The long-QT syndrome: A silent killer
Keywords:
MedicineAbstract
Introduction: Sudden cardiac death is a striking phenomenon, affecting seemingly healthy individuals without warning. The long-QT syndrome is a common cause of sudden cardiac death that can either be inherited or acquired. While congenital long-QT syndrome comprises a heterogeneous group of hereditary disorders affecting ion channels in the heart, acquired long-QT syndrome is usually a result of pharmacological therapy.
Main Body: Various mutations in twelve different genes have been linked with the long-QT syndrome to date. This condition is characterised by a pro-longed QT-interval on ECG, which signifies a delay in ventricular repolarisation. The clinical presentation of this syndrome can range from symptoms of dizziness and syncope to sudden death. Diagnosing long-QT syndrome is difficult due to variable penetrance in its inheritance and the existence of yet unidentified causative mutations.
Discussion and Conclusions: Accurate diagnosis of the long-QT syndrome is essential as this condition may predispose an individual to sudden cardiac death. Prophylactic therapy for the syndrome exists and therefore early identification of those at risk is crucial in reducing the number of preventable cardiac deaths. Research must continue to discover all mutations re- sponsible for sudden cardiac death so that therapeutic strategies can be developed to combat this silent killer.
References
1. Department of Health and Children. Reducing the risk: a strategic approach. The report of the task force on sudden cardiac death. Dublin; 2006 [cited 2010 Feb 22]. Available from: http://www.dohc.ie/ publications/pdf/sudden_cardiac_death.pdf
2. Healy A. New centre launched for detecting cardiac risk. The Irish Times [online newspaper]. 2008 Nov 11 [cited 2009 Nov 29]; para. 2. Available from: http://www.irishtimes.com/newspaper/ health/2008/1111/1225925650169.html.
3. Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: Clinical and research implications. Prog Cardiovasc Dis 2008;51(3):213–28.
4. Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29:1670-80.
5. Roden DM. Long-QT syndrome. N Engl J Med 2008;358:169-76.
6. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178-85.
7. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009;120;1761-7.
8. Saenen JB, Vrints CJ. Molecular aspects of the congenital and acquired long QT syndrome: clinical implications. J Mol Cell Cardiol 2008;44:63346.
9. Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol 2007;50(14):1335-40.
11. Jervell A, Lange-Nielson F. Congenital deaf mutism, functional heart disease with prolongation of the QT interval, and sudden death. Am Heart J 1957;54:59-78. 12. Imboden M, Swan H, Denjoy I, Van Langen IM, Latinen-Forsblom PJ, Napolitano C, et al. Female predominance and transmission distortion in the long-QT syndrome. N Eng J Med 2006;355:2744-51.
13. Ueda K, Valdivia C, Medeiros-Domingo A, Tester DJ, Vatta M, Farrugia G, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci 2008;105:9355–60.
14. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11.
15. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase- anchoring protein causes long-QT syndrome. Proc Nat Acad Sci 2007;104(52):20990-5.
16. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, et al. Mutations
TSMJ | 2010 | Volume 11
in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001;105:511-9.
17. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119(1):19-31.
18. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet 1996;12(1):17-23. 19. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage- gated potassium channel family. Science 1995;269:92- 5.
20. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003;421(6923):634-9.
21. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996;384(6604):80-3.
22. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97(2):175-87.
23. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 2006;114(20):2104-12. 24. Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde- Torres P, Itty A, Ye B, et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation 2007;116(2):134-42.
25. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103(1):89-95.
26. Moss AJ. Long QT syndrome. JAMA 2003;289:2041- 4.
27. Ashley EA, Niebauer J. Cardiology explained [Online]. 2004 [cited 2009 Oct 28]; Available from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?boo k=cardio&part=A548&rendertype=figure&id=A632 28. Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis 2008;3:18.
29. Goldenberg I, Moss AJ. Long QT Syndrome. J Am Coll Cardiol 2008;51(24):2291-2300.
30. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med 2006;258:39-47.
31. Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, 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.
32. Vincent GM. Role of DNA testing for diagnosis, management and genetic screening in long QT syndrome, hypertrophic cardiomyopathy and Marfan syndrome. J Cardiovasc Electrophysiol 2001;86:12-14. 33. Cardiac Risk in the Young. SADS sudden arrhythmic death syndrome. [Online]. 2003 [cited 2009 Sept 28]; Available from: http://www.sads.org. uk/causes_of_sads.htm
34. Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999;99(4):518-28.|
35. Kaufman ES. Efficient genotyping for congenital
LITERATURE REVIEW
long QT syndrome. JAMA 2005;294:3027-28.
36. Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, 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.
37. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Society. Eur Heart J 2006;27(17):2099-140.
38. Patel C, Antzelevitch C. Pharmacological approach to the treatment of long and short QT syndromes. Pharmacol Ther 2008;118(1):138–51.
39. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, 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.
40. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation 2000;101(14):1698– 706.
41. 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.
42. Wolf MJ, Zelster IJ, Salerno J and colleagues. Electrical storm in children with an implantable cardioverter defibrillator: clinical features and outcome. Heart Rhythm 2007;4(May Suppl):S43.
43. Goldschlager N, Epstein AE, Grubb BP. Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med 2003;163(2):151-62.
44. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 248(19):1866- 74.
2. Healy A. New centre launched for detecting cardiac risk. The Irish Times [online newspaper]. 2008 Nov 11 [cited 2009 Nov 29]; para. 2. Available from: http://www.irishtimes.com/newspaper/ health/2008/1111/1225925650169.html.
3. Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: Clinical and research implications. Prog Cardiovasc Dis 2008;51(3):213–28.
4. Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29:1670-80.
5. Roden DM. Long-QT syndrome. N Engl J Med 2008;358:169-76.
6. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178-85.
7. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009;120;1761-7.
8. Saenen JB, Vrints CJ. Molecular aspects of the congenital and acquired long QT syndrome: clinical implications. J Mol Cell Cardiol 2008;44:63346.
9. Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol 2007;50(14):1335-40.
11. Jervell A, Lange-Nielson F. Congenital deaf mutism, functional heart disease with prolongation of the QT interval, and sudden death. Am Heart J 1957;54:59-78. 12. Imboden M, Swan H, Denjoy I, Van Langen IM, Latinen-Forsblom PJ, Napolitano C, et al. Female predominance and transmission distortion in the long-QT syndrome. N Eng J Med 2006;355:2744-51.
13. Ueda K, Valdivia C, Medeiros-Domingo A, Tester DJ, Vatta M, Farrugia G, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci 2008;105:9355–60.
14. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11.
15. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase- anchoring protein causes long-QT syndrome. Proc Nat Acad Sci 2007;104(52):20990-5.
16. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, et al. Mutations
TSMJ | 2010 | Volume 11
in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001;105:511-9.
17. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119(1):19-31.
18. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet 1996;12(1):17-23. 19. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage- gated potassium channel family. Science 1995;269:92- 5.
20. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003;421(6923):634-9.
21. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1996;384(6604):80-3.
22. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97(2):175-87.
23. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 2006;114(20):2104-12. 24. Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde- Torres P, Itty A, Ye B, et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation 2007;116(2):134-42.
25. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103(1):89-95.
26. Moss AJ. Long QT syndrome. JAMA 2003;289:2041- 4.
27. Ashley EA, Niebauer J. Cardiology explained [Online]. 2004 [cited 2009 Oct 28]; Available from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?boo k=cardio&part=A548&rendertype=figure&id=A632 28. Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis 2008;3:18.
29. Goldenberg I, Moss AJ. Long QT Syndrome. J Am Coll Cardiol 2008;51(24):2291-2300.
30. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med 2006;258:39-47.
31. Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, 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.
32. Vincent GM. Role of DNA testing for diagnosis, management and genetic screening in long QT syndrome, hypertrophic cardiomyopathy and Marfan syndrome. J Cardiovasc Electrophysiol 2001;86:12-14. 33. Cardiac Risk in the Young. SADS sudden arrhythmic death syndrome. [Online]. 2003 [cited 2009 Sept 28]; Available from: http://www.sads.org. uk/causes_of_sads.htm
34. Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation 1999;99(4):518-28.|
35. Kaufman ES. Efficient genotyping for congenital
LITERATURE REVIEW
long QT syndrome. JAMA 2005;294:3027-28.
36. Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, 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.
37. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Society. Eur Heart J 2006;27(17):2099-140.
38. Patel C, Antzelevitch C. Pharmacological approach to the treatment of long and short QT syndromes. Pharmacol Ther 2008;118(1):138–51.
39. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, 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.
40. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation 2000;101(14):1698– 706.
41. 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.
42. Wolf MJ, Zelster IJ, Salerno J and colleagues. Electrical storm in children with an implantable cardioverter defibrillator: clinical features and outcome. Heart Rhythm 2007;4(May Suppl):S43.
43. Goldschlager N, Epstein AE, Grubb BP. Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med 2003;163(2):151-62.
44. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 248(19):1866- 74.
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2010-01-01
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Crowley, C. (2010). The long-QT syndrome: A silent killer. Trinity Student Medical Journal , 11(1), Page 66–71. Retrieved from https://ojs.tchpc.tcd.ie/index.php/tsmj/article/view/1862
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