Antibody-mediated imbalance of myocardial energy metabolism. A causal factor of cardiac failure?
The ADP-ATP carrier of the inner mitochondrial membrane is an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain carrier-specific autoantibodies that inhibit the transmembrane nucleotide transport on isolated mitochondria. Guinea pigs immunized with the isolated ADP-ATP carrier protein also generate specific carrier-inactivating antibodies. In this study, we measured the cardiac function of guinea pigs immunized with the ADP-ATP carrier by determining the external heart work (EHW) of their isolated perfused spontaneously beating hearts stimulated by 4.0 mmol/L calcium and aortic ligature. Further, the electrogenic transport activity of the ADP-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. The 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) declined from 4.9 kJ/mol ATP in nonimmunized control hearts to 2.3 kJ/mol ATP in the hearts of the immunized guinea pigs (P < .005). The decisive result of this study, however, is the close relation observed between 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-mediated carrier dysfunction (creating the observed imbalance in myocardial energy metabolism) is responsible for the impairment of cardiac function. Our data support the hypothesis that immunopathic mechanisms in myocarditis and dilated cardiomyopathy can trigger subsequent heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Schultheiss
H P
HP
Medizinische Klinik B, Heinrich-Heine Universität, Düsseldorf, Germany.
Schulze
K
K
Schauer
R
R
Witzenbichler
B
B
Strauer
B E
BE
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000502:physiology*; D002311:Cardiomyopathy, Dilated; D004734:Energy Metabolism; D005260:Female; D006168:Guinea Pigs; D006333:Heart Failure / Q000209:etiology*; D007114:Immunization; D000226:Mitochondrial ADP, ATP Translocases / Q000276:immunology*; D009205:Myocarditis / Q000150:complications; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion
D000906:Antibodies; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases