Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function.

Abstract

The adenosine diphosphate (ADP)-adenosine triphosphate (ATP) carrier of the inner mitochondrial membrane is identified as an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain autoantibodies to the ADP-ATP carrier capable of inhibiting nucleotide transport in vitro. Recently, an antibody-related infringement of energy metabolism was shown in intact perfused hearts isolated from guinea pigs immunized with the ADP-ATP carrier. A decreased cytosolic-mitochondrial difference of the phosphorylation potential of ATP was measured that originated from a reduction in mitochondrial-cytosolic nucleotide transport. Nonimmunized animals did not show these changes in energy metabolism, despite being in a comparable metabolic state and performing equal external heart work. To establish whether antibodies to the ADP-ATP carrier can also alter cardiac function, hemodynamic parameters of isolated hearts of guinea pigs that were preimmunized with the carrier protein were measured. Cardiac metabolism was stimulated by exposing the hearts to a high calcium concentration in conjunction with a maximum elevation of the afterload. Mean aortic pressure, stroke volume, stroke work, and external heart work were found to be lowered significantly (p<0.005). The external heart work of the immunized hearts reached only about 201% of the level performed by control hearts. Myocardial oxygen consumption was lowered 2.5-fold, whereas the extent of lactate production was found to be more than doubled. These results show a diminished cardiac performance of hearts from animals immunized with the ADP-ATP carrier. Our findings demonstrate that autoimmunity to the ADP-ATP carrier may contribute to the pathophysiology of dilated cardiomyopathy as a subsequent stage of myocarditis by causing an autoantibody-mediated reduction in cardiac function on the basis of an imbalance between energy delivery and demand. (Circulation 1990;81:959-969 of the animals were measured. While mitochondrial ATP and cytosolic ADP levels were raised, mitochondrial ADP and cytosolic ATP levels declined. As a consequence, the mitochondrial value of the phosphorylation potential of ATP was markedly higher and the cytosolic value was lower than in the hearts of nonimmunized control animals.7 These data indicate that the autoantibodies found in patients with myocarditis and dilated cardiomyopathy may not be merely an epiphenomenon. Furthermore, our results provide first evidence for a possible novel mechanism of an immunologically mediated dysfunction of the myocardial cell, namely, due to energy deficiency. The present study was designed to consider whether this observed disturbance in myocardial energy metabolism also leads to an alteration of myocardial function. Methods Isolation of the ADP-ATP CarrierBeef heart mitochondria were isolated as described by Smith.8 The solubilization and isolation of the ADP-ATP carrier followed the procedure previously described.9-12 The bovine and the guinea pig antigen are equally suited for immun...

Myopathy with mitochondrial alterations in patients with primary biliary cirrhosis and antimitochondrial antibodies

“…In certain patients with idiopathic dilated cardiomyopathies, autoantibodies directed against carrier proteins located on the inner mitochondrial membrane can inhibit the transport function of these enzymes and may contribute to the pathogenesis of cardiac dysfunction (29,30). Both patients in the present study had evidence of severe dilated cardiomyopathy .…”

Defective circulating CD4+LAP+ regulatory T cells in patients with dilated cardiomyopathy

“…In animal models, in vivo induced by mucosal administration of anti-CD3 antibody [20,[23][24][25][26][27] or soluble antigen [21,22] or adoptive-transferred [24] CD4 + LAP + T regs could suppress several autoimmune There is compelling evidence that inflammation and autoimmune abnormalities play important roles in the development and progression of DCM [2,3]. Circulating abnormal T cell activation and autoantibodies of the IgG3 class against diverse myocardial antigens have been identified in patients with DCM and are thought to play a causative role in the pathogenesis of DCM [4][5][6][7][8][9][10]. Therefore, we deduced that CD4 + LAP + T regs fail to suppress autoimmunity efficiently in DCM as a result of defects in the number and suppressive function.…”

Identification of Autoantibodies With the Corresponding Antigen for Repetitive Coxsackievirus Infection-Induced Cardiomyopathy

“…13 Dorffel et al demonstrated that the extraction of autoimmunoreactive antibodies by immunoadsorption results in a functional improvement in hemodynamics in DCM patients. 14 Those authors have proven indirectly that autoantibodies against the ADP-ATP carrier, 15 contractile proteins of cardiomyocytes, and the cardiac 1-adrenergic receptor 16,17 contribute to cardiac malfunction in DCM. They proposed that the immunoadsorption may be an additional therapeutic possibility for the acute hemodynamic stabilization of patients with severe DCM.…”