Karsten Eckhard Schober,     Columbus, Ohio

Pathophysiology

Myocarditis has both infectious and noninfectious causes. Cardiotropic viruses, including those with ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) cores, are the predominant pathogens that lead to myocardial inflammation in humans. Current speculation is that up to 30% of human myocarditis is virus associated. However, with the exception of canine parvovirus and to a lesser degree canine distemper virus, the importance of viruses in the development of myocarditis in dogs and cats is largely undetermined. A recent study using polymerase chain reaction (PCR) analysis on formalin-fixed paraffin-embedded myocardium from adult dogs with myocardial disease failed to demonstrate an association between prior infection with canine adenovirus type 1 or 2, herpesvirus, or parvovirus and the development of DCM or active myocarditis (Maxson et al, 2001).

Current knowledge of the pathogenesis of viral myocarditis stems mostly from laboratory animal studies. A viral infection of the heart follows a standard progression. Most viral pathogens enter the body through the upper respiratory or gastrointestinal tract. Genetic susceptibilities that alter the autoimmune response to viral infections may be important at this stage. The acute phase (days 0 through 3; viremic phase; fulminant myocarditis) is characterized by systemic viremia, virus binding to myocyte receptors and coreceptors, virus invasion into cardiomyocytes, and virus replication causing myocyte injury. Macrophage activation leads to the production and release of proinflammatory cytokines, including tumor necrosis factor, interferon-γ, various interleukins, and inducible nitric oxide. The subacute phase (days 4 through 14; inflammatory phase; postviral or lymphocytic myocarditis) is characterized by clearance of the viruses by natural killer cells, cytokines, perforin, and neutralizing antibodies. Attracted by cytokine release, mononuclear cells such as cytotoxic T and B lymphocytes enter the myocardium and may cause extensive cellular damage. By the end of this stage the virus already has been cleared from the body, but the ongoing immune response mediates the myocardial damage and cell death. In the final or chronic phase (days 15 and beyond; healing phase; chronic myocarditis) there is evidence of myofiber dropout and replacement fibrosis. Most patients recover completely. However, in others viral persistence and host-pathogen interactions lead to chronic inflammation, repetitive cycles of myocardial injury and repair, apoptosis, coronary microvascular spasm, and autoimmune effects. These responses can result in continued myocardial injury and slow evolution to DCM and heart failure. This may occur even after many years, and some cases of idiopathic DCM in dogs and cats may represent unrecognized viral myocarditis.

Slow-growing nonviral agents such as Trypanosoma cruzi also may cause chronic myocarditis with progressive DCM-like pathologic features after a prolonged latent period (Meurs et al, 1995). More recently, Bartonella spp. causing cardiac arrhythmias, endocarditis, and myocarditis in dogs have been identified. Cardiotoxic drugs (e.g., anthracyclines) and drug hypersensitivity reactions have been associated with myocarditis in people. The severity of histopathologic lesions resulting from any of these agents varies with the severity of the insult and the nature and magnitude of the host-toxin interaction. Cardiac injury and myocarditis in critically ill patients often is severe but most commonly remains unrecognized. Potential mechanisms for myocarditis in such patients include excess nitric oxide and proinflammatory cytokine production, endotoxins, direct bacterial damage, and ischemia and reperfusion. Traumatic injury of the heart caused by nonpenetrating chest trauma (referred to as traumatic myocarditis) may be associated with myocardial contusion, intramyocardial bleeding, inflammation, and myocardial degeneration and necrosis. Clinically relevant myocardial dysfunction is a rare consequence and almost always is reversible, and arrhythmias usually are benign. There is no evidence of long-term myocardial damage and dysfunction after traumatic myocarditis in dogs and cats (Abbott, 1995).

Pathologic Features

Patchy myocardial discoloration and minute bleeding may be seen on gross pathologic examination. Histopathologic hallmarks include inflammatory cell invasion, interstitial edema, and myocyte degeneration and necrosis. The term myocarditis commonly is reserved for cases in which the infiltrates are extensive and diffuse. Focal cellular infiltrates as seen in some types of cardiomyopathy, noncardiac disease, or hypersensitivity reaction are of uncertain significance and may occur without degeneration and necrosis. The inflammatory infiltrate may be predominantly lymphocytic (most often mature T lymphocytes) with a large histiocytic component as commonly is seen after viral infection or during the postviral autoimmune phase; eosinophilic as found with drug hypersensitivity, parasitic cause, or hypereosinophilic syndrome; or mixed in a variety of conditions. Neutrophils usually are associated with bacterial infections. The presence of large numbers of B lymphocytes and plasma cells should raise the possibility of bacterial infection as well as a toxic cause. Morphometric quantification of the lesions is essential, with 10 to 14 leukocytes/mm² representing the cutoff between the presence and absence of myocarditis in human patients. Immunohistochemical staining for T lymphocytes (CD4⁺ and CD8⁺) may be needed to establish the diagnosis. Depending on the causative agent, there may be more specific histologic features. Healing often is associated with interstitial fibrosis. A viral origin of myocarditis can be proved only if viral particles such as inclusion bodies or the virus itself are detected within an altered myocardium. This has become possible through molecular analysis of necropsy and endomyocardial biopsy (EMB) specimens using novel techniques of viral gene amplification, including PCR and in situ hybridization. The histologic diagnosis of myocarditis was clarified by the Dallas criteria (see the following section on clinical manifestations and diagnosis), but these unfortunately did not include immunohistochemical findings demonstrating a T cell–mediated immune response. Therefore the sensitivity of the Dallas criteria in the diagnosis of myocarditis is limited. The clinicopathologic classification of primary myocarditis is based on the onset of illness, left ventricular function, EMB findings, and clinical and histologic outcomes and defined four classes of myocarditis: fulminant, acute, chronic active, and chronic persistent. This classification has not yet gained wide acceptance in veterinary medicine.

Clinical Manifestations and Diagnosis

Myocarditis can give rise to diverse clinical features. It may follow upper respiratory or gastrointestinal tract infections, surgery, vaccination, or recent drug exposure. General constitutional symptoms, particularly fever, anorexia, soft cough, muscle pain, exercise intolerance, and diarrhea, often are reported. There is no specific clinical sign on which to base the diagnosis. Classically the combination of an acute infective illness and myocardial abnormalities such as a sudden onset of unexplained ventricular arrhythmia, syncope, episodic weakness, mild and often transient ventricular dysfunction, acute congestive heart failure (CHF), or sudden death may suggest the diagnosis. Myocarditis often is considered when ventricular premature complexes are identified in the absence of a known breed predisposition to cardiomyopathy or are associated with a systemic illness or infection. Thoracic auscultation may disclose evidence of an arrhythmia, a cardiac murmur, or abnormal lung sounds such as crackles.

Electrocardiographic (ECG) findings are variable and may include persistent sinus tachycardia; ST-segment, QT, and T-wave abnormalities; ventricular or supraventricular ectopy; and atrioventricular (AV) conduction disturbances, including complete AV block. Although such ECG findings are nonspecific, the ECG has the virtue of drawing attention to the heart and leading to cardiac biomarker, echocardiographic, and other investigations.

Radiographic findings may be unremarkable or reflect cardiomegaly, CHF, or pulmonary infection. As with other noninvasive techniques, echocardiographic findings may be unremarkable or nonspecific; however, in most cases of symptomatic myocarditis the echocardiogram shows abnormalities. Diffuse or focal nodular thickening and heterogeneous granular texture of the myocardium, smaller ventricular cavity, and pericardial effusion have been observed in human acute (or fulminant) myocarditis. Segmental or generalized ventricular wall motion abnormalities and chamber hypokinesis have been reported in people and cats with histologically proven myocarditis. However, such changes may be confused with abnormalities caused by myocardial ischemia or infarction. The most important aspect of echocardiography may be its ability to exclude other types of myocardial and valvular heart diseases.

Serum proteomics, including the analysis of circulating biomarkers of myocardial injury such as cardiac troponin (cTn) concentration, is a promising approach to diagnose acute myocardial injury. Certainly the findings of ventricular arrhythmia with a significantly elevated cTn level should prompt consideration of myocarditis in the differential diagnosis. Unfortunately, blood cTn level is not altered consistently in myocarditis, nor is cTn elevation specific for myocardial inflammation. In addition, the time window for diagnosis may be relatively brief. Nevertheless, elevation of serum cTn concentration in association with a strong clinical suspicion may aid in the early presumptive diagnosis of acute myocarditis, in which significant myocytolysis and myocardial necrosis may occur (Web Figure 63-1). Experimental studies in mice and clinical studies in humans with histologically proven myocarditis reported a high sensitivity of cTn level in the diagnosis of fulminant or acute myocarditis and a close relationship between serum concentrations of cTn and the severity of myocardial inflammation. The value of cTn in the diagnosis of chronic myocarditis is limited. Serologic testing for known infectious causes (including toxoplasmosis, borreliosis, rickettsial diseases, bartonellosis, and Chagas’ disease) may identify the causative antigen and assist in development of further treatment plans. The identification of novel biomarkers of cardiac inflammation in peripheral blood, including analysis of messenger RNA and specific proteins (e.g., antimyocardial antibodies such as antimyosin and antitroponin) is under way.