The American Journal of Medicine
Volume 110, Issue 5 , Pages 385-398 , 1 April 2001

Molecular biology and the prolonged QT syndromes

  • Jeffrey A Towbin, MD

      Affiliations

    • Department of Pediatrics (Cardiology) (JAT, MV), Baylor College of Medicine, Houston, Texas, USA
    • Corresponding Author InformationRequests for reprints should be addressed to Jeffrey A. Towbin, MD, Pediatric Cardiology, Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, Texas 77030
    • ,
  • Matteo Vatta, PhD

      Affiliations

    • Department of Molecular and Human Genetics (JAT), Baylor College of Medicine, Houston, Texas, USA

References 

  1. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, function heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59–68
  2. Meissner FL. Taubstummheit und Taubstummenbildung. Leipzig and Heidelberg. Winter 1856:119–120.
  3. Romano C, Gemme G, Pongiglione R. Antmie cardiache rare in eta pediatrica. Clin Pediatr. 1963;45:656–683.
  4. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–106
  5. Moss AJ, Schwartz PJ, Crampton R, et al.  The long QT syndrome (prospective longitudinal study of 328 families). Circulation. 1991;84:1136–1144
  6. Hashiba K. Sex differences in phenotypic manifestation and gene transmission in the Romano-Ward syndrome. Ann NY Acad Sci. 1992;644:142–156
  7. Rautaharju PM, Zhou SH, Wong S, et al.  Differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–695
  8. Schwartz PJ. Idiopathic long syndrome, progress and questions. Am Heart J. 1985;109:399–411
  9. Schwartz PJ, Zaza A, Locati E, Moss AJ. Stress and sudden death. The case of the long QT syndrome. Circulation. 1991;83:II71–II80
  10. Schwartz PJ, Locati EH, Napolitano C, Priori SG. The long QT syndrome. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: WB Saunders Company, 1996:788–811.
  11. Horn CA, Beckman RH, Dick M, Lacina SJ. The congenital long QT syndrome (an unusual cause of childhood seizures). Am J Dis Child. 1986;140:659–661
  12. Ratshin RA, Hunt D, Russell RO, Rackley CE. QT-interval prolongation, paroxysmal ventricular arrhythmias, and convulsive syncope. Ann Intern Med. 1971;75:19–24
  13. Bazett HC. An analysis of the time relations of electrocardiogram. Heart. 1918;7:353–370
  14. Ewing DJ, Boland O, Neilson JMM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia. 1991;34:182–185
  15. Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in children. J Am Coll Cardiol. 1990;16:674–680
  16. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 76;10:744–745.
  17. Schwartz PJ, Priori SG, Dumaine R, et al.  A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med. 2000;343:262–267
  18. Jervell A. Surdocardiac and related syndromes in children. Adv Intern Med. 1971;17:425–438
  19. Fraser GR, Froggatt P, Murphy T. Genetical aspects of the cardio-auditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Am Hum Genet. 1964;28:133–156
  20. Fraser GR, Froggatt P, James TN. Congenital deafness associated with electrocardiographic abnormalities, fainting attacks and sudden death. A recessive syndrome. QJ Med. 1964;33:361–385
  21. Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am Heart J. 1975;89:378–390
  22. Fermini B, Jurkiewicz NK, Jow B, et al.  Use-dependent effects of the class III antiarrhythmic agent NE-10064 (Azimilide) on cardiac repolarization (block of delayed rectifier potassium and L-type calcium currents). J Cardiovasc Pharmacol. 1995;26:259–271
  23. Lipka LJ, Dizon JM, Reiffel JA. Desired mechanisms of drugs for ventricular arrhythmia; class III antiarrhythmic agents. Am Heart J. 1995;130:632–640
  24. Sedgwick ML, Lip G, Rae AP, Cobbe SM. Chem cardioversion of atrial fibrillation with intravenous dofetilide. Int J Cardiol. 1995;49:159–166
  25. Sedgwick ML, Rasmussen HS, Cobbe SM. Effects of the class III antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and QT interval dispersion in stable angina pectoris. Am J Cardiol. 1992;70:1432–1437
  26. Vaughan Williams EM. A classification of antiarrhythmic action reassessed after a decade of new drugs. J Clin Pharmacol. 1984;24:129–147
  27. Roden DM, Bennett PB, Snyders DJ, Balser JR, Hondeghem LM. Quinidine delays IK activation in guinea pig ventricular myocytes. Circ Res. 1988;62:1055–1058
  28. Carlsson L, Abrahamsson C, Andersson B, Duker G, Schiller-Linhardt G. Proarrhythmic effects of the class III agent almokalant (importance of infusion rate, QT dispersion, and early afterdepolarizations). Cardiovasc Res. 1993;27:2186–2193
  29. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. J Am Med Assoc. 1993;269:1532–1536
  30. Echizen H, Kawasaki H, Chiba K, Tani M, Ishizaki T. A potent inhibitory effect of erythromycin and other macrolide antibiotics on the mono-N-dealkylation metabolism on disopyramide with human liver microsomes. J Pharmacol Exp Ther. 1993;264:1425–1431
  31. Lewin MB, Bryant RM, Fenrick AL, Grifka RG. Cisapride-induced long QT interval. J Pediatr. 1996;128:279–281
  32. Roden DM, Spooner PM, and the NIH Working Group. Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. J Cardiovasc Electrophysiol. 2000;10:1664–1683.
  33. 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
  34. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome (an update). Circulation. 1993;88:782–784
  35. Keating MT, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704–706
  36. Jackman WM, Szabo B, Friday DJ, et al.  Ventricular tachyarrhythmias related to early afterdepolarizations and triggered firing (relationship to QT interval prolongation and potential therapeutic role for calcium channel blocking agents). J Cardiovasc Electrophysiol. 1990;1:170–195
  37. Shimizu W, Ohe T, Kurita T, Tokuda T, Shimomura K. Epinephrine-induced ventricular premature complexes due to early afterdepolarizations and effects of verapamil and propranolol in a patient with congenital long QT syndrome. J Cardiovasc Electrophysiol. 1994;5:438–444
  38. Towbin JA, Li H, Taggart T, et al.  Evidence of genetic heterogeneity in Romano-Ward long QT syndrome (analysis of 23 families). Circulation. 1994;90:2635–2644
  39. Benhorin J, Kalman YM, Madina A, et al.  Evidence of genetic heterogeneity in the long QT syndrome. Science. 1993;260:1960–1962
  40. Jiang C, Atkinson D, Towbin JA, et al.  Two long QT syndrome loci map to chromosome 3 and 7 with evidence for further heterogeneity. Nature Genet. 1994;8:141–147
  41. Schott J, Charpentier F, Peltier S, et al.  Mapping of a gene for long QT syndrome to chromosome 4q25–27. Am J Hum Genet. 1995;57:1114–1122
  42. Abbott GW, Sesti F, Splawski I, et al.  MiRP1 forms IKr potassium channels with HERG, and is associated with cardiac arrhythmia. Cell. 1999;97:175–187
  43. Priori SG, Schwartz PJ, Napolitano C, et al.  A recessive variant of the Romano-Ward long-QT syndrome. Circulation. 1998;97:2420–2425
  44. Li H, Chen Q, Moss AJ, et al.  New mutations in the KVLQT1 potassium channel that cause long QT syndrome. Circulation. 1998;97:1264–1269
  45. Wang Q, Curran ME, Splawski I, et al.  Positional cloning of a novel potassium channel gene (KVLQT1 mutations cause cardiac arrhythmias). Nature Genet. 1996;12:17–23
  46. Barhanin J, Lesage F, Guillemare E, Finc M, Lazdunski M, Romey G. KVLQT1 and IsK (minK) proteins associate to form the Iks cardiac potassium current. Nature. 1996;384:78–80
  47. 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
  48. Demolombe S, Baro I, Pereon Y, et al. A dominant negative isoform of the long QT syndrome 1 gene product. J Biol Chem. 1998;273:6837–6843.
  49. Shalaby FY, Levesque PC, Yang WP, et al.  Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation. 1997;96:1733–1736
  50. Wollnick B, Schreeder BC, Kubish C, Esperer HD, Wieacker P, Jensch TJ. Pathophysiological mechanisms of dominant and recessive KVLQTI K+ channel mutations found in inherited cardiac arrhythmias. Human Molec Genet. 1997;6:1943–1949
  51. Chouabe C, Neyroud N, Richard PK, et al. 2000 Novel mutations in KVLQT1 that affect IKs activation through interactions with IsK. Cardiovasc Res. 45:971–980.
  52. Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V, Beggs AH. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Circulation. 1998;97:142–146
  53. Warmke JE, Ganetzky B. A family of potassium channel genes related to Eag in Drosophila and mammals. Proc Natl Acad Sci USA. 1994;91:3438–3442
  54. 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
  55. Schulze-Bahr E, Haverkamp W, Funke H. The long-QT syndrome. N Engl J Med. 1995;333:1783–1784
  56. Trudeau MC, Warmke J, Ganetzky B, Robertson G. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92–95
  57. Sanguinetti MC, Curran ME, Spector PS, Keating MT. Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci USA. 1996;93:2208–2212
  58. Furutani M, Trudeau MC, Hagiwara N, et al.  Novel mechanism associated with an inherited cardiac arrhythmia. Defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation. 1999;99:2290–2294
  59. Zhou Z, Gong Q, Miles L, et al.  HERG channel dysfunction in human long QT syndrome. J Biol Chem. 1998;263:21061–21066
  60. McDonald TV, Yu Z, Ming Z, et al.  A MinK-HERG complex regulates the cardiac potassium current IKr. Nature. 1997;388:289–292
  61. Bianchi L, Shen Z, Dennis AT, et al.  Cellular dysfunction of LQT5-minK mutants (abnormalities of IKs, IKr and trafficking in long QT syndrome). Hum Molec Genet. 1999;8:1499–1507
  62. George AL, Varkony TA, Drakin HA, et al.  Assignment of the human heart tetrodotoxin-resistant voltage-gated Na channel α-subunit gene (SCN5A) to band 3p21. Cytogenet Cell Genet. 1995;68:67–70
  63. Wang Q, Shen J, Splawski I, et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80:805–811
  64. Hartmann HA, Colom LV, Sutherland ML, Noebels JL. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nature Neurosci. 1999;2:593–595
  65. Gellens M, George AL, Chen L, Chahine M, Horn R, Barchi R, et al. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci USA. 1992;89:554–558
  66. Bennett PB, Yazawa K, Makita N, George AL. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376:683–685
  67. Dumaine R, Wang Q, Keating MT, et al.  Multiple mechanisms of sodium channel-linked long QT syndrome. Circ Res. 1996;78:916–924
  68. An RH, Wang XL, Kerem B, et al.  Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha and beta 1 subunits. Circ Res. 1998;83:141–146
  69. Benhorin J, Taub R, Goldmit M, et al.  Effects of flecainide in patients with new SCN5A mutation. Mutation-specific therapy for long-QT syndrome?. Circulation. 2000;101:1698–1706
  70. Chen Q, Kirsch GE, Zhang D, et al.  Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293–296
  71. Schott J-J, Alshinawi C, Kyndt F, et al.  Cardiac conduction defects associated with mutations in SCN5A. Nature Genet. 1999;23:20–21
  72. Honore E, Attali B, Heurteaux C, et al.  Cloning, expression, pharmacology and regulation of a delayed rectifier K+ channel in mouse heart. EMBO J. 1991;10:2805–2811
  73. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nature Genet. 1997;17:338–340
  74. Chouabe C, Neyroud N, Guichency P, Lazdunski M, Romey G, Barhanin J. Properties of KVLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J. 1997;16:5472–5479
  75. Vetter DE, Mann JR, Wangemann P, et al.  Inner ear defects induced by null mutation of the IsK gene. Neuron. 1996;17:1251–1264
  76. Franqueza L, Lin M, Splawski I, Keating MT, Sanguinetti MC. Long QT syndrome-associated mutations in the S4-S5 linker of KVLQT1 potassium channels modify gating, and interaction with minK subunits. J Biol Chem. 1999;274:21063–21070
  77. Lehmann MH, Timothy KW, Frankovich D, et al.  Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol. 1997;29:93–99
  78. Moss AJ, Zareba W, Benhorin J, et al.  Electrocardiographic T-wave patterns in genetically distinct forms of the hereditary long-QT syndrome. Circulation. 1995;92:2929–2934
  79. Neyroud N, Tesson F, Denjoy I, et al.  A novel mutation on the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet. 1997;15:186–189
  80. Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT. Brief report (molecular basis of the long-QT syndrome associated with deafness). N Engl J Med. 1997;336:1562–1567
  81. Chen Q, Zhang D, Gingell RL, et al.  Homozygous deletion in KVLQTI associated with Jervell and Lange-Nielsen syndrome. Circulation. 1999;99:1344–1347
  82. Schulze-Bahr E, Wang Q, Wedekind H, et al.  KCNE1 mutations cause Jervell, and Lange-Nielsen syndrome. Nature Genet. 1997;17:267–268
  83. Tyson J, Transbjaerg L, Bellman S, et al.  IsK and KVLQT1. Mutation in either of the two subunits of the slow component or the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Human Molec Genet. 1997;6:2179–2185
  84. Mohammad-Panah R, Demolombe S, Neyroud N, et al.  Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. Am J Human Genet. 1999;64:1015–1023
  85. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome. Clinical impact. Circulation. 1999;99:529–533
  86. Zareba W, Moss AJ, Schwartz PJ, et al.  Influence of the genotype on the clinical course of the long-QT syndrome. N Engl J Med. 1998;339:960–965
  87. Ackerman MJ, Tester DJ, Porter CJ, Edwards WD. Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning. N Engl J Med. 1999;341:1121–1115.
  88. 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
  89. Hajj Ali RH, Zareba W, Moss AJ, et al.  Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol. 2000;85:457–461
  90. Wilde AA, Jongblood RJ, Doevendans PA, et al.  Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol. 1999;33:327–332
  91. Moss AJ, Zareba W, Hall WJ, et al.  Effectiveness and limitations of β-blocker therapy the congenital long-QT syndrome. Circulation. 2000;101:616–623
  92. Eldar M, Griffin JC, Abbott JA, et al.  Permanent cardiac pacing in patients with the long QT syndrome. J Am Coll Cardiol. 1987;10:600–607
  93. Moss AJ, Liu JE, Gottlieb S, Locati E, Schwartz PJ, Robinson JL. Efficacy of permanent pacing in the management of high risk patients with long QT syndrome. Circulation. 1991;84:1524–1529
  94. Viskin S. Cardiac pacing in the long QT syndrome (review of available data and practical recommendations). J Cardiovasc Electrophysiol. 2000;11:593–600
  95. Schwartz PJ, Locati E, Moss AJ, Crampton RS, Trazzi R, Ruberti U. Left cardiac sympathetic denervation in the therapy of the congenital long QT syndrome (a worldwide report). Circulation. 1991;84:503–511
  96. Platia EV, Griffith LSC, Watkins L, Mirowski M, Mower MM, Reid PR. Management of the prolonged QT syndrome and recurrent ventricular fibrillation with an implantable cardioverter-defibrillator. Clin Cardiol. 1985;8:490–493
  97. Moss AJ, Hall WJ, Cannom DS, et al, for the MADIT Investigators. Improved survival with an implanted defibrillator in patients with coronary disease at high risk of ventricular arrhythmias. N Engl J Med. 1996;335:1933–1940.
  98. Schwartz PJ, Priori SG, Locati EH, et al.  Long QT syndrome patients with mutations of SCN5A, and HERG have differential responses to Na+ channel blockade, and to increase in heart rate. Circulation. 1995;92:3381–3386
  99. Compton SJ, Lux RL, Ramsey MR, et al.  Genetically defined therapy of inherited long-QT syndrome. Circulation. 1996;94:1018–1022
  100. Roden DM, Lazzara R, Rosen M, et al. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. Circulation. 1996;94:1996–2012.

PII: S0002-9343(00)00715-4

The American Journal of Medicine
Volume 110, Issue 5 , Pages 385-398 , 1 April 2001

Article Tools

* Image Usage & Resolution