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. 2000 Dec;79(6):3095–3104. doi: 10.1016/S0006-3495(00)76544-1

Determinants of excitability in cardiac myocytes: mechanistic investigation of memory effect.

T J Hund 1, Y Rudy 1
PMCID: PMC1301186  PMID: 11106615

Abstract

The excitability of a cardiac cell depends upon many factors, including the rate and duration of pacing. Furthermore, cell excitability and its variability underlie many electrophysiological phenomena in the heart. In this study, we used a detailed mathematical model of the ventricular myocyte to investigate the determinants of excitability and gain insight into the mechanism by which excitability depends on the rate and duration of pacing (the memory effect). Results: i) The primary determinant of excitability depends upon the duration (T) of the stimulus. ii) For a short T, excitability is determined by the difference between the threshold membrane potential and the resting membrane potential. iii) For a long T, excitability is determined by the resting membrane resistance, R(m). iv) In the case of long T, pacing induced changes in [Na(+)](i) and [Ca(2+)](i) over time affect R(m) and excitability by shifting the current-voltage (IV) curve in the vertical direction and are responsible for the memory effect. CONCLUSIONS: The results have important implications during an arrhythmia, where a cardiac cell may be subjected to rapid repetitive excitation for an extended period of time. Effective anti-arrhythmic strategies may be developed to exploit the R(m) dependence of excitability for a long T.

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Selected References

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  1. Boyett M. R., Jewell B. R. Analysis of the effects of changes in rate and rhythm upon electrical activity in the heart. Prog Biophys Mol Biol. 1980;36(1):1–52. doi: 10.1016/0079-6107(81)90003-1. [DOI] [PubMed] [Google Scholar]
  2. Buchanan J. W., Jr, Saito T., Gettes L. S. The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting membrane potential changes on conduction velocity and dV/dtmax in guinea pig myocardium. Circ Res. 1985 May;56(5):696–703. doi: 10.1161/01.res.56.5.696. [DOI] [PubMed] [Google Scholar]
  3. Chialvo D. R., Michaels D. C., Jalife J. Supernormal excitability as a mechanism of chaotic dynamics of activation in cardiac Purkinje fibers. Circ Res. 1990 Feb;66(2):525–545. doi: 10.1161/01.res.66.2.525. [DOI] [PubMed] [Google Scholar]
  4. Damiano B. P., Rosen M. R. Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation. 1984 May;69(5):1013–1025. doi: 10.1161/01.cir.69.5.1013. [DOI] [PubMed] [Google Scholar]
  5. Davidenko J. M., Levi R. J., Maid G., Elizari M. V., Rosenbaum M. B. Rate dependence and supernormality in excitability of guinea pig papillary muscle. Am J Physiol. 1990 Aug;259(2 Pt 2):H290–H299. doi: 10.1152/ajpheart.1990.259.2.H290. [DOI] [PubMed] [Google Scholar]
  6. Dominguez G., Fozzard H. A. Influence of extracellular K+ concentration on cable properties and excitability of sheep cardiac Purkinje fibers. Circ Res. 1970 May;26(5):565–574. doi: 10.1161/01.res.26.5.565. [DOI] [PubMed] [Google Scholar]
  7. Faber G. M., Rudy Y. Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys J. 2000 May;78(5):2392–2404. doi: 10.1016/S0006-3495(00)76783-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fast V. G., Kléber A. G. Role of wavefront curvature in propagation of cardiac impulse. Cardiovasc Res. 1997 Feb;33(2):258–271. doi: 10.1016/s0008-6363(96)00216-7. [DOI] [PubMed] [Google Scholar]
  9. Girouard S. D., Pastore J. M., Laurita K. R., Gregory K. W., Rosenbaum D. S. Optical mapping in a new guinea pig model of ventricular tachycardia reveals mechanisms for multiple wavelengths in a single reentrant circuit. Circulation. 1996 Feb 1;93(3):603–613. doi: 10.1161/01.cir.93.3.603. [DOI] [PubMed] [Google Scholar]
  10. Kucera J. P., Kléber A. G., Rohr S. Slow conduction in cardiac tissue, II: effects of branching tissue geometry. Circ Res. 1998 Oct 19;83(8):795–805. doi: 10.1161/01.res.83.8.795. [DOI] [PubMed] [Google Scholar]
  11. Luke R. A., Saffitz J. E. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991 May;87(5):1594–1602. doi: 10.1172/JCI115173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Luo C. H., Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res. 1994 Jun;74(6):1071–1096. doi: 10.1161/01.res.74.6.1071. [DOI] [PubMed] [Google Scholar]
  13. Luo C. H., Rudy Y. A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. Circ Res. 1994 Jun;74(6):1097–1113. doi: 10.1161/01.res.74.6.1097. [DOI] [PubMed] [Google Scholar]
  14. Luo C. H., Rudy Y. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. Circ Res. 1991 Jun;68(6):1501–1526. doi: 10.1161/01.res.68.6.1501. [DOI] [PubMed] [Google Scholar]
  15. Marban E., Robinson S. W., Wier W. G. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest. 1986 Nov;78(5):1185–1192. doi: 10.1172/JCI112701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nattel S. Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation. Cardiovasc Res. 1999 May;42(2):298–308. doi: 10.1016/s0008-6363(99)00022-x. [DOI] [PubMed] [Google Scholar]
  17. Noble D., Stein R. B. The threshold conditions for initiation of action potentials by excitable cells. J Physiol. 1966 Nov;187(1):129–162. doi: 10.1113/jphysiol.1966.sp008079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Peon J., Ferrier G. R., Moe G. K. The relationship of excitability to conduction velocity in canine Purkinje tissue. Circ Res. 1978 Jul;43(1):125–135. doi: 10.1161/01.res.43.1.125. [DOI] [PubMed] [Google Scholar]
  19. Peters N. S., Coromilas J., Hanna M. S., Josephson M. E., Costeas C., Wit A. L. Characteristics of the temporal and spatial excitable gap in anisotropic reentrant circuits causing sustained ventricular tachycardia. Circ Res. 1998 Feb 9;82(2):279–293. doi: 10.1161/01.res.82.2.279. [DOI] [PubMed] [Google Scholar]
  20. Ravens U., Himmel H. M. Drugs preventing Na+ and Ca2+ overload. Pharmacol Res. 1999 Mar;39(3):167–174. doi: 10.1006/phrs.1998.0416. [DOI] [PubMed] [Google Scholar]
  21. Rohr S., Kucera J. P., Kléber A. G. Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circ Res. 1998 Oct 19;83(8):781–794. doi: 10.1161/01.res.83.8.781. [DOI] [PubMed] [Google Scholar]
  22. Rosen M. R., Cohen I. S., Danilo P., Jr, Steinberg S. F. The heart remembers. Cardiovasc Res. 1998 Dec;40(3):469–482. doi: 10.1016/s0008-6363(98)00208-9. [DOI] [PubMed] [Google Scholar]
  23. Rosenbaum M. B., Blanco H. H., Elizari M. V., Lázzari J. O., Davidenko J. M. Electrotonic modulation of the T wave and cardiac memory. Am J Cardiol. 1982 Aug;50(2):213–222. doi: 10.1016/0002-9149(82)90169-2. [DOI] [PubMed] [Google Scholar]
  24. Shaw R. M., Rudy Y. Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure. Circ Res. 1997 Jan;80(1):124–138. doi: 10.1161/01.res.80.1.124. [DOI] [PubMed] [Google Scholar]
  25. Shaw R. M., Rudy Y. Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration. Cardiovasc Res. 1997 Aug;35(2):256–272. doi: 10.1016/s0008-6363(97)00093-x. [DOI] [PubMed] [Google Scholar]
  26. Shaw R. M., Rudy Y. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ Res. 1997 Nov;81(5):727–741. doi: 10.1161/01.res.81.5.727. [DOI] [PubMed] [Google Scholar]
  27. Smith J. H., Green C. R., Peters N. S., Rothery S., Severs N. J. Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol. 1991 Oct;139(4):801–821. [PMC free article] [PubMed] [Google Scholar]
  28. Spach M. S., Dolber P. C. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res. 1986 Mar;58(3):356–371. doi: 10.1161/01.res.58.3.356. [DOI] [PubMed] [Google Scholar]
  29. Spear J. F., Moore E. N. Supernormal excitability and conduction in the His-Purkinje system of the dog. Circ Res. 1974 Nov;35(5):782–792. doi: 10.1161/01.res.35.5.782. [DOI] [PubMed] [Google Scholar]
  30. Ursell P. C., Gardner P. I., Albala A., Fenoglio J. J., Jr, Wit A. L. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res. 1985 Mar;56(3):436–451. doi: 10.1161/01.res.56.3.436. [DOI] [PubMed] [Google Scholar]
  31. Viswanathan P. C., Shaw R. M., Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation. 1999 May 11;99(18):2466–2474. doi: 10.1161/01.cir.99.18.2466. [DOI] [PubMed] [Google Scholar]
  32. WEIDMANN S. The electrical constants of Purkinje fibres. J Physiol. 1952 Nov;118(3):348–360. doi: 10.1113/jphysiol.1952.sp004799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wang Y., Rudy Y. Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1019–H1029. doi: 10.1152/ajpheart.2000.278.4.H1019. [DOI] [PubMed] [Google Scholar]
  34. Zeng J., Laurita K. R., Rosenbaum D. S., Rudy Y. Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization. Circ Res. 1995 Jul;77(1):140–152. doi: 10.1161/01.res.77.1.140. [DOI] [PubMed] [Google Scholar]
  35. Zeng J., Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J. 1995 Mar;68(3):949–964. doi: 10.1016/S0006-3495(95)80271-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

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