Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance

Abstract

Dilated cardiomyopathy (DCM) is a relevant cause of heart failure and a common indication for heart transplantation. It may be idiopathic, familial/genetic, viral, autoimmune or immune‐mediated associated with a viral infection. Myocarditis is an inflammatory disease of the myocardium; it may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Thus, in a patient subset, myocarditis and DCM are thought to represent the acute and chronic stages of an organ‐specific autoimmune disease of the myocardium. In keeping with this hypothesis, autoimmune features in patients with myocarditis/DCM include: familial aggregation; a weak association with HLA‐DR4; abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy; and detection of organ‐ and disease‐specific cardiac autoantibodies of the IgG class in the sera of affected patients and symptom‐free relatives. The cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. Two of these, first identified using immunoblotting and confirmed by ELISA, are the atrial‐specific α‐ and the ventricular and skeletal muscle β‐heavy chain isoform. The α‐myosin isoform fulfils the expected criteria for organ‐specific autoimmunity, in that immunization with cardiac, but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of myocarditis/DCM; in addition, α‐myosin is entirely cardiac‐specific. Additional antigenic targets of heart‐reactive autoantibodies include unknown sarcolemmal proteins, mitochondrial enzymes, β‐adrenergic and muscarinic receptors. For some of these antibodies, there is in vitro evidence for a functional role. The organ‐specific cardiac autoantibodies detected by immunofluorescence in symptom‐free relatives were associated with echocardiographic features suggestive of early disease. Mid‐term follow‐up suggests that these antibodies are predictive markers of progression to DCM among symptom‐free relatives with or without abnormal echocardiographic findings.