Myocardial inflammation underlies cardiac dysfunction in a wide spectrum of disorders, from lymphocytic myocarditis (1,2) to idiopathic dilated cardiomyopathy (IDC) (3). Animal models and clinical studies support viral etiologies in the majority of cases, although specific infectious agents are documented in only a fraction of cases. Despite this inflammatory pathogenesis and scores of anecdotal series that suggest a therapeutic role for immunosuppression, controlled trials have consistently failed to demonstrate clinical benefit (4,5,6). Endomyocardial biopsy, once widely used for diagnosis, is currently not recommended for the majority of cases given the absence of specific biopsy-guided therapies (7). Giant-cell myocarditis remains one exception because biopsy confirmation of this aggressive disorder may assist in therapeutic decisions, including the consideration of immunosuppressive therapy (8). The potential future role for immune modulatory therapy is an intense area of investigation.

Primary idiopathic dilated cardiomyopathy is a leading cause of congestive heart failure in the United States, particularly among young people (9). Myocardial inflammation, or myocarditis, is postulated as the initiating cardiac injury, which subsequently progresses to ventricular dysfunction. Despite this hypothesis, signs of systemic inflammation are rarely seen at presentation with IDC. Although myocarditis is believed to be a frequent precursor of IDC (10), it is an often suspected but infrequently diagnosed disorder. The degree to which myocarditis and IDC represent distinct disorders versus separate time points in the same inflammatory progression is a matter of significant controversy. Over the last two decades, the search for mechanistic-based therapies for primary dilated cardiomyopathy has focused on the inflammatory pathogenesis.

Guided by introduction of the stethoscope by Laënnec, early-nineteenth-century clinicians divided cardiac disorders into valvular and nonvalvular (11). “Carditis” was a subset of nonvalvular disease that included vascular and inflammatory forms of cardiac dysfunction. The term carditis was gradually replaced by myocarditis, which continued for the remainder of the century to be a broad category of nonvalvular forms of myocardial dysfunction. In the early part of the twentieth century, coronary artery disease became recognized as an etiology for myocardial dysfunction distinct from myocardial inflammation, and the concept of “myocarditis” evolved to the modern application. By the mid-twentieth century, the search for infectious etiologies intensified, with increased recognition of the importance of viral pathogens (12,13,14). The introduction of transvenous endomyocardial biopsy (EMB) in the latter part of the twentieth century (15) heralded a new age of understanding for primary dilated cardiomyopathy in which an apparent heterogeneous group of disorders could now be divided into distinct pathologic subsets. With the widespread growth
in cardiac transplantation in the 1980s, it was recognized that the common form of cellular inflammation in native hearts, lymphocytic myocarditis, was histologically similar to cardiac allograft rejection. This supported a hypothesized autoimmune pathogenesis and led to a randomized clinical trial of immunosuppression, the Myocarditis Treatment Trial (MTT) (5). The clinical use of endomyocardial biopsy reached its zenith by the early 1990s and has subsequently declined in the absence of biopsy-guided therapeutic interventions. Molecular genetic techniques have recently been used to enhance the diagnostic power of endomyocardial biopsy (16). Systemic inflammatory mediators, including cytokines (1), chemokines (17), and autoantibodies (18), have been investigated as surrogate markers for cardiac inflammation.

With the increasing use of endomyocardial biopsy for diagnosis, the term myocarditis gradually became synonymous with left ventricular (LV) dysfunction with histologic evidence of cellular inflammation. As recently as 1995, the World Health Organization task force defined inflammatory cardiomyopathy as “myocarditis in association with myocardial dysfunction. Myocarditis is an inflammatory disease of the myocardium and is diagnosed by established histologic, immunologic, and immunohistochemical criteria” (19). Under current practice, endomyocardial biopsy data are not available for most subjects, and therefore reliance on strict histologic criteria is not practical. Myocarditis is commonly diagnosed as “suspected” inflammation of the myocardium; however, no clearly defined criteria exist. With this broadened clinical definition, the distinction between inflammatory myocarditis and recent onset IDC can become somewhat obscured (20,21,22).

Inflammatory cardiomyopathies can be subdivided into more distinct subsets based on the clinical setting of presentation (e.g., pregnancy) or diagnostic histopathology (Table 88.1). Among those patients with biopsy-proven inflammation, most have “lymphocytic myocarditis” based on lymphocyte predominance in the myocardial cellular infiltrates (23). An eosinophilic predominance can be seen in myocarditis associated with an allergic reaction or with peripheral eosinophilia (24,25,26,27). Lymphocytic myocarditis is seen in approximately 10% of biopsied patients (5), whereas 1% to 2% are diagnosed with giant-cell myocarditis, defined by the presence of multinucleated giant cells (28). The distinction between this disorder and lymphocytic myocarditis is critically important because giant-cell myocarditis is a much more aggressive pathologic process with a distinct natural history (8,28).

Myocarditis can also be seen as part of systemic autoimmune disorders such as sarcoidosis (29) and systemic lupus erythematosus (30). The histologic appearance of myocarditis in systemic disorders may be similar to that of the isolated viral myocarditis. The role of immunosupression is determined by the systemic illness because the myocardium will respond to treatment of the overall disorder. The granulomas of cardiac sarcoid in particular can be difficult to distinguish from those of its histologic mimic, giant-cell myocarditis (31). This distinction is critical because sarcoid is a less aggressive disorder and more likely to respond to corticosteroids.

The prevalence of primary idiopathic dilated cardiomyopathy has been estimated at 0.4 per 1,000, with an annual incidence of 0.08 per 1,000 (33). This corresponds to approximately 120,000 cases within the United States alone, with 24,000 new cases each year. The prevalence of histologic myocarditis varies widely in published series (Table 88.2) but can be best estimated from multicenter studies at 10% to 20% of patients with
new-onset IDC (5,6,34). The Myocarditis Treatment Trial (MTT) noted biopsies that were positive for inflammation in only 10% of 2,233 screened patients (5). In a similar fashion, the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases reported positive biopsies in 17.2% of the first 3,055 patients screened (34). Evidence of myocarditis may be found in 1% to 9% of routine autopsy cases (35,36,37) and up to 20% of those that are performed for unexplained sudden cardiac death in young people (38,39). The true prevalence of these subacute forms of myocarditis is difficult to determine because the majority of cases resolve with no long-term clinical sequelae (40).

The murine models of myocarditis initiated with the cardiotropic ribonucleic acid virus Coxsackie virus group B (41) or encephalomyocarditis virus (42) are the most extensively studied. After uptake by receptor-mediated endocytosis, viral proteins are translated, and replication of viral particles is initiated in the cytoplasm of the myocyte. Direct virally induced myocyte necrosis can be seen within 3 days, before any inflammatory infiltrates. Subsequently, macrophage activation leads to cytokine expression, including interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-α), and interferon-γ (10). Cytokine expression, particularly IL-2, results in the activation of natural killer (NK) cells (43). Endogenous interferons likely also play a direct role in limiting viral replication.

Within 7 days of viral inoculation, infiltrates of antigen-specific T lymphocytes are seen throughout the myocardium. These cells can be subclassed based on surface antigens and function into T-helper (CD4+) cells and cytotoxic T-lymphocyte (CD8+) cells (10, 44). Viral antigens are reduced to peptides and placed in the cell membrane of target cells bound to the major histocompatibility complex (MHC) for presentation to T-cell receptors. The recognition by cytotoxic T-lymphocyte receptors of viral peptide presented by MHC class I antigens initiates myocyte damage of virally infected cells (45). The induction of intracellular adhesion molecule-1 as well as MHC class I molecules by interferon-γ and TNF-α plays an important facilitator role (46).

Of the mononuclear cells in the myocardium, 10% to 20% are B lymphocytes (47). T cell–depleted murine strains inoculated with encephalomyocarditis virus have less myocardial damage and overall less severe myocarditis than do T cell–competent strains (48). In this model, viral titers, the development of neutralizing antibody titers, and viral clearing were similar in T cell–competent and T cell–depleted strains. Although it does not participate directly in cytotoxicity, B cell–mediated humoral mechanisms play an important role in the overall elimination of viral particles.

Approximately 15 days after viral inoculation, culturable virus is no longer detected. By 90 days after inoculation, inflammatory cell infiltrates are no longer seen; however, ventricular enlargement and myocardial fibrosis become prominent (49). This chronic postviral phase closely replicates the clinical presentation of patients with IDC. Viral nucleic acid can be detected by polymerase chain reaction in only a small percentage of mice at 90 days after inoculation (50) and, in a similar fashion, is only seen in a minority of patients with dilated cardiomyopathy (51,52,53). The absence of detectable virus for the majority of subjects (murine or human) has powered speculation that this phase of chronic insidious myocardial injury is driven by persistent autoimmune pathologic mechanisms.

Clinical studies of myocarditis suggest that a viral trigger initiates an immune pathogenesis. Enteroviruses, in particular Coxsackie B, are the most common viral agents (54). Adenovirus, influenza A and B, and hepatitis C have also been implicated as important viral pathogens (55,56) (Table 88.3). Human immunodeficiency virus (HIV) infection has been associated with myocarditis and dilated cardiomyopathy (57,58,59). Additional viral genomes, cytomegalovirus and adenovirus in particular, have also been detected in the myocardium of HIV-positive patients with lymphocytic myocarditis (60).

Chagas disease is caused by parasitism with the protozoa Trypanosoma cruzi and is endemic in parts of South America (61). Serologic epidemiology studies indicate that between 15 and 20 million people are infected in Central and South America, with more than 60 million people at risk (62). This disorder is not seen among U.S. patients in the absence of a significant travel history to endemic areas. Among immunocompromised hosts, myocarditis associated with Toxoplasma (63,64) or Aspergillus (65,66) has been reported, but generally only with signs of other systemic infestation and only rarely as an isolated myocarditis.

Noninfectious triggers can also initiate myocardial inflammation, as demonstrated by peripartum cardiomyopathy (PPCM), the syndrome of dilated cardiomyopathy that presents in the last month of pregnancy or in the first few months postpartum (67,68,69). This disorder is phenotypically similar to the virally initiated syndrome; however the initiating stimulus is likely fetal or placental antigen rather than viral peptides. Modulation of maternal immunity is an important aspect of fetal tolerance during routine pregnancy (70,71). Exacerbations of autoimmune disorders such as multiple sclerosis typically decline during pregnancy, with a subsequent rebound increase noted in the postpartum period (72). The period of autoimmune “rebound” phenomenon postpartum is also the most common time for women to present with PPCM. Lymphocytic infiltrations of the myocardium can be seen in this disorder (73), particularly in patients biopsied soon after delivery. Multiparity is frequently proposed as a risk factor (74), which suggests
that previous exposure to fetal paternal antigens facilitates the development of a pathologic immune response.

Toxins, namely alcohol and chemotherapeutic agents such as doxorubicin (75,76,77), can also initiate a progression to dilated cardiomyopathy. In contrast to the virally initiated and peripartum syndrome, these agents appear to act through direct myocardial toxicity. In these syndromes, myocardial inflammation may be more the result rather than the cause of myocardial injury. In addition, up to 25% of primary dilated cardiomyopathies may be familial in etiology (78). Responsible genetic loci have been delineated for several pedigrees and mutations identified in several cytoskeletal proteins, including dystrophin (79), cardiac actin (80), and the myosin heavy chain itself (81). Although inherited abnormalities of the inflammatory response may be important in some pedigrees (82,83,84,85), in general, the mechanism of cardiac dysfunction in familial cardiomyopathy appears quite distinct from that evident in the more common sporadic cases.

The histologic appearance of lymphocytic myocarditis is indistinguishable from acute allograft rejection in the transplanted heart (86), with a predominance of T lymphocytes. In murine models, whether the initial immune response is self-limited or results in progressive inflammation and cardiomyopathy is strain dependent (87), which supports a strong role of genetic background in determining outcome. Genetic susceptibility is equally important in clinical studies because human leukocyte antigen genotypes appear to confer an increased risk of the development of dilated cardiomyopathy (88). Perpetuation of myocardial inflammation appears to require an antigenic similarity of myocardial and viral peptides and a genetic “background” that facilitates the pathologic chronic immune response (89,90).

Cytokines play an important role in the progression of cardiomyopathy (91,92), and myocardial expression and plasma levels of TNF-α and IL-6 increase as functional status worsens (93,94). Expression of inflammatory mediators can elicit cellular infiltration of the myocardium and contribute to the decline in cardiac function. Myocardial cytokine expression plays a critical role in the progression of heart failure from the compensated to the end-stage phenotype.