Myocarditis

I. What every physician needs to know.

Myocarditis is an inflammatory disease of the myocardium often associated with cardiac dysfunction. There is a broad spectrum of initial clinical presentations ranging from mild dyspnea to cardiogenic shock. Thus, the diagnosis of myocarditis requires a high level of suspicion. Many cases will resolve spontaneously, but up to 30% will progress to dilated cardiomyopathy. Viruses are the most common cause of myocarditis in North America and Europe. Other causes include bacterial or parasitic infections, toxins, and autoimmune disorders. The pathophysiology of this disease involves direct cardiac myocyte injury followed by activation of cell-mediated immunity and cytokines leading to further destruction of myocytes.

Causes of myocarditis

Viruses are the most common cause of myocarditis, with adenovirus, enterovirus (especially coxsackie), parvovirus B-19, human herpesvirus 6, hepatitis C, and human immunodeficiency virus (HIV) accounting for the majority of cases. Before high active antiretroviral therapy (HAART), more than 50% of HIV-positive patients had evidence of myocarditis. There are differences in the most prevalent viruses based on patient age and region of the world.

Bacteria can also cause myocarditis, with the list including diphtheria, streptococcus, mycobacteria, and mycoplasma among others. Borrelia burgdorferi is a spirochete that causes myocarditis in Lyme disease. Parasites may also cause myocardial inflammation with the classic form being Chagas disease due to Trypanosoma cruzi.

Drug-induced myocarditis is another etiology and is provoked by either a direct toxic effect or a hypersensitivity reaction leading to an eosinophilic infiltrate in the heart. Cocaine and anthracyclines classically have a direct toxic effect whereas antibiotics (penicillins, cephalosporins, sulfonamides), antidepressants (tricyclics), and antipsychotics (clozapine) tend to provoke a hypersensitivity reaction.

Several autoimmune processes may result in myocarditis including systemic lupus erythematosus and other collagen vascular diseases. Giant cell myocarditis is a rare autoimmune form defined by the presence of multinucleated giant cells and associated with a poor prognosis without transplant. Other systemic disorders that are associated with myocarditis include celiac disease, hypereosinophilic syndrome, Churg-Strauss, and sarcoidosis.

II. Diagnostic Confirmation: Are you sure your patient has Myocarditis?

The gold-standard diagnosis of myocarditis is based on endomyocardial biopsy (EMB). The Dallas criteria, developed in 1986, define myocarditis as an inflammatory infiltrate with or without myocyte necrosis. However, EMB has a low yield due to sampling error and is diagnostic in only 10-20% of suspected cases. The most recent American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines (2007) move away from the use of EMB in most cases, focusing instead on noninvasive imaging techniques such as cardiac magnetic resonance imaging (MRI) to support the diagnosis. However, a more recent European Society of Cardiology position statement (2013) suggests that all patients with clinically suspected myocarditis should be considered for EMB. This paper argues that newer immunohistochemistry and viral genome analysis have significantly increased the yield of EMB as compared with the Dallas criteria. In addition to confirming the diagnosis of myocarditis, EMB may identify the underlying etiology and type of inflammation, thereby clarifying prognosis and best treatment. Further discussion of EMB is found in Section II-E-3.

A. History Part I: Pattern Recognition:

The clinical diagnosis of myocarditis is complex due to its broad range of presentations, ranging from mild and reversible to indolent and chronic or even acutely life-threatening. The most common presentation is that of a nonischemic dilated cardiomyopathy with symptoms of heart failure for weeks to months. Symptoms include dyspnea, poor exercise tolerance, chest pain, palpitations, and syncope. Other patients have an acute coronary syndrome-like presentation with chest pain and ischemic-like electrocardiogram (EKG) changes with or without elevated troponin levels, all in the absence of angiographic evidence of coronary artery disease. New onset atrial or ventricular arrhythmias or heart block may be seen. Some patients experience a preceding viral prodrome weeks to months before onset with fever, myalgias, and respiratory or gastrointestinal (GI) symptoms.

Signs and symptoms may vary depending on etiology of the myocarditis with typical patterns including:

Fulminant (in 10% of cases, from any cause): abrupt onset of severe congestive heart failure (CHF) symptoms rapidly progressing to cardiogenic shock.
Hypersensitivity: rash, fever, eosinophilia, temporal relation to new medications.
Giant-cell: associated with autoimmune disorders and thymoma, ventricular tachycardia, high-grade heart block. Slow but relentless progression to early death.
Cardiac sarcoidosis: ventricular arrhythmias, 2nd or 3rd degree heart block, no response to standard care.

B. History Part 2: Prevalence:

Young adults are the most common age group affected, with the mean age at onset ranging from 20-50 years old depending on the specific cause. The incidence of biopsy-proven myocarditis in cases of unexplained heart failure is about 10%, though this is likely an underestimate given the limitations of EMB as discussed above. Autopsy studies in young patients and athletes with sudden cardiac death have shown a 12% incidence of myocarditis. HIV and certain autoimmune disorders increase risk for developing myocarditis.

C. History Part 3: Competing diagnoses that can mimic Myocarditis.

Myocarditis may present like an acute coronary syndrome, with similar symptoms, EKG abnormalities, and elevated cardiac biomarkers. Acute coronary syndrome (ACS) must be ruled out in these cases. Pericarditis is another mimic of myocarditis in terms of symptoms and EKG changes. All of the other causes of congestive heart failure must also be considered, especially the dilated cardiomyopathies such as ischemic and substance-induced.

D. Physical Examination Findings.

Physical exam will look like congestive heart failure, with jugular venous distention, pulmonary rales, peripheral edema, pulsatile liver, and perhaps a laterally displaced point of maximal impulse (PMI).

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Standard labs should be ordered, including complete blood count (CBC) and chemistry panel. Leukocytosis may be present. There may also be elevated erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP), though none of these findings are specific. Cardiac biomarkers are NOT elevated in the majority of patients; troponin is positive in about 34% of cases and creatinine kinase/creatinine kinase-myocardial band (CK/CK-MB) is even less sensitive. Higher levels of troponin do predict poorer outcome. Brain natriuretic peptide (BNP) may be elevated but is also not specific for myocarditis.

Autoantibodies to several cardiac and muscle-specific autoantigens are found in some patients with myocarditis, but availability of these assays is limited in most hospitals at this time. Some examples of these autoantibodies include anti-sarcolemmal, anti-beta adrenergic receptor, and anti-adenine nucleotide translocator antibodies.

EKG is abnormal about half the time, with sinus tachycardia and nonspecific ST-T abnormalities being the most common finding. ST elevations or depressions, PR depression, pathologic Q waves, arrhythmias, or heart block may also be present.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Echocardiogram and cardiac MRI are the main imaging tests used in the workup of myocarditis. Echo is most helpful for ruling out other causes of heart failure, as no pattern is specific to myocarditis, which may look like a dilated, hypertrophic, or restrictive cardiomyopathy. Left ventricular (LV) systolic dysfunction is common with segmental wall motion abnormalities and/or global hypokinesis. Up to a quarter of patients have right ventricular (RV) dysfunction as well. Diastolic filling pressures are often elevated and a small pericardial effusion may be present.

Contrast-enhanced cardiac MRI is becoming a more commonly used test for suspected myocarditis, with diagnosis confirmed by meeting 2 of 3 specific radiologic findings called the Lake Louise criteria. MRI may also be used to suggest the best location for endomycardial biopsy, thereby greatly increasing the pathologic yield of this test.

3.What further investigations (if any) should be performed to help establish the diagnosis? How should the results be interpreted?

As discussed in the introduction to Section II above, the role of endomyocardial biopsy in the diagnosis of myocarditis is controversial, with the 2007 ACC/AHA/ESC scientific statement generally guiding clinicians away from EMB and the 2013 ESC position statement recommending it for most patients with clinically suspected myocarditis.

The 2007 ACC/AHA/ECS statement recommends endomyocardial biopsy as a class I indication in two situations relevant to myocarditis:

Unexplained new onset heart failure of < 2 weeks duration associated with normal-sized or dilated left ventricle with hemodynamic compromise
Unexplained new onset heart failure of 2 weeks to 3 months duration associated with a dilated left ventricle and new arrhythmias, Mobitz type II second- or third-degree heart block, or failure to respond to usual care within 1-2 weeks

These recommendations are designed to pick up cases of giant cell myocarditis, for which immunosuppressive therapy may be indicated and which is likely to progress to requiring transplant within months.

The 2013 ECS statement supports consideration of EMB for all patients with clinically suspected myocarditis, noting the low complication rate and the potential benefit in determining individual prognosis and specific treatment options.

EMB should be performed early in the course of disease and multiple samples should be taken.Tissue is analyzed for histology, immunohistochemistry, and viral polymerase chain reaction (PCR) (which should also be run on serum).

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Viral serologies are not useful given the prevalence of circulating immunoglobulin G (IgG) antibodies to cardiotropic viruses in the general population.

III. Default Management.

A. Immediate management.

Initial management will vary depending on the individual patient presentation but should include:

Monitor on telemetry
Rule out acute coronary syndrome with serial enzymes and EKGs
Initiate diuresis and afterload reduction if evidence of severe volume overload
Stabilize life-threatening atrial or ventricular arrhythmias
Initiate temporary pacemaker for complete heart block
Aggressively manage cardiogenic shock with inotropes
Consider ventricular assist devices or extracorporeal membrane oxygenation (ECMO) in acute/fulminant cases with cardiogenic shock (as a bridge to transplant or recovery)

B. Physical Examination Tips to Guide Management.

Monitor volume status by looking for elevated jugular venous pressure, hepato-jugular reflux, lung crackles, and peripheral edema. Listen to heart sounds for evidence of arrhythmias (though patient will likely be on telemetry).

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Check serial cardiac enzymes every 6-8 hours if initial set is elevated (or if symptoms are acute in onset).

Follow electrolytes and creatinine daily while diuresing.

D. Long-term management.

Therapy is that of standard congestive heart failure management, including angiotensin converting enzyme (ACE)-inhibitors or angiotension receptor blockers (ARBs), Beta-blockers, and diuretics as needed to maintain euvolemia. Aldosterone antagonists are indicated in patients with persistent New York Heart Association (NYHA) class III-IV symptoms. There are no clinical trials of these agents specifically in myocarditis patients. Experts recommend that patients refrain from vigorous activity for at least 6 months based on animal studies showing increased risk of death with sustained exertion.

Conventional management of arrhythmias is recommended, including medications and automatic implantable cardioverter-defibrillator (AICD) if indicated. However, implantation of an AICD for primary prevention in patients with low ejection fraction should be deferred for several months as recovery of left ventricular ejection fraction (LVEF) may occur. Similarly, in patients with heart block who may require a pacemaker, the temporary variety is often used initially since the condition may improve over weeks.

Immune modulation in myocarditis

There has been interest in the use of immunosuppressant and immunomodulatory medications for myocarditis. More than 20 uncontrolled observational studies have shown benefit. However, given the natural history of myocarditis to improve over time in many patients with best supportive care, randomized controlled trials are paramount. And, unfortunately, most randomized control trials (RCTs) have not shown a benefit for the typical patient with unspecified myocarditis. The Myocarditis Treatment Trial, for example, randomized 111 patients with biopsy-confirmed disease and a LVEF < 45% to 24 weeks of prednisone and either cyclosporine or azathioprine. Ejection fraction (EF) improved to a similar degree in both groups and there was no mortality benefit (Mason 1995).

The most notable exception to this lack of benefit from immune suppression is giant cell myocarditis, with evidence of improved long-term survival with the use of high-dose steroids and azathioprine and/or cyclosporine. A retrospective study showed an average survival of 12 months in those treated with immunosuppression vs 3 months in those who did not (Cooper 1997). The monoclonal antibody muromonab-CD3 (OKT3) is now often combined with this regimen. Patients with myocarditis thought to be due to systemic autoimmune disease such as systemic lupus erythematosus (SLE) or scleroderma are also frequently treated with immunosuppressants. Newer trials have focused on specific subsets of myocarditis patients. One RCT comparing prednisone and azathioprine with placebo in patients with increased human leukocyte antigen (HLA) expression on endomyocardial specimens showed improved ejection fraction at 2 years in the active treatment group, though no improvement in the primary composite end-point of death, transplant or hospital readmission (Wojnicz 2001).

Patients who lack a persistent myocardial viral genome or who have circulating cardiac antibodies may be more likely to respond to immunosuppression. An RCT of prednisone and azathioprine in patients with chronic virus-negative inflammatory cardiomyopathy showed improved ejection fraction in the treatment group (Frustaci 2009).

Another treatment that shows some promise in patients with cardiac autoantibodies is immunoadsorption (IA). Similar to plasmapheresis, IA is an extracorporeal method of removing patient immunoglobulins, including pathogenic autoantibodies, from plasma. A study of 45 patients with dilated cardiomyopathy found hemodynamic and LVEF improvements only in patients that had cardiodepressant antibodies present (Staudt 2004). Of note, this study excluded patient with acute myocarditis on biopsy. A phase 4 clinical trial of IA is in progress.

Antiviral therapies, including interferon, have shown promise in case studies and small pilot studies of patients with persistent viral myocarditis. But the only large clinical study of interferon showed no benefit. Intravenous immunoglobulin (IVIG) similarly showed some benefit in case studies and small pilot studies but not in larger randomized controlled trials.

To summarize, immunomodulatory therapy does not appear to be beneficial in the typical adult patient without giant cell or autoimmune myocarditis. Specific subsets of patients may show improved ejection fraction with prednisone and azathioprine, though entry into these trials was based on non-standard testing on endomyocardial biopsy samples. Many patients in the community are diagnosed with myocarditis on the basis of clinical findings and non-invasive testing rather than EMB, making these trials more difficult to generalize to clinical practice. As detailed above, updated recommendations from the European Society of Cardiology place increased emphasis on use of routine EMB in these patients, given implications for treatment. Further studies of immunosuppressive medications and immune modulators are ongoing, with current interest in transfer or stimulation of regulatory T cells and humanized monoclonal antibodies, especially anti-interleukin-17.

E. Common Pitfalls and Side-Effects of Management.

See sections for congestive heart failure, atrial fibrillation, ventricular tachycardia.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

ACE inhibitors and ARBs are beneficial in management of cardiomyopathy including myocarditis in patients with stable chronic kidney disease, however, if acute injury is present these agents should be held until resolution. Spironolactone must be very closely monitored in patients with chronic kidney disease (CKD) due to risk of hyperkalemia. The management of volume overload is also complicated in patients with CKD.

B. Liver Insufficiency.

No change in standard management, though hypoalbuminemia may complicate efforts at diuresis.

C. Systolic and Diastolic Heart Failure.

No change in standard management as most patients presenting with myocarditis will have evidence of systolic and/or diastolic heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease.

In patients with coronary artery disease (CAD), acute coronary syndrome should be at the top of the differential diagnosis in a patient presenting with the nonspecific cardiopulmonary symptoms of myocarditis. Serial cardiac enzymes and EKGs should be done and there should be a low threshold for further risk stratification or cardiac catheterization if history, enzymes, or EKG remains consistent with ACS.