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Treatment and prognosis of myocarditis in adults

Treatment and prognosis of myocarditis in adults
Literature review current through: Jan 2024.
This topic last updated: Aug 11, 2022.

INTRODUCTION — Myocarditis refers to inflammation of the heart muscle [1]. The diagnosis may be suspected by clinical and noninvasive features and is confirmed by histopathologic criteria on endomyocardial biopsy. The clinical manifestations of this disorder vary greatly from asymptomatic changes on an electrocardiogram to fulminant heart failure (HF). (See "Clinical manifestations and diagnosis of myocarditis in adults".)

This topic will review the prognosis and treatment of myocarditis in adults. Treatment of myocarditis consists of both specific therapy aimed at the cause of the myocarditis and nonspecific therapy aimed at the clinical manifestations such as HF and arrhythmias. The etiology, incidence, pathogenesis, clinical manifestations, and diagnosis of myocarditis are discussed separately. (See "Myocarditis: Causes and pathogenesis" and "Clinical manifestations and diagnosis of myocarditis in adults".)

A significant minority of patients with pericarditis also have myocarditis. Myocarditis associated with pericarditis, including vaccinia-associated disease (myocarditis and/or pericarditis), is discussed separately. (See "Myopericarditis".)

Myocardial injury (including clinically suspected myocarditis and coronavirus 2019 [COVID-19] vaccination-related myocarditis) in patients with COVID-19 is discussed separately. (See "COVID-19: Evaluation and management of cardiac disease in adults".)

NATURAL HISTORY AND PROGNOSIS

Variable disease course — The course of myocarditis varies with the presenting clinical syndrome.

Seroepidemiologic studies suggest that the majority of cases of Coxsackie B virus infection are subclinical and have a benign course [2].

In hospital- or clinic-based referral populations, the prognosis of myocarditis varies with the type or cause and the severity of presenting symptoms [3]. The spectrum of myocarditis outcomes is illustrated by the following observations:

In the majority of asymptomatic patients who develop inflammation as evidenced by electrocardiographic changes, the inflammatory process is apparently self-limited without overt sequelae. A minority of initially asymptomatic patients develop HF, serious arrhythmias, or disturbances of conduction. Rarely, postviral myocarditis is fatal due to myocardial failure or sudden, unexpected death [4].

Acute myopericarditis, defined as clinical pericarditis with elevated troponin and preserved left ventricular function, is associated with low risk of HF or death (eg, no HF or deaths among 114 patients at median three-year follow-up [5]). The rate of recurrent or chronic myopericarditis is 10 to 15 percent [6]. (See "Myopericarditis", section on 'Follow-up and prognosis'.)

In contrast, most patients with symptomatic postviral or lymphocytic myocarditis present with HF and dilated cardiomyopathy (DCM). However, subtle signs and symptoms of cardiac involvement may be overshadowed by systemic manifestations of the viral infection. As an example, in the United States Myocarditis Treatment Trial, 89 percent of subjects reported a syndrome consistent with a viral prodrome [7].

Worse outcomes have been reported by studies of patients with biopsy-proven myocarditis. As an example, a case series of 174 patients with biopsy-proven myocarditis from Padua, Italy, in which over half of the patients had baseline symptomatic or asymptomatic left ventricular and/or right ventricular systolic dysfunction, reported an actuarial rate of death or transplantation of 13 percent at two years [8]. In a series of 203 patients from Germany with myocarditis with viral genome detected on endomyocardial biopsy (EMB), the prognosis was similar with 19.2 percent all-cause mortality at 4.7 years [9]. Higher mortality rates were noted in a large single-center registry of biopsy-proven myocarditis from Massachusetts General Hospital [10]. Of 112 consecutive patients with histopathologic confirmation of myocarditis, rates of death or transplantation were 21 and 44 percent at one and five years, respectively.

In contrast, the risk of death or transplantation in a series of 466 patients with myocarditis diagnosed by cardiovascular magnetic resonance (CMR) imaging or EMB from Northern Italy was only 17 percent over 10 years [6].

The disease course for patients with fulminant myocarditis differs from that in patients with nonfulminant myocarditis as discussed below. (See 'Fulminant myocarditis' below.)

Myocarditis is a cause of ventricular and atrial arrhythmias [11]. Although only a small fraction of patients with lymphocytic myocarditis present with ventricular arrhythmias, as many as one-third of patients diagnosed with idiopathic ventricular tachycardia may have myocarditis [12-14]. Myocarditis also causes some cases of atrial fibrillation [15,16].

In a significant minority of patients with acute myocarditis, impaired ventricular function, arrhythmias, and/or disturbances of conduction may persist for months to years; this can be due to residual scar tissue, persistent active myocarditis, or occasionally persistent viral infection [17-19]. In a review of 1230 patients with initially unexplained cardiomyopathy, 9 percent had myocarditis [3]. In patients who present with ventricular arrhythmias, polymorphic ventricular arrhythmias are more common in the acute phase and monomorphic ventricular arrhythmias are more common in the chronic phase [11]. (See "Causes of dilated cardiomyopathy".)

Predictors of outcome

Clinical predictors — Patients presenting with complicated acute myocarditis (defined as initial left ventricular ejection fraction [LVEF] <50 percent, sustained ventricular arrhythmias, or low cardiac output syndrome requiring inotropes or mechanical circulatory support) are at increased risk for adverse cardiac events compared with patients without these risk factors. The prognostic value of these risk factors was evaluated in a retrospective multicenter study of 443 patients (median age 34 years) with acute myocarditis diagnosed by either EMB or by presence of the combination of biomarker elevation (troponin or creatine kinase MB) plus two CMR criteria for myocarditis (edema and late gadolinium enhancement in a non-ischemic pattern); 26.8 percent of patients presented with complicated acute myocarditis and 73.4 percent had an uncomplicated presentation [20]. During the initial hospitalization, among patients with a complicated presentation, the mortality rate was 8.5 percent, heart transplantation was required by 3.4 percent, and mechanical circulatory support was required by 19.5 percent; none of these in-hospital events occurred in patients with an uncomplicated presentation. After discharge during a median of 35 months of follow-up, cardiac death (1.9 percent), cardiac transplantation (1.9 percent), and sustained ventricular tachycardia requiring shock or ablation (3.8 percent) occurred in the group with complicated presentation but did not occur in any patients with an uncomplicated presentation. EMB was performed in 12.6 percent of patients (39.8 percent of those with a complicated presentation and 2.8 percent of those with an uncomplicated presentation), so the study provided limited information on the relationship between clinical presentation and EMB results.

Predictive value of autoantibodies — Cardiac-specific autoantibodies have been identified in subsets of patients with acute or chronic myocarditis [6,21,22] and appear to be associated with a worse prognosis in patients with chronic myocarditis and a better prognosis in patients with acute myocarditis. Presence of autoantibodies was associated with increased risk of progression from chronic myocarditis to DCM (figure 1) [21]. As an example, the presence of anti-alpha myosin autoantibodies was associated with lower likelihood of improvement in left ventricular systolic and diastolic function in a series of 33 patients with chronic myocarditis [21]. Patients with antibodies had no improvement in LVEF at six months compared with a 9 percent absolute increase in those without antibodies. Similarly, the presence of anti-heart antibodies in relatives of patients with idiopathic DCM predicted future left ventricular dilation [22].

By contrast, in patients with acute myocarditis, higher titers of IgG were associated with better left ventricular function in the Myocarditis Treatment Trial [7]. One possible explanation is that the acute immune response to viral infection usually serves to eliminate the pathogen and improve heart function, but in genetically susceptible patients, autoimmunity is induced, leading to progression to chronic DCM. (See "Myocarditis: Causes and pathogenesis", section on 'Autoimmune mechanisms'.)

Prognosis based on etiology — The available data suggest that prognosis of myocarditis likely varies among clinicopathologic types.

Lymphocytic myocarditis — Lymphocytic myocarditis has a variable course, including the following presentations:

Some patients have subclinical disease

Some have indolent disease that progresses to DCM

Others present with fulminant disease that may be fatal or may fully resolve after acute hemodynamic support

In one report of 27 patients (mean age 47) with myocardial biopsy-proven definite or borderline myocarditis, the five-year survival was 56 percent, similar to that in a comparison cohort of patients with idiopathic DCM without myocarditis (figure 2) [23].

Predictors of adverse outcome in acute myocarditis include severity of left ventricular or biventricular dysfunction [8,24]. In a series of 109 cases with Dallas criteria positive (active or borderline) myocarditis, findings at presentation that were predictive of subsequent death or transplantation were syncope (relative risk 8.5), bundle branch block (relative risk 2.9), and an LVEF <40 percent (relative risk 2.9) [24]. Although borderline histology was protective, this was not seen in other series [23,25]. In a prospective study on 174 patients with biopsy-proven myocarditis, presence of signs and symptoms of biventricular dysfunction was the main predictor of death or heart transplantation [8].

Another adverse prognostic factor is the development of secondary pulmonary hypertension. This was illustrated in a prospective study of 1134 patients with a new cardiomyopathy who underwent right heart catheterization and EMB and were followed for 4.4 years [26]. In a multivariate model, mean pulmonary artery pressure was the most important hemodynamic predictor of death, especially in the 93 patients (8.3 percent) with a diagnosis of myocarditis. For each 5 mmHg increase in baseline mean pulmonary artery pressure, the mortality in those with and without myocarditis increased with a relative hazard of 1.85 and 1.23, respectively.

Fulminant myocarditis — Fulminant myocarditis is defined as myocarditis with new onset severe HF requiring parenteral inotropic or mechanical circulatory support. Patients with fulminant myocarditis face high mortality risk. In a contemporary series of 187 patients with acute myocarditis, individuals with a fulminant presentation had a lower rate of in-hospital heart transplant-free survival (74.5 versus 100 percent) as well as lower transplant-free survival at 9 years (64.5 versus 100 percent) than patients with nonfulminant myocarditis [27]. Although there was greater improvement in LVEF during hospitalization among patients with fulminant myocarditis (32 versus 3 absolute percentage points), the proportion of patients with LVEF <55 percent remained higher with fulminant myocarditis than with nonfulminant myocarditis (29 versus 9 percent).

By contrast, older studies of patients with acute myocarditis suggested that lymphocytic fulminant myocarditis may be associated with better prognosis than nonfulminant myocarditis [25,28]. Differing results in the later study compared with earlier studies likely reflect differences in patient populations. In the earlier studies, patients presented primarily with dilated cardiomyopathy with diagnosis confirmed by Dallas or similar criteria on EMB (more likely to identify severe cases), while in the later study, patients presented with a greater spectrum of symptoms ranging from chest pain and palpitations to dyspnea, and diagnosis was confirmed by CMR imaging or immunohistochemistry on EMB, so less severe cases of myocarditis were included.

Persistence of viral genome — An important predictor of outcome in patients with viral myocarditis may be the persistence of the viral genome in the myocardium. This was suggested in a consecutive series of 172 patients with biopsy-proven viral infection; the patients had a relatively long duration of symptoms (5.1 months) before the initial EMB and were already on a reasonable HF regimen [29]. Among the 151 patients with a single infection (most frequently enterovirus), follow-up biopsy at a median of 6.8 months revealed spontaneous clearance of the viral genome in 55 (36 percent). These patients had a significant increase in LVEF (from 50 to 58 percent), while those with persisting viral genomes had a significant reduction in LVEF (from 54 to 51 percent).

Persistence of viral genome may also identify patients particularly unlikely to respond to immunosuppressive therapy [30]. (See 'Immunosuppressive therapy' below.)

However, other case series in which parvovirus B19 was the most frequent pathogen have not demonstrated an effect of viral genome on the risk of death or heart transplantation, raising a possibility that viral genomes may sometimes reflect latent and not active viral infection [31].

Although these data suggest that persistence of viral genome may predict a gradual deterioration of left ventricular function in chronic DCM, a clinical role for EMB in the management of such patients will depend upon more definitive evidence of effective treatment of viral cardiomyopathy.

Predictive value of serologic markers — Although clinical parameters are only partly predictive of outcome, serologic markers, particularly soluble Fas ligand (FasL) and interleukin (IL)-10, may be useful in acute, severe myocarditis. Fas (CD95), a member of the tumor necrosis factor receptor family, is expressed following B-cell activation. Binding of Fas with its natural ligand (FasL, which is expressed on activated T-cells) triggers apoptotic cell death. As a result, Fas regulates clonal expansion of autoreactive B-cells.

In one series, serum concentrations of soluble Fas and FasL were significantly higher in patients with acute myocarditis (predominantly lymphocytic) compared with normals or patients with an old myocardial infarction [32]. Among the patients with myocarditis, Fas and FasL concentrations were significantly higher in those who died during hospitalization compared with those discharged from the hospital after recovery.

Further support for the role of Fas comes from a study of 20 patients with recent-onset idiopathic DCM [33]. The patients in the highest tertile of Fas expression in the myocardium had minimal improvement in LVEF at six months compared with those in the intermediate and lowest tertiles (3 versus 10 and 21 percent, respectively).

A higher serum IL-10 concentration on admission may be predictive of cardiogenic shock and death in patients with fulminant (predominantly lymphocytic) myocarditis [34]. Higher peripheral blood Th17 cellular activity and lower T regulatory cells are associated with subsequent HF [35].

In a series of 466 patient with myocarditis, a high titer of organ-specific antiheart antibodies (hazard ratio [HR] 4.2, 95% CI 1.2-14.7) and antinuclear antibodies (HR 5.2, 95% CI 2.1-12.8) were independent predictors of death or heart transplantation [6].

Overlap with recent-onset idiopathic dilated cardiomyopathy — Some patients presenting with recent-onset (≤6 months) idiopathic DCM have myocarditis. The prognosis in patients with recent-onset idiopathic DCM may be fairly good. In a multicenter registry of 377 patients with acute DCM who received contemporary HF treatment and an average baseline LVEF of 24 percent at entry, LVEF improved to 40 percent at six months [36]. Transplant-free survival at one, two, and four years was 94, 92, and 88 percent, respectively.

Giant cell myocarditis — Idiopathic giant cell myocarditis (GCM) is a rare and frequently fatal type of myocarditis. In contrast to the variable clinical course of DCM due to lymphocytic myocarditis, the clinical course in GCM is usually characterized by acute or fulminant deterioration in left ventricular systolic function despite standard HF treatment, frequent ventricular arrhythmias, and heart block.

The prognosis of GCM with no or limited immunosuppressive therapy is poor. In a study published in 1997 based on international case reports of 63 patients with GCM, the presenting symptoms were HF (75 percent), ventricular arrhythmias (14 percent), and heart block (5 percent) [37]. Initial symptoms resembling an acute myocardial infarction were present in 6 percent. The rate of death or cardiac transplant was 89 percent and the median survival from onset of symptoms was 5.5 months. This represents a significantly worse prognosis compared with lymphocytic or presumed viral myocarditis. As an example, in the Myocarditis Treatment Trial, approximately 50 percent of patients with lymphocytic myocarditis were alive without cardiac transplant at five years [7].

Treatment with a combination of immunosuppressive agents may improve prognosis [37-39]. A report from Helsinki of 32 patients with GCM (including 26 patients treated with combined immunosuppression [two to four drugs]) found survival rates similar to those previously reported for lymphocytic myocarditis [38]. The Kaplan-Meier estimates of transplant-free survival from symptom onset were 69 percent at one year, 58 percent at two years, and 52 percent at five years. The risk of ventricular arrhythmias was high. Of the transplant-free survivors, 10 of 17 experienced sustained ventricular tachycardia during follow-up with three receiving appropriate implantable cardioverter-defibrillator shocks. (See 'Giant cell myocarditis' below.)

Eosinophilic myocarditis — Myocarditis characterized by a predominantly eosinophilic infiltrate may occur in association with malignancy, parasite infection, hypersensitivity myocarditis (HSM), endomyocardial fibrosis, and with the idiopathic hypereosinophilic syndrome. (See "Myocarditis: Causes and pathogenesis", section on 'Hypersensitivity myocarditis'.)

HSM presents as sudden death or rapidly progressive HF sometimes with rash, fever, and peripheral eosinophilia. Necrotizing eosinophilic myocarditis has an exceptionally poor prognosis with most cases diagnosed at autopsy.

In contrast, eosinophilic myocarditis associated with the hypereosinophilic syndrome typically evolves over weeks to months. The presentation is usually biventricular HF, although arrhythmias may lead to sudden death [40]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Celiac disease — Limited data suggest a risk of progression with HF and arrhythmias in untreated patients with myocarditis or DCM associated with celiac disease. Case reports have described celiac disease, often clinically unsuspected, associated with myocarditis or DCM [41-43]. In one series of nine patients with celiac disease and autoimmune myocarditis, none had classic gastrointestinal symptoms of celiac disease (recurrent abdominal pain, diarrhea, and weight loss), but all had iron deficiency anemia refractory to iron replacement [41].

Cardiac sarcoidosis — The prognosis of cardiac sarcoidosis is worse in patients with cardiac symptoms and signs as discussed separately. (See "Management and prognosis of cardiac sarcoidosis".)

Nonviral infectious — The prognosis of myocarditis caused by nonviral infectious agents such as Mycoplasma pneumoniae and Lyme disease (Borrelia burgdorferi) is discussed separately. (See "Mycoplasma pneumoniae infection in adults" and "Lyme carditis".)

GENERAL MANAGEMENT — Treatment of myocarditis includes general measures common to patients with various types of myocarditis or cardiomyopathy as well as therapy targeting specific disorders.

Treatment of myocarditis includes general nonspecific measures to treat the sequelae of heart disease, including HF therapy and treatment of arrhythmias according to current guidelines, and in select cases, anticoagulation. Our approach is generally similar to that in the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases position statement [44].

Heart failure therapy — Patients with myocarditis with HF should receive standard therapy for acute and chronic HF, depending upon the clinical presentation. (See "Treatment of acute decompensated heart failure: General considerations" and "Treatment of acute decompensated heart failure: Specific therapies" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Agents — The management of acute HF and the transition between acute and chronic HF therapy is discussed separately. Beta blocker therapy is decreased or withheld in patients with more than mild acute decompensated HF. (See "Treatment of acute decompensated heart failure: Specific therapies".)

Treatment of hemodynamically stable HF with reduced ejection fraction includes diuresis as needed, and early initiation of angiotensin converting enzyme (ACE) inhibitor (or angiotensin receptor blocker), and evidence-based beta blocker (carvedilol, extended release metoprolol, or bisoprolol) with addition of mineralocorticoid receptor antagonist in patients with persistent symptomatic HF with left ventricular ejection fraction ≤35 percent (with exclusions for patients at risk for hyperkalemia). (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

ACE inhibitor and beta blocker therapy may have specific benefits in patients with myocarditis, in addition to their proven benefits in reducing morbidity and mortality in patients with systolic HF generally. A study in murine coxsackievirus myocarditis showed that captopril administration on day three led to less myonecrosis and dystrophic calcification, suggesting benefits by mechanisms other than vasodilatation [45]. In a murine model of coxsackievirus myocarditis, treatment with a nonselective beta blocker improved outcome [46]. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

Although digoxin provides symptomatic benefit in patients with systolic HF generally, its efficacy and safety in patients with myocarditis is uncertain. Digoxin increased mortality in a mouse model of viral myocarditis [47]. Since the effects of digoxin in acute clinical myocarditis are uncertain, we avoid its use in this setting [48].

Mechanical circulatory support and transplantation — Potential options for patients with refractory HF despite optimum medical therapy include mechanical circulatory support and cardiac transplantation. (See "Treatment of advanced heart failure with a durable mechanical circulatory support device" and "Management of long-term mechanical circulatory support devices" and "Heart transplantation in adults: Indications and contraindications".)

Hemodynamically unstable patients with HF may require mechanical circulatory support (eg, ventricular assist device [VAD]) or extracorporeal membrane oxygenation.

Mechanical circulatory support with a VAD should be considered when HF is intractable or when cardiogenic shock does not respond to medical therapy [49,50]. Several reports suggest that in some patients, these devices can be used successfully as a bridge to spontaneous recovery in the setting of fulminant myocarditis. Among patients with fulminant myocarditis with cardiogenic shock treated with a VAD, a more rapid initial course is associated with greater likelihood of recovery. In a series of 24 patients implanted with VADs for fulminant myocarditis, patients who recovered had a more acute initial decompensation (ie, 7 versus 22 days from onset of symptoms to VAD implantation) than those who required heart transplantation [51]. Similarly, in a case series of 373 patients with recent-onset nonischemic cardiomyopathy, presence of myocarditis was the strongest predictor of bridge to recovery [52].

Candidacy for cardiac transplantation should be considered in patients with chronic myocarditis presenting as an intractable cardiomyopathy with refractory HF. Although a case series of 12 patients with active lymphocytic myocarditis at the time of transplant suggested an increased surgical risk in such patients [53], patients with biopsy-proven myocarditis (n = 142) in the much larger United Network for Organ Sharing registry did at least as well as other cardiac transplantation patients over one-year follow-up [54]. (See "Heart transplantation in adults: Prognosis".)

When mechanical circulatory support is anticipated, a diagnosis of giant cell myocarditis (GCM) may lead to use of a biventricular device because of the likelihood of progressive right ventricular failure and to an early heart transplant listing. Transplantation is an effective therapy for GCM. Among 34 patients who underwent transplantation for this disease, recurrence was documented in nine after an average follow-up of three years [55]. Posttransplantation survival was 71 percent at three years despite a 25 percent rate of histologic recurrence on posttransplant endomyocardial biopsy.

Therapy for arrhythmias — Patients with myocarditis can develop both tachy- and bradyarrhythmias. Because these arrhythmias often resolve after the acute phase of myocarditis, therapy is generally supportive.

Electrocardiographic monitoring can permit early detection of asymptomatic yet potentially life-threatening arrhythmias and/or conduction defects. For this reason, it is recommended that patients with acute and often unstable myocarditis be admitted to the hospital.

Our suggested approach is in broad agreement with major society guidelines [56]:

Antiarrhythmic therapy should not be given for asymptomatic atrial and ventricular premature beats or for asymptomatic nonsustained arrhythmias. (See "Supraventricular premature beats" and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation" and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".)

When antiarrhythmic therapy is necessary (as indicated below), options include amiodarone, dofetilide (with precautions for potential proarrhythmia), and in patients without class IV HF, cautious use of beta blockers or calcium channel blockers. Due to the proarrhythmic and negative inotropic effects, other class I and III antiarrhythmic drugs are generally avoided in patients with acute myocarditis.

Supraventricular tachycardias (SVTs) can induce or aggravate HF. For sustained, symptomatic SVT, restoration of sinus rhythm is the recommended initial approach. For recurrent sustained SVT, options include rate control therapy and antiarrhythmic therapy. The specific approach to restoring sinus rhythm, controlling the ventricular rate, and selecting an antiarrhythmic drug depends upon the arrhythmia and the overall clinical scenario. (See "Overview of the acute management of tachyarrhythmias".)

For ventricular arrhythmias:

Symptomatic nonsustained ventricular tachycardia can be treated with antiarrhythmic drugs. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".)

Sustained ventricular arrhythmias should be treated with urgent cardioversion, and recurrent arrhythmias should be treated with antiarrhythmic drugs. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

Role of implantable cardioverter-defibrillator (ICD) therapy:

-ICD implantation is generally deferred in patients with acute myocarditis since myocarditis and arrhythmia risk may resolve. A potential role for a wearable cardioverter-defibrillator for patients at risk for sudden cardiac arrest has been suggested but the evidence to support such therapy is scant [57].

-ICD implantation can be beneficial in patients with life-threatening ventricular arrhythmias who are not in the acute phase of myocarditis, who are receiving optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than one year. Data are lacking regarding specific late risks of VT and sudden cardiac arrest in subjects with myocarditis who present with VT or sudden cardiac arrest, so this recommendation is based solely upon indirect data on patients with various types of heart disease (particularly ischemic heart disease). (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

Complete heart block and/or symptomatic bradycardia are indications for pacing during the acute phase of myocarditis. This conduction abnormality is often transient; as a result, use of a temporary pacemaker should be the first step.

Anticoagulation — Indications for anticoagulation in patients with myocarditis include standard general indications such as evidence of systemic embolism or presence of acute left ventricular thrombus. Standard criteria for anticoagulation for atrial fibrillation should be applied; most patients with atrial fibrillation and HF meet criteria for long-term anticoagulation due to the significantly increased risk of embolization. Indications for anticoagulation should be reassessed if atrial fibrillation and HF resolve. In contrast, HF and/or low ejection fraction in patients with sinus rhythm are not generally accepted as indications for anticoagulation. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism' and "Antithrombotic therapy in patients with heart failure" and "The management of atrial fibrillation in patients with heart failure", section on 'Anticoagulation'.)

Things to avoid

Nonsteroidal antiinflammatory drugs — In animal models of myocarditis, nonsteroidal antiinflammatory drugs are not effective [58-60]. To the contrary, they may actually enhance the myocarditic process and increase mortality.

In addition, nonsteroidal antiinflammatory drugs should be avoided in patients with HF generally, given the risk of HF exacerbation and possible risk of increase mortality. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'Nonsteroidal anti-inflammatory drugs'.)

Heavy alcohol consumption — We suggest alcohol restriction to at most one alcoholic drink per day (14 to 15 g alcohol), since heavy alcohol intake may enhance the severity of the myocarditis [61]. However, the optimum threshold for alcohol consumption in this clinical setting is uncertain. (See "Cardiovascular benefits and risks of moderate alcohol consumption".)

Exercise — Physical activity should be restricted to reduce the work of the heart during the acute phase of myocarditis, especially when there is fever, active systemic infection, or HF. The efficacy of this recommendation has been demonstrated in animal models. Exercise in murine coxsackievirus infection increased viral replication in the heart and heart weight compared with controls [62]. The optimum duration of exercise restriction is uncertain. We agree with the American Heart Association/American College of Cardiology Foundation scientific statement on sports participation recommendation of three to six months abstinence from competitive sports after myocarditis. Before clearance, patients should be assessed with a symptom-limited exercise test, Holter monitor, and echocardiogram [63,64]. This recommendation is based upon expert opinion.

MANAGEMENT OF SPECIFIC DISORDERS — Limited data are available to support specific therapies directed at the causes of myocarditis. Immunosuppressive therapy is suggested for specific autoreactive disorders such as giant cell myocarditis (GCM), sarcoidosis, noninfectious eosinophilic myocarditis, and autoreactive myocarditis in the context of known extracardiac autoimmune disease (eg, lupus myocarditis). For lymphocytic myocarditis, combination immunosuppressive therapy is an option in select patients with biopsy-proven, virus-negative lymphocytic myocarditis refractory to standard HF therapy.

Lymphocytic myocarditis

Overview of therapy for lymphocytic myocarditis — The efficacy of antiviral, immunosuppressive, and intravenous immune globulin therapies in patients with lymphocytic myocarditis has not been established. Participation in a randomized, controlled trial comparing combination immunosuppressive therapy with standard therapy may be an option for select patients such as those with biopsy-proven, virus-negative lymphocytic chronic myocarditis refractory to standard symptomatic HF therapy. (See 'Immunosuppressive therapy' below.)

Antiviral therapy — Although viral infection is the most common identified cause of lymphocytic myocarditis [2,65], the efficacy of antiviral therapy for myocarditis is uncertain. Routine antiviral therapy is not recommended to treat myocarditis.

Antiviral therapy with ribavirin or interferon alfa reduces the severity of myocardial lesions and mortality in experimental murine myocarditis due to Coxsackievirus B3 [66-69]. However, this beneficial effect is seen only if therapy is started prior to inoculation or soon thereafter. The applicability of these findings to humans is therefore uncertain, since patients with viral myocarditis are usually not seen in the earlier stages. A case report suggested possible benefit from alpha interferon in patients with enterovirus-proven myocarditis [70].

Preliminary data suggest that antiviral therapy with interferon beta may be beneficial for patients with chronic dilated cardiomyopathy (DCM) and evidence of viral genome in endomyocardial biopsy (EMB) specimens by the polymerase chain reaction (PCR). In the randomized controlled multicenter Beta Interferon for Chronic Cardiomyopathy trial, 143 patients with DCM with evidence of myocarditis and confirmed myocardial viral infection were randomly assigned to interferon beta or placebo; preliminary results were presented in abstract form [71]. Treatment with beta interferon significantly reduced myocardial viral load but virus (particularly parvovirus B19) persisted in some patients [72]. Beta interferon improved patient global assessment compared with placebo at 24 weeks and improved New York Heart Association functional class compared with placebo at 12 weeks but not at 24 weeks [71].

Immunosuppressive therapy — Preliminary studies suggest that immunosuppressive therapy may be beneficial in selected patients with chronic myocarditis but immunosuppressive therapy has not proven to be effective in acute lymphocytic myocarditis of unspecified etiology. Further study is needed to identify an effective regimen for chronic myocarditis and to determine if the absence of viral genomes on EMB identifies patients who are more likely to improve with immunosuppressive therapy [30,73].

Because inflammation may persist in the myocardium after clearance of the initial pathogen, triggered by endogenous autoantigens, it has been postulated that immunosuppressive therapy might be effective in select cases of myocarditis, as supported by some experimental work. However, the effect of immunosuppression varies with the mouse strain, virus, and treatment and timing of therapy. As an example, mycophenolate mofetil inhibited the development of Coxsackie B virus myocarditis [74]. Conversely, both glucocorticoids and cyclosporine exacerbate acute murine viral myocarditis [75,76].

A systematic review including eight randomized controlled trials found that glucocorticoid therapy did not reduce mortality or improve functional status in patients with viral myocarditis, though improvement in left ventricular ejection fraction (LVEF) was suggested [77]. Although some observational, mostly uncontrolled, clinical studies have suggested clinical benefit from combination immunosuppressive therapy with glucocorticoids, azathioprine, or cyclosporine [78,79], evaluation of true effectiveness is difficult in myocarditis because of the high rate of spontaneous recovery [80,81]. A multicenter registry reported that azathioprine and prednisone may prolong transplant-free survival compared with control patients with acute and chronic myocarditis who did not receive immunosuppression over a 10-year follow-up [82].

No benefit from immunosuppressive therapy was found in acute myocarditis of unspecified etiology. In the randomized, controlled trial Myocarditis Treatment Trial, 111 patients with a histopathologic diagnosis of myocarditis of unspecified etiology and an LVEF of less than 45 percent were randomly assigned to receive conventional therapy alone or immunosuppression with either cyclosporine or azathioprine for 28 weeks [7]. In all patients, the LVEF improved from 25 to 34 percent and the mortality rate was 20 percent at one year and 56 percent at 4.3 years. There was no difference in outcome in the two treatment groups. A more robust inflammatory response was associated with less severe disease and a greater improvement in cardiac function.

In contrast to the lack of benefit seen in acute myocarditis of unspecified etiology, patients with chronic myocardial inflammation may respond to immunomodulatory therapy, as suggested by two randomized controlled trials:

In a trial of 84 patients with a DCM of greater than six months duration who had evidence of chronic inflammation on biopsy, the patients were randomly assigned to receive either immunosuppression (with glucocorticoid plus azathioprine) or placebo for three months and then were followed for two years [83]. There was no difference in the primary end point (death, heart transplantation, or hospital readmission) at two years (23 versus 21 percent for placebo). However, patients treated with immunosuppressive therapy had a significantly greater improvement in LVEF and clinical status.

A randomized trial (the Tailored Immunosuppression in Inflammatory Cardiomyopathy [TIMIC] study) compared outcomes with immunosuppressive treatment (glucocorticoid plus azathioprine) as compared with placebo in a chronic stable DCM population [73]. Of 512 patients with LVEF ≤45 percent who were screened with EMB, 85 subjects without viral genomes by PCR were assigned to either azathioprine and prednisone or placebo for six months. The immunohistologic criteria were the presence of >14 CD45 or >2 CD3 positive T cells per high power field. The presence of circulating anti-heart antibodies was not required for enrollment. The LVEF improved by >10 percent in 38 of 43 patients treated with immunosuppression, compared with none of the patients treated with placebo. The placebo-treated patients' mean LVEF declined from 27.8 percent to 19.7 percent after six months. Clinical improvement in the immunosuppression treated subjects was reflected in significantly lower average New York Heart Association functional class (table 1) at six months.

There are several possible explanations for the lack of effect on event-free survival in the studies of acute cardiomyopathy:

Most patients with acute cardiomyopathy improve with standard HF care. As a result, an additive effect of immunosuppressive treatment is not detectable, because of this improvement in the control arms.

Patients in the Myocarditis Treatment Trial were treated without excluding those with active or chronic viral myocarditis, in whom immunosuppression is not indicated and may be detrimental [30,75,76]. Conversely, immunosuppression was beneficial in patients with virus-negative autoreactive acute and chronic myocarditis with or without positive serum anti-heart autoantibodies [30,73].

Immunohistochemical markers of immune activation may be more sensitive compared with the standard Dallas criteria to identify a patient population, especially in chronic DCM, in which there may be benefit to immunosuppression [83,84].

It is possible that further studies may identify a subset of patients with acute myocarditis responsive to such a regimen [85,86].

A possible relationship between responsiveness to immunosuppressive therapy and presence of cardiac autoantibodies was suggested by an uncontrolled study of 41 patients with progressive HF for six months or more who were unresponsive to standard therapy and who had active lymphocytic myocarditis on biopsy [30]. All 41 were treated with prednisone and azathioprine. The following findings were noted:

Twenty patients were nonresponders (no improvement in LVEF), 17 had viral genomes in biopsy specimens, and none had cardiac autoantibodies.

Twenty-one patients were responders (rapid improvement in LVEF from 26 to 47 percent) with evidence of healed myocarditis on repeat myocardial biopsy; 19 had cardiac autoantibodies (identified by indirect immunofluorescence) and only three had viral genomes in biopsy specimens (all hepatitis C virus).

Although it is possible that the presence of cardiac autoantibodies simply identified patients who had spontaneous improvement, other data cited above suggested that such patients may have a worse prognosis [21]. Further support for the pathogenicity of autoantibodies, perhaps particularly those of the IgG3 subclass, comes from clinical improvement following immunoadsorption against columns that remove these antibodies in patients with idiopathic DCM [87-90].

Limited data are available on the use of immunosuppressive therapy of lymphocytic myocarditis in the setting of unexplained ventricular arrhythmias. In one study, 17 of 65 patients had unexplained ventricular arrhythmias in the apparent absence of structural heart disease [91]. Twelve of these patients underwent EMB and six had evidence of lymphocytic myocarditis. These six patients were treated with prednisone and azathioprine; none had recurrent spontaneous arrhythmias and none had ventricular arrhythmias that could be induced by electrophysiologic stimulation despite cessation of antiarrhythmic medications. Since data are limited, the indications for and value of detection of myocarditis in this setting are controversial. (See "Endomyocardial biopsy", section on 'Unexplained arrhythmias'.)

Intravenous immune globulin

Myocarditis — Intravenous immune globulin (IVIG) has antiviral and immunomodulatory effects, suggesting that it may play a role in the treatment of viral myocarditis. However, a systematic review concluded that there are insufficient data from methodologically strong studies to recommend routine IVIG therapy in patients with acute myocarditis [92]. There are no controlled randomized data on IVIG in pediatric or adult patients with acute or chronic myocarditis or DCM with biopsy-proven viral or autoreactive myocardial inflammation.

Dilated cardiomyopathy — The efficacy of IVIG in treating DCM is uncertain. As noted above, some patients with DCM have evidence of myocarditis. Although viral infection is the most commonly identified cause for myocarditis presenting as DCM, investigation does not reveal an etiology in approximately 50 percent of patients. The majority of these cases probably result from an occult infection, an autoimmune process, or the early stages of a genetically determined myocardial disease. The possible role of autoimmunity has led to evaluation of the effectiveness of IVIG in patients with DCM.

As described below, a small randomized trial found no benefit in patients with acute (recent-onset) DCM [80] but another trial suggested a benefit in patients with chronic DCM [93].

The randomized controlled IMAC trial of 62 patients with recent-onset (≤6 months of symptoms) DCM with LVEF ≤40 percent found that the improvement in LV function was the same with IVIG (1 g/kg per day for two days) and placebo [80]. Eleven percent of patients had "Dallas criteria" positive myocarditis. At one year, both groups of patients did well as the LVEF rose from 25 percent at baseline to 42 percent. Thirty-six percent had a normal LVEF, and the transplant-free survival at one and two years was 92 and 88 percent. [80].

In contrast, in a randomized, placebo-controlled trial of 40 patients with chronic DCM of unspecified etiology, IVIG significantly improved LVEF, while no improvement in LVEF was seen with placebo [93].

Giant cell myocarditis — Observational data suggest that patients with GCM treated with certain immunosuppressive regimes have improved survival compared with patients who do not receive immunosuppressive treatment [37,94]. Among 22 patients treated with immunosuppressive medications that included cyclosporine, the average transplant-free survival was 13 months compared with only three months among 30 patients who did not receive therapy [37]. These results were confirmed in a prospective uncontrolled study of 11 patients with GCM who were treated with one year of cyclosporine and glucocorticoids; nine patients also received 7 to 10 days of muromonab-CD3 [94]. Among the 11 patients, there was only one death and two transplantations during one-year follow-up. A benefit from immunosuppressive therapy was also suggested by a study of 32 patients with GCM, including 26 patients treated with combined immunosuppression (two to four drugs; including cyclosporine in 20 patients) [38]. Among the 26 patients treated with immunosuppression, the Kaplan-Meier estimate of transplant-free survival from diagnosis was 77 percent at one year, 63 percent at two years, and 63 percent at five years.

Myocardial inflammation appears mediated by T cells and giant cells. Therapy directed at T cells may therefore be of benefit, as suggested by case reports of treatment with muromonab-CD3 [94-96]. Further study is needed to determine the efficacy of this approach.

Eosinophilic myocarditis — Eosinophilic myocarditis may occur in association with malignancy, parasite infection, hypersensitivity myocarditis (HSM), vaccine exposure, endomyocardial fibrosis, and with the idiopathic hypereosinophilic syndrome. (See "Myocarditis: Causes and pathogenesis", section on 'Hypersensitivity myocarditis' and "Approach to the patient with unexplained eosinophilia" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis" and "Endomyocardial fibrosis".)

Treatment of the various types of eosinophilic myocarditis includes high-dose glucocorticoid therapy and removal of the offending drug (in the case of HSM) or treatment of the underlying disorder (eg, parasite infection or hypereosinophilic syndrome) [97]. (See "Hypereosinophilic syndromes: Treatment".)

Cardiac sarcoidosis — Treatment of cardiac sarcoidosis, including the role of glucocorticoid therapy and implantable cardioverter defibrillator implantation, is discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

Treatment of non-viral infections — In addition, myocarditis is infrequently caused by non-viral infectious agents that can be treated according to specific etiology (table 2), such as Mycoplasma or Lyme disease (Borrelia burgdorferi) (table 2) [2]. Of note, though specific therapy is available for these causes, it has not been established that such therapy favorably affects the myocarditic process. (See "Lyme carditis" and "Mycoplasma pneumoniae infection in adults".)

Celiac disease — Improved cardiac function and arrhythmias have been reported in patients with celiac disease and myocarditis or DCM following a gluten-free diet with or without immunosuppressive therapy, but controlled data are lacking [41,42]. (See "Myocarditis: Causes and pathogenesis", section on 'Celiac disease'.)

Experimental therapies — A number of experimental therapies have been evaluated in rodent models of myocarditis, including verapamil [98], anti-tumor necrosis factor antibodies [99], opiate receptor antagonists [100], and the nasal administration of cardiac myosin, which induces antigen-specific tolerance and suppresses the autoimmune response to native cardiac myosin induced by viral infection [101]. The relevance of these therapies to human disease remains to be determined.

The possible beneficial effect of herbal remedies in viral myocarditis was evaluated in a review [102]. Forty randomized trials including 3448 patients were included; all trials were conducted and published in China. The methodologic quality of the trials was generally low. Significant effects on arrhythmia, cardiac enzymes, and/or cardiac function were seen in studies of three agents. Further study of these agents may be justified [103], but clinical use cannot be recommended at present.

FOLLOW-UP — As noted above, most patients with acute myocarditis have partial or full clinical recovery. In some cases, however, the process may continue subclinically, eventually becoming severe enough to produce symptoms, often with dilated cardiomyopathy [17-19,23,104,105]. The likelihood of these late complications is increased in patients who present with greatly diminished left ventricular function.

As a result, all patients with myocarditis should be followed, initially at intervals of one to three months. Physical activity, especially competitive sports, should be permitted only gradually, and their tolerance monitored. The examiner should be alert to persistent or recurring S3 and S4 gallops. Echocardiography should be used for monitoring the size of the cardiac chambers, valve function, and the left ventricular ejection fraction. If the echocardiogram does not provide the necessary information, CMR, nuclear testing, or cardiac computed tomography are alternatives, depending upon availability. We assess cardiac function at one and six months and then yearly or as indicated by symptoms.

PREVENTION — Vaccination has been effective in preventing some forms of viral myocarditis but the role for vaccination and other types of infection control in preventing other types of myocarditis is largely unknown [106]. As a result of the widespread use of vaccination in developed countries, myocarditis secondary to measles, rubella, mumps, poliomyelitis, and influenza is now rare. Similarly, the recognition of trichinellosis by meat inspection has all but eliminated this infection. It is possible that vaccines against other cardiotropic viruses may prevent viral myocarditis, as suggested by success with this approach in murine models [106].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Myocarditis" and "Society guideline links: Acute rheumatic fever and rheumatic heart disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Myocarditis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Natural history and prognosis – The prognosis of myocarditis varies widely and varies with the underlying cause and the severity of presenting symptoms. (See 'Variable disease course' above.)

Lymphocytic myocarditis – Patients with lymphocytic myocarditis may have subclinical disease, slowly progressive disease leading to dilated cardiomyopathy (DCM), or fulminant disease that may be fatal or may fully resolve with supportive care. (See 'Lymphocytic myocarditis' above.)

Giant cell myocarditis – The clinical course for giant cell myocarditis (GCM) usually includes acute or fulminant deterioration in left ventricular systolic function despite standard treatment for heart failure (HF), frequent ventricular arrhythmias, and heart block. (See 'Giant cell myocarditis' above.)

Eosinophilic myocarditis – Eosinophilic myocarditis occurs in a variety of clinical settings, including hypersensitivity myocarditis (typically with a rapidly progressive course) and hypereosinophilic syndrome (typically with a more gradual course of biventricular HF). (See 'Eosinophilic myocarditis' above.)

Celiac disease – Patients with myocarditis or DCM associated with celiac disease are at risk for progressive HF and arrhythmias if untreated. (See 'Celiac disease' above.)

General management – Treatment of myocarditis includes general measures, including HF therapy and treatment of arrhythmias. Potential options for patients with refractory HF despite optimum medical therapy include mechanical circulatory support (eg, ventricular assist devices) and cardiac transplantation. (See 'General management' above.)

Management of specific disorders – Immunosuppressive therapy is suggested for specific autoreactive disorders such as GCM, sarcoidosis, noninfectious eosinophilic myocarditis, and autoreactive myocarditis in the context of known extracardiac autoimmune disease (eg, lupus myocarditis). (See 'Management of specific disorders' above.)

Things to avoid – Patients with myocarditis should avoid nonsteroidal antiinflammatory drugs, heavy alcohol consumption, and exercise. (See 'Things to avoid' above.)

Follow-up – All patients with myocarditis should receive routine follow-up, including serial echocardiography (or other cardiac imaging). (See 'Follow-up' above.)

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Topic 4935 Version 21.0

References

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