We recently described autoantibodies to the ADP/ATP carrier of the inner mitochondrial membrane as an organ specific autoantigen found in high frequencies in sera of patients with myocarditis and dilated cardiomyopathy. These antibodies not only showed an intracellular binding at the mitochondrial membrane, but also crossreact with antigenic determinants at the cardiac myocyte plasma membrane. They therefore may account, at least in part, for the so-called sarcolemmal-bound IgG of heart-reactive autoantibodies found to be associated with these diseases. Heart muscle diseases are associated with electrocardiographic abnormalities such as complex ventricular arrhythmias and disturbed ventricular function. Our data indicate that abnormalities in current spread and impaired heart contractility might also be caused by an antibody mediated disturbance of calcium channel gating leading to prolongation of the action potential and potentiation of tension. The enhanced calcium permeability of the cell may moreover cause calcium overload and cell death. The calcium channel complex plays a central role in cardiac contractility. Disturbing calcium channel gating by antibodies might therefore contribute to the pathogenesis of these diseases.

Heart-reactive antibodies against cell surface and intracellular components have been described in myocarditis [1, 6, 12]. During recent years studies by our group have characterized the adenosine di-/triphosphate (ADP/ATP) carrier of the inner mitochondrial membrane as an autoantigen in myocarditis and dilated cardiomyopathy [14, 15, 18]. The ADP/ATP carrier is a highly specific transport system for the transfer of ATP to the cytosol with its energy-consuming processes and the return of ADP to the inner mitochondrial space for rephosphorylation [7]. Autoantibodies to the ADPI/ATP carrier were shown to be organ specific [15]. They inhibit the nucleotide transport not only in vitro [15, 18], but also in vivo [18, 20] (also Schultheiss et al., this volume).

Our study shows that antibodies, specific to the ADP/ATP carrier of the inner mitochondrial membrane, crossreact with the cell surface of cardiac myocytes, where the calcium channel seems to be the antigenic determinant. The antibodies enhanced the calcium current and suppressed its inactivation. Affinity-purified antibodies (IgG) exhibit an acute cytotoxic effect, which required extracellular calcium and was prevented by calcium channel blockers. Our findings suggest that antibody-mediated cytotoxicity results secondary to calcium overload caused by enhanced cellular calcium permeability, requiring no complement-dependent process.

Hi iv Contents Lyme borreliosis as a cause of myocarditis and heart muscle disease The possible value of synthetic peptides in the diagnosis and therapy of myocarditis and dilated cardiomyopathy Voltage-activated calcium channels comprise a group of similar yet distinct proteins or protein complexes that differ in electrophysiological properties, modulation by phosphorylation and GTP-binding proteins and in their relative sensitivity to organic calcium channel blockers. Cloning of the cDNA of L-type calcium channels from skeletal muscle, heart and smooth muscle opens the way to understanding the molecular basis of channel function and regulation and provides means of studying calcium channels in other tissues.