Skip to main content
Log in

Pharmacological Modification of the Dispersion of Repolarization in the Heart: Importance of the M Cells

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Summary. Several in vitro and in vivo investigations have provided data supporting the existence of M cells in the deep subepicardial layers of the ventricles in a number of species. Characterized by unique electrophysiological and pharmacological features, this population of cells is regarded to have a significant role in creating dispersion of repolarization in the ventricular wall and thus contribute importantly to arrhythmogenesis, in particular to intramural reentry and triggered activity. Focusing on M cells, the authors summarize recent findings and concepts concerning the pharmacological heterogeneity of different cell and tissue types found within the ventricles and explore how these differences may contribute to electrocardiographic manifestations. On the basis of literarary data and of their own results they conclude that studying the electrical and pharmacological inhomogeneity within the ventricular wall may provide a better understanding of the pathophysiological processes that give rise to cardiac rhythm disturbances and the mechanisms by which antiarrhythmic agents act to suppress and in some cases aggravate arrhythmias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: Electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res 1991;69:1427–1449.

    Google Scholar 

  2. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: The role of M cells in the generations of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 1994;23:259–277.

    Google Scholar 

  3. Gilmour RF, Zipes DP. Different electrophysiological responses of canine endocardium and epicardium to combined hyperkalemia, hypoxia, and acidosis. Circ Res 1980;46:814–825.

    Google Scholar 

  4. Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res 1988;62:116–126.

    Google Scholar 

  5. Litovsky SH, Antzelevitch C. Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circ Res 1990;67:615–627.

    Google Scholar 

  6. Krishnan SC, Antzelevitch C. Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. Circ Res 1991;69:277–291.

    Google Scholar 

  7. Fedida D, Giles WR. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol (Lond) 1991;442:191–206.

    Google Scholar 

  8. Furukawa T, Kimura S, Cuevas J, et al. Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia. Circ Res 1991;68:1693–1702.

    Google Scholar 

  9. Furukawa T, Kimura S, Furukawa N, Bassett AL, Myerburg RJ. Potassium rectifier currents differ in myocytes of endocardial and epicardial origin. Circ Res 1992;70:91–103.

    Google Scholar 

  10. Tande PM, Mortensen E, Refsum H. Rate-dependent differences in dog epi-and endocardial monophasic action potential configuration in vivo. Am J Physiol 1991;261:H1387–1391.

    Google Scholar 

  11. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophysiologic properties in the deep subepicardium of the canine ventricle: the M cell. Circ Res 1991;68:1729–1741.

    Google Scholar 

  12. Sicouri S, Antzelevitch C. Afterdepolarizations and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: The effects of acetylstrophantidin and Bay K 8644. PACE 1991;14:1714–1720.

    Google Scholar 

  13. Sicouri S, Antzelevitch C. Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol 1993;4:48–58.

    Google Scholar 

  14. Sicouri S, Moro S, Elizari MV. d-Sotalol induces marked action potential prolongation and early afterdepolarizations in M but not epicardial or endocardial cells of the canine ventricle. J Cardiovasc Pharmacol Therapeut 1997;2(I):27–38.

    Google Scholar 

  15. Sicouri S, Antzelevitch D, Heilmann C, Antzelevitch C. Effects of sodium channel block with mexiletine to reverse action potential prolongation in in vitro models of the long QT syndrome. J Cardiovasc Electrophysiol 1997;8:1280–1290.

    Google Scholar 

  16. Sicouri S, Moro S, Litovsky S, Elizari M, Antzelevitch C. Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart. J Cardiovasc Electrophysiol 1997;8:1269–1279.

    Google Scholar 

  17. Sicouri S, Fish J, Antzelevitch C. Distribution of M cells in the canine ventricle. J Cardiovasc Electrophysiol 1994;5:824–837.

    Google Scholar 

  18. Sicouri S, Quist M, Antzelevitch C. Evidence for the presence of M cells in the guinea pig ventricle. J Cardiovasc Electrophysiol 1996;7:503–511.

    Google Scholar 

  19. Weirich J, Bernhardt R, Loewen N, Wenzel W, Antoni H. Regional-and species-dependent effects of K+-channel blocking agents on subendocardium and mid-wall slices of human, rabbit, and guinea pig myocardium. Pflugers Arch 1996;431:R130 (Abstract).

    Google Scholar 

  20. Drouin E, Charpentier F, Gauthier C, Laurent K, Le Marec H. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. J Am Coll Cardiol 1995;26:185–192.

    Google Scholar 

  21. Rodriguez-Sinovas A, Cinca J, Tapias A, Armadans L, Tresanchez M, Soler-Soler J. Lack of evidence of M cells in porcine left ventricular myocardium. Cardiovasc Res 1997;33:307–313.

    Google Scholar 

  22. Antzelevitch C. The M cell. Invited editorial comment. J Cardiovasc Pharmacol Therapeut 1997;2(I):73–76.

    Google Scholar 

  23. Liu DW, Gintant GA., Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of canine left ventricle. Circ Res 1993;72:671–687.

    Google Scholar 

  24. Baláti B, Varró A, Papp JGy. Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres. Acta Physiol Scand 1998;164:181–190.

    Google Scholar 

  25. Yan GX, Shimizu W, Antzelevitch C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation 1998;98:1921–1927.

    Google Scholar 

  26. Wang Y, Robert J, Hariman RJ, et al. A method for recording of intramyocardial monophasic action potential in intact dogs: in vivo evidence of M cells. PACE 1992;15:559 (Abstract).

    Google Scholar 

  27. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes: A weaker IKs contributes to the longer action potential of the M cell. Circ Res 1995;76:351–365.

    Google Scholar 

  28. Eddlestone GT, Zygmunt AC, Antzelevitch C. Larger late sodium current contributes to the longer action potential of the M cell in canine ventricular myocardium. PACE 1996;19:II-569 (Abstract).

    Google Scholar 

  29. Antzelevitch C, Davidenko JM, Sicouri S, et al. Quinidine-induced early afterdepolarizations and triggered activity. J Electrophysiol 1989;5:323–338.

    Google Scholar 

  30. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996;93:372–379.

    Google Scholar 

  31. Chauhan VS, Skanes AC, Tang ASL. Dynamics and dispersion of QT intervals: Q-wave versus non Q-wave myocardial infarction. Circulation 1996;94:I-433 (Abstract).

    Google Scholar 

  32. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX. Cellular and ionic mechanisms underlying erythromycin-induced long QT and torsade de pointes. J Am Coll Cardiol 1996;28:1836–1848.

    Google Scholar 

  33. Rose J, Winslow R, Jafri S, Marban E, Tomaselli GF. Role of Ito in determining action potential duration in rabbit ventricular myocytes. Circulation 1998;(Suppl I):648 [Abstract].

    Google Scholar 

  34. Davidenko JM, Cohen L, Goodraw R, Antzelevitch C. Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers: Effects of stimulation rate, potassium and magnesium. Circ 1989;79:674–686.

    Google Scholar 

  35. January CT, Moscucci A. Cellular mechanisms of early afterdepolarizations. Ann NY Acad Sci 1992;644:23–31.

    Google Scholar 

  36. Zeng J, Rudy Y. Early afterdepolarizations in cardiac myocytes: Mechanisms and rate-dependence. Biophys J 1995;68:949–964.

    Google Scholar 

  37. Burashnikov A, Antzelevich C. Mechanisms underlying early afterdepolarization activity are different in canine Purkinje and M cell preparations. Role of intracellular calcium. Circulation 1996;94:I-527 (Abstract).

    Google Scholar 

  38. Nattel S, Quantz MA. Pharmacological response of quinidine induced early afterdepolarizations in canine cardiac Purkinje fibres: Insights into underlying ionic mechanisms. Cardiovasc Res 1988;22:808–817.

    Google Scholar 

  39. Tan HL, Hou CJY, Lauer MR, Sung RJ. Electrophysiologic mechanisms of the Long QT Interval Syndromes and Torsade de Pointes. Ann Intern Med 1995;122:701–714.

    Google Scholar 

  40. Stramba-Badiale M, Nador F, Porta N, et al. QT interval prolongation and risk of life-threatening arrhythmias during toxoplasmosis prophylaxis with spiramycin in neonates. Am Heart J 1997;133:108–111.

    Google Scholar 

  41. El-Sherif N, Zeiler RH, Craelius W, Gongh WB, Henkin R. QTU prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations: Afterdepolarizations and ventricular arrhythmias. Circ Res 1988;63:286–305.

    Google Scholar 

  42. Egan TM, Noble D, Noble SJ, Powell T, Spindler AJ, Twist VW. Sodium-calcium exchange during the action potential in guinea-pig ventricular cells. J Physiol 1989;411:639–661.

    Google Scholar 

  43. Feld GK, Venkatesh N, Singh BN. Pharmacologic conversion and suppression of experimental canine atrial flutter: Differing effects of d-sotalol, quinidine, and lidocaine and significance of changes in refractoriness and conduction. Circulation 1986;74:197–204.

    Google Scholar 

  44. Woosley RL, Barbey JT, Wang T, Func-Brentano C. Concentration/response relations for the multiple antiarrhythmic actions of sotalol. Am J Cardiol 1990;65:22A–27A.

    Google Scholar 

  45. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1996;92:1517–1525.

    Google Scholar 

  46. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current: Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990;96:195–215.

    Google Scholar 

  47. Taggart P, Sutton PMI, Donaldson R. d-Sotalol: A new potent class III antiarrhythmic agent. Clin Sci 1985;69:631–636.

    Google Scholar 

  48. Shimizu W, Kurita T, Suyama K, Aihara N, Kamakura S, Shimomura K. Reverse use dependence of human ventricular repolarization by chronic oral sotalol in monophasic action potential recordings. Am J Cardiol 1996;77:1004–1008.

    Google Scholar 

  49. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996;348:7–12.

    Google Scholar 

  50. Hiromasa S, Coto H, Li ZY, Maldonado C, Kupersmith J. Dextrorotatory isomer of sotalol: Electrophysiologic effects and interaction with verapamil. Am Heart J 1988;116:1552–1557.

    Google Scholar 

  51. Burashnikov A, Antzelevich C. Acceleration-induced early afterdepolarizations and triggered activity. Circulation 1995;92:I-434 (Abstract).

    Google Scholar 

  52. Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: A critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988;31:115–172.

    Google Scholar 

  53. Vos MA, Verduyn SC, Gorgels APM, Lipcsei GC, Wellens HJJ. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation 1995;91:864–872.

    Google Scholar 

  54. Burashnikov A, Antzelevich C. Mechanisms of acceleration-induced early afterdepolarization activity and action potential prolongation in tissues isolated from the M region of the canine ventricle. PACE 1996;19:II-645 (Abstract).

    Google Scholar 

  55. Chezalviel-Guilbert F, Davy JM, Poirier JM, Weissenburger J. Mexiletine antagonizes the effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes. J Am Coll Cardiol 1995;26:787–792.

    Google Scholar 

  56. Berman ND, Loukides JE. A comparison of the cellular electrophysiology of mexiletine and sotalol, singly and combined, in canine Purkinje fibres. J Cardiovasc Pharmacol 1988;12:286–292.

    Google Scholar 

  57. Varró A, Lathrop DA. Sotalol and mexiletine: Combination of rate-dependent electrophysiological effects. J Cardiovasc Pharmacol 1990;16:557–567.

    Google Scholar 

  58. Shimizu W, Tanaka K, Suenaga K, Wakamoto A. Bradycardia-dependent early afterdepolarizations in a patient with QTU prolongation and torsade de pointes in association with marked bradycardia and hypokalemia. PACE 1991;14:1105–1111.

    Google Scholar 

  59. Wang Q, Shen J, Slawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805–811.

    Google Scholar 

  60. Wang Q, Curran ME, Splawsky I, et al. Positional cloning of a novel potassium channel gene: KvLQTl mutations cause cardiac arrhythmias. Nat Genet 1996;12:17–23.

    Google Scholar 

  61. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795–803.

    Google Scholar 

  62. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81:299–307.

    Google Scholar 

  63. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 1996;384:80–83.

    Google Scholar 

  64. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current. Nature 1996;384:78–80.

    Google Scholar 

  65. Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 1997;96:2038–2047.

    Google Scholar 

  66. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential response to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy. Circulation 1995;92:3381–3386.

    Google Scholar 

  67. Dumaine R, Wang Q, Keating MT, et al. Multiple mechanisms of Na+ channel-linked long-QT syndrome. Circ Res 1996;78:916–924.

    Google Scholar 

  68. Roden DM, Hoffman BF. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibres: Relationship to potassium-and cycle length. Circ Res 1986;56:857–867.

    Google Scholar 

  69. Rubart M, Pressler ML, Pride HP, Zipes DP. Electrophysiological mechanisms in a canine model of erythromycin-associated long QT-syndrome. Circulation 1993;88:1832–1844.

    Google Scholar 

  70. Fazekas T, Krassói I, Lengyel C, Varro A, Papp JGy. Suppression of erythromycin-induced early afterdepolarizations and torsade de pointes ventricular tachycardia by mexiletine. PACE 1998;21:147–150.

    Google Scholar 

  71. January CT, Riddle JM, Salata JJ, et al. A model for early afterdepolarizations: Induction with the Ca2+ channel agonist Bay K 8644. Circ Res 1988;62:563–571.

    Google Scholar 

  72. Priori S, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol 1990;1:15–30.

    Google Scholar 

  73. Burashnikov A, Antzelevich C. β-Adrenergic stimulation produces transient action potential prolongation in canine ventricular M cells but not in Purkinje, epicardial or endocardial cells when the contribution of IKr is reduced. PACE 1996;19:II-293 (Abstract).

    Google Scholar 

  74. January CT, Riddle JM. Early afterdepolarizations: Mechanisms of induction and block. A role for L-type Ca2+ current. Circ Res 1989;64:977–990.

    Google Scholar 

  75. Burashnikov A, Antzelevich C. α-Agonists produce opposite effect on action potential duration in Purkinje and M cells isolated from the canine left ventricle. PACE 1995;18:II-935 (Abstract).

    Google Scholar 

  76. El-Sherif N, Caref E, Yin H, Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns. Circ Res 1996;79:474–492.

    Google Scholar 

  77. Weissenburger J, Nesterenko V, Antzelevitch C. Intramural monophasic action potentials (MAP) display steeper APD-rate relations and higher sensitivity to class III agents than epicardial and endocardial MAPs: characteristics of the M cell in vivo. Circulation 1995;92:I-300 (Abstract).

    Google Scholar 

  78. Lee KS, Tsai TD, Lee EW. Membrane activity of class III antiarrhythmic compounds; a comparison between ibutilide, d-sotalol, E-4031, sematilide and dofetilide. Eur J Pharmacol 1993;234:43–53.

    Google Scholar 

  79. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Circulation 1995;91:1799–1806.

    Google Scholar 

  80. Roden DM. Ibutilide and the treatment of atrial arrhythmias. A new drug—almost unheralded—is now available to US physicians. [Editorial]. Circulation 1996;94:1499–1502.

    Google Scholar 

  81. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady-state tetrodotoxin-sensitive (“window”) sodium current in cardiac Purkinje fibres. Pflugers Arch 1979;379:137–142.

    Google Scholar 

  82. Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Physiol 1979;236:H561–567.

    Google Scholar 

  83. Varró A, Nakaya Y, Elharrar V, Surawicz B. The effects of amiodarone on repolarization and refractoriness of cardiac fibres. Eur J Pharmacol 1988;154:11–18.

    Google Scholar 

  84. Papp JGY, Németh M, Krassói I, Mester L, Hála O, Varró A. Differential electrophysiologic effects of chronically administered amiodarone on canine Purkinje fibres versus ventricular muscle. J Cardiovasc Pharmacol Therapeut 1996;1:287–296.

    Google Scholar 

  85. Carmeliet E. Slow inactivation of the sodium current in rabbit cardiac Purkinje fibres. Pflügers Arch 1987;408:18–26.

    Google Scholar 

  86. Varró A, Virág L, Papp JGy. Comparison of the chronic and acute effects of amiodarone on the calcium and potassium currents in isolated rabbit cardiac myocytes. Br J Pharmacol 1996;117:1181–1186.

    Google Scholar 

  87. Drouin E, Lande G, Charpentier F. Amiodarone reduces transmural heterogeneity of repolarization in the human heart. J Am Coll Cardiol 1998;32:1063–1067.

    Google Scholar 

  88. Kontopoulos A, Manoudis F, Filindris A, Metaxas P. Sotalol-induced torsade de pointes. Postgrad Med J 1981;57:321–323.

    Google Scholar 

  89. Weissenburger J, Nesterenko V, Antzelevitch C. M cells contribute to transmural dispersion of repolarization and to the development of torsade de pointes in the canine heart in vivo. PACE 1996;19:II-707 (Abstract).

    Google Scholar 

  90. Duker GD, Linhardt GS, Rahmberg M. An animal model for studying class III-induced proarrhythmias in the halothane-anesthetized dog. J Am Coll Cardiol 1994;323:326A.

    Google Scholar 

  91. Sun ZQ, Eddlestone GT, Antzelevitch C: Ionic mechanisms underlying the effects of sodium pentobarbital to diminish transmural dispersion of repolarization. PACE 1997;20:II-1116 (Abstract).

    Google Scholar 

  92. Carlsson L, Abrahamson C, Drews L, Duker G. Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization. Circulation 1992;85:1491–1500.

    Google Scholar 

  93. Lathrop DA, Nánási PP, Varró A. In vitro cardiac models of dog Purkinje fibre triggered and spontaneous electrical activity: Effects of nicorandil. Br J Pharmacol 1990;99:119–123.

    Google Scholar 

  94. Antzelevitch C, Yan GX, Shimizu W, Burashnikov A. Electrical heterogeneity, the ECG, and cardiac arrhythmias. In: Zipes DP, Jalife J (end). Cardiac Electrophysiology: From Cell to Bedside, 3rd ed. Philadelphia: WB Saunders Co., 1998: Chapter 26.

    Google Scholar 

  95. Salata JJ, Jurkiewicz NK, Wang J, Evans BE, Orme HT, Sanguinetti MC. A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol 1998;53:220–230.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baláti, B., Varró, A. & Papp, J.G. Pharmacological Modification of the Dispersion of Repolarization in the Heart: Importance of the M Cells. Cardiovasc Drugs Ther 13, 491–505 (1999). https://doi.org/10.1023/A:1007819503060

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007819503060

Navigation