Anti-heart autoantibodies in familial dilated cardiomyopathy

Familial aggregation is a feature of myocarditis and dilated cardiomyopathy (DCM). Myocarditis, a clinically polymorphic inflammatory disease of the myocardium, is diagnosed by endomyocardial biopsy (EMB) and may lead to DCM. Mutations in several genes encoding myocyte structural proteins are known monogenic DCM causes, but because of high etiologic and genetic heterogeneity, the gene defects identified so far account for a minority of cases. In the last decade, it has been discovered that autoimmunity plays a pivotal role in myocarditis and DCM that are thought to represent different stages of an organ-specific autoimmune disease in genetically predisposed individuals. None of the available genetic studies in familial DCM has taken into account the autoimmune phenotype markers in the characterization of index patients and relatives, thus it is not known whether or not the described gene defects are involved in the autoimmune form of the disease. In animal models autoimmune myocarditis/DCM can be induced by viral infection, immunization with heart-specific autoantigens, or develop spontaneously in genetically predisposed strains. It may be cell or antibody-mediated; susceptibility is based upon multiple MHC and non-MHC genes. In patients, the diagnosis of autoimmune myocarditis/DCM requires exclusion of viral genome on EMB and detection of serum heart-reactive autoantibodies. They are found in index patients and relatives from about 60% of both familial and non-familial pedigrees and predict DCM development among healthy relatives. Some antibodies have functional effects on cardiac myocytes in vitro, in animal models and possibly in a DCM subset without inflammation, responsive to extracorporeal immunoadsorption. Cardiac-specific autoantibodies, which are shown to be disease-specific for myocarditis/DCM, can be used as biomarkers for identifying patients in whom, in the absence of active infection of the myocardium, immunosuppression and/or immunomodulation may be beneficial and their relatives at risk. Future studies should clarify genetic basis of human autoimmune myocarditis/DCM as well as genotype/immune phenotype correlations.