A young man with acute chest pain

FURTHER TESTING

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰