Responsiveness of the myofilaments to Ca2+ in human heart failure: implications for Ca2+ and force regulation

  • R. J. Hajjar
  • W. Grossman
  • Judith K. Gwathmey
Conference paper


Myofilament calcium sensitivity and maximal calcium-activated force are fundamental properties of the contractile proteins in the heart. We examined these properties in normal human right-ventricular trabeculae carneae obtained from hearts of brain-dead patients with no known cardiac disease, and from patients with end-stage heart failure undergoing cardiac transplantation. There were no differences in calcium-activation of the control and myopathic muscles from chemically-skinned trabeculae or from intact tetanized preparations. We then tested the effect of DPI 201–106 (4-[3-(4-diphenylmethyl-l-piperazinyl)-2-hydroxypropoxy]-lH-indole-carbonitrile), a new inotropic agent, in both preparations. In myopathic muscles, 1 μM DPI sensitized the myofilaments to Ca2+, as evidenced by a significant shift of the [Ca2+]-force relationship towards lower [Ca2+], in both skinned and intact preparations. On the other hand, the same concentration of DPI did not affect the calcium-activation in control muscles in both preparations. We also found that the twitch [Ca2+]-force relationship, which has been used as an indication of myofilament sensitivity, was dissociated from the steady-state [Ca2+]-force relationship, and was shifted along the [Ca2+] axis by modulation in the time-course of the twitch and [Ca2+]i; and not by the sensitivity of the myofilaments to Ca2+. Protein kinase C stimulation differentially altered the responsiveness of the myofilaments to Ca2+ in normal and myopathic muscle fibers. We propose that even though calcium activation and maximal calcium-activated force are unaltered in myopathic hearts there are changes in thin filament regulation in myopathic hearts that result in altered responses to agents that directly act on the thin filaments, and that the potential for force development is similar in normal and myopathic human hearts.

Key words

Myofilaments calcium human protein kinase C cardiomyopathy 


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  1. 1.
    Alpert NR, Mulieri LA (1982) Increased myothermal economy of isometric force generation in compensated hypertrophy induced by pulmonary artery constriction in rabbit: A characterization of heat liberation in normal and hypertrophied right ventricular papillary muscles. Circ Res 50: 491–500Google Scholar
  2. 2.
    Anderson PAW, Oakley A, Allen PD (1989) Human troponin T expression in normal and end-stage heart failure patients. Circulation 80 (Suppl I I ): 503 (Abs)Google Scholar
  3. 3.
    Anderson PAW, Moore GE, Nassar RN (1988) Developmental changes in rabbit left ventricular troponin T. Circ Res 63: 742–747PubMedGoogle Scholar
  4. 4.
    Blinks JR, Wier WG, Hess P, Prendergast FG (1982) Measurement of Ca2+ concentrations in living cells. Prog Biophys Mol Biol 40: 1–114.PubMedCrossRefGoogle Scholar
  5. 5.
    Brandt PW, Cox RN, Kawai M, Robinson T (1982) Regulation of tension in skinned muscle fibers. J Gen Physiol 997–1016Google Scholar
  6. 6.
    Brenner B (1988) Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: Implications for regulation of muscle contraction. Proc Natl Acad Sci 85: 3265–3269PubMedCrossRefGoogle Scholar
  7. 7.
    Colucci WS, Wright RF, Braunwald E (1986) New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. First of two parts. New Engl J Med 314: 290–301Google Scholar
  8. 8.
    Colucci WS, Wright RF, Braunwald E (1986) New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. Second of two parts. New Engl J Med 314: 349–358Google Scholar
  9. 9.
    Dieckman LJ, Solaro RJ (1990) Effect of thyroid status on thin-filament Ca2+ regulation and expression of troponin I in perinatal and adult rat hearts. Circ Res 67: 344–351PubMedGoogle Scholar
  10. 10.
    Endo M, lino M (1980) Specific perforation of muscle cell membranes with preserved SR functions by saponin treatment. J Muscle Res Cell Motility 1: 89–100CrossRefGoogle Scholar
  11. 11.
    Fabiato A, Fabiato F (1979) Calculator programs for computing the compositions of the solutions containing multiple metals and ligands used for experiments in skinned muscle cells. J Physiol (Paris) 1979; 75: 463–505Google Scholar
  12. 12.
    Fabiato A (1981) Myoplasmic free calcium concentration reached during the twitch of an intact isolated cardiac cell and during calcium induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac cell from the adult rat or rabbit ventricle. J Gen Physiology 1981; 78: 457–497CrossRefGoogle Scholar
  13. 13.
    Feldman MD, Copelas L, Gwathmey JK, Phillips P, Warren SE, Schoen FJ, Grossman W, Morgan JP (1987) Deficient production of cyclic AMP: pharmocological evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75 (2): 331–339PubMedCrossRefGoogle Scholar
  14. 14.
    Gwathmey JK, Warren SE, Briggs GM, Copelas L, Feldman FD, Philips PJ, Callahan M, Schoen FJ, Grossman W, Morgan JP (1991) Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole. J Clin Invest 1991; 87: 1023–1031CrossRefGoogle Scholar
  15. 15.
    Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP (1990) Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest 85: 1599–1613PubMedCrossRefGoogle Scholar
  16. 16.
    Gwathmey JK, Hajjar RJ (1990) Intracellular calcium related to force development in twitch contraction of mammalian myocardium. Cell Calcium 11: 531–538PubMedCrossRefGoogle Scholar
  17. 17.
    Gwathmey JK, Hajjar RJ (1990) Relation between steady-state force and intracellular [Ca2+] in intact human myocardium: Index of myofibrillar response to Ca2+. Circulation 82: 1266–78PubMedCrossRefGoogle Scholar
  18. 18.
    Gwathmey JK, Copelas L, MacKinnon, Schoen F, Feldman M, Grossman W, Morgan JP (1987) Abnormal intracellular calcium handling in myocardium from patients with end- stage heart failure. Circ Res 61: 70–76PubMedGoogle Scholar
  19. 19.
    Gwathmey JK, Morgan JP (1985) Altered calcium handling in experimental pressure- overload hypertrophy in the ferret. Circ Res 57: 836–843PubMedGoogle Scholar
  20. 20.
    Hajjar RJ, Gwathmey JK (1991) Contractile dysfunction in failing human hearts: Role of cross-bridge interactions. Circulation 84: 447 (abstract)Google Scholar
  21. 21.
    Hajjar RJ, Gwathmey JK (1990) Modulation of calcium-activation in control and pressure-overload hypertrophied ferret hearts: Effect of DPI 201–106 on myofilament calcium responsiveness. J Mol Cell Cardiol 23: 65–75CrossRefGoogle Scholar
  22. 22.
    Hajjar RJ, Gwathmey JK, Briggs GM, Morgan JP (1988) Differential effect of DPI on the sensitivity of the myofilaments to Ca2+ in intact and skinned trabeculae from control and myopathic human hearts. J Clin Invest 82: 1578–1584PubMedCrossRefGoogle Scholar
  23. 23.
    Hasenfuss G, Mulieri LA, Blanchard EM, Holubarsch C, Leavitt BJ, Ittleman F, Alpert NR (1991) Energetics of isometric force development in control and volume-overload human myocardium. Circ Res 68: 836–846PubMedGoogle Scholar
  24. 24.
    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
  25. 25.
    Katoh N, Wise BC, Kuo JF (1983) Phosphorylation of cardiac troponin inhibitory subunit (Tnl) and tropomyosin-binding subunit (troponin T) by cardiac phospholipid-sensitive Ca2+-dependent protein kinase. Biochemistry 209: 189–195Google Scholar
  26. 26.
    Katz AM (1983) Physiology of the heart. Raven Press, 1983, New YorkGoogle Scholar
  27. 27.
    Katz AM (1990) Cardiomyopathy of overload: A major determinant of prognosis in congestive heart failure. N Eng J Med 322: 100–110CrossRefGoogle Scholar
  28. 28.
    Kitada Y, Narimatsu A, Matsumura N, Endo M (1987) Contractile proteins: Possible targets for the cardiotonic action of MCI-154, a novel cardiotonic agent? Eur J Pharm 134: 229–231CrossRefGoogle Scholar
  29. 29.
    Marban E, Kusuoka H (1987) Maximal Ca2+ -activated force and myofilament sensitivity in intact mammalian hearts. J Gen Physiology 90: 609–623CrossRefGoogle Scholar
  30. 30.
    Maughan D. Use of functionally skinned tissue in studying altered contractility in hypertrophied myocardium (1983) In: Alpert NR (ed) Perspectives in Cardiovascular Research, Vol. 7 Myocardial Hypertrophy and Failure. Raven Press, New York, pp 337–343Google Scholar
  31. 31.
    Mecardier JJ, Bouveret P, Gorga L, Schiaffino S, Clark WA, Zak R, Swynghedauw B, Schwartz K (1983) Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res 53: 52–62Google Scholar
  32. 32.
    Morano I, Bletz C, Wojciechowski R, Ruegg JC (1991) Modulation of cross-bridge kinetics by myosin isoenzymes in skinned human heart fibers. Circ Res 68: 614–618PubMedGoogle Scholar
  33. 33.
    Pagani ED, Alousi AA, Grant AM, Older TM, Dziuban SW, Allen PD (1988) Changes in myofibrillar content and Mg-ATPase activity in ventricular tissues from patients with heart failure caused by coronary artery disease, cardiomyopathy, or mitral valve insufficiency. Circ Res 63: 380–385PubMedGoogle Scholar
  34. 34.
    Perreault CL, Meuse A J, Bentivegna LA, Morgan JP (1990) Abnormal intracellular calcium handling in acute and chronic heart failure: role in systolic and diastolic dysfunction. Eur Heart J 11 (Suppl C): 8–21PubMedGoogle Scholar
  35. 35.
    Rüegg JC (1986) Effects of new inotropic agents on Ca2 + sensitivity of contractile proteins. Circulation 73 (suppl III): 78–84Google Scholar
  36. 36.
    Rüegg JC, Brewer S, Zeugner C, Trayer IP (1989) Peptides from the myosin heavy chain are calcium sensitizers of skinned skeletal muscle fibers. J Muscle Res Cell Motil 10: 152–162CrossRefGoogle Scholar
  37. 37.
    Salzmann R, Scholtysik G, Clark B, Berthod R (1986) Cardiovascular actions of DPI 201–106, a novel cardiotonic agent. J Cardiovasc Pharm 8: 1035–1043CrossRefGoogle Scholar
  38. 38.
    Scheuer J, Bhan AK (1979) Cardiac contractile proteins. Circulation Research 45: 1–12PubMedGoogle Scholar
  39. 39.
    Schier JJ, Adelstein RS (1982) Structural and enzymatic comparison of human cardiac muscle myosin isolated from infants, adults, and patients with hypertrophic cardiomyopathy. J Clin Invest 69: 816–825PubMedCrossRefGoogle Scholar
  40. 40.
    Scholtysik G, Salzmann R, Berthold R, Herzig JW, Quast U, Markstein R (1985) DPI 201–106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory effects. Arch Pharm 329: 316–325Google Scholar
  41. 41.
    Tobacman LS, Lee R (1987) Isolation and functional comparison of bovine cardiac troponin T isoforms. J Biol Chem 262 (9): 4059–64PubMedGoogle Scholar
  42. 42.
    Ventura-Clapier R, Mekhfi H, Olivero P, Swynghedauw B (1988) Pressure-overload changes cardiac skinned-fiber mechanics in rats, not in guinea pigs. Am J Physiol 254: H517–H524PubMedGoogle Scholar
  43. 43.
    Yue DT, Marban E, Wier WG (1986) Relationship between force and intracellular [Ca2+] in tetanized mammalian heart muscle. J Gen Physiol 17: 223–242CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • R. J. Hajjar
    • 1
    • 2
    • 3
    • 4
    • 5
  • W. Grossman
    • 1
    • 2
    • 3
    • 4
    • 5
  • Judith K. Gwathmey
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
  1. 1.Cardiovascular DivisionCharles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital BostonBostonUSA
  2. 2.Department of MedicineBeth Israel Hospital (WG, JKG)BostonUSA
  3. 3.Department of Cellular and Molecular Physiology (JKG)Medical ServicesBostonUSA
  4. 4.Massachusetts General Hospital (RJH)BostonUSA
  5. 5.Harvard Medical SchoolBostonUSA
  6. 6.Beth Israel HospitalBostonUSA

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