Current Cardiology Reports

, 13:364 | Cite as

Genetics of Sudden Cardiac Death

  • Alon Barsheshet
  • Andrew Brenyo
  • Arthur J. Moss
  • Ilan Goldenberg
Article

Abstract

Advances in genetic testing technology have led to a proliferation of new genetic tests and accelerated developments in the field of cardiovascular genetic medicine. These advances enhance presymptomatic diagnosis and can establish a definitive molecular diagnosis for symptomatic patients at risk for sudden cardiac death. Most importantly, genotype-phenotype correlations can add important information for predicting outcome and selecting treatment for patients with inherited arrhythmic disorders. This paper reviews the current data regarding genotype-phenotype correlations and the role of clinical genetic testing in diagnosis, prognosis, and management of inheritable disorders leading to sudden cardiac death.

Keywords

Sudden cardiac death SCD Genetics Arrhythmia Genetic testing Genes Risk assessment Diagnosis Prognosis Aborted cardiac arrest Hypertrophic cardiomyopathy Dilated cardiomyopathy ARVC/D Long QT syndrome LQTS Short QT syndrome Brugada syndrome Catecholaminergic polymorphic ventricular tachycardia CPVT 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy–a Heart Failure Society of America practice guideline. J Card Fail. 2009;15:83–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Roden DM, American Heart Association. Cardiovascular genetics and genomics. Chichester: Wiley-Blackwell; 2009.CrossRefGoogle Scholar
  3. 3.
    Ho CY. Genetics and clinical destiny: Improving care in hypertrophic cardiomyopathy. Circulation. 2010;122:2430–40.PubMedCrossRefGoogle Scholar
  4. 4.
    Wang L, Seidman JG, Seidman CE. Narrative review: Harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med. 2010;152:513–20.PubMedGoogle Scholar
  5. 5.
    • Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2008;83:630–8. This study explores the influence of a positive genetic test for HCM on clinical outcome and shows that patients with myofilament-positive HCM test results had a poorer prognosis than patients with myofilament-negative HCM tests.PubMedCrossRefGoogle Scholar
  6. 6.
    Niimura H, Patton KK, McKenna WJ, et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002;105:446–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein c mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44:1903–10.PubMedCrossRefGoogle Scholar
  8. 8.
    Ingles J, Doolan A, Chiu C, et al. Compound and double mutations in patients with hypertrophic cardiomyopathy: Implications for genetic testing and counselling. J Med Genet. 2005;42:e59.PubMedCrossRefGoogle Scholar
  9. 9.
    Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionals. Genet Med. 2010;12:655–67.PubMedGoogle Scholar
  10. 10.
    •• Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed modification of the task force criteria. Eur Heart J. 2010;31:806–14. The criteria to diagnose ARVC/D have been modified to incorporate emerging diagnostic modalities and advances in the genetics of ARVC.PubMedCrossRefGoogle Scholar
  11. 11.
    Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death–executive summary: A report of the 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 of patients with ventricular arrhythmias and the prevention of sudden cardiac death) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J. 2006;27:2099–140.PubMedCrossRefGoogle Scholar
  12. 12.
    Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5:258–67.PubMedCrossRefGoogle Scholar
  13. 13.
    Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;36:1162–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002;71:1200–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Coonar AS, Protonotarios N, Tsatsopoulou A, et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (naxos disease) maps to 17q21. Circulation. 1998;97:2049–58.PubMedGoogle Scholar
  16. 16.
    Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998;39:418–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Dalal D, Molin LH, Piccini J, et al. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation. 2006;113:1641–9.PubMedCrossRefGoogle Scholar
  18. 18.
    van Tintelen JP, Entius MM, Bhuiyan ZA, et al. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006;113:1650–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Dalal D, James C, Devanagondi R, et al. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2006;48:1416–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Bauce B, Nava A, Beffagna G, et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Hear Rhythm. 2010;7:22–9.CrossRefGoogle Scholar
  21. 21.
    Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16:927–35.PubMedCrossRefGoogle Scholar
  22. 22.
    Kaufman ES, McNitt S, Moss AJ, et al. Risk of death in the long QT syndrome when a sibling has died. Hear Rhythm. 2008;5:831–6.CrossRefGoogle Scholar
  23. 23.
    Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291–300.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    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;54:59–68.PubMedCrossRefGoogle Scholar
  26. 26.
    Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: Natural history, molecular basis, and clinical outcome. Circulation. 2006;113:783–90.PubMedCrossRefGoogle Scholar
  27. 27.
    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
  28. 28.
    Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105:511–9.PubMedCrossRefGoogle Scholar
  29. 29.
    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;119:19–31.PubMedCrossRefGoogle Scholar
  30. 30.
    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;103:89–95.PubMedGoogle Scholar
  31. 31.
    Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol. 1999;84:876–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999;74:1088–94.PubMedCrossRefGoogle Scholar
  33. 33.
    Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49:1092–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Buber Y, Jehu M, Moss AJ, et al. Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Circulation. 2011;123:2784–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Moss AJ, Shimizu W, Wilde AA, 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;115:2481–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops are associated with increased risk for cardiac events in type-1 long QT syndrome [abstract]. Circulation. 2010;122:A13466.Google Scholar
  37. 37.
    • Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009;54:2052–62. This valuable study demonstrates the importance of mutation location among patients with LQTS type 2. Patients with missense mutations in the transmembrane pore region had a significantly higher cardiac event rate than patients with other missense mutations.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu JF, Moss AJ, Jons C, et al. Mutation-specific risk in two genetic forms of type 3 long QT syndrome. Am J Cardiol. 2010;105:210–3.PubMedCrossRefGoogle Scholar
  39. 39.
    • 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. Hear Rhythm. 2010;7:1411–8. This study is worthy of note, as it shows a high prevalence of double mutations among genotyped LQTS probands (8.4%) and confirms the occurrence of more severe disease manifestations among carriers of double mutations as compared with one mutation.CrossRefGoogle Scholar
  40. 40.
    •• 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. 2010;57:51–9. In this study, we showed that genotype-confirmed LQTS patients with normal-range QTc make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for life-threatening cardiac events in this LQTS subgroup.CrossRefGoogle Scholar
  41. 41.
    Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation. 2003;108:965–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96:800–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57:802–12.PubMedCrossRefGoogle Scholar
  45. 45.
    Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43:1494–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20:1391–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Hermida JS, Lemoine JL, Aoun FB, et al. Prevalence of the Brugada syndrome in an apparently healthy population. Am J Cardiol. 2000;86:91–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Miyasaka Y, Tsuji H, Yamada K, et al. Prevalence and mortality of the brugada-type electrocardiogram in one city in japan. J Am Coll Cardiol. 2001;38:771–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111:659–70.PubMedCrossRefGoogle Scholar
  50. 50.
    Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52:1567–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Benito B, Brugada R, Brugada J, et al. Brugada syndrome. Prog Cardiovasc Dis. 2008;51:1–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Rook MB. Bezzina Alshinawi C, Groenewegen WA, et al.: Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc Res. 1999;44:507–17.PubMedCrossRefGoogle Scholar
  54. 54.
    Vatta M, Dumaine R, Antzelevitch C, et al. Novel mutations in domain I of SCN5A cause Brugada syndrome. Mol Genet Metab. 2002;75:317–24.PubMedCrossRefGoogle Scholar
  55. 55.
    Vatta M, Dumaine R, Varghese G, et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002;11:337–45.PubMedCrossRefGoogle Scholar
  56. 56.
    Cordeiro JM, Barajas-Martinez H, Hong K, et al. Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome. Circulation. 2006;114:2026–33.PubMedCrossRefGoogle Scholar
  57. 57.
    Casini S, Tan HL, Bhuiyan ZA, et al. Characterization of a novel SCN5A mutation associated with Brugada syndrome reveals involvement of DIIIS4-S5 linker in slow inactivation. Cardiovasc Res. 2007;76:418–29.PubMedCrossRefGoogle Scholar
  58. 58.
    Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Delpon E, Cordeiro JM, Nunez L, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1:209–18.PubMedCrossRefGoogle Scholar
  60. 60.
    London B, Michalec M, Mehdi H, et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na + current and causes inherited arrhythmias. Circulation. 2007;116:2260–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Di Diego JM, Cordeiro JM, Goodrow RJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002;106:2004–11.PubMedCrossRefGoogle Scholar
  62. 62.
    Smits JP, Eckardt L, Probst V, et al. Genotype-phenotype relationship in Brugada syndrome: Electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002;40:350–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Meregalli PG, Tan HL, Probst V, et al. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Hear Rhythm. 2009;6:341–8.CrossRefGoogle Scholar
  64. 64.
    Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91:1512–9.PubMedGoogle Scholar
  65. 65.
    Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol. 1999;34:2035–42.PubMedCrossRefGoogle Scholar
  66. 66.
    Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRYR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103:196–200.PubMedGoogle Scholar
  67. 67.
    Laitinen PJ, Brown KM, Piippo K, et al. Mutations of the cardiac ryanodine receptor (RYR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103:485–90.PubMedGoogle Scholar
  68. 68.
    Lahat H, Eldar M, Levy-Nissenbaum E, et al. Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: Clinical features and assignment of the disease gene to chromosome 1p13-21. Circulation. 2001;103:2822–7.PubMedGoogle Scholar
  69. 69.
    di Barletta MR, Viatchenko-Karpinski S, Nori A, et al. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2006;114:1012–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106:69–74.PubMedCrossRefGoogle Scholar
  71. 71.
    Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet. 2005;42:863–70.PubMedCrossRefGoogle Scholar
  72. 72.
    Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med. 1994;331:1564–75.PubMedCrossRefGoogle Scholar
  73. 73.
    Goldberger JJ, Cain ME, Hohnloser SH, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Hear Rhythm. 2008;5:e1–21.CrossRefGoogle Scholar
  74. 74.
    Maron BJ. Hypertrophic cardiomyopathy: A systematic review. JAMA. 2002;287:1308–20.PubMedCrossRefGoogle Scholar
  75. 75.
    Maron BJ, Spirito P, Shen WK, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–12.PubMedCrossRefGoogle Scholar
  76. 76.
    Spirito P, Autore C, Rapezzi C, et al. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation. 2009;119:1703–10.PubMedCrossRefGoogle Scholar
  77. 77.
    Corrado D, Leoni L, Link MS, et al. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2003;108:3084–91.PubMedCrossRefGoogle Scholar
  78. 78.
    Turrini P, Corrado D, Basso C, et al. Dispersion of ventricular depolarization-repolarization: A noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy. Circulation. 2001;103:3075–80.PubMedGoogle Scholar
  79. 79.
    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;117:2184–91.PubMedCrossRefGoogle Scholar
  80. 80.
    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;97:2237–44.PubMedGoogle Scholar
  81. 81.
    Zareba W, Moss AJ, Sheu G, et al. Location of mutation in the kcnq1 and phenotypic presentation of long QT syndrome. J Cardiovasc Electrophysiol. 2003;14:1149–53.PubMedCrossRefGoogle Scholar
  82. 82.
    Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49:329–37.PubMedCrossRefGoogle Scholar
  83. 83.
    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;296:1249–54.PubMedCrossRefGoogle Scholar
  84. 84.
    Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84:1136–44.PubMedGoogle Scholar
  85. 85.
    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 2010Google Scholar
  86. 86.
    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;339:960–5.PubMedCrossRefGoogle Scholar
  87. 87.
    Goldenberg I, Zareba W, Moss AJ. Long QT syndrome. Curr Probl Cardiol. 2008;33:629–94.PubMedCrossRefGoogle Scholar
  88. 88.
    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;44:117–25.PubMedCrossRefGoogle Scholar
  89. 89.
    Westenskow P, Splawski I, Timothy KW, et al. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109:1834–41.PubMedCrossRefGoogle Scholar
  90. 90.
    Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105:1342–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation. 2003;108:3092–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Gehi AK, Duong TD, Metz LD, et al. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006;17:577–83.PubMedCrossRefGoogle Scholar
  93. 93.
    Delise P, Allocca G, Marras E, et al. Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach. Eur Heart J. 2011;32:169–76.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Alon Barsheshet
    • 1
  • Andrew Brenyo
    • 1
  • Arthur J. Moss
    • 1
  • Ilan Goldenberg
    • 1
  1. 1.Heart Research Follow-up ProgramUniversity of Rochester Medical CenterRochesterUSA

Personalised recommendations