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Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure

  • M. B. CannellEmail author
  • D. J. Crossman
  • C. Soeller
Original Paper

Abstract

Using a Monte–Carlo model of L-type Ca2+ channel (DHPR) gating, we have examined the effect of changes in the early time course of the action potential as seen in human heart failure on excitation contraction coupling. The time course of DHPR Ca2+ influx was coupled into a simple model of sarcoplasmic reticulum Ca2+ release. Our model shows that the loss of the initial spike in human heart failure should reduce the synchrony of Ca2+ spark production and lead to the appearance of late Ca2+ sparks and greater non-uniformity of intracellular Ca2+. Within the junctional space of the cardiac dyad, a small increase in the mean distance of a DHPR from a RyR results in a marked decrease in the ability of the DHPR-mediated increase in local [Ca2+] concentration to activate RyRs. This suggests that the efficiency of EC coupling may be reduced if changes in micro-architecture develop and such effects have been noted in experimental models of heart failure. High resolution imaging of t-tubules in tachycardia-induced heart failure show deranged t-tubule structure. While in normal human hearts t-tubules run mainly in a radial direction, t-tubules in the heart failure samples were oriented more toward the long axis of the cell. In addition, t-tubules may become dilated and bifurcated. Our data suggest that changes in the micro-architecture of the cell and membrane structures associated with excitation–contraction coupling, combined with changes in early action potential configuration can reduce the efficiency by which Ca2+ influx via DHPRs can activate SR calcium release and cardiac contraction. While the underlying cause of these effects is unclear, our data suggest that geometric factors can play an important role in the pathophysilogy of the human heart in failure.

Keywords

Heart failure t-tubule Calcium Action potential EC coupling DHPR SR Human 

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Notes

Acknowledgement

This work was supported by the Auckland Medical Research Foundation and the Health Research Council of New Zealand.

References

  1. Antzelevitch C, Fish J (2001) Electrical heterogeneity within the ventricular wall. Basic Res Cardiol 96:517–527PubMedCrossRefGoogle Scholar
  2. Balijepalli RC, Lokuta AJ, Maertz NA, Buck JM, Haworth RA, Valdivia HH, Kamp TJ (2003) Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure. Cardiovasc Res 59(1): 67–77Google Scholar
  3. Barrans JD, Allen PD, Stamatiou D, Dzau VJ, Liew CC (2002) Global gene expression profiling of end-stage dilated cardiomyopathy using a human cardiovascular-based cDNA microarray. Am J Pathol 160:2035–2043PubMedGoogle Scholar
  4. Bers DM (2002) Cardiac excitation–contraction coupling. Nature 415:198–205PubMedCrossRefADSGoogle Scholar
  5. Beuckelmann DJ, Nabauer M, Erdmann E (1992) Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation 85:1046–1055PubMedGoogle Scholar
  6. Beuckelmann DJ, Nabauer M, Erdmann E (1993) Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res 73:379–385PubMedGoogle Scholar
  7. Birkeland JA, Sejersted OM, Taraldsen T, Sjaastad I (2005) EC-coupling in normal and failing hearts. Scand Cardiovasc J 39:13–23PubMedGoogle Scholar
  8. Bridge JH, Ershler PR, Cannell MB (1999) Properties of Ca2+ sparks evoked by action potentials in mouse ventricular myocytes. J Physiol 518:469–478PubMedCrossRefADSGoogle Scholar
  9. Cannell MB, Soeller C (1997) Numerical analysis of ryanodine receptor activation by L-type channel activity in the cardiac muscle diad. Biophys J 73:112–122PubMedGoogle Scholar
  10. Cannell MB, Soeller C (1998) Sparks of interest in cardiac excitation–contraction coupling. Trends Pharmacol Sci 19:16–20PubMedCrossRefGoogle Scholar
  11. Cannell MB, Cheng H, Lederer WJ (1994) Spatial non-uniformities in [Ca2+]i during excitation–contraction coupling in cardiac myocytes. Biophys J 67:1942–1956PubMedGoogle Scholar
  12. Cannell MB, Cheng H, Lederer WJ (1995) The control of calcium release in heart muscle. Science 268:1045–1049PubMedADSGoogle Scholar
  13. Chance EM, Curtis AR, Jones IP, Kirby CR (1977) FACSIMILE: a computer program for flow and chemistry simulation, and general initial value problems. Computer Science and systems division, AERE Harwell, Oxford. HMSO, London, UKGoogle Scholar
  14. Cheng H, Lederer WJ, Cannell MB (1993) Calcium sparks: elementary events underlying excitation–contraction coupling in heart muscle. Science 262:740–744PubMedADSGoogle Scholar
  15. Cheng H, Cannell MB, Lederer WJ (1994) Propagation of excitation–contraction coupling into ventricular myocytes. Pflugers Arch 428:415–417PubMedCrossRefGoogle Scholar
  16. Cheng H, Lederer MR, Lederer WJ, Cannell MB (1996) Calcium sparks and [Ca2+]i waves in cardiac myocytes. Am J Physiol 270:C148–C159PubMedGoogle Scholar
  17. Fabiato A (1985) Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 85:247–289PubMedCrossRefGoogle Scholar
  18. Gomez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ (1997) Defective excitation–contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276:800–806PubMedCrossRefGoogle Scholar
  19. Grantham CJ, Main MJ, Cannell MB (1994) Fluspirilene block of N-type calcium current in NGF-differentiated PC12 cells. Br J Pharmacol 111:483–488PubMedGoogle Scholar
  20. Hasenfuss G, Pieske B (2002) Calcium cycling in congestive heart failure. J Mol Cell Cardiol 34:951–969PubMedCrossRefGoogle Scholar
  21. He J, Conklin MW, Foell JD, Wolff MR, Haworth RA, Coronado R, Kamp TJ (2001) Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure. Cardiovasc Res 49:298–307PubMedCrossRefGoogle Scholar
  22. Hinch R (2004) A mathematical analysis of the generation and termination of calcium sparks. Biophys J 86:1293–1307PubMedGoogle Scholar
  23. Houser SR, Piacentino V 3rd, Mattiello J, Weisser J, Gaughan JP (2000) Functional properties of failing human ventricular myocytes. Trends Cardiovasc Med 10:101–107PubMedCrossRefGoogle Scholar
  24. Imredy JP, Yue DT (1994) Mechanism of Ca(2+)-sensitive inactivation of L-type Ca2+ channels. Neuron 12:1301–1318PubMedCrossRefGoogle Scholar
  25. Iyer V, Mazhari R, Winslow RL (2004) A computational model of the human left-ventricular epicardial myocyte. Biophys J 87:1507–1525PubMedCrossRefGoogle Scholar
  26. Kaab S, Dixon J, Duc J, Ashen D, Nabauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98:1383–1393PubMedGoogle Scholar
  27. Kostin S, Hein S, Arnon E, Scholz D, Schaper J (2000) The cytoskeleton and related proteins in the human failing heart. Heart Fail Rev 5:271–280PubMedCrossRefGoogle Scholar
  28. Kubo H, Margulies KB, Piacentino V 3rd, Gaughan JP, Houser SR (2001) Patients with end-stage congestive heart failure treated with beta-adrenergic receptor antagonists have improved ventricular myocyte calcium regulatory protein abundance. Circulation 104:1012–1018PubMedGoogle Scholar
  29. Lew WY, Hryshko LV, Bers DM (1991) Dihydropyridine receptors are primarily functional L-type calcium channels in rabbit ventricular myocytes. Circ Res 69:1139–1145PubMedGoogle Scholar
  30. Litwin SE, Zhang D, Bridge JH (2000) Dyssynchronous Ca(2+) sparks in myocytes from infarcted hearts. Circ Res 87:1040–1047PubMedGoogle Scholar
  31. Lopez-Lopez JR, Shacklock PS, Balke CW, Wier WG (1995) Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science 268:1042–1045PubMedADSGoogle Scholar
  32. Louch WE, Bito V, Heinzel FR, Macianskiene R, Vanhaecke J, Flameng W, Mubagwa K, Sipido KR (2004) Reduced synchrony of Ca2+ release with loss of T-tubules-a comparison to Ca2+ release in human failing cardiomyocytes. Cardiovasc Res 62:63–73PubMedCrossRefGoogle Scholar
  33. Maron BJ, Ferrans VJ, Roberts WC (1975) Ultrastructural features of degenerated cardiac muscle cells in patients with cardiac hypertrophy. Am J Pathol 79:387–434PubMedGoogle Scholar
  34. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel V(ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376PubMedCrossRefGoogle Scholar
  35. Nabauer M, Kaab S. (1998) Potassium channel down-regulation in heart failure. Cardiovasc Res 37:324–334PubMedCrossRefGoogle Scholar
  36. Norton GR, Woodiwiss AJ, Gaasch WH, Mela T, Chung ES, Aurigemma GP, Meyer TE (2002) Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction. J Am Coll Cardiol 39:664–671PubMedCrossRefGoogle Scholar
  37. Page E, McCallister LP (1973) Quantitative electron microscopic description of heart muscle cells. Application to normal, hypertrophied and thyroxin-stimulated hearts. Am J Cardiol 31:172–181PubMedCrossRefGoogle Scholar
  38. Page E, Surdyk-Droske M (1979) Distribution, surface density, and membrane area of diadic junctional contacts between plasma membrane and terminal cisterns in mammalian ventricle. Circ Res 45:260–267PubMedGoogle Scholar
  39. Piacentino V 3rd, Weber CR, Chen X, Weisser-Thomas J, Margulies KB, Bers DM, Houser SR (2003) Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res 92:651–658PubMedCrossRefGoogle Scholar
  40. Rodriguez P, Kranias EG (2005) Phospholamban: a key determinant of cardiac function and dysfunction. Arch Mal Coeur Vaiss 98:1239–1243PubMedGoogle Scholar
  41. Sah R, Ramirez RJ, Backx PH (2002) Modulation of Ca(2+) release in cardiac myocytes by changes in repolarization rate: role of phase-1 action potential repolarization in excitation–contraction coupling. Circ Res 90:165–173PubMedCrossRefGoogle Scholar
  42. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, Friedl A, Bleese N (1991) Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 83:504–514PubMedGoogle Scholar
  43. Shacklock PS, Wier WG, Balke CW (1995) Local Ca2+ transients (Ca2+ sparks) originate at transverse tubules in rat heart cells. J Physiol 487(Pt 3):601–608PubMedGoogle Scholar
  44. Shorofsky SR, Aggarwal R, Corretti M, Baffa JM, Strum JM, Al-Seikhan BA, Kobayashi YM, Jones LR, Wier WG, Balke CW (1999) Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks. Circ Res 84:424–434PubMedGoogle Scholar
  45. Smith GD, Keizer JE, Stern MD, Lederer WJ, Cheng H (1998) A simple numerical model of calcium spark formation and detection in cardiac myocytes. Biophys J 75:15–32PubMedGoogle Scholar
  46. Sobie EA, Dilly KW, dos Santos Cruz J, Lederer WJ, Jafri MS (2002) Termination of cardiac Ca(2+) sparks: an investigative mathematical model of calcium-induced calcium release. Biophys J 83:59–78PubMedGoogle Scholar
  47. Soeller C, Cannell MB (1997) Numerical simulation of local calcium movements during L-type calcium channel gating in the cardiac diad. Biophys J 73:97–111PubMedGoogle Scholar
  48. Song LS, Sobie EA, McCulle S, Lederer WJ, Balke CW, Cheng H (2006) Orphaned ryanodine receptors in the failing heart. Proc Natl Acad Sci USA 103:4305–4310PubMedCrossRefADSGoogle Scholar
  49. Stern MD (1992) Theory of excitation–contraction coupling in cardiac muscle. Biophys J 63:497–517PubMedCrossRefGoogle Scholar
  50. Stern MD, Pizarro G, Rios E (1997) Local control model of excitation–contraction coupling in skeletal muscle. J Gen Physiol 110:415–440PubMedCrossRefGoogle Scholar
  51. Tan FL, Moravec CS, Li J, Apperson-Hansen C, McCarthy PM, Young JB, Bond M (2002) The gene expression fingerprint of human heart failure. Proc Natl Acad Sci USA 99:11387–11392PubMedCrossRefADSGoogle Scholar
  52. Taur Y, Frishman WH (2005) The cardiac ryanodine receptor (RyR2) and its role in heart disease. Cardiol Rev 13:142–146PubMedCrossRefGoogle Scholar
  53. Tomaselli GF, Beuckelmann DJ, Calkins HG, Berger RD, Kessler PD, Lawrence JH, Kass D, Feldman AM, Marban E (1994) Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90:2534–2539PubMedGoogle Scholar
  54. Ward ML, Pope AJ, Loiselle DS, Cannell MB (2003) Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat hearts. J Physiol 546:537–550PubMedCrossRefGoogle Scholar
  55. Wickenden AD, Kaprielian R, Kassiri Z, Tsoporis JN, Tsushima R, Fishman GI, Backx PH (1998) The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure. Cardiovasc Res 37:312–323PubMedCrossRefGoogle Scholar
  56. Yano M, Yamamoto T, Ikeda Y, Matsuzaki M (2006) Mechanisms of disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat Clin Pract Cardiovasc Med 3:43–52PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medicine and Health SciencesUniversity of AucklandAucklandNew Zealand

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