Schulze K, Becker B F, Schauer R, Schultheiss H P
Department of Internal Medicine, University of Munich, FRG.
Circulation. 1990 Mar;81(3):959-69. doi: 10.1161/01.cir.81.3.959.
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 less than 0.005). The external heart work of the immunized hearts reached only about 20% 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.
线粒体内膜的二磷酸腺苷（ADP）-三磷酸腺苷（ATP）载体被确定为心肌炎和扩张型心肌病中的一种自身抗原。这些疾病患者的血清中含有针对ADP-ATP载体的自身抗体，该抗体在体外能够抑制核苷酸转运。最近，在用ADP-ATP载体免疫的豚鼠分离出的完整灌注心脏中，发现了与抗体相关的能量代谢损害。测量到ATP磷酸化电位的胞质-线粒体差异降低，这源于线粒体-胞质核苷酸转运的减少。尽管处于相似的代谢状态且心脏外部做功相同，但未免疫的动物并未出现这些能量代谢变化。为了确定针对ADP-ATP载体的抗体是否也能改变心脏功能，对预先用载体蛋白免疫的豚鼠分离心脏的血流动力学参数进行了测量。通过将心脏暴露于高钙浓度并同时使后负荷最大程度升高来刺激心脏代谢。发现平均主动脉压、每搏量、每搏功和心脏外部做功均显著降低（p小于0.005）。免疫心脏的外部做功仅达到对照心脏的约20%。心肌耗氧量降低了2.5倍，而乳酸生成量则增加了一倍多。这些结果表明，用ADP-ATP载体免疫的动物心脏的心脏功能降低。我们的研究结果表明，针对ADP-ATP载体的自身免疫可能通过在能量供应与需求失衡的基础上导致自身抗体介导的心脏功能降低，从而在心肌炎的后续阶段促成扩张型心肌病的病理生理学发展。
