Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis.

Myocarditis and dilated cardiomyopathy may represent acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium. 1-3 Myocarditis is an inflammatory disease of the heart that is characterized by a cellular infiltrate in the myocardium, and dilated cardiomyopathy is a chronic heart muscle disease characterized by ventricular hypertrophy. 1-4 Dilated cardiomyopathy is a primary cause of severe heart failure with subsequent transplantation or death within several years after diagnosis. 1,5 The direct result of cellular infiltration of the myocardium is necrosis and loss of myocytes leading to the development of contractile dysfunction and ventricular dilatation. The loss of myocytes and formation of scar tissue in the myocardium would lead to loss of contractile function and ventricular enlargement. In a small percentage of individuals, loss of myocyte function and development of dilated cardiomyopathy can result from mutations in or viral proteolytic digestion of dystrophin or dystrophin-associated glycoproteins that lead to cytoskeletal disruption and loss of overall contractile function in the heart. 4,6-8 However, the most common cause of myocarditis is viral infection. An exhaustive list of myocarditis-inducing agents including microbial pathogens and toxins is provided by Brown and O’Connell 2 in a review of myocarditis and dilated cardiomyopathy. Among the most common viral causes of human myocarditis are coxsackieviruses. 2,9-11 Mouse models of coxsackievirus-induced myocarditis were studied by Woodruff and colleagues 12-14 who demonstrated that lymphocytes from mouse models of myocarditis could destroy cardiomyocytes in culture. Gauntt and colleagues 15 also investigated the role of virulent myocarditic versus nonvirulent amyocarditic coxsackieviruses in mouse models of myocarditis. In their studies, there appeared to be several stages of disease in their mouse model. The first early stage of viral replication and cell lysis in the heart showed no evidence of heart failure or cellular inflammation, however, with the onset of specific immune responses, cellular infiltration of the myocardium was observed in susceptible mice. The cellular infiltrates in the myocardium were minimal to severe and led to the loss of myocytes by necrosis. The development of dilated cardiomyopathy is thought to represent the third and more chronic stage of heart disease that develops after the cellular inflammation. 16 It would follow that once the damage has been done to the cardiomyocyte function either by elimination of large numbers of myocytes because of inflammation, necrosis, and scarring or by disruption of the cytoskeleton so that the myocyte is dysfunctional, then anti-inflammatory therapy would not be effective. Anti-inflammatory therapies would only be efficacious during the time of inflammatory onset. In fact, immunosuppressive therapy was not effective in the Myocarditis Trial. 2 By the time myocarditis symptoms present, many cases may have already advanced to a stage in which necrosis and scarring have already led to ventricular dilatation and contractile dysfunction. For comparison, in rheumatic carditis, the valve is insidiously and permanently damaged by autoimmune attack after streptococcal pharyngitis. In rheumatic carditis, valve injury may not be evident until a heart murmur is perceived that reflects the scarred valve. In myocarditis, the end-stage of disease may represent a physical, structural defect as a result of autoimmune-mediated damage during the inflammatory stage of the disease.