Myocarditis

General Considerations

Myocarditis is defined simply as an inflammatory process with necrosis that involves the myocardium. In the past, the myocardial injury was believed to be a direct result of the cytotoxic effects of the relevant organisms. Even as early as 1806, however, it was thought that a persistent inflammatory process following such an infection (eg, diphtheria) of the myocardium led to progressive cardiac damage and dysfunction. When the term myocarditis was irst introduced in 1837 as inflammation or degeneration of the heart, the diagnosis could be made only postmortem. Fortunately, endomyocardial biopsy now allows the sampling of human myocardial tissue during life and thus the accurate antemortem diagnosis of myocarditis.

Pathophysiology

The histologic hallmark of myocarditis is a focal patchy or diffuse inflammatory infiltrate with adjacent myocyte injury. The inflammation may not be restricted to the myocardium but may also involve the adjacent endocardium, pericardium, and valvular structures.

Myocarditis is most commonly initiated by viral infection (Table 16–1). Initiation of the pathophysiologic abnormalities, however, may result from a variety of insults, including drugs, toxins, hypersensitivity reactions, collagen vascular diseases, and autoimmune reactions. The most common agent associated with myocarditis in the United States and Western Europe in immunocompetent hosts is human coxsackievirus B infection. Other viruses, bacteria, rickettsiae, spirochetes, fungi, protozoans, or metazoans can also produce myocarditis; such causes are uncommon, however (see Table 16–1). Successful identification of the most common offending pathogens depends on knowledge of the geographic region's relevant endemic and epidemic infectious diseases, the inhabitants' immunization status, host immunocompetence, and the sophistication and availability of public health services.

Several mechanisms of myocardial damage have been proposed. (1) Direct injury of myocytes by the infectious agent. (2) Myocyte injury caused by a toxin such as that from Corynebacterium diphtheriae. (3) Myocyte injury as a result of infection-induced immune reaction or autoimmunity.
The autoimmunity hypothesis is the most widely accepted theory. It is believed that the viral infection triggers a cell-mediated immunologic response that ultimately causes myocardial injury, the myocardial injury persists despite viral clearance.
In the murine model, coxsackievirus B3 causes an infectious phase, which lasts 7–10 days, and is characterized by active viral replication. During this phase initial myocyte injury takes place, causing the release of antigenic intracellular components such as myosin into the bloodstream. Subsequently, after viral clearance, a second phase of myocyte damage will start. This phase is immune-mediated by CD8 lymphocytes and autoantibodies against various myocyte components. Antimyosin antibodies were isolated from mice that developed myocarditis following coxsackievirus B infection, as well as from patients with myocarditis. Antigenic mimicry, the cross reactivity of antibodies to both virus and myocardial proteins, occurs when an infectious agent shares an identical antigen with the normal myocyte. This mechanism is documented in animal models, and it may play a role in humans. Myocyte injury may be a direct result of CD8 lymphocyte infiltration. The local release of cytokines, such as interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor (TNF), and nitric oxide may play a role in determining the T-cell reaction and the subsequent degree of autoimmune perpetuation. These cytokines may also cause reversible depression of myocardial contractility without causing cell death.

The popularity of the autoimmune hypothesis deemphasizes the role of the virus. Animal studies show, however, that viral proliferation itself might cause myocarditis. Some studies demonstrate the persistence of viral genomic fragments in myocardial cells of patients with active myocarditis and in some patients with dilated cardiomyopathy. Although these fragments may not be infectious, viral RNA may still serve as a persistent antigen to drive the immunologic response.
Exposure to cardiotropic viruses, presumably followed by a viral infection of the myocardium, is common. Based on the detection of serum antibodies to cardiotropic viruses, approximately 70% of the adult population has had prior exposure. Nonetheless, resultant abnormalities in cardiac function or symptomatic heart failure are unusual. The host factors predisposing to these deleterious immune responses are as yet undefined. Immunocompromised patients, such as pregnant women and patients with AIDS, are predisposed to myocarditis. The susceptibility to viral myocarditis may also be age-related, or, based on familial occurrence, genetically predetermined.

Clinical Findings

Myocarditis is most commonly asymptomatic, with no evidence of left ventricular dysfunction. The clinical manifestations of myocarditis are protean, when they are present. Myocardial involvement may be overshadowed or completely masked by the constitutional symptoms of the illness or other organ dysfunction. Cardiac symptoms may result from systolic or diastolic left ventricular dysfunction or from tachyarrhythmias or bradyarrhythmias. Patients frequently present days to weeks after an acute febrile illness, particularly a flu-like syndrome. In the Myocarditis Treatment Trial, 59% of patients diagnosed with active myocarditis described an antecedent viral syndrome. Common constitutional symptoms included fever, malaise, fatigue, arthralgias, myalgias, and skin rash.

Chest discomfort is a common symptom and is typically pericardial in nature; ischemic or atypical pain may also occur. In the Myocarditis Trial, 35% of patients with myocarditis and heart failure had associated chest pain. Occasionally patients present with the syndrome of acute myocardial infarction with ischemic chest pain, electrocardiographic (ECG) abnormalities, elevated cardiac isoenzymes, or evidence of left ventricular wall motion abnormalities. Viral coronary arteritis and vasospasm have been implicated as the cause of this syndrome; the epicardial coronary arteries are usually widely patent.

The acute onset of symptoms of congestive heart failure in a young person or in a patient without known coronary artery disease often suggests the diagnosis of myocarditis. Classic symptoms of congestive heart failure, including dyspnea, fatigue, decreased exercise tolerance, palpitations, and right heart failure, may be present. This constellation of signs and symptoms may be indistinguishable from dilated cardiomyopathy. It should be noted that because the metabolic demands on the heart associated with fever or a viral illness may initiate the first episode of congestive heart failure in patients with asymptomatic left ventricular dysfunction or reduced cardiac reserve, heart failure following a viral syndrome does not necessarily imply myocarditis.
Patients may also present with other symptoms that have been described in myocarditis: dizziness, syncope, or palpitations caused by atrial and ventricular arrhythmias and conduction disturbances. Myocarditis may present as sudden death, as a result of malignant ventricular arrhythmias or complete heart block; systemic and pulmonary thromboemboli have also been noted.

Treatment

Patients with suspected acute myocarditis should be hospitalized and monitored closely for evidence of worsening congestive heart failure, arrhythmias, conduction disturbances, or emboli. Bed rest is essential, and activities that increase cardiac workload should be strongly discouraged. In the animal model, exercise has been shown to both intensify the inflammatory process in the myocardium and increase morbidity and mortality. Activities should be restricted until clinical improvement occurs or a follow-up biopsy documents the resolution of inflammation.
Antipyretics, other than nonsteroidal antiinflammatory drugs (NSAIDs), should be given to febrile patients, and analgesics are helpful in dealing with pleuropericardial chest pain. Hypoxia, decrease in cardiac output, and tachycardia warrant the administration of supplemental oxygen. If anemia is present, correcting it may improve cardiopulmonary function. The use of tobacco and alcohol should be strongly discouraged.

Patients with congestive heart failure should be treated by restricting sodium and fluids and by administering diuretics, angiotensin-converting enzyme (ACE) inhibitors, b-blockers, and spironolactone. Patients with fulminant disease manifesting as cardiogenic shock will require more aggressive therapy with intravenous vasodilators and inotropic agents such as dobutamine or milrinone. Occasionally cases may be refractory to conservative measures and require intraaortic balloon counterpulsation or a left ventricular assist device. Recent reports have demonstrated that early aggressive approach with mechanical circulatory support might help as a “bridge to recovery.” As a last resort, cardiac transplantation may be considered in patients with acute myocarditis if all other measures have failed and the patient's condition is rapidly deteriorating. Unfortunately, an increased morbidity and mortality in transplant rejection results from the activated immunologic system that the donor heart encounters.

Antiarrhythmic agents are warranted in patients with tachyarrhythmias or ventricular arrhythmias. It is best to avoid agents with strong negative inotropic effects. Occasionally amiodarone or an implantable cardioverter defibrillator may be used after all other attempts at controlling arrhythmia have failed. These measures must be used only as a last resort, however, because myocarditis frequently resolves spontaneously. Patients with symptomatic bradyarrhythmias or high-grade conduction blocks will benefit from the implantation of a pacemaker.
Anticoagulation therapy is indicated in patients with systemic or pulmonary emboli or mural thrombi detected by echocardiography or ventriculography. Patients with active myocarditis and even mild left ventricular dysfunction should probably receive anticoagulation (animal models have demonstrated a propensity toward mural thrombi). Anticoagulation may be contraindicated in patients with coexisting pericarditis.

Immunosuppressive therapy has been reported in few studies with disappointing results. The largest controlled trial to date is the Myocarditis Treatment Trial, which compared conventional therapy alone to conventional therapy plus one of two immunosuppressive combinations: the first is cyclosporine and prednisone, the second is azathioprine and prednisone. In this study significant differences in left ventricular ejection fraction (LVEF) or left ventricular diastolic diameter at 28 or 52 weeks could not be detected among the groups, largely due to unexpected spontaneous improvement in those not receiving immunosuppression therapy. No significant difference in survival occurred during the follow-up period.

Intravenous immune globulin was suggested to be useful by some reports. A recent report randomized 62 patients with recent-onset (less than 6 months of symptoms) dilated cardiomyopathy to receive intravenous immune globulin or placebo. No treatment effect was found in improving LVEF at 12 months, although both groups had a 14% increase in LVEF. Based on all available studies, immunosuppressive therapy is generally not indicated except in a few special cases.

The prognosis in giant cell myocarditis is very poor, and immunosuppressive therapy may be helpful. Another situation where immunosuppressive therapy may be indicated is myocarditis associated with underlying immune diseases like systemic lupus erythematosus (SLE). In a small percentage of myocarditis patients the disease may recur after initial resolution, in these patients immunosuppressive therapy may help in decreasing the recurrences.

A recently published study randomized 84 patients with idiopathic cardiomyopathy of more than 6 months duration to receive immunosuppressive therapy (prednisone and azathioprine) or placebo for 3 months with a 2-year follow-up. All these patients had positive HLA in their endomyocardial biopsy specimens. The author hypothesized that the presence of HLA in the myocardium will identify a population of patients with inflammatory cardiomyopathy due to immune process. After 2 years a composite of death, heart transplantation, or hospital readmission did not differ between the study groups. The patients in the immunosuppression arm, however, showed significant improvement in LVEF at 3 months and 3 years, as well as improvement in New York Heart Association (NYHA) functional class. This study restores the interest in immunosuppressive therapy as a treatment for myocarditis; however, more work needs to be done to evaluate different immune markers that will help identify the subgroups of patients that will benefit from such treatment.