Myocarditis

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Chapter 25

Myocarditis

1. What is myocarditis?

    Myocarditis is an inflammatory disease of the heart muscle that can cause acute heart failure, heart block, sudden death, and chronic dilated cardiomyopathy.

    Myocarditis can be classified by cause, histology, immunohistology clinicopathologic, and clinical criteria. The clinicopathologic classification consists of the following four categories:

Most myocarditis in developed countries results from a viral infection and the immune reaction to viral injury.

2. What is the pathogenesis of myocarditis?

    Most of the information about the pathogenesis of myocarditis derives from animal models rather than human studies. From these experiments, the progression from acute viral injury to chronic dilated cardiomyopathy can be simplified into a three-phase process:

image Phase 1, sometimes called acute viral, occurs after viral entry and proliferation in the myocardium and results in direct tissue injury even before an inflammatory reaction.

image Phase 2, called subacute immune, is characterized by activation of the innate and acquired immune response. The innate immune response leads to upregulation of a variety of inflammatory mediators like interferons, tumor necrosis factor, and nitric oxide, which ultimately result in an influx of tissue-specific T and B cells (acquired immune response) into the heart. If the inflammatory response persists, a chronic myopathic phase (phase 3) with fibrosis and remodeling with dilation of the ventricles may develop in susceptible individuals.

image In phase 3, immune activation may persist and contribute to progressive cardiomyopathy.

In any phase, inflammation and fibrosis may lead to ventricular arrhythmias or heart block.

3. What is the clinical presentation of myocarditis?

    The clinical presentation of myocarditis in adults is highly variable. Patients may report a viral prodrome of fever, rash, myalgias, arthralgias, fatigue, and respiratory or gastrointestinal symptoms in the days to weeks before cardiac symptoms, which range from mild dyspnea to chest pain and cardiogenic shock. Chest pain in myocarditis can mimic typical angina and be associated with electrocardiographic (ECG) changes, including ST segment elevation. There may be a rise in biomarkers of cardiac injury (e.g., troponins). The pattern of troponin elevation is typically longer than is seen following an acute coronary thrombosis. If the pericardium is involved, patients can present with symptoms typical of pericarditis. Cardiac rhythm disturbances are not uncommon and may include new-onset atrial or ventricular arrhythmias or high-grade atrioventricular (AV) block with syncope.

    In contrast to adults with myocarditis, children often have a more fulminant presentation and may require advanced circulatory support for ventricular failure in early stages of their disease. Despite a severe presentation, recovery after a period of hemodynamic support is not uncommon.

4. What is the incidence of myocarditis and who does it affect?

    The population-based incidence of myocarditis is not known because of the variable clinical presentation and lack of a specific, noninvasive diagnostic test. In referral cohorts of patients with otherwise unexplained acute to subacute heart failure, the incidence of biopsy-proven myocarditis is 9% to 10% using histologic criteria, and up to 40% using newer immunostain-based diagnostic standards. Recently, inflammation (using newer immunostains) has been observed in up to 40% of biopsies from patients with chronic, severe dilated cardiomyopathy.

    The mean age of adults diagnosed with myocarditis ranges from 20 to 51 years in most series. Most studies report a slight predominance of men, which may be partly mediated by testosterone. Testosterone increases post-viral inflammation in animal models of myocarditis. Myocarditis should be considered in select patients who develop cardiac symptoms and who also have risk factors for human immunodeficiency virus (HIV) infection, Chagas disease, and rheumatic fever.

5. What are the causative agents of myocarditis?

    Myocarditis can be triggered by many infectious pathogens, including viruses, bacteria, Chlamydia, rickettsia, fungi, and protozoans, as well as systemic toxic and hypersensitivity reactions (Table 25-1).

TABLE 25-1

CAUSES OF MYOCARDITIS

image

HIV, Human immunodeficiency virus.

∗Frequent cause of myocarditis.

From Elamm C, Fairweather D, Cooper LT: Pathogenesis and diagnosis of myocarditis, Heart 98:835-840, 2012.

    Viral infection is the most commonly reported cause of myocarditis in Western Europe and North America. Currently, the most commonly identified viruses in reports from Germany and the United States are parvovirus B19 and human herpesvirus 6 (HHV-6). Enteroviruses, in particular coxsackievirus B (CVB), were the most commonly identified viruses from the 1950s until the 1990s. CVB still causes regional clusters of myocarditis, although the overall reported rate of CVB infection had declined.

    Cytomegalovirus (CMV) can cause myocarditis in patients posttransplant and early infection posttransplant correlates with coronary allograft vasculopathy.

    In the developing world, rheumatic carditis and, to a lesser degree, Trypanosoma cruzi, still contribute substantially to the global burden of disease. Scorpion bites have been reported to have a high rate of myocarditis in India.

    Hypersensitivity myocarditis is an autoimmune reaction that is often drug-related and should be suspected when there is a temporal association between the onset of heart failure and the start of a new medication. Numerous medications, including the antipsychotic clozapine (Clozaril), anticonvulsants, and antibiotics have been implicated.

6. What are some of the clinical presentations of nonviral infectious myocarditis?

image Bacteria: Bacterial myocarditis is far less common than viral-induced myocarditis. Corynebacterium diphtheriae can cause myocarditis associated with bradycardia in people not previously immunized. Clostridium organisms and bacteremia from any source may result in endocarditis and adjacent myocarditis. Other bacterial pathogens to consider include meningococci, streptococci, and Listeria organisms.

image Spirochetes: The tick-borne spirochete Borrelia burgdorferi causes Lyme disease. The initial infection is often marked by a rash followed in weeks or months by involvement of other organ systems, including the heart and nervous system, and joints. Heart block or symptomatic ventricular arrhythmias in the setting of cardiomyopathy should raise suspicion for Lyme disease, particularly in endemic areas such as parts of New England or the upper Mississippi River valley. Full recovery is typical, although carditis sometimes persists. Co-infection with Ehrlichia organisms has been reported.

image Protozoa: Infection with the protozoa Trypanosoma cruzi causes Chagas disease, which is encountered in Central and South America. It may be transmitted by direct inoculation by reduviid insects, through blood transfusions, or, rarely, oral inoculation. Chagas disease can present as acute myocarditis, but more commonly presents as a chronic cardiomyopathy characterized by segmental wall motion abnormalities, apical aneurysms, and ECG changes, including right bundle branch block (RBBB), left anterior fascicular block (LAFB), and AV block.

7. What is giant cell myocarditis?

    Giant cell myocarditis (GCM) is a fulminant, rapidly progressive disease that is usually fatal and that affects young, otherwise healthy individuals. It is considered to be primarily autoimmune in nature because of its association with a variety of autoimmune disorders and with thymoma. GCM presents most commonly with a few days to weeks of new heart failure symptoms, often associated with ventricular arrhythmias or, sometimes, heart block. Unlike lymphocytic myocarditis, patients do not usually improve with guideline-based treatment. The diagnosis requires an endomyocardial biopsy.

    The initial treatment may include mechanical circulatory support and sometimes transplantation. Immunosuppression that includes cyclosporine may prolong transplant-free survival.

8. What are the ECG findings in myocarditis?

    The ECG has a low sensitivity for diagnosing myocarditis. Nonspecific ECG changes in myocarditis include sinus tachycardia, ST and T wave abnormalities, and ST segment elevation mimicking an acute myocardial infarction. There may also occasionally be atrial or ventricular conduction delays, or supraventricular and ventricular arrhythmias. The presence of a widened QRS or Q waves are associated with higher rates of cardiac death or heart transplantation.

9. What are the echocardiographic findings in myocarditis?

    There are no specific echocardiographic features of myocarditis. Echocardiography is used mainly to exclude other causes of heart failure, such as valvular, congenital, or pericardial disease. Impaired right ventricular (RV) function is an independent predictor of death or the need for cardiac transplantation. Patients with fulminant myocarditis tend to present with near normal cardiac chamber dimensions and thickened walls compared with patients with a longer duration of symptoms who have greater left ventricular (LV) dilation and normal wall thickness. Patients who meet the clinicopathologic criteria for fulminant myocarditis have a greater rate of full recovery if they survive their initial illness. Therefore, echocardiography has a value in classifying patients with acute myocarditis and may provide prognostic information.

10. Are cardiac biomarkers useful?

    Troponin I was found to be elevated in only 34% of subjects with acute myocarditis in the US Myocarditis Treatment trial cohort who were enrolled an average of 1 month after symptom onset. In a study of more acutely ill patients seen in a hospital setting, creatine kinase MB isozyme (CK-MB) levels greater than 29.5 ng/mL predicted in-hospital mortality with a sensitivity of 83% and a specificity of 73%. B-type natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP) are probably useful confirmatory tests for the diagnosis of heart failure in cases of suspected myocarditis.

11. Are inflammatory markers and viral serology useful?

    Nonspecific serum markers of inflammation, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocyte count, are often elevated in myocarditis patients, but normal values do not exclude an acute myocardial inflammatory process. The diagnostic value of viral serology is limited by the fact that most viral infections believed to be involved in the pathogenesis of myocarditis are highly prevalent in the general population. Antibody levels also vary over the time course of the disease. For example, IgM antibodies against parvovirus B19 are only detectable for a short period after acute infection. In a recent study, there was a poor correlation between myocardial viral genome polymerase chain reaction (PCR) results and viral serology. Therefore, routine viral serology for the diagnosis of a specific pathogen in suspected acute myocarditis is not recommended.

12. What is the gold standard to diagnose myocarditis?

    Endomyocardial biopsy (EMB) remains the gold standard for diagnosing myocarditis. According to the Dallas criteria, acute myocarditis is defined as histologic evidence of inflammatory cell infiltrates associated with myocyte necrosis. However, sampling error caused by patchy involvement of the myocardium, high interobserver variability, and lack of correlation with clinical outcomes limit the utility of these criteria. Although approximately 6 biopsy samples are routinely obtained (using a Stanford Caves bioptome), a post mortem analysis of histologically proven myocarditis cases found that more than 17 samples are needed to diagnose myocarditis with an 80% sensitivity.

    Figure 25-1 presents histologic examples of myocarditis.

13. Should an endomyocardial biopsy be performed on every patient with suspected myocarditis?

    Because of the limitations mentioned above, as well as cost and risk of the procedure, EMB should be used selectively in those patients in whom the likely incremental information gained will meaningfully impact prognosis or treatment. The 2007 American Heart Association/American College of Cardiology/European Society of Cardiology (AHA/ACC/ESC) Scientific Statement limited the class I indications to only two clinical scenarios:

14. Is there a role for cardiac magnetic resonance imaging (CMR) in myocarditis?

    CMR is useful to distinguish ischemic from nonischemic cardiomyopathy in the setting of acute dilated cardiomyopathy. Criteria suggested by an expert panel recommended that both T1- and T2-weighted imaging be used when myocarditis is suspected. CMR in acute myocarditis may demonstrate regional rather than global involvement. CMR may have a diagnostic synergy when combined with EMB, and may also be useful in guiding EMB to suspected areas of myocardial involvement.

15. What is the treatment of lymphocytic myocarditis?

    The mainstay of treatment for myocarditis presenting as recent-onset dilated cardiomyopathy is supportive therapy for LV dysfunction. Most patients with acute myocarditis presenting with dilated cardiomyopathy respond well to standard heart failure therapy, including diuretics and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists, as well as treatment with β-blockers once clinically stabilized.

    Therapy for nonsustained arrhythmias is also supportive, as arrhythmias usually resolve after the acute phase of the disease. However, patients with symptomatic or sustained ventricular tachycardia that persists after the acute inflammatory phase of myocarditis usually require an implantable cardioverter-defibrillator (ICD).

    Digoxin and nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided, as they have been associated with increased mortality in animal models. Sustained aerobic exercise during acute viral myocarditis leads to increased mortality in animals. Therefore, strictly limiting aerobic physical activity until myocarditis is resolved is recommended.

16. Is there a role for antiviral and immunosuppressive therapy?

    In the setting of acute lymphocytic myocarditis, there is no established role for immunosuppressive or antiviral therapy. In patients with acute GCM, however, transplant-free survival is probably improved with cyclosporine and corticosteroids treatment. The role of antiviral and immunosuppressive treatments in select groups of patients with chronic dilated cardiomyopathy and evidence of either viral infection or myocarditis is an area of current research.

17. When does the patient with myocarditis need mechanical circulatory support and when should patients be considered for cardiac transplantation?

    Mechanical circulatory support may be effective in patients presenting with cardiogenic shock despite optimal medical intervention. Extracorporeal membrane oxygenation support may be beneficial for adult and pediatric patients with fulminant myocarditis and profound shock, as short-term recovery can occur within days. For patients with cardiogenic shock due to acute myocarditis who deteriorate despite optimal medical management, recovery is more likely to be prolonged, and implantation of a ventricular assist device as a bridge to transplantation or recovery may be a more effective alternative. For those patients who are refractory to medical therapy and mechanical circulatory support, cardiac transplantation should be considered. The overall rate of survival after cardiac transplantation for myocarditis in adults is similar to that for other causes of cardiac failure.

18. What is the prognosis of myocarditis?

    Prognosis is overall very good for adult patients with acute lymphocytic myocarditis who have mild symptoms and preserved LV ejection fraction (LVEF). Predictors of death or need for cardiac transplantation from various case series include presentation with syncope, RV systolic dysfunction, lower LVEF, elevated pulmonary artery pressure, advanced New York Heart Association (NYHA) class, and widened QRS and Q waves on presenting ECG.

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