ANTIBODY-MEDIATED IMBALANCE OF MYOCARDIAL ENERGY-METABOLISM - A CAUSAL FACTOR OF CARDIAC-FAILURE

The ADP-ATP carrier of the inner mitochondrial membrane is an autoanti gen in myocarditis and dilated cardiomyopathy. Sera of patients with t hese diseases contain carrier-specific autoantibodies that inhibit the transmembrane nucleotide transport on isolated mitochondria. Guinea p igs immunized with the isolated ADP-ATP carrier protein also generate specific carrier-inactivating antibodies. In this study, we measured t he cardiac function of guinea pigs immunized with the ADP-ATP carrier by determining the external heart work (EHW) of their isolated perfuse d spontaneously beating hearts stimulated by 4.0 mmol/L, calcium and a ortic ligature. Further, the electrogenic transport activity of the AD P-ATP carrier was estimated by calculating the cytosolic-mitochondrial difference of the phosphorylation potential of ATP [Delta G(cyt-mit)] in the freeze-clamped isolated hearts by nonaqueous fractionation. Th e EHW of immunized guinea pigs was seen to be reduced by 54% (P<.005) compared with nonimmunized control guinea pigs, and Delta G(cyt-mit) d eclined from 4.9 kJ/mol ATP in nonimmunized control hearts to 2.3 kJ/m ol ATP in the hearts of the immunized guinea pigs (P<.005). The decisi ve result of this study, however, is the close relation observed betwe en the magnitude of reduction of Delta G(cyt-mit) and the size of the decrease in EHW (r=.87). Therefore, it seems plausible that antibody-m ediated carrier dysfunction (creating the observed imbalance in myocar dial energy metabolism) is responsible for the impairment of cardiac f unction. Our data support the hypothesis that immunopathic mechanisms in myocarditis and dilated cardiomyopathy can trigger subsequent heart failure. The underlying pathophysiological reason seems to be a metab olic disorder initiated by the antibody-mediated inactivation of the A DP-ATP carrier.