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. 2006 Oct 27;7(4):332–342. doi: 10.1111/j.1542-474X.2002.tb00182.x

Effects of Sympathetic Stimulation on Various Repolarization Indices in the Congenital Long QT Syndrome

Wataru Shimizu 1
PMCID: PMC7027645  PMID: 12431311

Abstract

Abstract Sympathetic stimulation or catecholamines modulate ventricular repolarization and provoke ventricular tachyarrhythmias in a variety of heart diseases and conditions. Among those, the congenital form of long QT syndrome (LQTS) has long been known to be a Rosetta stone for sympathetic‐related ventricular tachyarrhythmias. Recent experimental studies employing arterially‐perfused ventricular wedge preparations as well as some clinical studies have greatly advanced our knowledge of the cellular mechanism of the T wave and the various repolarization indices in the ECG, as well as the effect of sympathetic stimulation on these repolarization indices under normal and long QT conditions. Differences in the time course of repolarization of the three predominant cell types, the epicardial, midmyocardial (M), and endocardial cells, across the ventricular wall give rise to voltage gradients responsible for the inscription of normal T waves as well as the manifestation of abnormal T waves in the congenital LQTS. The data from the wedge experiments suggest that the repolarization time of the longest M cell action potential determines the Q‐Tend interval, while that of the epicardial action potential determines the Q‐Tpeak interval. Therefore, Tpeak‐end interval in the ECG may provide an index of transmural dispersion of repolarization (TDR). In this review article, sympathetic stimulation with isoproterenol or epinephrine infusion is demonstrated to modulate differentially these repolarization indices in the ECG as well as the action potentials of the three cells between the LQT1, LQT2, and LQT3 syndromes both experimentally and clinically, explaining the differences in the sensitivity of genotypes of congenital LQTS to sympathetic stimulation. A.N.E. 2002;7(4):332‐‐342

Keywords: sympathetic stimulation, LQTS, T wave, QT interval, dispersion of repolarization, genotype

REFERENCES

  • 1. Schwartz PJ, Zipes DP. Autonomic modulation of cardiac arrhythmias, in Zipes DP, Jalife J (eds): Cardiac Electro‐physiology: From Cell to Bedside. 3rd edition Philadelphia , W.B. Saunders Co., 1999, pp. 300–314. [Google Scholar]
  • 2. Schwartz PJ, Periti M, Malliani A. The long QT syndrome Am Heart J 1975;89: 378–390. [DOI] [PubMed] [Google Scholar]
  • 3. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome: A prospective international study. Circulation 1985;71:17–21. [DOI] [PubMed] [Google Scholar]
  • 4. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome: Prospective longitudinal study of 328 families. Circulation 1991;84:1136–1144. [DOI] [PubMed] [Google Scholar]
  • 5. Zipes DP. The long QT interval syndrome: A Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991;84:1414–1419. [DOI] [PubMed] [Google Scholar]
  • 6. Shimizu W, Ohe T, Kurita T, et al. Early afterdepolariza‐tions induced by isoproterenol in patients with congenital long QT syndrome. Circulation 1991;84:1915–1923. [DOI] [PubMed] [Google Scholar]
  • 7. Roden DM, Lazzara R, Rosen MR, et al. Multiple mechanisms in the long QT syndrome: Current knowledge, gaps, and future directions. Circulation 1996;94:1996–2012. [DOI] [PubMed] [Google Scholar]
  • 8. Surawicz B: Electrophysiologic substrate of torsade de pointes: Dispersion of repolarization or early afterdepolar‐izations J Am Coll Cardiol 1989;14:172–184. [DOI] [PubMed] [Google Scholar]
  • 9. Sicouri S, Antzetevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepi‐cardium of the canine ventricle. The M cell. Circ Res 1991;68: 1729–1741. [DOI] [PubMed] [Google Scholar]
  • 10. Antzelevitch C, Yan G X, Shimizu W, et al. Electrical heterogeneity, the ECG, and cardiac arrhythmias In Zipes D P, Jalife J, (eds): Cardiac Electrophysiology: From Cell to Bedside, 3rd edition Philadelphia , W.B. Saunders Co., 1999, pp. 222–238. [Google Scholar]
  • 11. Antzelevitch C, Shimizu W, Yan G X, et al: The M cell: Its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999;10:1124–1152. [DOI] [PubMed] [Google Scholar]
  • 12. Antzetevitch 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. [DOI] [PubMed] [Google Scholar]
  • 13. Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electrophysiologic properties of epicardium, mid‐myocardium, and endocardium: In vitro and in vivo correlations. Circulation 1996;94:1981–1988. [DOI] [PubMed] [Google Scholar]
  • 14. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (1kr and 1ks in canine ventricular epicardial, midmyocardial, and endocardial myocytes: A weaker 1ks contributes to the longer action potential of the M cell. Circ Res 1995;76:351–365. [DOI] [PubMed] [Google Scholar]
  • 15. Drouin E, Charpentier F, Gauthier C, et al. Electrophysiological characteristics of cells spanning the left ventricular wall of human heart: Evidence for the presence of M cells. J Am Coll Cardiol 1995;26:185–192. [DOI] [PubMed] [Google Scholar]
  • 16. Zygmunt AC, Eddlestone GT, Thomas GP, et al. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol 2001; 281: H689–H697. [DOI] [PubMed] [Google Scholar]
  • 17. Zygmunt AC, Goodrow RJ, Antzelevitch C.1Na‐Ca contributes to electrical heterogeneity within the canine ventricle. Am J Physiol 2000;278:H1671–H1678. [DOI] [PubMed] [Google Scholar]
  • 18. Antzelevitch C, Sun ZQ, Zhang ZQ, et al., Cellular and ionic mechanisms underlying erythromycin‐induced long QT and torsade de pointes. J Am Coll Cardiol 1996;28: 1836–1848. [DOI] [PubMed] [Google Scholar]
  • 19. Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolariza‐tion and preventing torsade de pointes in LQT2 and LQT3 models of the long QT syndrome. Circulation 1997;96: 2038–2047. [DOI] [PubMed] [Google Scholar]
  • 20. Shimizu W, Antzelevitch C. Cellular basis for the electro‐cardiographic features of the LQT1 form of the long QT syndrome: Effects of β‐adrenergic agonists, antagonists and sodium channel blockers on transmural dispersion of repo‐larization and torsade de pointes. Circulation 1998;98: 2314–2322. [DOI] [PubMed] [Google Scholar]
  • 21. 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. [DOI] [PubMed] [Google Scholar]
  • 22. Yan GX, Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long QT syndrome. Circulation 1998;98:1928–1936. [DOI] [PubMed] [Google Scholar]
  • 23. Antzelevitch C, Shimizu W, Yan G X, et al. Cellular basis for QT dispersion. J Electrocardiol 1998;30:168–175. [DOI] [PubMed] [Google Scholar]
  • 24. Shimizu W, Antzelevitch C. Cellular and ionic basis for T wave alternans under long QT conditions. Circulation 1999;99:1499–1507. [DOI] [PubMed] [Google Scholar]
  • 25. Shimizu W, MacMahon B, Antzelevitch C. Sodium pento‐barbital reduces transmural dispersion of repolarization and prevents torsade de pointes in models of acquired and congenital long QT syndrome. J Cardiovasc Electrophysiol 1999;10:154–164. [DOI] [PubMed] [Google Scholar]
  • 26. Shimizu W, Antzelevitch C. Cellular basis for long QT, transmural dispersion of repolarization and Torsade de Pointes in the long QT syndrome. J Electrocardiol 1999;32: 177–184. [DOI] [PubMed] [Google Scholar]
  • 27. Shimizu W, Antzelevitch C. Differential effects of beta‐adrenergic agonists and antagonists in LQT1, LQT2, and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000;35:778–786. [DOI] [PubMed] [Google Scholar]
  • 28. Shimizu W, Antzelevitch C. Effects of a K‐ channel opener to reduce transmural dispersion of repolarization and prevent Torsade de Pointes in LQT1, LQT2, and LQT3 models of the long QT syndrome. Circulation 2000;102:706–712. [DOI] [PubMed] [Google Scholar]
  • 29. Antzelevitch C, Yan G X, Shimizu W, et al. Electrophysi‐ologic characteristics of M cells and their role in arrhythmias In Franz M R. (ed): Monophasic Action Potentials. Bridging Cell and Bedside. Futura Publishing Company, Inc., Armonk , NY , 2000, pp. 583–604. [Google Scholar]
  • 30. Burnes JE, Ghanem RN, Waldo AL, et al. Imaging dispersion of myocardial repolarization. I. Comparison of body‐surface and epicardial measures. Circulation 2001;104:1299–1305. [DOI] [PubMed] [Google Scholar]
  • 31. Curran ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80: 795–803. [DOI] [PubMed] [Google Scholar]
  • 32. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80: 805–811. [DOI] [PubMed] [Google Scholar]
  • 33. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17–23. [DOI] [PubMed] [Google Scholar]
  • 34. Splawski I, Tristani‐Firouzi M, Lehmann MH, et al. Mutations in the hminK gene cause long QT syndrome and suppress 1Ks function. Nat Genet 1997;7:338–340. [DOI] [PubMed] [Google Scholar]
  • 35. Sanguinetti MC, Curran ME, Zou AR, et al. Coassembly of KvLQTl and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 1996;384:80–83. [DOI] [PubMed] [Google Scholar]
  • 36. Barhanin J, Lesage F, Guillemare E, et al. KvLQTl and IsK (minK) proteins associate to form the 1Ks cardiac potassium current. Nature 1996;384: 78–80. [DOI] [PubMed] [Google Scholar]
  • 37. Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81:299–307. [DOI] [PubMed] [Google Scholar]
  • 38. Abbott GW, Sesti F, Splawski I, et al. MiRPl forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–187. [DOI] [PubMed] [Google Scholar]
  • 39. Moss AJ, Zareba W, Benhorin J, et al. EGG T‐wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929–2934. [DOI] [PubMed] [Google Scholar]
  • 40. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST‐T‐wave patterns and repolarization parameters in congenital long QT syndrome: ECG findings identify genotypes. Circulation 2000;102:2849–2855. [DOI] [PubMed] [Google Scholar]
  • 41. Zareba W, Moss AJ, Schwartz P, et al, Influence of the genotype on the clinical course of the long QT syndrome. N Eng J Med 1998;339: 960–965. [DOI] [PubMed] [Google Scholar]
  • 42. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 1999;84:876–879. [DOI] [PubMed] [Google Scholar]
  • 43. Wilde AAM, Jongbloed RJE, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG‐related (LQT2) patients from KVLQT1‐related patients (LQT1). J Am Coll Cardiol 1999;33:327–332. [DOI] [PubMed] [Google Scholar]
  • 44. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype‐phe‐notype correlation in the long QT syndrome: Gene‐specific triggers for life‐threatening arrhythmias. Circulation 2001;103:89–95. [DOI] [PubMed] [Google Scholar]
  • 45. Zygmunt AC: Intracellular calcium activates chloride current in canine ventricular myocytes. Am J Physiol 1994;267:H1984–H1995. [DOI] [PubMed] [Google Scholar]
  • 46. Noda T, Takaki H, Kurita T, et al. Gene‐specific response of dynamic ventricular repolarization to sympathetic stimulation in LQTl, LQT2, and LQT3 forms of congenital long QT syndrome. Eur Heart J 2002;23:911–983. [DOI] [PubMed] [Google Scholar]
  • 47. Tanabe Y, Inagaki M, Kurita T, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQTl than LQT2 forms of congenital long QT syndrome. J Am Coll Cardiol 2001;37:911–919. [DOI] [PubMed] [Google Scholar]

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