Myocarditis and acute myopathies

Myocarditis

Myocarditis is defined as inflammation of heart muscle. Many different etiologic agents have been implicated in this disease, but viral infections are the most common cause. Myocarditis can be associated with autoimmune and other systemic diseases and can be caused by adverse drug reactions. The clinical picture of myocarditis varies widely, from asymptomatic patients who fully recover without specific therapy and who suffer no long-term sequelae, to critically ill patients with heart failure and cardiogenic shock. There are no standardized, specific, and widely agreed-upon criteria for making the diagnosis of myocarditis or for determining a specific cause in many patients. Last, there has been controversy regarding the most appropriate medical therapy for this condition.

On pathologic examination of myocardial biopsy specimens or at autopsy, myocarditis is usually apparent as infiltration of myocardium with lymphocytes, macrophages, and fibroblasts, accompanied by myocyte necrosis (myocytolysis). It is this type of myocarditis, termed lymphocytic myocarditis, that will be referred to in this chapter unless otherwise specified. Other types of inflammatory reactions are seen less frequently in myocarditis and involve giant cells, eosinophils, or granulomas and can be associated with specific clinical conditions.

The global incidence of myocarditis is estimated at 22 cases/100,000 annually. It is more common in males, and more severe cases tend to occur in women and children. In most patients with myocarditis, a specific cause is not found. It is presumed that in North America and Europe, the most common etiologic agent is viral. Identification of particular viral etiologies may vary by geography and over time. Coxsackie B enterovirus was felt to be the most common cause up to the 1990s, but human herpesvirus 6, cytomegalovirus, and parvovirus B19 have been implicated as causative agents more frequently over the past 20 years. Hepatitis C has also been found to be a common etiology in some populations. Other viral causes include H1N1 influenza A, Epstein-Barr virus (EBV), and herpes simplex 1 and 2. Myocarditis is a common finding in patients infected with human immunodeficiency virus (HIV). However, the causative agent responsible in these cases may be HIV or a secondary viral infection such as cytomegalovirus. ^{, ,} Infectious illnesses such as Lyme disease, acute rheumatic fever, and diphtheria often have myocarditis as a prominent feature. In Central and South America, the most common cause of myocarditis is the protozoan Trypanosoma cruzi , the cause of Chagas disease ( Table 74.1 ). Systemic and autoimmune diseases such as systemic lupus erythematosus (SLE), polymyositis, scleroderma, sprue, Whipple disease, and sarcoidosis can be complicated by myocarditis, and myocarditis can be a feature of infiltrative cardiomyopathies seen in hemochromatosis or amyloidosis. Other specific forms of myocarditis include hypersensitivity or eosinophilic myocarditis, which can be caused by allergic reactions to medications, including smallpox vaccination, and giant cell myocarditis (GCM). Lastly, myocarditis can be associated with doxorubicin cardiomyopathy or with peripartum cardiomyopathy ( Box 74.1 ).

In 2020 an international pandemic of an acute respiratory illness occurred, called coronavirus disease 2019 (COVID-19), caused by infection with a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The illness is characterized by pneumonia, often progressing to acute respiratory failure. Seven to twenty-eight percent of patients hospitalized with this illness demonstrate acute cardiac injury, defined as a combination of elevated serum troponin, electrocardiogram (ECG) changes consistent with myocardial injury, and/or left ventricular (LV) systolic dysfunction demonstrated on ECG. Myocarditis may be a mechanism of cardiac injury in some of these patients. However, there have only been a very small number of patients with a diagnosis of myocarditis that was confirmed by cardiac magnetic resonance imaging (MRI) or tissue sampling. One report described cardiomegaly, localized ST-segment elevation on ECG, marked troponin elevation, and acute heart failure associated with low left ventricular ejection fraction (LVEF) in a patient with COVID-19 pneumonia. Another report described biventricular heart failure and cardiac MRI findings diagnostic of acute myocarditis. LV function returned to normal within weeks in both cases. ^, One report described a patient with cardiogenic shock; impaired LV systolic function; no coronary artery obstruction; and endomyocardial biopsy showing low-grade interstitial and endocardial inflammation with macrophages, myocyte lysis, and viral particles seen in interstitial cells. There have also been reports of a mild mononuclear cell infiltrate on myocardial specimens at autopsy in patients who died from COVID-19 illness. Other causes of myocardial damage are also likely in these patients, including infection-mediated coronary vasculitis, microvascular coronary thrombosis, stress cardiomyopathy, exacerbation of atherosclerotic coronary artery disease, oxygen supply-demand mismatch, and a hyperinflammatory state causing a cardiomyopathy similar to that associated with sepsis.

Unfortunately, it is difficult to make a clinical diagnosis of a specific viral cause of myocarditis. Antiviral antibody titers in acute- and convalescent-phase sera do not aid in the diagnosis, as viruses are highly prevalent in the general population, and antibody levels vary over time and do not correlate well with the onset of symptoms of acute myocarditis. ^, Viral cultures of tissue specimens are unreliable. The identification of viral genomes incorporated in myocyte DNA by the use of methods such as polymerase chain reaction (PCR) is highly suggestive but does not specifically prove that the virus is the cause.

Pathogenesis

Based on observations of human myocarditis and murine models of the disease caused by coxsackie B3, the pathogenesis of viral myocarditis can be described in three stages. ^, The first stage is initiated by viral infection and replication within myocytes. Viral proteases and activation of proinflammatory cytokines initiate myocyte damage. The presence of this viral replication phase is difficult to detect clinically, because patients may be asymptomatic during this phase or may only have nonspecific viremic symptoms. In addition, there is no rapid screening test to confirm most viral infections. Parvovirus B19 may preferentially infect endothelial cells in coronary arteries, venules, and capillaries, and myocardial damage may be a result of impaired blood flow.

The second stage involves host immune activation. Stimulation of cellular immunity and humoral responses attenuates viral proliferation and can result in recovery from the illness. However, unabated immune activation can result in activated T cells targeting myocardial antigens that cross-react with viral peptides. This leads to release of cytokines such as tumor necrosis factor, interleukin-1, and interleukin-6, resulting in further damage to myocytes and the cytoskeleton. ^, Activation of CD4 cells and antibody production plays a less important pathogenetic role. This secondary immune response to viral infection may play a greater role in disease pathogenesis than the primary infection and may be genetically influenced. Incomplete clearing of virus or recurrent viral replication may also cause persistence of inflammation and myocardial damage. Evidence supporting these mechanisms includes the following: Myocardial biopsy with recombinant DNA techniques can detect viral genomes in 20%–35% of patients. Tissue-specific autoantibodies have been detected in 25%–73% of patients with evidence of myocarditis on biopsy, with antibodies directed against contractile, structural, and mitochondrial myocyte proteins. Inappropriate expression of the major histocompatibility complex can frequently be demonstrated on biopsy specimens. Elevated levels of inflammatory cytokines are detected in patients with active myocarditis.

Either persistent overactivation of cellular immune activity or incomplete clearing with persistent or recurrent viral replication can lead to the third stage, which is marked by cellular apoptosis, ongoing necrosis, and fibrosis. Significant myocardial damage leads to LV dilatation and remodeling, neurohormonal activation, systolic dysfunction, and manifestations of heart failure. ^, These processes can then abate, with reduction in LV size and improvement of LV function, or can continue to progress with development of dilated cardiomyopathy, worsening ventricular function, and chronic heart failure. Chronic dilated cardiomyopathy is the major long-term sequela of acute myocarditis ( Fig. 74.1 ).

Clinical presentation and diagnosis

The incidence of myocarditis is difficult to determine, as many cases are mild with subclinical disease. Myocarditis is diagnosed on clinical grounds, as there are no specific clinical diagnostic criteria. The presentation of myocarditis varies widely. Patients can be asymptomatic, as myocarditis is found in 1%–10% of autopsy specimens of young adults who had no history of cardiac illness. Myocarditis can be found at autopsy in up to 20% of cases of young, apparently healthy adults who die suddenly and unexpectedly. ^{, ,} It is estimated to be the third most common cause of sudden cardiac death in young athletes.

Patients with myocarditis most commonly present with dyspnea (72%), chest pain (32%), and symptoms of arrhythmia (18%). The presentation may be indistinguishable from acute coronary syndromes caused by coronary artery disease. There may be a preceding viral prodrome with fever, malaise, and arthralgias. Physical examination can show fever, tachycardia, S3 and S4 gallop sounds, and a pericardial rub if pericarditis is present. Signs of heart failure can be present, including pulmonary rales and wheezes, elevated jugular venous pressure, and peripheral edema. Murmurs of mitral regurgitation and tricuspid regurgitation may be heard. Infrequently, the presentation is fulminant and severe, with acute heart failure, pulmonary edema, and cardiogenic shock.

The differential diagnosis includes acute myocardial infarction (AMI), isolated pericarditis, or chest pain from pulmonary causes, including pulmonary embolism or pneumonia. Generalized sepsis is also a consideration. Myocarditis involving the right ventricle may mimic findings in right ventricular (RV) cardiomyopathy.

Laboratory findings can include leukocytosis, eosinophilia, and an elevated erythrocyte sedimentation rate. The cardiac biomarkers creatine phosphokinase (CPK), troponin T, and troponin I may be elevated, with sensitivity of troponin I reported at 34%–53% and specificity of 89%. ^, Rheumatologic serologic markers and HIV status should be evaluated in selected cases.

The 12-lead ECG is an insensitive test for the diagnosis of myocarditis. ECG findings are nonspecific and include sinus tachycardia and nonspecific ST-segment depression and T-wave inversion most often. Patients may present with chest pain and ST-segment elevation with a picture mimicking AMI or acute pericarditis. More severe cases can be associated with supraventricular or ventricular arrhythmias, conduction disturbances, and heart block. QTc prolongation over 440 msec, QRS duration over 120 msec, and abnormal QRS axis have been associated with a poorer prognosis.

Echocardiography is essential to diagnose and quantitate regional and global LV wall motion abnormalities, LV and RV size and function, the presence of pericardial effusion, and valvular regurgitation. RV involvement may be seen in 25% of patients. Fulminant myocarditis is characterized by a nondilated left ventricle with severe systolic dysfunction and increased wall thickness reflecting myocardial edema. Pericardial effusion may be present. Cardiac catheterization and coronary angiography are often necessary to exclude acute ischemia resulting from coronary artery disease as the cause of chest pain or acute heart failure ( Box 74.2 ).