Myocarditis

Highlights
Summary Overview

Basics
Definition Epidemiology Aetiology Pathophysiology Classification

Prevention
Primary Secondary

Diagnosis
History & examination Tests Differential Step-by-step Criteria Guidelines Case history

Treatment
Details Step-by-step Guidelines

Evidence

Follow Up
Recommendations Complications Prognosis

Resources
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History & exam

Key factors

presence of risk factors viral syndrome (prior) autoimmune disease infectious disease medications or toxins

Other diagnostic factors

age <50 years chest pain dyspnoea orthopnoea syncope fatigue palpitations rales elevated neck veins S3 gallop S3 and S4 summation gallop pericardial friction rub peripheral hypoperfusion sinus tachycardia atrial and ventricular arrhythmias hypotension altered sensorium lymphadenopathy History & exam details

Diagnostic tests
1st tests to order

12-lead ECG CXR serum CK

serum CK-MB serum troponin (I or T) serum B-type natriuretic peptide two-dimensional echocardiogram

Tests to consider

endomyocardial biopsy (EMB) coronary angiography cardiac MRI

Emerging tests

MRI-guided EMB Diagnostic tests details

Treatment details
Acute
haemodynamically stable: no evidence of left ventricular systolic dysfunction supportive care treatment of underlying cause haemodynamically stable: evidence of left ventricular systolic dysfunction angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers

treatment of underlying cause beta-blockers oral vasodilators/nitrates diuretics aldosterone antagonists long-term anticoagulation therapy haemodynamically unstable intravenous arterial vasodilator + invasive haemodynamic monitoring treatment of underlying cause intravenous glyceryl trinitrate intravenous inotropes or vasopressors refractory cardiogenic shock: adult patients intra-aortic balloon pump left ventricular assist device refractory cardiogenic shock: paediatric patients extracorporeal cardiopulmonary resuscitation with VA-ECMO

o o

Ongoing
end-stage heart failure or refractory lifethreatening arrhythmias heart transplantation + existing heart failure medications

destination left ventricular assist device therapy + anticoagulation + existing heart failure therapy Treatment details

Summary

Myocarditis describes a heterogeneous group of disorders characterised by myocardial inflammation in the absence of predominant acute or chronic ischaemia. Can affect all age groups with an apparent slightly higher incidence in males than females and equal incidence in black people and white people. May present as fulminant, acute or chronic myocarditis. Treatment is usually supportive care and conventional heart failure therapy. More severe presentations may need aggressive vasopressor or inotropic pharmacological support or mechanical haemodynamic assist devices such as intra-aortic balloon pump or left ventricular assist device. Occasionally, some cases do not respond to conventional therapy and progress to heart transplantation or death. Prognosis is variable but is related to presentation and underlying aetiology. Most cases of viral myocarditis are asymptomatic and spontaneously resolve. Patients who present with mild to moderate heart failure tend to improve or

recover but may progress to chronic severe heart failure. Surprisingly, patients who present with fulminant, acutely decompensated heart failure almost universally recover back to baseline function, if death is prevented through management in the acute phase.

Definition
Myocarditis is clinically and pathologically defined as inflammation of the myocardium in the absence of the predominant acute or chronic ischaemia characteristic of CAD. It is a clinical syndrome of non-ischaemic myocardial inflammation resulting from a heterogeneous group of infectious, immune, and non-immune diseases. Histopathologically, it is characterised by an inflammatory cellular infiltrate with or without evidence of myocyte injury. [1] View image

Epidemiology
The extreme variability of clinical manifestations and frequently insidious onset of symptoms makes the true incidence and prevalence of myocarditis difficult to determine. Autopsy studies reveal myocarditis in 1% to 9% of routine postmortem examinations, and a prospective postmortem study of sudden cardiac death in young adults suggests myocarditis as the aetiology in approximately 10% of cases. [13] [14] Additionally, a large prospective trial of patients with dilated cardiomyopathy reveals myocarditis as the aetiology in 9% of patients. [15]

Aetiology
Common aetiologies [4] [10] [16] Infectious causes:

 o o o o o o o o o o o o o o o o o o o o o o

Viral Influenza A Adenovirus Coxsackie B virus Hepatitis C virus HIV Echovirus EBV CMV Parvovirus HSV Bacterial Mycobacterial Streptococcal species Mycoplasma pneumoniae Treponema pallidum TB Staphylococcal species Clostridium species Neisseria gonorrhea Mycotic Aspergillus species Candida species Coccidiomycosis Cryptococcus species

o o o o o o o o o o

Histoplasma species Sporotrichosis species Blastomycosis Protozoal Trypanosoma cruzi (Chagas' disease) African trypanosomiasis (sleeping sickness) Toxoplasmosis Malaria Parasitic Schistosomiasis Larva migrans

Non-infectious causes:
o o o o o o o o o o Toxins/drug related Anthracyclines Arsenic Carbon monoxide Ethanol Iron Interleukin-2 Cocaine Smallpox vaccination Hypersensitivity Antibiotics (penicillins, cephalosporins, sulphonamides, amphotericin B) Thiazide diuretics

o o o o o o o o o o o o o o

Antiepileptics (carbamazepine, phenytoin, phenobarbital) Digoxin Lithium Amitriptyline Dobutamine Snake bites Systemic disorders Collagen-vascular diseases Inflammatory bowel disease Giant-cell myocarditis Diabetes mellitus Sarcoidosis Thyrotoxicosis Wegener's granulomatosis Loeffler's syndrome

Pathophysiology
The pathogenesis of myocarditis is not entirely clear. However, in viral-mediated myocarditis, animal models have implicated 3 significant mechanisms: [17] [16] An infectious organism directly invades the myocardium

Local and systemic immunological activation quickly ensues Cellular (CD4+) and humoral (B-cell clonal multiplication) activation occurs, causing worsening local inflammation, anti-heart antibody production and further myonecrosis. All 3 may occur in the same host. However, the predominant pathway may differ depending on the individual characteristics of the infectious species and the innate defenses of the host organism. The first phase is characterised by viraemia in the host organism. During this time, the cardiotropic RNA virus enters the host myocyte via receptor-mediated endocytosis. [18] Here, the viral RNA is translated into viral protein, and the viral genome is incorporated into the host-cell DNA as doublestranded RNA. This latter mechanism has been shown to cleave dystrophin, which is thought to directly cause myocyte dysfunction. During the second and third phases, macrophages, natural killer cells, and other inflammatory cells infiltrate the myocardium. Once in the myocardium, these cells express inflammatory cytokines including interleukin-1, interleukin-2, interferon-gamma, and

TNF. [19] This results in increased cytokine production and causes endothelial cell activation resulting in further infiltration of inflammatory cells. TNF alone also acts as a negative inotrope. [20] In addition, auto-antibodies directed against myocardial contractile and structural proteins are produced. This is thought to have cytopathic effects on energy metabolism, calcium homeostasis and signal transduction, and also to cause complement activation resulting in the lysis of myocytes.[21] View image

Classification

[2] Fulminant myocarditis: presentation with acute illness following a distinct viral syndrome. Histological study reveals multiple foci of active myocarditis. Clinical presentation consists of severe cardiovascular compromise and ventricular dysfunction. This subgroup typically either resolves spontaneously or results in death.
Clinicopathological classification

Acute myocarditis: presentation with insidious onset of illness and evidence of established ventricular dysfunction. This subgroup may progress to dilated cardiomyopathy.

Chronic active myocarditis: presentation with insidious onset of illness with clinical and histological relapses with development of left ventricular dysfunction and associated chronic recurrent inflammatory changes. Chronic persistent myocarditis: presentation with insidious onset of illness characterised by a persistent histological infiltrate frequently with foci of myocyte necrosis. Clinically, no ventricular dysfunction is present despite other cardiovascular symptoms (such as palpitations or chest pain).
Important variants Lymphocytic (viral) myocarditis

The most common cause of myocarditis in the US, it is characterised by myocardial infiltrate with lymphocytes as the predominant inflammatory cell. [3] [4]
Chagas' heart disease

Trypanosoma cruzi infection-associated myocarditis is the most common cause of heart failure worldwide. [5] Histopathologically characterised by a predominantly lymphocytic cellular myocardial infiltrate in the setting of a known history of T

cruzi infection. Using specialised sensitive immunohistochemical techniques and PCR amplification methods, parasitic antigens can be found by endomyocardial biopsy. [6]
Giant-cell myocarditis

A rare and frequently fatal inflammatory disorder of cardiac muscle histologically characterised by: Inflammatory infiltrate with the presence of multi-nucleated giant cells Widespread degeneration and necrosis of myocardial fibres Absence of granulomas (to distinguish from cardiac sarcoidosis). Despite partial improvement to aggressive immunosuppressive therapy, the prognosis is poor but improves significantly with cardiac transplantation. [7]
Hypersensitivity myocarditis

A form of autoimmune myocardial inflammation that is often drug related and clinically usually presents with acute rash, fever, and peripheral

eosinophilia. [8] Histologically, it is most often characterised by a myocardial interstitial infiltrate with prominent eosinophils but little myocyte necrosis. [9]

Primary prevention
Very little is known regarding effective measures to prevent myocarditis. Current aims of primary prevention are limited to preventing the development of a condition known to be associated with myocarditis. An example is having safe-sex practices to prevent infection with HIV.

Secondary prevention
Ethanol abstinence is encouraged in all patients with a history of myocarditis, although the effects of modest alcohol consumption on non-alcohol-related cardiomyopathy are unknown.
Monitoring
Recommended follow-up is dictated by the clinical course of the individual patient. Patients who exhibit only mild symptoms with prompt resolution of symptoms should be followed closely initially, but monitoring can be quickly spaced out to annual visits unless symptoms recur. However, patient with persistent LV dysfunction or evidence of progression of myocardial inflammation warrant regular follow-up at least every few months or sooner until the patient is stable clinically. [31] [41]

Patient Instructions
Patient instruction depends on individual patient characteristics. Universal limitation of salt and water intake for volume and BP management is recommended for all patients with myocarditis. Home BP measurement and daily weight recordings with frequent communication with the general practitioner are ideal.

Complications
Complicationhide all

atrial fibrillation see our comprehensive coverage of Acute atrial fibrillatio Often occurs in the setting of increased intra-atrial press result of LV systolic and diastolic dysfunction and mitral v

ventricular tachyarrhythmias see our comprehensive coverage of Sustained ventricula Most commonly associated with Chagas' disease myoca aetiologies of myocarditis.[6]

dilated cardiomyopathy see our comprehensive coverage of Assessment of card Presumably occurs due to progression of original diseas should be treated with standard heart failure therapies an specialist.

sudden cardiac death Usually caused by ventricular tachycardia or ventricular f dilated cardiomyopathy. multisystem organ failure

Rarely occurs as a result of either acute presentation of the result of end-stage heart failure secondary to chronic

Prognosis
Given the limitations in current methods of diagnosing myocarditis, it is not surprising that its natural history and associated prognosis are as varied as its clinical presentations. A study looking at the outcomes of patients presenting with acute myocarditis found no connection between clinical variables and prognosis. [59] Despite this, multiple factors have been linked to a favourable or poorer outcome. A definite association exists between the myocarditis-associated risk factor or specific type of myocarditis and the prognosis of the patient. [4] Also, the severity of illness at presentation tends to correlate with long-term outcome.

Endomyocardial biopsy (EMB) DNA PCR persistence of cardiotropic viral genome

The prognosis of patients in whom the EMB DNA PCR analysis is positive for a cardiotropic viral genome has been studied. Those who have persistently positive viral genome analysis on EMB demonstrate worsening left ventricular (LV) ejection fraction and outcome when compared with those who test negative on subsequent EMBs. [60]

Fulminant myocarditis
Patients who present with fulminant myocarditis surprisingly tend to have better outcomes than those who present with a clinically milder acute myocarditis. An 11-year study of patients presenting with myocarditis showed a 93% survival free of heart transplantation in patients with fulminant myocarditis as opposed to 45% in patients who presented with acute myocarditis.[61]

Giant-cell myocarditis

Despite modest improvement in mortality with immunosuppressive therapy, patients with giant-cell myocarditis have the worst outcomes with a median survival of 5.5 months from the onset of heart failure symptoms. [50]

Presentation mimicking MI
Patients presenting with chest pain and ECG changes similar to those seen in ST-segment elevation MI have almost uniform recovery without any residual cardiac dysfunction. [12]

Histological resolution of myocardial inflammation

Patients with histological resolution of myocardial cellular infiltration on repeat EMB tend to have improvement in cardiac function and a favourable clinical outcome. [62]

Serum immunological markers

Patients with idiopathic cardiomyopathy and elevated levels of serum TNFalpha receptor-1 and fas at presentation have a worse clinical course and are more likely to not recover LV function than those with lower levels. [63]

Case history #1
A 43-year-old man with no significant medical history presents with 3 days of progressive fatigue, dyspnoea on exertion and while lying in the supine position, and lower-extremity swelling. He reports having a flu-like illness consisting of fevers, myalgias, fatigue, and respiratory symptoms 2 weeks prior that resolved spontaneously. On examination the patient has an elevated jugular venous pressure, bilateral pulmonary rales, and a heart rate of 104 bpm with an audible left ventricular S3 gallop. He is mildly dyspnoeic at rest but becomes markedly dyspnoeic with minimal exertion.

Case history #2
A 49-year-old man originally from Argentina with a 3-year history of CHF presents to the emergency department with syncope while at work. He reports speaking with a co-worker then suddenly awaking on the floor of the

office. The patient's wife states that the patient has had 2 similar episodes in the past. The patient is euvolaemic with non-distended neck veins and a normal lung examination. Cardiac examination reveals a laterally displaced apex, and regular rate and rhythm without murmur or gallop but frequent ectopy.

Other presentations
The clinical manifestation of myocarditis is highly variable and ranges from asymptomatic ECG abnormalities to cardiogenic shock. [10] [11] When cardiac involvement manifests clinically, it typically occurs 7 to 10 days after a systemic illness. Chest pain occurs in 35% of patients and may be typical, atypical, or positional in nature. [4] Occasionally, patients present with ischaemic-sounding chest pain and ST-segment elevations on ECG that mimic acute coronary syndrome. Left ventricular dysfunction tends to be global instead of regional, and coronary angiography is normal. [12] Rarely, patients with myocarditis present with sudden cardiac death, usually due to ventricular arrhythmias.

Differential diagnosis
Condition Acute coronary syndrome Differentiating signs/symptoms

Patients presenting with MI tend to be older and have traditional risk factors for coronary atherosclerosis when compared with patients with myocarditis.

Dilated cardiomyopathy

There can be considerable overlap between dilated cardiomyopathy and myocarditis. As many as 16% of patients presenting with acute dilated cardiomyopathy who undergo endomyocardial biopsy are found to have biopsyconfirmed myocarditis. [36] A family history of dilated cardiomyopathy, a known history of exposure to a direct cardiotoxin (e.g., ethanol), or the absence of elevations of markers of myocardial injury make myocarditis

less likely. Pericarditis It can be difficult, if not impossible, to distinguish patients presenting with pericarditis from those with myocarditis based on history and physical examination alone. Both syndromes can exhibit typical or positional chest pain, and both are commonly preceded by a fever and/or a viral syndrome. The presence of signs or symptoms of heart failure suggests

myocarditis as the aetiology, as isolated pericarditis does not impair left ventricular (LV) function. Stress-induced cardiomyopathy (broken heart syndrome, Takotsubo cardiomyopathy) Patients with stressinduced cardiomyopathy can present similarly to those with acute myocarditis. A history of an acute emotional or physical stressor within the prior 2 weeks with a rather rapid clinical deterioration supports a diagnosis of stress-induced cardiomyopathy. [37 ]

Rapid recovery back to baseline within 4 to 8 weeks is the rule for stressinduced cardiomyopathy, the occurrence of which supports its diagnosis.

History & examination

Key diagnostic factorshide all
presence of risk factors (common) Risk factors include HIV and other infections, smallpox vaccination, autoimmune/immunemediated diseases, and peri-partum and postpartum periods. viral syndrome (prior) (common) A viral prodrome of fever, myalgias, respiratory symptoms, or gastroenteritis in the 2 to 3 weeks preceding initial presentation is common in patients presenting with myocarditis. autoimmune disease (common) Many autoimmune diseases are associated with myocarditis.

infectious disease (common) Many infectious diseases are associated with myocarditis. medications or toxins (uncommon) Known causative medications and toxins include anthracyclines, arsenic, carbon monoxide, ethanol, iron, interleukin-2, cocaine, smallpox vaccination, antibiotics (penicillins, cephalosporins, sulphonamides, amphotericin B), thiazide diuretics, antiepileptics (carbamazepine, phenytoin, phenobarbital), digoxin, lithium, amitriptyline, dobutamine, and snake bites. Other diagnostic factorshide all age <50 years (common) Patients with myocarditis tend to be younger (<50 years) than those presenting with more common cardiac conditions such as acute coronary syndrome. chest pain (common) Occurs in 35% of patients presenting with myocarditis and can be typical, atypical, or pericardial in nature. [4] dyspnoea (common) Common symptom in patients with myocarditis. orthopnoea (common) Myocarditis manifesting as new-onset CHF frequently causes orthopnoea.

fatigue (common) Common complaint in patients presenting with myocarditis. palpitations (common) Often described by patients presenting with myocarditis. rales (common) Typical finding in patients with CHF secondary to myocarditis. elevated neck veins (common) Secondary to volume overload. Common in CHF caused by myocarditis. S3 gallop (common) Frequently accompanies myocarditis manifested as CHF. sinus tachycardia (common) As a compensatory means to increase cardiac output, one of the first signs to develop in patients presenting with CHF caused by myocarditis. atrial and ventricular arrhythmias (common) Include refractory arrhythmias and malignant rhythms such as sustained ventricular tachycardia. Are often present during the acute presentation of myocarditis. syncope (uncommon)

Syncope caused by ventricular arrhythmias is a rare but possible presenting symptom of myocarditis. S3 and S4 summation gallop (uncommon) Occasionally presents in the setting of myocarditis with CHF. pericardial friction rub (uncommon) Myocarditis often extends to the pericardium (myopericarditis) and can cause an audible pericardial friction rub. peripheral hypoperfusion (uncommon) As evidenced by renal failure, elevated serum lactate or other sign of end-organ damage, can be associated with myocarditis-induced cardiogenic shock. hypotension (uncommon) Myocarditis can cause present as profound left ventricular systolic dysfunction resulting in hypotension. altered sensorium (uncommon) Altered mental status, particularly in the elderly, can be the first apparent sign of myocarditisinduced CHF, even in the setting of normal BP. lymphadenopathy (uncommon) Focal or diffuse lymphadenopathy can be present in patients with sarcoidosis-associated myocarditis.

Risk factorshide all

Strong infection (non-HIV) Many viral, bacterial, and fungal infections have been implicated in the pathogenesis of myocarditis. [16] The most common cause of myocarditis worldwide isTrypanosoma cruzi with an estimated 18 million people infected. [5] In the US, adenoviruses and enteroviruses, such as Coxsackie B, are believed to be the predominant cause. [22] In Germany, parvovirus B19 is the organism most prevalently isolated from endomyocardial biopsy, while in Japan hepatitis C virus is most commonly implicated. [23] [24] HIV infection HIV disease places a person at very high risk of developing myocarditis. In a postmortem study of patients with AIDS, 67% were found to have biopsy-confirmed myocarditis. [23] Also, prospective data suggest that the yearly incidence of developing myocarditis is 1.6% in asymptomatic HIV-positive patients; this incidence increases among patients with CD4 counts <400 cells/mm^3. [24] smallpox vaccination

In the age of bioterrorism, increasing use of the smallpox vaccine is associated with increasing incidence of myocarditis. In one study involving military recruits who received the smallpox vaccine, the incidence of myocarditis was 7.8 cases per 100,000.[25] autoimmune/immune-mediated diseases SLE, scleroderma, and other immune-mediated diseases such as sarcoidosis place patients at markedly increased risk of developing myocarditis. [26][27] [28] peripartum and postpartum periods There is a strong association between women in the peripartum or postpartum period and the development of myocarditis. [4] [10]

Weak drugs and toxins Hypersensitivity myocarditis is associated with many medications. [29] [30] Drugs and toxic exposures that are known to cause myocarditis include anthracyclines, arsenic, carbon monoxide, ethanol, iron, interleukin-2, cocaine, antibiotics (penicillins, cephalosporins, sulphonamides, amphotericin B), thiazide diuretics, antiepileptics (carbamazepine,

phenytoin, phenobarbital), digoxin, lithium, amitriptyline, dobutamine, and snake bites.

Diagnostic tests
1st tests to orderhide all
Test

12-lead ECG Should be ordered immediately on presentation in anyon

CXR Should be ordered immediately in any person presenting

serum CK Should be ordered immediately when evaluating anyone

serum CK-MB Should be ordered immediately when evaluating anyone

serum troponin (I or T) Should be ordered immediately when evaluating anyone Troponin (I or T) levels have been shown to be a more re than CK-MB and CK.

serum B-type natriuretic peptide May be helpful in distinguishing primary cardiac from prim dyspnoea when the physical examination and initial work used to support the history and physical examination.

two-dimensional echocardiogram Should be ordered in every patient suspected of having m

Tests to considerhide all

Test

endomyocardial biopsy (EMB) Should be performed when it is believed that the results subsequent therapeutic decisions. [29] Should also be c an acute reduction in cardiac function not responsive to m risks and benefits of EMB should always be carefully ass presentation, as the risk of arrhythmia or ventricular perf image

coronary angiography Should be performed when the presenting symptoms an the acute coronary syndromes.

cardiac MRI Can be performed when trying to distinguish between my disease using typical findings on MRI. [33]

Emerging testshide all

Test

MRI-guided EMB Still in the developmental phase and requires validation i

MRI-guided EMB is a promising new technology that app sensitivity of EMB in the diagnosis of myocarditis. [35]

Step-by-step diagnostic approach

The diagnostic standard for establishing the diagnosis of myocarditis is the endomyocardial biopsy. However, this test has a yield of 10% to 20% and is not indicated for most patients with suspected myocarditis. [4] [31] Thus, the appropriate evaluation of patients with suspected myocarditis begins with a complete history and physical examination. If myocarditis is still suspected, then further work-up with a 12-lead ECG, laboratory evaluation of cardiac biomarkers and two-dimensional echo should be performed. There is no general consensus on which patients should undergo endomyocardial biopsy. However, the current American College of Cardiology/American Heart Association guidelines recommend biopsy when it is believed that the results "will have a meaningful effect on subsequent therapeutic decisions". [31] Nuclear imaging with radionucleotide monoclonal antibodies has been used to diagnose myocarditis, but its lack of specificity and excessive cost have made it largely unavailable for clinical use. [32] Contrast-enhanced cardiac MRI has been shown to assist in the diagnosis of myocarditis by providing detailed tissue characterisation; however, its utility needs to be validated in larger studies. [33]

History
Patients presenting with myocarditis are usually aged <50 years. A history of viral prodrome 2 to 3 weeks prior to the onset of myocarditis is commonly present. Symptoms may include chest pain, dyspnoea, orthopnoea, syncope, fatigue, and palpitations. The patient's medical history may be significant for autoimmune disease such as collagen-vascular diseases as well as inflammatory bowel disease, diabetes mellitus, sarcoidosis, thyrotoxicosis, Wegener's granulomatosis, or Loeffler's syndrome. In addition, a history of travel to endemic areas where causative organisms are found may suggest a specific infectious aetiology. A thorough medication history along with other possible exposures to toxic substances or cocaine should be obtained to exclude any drug or toxic aetiologies. These include anthracyclines, arsenic, carbon monoxide, ethanol, iron, interleukin-2, cocaine, smallpox vaccination, antibiotics (penicillins, cephalosporins, sulphonamides, amphotericin B), thiazide diuretics, antiepileptics (carbamazepine, phenytoin, phenobarbital), digoxin, lithium, amitriptyline, dobutamine, and snake bites.

Physical examination
A thorough examination for both the cardiorespiratory findings and other general findings that may point to possible aetiology should be performed. Findings can include rales, elevated neck veins, S3 gallop, S3 and S4 summation gallop, pericardial friction rub, peripheral hypoperfusion, sinus tachycardia, atrial and ventricular arrhythmias, hypotension, altered sensorium, and lymphadenopathy.

12-lead ECG
A 12-lead ECG should be ordered immediately on presentation in anyone with chest pain or cardiac symptoms. In myocarditis it most commonly displays non-specific ST-segment and T-wave abnormalities; however, STsegment elevation and depression frequently occur.

Laboratory evaluation

Cardiac biomarkers should be ordered immediately in any patient with suspected myocarditis. CK and CK-MB levels are often mildly elevated. Troponin (I or T) levels have shown to be a more reliable indicator of myocardial damage. Serum B-type natriuretic peptide may be helpful in distinguishing primary cardiac from primary pulmonary aetiologies of dyspnoea when the physical examination and initial work-up is unclear or non-specific. In myocarditis it is elevated in response to ventricular distention such as occurs in CHF.

Two-dimensional echocardiogram
This should be ordered in every patient suspected of having myocarditis. Myocarditis can cause global and regional left ventricular motion abnormalities and dilatation.View imageView image

Endomyocardial biopsy (EMB)

This is recommended if it is believed that the results will have a meaningful effect on subsequent therapeutic decisions. [31] View image EMB should also be considered when patients experience an acute reduction in cardiac function not responsive to medical therapy. [11] The potential risks and benefits of EMB should always be carefully assessed, particularly during the acute presentation, as the risk of arrhythmia or ventricular perforation is highest at this time. Specific indications for EMB include: [34]

Exclusion of potential common aetiologies of dilated cardiomyopathy (familial, ischaemic, alcohol, postpartum, cardiotoxic exposures) Sub-acute or acute symptoms of heart failure refractory to standard management Substantial worsening of ejection fraction despite optimised pharmacological therapy

Development of haemodynamically significant arrhythmias, particularly progressive heart block and ventricular tachycardia Heart failure with concurrent rash, fever, or peripheral eosinophilia History of collagen-vascular disease such as SLE, scleroderma, or polyarteritis nodosum New-onset cardiomyopathy in the presence of known amyloidosis, sarcoidosis, or haemochromatosis Suspicion for giant-cell myocarditis (young age, new subacute heart failure, or progressive arrhythmia without apparent aetiology).

Other tests Coronary angiography: this should be performed when the presenting symptoms and findings are indistinguishable from the acute coronary syndromes.
Cardiac MRI: this is emerging as an important tool in the diagnosis of myocarditis, particularly when trying to distinguish acute myocarditis from acute MI.

MRI-guided EMB: this is a promising new technology that seems to significantly increase the sensitivity of EMB in the diagnosis of myocarditis. [35] This is still in the developmental phase and requires validation in larger studies.
Click to view diagnostic guideline references.

Diagnostic criteria
Dallas criteria

[1]

Active myocarditis: the presence of an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischaemic damage associated with CAD. Borderline myocarditis: the presence of an inflammatory infiltrate of the myocardium without necrosis or degeneration of adjacent myocytes.
World Health Organization Marburg Classification
First biopsy:

[38]

Acute (active) myocarditis: a clear-cut infiltrate (diffuse, focal or confluent) of >14 leukocytes/mm^2 (preferably activated T cells). The amount of the infiltrate should be quantified by immunohistochemistry. Necrosis or degeneration is

compulsory; fibrosis may be absent or present and should be graded

Chronic myocarditis: an infiltrate of >14 leukocytes/mm^2 (diffuse, focal or confluent, preferably activated T cells). Quantification should be made by immunohistochemistry. Necrosis or degeneration is usually not evident; fibrosis may be absent or present and should be graded No myocarditis: No infiltrating cells or <14 leukocytes/mm^2.
Subsequent biopsies:

Ongoing (persistent) myocarditis. Criteria as in acute or chronic myocarditis Resolving (healing) myocarditis. Criteria as in acute or chronic myocarditis, but the immunological process is sparser than in the first biopsy Resolved (healed) myocarditis. Corresponds to the Dallas classification.
The amount and distribution of fibrosis should be described similarly as no (grade 0), mild (grade 1), moderate (grade 2) or severe (grade 3).

Localisation or formation of fibrosis should be outlined as endocardial, replacement, or interstitial.

Expanded criteria for diagnosis of myocarditis

[39]

Suspicious for myocarditis = 2 positive categories Compatible with myocarditis = 3 positive categories High probability of being myocarditis = all 4 categories positive.
NOTE: Any matching feature in category = positive for category Category I: clinical symptoms

Clinical heart failure Fever Viral prodrome Fatigue Dyspnoea on exertion Chest pain

Palpitations Pre-syncope or syncope

Category II: evidence of cardiac structural/functional perturbation in the absence of regional coronary ischaemia

Echo evidence Regional wall motion abnormalities Cardiac dilation Regional cardiac hypertrophy Troponin release Troponin result has high sensitivity (>0.1 nanogram/mL) Positive indium-111 antimyosin scintigraphy and normal coronary angiography or absence of reversible ischaemia by coronary distribution on perfusion scan
Category III: cardiac MRI

Increased myocardial T2 signal on inversion recovery sequence Delayed contrast enhancement following gadolinium-diethylenetriamine pentaacetic acid (DTPA) infusion.
Category IV: myocardial biopsy, pathological, or molecular analysis

Pathology findings compatible with Dallas criteria Presence of viral genome by PCR or in situ hybridisation.
New York Heart Association functional classification
Class:

[40]

Patients have cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnoea, or anginal pain Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea, or anginal pain

Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea, or anginal pain Patients have cardiac disease resulting in an inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

Treatment Options

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group haemodynamic ally stable: no evidence of left ventricular systolic dysfunction

Treatme Treatmenthide all nt line 1st supportive care treatment of underlying cause Lymphocytic myocarditis does not require any therapy targeted at the underlying cause and the management is supportive. Giant-cell myocarditis is treated with a combination of systemic corticosteroids and another immunosuppressive agent such as ciclosporin, muromonab-CD3, or azathioprine. While giant-cell

Patient group end-stage heart failure or refractory lifethreatening arrhythmias

Treatment Treatmenthide all line 1st heart transplantation + existing heart failure medications Heart transplantation markedly improves survival and New York Heart Association (NYHA) functional class in patients with endstage heart failure or refractory lifethreatening arrhythmias. [31] It should also be considered in haemodynamically unstable patients who do not respond to other treatments. Post-transplantation patients are treated with similar

Patient group end-stage heart failure or refractory lifethreatening arrhythmias

Treatment Treatmenthide all line 1st heart transplantation + existing heart failure medications Heart transplantation markedly improves survival and New York Heart Association (NYHA) functional class in patients with endstage heart failure or refractory lifethreatening arrhythmias. [31] It should also be considered in haemodynamically unstable patients who do not respond to other treatments. Post-transplantation patients are treated with similar

Treatment approach
The mainstay of therapy for myocarditis is supportive care and conventional heart failure therapy. [31] [41] There can be considerable overlap between dilated cardiomyopathy and myocarditis; as many as 16% of patients presenting with acute dilated cardiomyopathy who undergo endomyocardial biopsy are found to have biopsy-confirmed myocarditis. [36]Treatment is therefore aimed at management of both the cardiomyopathy and myocarditis in those patients with concomitant cardiomyopathy. The routine use of immunosuppressive agents in patients with myocarditis is not recommended. [11]

End-organ hypoperfusion or cardiogenic shock

A small proportion of patients with acute myocarditis will present with fulminant heart failure or cardiogenic shock requiring invasive haemodynamic monitoring and aggressive pharmacological therapy. A pulmonary artery catheter may be inserted to help optimise cardiac filling pressures and for rapid titration of cardiovascular therapies. This may include vasopressors such as norepinephrine (noradrenaline) or positive inotropes such as dobutamine. [42] Rarely, mechanical assist devices are needed as a bridge to recovery, or heart transplantation is needed for patients who do not respond to treatment. [43]

LV systolic dysfunction: supportive care and conventional heart failure therapy

An ACE inhibitor or angiotensin II receptor blocker (ARB) should be started as early as possible. Diuretic therapy and vasodilators are used in both the acute and chronic setting with the goal of optimising intracardiac filling pressures and increasing cardiac output. ACE inhibitor or ARB:

In addition to the demonstrated efficacy in chronic heart failure, animal studies suggest that when started early in the course of acute myocarditis,

renin-angiotensin antagonists improve survival and inhibit progression to dilated cardiomyopathy. [44]
Vasodilators:

Oral arterial (hydralazine) and venous (nitrates) vasodilators acutely improve cardiac output and decrease pulmonary and LV filling pressures. [42] Also, a survival benefit has been noted in chronic heart failure patients taking this combination of therapy. [31]
Beta-blockers:

Similarly, beta-blockers should be started once the patient is no longer in acutely decompensated heart failure In animal models of acute myocarditis, the early initiation of beta-adrenergic blockers has been shown to reduce myocardial inflammation. [45] [46]
Aldosterone antagonist:

An aldosterone antagonist should be started in patients with New York Heart Association class III or IV heart failure. [31]
Diuretic therapy:

Diuretics improve haemodynamics and patient comfort

Volume status should be monitored.

Immunosuppressive therapies and intravenous immunoglobulin (IVIG)

Because the long-term myocardial changes associated with myocarditis seem to be mediated by abnormal cellular and humoral immune activation, it is hypothesised that immunosuppression should be an effective form of treatment. Despite this rationale, immune suppression trials aimed at attenuating the inflammatory response in myocarditis have been largely disappointing. [11] Well-designed prospective randomised controlled trials (RCTs) involving immune suppression with corticosteroids with or without ciclosporin or azathioprine for the treatment of biopsy-confirmed myocarditis showed no long-term improvement in LV ejection fraction (LVEF) or survival benefit. [47] [48] [B Evidence] Similarly, the use of IVIG for treatment of acute myocarditis has been evaluated in several small studies. An RCT of patients with newly diagnosed acute dilated cardiomyopathy found no benefit in mortality or improvement in LVEF in those treated with IVIG as compared with standard care. [49] [B Evidence] This lack of benefit persisted in those patients with biopsy-confirmed myocarditis. These data suggest that standard immune suppression regimens cannot be recommended for the routine treatment of myocarditis. The decision to use them or not should be determined on a case-by-case basis. In addition, exceptions to this include patients with giant-cell myocarditis or myocarditis secondary to autoimmune diseases; both of these patient populations have been shown to benefit from aggressive early immune suppression. [4] [50]

Therapy targeted at specific cause of myocarditis

Lymphocytic (viral) myocarditis

Lymphocytic myocarditis is primarily treated with supportive care and standard heart failure therapies. As with all aetiologies of myocarditis, patients presenting with fulminant heart failure and

cardiogenic shock may require invasive haemodynamic monitoring, aggressive therapy with intravenous diuretics or inotropes, and even mechanical haemodynamic support devices. Given the high rate of recovery, aggressive therapy is recommended, especially early in the course of the disease.

For the most part, immunosuppressive therapy has been shown to be ineffective in viral myocarditis. There are insufficient data to support a benefit of intravenous gamma globulin.[51] Novel therapies with immune-modulating drugs such as interferon-beta have shown great promise in phase II trials. [52]
Giant-cell myocarditis

This is a rare and rapidly progressive disease that is probably the most fatal of all causes of myocarditis. [7] Although aggressive immunosuppressive regimens have been shown to only modestly improve survival, limited data suggest that it prolongs life sufficiently to enable more effective treatment with heart transplantation. [50] [53]
Autoimmune-related myocarditis

Patients with myocarditis due to systemic autoimmune diseases generally have a significant

response to aggressive immunosuppressive regimens including systemic corticosteroids. Animal studies with immune-modulating therapies such as rapamycin and mycophenolate mofetil are promising.
Hypersensitivity myocarditis

Hypersensitivity myocarditis is thought to be related to an allergic reaction to a variety of drugs. With the removal of the offending agent and treatment with systemic corticosteroids, clinical improvement is the rule. [54]
Chagasic myocarditis

Chagas' disease is the most common cause of myocarditis in the world. Antiparasitic therapy during the acute phase of infection is usually curative. At present, there are 2 drugs available with established efficacy for the treatment of acute-phase and early chronic-phase Chagas' disease: benznidazole and nifurtimox. These drugs are not currently available in the US, but can be obtained from the CDC and used under investigational protocols. [CDC: Chagas disease] (external link) Heart failure treatment of this disease is mainly symptom management. A permanent pacemaker with defibrillator is often necessary because of conduction abnormalities and ventricular arrhythmias. Immunosuppressive therapy

is controversial; heart transplantation is often necessary for refractory heart failure. [10]
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