Skip to main content
SpringerLink
Log in

Long QT Syndrome

  • Chapter
  • First Online:
Clinical Cardiogenetics

Abstract

The so-called congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome predisposing to life-threatening ventricular arrhythmias and sudden death. It is caused by prolongation of the repolarization phase of the cardiac action potential, which may manifest as lengthening of the heart rate-corrected QT interval (QTc) on the surface electrocardiogram (ECG). This chapter reviews the clinical presentation of LQTS, its diagnosis, and principles of management in the context of recent clinical advances and molecular genetics, with a focus on the most common forms of LQTS – LQT1, LQT2, and LQT3.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54(1):59–68.

    Article  CAS  PubMed  Google Scholar 

  2. Romano C, Gemme G, Pongiglione R. Rare cardiac arrhythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation (presentation of 1st case in Italian Pediatric literature). Clin Pediatr (Bologna). 1963;45:656–83.

    CAS  Google Scholar 

  3. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–6.

    CAS  PubMed  Google Scholar 

  4. Keating M, 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(5006):704–6.

    Article  CAS  PubMed  Google Scholar 

  5. Jiang C, Atkinson D, Towbin JA, et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet. 1994;8(2):141–7. doi:10.1038/ng1094-141.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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(1):17–23. doi:10.1038/ng0196-17.

    Article  PubMed  Google Scholar 

  9. Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761–7. doi:10.1161/CIRCULATIONAHA.109.863209.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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. doi:10.1016/j.jacc.2006.10.010.

    Article  PubMed  Google Scholar 

  11. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29(13):1670–80. doi:10.1093/eurheartj/ehn219.

    Article  PubMed  Google Scholar 

  12. Papadakis M, Raju H, Behr ER, et al. Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous interpretation. Circ Arrhythm Electrophysiol. 2013;6(3):588–96. doi:10.1161/CIRCEP.113.000111.

    Article  CAS  PubMed  Google Scholar 

  13. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–63. doi:10.1016/j.hrthm.2013.05.014.

    Article  PubMed  Google Scholar 

  14. Wilde AAM, Behr ER. Genetic testing for inherited cardiac disease. Nat Rev Cardiol. 2013;10(10):571–83. doi:10.1038/nrcardio.2013.108.

    Article  CAS  PubMed  Google Scholar 

  15. 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. doi:10.1016/j.hrthm.2011.05.020.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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. doi:10.1161/CIRCULATIONAHA.106.665406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tester DJ, Benton AJ, Train L, Deal B, Baudhuin LM, Ackerman MJ. Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing. Am J Cardiol. 2010;106(8):1124–8. doi:10.1016/j.amjcard.2010.06.022.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hedley PL, Kanters JK, Dembic M, et al. The role of CAV3 in long-QT syndrome: clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote. Circ Cardiovasc Genet. 2013;6(5):452–61. doi:10.1161/CIRCGENETICS.113.000137.

    Article  CAS  PubMed  Google Scholar 

  20. Burashnikov A, Antzelevitch C. Block of I(Ks) does not induce early afterdepolarization activity but promotes beta-adrenergic agonist-induced delayed afterdepolarization activity. J Cardiovasc Electrophysiol. 2000;11(4):458–65.

    Article  CAS  PubMed  Google Scholar 

  21. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation. 2006;114(20):2096–103. doi:10.1161/CIRCULATIONAHA.106.642694.

    Article  PubMed  Google Scholar 

  22. Viswanathan PC, Rudy Y. Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc Res. 1999;42(2):530–42.

    Article  CAS  PubMed  Google Scholar 

  23. Antzelevitch C. M cells in the human heart. Circ Res. 2010;106(5):815–7. doi:10.1161/CIRCRESAHA.109.216226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Burashnikov A, Antzelevitch C. Acceleration-induced action potential prolongation and early afterdepolarizations. J Cardiovasc Electrophysiol. 1998;9(9):934–48.

    Article  CAS  PubMed  Google Scholar 

  25. Kim TY, Kunitomo Y, Pfeiffer Z, et al. Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1. Heart Rhythm. 2015;12(1):220–8. doi:10.1016/j.hrthm.2014.10.003.

    Article  PubMed  Google Scholar 

  26. Johnson JN, Tester DJ, Perry J, Salisbury BA, Reed CR, Ackerman MJ. Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm. 2008;5(5):704–9. doi:10.1016/j.hrthm.2008.02.007.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zellerhoff S, Pistulli R, Mönnig G, et al. Atrial Arrhythmias in long-QT syndrome under daily life conditions: a nested case control study. J Cardiovasc Electrophysiol. 2009;20(4):401–7. doi:10.1111/j.1540-8167.2008.01339.x.

    Article  PubMed  Google Scholar 

  28. Mandyam MC, Soliman EZ, Alonso A, et al. The QT interval and risk of incident atrial fibrillation. Heart Rhythm. 2013;10(10):1562–8. doi:10.1016/j.hrthm.2013.07.023.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Batra AS, Silka MJ. Mechanism of sudden cardiac arrest while swimming in a child with the prolonged QT syndrome. J Pediatr. 2002;141(2):283–4. doi:10.1067/mpd.2002.126924.

    Article  PubMed  Google Scholar 

  30. Thomas D, Kiehn J, Katus HA, Karle CA. Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, I(Kr), and the underlying hERG ion channel. Basic Res Cardiol. 2004;99(4):279–87. doi:10.1007/s00395-004-0474-7.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Study group on molecular basis of arrhythmias of the working group on arrhythmias of the european society of cardiology. Eur Heart J. 1999;20(3):174–95.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Makita N, Behr E, Shimizu W, et al. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest. 2008;118(6):2219–29. doi:10.1172/JCI34057.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Postema PG, Van den Berg M, Van Tintelen JP, et al. Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide. Neth Heart J. 2009;17(11):422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Porta A, Girardengo G, Bari V, et al. Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1. J Am Coll Cardiol. 2015;65(4):367–74. doi:10.1016/j.jacc.2014.11.015.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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. doi:10.1056/NEJM199810013391404.

    Article  CAS  PubMed  Google Scholar 

  38. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. doi:10.1056/NEJMoa022147.

    Article  PubMed  Google Scholar 

  39. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329–37. doi:10.1016/j.jacc.2006.08.057.

    Article  PubMed  Google Scholar 

  40. Migdalovich D, Moss AJ, Lopes CM, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm. 2011;8(10):1537–43. doi:10.1016/j.hrthm.2011.03.049.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol. 2000;36(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  42. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the Europe. Eur Heart J. 2015;36(41):2793–867. doi:10.1093/eurheartj/ehv316.

    Article  PubMed  Google Scholar 

  43. Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011;124(20):2181–4. doi:10.1161/CIRCULATIONAHA.111.062182.

    Article  PubMed  Google Scholar 

  44. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J. 2013;34(40):3109–16. doi:10.1093/eurheartj/eht089.

    Article  PubMed  Google Scholar 

  45. Johnson JN, Grifoni C, Bos JM, et al. Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy. Eur Heart J. 2011;32(9):1114–20. doi:10.1093/eurheartj/ehr021.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Madias C, Fitzgibbons TP, Alsheikh-Ali AA, et al. Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes. Heart Rhythm. 2011;8(4):555–61. doi:10.1016/j.hrthm.2010.12.012.

    Article  PubMed  Google Scholar 

  47. Gray B, Ingles J, Medi C, Semsarian C. Prolongation of the QTc interval predicts appropriate implantable cardioverter-defibrillator therapies in hypertrophic cardiomyopathy. JACC Heart Fail. 2013;1(2):149–55. doi:10.1016/j.jchf.2013.01.004.

    Article  PubMed  Google Scholar 

  48. Behr ER, Roden D. Drug-induced arrhythmia: pharmacogenomic prescribing? Eur Heart J. 2013;34(2):89–95. doi:10.1093/eurheartj/ehs351.

    Article  PubMed  Google Scholar 

  49. Arizona Center for Education and Research on Therapeutics (AZCERT). 2016. crediblemeds.org

  50. Neyroud N, Tesson F, Denjoy I, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet. 1997;15(2):186–9. doi:10.1038/ng0297-186.

    Article  CAS  PubMed  Google Scholar 

  51. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109(15):1834–41. doi:10.1161/01.CIR.0000125524.34234.13.

    Article  PubMed  Google Scholar 

  52. 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(11):1161–8. doi:10.1111/j.1540-8167.2006.00587.x.

    Article  PubMed  Google Scholar 

  53. Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol. 1994;35(3):326–30. doi:10.1002/ana.410350313.

    Article  CAS  PubMed  Google Scholar 

  54. Sansone V, Griggs RC, Meola G, et al. Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol. 1997;42(3):305–12. doi:10.1002/ana.410420306.

    Article  CAS  PubMed  Google Scholar 

  55. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119(1):19–31. doi:10.1016/j.cell.2004.09.011.

    Article  CAS  PubMed  Google Scholar 

  56. Lepeschkin E, Surawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation. 1952;6(3):378–88.

    Article  CAS  PubMed  Google Scholar 

  57. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115(20):2613–20. doi:10.1161/CIRCULATIONAHA.106.661082.

    Article  PubMed  Google Scholar 

  58. Kukla P, Biernacka EK, Baranchuk A, Jastrzebski M, Jagodzinska M. Electrocardiogram in Andersen-Tawil syndrome. New electrocardiographic criteria for diagnosis of type-1 Andersen-Tawil syndrome. Curr Cardiol Rev. 2014;10(3):222–8.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol. 2004;37(Suppl):81–90.

    Article  PubMed  Google Scholar 

  60. Bogossian H, Frommeyer G, Ninios I, et al. New formula for evaluation of the QT interval in patients with left bundle branch block. Heart Rhythm. 2014;11(12):2273–7. doi:10.1016/j.hrthm.2014.08.026.

    Article  PubMed  Google Scholar 

  61. 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. doi:10.1016/j.hrthm.2005.02.011.

    Article  PubMed  Google Scholar 

  62. Postema PG, De Jong JSSG, Van der Bilt IAC, Wilde AAM. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm. 2008;5(7):1015–8. doi:10.1016/j.hrthm.2008.03.037.

    Article  PubMed  Google Scholar 

  63. Hibino S, Ueda N, Horiba M, et al. Detection of QT prolongation through approximation of the T wave on Gaussian mixture modeling. Circ J. 2013;77(11):2728–35.

    Article  PubMed  Google Scholar 

  64. Chiladakis J, Kalogeropoulos A, Koutsogiannis N, et al. Optimal QT/JT interval assessment in patients with complete bundle branch block. Ann Noninvasive Electrocardiol. 2012;17(3):268–76. doi:10.1111/j.1542-474X.2012.00528.x.

    Article  PubMed  Google Scholar 

  65. Cobos MA. Assessment of QT and JT intervals in bundle branch block: a new formula. Circulation. 2013;128:A176.

    Google Scholar 

  66. Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is “normal”. J Cardiovasc Electrophysiol. 2006;17(3):333–6. doi:10.1111/j.1540-8167.2006.00408.x.

    Article  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  Google Scholar 

  69. Kop WJ, Krantz DS, Nearing BD, et al. Effects of acute mental stress and exercise on T-wave alternans in patients with implantable cardioverter defibrillators and controls. Circulation. 2004;109(15):1864–9. doi:10.1161/01.CIR.0000124726.72615.60.

    Article  PubMed  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. Takasugi N, Goto H, Takasugi M, et al. Prevalence of microvolt T-wave alternans in patients with long QT syndrome and its association with Torsade de Pointes. Circ Arrhythm Electrophysiol. 2016;9(2):e003206. doi:10.1161/CIRCEP.115.003206.

    PubMed  Google Scholar 

  72. Veldkamp MW, Wilders R, Baartscheer A, Zegers JG, Bezzina CR, Wilde AAM. Contribution of sodium channel mutations to bradycardia and sinus node dysfunction in LQT3 families. Circ Res. 2003;92(9):976–83. doi:10.1161/01.RES.0000069689.09869.A8.

    Article  CAS  PubMed  Google Scholar 

  73. 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. doi:10.1016/j.hrthm.2011.05.018.

    Article  PubMed  Google Scholar 

  74. 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. doi:10.1161/CIRCULATIONAHA.111.028258.

    Article  PubMed  Google Scholar 

  75. de Noronha SV, Behr ER, Papadakis M, et al. The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths. Europace. 2014;16(6):899–907. doi:10.1093/europace/eut329.

    Article  PubMed  Google Scholar 

  76. 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.

    Article  CAS  PubMed  Google Scholar 

  77. Seethala S, Singh P, Shusterman V, Ribe M, Haugaa KH, Němec J. QT adaptation and intrinsic QT variability in congenital long QT syndrome. J Am Heart Assoc. 2015;4(12). doi:10.1161/JAHA.115.002395.

  78. Page A, Aktas MK, Soyata T, Zareba W, Couderc J-P. “QT clock” to improve detection of QT prolongation in long QT syndrome patients. Heart Rhythm. 2016;13(1):190–8. doi:10.1016/j.hrthm.2015.08.037.

    Article  PubMed  Google Scholar 

  79. van den Berg MP, Haaksma J, Veeger NJGM, Wilde AAM. Diurnal variation of ventricular repolarization in a large family with LQT3-Brugada syndrome characterized by nocturnal sudden death. Heart Rhythm. 2006;3(3):290–5. doi:10.1016/j.hrthm.2005.11.023.

    Article  PubMed  Google Scholar 

  80. 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. doi:10.1016/j.jacc.2009.12.015.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Aziz PF, Wieand TS, Ganley J, et al. Genotype- and mutation site-specific QT adaptation during exercise, recovery, and postural changes in children with long-QT syndrome. Circ Arrhythm Electrophysiol. 2011;4(6):867–73. doi:10.1161/CIRCEP.111.963330.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Adler A, van der Werf C, Postema PG, et al. The phenomenon of “QT stunning”: the abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome. Heart Rhythm. 2012;9(6):901–8. doi:10.1016/j.hrthm.2012.01.026.

    Article  PubMed  PubMed Central  Google Scholar 

  83. 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. doi:10.1016/j.hrthm.2008.08.038.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 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. doi:10.1161/CIRCULATIONAHA.105.600445.

    Article  CAS  PubMed  Google Scholar 

  85. Khositseth A, Hejlik J, Shen W-K, Ackerman MJ. Epinephrine-induced T-wave notching in congenital long QT syndrome. Heart Rhythm. 2005;2(2):141–6. doi:10.1016/j.hrthm.2004.11.008.

    Article  PubMed  Google Scholar 

  86. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen W-K, 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. doi:10.4065/77.5.413.

    Article  CAS  PubMed  Google Scholar 

  87. 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.

    Article  CAS  PubMed  Google Scholar 

  88. Krahn AD, Healey JS, Chauhan VS, et al. Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved ejection fraction registry. Circ Arrhythm Electrophysiol. 2012;5(5):933–40. doi:10.1161/CIRCEP.112.973230.

    Article  CAS  PubMed  Google Scholar 

  89. 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. doi:10.1001/jama.296.10.1249.

    Article  CAS  PubMed  Google Scholar 

  90. Goldenberg I, Moss AJ, Peterson DR, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008;117(17):2184–91. doi:10.1161/CIRCULATIONAHA.107.701243.

    Article  PubMed  PubMed Central  Google Scholar 

  91. 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.

    Article  CAS  PubMed  Google Scholar 

  92. Goldenberg I, Moss AJ, Bradley J, et al. Long-QT syndrome after age 40. Circulation. 2008;117(17):2192–201. doi:10.1161/CIRCULATIONAHA.107.729368.

    Article  PubMed  Google Scholar 

  93. Anneken L, Baumann S, Vigneault P, et al. Estradiol regulates human QT-interval: acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking. Eur Heart J. 2016;37(7):640–50. doi:10.1093/eurheartj/ehv371.

    Article  PubMed  Google Scholar 

  94. 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(1):60–4. doi:10.1016/j.hrthm.2004.01.006.

    Article  PubMed  Google Scholar 

  95. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49(10):1092–8. doi:10.1016/j.jacc.2006.09.054.

    Article  PubMed  Google Scholar 

  96. Meregalli PG, Westendorp ICD, Tan HL, Elsman P, Kok WEM, Wilde AAM. Pregnancy and the risk of torsades de pointes in congenital long-QT syndrome. Neth Heart J. 2008;16(12):422–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104(5):557–62.

    Article  CAS  PubMed  Google Scholar 

  98. 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. doi:10.1016/j.hrthm.2008.02.029.

    Article  PubMed  PubMed Central  Google Scholar 

  99. 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. doi:10.1016/j.jacc.2009.05.029.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Goldenberg I, Mathew J, Moss AJ, et al. Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification. J Am Coll Cardiol. 2006;48(5):1047–52. doi:10.1016/j.jacc.2006.06.033.

    Article  PubMed  Google Scholar 

  101. Goldenberg I, Horr S, Moss AJ, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57(1):51–9. doi:10.1016/j.jacc.2010.07.038.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Itoh H, Shimizu W, Hayashi K, et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010;7(10):1411–8. doi:10.1016/j.hrthm.2010.06.013.

    Article  PubMed  Google Scholar 

  103. Mullally J, Goldenberg I, Moss AJ, et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm. 2013;10(3):378–82. doi:10.1016/j.hrthm.2012.11.006.

    Article  PubMed  Google Scholar 

  104. 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. doi:10.1161/CIRCULATIONAHA.107.726950.

    Article  CAS  PubMed  Google Scholar 

  105. 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.

    Article  CAS  PubMed  Google Scholar 

  106. Crotti L, Lundquist AL, Insolia R, et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation. 2005;112(9):1251–8. doi:10.1161/CIRCULATIONAHA.105.549071.

    Article  PubMed  Google Scholar 

  107. Duchatelet S, Crotti L, Peat RA, et al. Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. Circ Cardiovasc Genet. 2013;6(4):354–61. doi:10.1161/CIRCGENETICS.113.000023.

    Article  CAS  PubMed  Google Scholar 

  108. de Villiers CP, van der Merwe L, Crotti L, et al. AKAP9 is a genetic modifier of congenital long-QT syndrome type 1. Circ Cardiovasc Genet. 2014;7(5):599–606. doi:10.1161/CIRCGENETICS.113.000580.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Earle N, Yeo Han D, Pilbrow A, et al. Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome. Heart Rhythm. 2014;11(1):76–82. doi:10.1016/j.hrthm.2013.10.005.

    Article  PubMed  Google Scholar 

  110. Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation. 2009;120(17):1657–63. doi:10.1161/CIRCULATIONAHA.109.879643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tomás M, Napolitano C, De Giuli L, et al. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. J Am Coll Cardiol. 2010;55(24):2745–52. doi:10.1016/j.jacc.2009.12.065.

    Article  PubMed  CAS  Google Scholar 

  112. Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: task force 10: the cardiac channelopathies: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2015;66(21):2424–8. doi:10.1016/j.jacc.2015.09.042.

    Article  PubMed  Google Scholar 

  113. Maron BJ, Zipes DP. Introduction: eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol. 2005;45(8):1318–21. doi:10.1016/j.jacc.2005.02.006.

    Article  PubMed  Google Scholar 

  114. Pelliccia A, Fagard R, Bjørnstad 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 My. Eur Heart J. 2005;26(14):1422–45. doi:10.1093/eurheartj/ehi325.

    Article  PubMed  Google Scholar 

  115. Pelliccia A, Zipes DP, Maron BJ. Bethesda conference #36 and the European Society of Cardiology consensus recommendations revisited a comparison of U.S. and European criteria for eligibility and disqualification of competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol. 2008;52(24):1990–6. doi:10.1016/j.jacc.2008.08.055.

    Article  PubMed  Google Scholar 

  116. Johnson JN, Ackerman MJ. Competitive sports participation in athletes with congenital long QT syndrome. JAMA. 2012;308(8):764–5. doi:10.1001/jama.2012.9334.

    Article  CAS  PubMed  Google Scholar 

  117. Johnson JN, Ackerman MJ. Return to play? Athletes with congenital long QT syndrome. Br J Sports Med. 2013;47(1):28–33. doi:10.1136/bjsports-2012-091751.

    Article  PubMed  Google Scholar 

  118. Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment “failures”. Circulation. 2009;119(2):215–21. doi:10.1161/CIRCULATIONAHA.108.772533.

    Article  CAS  PubMed  Google Scholar 

  119. Goldenberg I, Bradley J, Moss A, et al. Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management. J Cardiovasc Electrophysiol. 2010;21(8):893–901. doi:10.1111/j.1540-8167.2010.01737.x.

    PubMed  PubMed Central  Google Scholar 

  120. Wilde AAM, Ackerman MJ. Beta-blockers in the treatment of congenital long QT syndrome: is one beta-blocker superior to another? J Am Coll Cardiol. 2014;64(13):1359–61. doi:10.1016/j.jacc.2014.06.1192.

    Article  PubMed  Google Scholar 

  121. Ruan Y, Liu N, Napolitano C, Priori SG. Therapeutic strategies for long-QT syndrome: does the molecular substrate matter? Circ Arrhythm Electrophysiol. 2008;1(4):290–7. doi:10.1161/CIRCEP.108.795617.

    Article  PubMed  Google Scholar 

  122. Funasako M, Aiba T, Ishibashi K, et al. Pronounced shortening of QT interval with mexiletine infusion test in patients with type 3 congenital long QT syndrome. Circ J. 2016;80(2):340–5. doi:10.1253/circj.CJ-15-0984.

    Article  PubMed  Google Scholar 

  123. Mazzanti A, Maragna R, Faragli A, et al. Gene-specific therapy with mexiletine reduces arrhythmic events in patients with long QT syndrome type 3. J Am Coll Cardiol. 2016;67(9):1053–8. doi:10.1016/j.jacc.2015.12.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008;19(12):1289–93. doi:10.1111/j.1540-8167.2008.01246.x.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Huang H, Priori SG, Napolitano C, O’Leary ME, Chahine M. Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels. Am J Physiol Heart Circ Physiol. 2011;300(1):H288–99. doi:10.1152/ajpheart.00539.2010.

    Article  CAS  PubMed  Google Scholar 

  126. Egashira T, Yuasa S, Suzuki T, et al. Disease characterization using LQTS-specific induced pluripotent stem cells. Cardiovasc Res. 2012;95(4):419–29. doi:10.1093/cvr/cvs206.

    Article  CAS  PubMed  Google Scholar 

  127. Wang Y, Liang P, Lan F, et al. Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. J Am Coll Cardiol. 2014;64(5):451–9. doi:10.1016/j.jacc.2014.04.057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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. doi:10.1161/CIRCULATIONAHA.110.950147.

    Article  PubMed  Google Scholar 

  129. Kusumoto FM, Calkins H, Boehmer J, et al. HRS/ACC/AHA expert consensus statement on the use of implantable cardioverter-defibrillator therapy in patients who are not included or not well represented in clinical trials. J Am Coll Cardiol. 2014;64(11):1143–77. doi:10.1016/j.jacc.2014.04.008.

    Article  PubMed  Google Scholar 

  130. 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. doi:10.1161/01.CIR.0000125523.14403.1E.

    Article  PubMed  Google Scholar 

  131. Desimone CV, Bos JM, Bos KM, et al. Effects on repolarization using dynamic QT interval monitoring in long-QT patients following left cardiac sympathetic denervation. J Cardiovasc Electrophysiol. 2015;26(4):434–9. doi:10.1111/jce.12609.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Schneider AE, Bos JM, Ackerman MJ. Effect of left cardiac sympathetic denervation on the electromechanical window in patients with either type 1 or type 2 long QT syndrome: A pilot study. Congenit Heart Dis. 2016. doi:10.1111/chd.12332.

    PubMed  Google Scholar 

  133. Takahashi K, Shimizu W, Miyake A, Nabeshima T, Nakayashiro M, Ganaha H. High prevalence of the SCN5A E1784K mutation in school children with long QT syndrome living on the Okinawa islands. Circ J. 2014;78(8):1974–9.

    Article  CAS  PubMed  Google Scholar 

  134. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2(10):1099–105. doi:10.1016/j.hrthm.2005.07.012.

    Article  PubMed  Google Scholar 

  135. Ghouse J, Have CT, Weeke P, et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015;36(37):2523–9. doi:10.1093/eurheartj/ehv297.

    Article  PubMed  Google Scholar 

  136. Mogensen J, van Tintelen JP, Fokstuen S, et al. The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the Europ. Eur Heart J. 2015;36(22):1367–70. doi:10.1093/eurheartj/ehv122.

    Article  PubMed  Google Scholar 

  137. Refsgaard L, Holst AG, Sadjadieh G, Haunsø S, Nielsen JB, Olesen MS. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012;20(8):905–8. doi:10.1038/ejhg.2012.23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114(20):2104–12. doi:10.1161/CIRCULATIONAHA.106.635268.

    Article  CAS  PubMed  Google Scholar 

  139. Nolte IM, Wallace C, Newhouse SJ, et al. Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS One. 2009;4(7):e6138. doi:10.1371/journal.pone.0006138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Arking DE, Pfeufer A, Post W, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006;38(6):644–51. doi:10.1038/ng1790.

    Article  CAS  PubMed  Google Scholar 

  141. Pfeufer A, Sanna S, Arking DE, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41(4):407–14. doi:10.1038/ng.362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Newton-Cheh C, Eijgelsheim M, Rice KM, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet. 2009;41(4):399–406. doi:10.1038/ng.364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kolder ICRM, Tanck MWT, Postema PG, et al. Analysis for genetic modifiers of disease severity in patients with long-QT syndrome type 2. Circ Cardiovasc Genet. 2015;8(3):447–56. doi:10.1161/CIRCGENETICS.114.000785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mellor G, Behr ER. Sudden unexplained death – treating the family. Arrhythmia Electrophysiol Rev. 2014;3(3):156–60. doi:10.15420/aer.2014.3.3.156.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, London, SW17 0QT, UK

    Yanushi D. Wijeyeratne BMedSci (Hons), BMBS, MRCP & Elijah R. Behr MA, MBBS, MD, FRCP

  2. Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, SW17 0RE, UK

    Yanushi D. Wijeyeratne BMedSci (Hons), BMBS, MRCP & Elijah R. Behr MA, MBBS, MD, FRCP

Authors
  1. Yanushi D. Wijeyeratne BMedSci (Hons), BMBS, MRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elijah R. Behr MA, MBBS, MD, FRCP
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elijah R. Behr MA, MBBS, MD, FRCP .

Editor information

Editors and Affiliations

  1. Department of Cardiology, St. Elisabeth-TweeSteden Ziekenhuis, Tilburg, The Netherlands

    Hubert F. Baars

  2. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands

    Pieter A. F. M. Doevendans

  3. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

    Arjan C. Houweling

  4. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    J. Peter van Tintelen

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Wijeyeratne, Y.D., Behr, E.R. (2016). Long QT Syndrome. In: Baars, H., Doevendans, P., Houweling, A., van Tintelen, J. (eds) Clinical Cardiogenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-44203-7_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-44203-7_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-44202-0

  • Online ISBN: 978-3-319-44203-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation