Dysfunction of the ADP/ATP carrier as a causative factor for the disturbance of the myocardial energy metabolism in dilated cardiomyopathy

  • H.-P. Schultheiss
Conference paper


The adenine nucleotide translocator (ADP/ATP carrier) plays a key role in nucleotide transport across the mitochondrial membrane. The quantity and function of this transport protein were investigated in myocardium from hearts with endstage failing dilated and ischemic cardiomyopathy, and were compared to measurements in nonfailing myocardium. In addition, lactate dehydrogenase (LDH) isoenzymes were determined. The concentration of the ADP/ATP carrier was significantly increased by 48% in myocardium from dilated cardiomyopathic hearts compared to control myocardium. The concentration of the carrier in explaitted hearts with ischemic cardiomyopathy did not differ from values in the normal human hearts. Analysis of carrier function revealed similar nucleotide exchange rates in control hearts and hearts with ischemic cardiomyopathy, whereas carrier function was reduced in most hearts with dilated cardiomyopathy. Compared to control hearts, in hearts with dilated cardiomyopathy and decreased nucleotide exchange rate, the carrier content was significantly higher, whereas the carrier content was only slightly increased compared to control in cardiomyopathic hearts with unchanged transport activity. Compared to control hearts, in dilated cardiomyopathy there was a significant increase in LDH5 and a decrease in LDH1 isoforms, indicating more anaerobic metabolism in failing dilated cardiomyopathic hearts.


ADP/ATP carrier mitochondria lactate dehydrogenase dilated cardiomyopathy nucleotide transport 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bashore TM, Magorien DJ, Letterio J, Shaffer P, Unverferth DV (1987) Histologic and biochemical correlates of left ventricular chamber dynamics in man. JACC 9: 734–742PubMedGoogle Scholar
  2. 2.
    Battini R, Ferrari S, Kaczmarek L, Calabretta B, Chen S, Baserga R (1987) J Biol Chem 262: 4355–4359PubMedGoogle Scholar
  3. 3.
    Bishop SP, Altschuld RA (1971) Evidence for increased glycolytic metabolism in cardiac hypertrophy and congestive heart failure. In: Alpert NA (ed). Cardiac Hypertrophy. New York: Academic Press pp 567–585Google Scholar
  4. 4.
    Everse J, Kaplan NO (1975) Mechanisms of action and biological functions of various dehydrogenase isoenzymes. In: Markert CL (ed). Isoenzymes. II. Physiological functions. New York: Academic pp 29–43Google Scholar
  5. 5.
    Houldsworth J, Attardi G (1988) Two distinct genes for ADP/ATP translocase are expressed at the mRNA level in adult human liver (cDNA library/Pex1 vector/HeLa cells/multiple mRNAs). Proc Natl Acad Sci 85: 377–381PubMedCrossRefGoogle Scholar
  6. 6.
    Ingwall JS, Kramer MF, Fifer MA, Lorell BH, Shemin R, Grossman W, Allen PD (1985) The creatine kinase system in normal and diseased human myocardium. N Engl J Med 313: 1050–1054PubMedCrossRefGoogle Scholar
  7. 7.
    Katz AM (1988) Cellular mechanisms in congestive heart failure. Am J Cardiol 62: 3A–8APubMedCrossRefGoogle Scholar
  8. 8.
    Katz AM (1990) Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med 322: 100–110PubMedCrossRefGoogle Scholar
  9. 9.
    Klingenberg M, Heidt HW (1982) The ADP/ATP translocation in mitochondria and its role in intracellular compartmentation. In: Sies H (ed). Metabolic Compartmentation. London: Academic Press pp 101–122Google Scholar
  10. 10.
    Klingenberg M (1985) The ADP/ATP carrier in mitochondrial membranes. In: Martonosi AN (ed). The Enzymes of Biological Membranes. Vol. 4. New York: Plenum Publishing pp 511–553Google Scholar
  11. 11.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with a folin phenol reagent. J Biol Chem 193: 265–275PubMedGoogle Scholar
  12. 12.
    Markert CL (1963) Lactate dehydrogenase isoenzymes: dissociation and re-combination of subunits. Science 140: 1329–1330PubMedCrossRefGoogle Scholar
  13. 13.
    Nadal-Ginard B, Markert CL (1975) Use of affinity chromatography for purification of lactate dehydrogenase and for assessing the homology and function of the A and B subunits. In:. Markert CL (ed). Isoenzymes. II. Physiological Functions. New York: Academic pp 45–67Google Scholar
  14. 14.
    Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC (1987) cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci 84: 7580–7584Google Scholar
  15. 15.
    Palmieri F, Klingenberg M (1979) Direct methods for measuring metabolite transport and distribution in mitochondria. In: Sydney F, Lester P (eds). Methods in Enzymology. Vol. 56. New York: Academic Press pp 279–301Google Scholar
  16. 16.
    Peters TJ, Wells G, Oakley CM, Brooksby I AB, Jenkins BS, Webb-People MM, Coltart DJ (1977) Enzymic analysis of endomyocardial biopsy specimens from patients with cardiomyopathies. Br Heart J 39: 1333–1338PubMedCrossRefGoogle Scholar
  17. 17.
    Schultheiss HP, Bispink G, Neuhofif V, Bolte HD (1981) Myocardial lactate dehydrogenase isoenzyme distribution in the normal heart. Basic Res Cardiol 76: 681–689PubMedCrossRefGoogle Scholar
  18. 18.
    Schultheiss HP, Klingenberg M (1984) Immunochemical characterization of the adenine nucleotide translocator: organ- and conformation specificity. Eur J Biochem 143: 599–605PubMedCrossRefGoogle Scholar
  19. 19.
    Schultheiss HP, Bolte HD (1985) Immunological analysis of auto-antibodies against the adenine nucleotide translocator in dilated cardiomyopathy. J Mol Cell Cardiol 17: 603–617PubMedCrossRefGoogle Scholar
  20. 20.
    Schultheiss HP, Klingenberg M (1985) Immunoelectrophoretic characterization of the ADP/ATP carrier from heart, kidney and liver. Arch Biochem Biophys 239: 273–279PubMedCrossRefGoogle Scholar
  21. 21.
    Schultheiss HP (1987) The mitochondrium as antigen in inflammatory heart disease. Eur Heart J 8: 203–210Google Scholar
  22. 22.
    Schultheiss HP (1989) The significance of autoantibodies against the ADP/ATP carrier for the pathogenesis of myocarditis and dilated cardiomyopathy - clinical and experimental data. Springer Semin Immunopathol 11: 15–30PubMedCrossRefGoogle Scholar
  23. 23.
    Schultheiss HP (1991) Disturbance of the myocardial energy metabolism in dilated cardiomyoapthy due to autoimmunological mechanisms. Circulation (in press)Google Scholar
  24. 24.
    Schulze K, Becker BF, Schultheiss HP (1989) Antibodies to the ADP/ATP carrier - an autoantigen in myocarditis and dilated cardiomyopathy - penetrate into myocardial cells and disturb energy metabolism in vivo. Circ Res 64: 179–192PubMedGoogle Scholar
  25. 25.
    Schulze K, Becker BF, Schauer R, Schultheiss HP (1990) Antibodies to the ADP/ATP carrier - an autoantigen in myocarditis and dilated cardiomyopathy - impair cardiac function. Circulation 81: 959–969PubMedCrossRefGoogle Scholar
  26. 26.
    Smith AD (1967) Preparation, properties and conditions for assay of mitochondria: slaughterhouse material, small scale. In: Sydney F, Lester P (eds). Methods in Enzymology. Vol. 10. New York: Academic Press pp 81–86Google Scholar
  27. 27.
    Unverferth DV, Magorien RD, Lewis RP, Leier CV (1983) The role of subendocardial ischemia in perpetuating myocardial failure in patients with nonischemic congestive cardiomyopathy. Am Heart J 105: 176–179PubMedCrossRefGoogle Scholar
  28. 28.
    Unverferth DV, Lee ShW, Wallick ET (1988) Human myocardial adenosine triphosphatase activities in health and heart failure. Am Heart J 115: 139PubMedCrossRefGoogle Scholar
  29. 29.
    Vatner SF (1988) Reduced subendocardial myocardial perfusion as one mechanism for congestive heart failure. Am J Cardiol 62: 94E–98EPubMedCrossRefGoogle Scholar
  30. 30.
    Weber KT, Janicki JS, Campbell C, Replogle R (1987) Pathophysiology of acute and chronic heart failure. Am J Cardiol 60: 3C–9CPubMedCrossRefGoogle Scholar
  31. 31.
    Weiss MB, Ellis K, Sciacca RR, Johnson LL, Schmidt DH, Cannon PJ (1976) Myocardial blood flow in congestive and hypertrophic cardiomyopathy. Relationship to peak wall stress and mean velocity of circumferential fiber shortening. Circulation 54: 884–494Google Scholar
  32. 32.
    Wendt VE, Stock TB, Hayden RO, Bruce TA, Gudbjarnason S, Bing RJ (1962) The hemodynamics and the cardiac metabolism in cardiomyopathy. Med Clin North Am 46: 1445–1469PubMedGoogle Scholar
  33. 33.
    Witzenbichler B, Christmann C, Schulze K, Schultheiss HP, Strauer BE (1991) Disturbance of the myocardial energy metabolism in A.SW/SN.J mice after viral infection with Coxsackie B3 virus. J Am Coll Cardiol 17: 264ACrossRefGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co.KG, Darmstadt 1992

Authors and Affiliations

  • H.-P. Schultheiss
    • 1
    • 2
  1. 1.Medical Clinic B, Dept. for Cardiology, Pneumology, and AngiologyHeinrich-Heine UniversityDüsseldorfGermany
  2. 2.Medizinische Klinik und Poliklinik B Abteilung für KardiologiePneumologie u. Angiologie Heinrich-Heine-Universität DüsseldorfDüsseldorf 1Germany

Personalised recommendations