Advertisement

Pathophysiology of cardiac hypertrophy and failure of human working myocardium: abnormalities in calcium handling

  • A. J. Meuse
  • C. L. Perreault
  • James P. Morgan

Summary

Abnormal intracellular calcium ([Ca2+]i) handling appears to be a major cause of both systolic and diastolic dysfunction in animals and human beings with hypertrophy and/or heart failure. We utilized the bioluminescent calcium indicator aequorin to examine the cyclical variations in intracellular calcium levels during isometric contractions. Studies of ventricular muscle from patients with end-stage heart failure exhibited three physiologic findings not seen in preparations taken from normal hearts including: 1) abnormalities in calcium handling; 2) deficient production of cyclic AMP; and 3) a reversed force-frequency relationship. These observations have important implications with regard to the pathogenesis and therapeutics of heart failure in man.

Key words

Calcium heart failure diastolic dysfunction systolic dysfunction 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Blinks JR (1986) Intracellular [Ca+ +] measurements. In: Fozzard HA, Haber E, Jennings RB (eds) The Heart and Cardiovascular System. New York Scientific Foundations, pp 671–701Google Scholar
  2. 2.
    Blinks Jr, Endoh M (1986) Modification of myofibillar responsiveness to Ca2+ as an inotropic mechanism. Circulation 76 (suppl III): 85Google Scholar
  3. 3.
    Blinks JR, Wier WG, Hess P, Prendergast FG (1982) Measurement of Ca2+ concentrations in living cells. Prog Biophys Mol Biol 40: 1PubMedCrossRefGoogle Scholar
  4. 4.
    Böhm M, Gierschik P, Jakobs KH, Pieske B, Schnabel P, Ungerer M, Erdmann E (1990) Increase in Galpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82: 1249–1265PubMedCrossRefGoogle Scholar
  5. 5.
    Brutsaert DL, Sys SU (1989) Relaxation and diastole of the heart. Physiol Rev 69: 1228–1315PubMedGoogle Scholar
  6. 6.
    Erdmann E, Böhm M (1989) Positive inotropic stimulation in the normal and insufficient human myocardium. Basic Res Cardiol 84: 125–133PubMedCrossRefGoogle Scholar
  7. 7.
    Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP (1987) Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75: 331–339PubMedCrossRefGoogle Scholar
  8. 8.
    Feldman MD, Gwathmey JK, Phillips P, Schoen F, Morgan JP (1988) Reversal of the force-frequency relationship in working myocardium from patients with end-stage heart failure. J Appl Cardiol 3: 272–283Google Scholar
  9. 9.
    Ginsburg R, Bristow MR, Billingham ME, Stinson EB, Schroeder JS, Harrison DC (1983) Study of the normal and failing isolated human heart: Decreased response of failing heart to isoproterenol. Am Heart J 3: 535–540Google Scholar
  10. 10.
    Grossman W, Lorell B (eds) (1988) Diastolic Relaxation of the Heart. Martinus Nijhoff, Boston pp. 1–305Google Scholar
  11. 11.
    Grossman W, McLaurin LP, Rolett EL (1979) Alterations in left ventricular relaxation and diastolic compliance in congestive cardiomyopathy. Cardiovasc Res 13: 514–52PubMedCrossRefGoogle Scholar
  12. 12.
    Gwathmey JK, Copelas L, Mackinnon R, Schoen FJ, Feldman MD, Grossman W, Morgan JP (1987) Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res 61: 70–76PubMedGoogle Scholar
  13. 13.
    Gwathmey JK, Morgan JP (1985) Altered calcium handling in experimental pressure- overload hypertrophy in the ferret. Circ Res 57: 836–843PubMedGoogle Scholar
  14. 14.
    Gwathmey JK, Morgan JP (1990) Calcium handling in myocardium from amphibian, avian and mammalian species: the search for two components. J Comp Physiol 161: 19–25Google Scholar
  15. 15.
    Gwathmey JK, Slawsky MT, Briggs GM, Morgan JP (1988) The role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium. J Clin Invest 82: 1592–1605PubMedCrossRefGoogle Scholar
  16. 16.
    Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP (1990) The role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest 85: 1599–1613PubMedCrossRefGoogle Scholar
  17. 17.
    Gwathmey JK, Warren SF, Briggs GM, Copelas L, Feldman MD, Phillips PJ, Callahan M Jr., Schoen FJ, Grossman W, Morgan JP (1991) Diastolic dysfunction in hyptertrophic cardiomyopathy: Effect on active force generation during systole. J Clin Invest 87: 1023–1031Google Scholar
  18. 18.
    Hajjar RJ, Gwathmey JK, Briggs GM, Morgan JP (1988) Differential effect of DPI 201-106 on the sensitivity of myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest 82: 1578–1584PubMedCrossRefGoogle Scholar
  19. 19.
    Hathaway DR, March KL (1989) Molecular cardiology: new avenues for the diagnosis and treatment of cardiovascular disease. J Am Coll Cardiol 13: 265–282PubMedCrossRefGoogle Scholar
  20. 20.
    Katz AM (1989) Changing strategies in the management of heart failure. J Am Coll Cardiol 13: 513–523PubMedCrossRefGoogle Scholar
  21. 21.
    Kihara Y, Grossman W, Morgan JP (1989) Direct Measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res 65: 1029–1044PubMedGoogle Scholar
  22. 22.
    Kihara Y, Morgan JP (1989) A comparative study of three methods for intracellular loading of the calcium indicator aequorin in ferret papillary muscles. Biochem Biophys Res Commun 162: 402–407PubMedCrossRefGoogle Scholar
  23. 23.
    Levine M, Meuse AJ, Watanabe J, Bentivegna L, Morgan JP (1990) Intracellular [Ca2+]f during ischemia in the blood perfused dog heart. Biophys J 57: 2: 173CrossRefGoogle Scholar
  24. 24.
    MacKinnon R, Gwathmey JK, Allen PD, Briggs GM, Morgan JP (1988) Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle. Circ Res 63: 1080–1089PubMedGoogle Scholar
  25. 25.
    Meuse AJ, Perreault CL, Grossman W, Morgan JP (1989) An experimental procedure for obtaining aequorin-loaded isolated mammalian cardiac myocytes. J Gen Physiol 94: 46Google Scholar
  26. 26.
    Morgan JP (1988) Intracellular calcium in heart failure. Cardiovasc Drugs Ther 1: 621–624PubMedCrossRefGoogle Scholar
  27. 27.
    Morgan JP (1989) Mechanism of action of inotropic drugs. In: Braunwald E (ed) Heart Disease Update. W.B. Saunders, Philadelphia, pp 136–144Google Scholar
  28. 28.
    Morgan JP, Bentivegna LA, Perreault CL, Meuse AJ, Allen PD, Ransil BJ, Grossman W, Gwathmey JK (1989) Molecular Biology of the Cardiovascular System. In: Roberts R, Sdineidej M (eds) UCLA Symposia on Molecular and Cellular Biology, New Series, Volume 131. Wiley Liss, New York, NY, pp 241–248Google Scholar
  29. 29.
    Morgan JP, Chesebro JH, Pluth JR, Puga FJ, Schaff HV (1984) Intracellular calcium transients in human working myocardium as detected with aequorin. J Am Coll Cardiol 3: 410–418PubMedCrossRefGoogle Scholar
  30. 30.
    Morgan JP, Erny RE, Allen PD, Grossman W, Gwathmey JK (1990) Abnormal intracellular calcium handling: A major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. Circulation 81 (Suppl III): 21–32Google Scholar
  31. 31.
    Morgan JP, Morgan KG (1984) Calcium and cardiovascular function: Intracellular calcium levels during contraction and relaxation of mammalian cardiac and vascular smooth muscle as detected with aequorin. Am J Med 77 (Suppl 5A): 33–46PubMedCrossRefGoogle Scholar
  32. 32.
    Morgan JP, Morgan KG (1989) Intracellular calcium and cardiovascular function in heart failure: effects of pharmacologic agents. Cardiovasc Drugs Ther 3 (Suppl 3): 959–970Google Scholar
  33. 33.
    Morgan JP, Perreault CL, Morgan KG (1991) The cellular basis of contraction and relaxation in cardiac and vascular smooth muscle. Am Heart J 121: 961–968PubMedCrossRefGoogle Scholar
  34. 34.
    Morgan JP, Wier WG, Hess P, Blinks JR (1983) Influence of Ca2 + channel blocking agents on calcium transients and tension development in isolated mammalian heart muscle. Circ Res 52 (Suppl I): 47–52Google Scholar
  35. 35.
    Näbauer M, Böhm M, Brown L, Diet F, Eichhorn MN, Kemkes B, Pieske B, Erdmann E (1988) Positive inotropic effects in isolated ventricular myocardium from non-failing and terminally failing human hearts. Eur J Clin Invest 18: 600–606PubMedCrossRefGoogle Scholar
  36. 36.
    Neumann J, Schmitz H, von Meyerinck L, Döring V, Kalmar P (1988) Increase in myocardial Gi-proteins in heart failure. Lancet 2: 936–946PubMedCrossRefGoogle Scholar
  37. 37.
    Perreault CL, Meuse AJ, Bentivegna L, Morgan JP (1990) Abnormal intracellular calcium handling in acute and chronic heart failure: Role in systolic and diastolic dysfunction. Eur Heart J 11: 8–21Google Scholar
  38. 38.
    Phillips PJ, Gwathmey JK, Feldman MD, Schoen FJ, Grossman W, Morgan JP (1990) Post-extrasystolic potentiation and the force-frequency relationship: Differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure. J Molec Cell Cardiol 22: 99–110Google Scholar
  39. 39.
    Poole-Wilson PA (1989) Relevance of the aetiology of heart failure to drug therapy. Eur Heart J 10 (Suppl B): 64–68PubMedGoogle Scholar
  40. 40.
    Rüegg JC (ed) (1988) Calcium in Muscle Activation. Springer, New York, pp 1–285Google Scholar
  41. 41.
    Shub C (1989) Heart failure and abnormal ventricular function. Pathophysiology and clinical correlation (Part 1). Chest 96: 636–640PubMedCrossRefGoogle Scholar
  42. 42.
    Shub C (1989) Heart failure and abnormal ventricular functiton. Pathophysiology and clinical correlation (Part 2). Chest 96: 906–914PubMedCrossRefGoogle Scholar
  43. 43.
    Swynghedauw B, Schwartz K, Lauer B, Lompre AM, Mercadier JJ, Samuel JL, Rappaport L (1988) Striated muscle overload. Eur Heart J 9(Suppl E):l–6Google Scholar
  44. 44.
    Warren SE, Hague NL, Morgan JP (1989) Normal intracellular calcium availability in the hypertrophic Syrian hamster. Clin Res 37: 305AGoogle Scholar
  45. 45.
    Wikman-Coffelt J, Steffanelli T, Wu ST, Parmley WW, Jasmin G (1991) Intracellular calcium transients in the cardiomyopathic hamster heart. Circ Res 68: 45–51PubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • A. J. Meuse
    • 1
  • C. L. Perreault
    • 1
    • 2
  • James P. Morgan
    • 1
    • 2
    • 3
  1. 1.Charles A. Dana Research Institute of the Harvard-Thorndike LaboratoryBeth Israel Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of Medicine (Cardiovascular Division)Beth Israel Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Cardiovascular DivisionBeth Israel HospitalBostonUSA

Personalised recommendations