Congenital Long QT Syndrome

  • David J. Tester
  • Peter J. Schwartz
  • Michael J. Ackerman
Chapter

Abstract

With an incidence as high as 1 in 2,000–2,500 live births, long QT syndrome (LQTS) is often characterized clinically by prolongation of the heart rate corrected QT interval (QTc) on a 12-lead surface electrocardiogram (ECG) and is associated with syncope, seizures, and sudden cardiac death due to ventricular arrhythmias usually following a precipitating event such as exertion, extreme emotion, or auditory stimulation. The phenotypic expression of LQTS varies profoundly from asymptomatic longevity to premature sudden cardiac death despite medical therapy. Therefore the clinical/genetic diagnostic evaluation and risk-stratification are highly important issues in the clinical management of LQTS. This chapter will review the historical background, epidemiology and prevalence, molecular genetics, and clinical presentations of LQTS, explore unique genotype – phenotype relationships that help define the various forms of the disorder, and provide a detailed outline for the diagnostic evaluation and clinical management of LQTS patients including current treatment strategies and recommendations.

Keywords

Long QT syndrome Ion channels QT interval Genetics Genetic testing Electrocardiogram Sudden death 

References

  1. 1.
    Moss AJ, Schwartz PJ. 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome. Circulation. 2005;111(9):1199–201.PubMedCrossRefGoogle Scholar
  2. 2.
    Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the QT interval, and sudden death. Am Heart J. 1957;54:59–68.PubMedCrossRefGoogle Scholar
  3. 3.
    Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell‘eta’ pediatrica. II. Accessi sincopali per fibrillazione ventricolare parossistica. Clin Peditr (Bologna). 1963;45:656–83.Google Scholar
  4. 4.
    Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–6.PubMedGoogle Scholar
  5. 5.
    Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc. 1998;73(3):250–69.PubMedCrossRefGoogle Scholar
  6. 6.
    Vincent GM. The molecular genetics of the long QT syndrome: genes causing fainting and sudden death. Annu Rev Med. 1998;49:263–74.PubMedCrossRefGoogle Scholar
  7. 7.
    Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49(2):240–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Goldenberg I, Moss AJ, Zareba W, et al. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol. 2006;17:1161–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang Y, Yang Y, Liang B, et al. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet. 2010;86(6):872–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Moss AJ, Long QT. Syndromes. Curr Treat Options Cardiovasc Med. 2000;2(4):317–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Schwartz PJ. Clinical applicability of molecular biology: the case of the long QT syndrome. Curr Control Trials Cardiovasc Med. 2000;1(2):88–91.PubMedCrossRefGoogle Scholar
  13. 13.
    Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84(3):1136–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006;296(10):1249–54.PubMedCrossRefGoogle Scholar
  15. 15.
    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(1):93–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation. 1998;97(22):2237–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation. 1998;97(5):451–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Tester DJ, Ackerman MJ. Genetics of cardiac arrhythmias. Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Elsevier/Saunders; 2012. p. 81–90.CrossRefGoogle Scholar
  20. 20.
    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(8):876–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999;74(11):1088–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Moss AJ, Zareba W, Benhorin J, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. 1995;92(10):2929–34.PubMedCrossRefGoogle Scholar
  23. 23.
    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(23):2849–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Wilde AA, Jongbloed 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(2):327–32.PubMedCrossRefGoogle Scholar
  25. 25.
    Khositseth A, Tester DJ, Will ML, Bell CM, Ackerman MJ. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm. 2004;1:60–4.PubMedCrossRefGoogle Scholar
  26. 26.
    Heradien MJ, Goosen A, Crotti L, et al. Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1-A341V mutation? J Am Coll Cardiol. 2006;48:1410–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Lehmann MH, Suzuki F, Fromm BS, et al. T wave “humps” as a potential electrocardiographic marker of the long QT syndrome. J Am Coll Cardiol. 1994;24(3):746–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med. 1992;327(12):846–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Dumaine R, Wang Q, Keating MT, et al. Multiple mechanisms of Na+ channel-linked long-QT syndrome. Circ Res. 1996;78(5):916–24.PubMedCrossRefGoogle Scholar
  30. 30.
    Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International long-QT syndrome Registry Research Group. N Engl J Med. 1998;339(14):960–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109(2):399–411.PubMedCrossRefGoogle Scholar
  32. 32.
    Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88(2):782–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011;124(20):2181–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med. 2006;259(1):39–47.PubMedCrossRefGoogle Scholar
  35. 35.
    Sy RW, van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011;124(20):2187–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to the brief ­tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol. 2010;55(18):1955–61.PubMedCrossRefGoogle Scholar
  37. 37.
    Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353–70.Google Scholar
  38. 38.
    Garson Jr A, Dick 2nd M, Fournier A, et al. The long QT syndrome in children. An international study of 287 patients. Circulation. 1993;87(6):1866–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Garson Jr A, Kertesz NJ, Towbin JA. Improved electrocardiographic identification of the long QT syndrome. J Am Coll Cardiol. 2001;37(Suppl A):467A.Google Scholar
  40. 40.
    Allan WC, Timothy K, Vincent GM, Palomaki GE, Neveux LM, Haddow JE. Long QT syndrome in children: the value of rate corrected QT interval and DNA analysis as screening tests in the general population. J Med Screen. 2001;8(4):173–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005;2(6):569–74.PubMedCrossRefGoogle Scholar
  42. 42.
    Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syndrome: a prospective international study. Circulation. 1985;71(1):17–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006;47(4):764–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Vincent GM, Timothy K, Fox J, Zhang L. The inherited long QT syndrome: from ion channel to bedside. Cardiol Rev. 1999;7(1):44–55.PubMedCrossRefGoogle Scholar
  45. 45.
    Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol. 1994;23(2):296–301.PubMedCrossRefGoogle Scholar
  46. 46.
    Lupoglazoff JM, Denjoy I, Berthet M, et al. Notched T waves on Holter recordings enhance detection of patients with LQt2 (HERG) mutations. Circulation. 2001;103(8):1095–101.PubMedCrossRefGoogle Scholar
  47. 47.
    Khositseth A, Hejlik J, Shen WK, Ackerman MJ. Epinephrine-induced T-wave notching in congenital long QT syndrome. Heart Rhythm. 2005;2:141–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89(1):45–50.PubMedCrossRefGoogle Scholar
  49. 49.
    Zareba W, Moss AJ, le Cessie S, Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol. 1994;23(7):1541–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Napolitano C, Priori SG, Schwartz PJ. Significance of QT dispersion in the long QT syndrome. Prog Cardiovasc Dis. 2000;42(5):345–50.PubMedCrossRefGoogle Scholar
  51. 51.
    Day CP, McComb JM, Campbell RW. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br Heart J. 1990;63(6):342–4.PubMedCrossRefGoogle Scholar
  52. 52.
    Priori SG, Napolitano C, Diehl L, Schwartz PJ. Dispersion of the QT interval. A marker of therapeutic efficacy in the idiopathic long QT syndrome. Circulation. 1994;89(4):1681–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Moennig G, Schulze-Bahr E, Wedekind H, et al. Clinical value of electrocardiographic parameters in genotyped individuals with familial long QT syndrome. Pacing Clin Electrophysiol. 2001;24(4 Pt 1):406–15.PubMedCrossRefGoogle Scholar
  54. 54.
    Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol. 1991;68(5):498–503.PubMedCrossRefGoogle Scholar
  55. 55.
    Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur Heart J. 1998;19(3):508–13.PubMedCrossRefGoogle Scholar
  56. 56.
    Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J Am Coll Cardiol. 1999;34(3):823–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 2011;8(11):1698–704.PubMedCrossRefGoogle Scholar
  59. 59.
    Horner JM, Ackerman MJ. Ventricular ectopy during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 2008;5(12):1690–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Ackerman MJ, Khositseth A, Tester DJ, Hejlik J, Shen WK, Porter CJ. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002;77(5):413–21.PubMedGoogle Scholar
  61. 61.
    Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol. 2003;41(4):633–42.PubMedCrossRefGoogle Scholar
  62. 62.
    Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation. 2006;113(11):1385–92.PubMedCrossRefGoogle Scholar
  63. 63.
    Nador F, Beria G, De Ferrari GM, et al. Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Circulation. 1991;84(4):1530–42.PubMedCrossRefGoogle Scholar
  64. 64.
    De Ferrari GM, Nador F, Beria G, Sala S, Lotto A, Schwartz PJ. Effect of calcium channel block on the wall motion abnormality of the idiopathic long QT syndrome. Circulation. 1994;89(5):2126–32.PubMedCrossRefGoogle Scholar
  65. 65.
    De Ferrari GM, Schwartz PJ. Long QT syndrome, a purely electrical disease? Not anymore. Eur Heart J. 2009;30(3):253–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Nakayama K, Yamanari H, Otsuka F, et al. Dispersion of regional wall motion abnormality in patients with long QT syndrome. Heart. 1998;80(3):245–50.PubMedGoogle Scholar
  67. 67.
    Savoye C, Klug D, Denjoy I, et al. Tissue Doppler echocardiography in patients with long QT syndrome. Eur J Echocardiogr. 2003;4(3):209–13.PubMedCrossRefGoogle Scholar
  68. 68.
    Haugaa KH, Edvardsen T, Leren TP, Gran JM, Smiseth OA, Amlie JP. Left ventricular mechanical dispersion by tissue Doppler imaging: a novel approach for identifying high-risk individuals with long QT syndrome. Eur Heart J. 2009;30(3):330–7.PubMedCrossRefGoogle Scholar
  69. 69.
    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(5):795–803.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80(5):805–11.PubMedCrossRefGoogle Scholar
  71. 71.
    Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308–39.PubMedCrossRefGoogle Scholar
  72. 72.
    Gollob MH, Blier L, Brugada R, et al. Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can J Cardiol. 2011;27(2):232–45.PubMedCrossRefGoogle Scholar
  73. 73.
    Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2:507–17.PubMedCrossRefGoogle Scholar
  74. 74.
    Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294(23):2975–80.PubMedCrossRefGoogle Scholar
  75. 75.
    Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102(10):1178–85.PubMedCrossRefGoogle Scholar
  76. 76.
    Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109:1834–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Schwartz PJ, Priori SG, Napolitano C. How really rare are rare diseases?: the intriguing case of independent compound mutations in the long QT syndrome. J Cardiovasc Electrophysiol. 2003;14(10):1120–1.PubMedCrossRefGoogle Scholar
  78. 78.
    Ackerman MJ, Tester DJ, Jones G, Will MK, Burrow CR, Curran M. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc. 2003;78:1479–87.PubMedCrossRefGoogle Scholar
  79. 79.
    Ackerman MJ, Splawski I, Makielski JC, et al. Spectrum and prevalence of cardiac sodium channel variants among Black, White, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/Long QT Syndrome genetic testing. Heart Rhythm. 2004;1:600–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009;120(18):1752–60.PubMedCrossRefGoogle Scholar
  81. 81.
    Landstrom AP, Ackerman MJ. The Achilles’ heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise. Clin Pharmacol Ther. 2011;90(4):496–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Tester DJ, Ackerman MJ. Genetic testing. In: Gussak I, Antzelevitch C, editors. Electrical diseases of the heart: genetics, mechanisms, treatment, prevention. London: Springer; 2008. p. 444–58.CrossRefGoogle Scholar
  83. 83.
    Kapa S, Tester DJ, Salisbury BA, Wilde AA, Ackerman MJ. Distinguishing long QT syndrome-causing mutations from “background” genetic noise. Heart Rhythm. 2008;5(5):S76.Google Scholar
  84. 84.
    Spazzolini C, Mullally J, Moss AJ, et al. Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy. J Am Coll Cardiol. 2009;54(9):832–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–74.PubMedCrossRefGoogle Scholar
  86. 86.
    Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation. 2006;113(6):783–90.PubMedCrossRefGoogle Scholar
  87. 87.
    Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995;76(10):744–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Splawski I, Timothy KW, Sharpe LM, et al. Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31.PubMedCrossRefGoogle Scholar
  89. 89.
    Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105(7):794–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Jons C, Moss AJ, Lopes CM, et al. Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. J Cardiovasc Electrophysiol. 2009;20(8):859–65.PubMedCrossRefGoogle Scholar
  91. 91.
    Shimizu W, Horie M, Ohno S, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: multicenter study in Japan. J Am Coll Cardiol. 2004;44(1):117–25.PubMedCrossRefGoogle Scholar
  92. 92.
    Moss AJ, Shimizu W, Wilde AAM, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Nagaoka I, Shimizu W, Itoh H, et al. Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome. Circ J. 2008;72(5):694–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Shimizu W, Moss A, Wilde A, et al. Genotype-phenotype aspects of type-2 long-QT syndrome. J Am Coll Cardiol. 2009;54(22):2052–62.PubMedCrossRefGoogle Scholar
  95. 95.
    Crotti L, Spazzolini C, Schwartz PJ, et al. The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification. Circulation. 2007;116(21):2366–75.PubMedCrossRefGoogle Scholar
  96. 96.
    Amin AS, Giudicessi JR, Tijsen AJ, et al. Variants in the 3′untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J. 2012;33(6):714–23.PubMedCrossRefGoogle Scholar
  97. 97.
    Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in ­congenital long-QT syndrome. Circulation. 2000;101(6):616–23.PubMedCrossRefGoogle Scholar
  98. 98.
    Atiga WL, Calkins H, Lawrence JH, Tomaselli GF, Smith JM, Berger RD. Beat-to-beat repolarization lability identifies patients at risk for sudden cardiac death. J Cardiovasc Electrophysiol. 1998;9(9):899–908.PubMedCrossRefGoogle Scholar
  99. 99.
    Zareba W. New electrocardiographic indices of risk stratification. J Electrocardiol. 2001;34:332.CrossRefGoogle Scholar
  100. 100.
    Steinbigler P, Haberl R, Nespithal K, Spiegl A, Schmucking I, Steinbeck G. T wave spectral variance: a new method to determine inhomogeneous repolarization by T wave beat-to-beat variability in patients prone to ventricular arrhythmias. J Electrocardiol. 1998;30(Suppl):137–44.PubMedCrossRefGoogle Scholar
  101. 101.
    Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J. 2001;22(16):1374–450.PubMedCrossRefGoogle Scholar
  102. 102.
    Bhandari AK, Shapiro WA, Morady F, Shen EN, Mason J, Scheinman MM. Electrophysiologic testing in patients with the long QT syndrome. Circulation. 1985;71(1):63–71.PubMedCrossRefGoogle Scholar
  103. 103.
    Nemec J, Ackerman MJ, Tester D, Hejlik J, Shen WK. Catecholamine provoked microvoltage T wave alternans in genotyped long QT syndrome. Pacing & Clinical Electrophysiology. 2003;26(8):1660–7.Google Scholar
  104. 104.
    Nemec J, Hejlik JB, Shen WK, Ackerman MJ. Catecholamine-induced T-wave lability in congenital long QT syndrome: a novel phenomenon associated with syncope and cardiac arrest. Mayo Clin Proc. 2003;78:40–50.Google Scholar
  105. 105.
    Priori SG, Maugeri FS, Schwartz PJ. The risk of sudden death as first cardiac event in asymptomatic patients with the long QT syndrome (abstract). Circulation. 1998;98(Suppl I):777.Google Scholar
  106. 106.
    Schwartz PJ. The long QT syndrome. Curr Probl Cardiol. 1997;22(6):297–351.PubMedCrossRefGoogle Scholar
  107. 107.
    Chatrath R, Bell CM, Ackerman MJ. Beta-blocker therapy failures in symptomatic probands with genotyped long-QT syndrome. Pediatr Cardiol. 2004;25(5):459–65.PubMedCrossRefGoogle Scholar
  108. 108.
    Viskin S, Fish R, Zeltser D, et al. Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Heart. 2000;83(6):661–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Eldar M, Griffin JC, Van Hare GF, et al. Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome. J Am Coll Cardiol. 1992;20(4):830–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Dorostkar PC, Eldar M, Belhassen B, Scheinman MM. Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation. 1999;100(24):2431–6.PubMedCrossRefGoogle Scholar
  111. 111.
    Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation. 2006;114:2096–103.PubMedCrossRefGoogle Scholar
  112. 112.
    Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD: true or false? Heart Rhythm. 2009;6(1):113–20.PubMedCrossRefGoogle Scholar
  113. 113.
    Horner JM, Kinoshita M, Webster TL, Haglund CM, Friedman PA, Ackerman MJ. Implantable cardioverter defibrillator therapy for congenital long QT syndrome: a single-center experience. Heart Rhythm. 2010;7(11):1616–22.PubMedCrossRefGoogle Scholar
  114. 114.
    Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them? Data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation. 2010;122(13):1272–82.PubMedCrossRefGoogle Scholar
  115. 115.
    Chatrath R, Porter CJ, Ackerman MJ. Role of transvenous implantable cardioverter-defibrillators in preventing sudden cardiac death in children, adolescents, and young adults. Mayo Clin Proc. 2002;77:226–31.PubMedCrossRefGoogle Scholar
  116. 116.
    Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14:337–41.PubMedCrossRefGoogle Scholar
  117. 117.
    Monnig G, Kobe J, Loher A, et al. Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up. Heart Rhythm. 2005;2(5):497–504.PubMedCrossRefGoogle Scholar
  118. 118.
    Kaufman ES, McNitt S, Moss AJ, et al. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008;5(6):831–6.PubMedCrossRefGoogle Scholar
  119. 119.
    Villain E, Denjoy I, Lupoglazoff JM, et al. Low incidence of cardiac events with B-blocking therapy in children with long QT syndrome. Eur Heart J. 2004;25:1405–11.PubMedCrossRefGoogle Scholar
  120. 120.
    Schwartz PJ, Locati E. The idiopathic long QT syndrome: pathogenetic mechanisms and therapy. Eur Heart J. 1985;6(Suppl D):103–14.PubMedCrossRefGoogle Scholar
  121. 121.
    Moss AJ, McDonald J. Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Engl J Med. 1971;285(16):903–4.PubMedCrossRefGoogle Scholar
  122. 122.
    Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109(15):1826–33.PubMedCrossRefGoogle Scholar
  123. 123.
    Collura CA, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm. 2009;6(6):752–9.PubMedCrossRefGoogle Scholar
  124. 124.
    Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996;94(5):1018–22.PubMedCrossRefGoogle Scholar
  125. 125.
    Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol. 2003;42:1777–82.PubMedCrossRefGoogle Scholar
  126. 126.
    Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with B-blockers. JAMA. 2004;292:1341–4.PubMedCrossRefGoogle Scholar
  127. 127.
    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(3):778–86.PubMedCrossRefGoogle Scholar
  128. 128.
    Shimizu W, Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation. 1997;96(6):2038–47.PubMedCrossRefGoogle Scholar
  129. 129.
    Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998;98(21):2314–22.PubMedCrossRefGoogle Scholar
  130. 130.
    Moss AJ, Windle JR, Hall WJ, et al. Safety and efficacy of flecainide in subjects with Long QT-3 syndrome (DeltaKPQ mutation): a randomized, double-blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005;10(4 Suppl):59–66.PubMedCrossRefGoogle Scholar
  131. 131.
    Khan IA, Gowda RM. Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol. 2004;95(1):1–6.PubMedCrossRefGoogle Scholar
  132. 132.
    Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000;102:945–7.PubMedCrossRefGoogle Scholar
  133. 133.
    Bankston JR, Kass RS. Molecular determinants of local anesthetic action of beta-blocking drugs: implications for therapeutic management of long QT syndrome variant 3. J Mol Cell Cardiol. 2010;48(1):246–53.PubMedCrossRefGoogle Scholar
  134. 134.
    Besana AP, Wang DW, George AL, Schwartz PJ. Nadolol block of Nav1.5 does not explain its efficacy in the long QT syndrome. J Cardiovasc Pharmacol. 2012;59:249–53.PubMedCrossRefGoogle Scholar
  135. 135.
    Vyas H, Johnson J, Houlihan R, Bauer BA, Ackerman MJ. Acquired long QT syndrome secondary to cesium chloride supplement. J Altern Complement Med. 2006;12(10):1011–4.Google Scholar
  136. 136.
    Fitzgerald PT, Ackerman MJ. Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm. 2005;2:S30–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Amin AS, Herfst LJ, Delisle BP, et al. Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome. J Clin Invest. 2008;118(7):2552–61.PubMedGoogle Scholar
  138. 138.
    Zipes DP, Ackerman MJ, Estes III NA, Grant AO, Myerburg RJ, Van Hare G. Task force 7: arrhythmias. J Am Coll Cardiol. 2005;45:1354–63.PubMedCrossRefGoogle Scholar
  139. 139.
    Pelliccia A, Fagard R, Bjornstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. 2005;26(14):1422–45.PubMedCrossRefGoogle Scholar
  140. 140.
    Maron BJ, Isner JM, McKenna WJ. 26th Bethesda conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. Task Force 3: hypertrophic cardiomyopathy, myocarditis and other myopericardial diseases and mitral valve prolapse. J Am Coll Cardiol. 1994;24(4):880–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Taggart NW, Haglund CM, Ackerman MJ. AB32-5: diagnostic miscues in congenital long QT syndrome. Heart Rhythm. 2006;3(5 Suppl 1):S67.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • David J. Tester
    • 1
  • Peter J. Schwartz
    • 2
  • Michael J. Ackerman
    • 3
  1. 1.Department of Medicine, Division of Cardiovascular DiseasesMayo ClinicRochesterUSA
  2. 2.Department of Molecular MedicineUniversity of Pavia and IRCCS Policlinico S. MatteoPaviaItaly
  3. 3.Department of Medicine, Division of Cardiovascular Diseases, Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterUSA

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