with myocyte necrosis is a pathological, though not specific, feature of fulminant myocarditis. Histologic findings can be classified according to the Dallas criteria, as follows: active myocarditis (i.e. evidence of infiltrating lymphocytes and myocytolysis); borderline myocarditis (i.e. lymphocytic infiltrate without myocytolysis); or negative (i.e. no evidence of myocytolysis or lymphocytic infiltrate), as illustrated in Figure 4.⁵⁹ Unfortunately, as histologic analysis is associated with a large degree of interobserver variability, the Dallas criteria underestimate the true incidence of myocarditis and fail to provide information on long-term prognosis.⁶⁰

Figure 4 Histologic classification of fulminant myocarditis by the Dallas criteria.⁵⁹

(A) 'Negative' findings—normal myocardium without any evidence of cellular infiltrate or cardiomyocyte necrosis (hematoxylin and eosin stain). (B) Borderline myocarditis—arrows indicate mild lymphocytic infiltrate (hematoxylin and eosin stain). (C) Fulminant myocarditis—intense myocardial inflammation and necrosis (hematoxylin and eosin staining). (D) Chronic myocarditis—extensive interstitial fibrosis and myocyte atrophy (Masson's trichrome staining). Scale bar 40 m.

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Diagnostic summary

As the clinical presentation of fulminant myocarditis lacks specific characteristics and because the individual diagnostic tests have limitations, a comprehensive approach that integrates clinical, echocardiographic, hemodynamic and histologic information is needed to differentiate between acute fulminant and nonfulminant myocarditis.^{56, 59} Previously, patients with suspected myocarditis were classified as having fulminant, acute, chronic active, or chronic persistent myocarditis on the basis of their clinical course, histological findings and response to immunosuppressive therapy (Table 3).⁶¹ In 2000, a classification system was proposed that was based on an analysis of data on 750 patients followed up for more than 7 years. This system incorporated echocardiographic findings, hemodynamic data obtained from right heart catheterization, and the Dallas histologic criteria (Table 4).²⁸ Under this new classification system, the distinguishing features of fulminant myocarditis as opposed to nonfulminant myocarditis included histological findings of more severe inflammation, lower mean arterial pressure, higher heart rate and higher right atrial and pulmonary capillary wedge pressure, but surprisingly did not include a low cardiac index. Also considered characteristic of fulminant myocarditis were normal left ventricular diastolic dimension and increased thickness of the interventricular septum; the latter feature might possibly result from increased myocardial edema.

Table 3 Clinicopathologic classification of myocarditis.⁶¹

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Table 4 Histologic, hemodynamic and echocardiographic characteristics of patients with acute fulminant versus nonfulminant myocarditis.²⁸

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Management

An algorithm for the management of acute-onset heart failure is outlined in Figure 5. Of note, no specific therapies for fulminant myocarditis exist. As patients with this disease present with hemodynamic instability and are often in cardiogenic shock, the first-line treatment is supportive care. The majority of these patients require inotropic support, in some cases with an intra-aortic balloon pump, to maintain blood pressure and improve cardiac output. If the patient does not respond to aggressive supportive therapy within a few hours to days, insertion of a ventricular assist device (VAD) should be considered. Mechanical assist devices can lead to favorable alterations in cellular and organ geometry and reduced wall stress, with improved cardiomyocyte function and patient survival.^{62, 63, 64, 65, 66} LVADs can be used, although biventricular assist devices are more commonly used, as biventricular failure often occurs in patients with fulminant myocarditis.

Figure 5 A clinical algorithm that outlines the management of acute-onset severe heart failure.

Coronary angiography is the recommended first-line investigation for most adults, especially those with risk factors for coronary atherosclerosis. Abbreviations: Bi-VAD, biventricular assist device; BiV-ICD, biventricular ICD; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; PCI, percutaneous coronary intervention.

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Every effort should be made to enable full ventricular recovery. An extracorporeal rather than an intracorporeal VAD is often chosen because of the ease by which this type of device is implanted and/or removed, and their ability to provide biventricular support.⁶² As an alternative to use of a VAD, extracorporeal membrane oxygenation (ECMO) can also be used to provide ventricular support in these patients; however, this technique is associated with serious adverse events such as vascular complications, hemolysis, and other conditions associated with a bedridden state.⁶⁷ ECMO is most beneficial in patients who present with cardiogenic shock or cardiac arrest and also have severe respiratory failure, and who consequently have inadequate oxygenation despite mechanical ventilation. In such a situation, ECMO will enable the patient to be stabilized and allows time to assess end-organ damage and the likelihood of recovery. In patients with predominant left ventricular dysfunction who require LVAD support, implantation of an assist device can be used either as a bridge to cardiac transplantation or as destination therapy.

Once the VAD has been inserted and the patient is hemodynamically stable, standard medical care for heart failure should be initiated—angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, -blockers, and aldosterone antagonists. Of note, digoxin should be used with caution as it increases the expression of proinflammatory cytokines and was associated with increased mortality in a murine model of viral myocarditis.⁶⁸ With aggressive supportive care, complete ventricular recovery usually occurs within several weeks after the onset of fulminant myocarditis (Table 5).⁶² In more than 50% of patients with fulminant myocarditis who receive a VAD, the extent of myocardial recovery is sufficient for patients to be weaned off their VAD and for the device to be removed. Unfortunately, the ability to predict which patients will achieve sustained myocardial recovery once the VAD is removed is suboptimal.⁶⁹ If full myocardial recovery is achieved, we recommend that the patient receive evidence-based pharmacologic treatment for heart failure indefinitely.

Table 5 Mechanical support for acute fulminant myocarditis: types of devices and survival.⁶²

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The role of immunosuppressive therapy in the treatment of fulminant myocarditis remains unclear. Although all available studies have limitations, a number of randomized clinical trials have assessed the efficacy of immunosuppressive therapies such as steroids, intravenous immunoglobulins (IVIG) or interferon on the resolution of myocarditis.^{5, 70, 71, 72, 73, 74} Overall, these trials have failed to demonstrate a beneficial effect of immunosuppression. To our knowledge, the ongoing European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) is the largest trial to evaluate the effects of immunosuppression on myocarditis.^{6, 75} This trial has the following four treatment groups: prednisolone and azathioprine for autoreactive (virus-negative) myocarditis; interferon- for enterovirus-positive myocarditis; high-dose IVIG for cytomegalovirus-positive myocarditis; and intermediate-dose IVIG for adenovirus-positive or parvovirus-positive myocarditis. Each group has a corresponding placebo-treated control group.

Of note, no trial—including the ESETCID—has enrolled patients with fulminant myocarditis. This condition has a low incidence, so a well-designed clinical study with adequate power is unlikely to be undertaken to assess the role of immunosuppressive agents in its treatment. Data from observational studies indicate that fulminant myocarditis is distinct from nonfulminant myocarditis in that patients with fulminant myocarditis have an excellent long-term survival with supportive therapy alone;⁴ this finding implies that these patients do not require immunosuppressive therapy. Unfortunately, because the clinical course of fulminant myocarditis differs from that of nonfulminant myocarditis, results from the ESETCID are unlikely to be capable of extrapolation to fulminant myocarditis.

Emerging technologies and novel treatment approaches

In 2000, Liu et al. discovered that coxsackieviruses and adenoviruses share a common receptor (termed the coxsackievirus and adenovirus receptor, hCAR) on the cardiomyocyte cell membrane, which raises the possibility that pharmacological inhibition of this virus–receptor interaction could be used to attenuate or halt viral infection of cardiomyocytes.¹³ If individuals who are susceptible to myocarditis could be identified during the early viremic stage, modulation of the enzymic activity of p56-LCK found in T cells could prevent infection or reduce disease severity.⁷⁶

The development of vaccines that target coxsackieviruses and adenoviruses—the most common viruses that cause myocarditis—could prevent the adverse consequences of these viral infections. Influenza virus is a rare cause of myocarditis, but the efficacy of influenza vaccine in prevention of fulminant myocarditis is not yet known. If effective vaccines can be developed, they should be incorporated into childhood vaccination programs, as children and young adults seem to be particularly susceptible to myocarditis.⁷⁷

The induction of immunologic tolerance to specific autoantigens is another potential strategy to attenuate the detrimental effects of myocarditis. Cardiac myosin is a possible target as it is a common autoantigen that can initiate an autoimmune response during the third phase of myocarditis.^{78, 79} In a mouse model of myocarditis, tolerance to myosin was achieved by the intranasal administration of cardiac myosin, which suppressed development of the disease.⁸⁰

Prognosis

If the disease is recognized quickly and appropriate supportive care is initiated early, long-term survival of patients with fulminant myocarditis is excellent. In one case series of patients with myocarditis, 2 of 15 individuals with fulminant myocarditis required mechanical ventricular assistance and the others were supported by high-dose vasopressor therapy.⁴ At 11 years after disease onset, 14 patients (93%) were alive and did not require a cardiac transplant (Figure 6). The patient who did not survive died during the index hospitalization. Of 132 patients with nonfulminant myocarditis only 85% survived without transplant 1 year after the initial biopsy and at 11 years this proportion was 45%. In that study fulminant myocarditis was a favorable predictor of transplant-free survival, independent of the severity of inflammation, patient's age, and hemodynamic status.

Figure 6 Kaplan–Meier curve that shows unadjusted transplantation-free survival among patients with acute fulminant or nonfulminant myocarditis.

Patients with fulminant myocarditis had an excellent long-term outcome.⁴ Reproduced from McCarthy RE et al. (2000) Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med 342: 690–695. Copyright © 2000 Massachusetts Medical Society. All rights reserved.

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Conclusions

Fulminant myocarditis is an uncommon illness that has clinical and histopathological features distinct from those of nonfulminant myocarditis. Clinically, fulminant myocarditis is characterized by an acute onset of severe hemodynamic instability, often in a previously healthy individual. The acting physician must be aware of and recognize other cardiovascular disorders that can mimic fulminant myocarditis. Endomyocardial biopsy is an important step in the correct diagnosis of this disease. The role of immunosuppressive therapies in patients with fulminant myocarditis remains unclear, despite the putative deleterious consequences of immune activation that occurs in this illness. If fulminant myocarditis is recognized promptly and supportive care with cardiac inotropes or mechanical VADs is initiated to treat hemodynamic collapse, the long-term prognosis of this condition is excellent and patients often have complete recovery of their ventricular function.

Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.The authors would like to acknowledge Dr Thomas E Rogers, Professor in Pathology at University of Texas Southwestern Medical Center, Dallas, TX, USA, for his invaluable help in obtaining the histologic images of endomyocardial biopsy slides.

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Subject areas under which this article appears: Cardiomyopathy and heart failure | Infection