Chapter 124

Myocarditis

John R. Butterly

Definition and Epidemiology

Myocarditis is the term used to include any pathologic process in which inflammation involving the myocardium is identified. The basic definition given by the World Health Organization (WHO) is “an inflammatory disease of the myocardium diagnosed by established histological, immunological and immunochemical criteria.”¹ There are multiple potential causes and therefore varying degrees of clinical presentations and outcomes. In addition, the presently accepted gold standard diagnostic test, endomyocardial biopsy (EMB), is infrequently used, so the criteria of this very specific definition will likely not apply to the majority of patients ultimately diagnosed with this condition. To further confuse this issue, the Dallas criteria,² defined as histologic evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of nonischemic origin, have been criticized as too insensitive, nonspecific, and inadequate to predict response to therapy in view of newer modalities of immunologic and molecular testing.³ Because of the aforementioned factors and the infrequent use of EMB, the actual incidence of myocarditis is not actually known, and there is a wide variation of reported incidences. For example, in autopsy studies of sudden cardiac death in adolescents and young adults, the prevalence of microscopic evidence of myocarditis has been variably reported to be 2% to 42%⁴^,⁵; biopsy-proven myocarditis has been reported at 9% and 16% in adults diagnosed with nonischemic, dilated cardiomyopathy⁶^,⁷ and in 46% of children with an identified cause of dilated cardiomyopathy.⁸

It is important to note the distinction between cardiomyopathy and myocarditis. Cardiomyopathy refers to any situation in which myocardial systolic or diastolic function is impaired and is generally categorized in three separate types; dilated, hypertrophic, or restrictive. There are multiple causes of systolic myocardial dysfunction, the most common in developed nations being ischemic in origin as a result of the presence of coronary artery disease. The most common cause of dilated cardiomyopathy is idiopathic (unexplained), whereas myocarditis is only one cause of dilated cardiomyopathy and accounts for less than 10% of all cases.⁹

Pathophysiology

Myocarditis is a heterogeneous condition and can be caused by a multitude of insults to the myocardium. The causative agent may be infectious, such as viral (including human immunodeficiency virus [HIV]), bacterial, protozoal (Chagas disease, a major cause of dilated cardiomyopathy in Latin America), spirochetal (Lyme disease), rickettsial, or fungal. A number of toxins can cause severe myocarditis; ethanol and certain chemotherapeutic agents belonging to the anthracycline family are among the most common. Myocarditis may also be the result of drug-induced allergies (including penicillin allergy) or autoimmune diseases such as systemic lupus erythematosus. Histologic diagnosis is made by examination of tissue obtained by EMB and depends on analysis of the type of inflammation present (lymphocytic, polymorphic, eosinophilic) as well as correlation with other systemic and physical findings. Frequently the cause remains undetermined, although new molecular techniques have shown that viruses seem to be the most important cause in North America and Europe. Viruses that have been identified include enteroviruses, adenoviruses, influenza, herpesvirus, Epstein-Barr virus, cytomegalovirus, hepatitis C, and HIV.¹⁰

The myocardium is damaged by direct viral cytopathic effects as well as by damage by autoantibodies that are triggered by the ongoing inflammatory process. Families with a genetic predisposition for developing viral-induced autoantibodies and subsequent dilated cardiomyopathy have been identified.¹¹

Clinical Manifestations

Initial presentation can be varied and ranges from mild symptoms of fever, atypical chest pain, fatigue, and palpitations with possible transient electrocardiographic changes to potentially fatal cardiogenic shock and/or arrhythmias and sudden death. Should myocarditis progress to significant systolic dysfunction, the symptoms would be the same as seen in any cause of left ventricular dysfunction (dyspnea on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea). In cases involving the right ventricle, either through direct involvement or because of the underlying left-sided failure, the patient may report ankle swelling, bloating, or loss of appetite as a result of the development of bowel edema. Chest pain, usually of the pleuritic kind, may be a prominent finding if there is pericardial involvement.

Myocarditis is more frequent in younger age groups, although it can occur at any age. The presentation may well be subtle, so the diagnosis should be considered in any patient with symptoms suggestive of a cardiac cause, with the understanding that other cardiac diagnoses such as coronary artery disease, endocarditis, or a noncardiac inflammatory process should always be ruled out. It must also be recognized that patients with established cardiac diagnoses, such as coronary disease or valvular heart disease, may also develop acute myocarditis, which should especially be considered if the signs and symptoms do not correlate well with the known existing condition. When this is suspected, the gold standard for diagnosis remains EMB.

Physical Examination

Resting tachycardia with an exaggerated chronotropic response to any exertion would be an expected finding on physical examination. Mild cases of myocarditis may include normal physical examination findings or just a low-grade fever and tachycardia. In cases that progress to significant systolic dysfunction, the physical findings would be the same as seen in any cause of left ventricular dysfunction (pulmonary rales, third or fourth heart sounds, or occasionally a murmur of mitral regurgitation [MR] caused by the functional MR seen in moderate to severe left ventricular dilation). There may be a pericardial friction rub in cases involving the pericardium. In cases in which right ventricular dysfunction is a prominent finding, one would see an elevation of the jugular venous pressure, evidence for hepatic congestion in the form of hepatic enlargement and possible right upper quadrant tenderness, and pedal edema, with development of ascites and anasarca in extreme cases. The astute clinician will be aware of the fact that patients with chronic heart failure may be symptomatic but have few if any obvious physical findings.

Diagnostics

There are no accepted, specific criteria for making a diagnosis of myocarditis short of EMB. The diagnosis is most frequently made by a combination of clinical presentation coupled with the results of noninvasive testing, most frequently echocardiography. Documentation of decreased left (and sometimes right) ventricular function in a more global distribution, and lack of regional wall motion abnormalities (RWMAs) that would be more suggestive of an ischemic cause, in the right clinical setting (e.g., fever, recent flulike illness) is suggestive of a diagnosis of acute myocarditis. In facilities experienced in cardiac magnetic resonance imaging (MRI) a more sensitive finding, in addition to the lack of RWMAs, would be evidence of patchy, focal edema and the presence of subepicardial foci of late gadolinium enhancement (LGE), a finding that is typical of acute myocarditis. Because of the lack of specific criteria in making this diagnosis, it is presently recommended that patients with a suspected diagnosis be referred to a tertiary center with expertise in cardiac MRI or EMB if deemed necessary.¹⁰

As is true with all patients suspected of having a cardiac diagnosis, an electrocardiogram (ECG) should be obtained initially. This is most often abnormal in patients with acute myocarditis, although there are no findings that would be specific for this diagnosis. The ECG might demonstrate all degrees of atrioventricular (AV) block, right or left bundle branch block, nonspecific ST-T wave changes or T-wave abnormalities, atrial fibrillation, or, more ominously, ventricular tachycardia. Of some possible help, the ST elevations that can be seen in acute myocarditis are more frequently concave upward, as they are in pericarditis, and more likely to be diffuse—that is, not restricted to any one specific vascular distribution.

All patients with suspected myocarditis should have an initial echocardiogram to evaluate degree of left and right ventricular dysfunction, chamber size, and wall thickness and to rule out other potential diagnoses such as valvular or ischemic disease. Although global ventricular dysfunction is the most common finding, one might see RWMAs, although not in the expected distribution of any one vascular territory. In addition, the echocardiogram may demonstrate significant wall thickening and depression of systolic function consistent with the acute edema seen in marked inflammatory conditions. Sequential echocardiograms are very useful in following possible progression or response to therapy. At present, echocardiography is preferable to nuclear studies owing to a lack of sensitivity and specificity of the latter with present techniques. As mentioned earlier, cardiac MRI, where available, can be very helpful and may be the imaging modality of choice in a facility with that expertise. Stress testing is not recommended in cases of suspected myocarditis owing to the risk of precipitating an arrhythmia in this setting (unless there is a need to rule out an ischemic cause for symptoms).

Biomarkers are helpful and confirmatory in making the diagnosis of acute myocarditis. The markers of acute inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will frequently be elevated, but of course are nonspecific as to cause. Specific cardiac biomarkers are more explicit, with troponins being more sensitive than creatine phosphokinase (CPK). These tests will not necessarily, however, help differentiate myocarditis from other cardiac conditions, and the results may be normal at the time of testing. This is also true of brain natriuretic peptide (BNP).

Testing for specific viral antibodies can be unreliable because infection with these agents is frequent in most populations without causing acute myocarditis. Proof of progression from immunoglobulin M (IgM) to IgG antibodies might be helpful, as might testing for HIV when suspected or Lyme disease in areas where it is known to be endemic. Testing for cardiac autoantibodies may be useful, although these tests are not routinely available.

Diagnostics

Myocarditis

Laboratory