Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating.
The image below depicts numerous lymphocytes with associated myocyte damage.
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H and E, low power, showing numerous lymphocytes with associated myocyte damage (photo courtesy of Dr. Donald Weilbaecher)
Signs and symptoms
Myocarditis usually manifests in an otherwise healthy person and can result in rapidly progressive (and often fatal) heart failure and arrhythmia. Patients with myocarditis have a clinical history of acute decompensation of heart failure, but they have no other underlying cardiac dysfunction or have low cardiac risk.
Patients with myocarditis may present with the following signs and symptoms:
Mild symptoms of chest pain (in concurrent pericarditis), fever, sweats, chills, dyspnea
In viral myocarditis: Recent history (≤1-2 wk) of flulike symptoms of fevers, arthralgias, and malaise or pharyngitis, tonsillitis, or upper respiratory tract infection
Palpitations, syncope, or sudden cardiac death due to underlying ventricular arrhythmias or atrioventricular block (especially in giant cell myocarditis)
Heart failure
See Clinical Presentation for more detail.
Diagnosis
The diagnosis of acute myocarditis is usually presumptive, based on patient demographics and the clinical course. Because many cases of myocarditis are not clinically obvious, a high degree of suspicion is required.
Patients with myocarditis usually present with signs and symptoms of acute decompensation of heart failure (eg, tachycardia, gallop, mitral regurgitation, edema) and, in those with concomitant pericarditis, with pericardial friction rub.
Specific findings in special cases are as follows:
Sarcoid myocarditis: Lymphadenopathy, also with arrhythmias, sarcoid involvement in other organs (up to 70%)
Acute rheumatic fever: Usually affects heart in 50-90%; associated signs, such as erythema marginatum, polyarthralgia, chorea, subcutaneous nodules (Jones criteria)
Hypersensitive/eosinophilic myocarditis: Pruritic maculopapular rash and history of using offending drug
Peripartum cardiomyopathy - Heart failure developing in the last month of pregnancy or within 5 months following delivery
Testing
Laboratory studies use to evaluate suspected myocarditis may include the following:
Complete blood count
Erythrocyte sedimentation rate level (and that of other acute phase reactants [eg, C-reactive protein])
Rheumatologic screening
Cardiac enzyme levels (eg, creatine kinase or cardiac troponins)
Serum viral antibody titers
Viral genome testing in endomyocardial biopsy
Electrocardiography
Imaging studies
The following imaging studies may be used to assess patients with suspected myocarditis:
Echocardiography: To exclude other causes of heart failure (eg, amyloidosis or valvular or congenital causes) and to evaluate the degree of cardiac dysfunction
Antimyosin scintigraphy: To identify myocardial inflammation
Cardiac angiography: To rule out coronary ischemia as cause of new-onset heart failure
Gadolinium-enhanced magnetic resonance imaging: To assess extent of inflammation and cellular edema; nonspecific
Procedures
Endomyocardial biopsy is the standard tool for diagnosing myocarditis. However, the use of routine endomyocardial biopsy in establishing the diagnosis of myocarditis rarely is helpful clinically, since histologic diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected.[2, 3]
The Heart Failure Society of America 2010 comprehensive heart failure practice guideline recommends considering endomyocardial biopsy for patients with acute deterioration of heart function of unknown origin that is not responding to medical treatment.[4]
See Workup for more detail.
Management
In general, treatment of either acute or chronic myocarditis is aimed at reducing congestion and improving cardiac hemodynamics in heart failure, as well as providing supportive therapy, with the hope of prolonging survival. Treatment of heart failure follows the same treatment regimen regardless of the underlying cause (ie, inhibitors, beta-adrenergic blockers).
Pharmacotherapy
Medications used in the management of myocarditis include the following:
Anticoagulation may be advisable as a preventive measure, as in other causes of heart failure, although no definitive evidence is available.
Antiarrhythmics can be used cautiously, although most antiarrhythmic drugs have negative inotropic effects that may aggravate heart failure. (Supraventricular arrhythmias should be converted electrically.) High-grade ventricular ectopy and ventricular tachyarrhythmia should be treated cautiously with beta blockers and antiarrhythmics.
Inotropic drugs (eg, dobutamine, milrinone) may be necessary for severe decompensation, although they are highly arrhythmogenic. Long-term treatment follows the same medical regimen, including angiotensin-converting enzyme inhibitors, beta blockers, and aldosterone receptor antagonists. However, in some instances, some of these drugs cannot be implemented initially because of hemodynamic instability.
Nonpharmacotherapy
Supportive care in patients with myocarditis includes the following:
Hemodynamic and cardiac monitoring
Administration of supplemental oxygen
Fluid management
Surgical option
Surgical intervention in myocarditis may include the following:
Temporary transvenous pacing for complete heart block
Cardiac transplantation
Extreme cases: Ventricular assist device or percutaneous circulatory support; left ventricular assistive devices (LVADs) and extracorporeal membrane oxygenation[5]
Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating. More specifically, it is described as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes."[6] Myocarditis usually manifests in an otherwise healthy person and can result in rapidly progressive (and often fatal) heart failure and arrhythmia. In the clinical setting, myocarditis is synonymous with inflammatory cardiomyopathy. It is diagnosed by established histologic, immunologic, and immunochemical criteria. (See Etiology, Clinical, and Workup.)
Lieberman further classified myocarditis as follows[7] :
Fulminant myocarditis - Follows a viral prodrome; distinct onset of illness consisting of severe cardiovascular compromise with ventricular dysfunction and multiple foci of active myocarditis; either resolves spontaneously or results in death
Acute myocarditis - Less distinct onset of illness, with established ventricular dysfunction; may progress to dilated cardiomyopathy
Chronic active myocarditis - Less distinct onset of illness, with clinical and histologic relapses; development of ventricular dysfunction associated with chronic inflammatory changes (including giant cells)
Chronic persistent myocarditis - Less distinct onset of illness; persistent histologic infiltrate with foci of myocyte necrosis but without ventricular dysfunction (despite symptoms, eg, chest pain, palpitations)
These terms are still used to describe the clinical presentation and progression of myocarditis, particularly in the absence of ongoing histologic evaluation. (See Etiology and Clinical.)
Patient education
Patients should be advised of the current understanding of the natural history of myocarditis and the strengths and limitations of different diagnostic testing and therapeutic options. (See Etiology, Clinical, Workup, Treatment, and Medications.)
Myocarditis is probably caused by a wide variety of infectious organisms, autoimmune disorders, and exogenous agents, with genetic and environmental predisposition. Most cases are presumed to be caused by a common pathway of host-mediated, autoimmune-mediated injury, although direct cytotoxic effects of the causative agent and damages due to cytokine expression in the myocardium may play some role in myocarditis etiology. Damage occurs through the following mechanisms:
Direct cytotoxic effect of the causative agent
Secondary immune response, which can be triggered by the causative agent
Cytokine expression in the myocardium (eg, tumor necrosis factor [TNF] ̶ alpha, nitric oxide synthase)
Aberrant induction of apoptosis[8]
Myocardial damage has 2 main phases, as follows:
Acute phase (first 2 wk) - Myocyte destruction is a direct consequence of the offending agent, which causes cell-mediated cytotoxicity and cytokine release, contributing to myocardial damage and dysfunction; detection of the causal agent is uncommon during this stage
Chronic phase (>2 wk) - Continuing myocyte destruction is autoimmune in nature, with associated abnormal expression of human leukocyte antigen (HLA) in myocytes (and in the case of viral myocarditis, persistence of the viral genome in myocardium)
Viral myocarditis
In viral myocarditis, viral isolates differ in tissue tropism and virulence. For example, coxsackievirus A9 is a self-limiting myocarditis, whereas coxsackievirus B3 causes severe myocarditis resulting in a high mortality rate. The induction of the coxsackie-adenovirus receptor (CAR) and the complement deflecting protein decay accelerating factor (DAF, CD55) may allow efficient internationalization of the viral genome.
Viral replication may lead to further disruption of metabolism and to perturbation of inflammation and its response. Vasospasm induced by endothelial cell viral infection may also contribute to further damage.[9]
New evidence of dystrophin disruption by expression of enteroviral protease 2A points to yet another unique pathogenic mechanism.[10] In contrast, some viruses (such as parvovirus B19) may focus on pericapillary depositions, contributing to diastolic dysfunction rather than to direct myocyte destruction. Regardless, viral persistence provides the necessary stimuli for autoimmune or other inflammatory responses.
Idiopathic myocarditis
Approximately 50% of the time, myocarditis is classified as idiopathic, although a report by Klugman et al found that 82% of the pediatric cases studied were considered idiopathic.[11] The investigators also determined that 3% of cases in the study had a known bacterial or viral etiology, and that 6% of cases were related to other diseases.
In idiopathic cases, a viral etiology is often suspected but unproved, even with sophisticated immunohistochemical and genomic studies. Studies on patients with idiopathic dilated cardiomyopathy found evidence of viral particles in endomyocardial biopsy specimens in up to two thirds of the patients.[12]
The frequency of myocarditis is difficult to ascertain, owing to the wide variation of clinical presentation. Incidence is usually estimated at 1-10 cases per 100,000 persons. Incidence of positive right ventricular biopsy findings in patients with suspected myocarditis is highly variable (ranging from 0-80%). According to estimates, as many as 1-5% of patients with acute viral infections may have involvement of the myocardium.
International occurrence
A population study in Finland found that, in a study of more than 670,000 healthy young male military recruits, 98 cases had myocarditis mimicking myocardial ischemia, 1 case presented as sudden death, and 9 cases presented as recent-onset dilated cardiomyopathy.[13, 14]
A Japanese 20-year series of 377,841 autopsies found idiopathic, nonspecific, interstitial, or viral myocarditis in only 0.11% of individuals.[15]
Race-, sex-, and age-related demographics
No particular race predilection is noted for myocarditis except for peripartum cardiomyopathy (a specific form of myocarditis that appears to have a higher incidence in patients of African descent).
The incidence of myocarditis is similar between males and females, although young males are particularly susceptible.
Patients are usually fairly young. The median age of patients affected with lymphocytic myocarditis is 42 years. Patients with giant cell myocarditis may be older (mean age 58 years), but this condition usually does not discriminate with respect to age, sex, or presenting symptoms.
Other susceptible groups include immunocompromised individuals, pregnant women, and children (particularly neonates).
Patients who survive fulminant myocarditis have a good prognosis. In a study of 147 cases of myocarditis monitored for an average of 5.6 years, 93% of the 15 patients with fulminant disease were alive without transplant 11 years after biopsy, compared with 45% of the 132 patients with less severe disease. Left ventricular dilation was not as severe in the fulminant cases as in the nonfulminant ones.[16, 17]
Expression of soluble Fas and Fas ligands at initial presentation appears to be a good serologic marker to predict the prognosis of acute myocarditis, while antimyosin autoantibodies are associated with development of worse cardiac dysfunction in chronic myocarditis.[18]
Predictors of death or need for heart transplantation after acute myocarditis in multivariate analyses include syncope, low ejection fraction, and left bundle-branch block, all indicators of advanced cardiomyopathy.[19]
Morbidity and mortality
Most patients with mild symptoms recover completely without any residual cardiac dysfunction, although a third subsequently developing dilated cardiomyopathy.[14, 20, 21, 22] Cardiogenic shock may occur in fulminant cases of myocarditis.
In the Myocarditis Treatment Trial, the 1-year mortality rate was 20% and the 4-year mortality rate was 56% in a population with symptomatic heart failure presentation and left ventricular ejection fraction lower than 45% at baseline.[23] Severe heart block requiring permanent pacemaker placement occurred in 1% of patients in the trial.
In a study of patients with giant cell myocarditis, 89% of patients either died or underwent transplantation, with median survival from symptom onset to death or transplantation being only 5.5 months.[24]
A study by Klugman et al reported a 92% survival rate among 216 pediatric patients with myocarditis.[11] According to the investigators, nonsurviving patients were characterized by a greater severity of illness at presentation and a frequent need for extracorporeal membrane oxygenation and other intensive care unit therapies. With regard to postpartum cardiomyopathy, the mortality rate at 1 year can be as high as 50%.
Patients with myocarditis have a clinical history of acute decompensation of heart failure, but they have no other underlying cardiac dysfunction or have low cardiac risk. The diagnosis is usually presumptive, based on patient demographics and the clinical course (eg, spontaneous recovery following supportive care).
Patients may present with mild symptoms of chest pain (in concurrent pericarditis), fever, sweats, chills, and dyspnea.
In viral myocarditis, patients may present with a history of recent (within 1-2 wk) flulike syndrome of fevers, arthralgias, and malaise or pharyngitis, tonsillitis, or upper respiratory tract infection.
Population studies suggest that adults may present with few symptoms, rather than the acute toxic state of cardiogenic shock or frank heart failure (fulminant myocarditis) that is often associated with myocarditis.
Symptoms of palpitations or syncope, or even sudden cardiac death, may develop, due to underlying ventricular arrhythmias or atrioventricular block (especially in giant cell myocarditis).
Adults may present with heart failure years after an initial index event of myocarditis (as many as 12.8% of patients with idiopathic dilated cardiomyopathy had presumed prior myocarditis in one case series).
Patients with myocarditis usually present with signs and symptoms of acute decompensation of heart failure (eg, tachycardia, gallop, mitral regurgitation, edema) and, in those with concomitant pericarditis, with pericardial friction rub. Specific findings in special cases are as follows:
Sarcoid myocarditis - Lymphadenopathy, also with arrhythmias, sarcoid involvement in other organs (up to 70%)
Acute rheumatic fever - Usually affects heart in 50-90%; associated signs, such as erythema marginatum, polyarthralgia, chorea, subcutaneous nodules (Jones criteria)
Hypersensitive/eosinophilic myocarditis - Pruritic maculopapular rash and history of using offending drug
Elevated erythrocyte sedimentation rate (and other acute phase reactants, such as C-reactive protein)
Rheumatologic screening - To rule out systemic inflammatory diseases
Elevated cardiac enzymes - Creatine kinase or cardiac troponins
Serum viral antibody titers - For viral myocarditis
Cardiac enzymes
Elevated cardiac enzymes are an indicator for cardiac myonecrosis. Cardiac troponin (troponin I or T), in particular, is elevated in at least 50% of patients with biopsy-proven myocarditis. Cardiac enzymes may also help to identify patients with resolution of viral myocarditis.
The test has 89% specificity and 34% sensitivity and increases more frequently than creatine kinase MB subunits (elevated in only 5.7% of patients with biopsy-proven myocarditis). However, these studies have been performed using standard clinical assays, and the sensitivity of newer-generation high-sensitivity cardiac troponin assays in diagnosing myocarditis may differ.
Viral antibody titers
Common viral antibody titers available for clinical evaluation include coxsackievirus group B, human immunodeficiency virus (HIV), cytomegalovirus, Ebstein-Barr virus, hepatitis virus family, and influenza viruses. Titers increase 4-fold or more, with a gradual fall during convalescence (nonspecific); hence, serial testing is required.
Antibody titer testing is rarely indicated in the diagnosis of viral myocarditis or any dilated cardiomyopathies, owing to its low specificity and the delayed rising of viral titers, which would have no impact on therapeutic decisions.
Viral genome
The presence of viral genome in endomyocardial biopsy samples is considered the criterion standard for viral persistence. However, the test lacks specificity, because the presence of viral genome can also be present in healthy controls. The most common viral genomes found include those of parvovirus and herpes simplex.
Histologic findings
Biopsy specimens from EMB should reveal the simultaneous findings of lymphocyte infiltration and myocyte necrosis.
Echocardiography is performed to exclude other causes of heart failure (eg, amyloidosis or valvular or congenital causes) and to evaluate the degree of cardiac dysfunction (usually diffuse hypokinesis and diastolic dysfunction). It also may allow gross localization of the extent of inflammation (ie, wall motion abnormalities, wall thickening, pericardial effusion). In addition, echocardiography may distinguish between fulminant and acute myocarditis by identifying near-normal left ventricular diastolic dimensions and increased septal thickness in fulminant myocarditis (versus increased left ventricular diastolic dimensions and normal septal thickness in acute myocarditis), with marked improvement in systolic function in time.
Antimyosin scintigraphy (using antimyosin antibody injections) can identify myocardial inflammation with high sensitivity (91-100%) and negative predictive power (93-100%) but has low specificity (31-44%) and low positive predictive power (28-33%). In contrast, gallium scanning is used to reflect severe myocardial cellular infiltration and has a good negative predictive value, although specificity is low. Positron emission tomography (PET) scanning has been used in selected cases (eg, sarcoidosis) to assess the degree and location of inflammation.
Cardiac angiography is often indicated to rule out coronary ischemia as a cause of new-onset heart failure, especially when clinical presentation mimics acute myocardial infarction. It usually shows high filling pressures and reduced cardiac outputs.
Gadolinium-enhanced magnetic resonance imaging (MRI) is used for assessment of the extent of inflammation and cellular edema, although it is still nonspecific. Delayed-enhanced MRI has also been used to quantify the amount of scarring that occurred following acute myocarditis.[25]
Monney et al suggested that cardiac magnetic resonance (CMR) scanning may be useful in patients with suspected acute coronary syndrome who are found not to have coronary artery disease. Despite preserved systolic function, a significant proportion of these patients were subsequently diagnosed with acute myocarditis on the basis of the CMR scan findings.[26]
Radunski et al evaluated the accuracy of T2, T1, and extracellular volume (ECV) quantification as novel quantitative tissue markers in comparison with standard "Lake-Louise" cardiac magnetic resonance (CMR) criteria to diagnose myocarditis. At 1.5-T, CMR was performed in 104 patients with myocarditis and 21 control subjects. Patients with myocarditis underwent CMR 2 weeks (interquartile range: 1 to 7 weeks) after presentation with new-onset heart failure or acute chest pain. The diagnostic accuracies of conventional CMR were 70% for T2w CMR, 59% for EGE, and 67% for LGE. The diagnostic accuracies of mapping techniques were 63% for myocardial T2, 69% for native myocardial T1, and 76% for global myocardial ECV. The diagnostic accuracy of CMR was significantly increased to 90% by a stepwise approach, using the presence of LGE and myocardial ECV ≥27% as diagnostic criteria, compared with 79% for the Lake-Louise criteria. ECV quantification with LGE imaging significantly improved the diagnostic accuracy of CMR, compared to standard Lake-Louise criteria.[27]
Bohnen et al tested the performance of novel quantitative T1 and T2 mapping cardiovascular magnetic resonance (CMR) techniques to identify active myocarditis in patients with recent-onset heart failure. The study population consisted of 31 consecutive patients with recent-onset heart failure, reduced left ventricular function, and clinically suspected myocarditis who underwent endomyocardial biopsy and CMR at 1.5 Tesla. Endomyocardial biopsy revealed active myocarditis in 16 of 31 patients. Patients with active myocarditis showed no significant differences from patients without active myocarditis in clinical characteristics, standard Lake-Louise CMR parameters, global myocardial T1, or extracellular volume fraction. However, median global myocardial T2 was significantly higher in patients with active myocarditis compared to patients without active myocarditis. A cutoff value for global myocardial T2 of ≥60 ms yielded a sensitivity, specificity, accuracy, negative and positive predictive value of 94% (70%-100%), 60% (32%-84%), 77% (60%-89%), 90% (56%-100%), and 71% (48%-89%) for active myocarditis, respectively. For assessing the activity of myocarditis in patients with recent-onset heart failure and reduced left ventricular function, T2 mapping seems to be superior to standard CMR parameters, global myocardial T1, and extracellular volume fraction values.[28]
Endomyocardial biopsy (EMB) is the criterion standard for the diagnosis of myocarditis, although it has limited sensitivity and specificity, as inflammation can be diffuse or focal. However, the use of routine EMB in establishing the diagnosis of myocarditis rarely is helpful clinically, since histologic diagnosis seldom has an impact on therapeutic strategies, unless giant cell myocarditis is suspected.[2, 3]
However, the Heart Failure Society of America 2010 comprehensive heart failure practice guideline recommends considering endomyocardial biopsy for patients with acute deterioration of heart function of unknown origin that is not responding to medical treatment.[4]
The risk of adverse events in endomyocardial biopsy approaches 6%, including complications in 2.7% of patients on sheath insertion and 3.3% on the biopsy procedure; there is also a 0.5% probability of perforation.[3]
Because of sampling technique, sensitivity may increase with multiple biopsies (50% for 1 biopsy, 90% for 7 biopsies). The standard is to obtain at least 4 or 5 biopsies, although false-negative rates still may be as high as 55%.
False-positive rates are also high, owing to small numbers of normally occurring lymphocytes in the myocardium and the difficulty in distinguishing between lymphocytes and other cells (such as eosinophils in hypersensitive/eosinophilic myocarditis). Moreover, wide interobserver variability in histologic interpretations is also a factor.
Noncaseating granulomas for sarcoid myocarditis are found in only 5% of cases by biopsies and in as many as 27% in autopsy series.
Persistent viral messenger ribonucleic acid (mRNA), which can be found in only 25-50% of patients with biopsy-proven acute myocarditis, often confers a poor prognosis. Epidemiologic results from the European Study on the Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) database found that only 11.8% of patients with suspected acute or chronic myocarditis and reduced ejection fractions had detectable viral genomes in biopsy samples.[29]
Electrocardiograms are often nonspecific (eg, sinus tachycardia, nonspecific ST- or T-wave changes). Occasionally, heart block (atrioventricular block or intraventricular conduction delay), ventricular arrhythmia, or injury patterns, with ST- or T-wave changes mimicking myocardial ischemia or pericarditis (pseudoinfarction pattern), may indicate poorer prognosis. Arrhythmia is common in Chagas heart disease. The following may be seen: right bundle-branch block with or without bifascicular block (50%), complete heart block (7-8%), atrial fibrillation (7-10%), and ventricular arrhythmia (39%).
The Dallas classification (1987) and the World Health Organization (WHO) Marburg classification (1996) are commonly used based on the patterns in the following histologic characteristics[6] :
Amount - None (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3)
Distribution - Focal (outside vessel lumen), confluent, diffuse, or reparative (in fibrotic areas)
The Dallas classification on initial biopsy is as follows:
Myocarditis - Myocardial necrosis, degeneration, or both, in the absence of significant coronary artery disease with adjacent inflammatory infiltrate with or without fibrosis
Borderline myocarditis - Inflammatory infiltrate too sparse or myocyte damage not apparent
No myocarditis
The Dallas classification on subsequent biopsy is as follows:
Ongoing (persistent) myocarditis with or without fibrosis
Resolving (healing) myocarditis with or without fibrosis
Resolved (healed) myocarditis with or without fibrosis
WHO Marburg criteria (1996) defines myocarditis as a minimum of 14 infiltrating leukocytes/mm2, preferably T cells (CD45RO), with as many as 4 macrophages possibly included.[29]
Because many cases of myocarditis are not clinically obvious, a high degree of suspicion is required to identify acute myocarditis. Fortunately, most patients have mild symptoms consistent with viral syndromes, and they recover with simple supportive care on an outpatient basis, including with slow rehabilitation and the implementation of evidence-based medical therapy. Repeat assessment with echocardiography may be helpful to determine the persistence of cardiac dysfunction.
Overall, neurohormonal agents are given in a similar manner as in patients presenting with new-onset heart failure. Serial assessment is needed to determine the potential resolution of acute myocarditis, and during the early recovery period, strenuous exercise and digoxin should be avoided. Data regarding the risks of relapse with drug withdrawal following recovery are not available, so it is generally not recommended in practice.
Transfer
Transfer to a tertiary care center with heart failure/transplant expertise may be warranted in fulminant cases in which surgical support may be necessary.
Deterrence and prevention
Vaccination should reduce the incidence of myocarditis caused by measles, rubella, mumps, poliomyelitis, and influenza. The development of vaccines for other cardiotropic viruses may prevent viral myocarditis in the future.
Diet and activity
Patients should consume a low-sodium diet similar to that for heart failure management. Bedrest and avoidance of athletic activities are recommended from anecdotal experiences (with lower incidence of arrhythmia).
Standard treatment of clinically significant disease includes the detection of dysrhythmia with cardiac monitoring, the administration of supplemental oxygen, and the management of fluid status.
Left ventricular dysfunction developing from myocarditis should be approached in much the same manner as other causes of congestive heart failure (CHF), with some exceptions. In general, sympathomimetic drugs should be avoided, because they increase the extent of myocardial necrosis and mortality.[30] Beta blockers should be avoided in the acutely decompensating phase of illness.
Patients who present with Mobitz II or complete heart block require temporary pacemaker placement. Very few patients require permanent pacer or automatic implantable cardioverter-defibrillator (AICD) placement.
Treatment of myocarditis includes supportive therapy for symptoms of acute heart failure with use of diuretics, nitroglycerin/nitroprusside, and angiotensin-converting enzyme (ACE) inhibitors. Inotropic drugs (eg, dobutamine, milrinone) may be necessary for severe decompensation, although they are highly arrhythmogenic. Long-term treatment follows the same medical regimen, including ACE inhibitors, beta blockers, and aldosterone receptor antagonists. However, in some instances, some of these drugs cannot be implemented initially because of hemodynamic instability.
Withdrawal of the offending agent is called for, if applicable (eg, cardiotoxic drugs, alcohol). Treat underlying infectious or systemic inflammatory etiology. Nonsteroidal anti-inflammatory agents should be avoided in the acute phase, as their use may impede myocardial healing and actually exacerbate the inflammatory process and increase the risk of mortality.
Anticoagulation may be advisable as a preventive measure, as in other causes of heart failure, although no definitive evidence is available.
Antiarrhythmics can be used cautiously, although most antiarrhythmic drugs have negative inotropic effects that may aggravate heart failure. (Supraventricular arrhythmias should be converted electrically.) High-grade ventricular ectopy and ventricular tachyarrhythmia should be treated cautiously with beta blockers and antiarrhythmics.
Patients are usually very sensitive to digoxin and should use it with caution and in low doses. (Digoxin increases expression of proinflammatory cytokines and mortality rate in animal models.)
Immunosuppression
Immunosuppression has not been demonstrated to change the natural history of infectious myocarditis. The Heart Failure Society of America 2010 guideline recommends against routine use of immunosuppressive therapy.[4] Three large-scale prospective clinical trials on immunosuppressive strategies have been performed in patients with myocarditis, none of which showed significant benefits (National Institutes of Health [NIH] prednisone trial[31] , Myocarditis Treatment Trial[23] , and Intervention in Myocarditis and Acute Cardiomyopathy [IMAC] trial[32] ). Empirical treatment with immunosuppression for systemic autoimmune disease, especially in giant cell myocarditis and sarcoid myocarditis, is often given based on evidence from small series.[24, 33]
Ongoing studies will determine if antiviral agents, immunosuppressants, or immunoabsorption therapies are beneficial in specific patient populations, although some small series have provided preliminary evidence demonstrating their potential efficacies.
In the previously mentioned study by Klugman et al, treatment rates among pediatric patients were as follows[11] :
Intravenous immunoglobulin (IVIG) - 49.1% of patients
Milrinone - 45% of patients
Epinephrine - 35% of patients
Mechanical ventilation - 25% of patients
Extracorporeal membrane oxygenation - 7% of patients
Cardiac transplantation - 5% of patients
Klugman and colleagues also found that IVIG did not affect survival rates, even in patients with extreme illness scores.
Complete heart block is an indication for temporary transvenous pacing. Implantable defibrillators rarely are indicated in lymphocytic myocarditis unless extensive scarring has occurred. In the case of frequent nonsustained or polymorphic ventricular ectopy or tachyarrhythmia, temporary or wearable defibrillator support (eg, LifeVest) may be considered.
Myocarditis carries a low threshold for ventilatory and circulatory support (such as intra-aortic balloon pump) because of the rapidly progressive course of decompensation and the potential for reversal. In extreme cases, circulatory support with a ventricular assist device or percutaneous circulatory support (such as TandemHeart or Impella) has been reported.
Left ventricular assistive devices (LVADs) and extracorporeal membrane oxygenation may be indicated for short-term circulatory support if needed for cardiogenic shock.[5]
For cardiac transplantation, survival rates have not been shown to be decreased in patients with acute myocarditis, although retrospective observations have been made that more posttransplant acute rejections and subsequent posttransplant vasculopathy may occur in these patients.
Transplantation has been shown to be particularly beneficial to those with biopsy-proven giant cell myocarditis; the 5-year survival rate after transplantation was 71%, despite a 25% incidence of posttransplantation recurrence, as seen in 9 of 34 patients in the Multicenter Giant Cell Myocarditis study.
Ongoing, chronic inflammation may cause dilated cardiomyopathy and subsequent heart failure. Patients with a history of myocarditis should be monitored at intervals of 1-3 months initially, with gradual return of physical activity.
Any evidence of residual cardiac dysfunction or remodeling should be treated in the same manner as chronic heart failure. The role of medical therapy in those with complete resolution of cardiac structure and performance within a short time is less well established, although conservatively, most would still receive ACE inhibitors or beta blockers at a minimum.
In general, treatment of either acute or chronic myocarditis is aimed at reducing congestion and improving cardiac hemodynamics in heart failure, as well as providing supportive therapy, with the hope of prolonging survival. Treatment of heart failure follows the same treatment regimen regardless of the underlying cause (ie, ACE inhibitors, beta-adrenergic blockers).
Intensive immunosuppressive therapy (eg, corticosteroids, azathioprine, cyclosporine, muromonab-CD3/OKT3) has been shown to have some benefit only in small-scale clinical studies in the treatment of giant cell myocarditis and has not been validated in large clinical trials. At this time, immunosuppressive therapy is not recommended for myocarditis until clear evidence is available from the results of multicenter trials.
Clinical Context:
Nitroglycerin is the drug of choice for patients who are not hypotensive. It provides excellent and reliable preload reduction, while higher doses provide mild afterload reduction.
The drug has rapid onset and offset (both within minutes), allowing for rapid clinical effects and rapid discontinuation of effects in adverse reactions.
Clinical Context:
Sodium nitroprusside is considered an afterload reducer. It is a potent direct smooth muscle–relaxing agent that results primarily in afterload reduction but can cause mild preload reduction. The drug produces improved cardiac output, but it can also cause precipitous decreases in blood pressure. Intra-arterial blood pressure monitoring is strongly recommended.
Sodium nitroprusside is an excellent medication in critically ill patients because of rapid onset and offset of action (within 1-2 min). It is excellent for use in cardiogenic pulmonary edema associated with relative hypertension in myocarditis.
Vasodilators reduce systemic vascular resistance, allowing more forward flow and improving cardiac output. This, in turn, improves myocardial oxygen supply, resulting in dilatation of epicardial and collateral vessels and improving blood supply to the ischemic myocardium.
Clinical Context:
Prevents conversion of Angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Clinical Context:
Enalapril is a competitive inhibitor of angiotensin-converting enzymes. It reduces angiotensin II levels, causing a decrease in aldosterone secretion.
Clinical Context:
Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Clinical Context:
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Rapidly absorbed, but bioavailability is significantly reduced with food intake. It achieves a peak concentration in an hour and has a short half-life. The drug is cleared by the kidney.
Impaired renal function requires reduction of dosage. Absorbed well PO. Give at least 1 h before meals. If added to water, use within 15 min.
Can be started at low dose and titrated upward as needed and as patient tolerates.
Clinical Context:
Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Following stabilization of heart failure symptoms, initiation of ACE inhibitors is the standard of care to delay disease progression in heart failure. Beta-adrenergic antagonists should be used only following resolution of congestive symptoms and clinical stabilization of the patient's condition.
Clinical Context:
Furosemide is the most commonly used loop diuretic. It increases the excretion of water by interfering with the chloride-binding cotransport system, resulting in inhibition of sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. Furosemide reduces preload through diuresis in 20-60 minutes. It may contribute to more rapid preload reduction through a direct vasoactive mechanism, but this is controversial.
As many as half of all patients with cardiogenic pulmonary edema (CPE) are total-body euvolemic. Furosemide is generally administered to all patients with CPE, but it is probably most useful in patients with total-body fluid overload. The oral form has a slower onset of action and, therefore, is generally not considered appropriate for treating these patients.
Clinical Context:
Acts from within the lumen of the thick ascending portion of the loop of Henle, where inhibits the Na/K/2Cl carrier system. Increases urinary excretion of sodium, chloride, and water, but does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.
Clinical Context:
Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.
Individualize dose to patient. Start at 1-2 mg IV; titrate to as high as 10 mg/d. Rarely, doses as high as 24 mg/d are used for edema but generally are not required for treatment of hyperkalemia.
One mg of bumetanide is equivalent to approximately 40 mg of furosemide.
Diuretics reduce preload. The initial drop in cardiac output produced by diuresis causes a compensatory increase in peripheral vascular resistance. With continuing diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline.
Clinical Context:
Blocks vasoconstriction and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACE inhibitors.
Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function, and delaying onset of end-stage renal disease.
Clinical Context:
Angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Clinical Context:
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACE inhibitors.
Angiotensin receptor blockers are as effective as ACE inhibitors in the treatment of heart failure. Their adverse-effect profile is similar to that of ACE inhibitors with regard to renal insufficiency or hyperkalemia but they do not cause potentiation of bradykinin and therefore do not cause cough.
Clinical Context:
Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate and ECG.
Clinical Context:
Nonselective beta- and alpha-adrenergic blocker. Also has antioxidant properties. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.
Avoid the use of beta-blockers in the very early treatment of fulminant myocarditis and in the acute phase of decompensated HF. Beta blockers have antiarrhythmic and antihypertensive properties, as well as the ability to reduce ischemia. They minimize the imbalance between myocardial supply and demand by reducing afterload and wall stress. Beta blockers ameliorate dynamic obstruction of the left ventricular outflow tract in patients with apical infarct and hyperdynamic basal segments. These agents work in multiple ways to treat heart failure. They should not be used acutely in patients with cardiogenic shock or signs of heart failure on presentation.
Clinical Context:
Bi-pyridine positive inotrope and vasodilator with little chronotropic activity. Different in mode of action from both digitalis glycosides and catecholamines. Selectively inhibits phosphodiesterase type III (PDE III) in cardiac and smooth vascular muscle, resulting in reduced afterload, reduced preload, and increased inotropy.
Clinical Context:
Produces vasodilation and increases inotropic state. At higher dosages may cause increased heart rate, exacerbating myocardial ischemia.
Wai Hong Wilson Tang, MD, Professor of Medicine, Section of Heart Failure and Cardiac Transplantation Medicine, Cleveland Clinic Foundation
Disclosure: Nothing to disclose.
Specialty Editors
Yasmine S Ali, MD, FACC, FACP, MSCI, President, LastSky Writing, LLC; Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: MCG Health, LLC; LastSky Writing, LLC; Philips Healthcare; Cardiac Profiles, Inc.; BBN Cardio Therapeutics.
Chief Editor
Henry H Ooi, MD, MRCPI, Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Assistant Professor of Medicine, Vanderbilt University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Paul Blackburn, DO, FACOEP, FACEP Attending Physician, Department of Emergency Medicine, Maricopa Medical Center
Paul Blackburn, DO, FACOEP, FACEP is a member of the following medical societies: American College of Emergency Physicians, American College of Osteopathic Emergency Physicians, American Medical Association, and Arizona Medical Association
Disclosure: Nothing to disclose.
Ethan A Booker, MD Attending Physician, Department of Emergency Medicine, Washington Hospital Center
Ethan A Booker, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital
David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Steven J Compton, MD, FACC, FACP Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals
Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society
Disclosure: Nothing to disclose.
David S Howes, MD Professor of Medicine and Pediatrics, Section Chief and Emergency Medicine Residency Program Director, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine
David S Howes, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Physicians-American Society of Internal Medicine, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Eric M Kardon, MD, FACEP Attending Emergency Physician, Georgia Emergency Medicine Specialists; Physician, Division of Emergency Medicine, Athens Regional Medical Center
Eric M Kardon, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.
George A Stouffer III, MD Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
James B Young, MD Chairman, Professor of Medicine, Department of Medicine, Cleveland Clinic Foundation
Disclosure: National Institute of Health Grant/research funds Independent Contractor
McNamara DM, Starling RC, Dec GW. Intervention in myocarditis and acute cardiomyopathy with immune globulin: results from the randomized placebo controlled IMAC trial. Circulation. 1999. 100(Suppl 1):I-21.
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