Hostname: page-component-78c5997874-xbtfd Total loading time: 0 Render date: 2024-11-20T05:07:38.419Z Has data issue: false hasContentIssue false
  • English
  • Français

Genetics of sudden cardiac death in children and young athletes

Published online by Cambridge University Press:  24 July 2012

Georgia Sarquella-Brugada ,
Oscar Campuzano ,
Anna Iglesias ,
Josep Sánchez-Malagón ,
Myriam Guerra-Balic ,
Josep Brugada  and
Ramon Brugada
Georgia Sarquella-Brugada
Affiliation:
Arrhythmia Unit, Cardiology Section, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain
Oscar Campuzano
Affiliation:
Cardiovascular Genetics Center, University of Girona, Girona, Spain
Anna Iglesias
Affiliation:
Cardiovascular Genetics Center, University of Girona, Girona, Spain
Josep Sánchez-Malagón
Affiliation:
Sport Science Department, Psychology School, University Ramon Llull, Barcelona, Spain
Myriam Guerra-Balic
Affiliation:
Sport Science Department, Psychology School, University Ramon Llull, Barcelona, Spain
Josep Brugada
Affiliation:
Arrhythmia Unit, Cardiology Section, Sant Joan de Déu Hospital, University of Barcelona, Barcelona, Spain Unit of Arrhythmias, Hospital Clinic de Barcelona, University of Barcelona, Barcelona, Spain
Ramon Brugada*
Affiliation:
Cardiovascular Genetics Center, University of Girona, Girona, Spain
*
Correspondence to: Dr R. Brugada, MD, PhD, FACC, FESC, School of Medicine, Cardiovascular Genetics Center, UdG-IdIBGi, University of Girona, Girona, Spain. Tel: +34 972 183366; Fax: +34 972 183367; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Sudden cardiac death is a rare but socially devastating event. The most common causes of sudden cardiac death are congenital electrical disorders and structural heart diseases. The majority of these diseases have an incomplete penetrance and variable expression; therefore, patients may be unaware of their illness. In several cases, physical activity can be the trigger for sudden cardiac death as first symptom. Our purpose is to review the causes of sudden cardiac death in sportive children and young adults and its genetic background. Symptomatic individuals often receive an implantable cardioverter-defibrillator, the preventive treatment for sudden cardiac death in most of cases due to channelopathies, which can become a challenging option in young and active patients. The identification of one of these diseases in asymptomatic patients has similarly a great impact on their everyday life, especially on their ability to undertake competitive physical activities, and the requirement of prophylactic treatment. We review main causes of sudden cardiac death in relation to its genetics and diagnostic work-up.

Keywords

Cardiologysudden deathgeneticsinfantadolescentexercise
Type
Review Article
Information
Cardiology in the Young , Volume 23 , Issue 2 , April 2013 , pp. 159 - 173
Copyright
Copyright © Cambridge University Press 2012 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

Both authors have contributed equally.

References

1. Liberthson, RR. Sudden death from cardiac causes in children and young adults. N Engl J Med 1996; 334: 1039–1044.Google Scholar
2. Tfelt-Hansen, J, Winkel, BG, Grunnet, M, et al. Cardiac channelopathies and sudden infant death syndrome. Cardiology 2011; 119: 21–33.Google Scholar
3. Corrado, D, Migliore, F, Bevilacqua, M, et al. Sudden cardiac death in athletes: can it be prevented by screening? Herz 2009; 34: 259–266.Google Scholar
4. Maron, BJ, Gohman, TE, Aeppli, D. Prevalence of sudden cardiac death during competitive sports activities in Minnesota high school athletes. J Am Coll Cardiol 1998; 32: 1881–1884.Google Scholar
5. Corrado, D, Basso, C, Rizzoli, G, et al. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003; 42: 1959–1963.CrossRefGoogle ScholarPubMed
6. O'Donovan, G, Blazevich, AJ, Boreham, C, et al. The ABC of physical activity for health: a consensus statement from the British Association of Sport and Exercise Sciences. J Sports Sci 2010; 28: 573–591.Google Scholar
7. 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: 1391–1396.Google Scholar
8. Antzelevitch, C, Brugada, P, Borggrefe, M, et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005; 2: 429–440.Google Scholar
9. 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: 337–345.Google Scholar
10. Postema, PG, Wolpert, C, Amin, AS, et al. Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart Rhythm 2009; 6: 1335–1341.Google Scholar
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: 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. Europace 2006; 8: 746–837.Google Scholar
12. Probst, V, Denjoy, I, Meregalli, PG, et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007; 115: 2042–2048.Google Scholar
13. Zipes, DP, Ackerman, MJ, Estes, NA 3rd, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005; 45: 1354–1363.Google Scholar
14. Schwartz, PJ, Stramba-Badiale, M, Crotti, L, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009; 120: 1761–1767.Google Scholar
15. Lupoglazoff, JM, Denjoy, I, Guicheney, P. [Value of genetic testing in the management of the congenital long QT syndrome]. Arch Mal Coeur Vaiss 2003; 96: 539–547.Google Scholar
16. Roden, DM. Keep the QT interval: it is a reliable predictor of ventricular arrhythmias. Heart Rhythm 2008; 5: 1213–1215.Google Scholar
17. 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.Google Scholar
18. Kapplinger, JD, Tester, DJ, Salisbury, BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 2009; 6: 1297–1303.Google Scholar
19. 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: 2184–2191.Google Scholar
20. Gussak, I, Brugada, P, Brugada, J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94: 99–102.Google Scholar
21. Templin, C, Ghadri, JR, Rougier, JS, et al. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J 2011; 32: 1077–1088.Google Scholar
22. Brugada, R, Hong, K, Dumaine, R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109: 30–35.Google Scholar
23. Gollob, MH, Redpath, CJ, Roberts, JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011; 57: 802–812.Google Scholar
24. 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: 442–449.CrossRefGoogle ScholarPubMed
25. Gaita, F, Giustetto, C, Bianchi, F, et al. Short QT Syndrome: a familial cause of sudden death. Circulation 2003; 108: 965–970.Google Scholar
26. Tester, DJ, Kopplin, LJ, Will, ML, et al. 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: 1099–1105.Google Scholar
27. Celiker, A, Erdogan, I, Karagoz, T, et al. Clinical experiences of patients with catecholaminergic polymorphic ventricular tachycardia. Cardiol Young 2009; 19: 45–52.Google Scholar
28. Priori, SG, Napolitano, C, Memmi, M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106: 69–74.Google Scholar
29. Denjoy, I, Postma, A, Lupoglazoff, JM, et al. [Catecholinergic ventricular tachycardia in children]. Arch Mal Coeur Vaiss 2005; 98: 506–512.Google Scholar
30. Wilde, AA, Bezzina, CR. Genetics of cardiac arrhythmias. Heart 2005; 91: 1352–1358.Google Scholar
31. Tester, DJ, Arya, P, Will, M, et al. Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. Heart Rhythm 2006; 3: 800–805.Google Scholar
32. Tester, DJ, Ackerman, MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation 2011; 123: 1021–1037.Google Scholar
33. Bar-Cohen, Y, Silka, MJ. Sudden cardiac death in pediatrics. Curr Opin Pediatr 2008; 20: 517–521.Google Scholar
34. Bos, JM, Ommen, SR, Ackerman, MJ. Genetics of hypertrophic cardiomyopathy: one, two, or more diseases? Curr Opin Cardiol 2007; 22: 193–199.Google Scholar
35. Tester, DJ, Ackerman, MJ. Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children. Annu Rev Med 2009; 60: 69–84.Google Scholar
36. Maron, BJ. Hypertrophic cardiomyopathy. Lancet 1997; 350: 127–133.Google Scholar
37. Decker, JA, Rossano, JW, Smith, EO, et al. Risk factors and mode of death in isolated hypertrophic cardiomyopathy in children. J Am Coll Cardiol 2009; 54: 250–254.Google Scholar
38. Moak, JP, Leifer, ES, Tripodi, D, et al. Long-term follow-up of children and adolescents diagnosed with hypertrophic cardiomyopathy: risk factors for adverse arrhythmic events. Pediatr Cardiol 2011; 32: 1096–1105.Google Scholar
39. Lim, PO, Morris-Thurgood, JA, Frenneaux, MP. Vascular mechanisms of sudden death in hypertrophic cardiomyopathy, including blood pressure responses to exercise. Cardiol Rev 2002; 10: 15–23.Google Scholar
40. Thomson, HL, Morris-Thurgood, J, Atherton, J, et al. Reflex responses of venous capacitance vessels in patients with hypertrophic cardiomyopathy. Clin Sci (Lond) 1998; 94: 339–346.Google Scholar
41. Santini, M, Russo, M, Botto, G, et al. Clinical and arrhythmic outcomes after implantation of a defibrillator for primary prevention of sudden death in patients with post-myocardial infarction cardiomyopathy: The Survey to Evaluate Arrhythmia Rate in High-risk MI patients (SEARCH-MI). Europace 2009; 11: 476–482.Google Scholar
42. Melacini, P, Maron, BJ, Bobbo, F, et al. Evidence that pharmacological strategies lack efficacy for the prevention of sudden death in hypertrophic cardiomyopathy. Heart 2007; 93: 708–710.Google Scholar
43. Pelliccia, A, Corrado, D, Bjornstad, HH, et al. Recommendations for participation in competitive sport and leisure-time physical activity in individuals with cardiomyopathies, myocarditis and pericarditis. Eur J Cardiovasc Prev Rehabil 2006; 13: 876–885.Google Scholar
44. Pahl, E, Sleeper, LA, Canter, CE, et al. Incidence of and risk factors for sudden cardiac death in children with dilated cardiomyopathy a report from the pediatric cardiomyopathy registry. J Am Coll Cardiol 2012; 59: 607–615.Google Scholar
45. Towbin, JA, Lowe, AM, Colan, SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296: 1867–1876.CrossRefGoogle ScholarPubMed
46. Charron, P, Arad, M, Arbustini, E, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2010; 31: 2715–2726.CrossRefGoogle Scholar
47. Jefferies, JL, Towbin, JA. Dilated cardiomyopathy. Lancet 2010; 375: 752–762.Google Scholar
48. Kass, S, MacRae, C, Graber, HL, et al. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nat Genet 1994; 7: 546–551.CrossRefGoogle ScholarPubMed
49. Taylor, MR, Fain, PR, Sinagra, G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41: 771–780.Google Scholar
50. Herman, DS, Lam, L, Taylor, MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012; 366: 619–628.Google Scholar
51. McNair, WP, Ku, L, Taylor, MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation 2004; 110: 2163–2167.Google Scholar
52. Dupuis, JM, Tabib, A, Reix, P, et al. [Sudden unexpected death of cardiac origin in the 6 to 18 years population. Pathologic data. Role of sports? How can we prevent it?]. Arch Pediatr 2005; 12: 1204–1208.Google Scholar
53. Maisch, B, Hufnagel, G, Kolsch, S, et al. Treatment of inflammatory dilated cardiomyopathy and (peri)myocarditis with immunosuppression and i.v. immunoglobulins. Herz 2004; 29: 624–636.Google Scholar
54. van Berlo, JH, de Voogt, WG, van der Kooi, AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med (Berl) 2005; 83: 79–83.Google Scholar
55. Williams, GD, Hammer, GB. Cardiomyopathy in childhood. Curr Opin Anaesthesiol 2011; 24: 289–300.Google Scholar
56. Denfield, SW, Webber, SA. Restrictive cardiomyopathy in childhood. Heart Fail Clin 2010; 6: 445–452, viii.Google Scholar
57. Hayashi, T, Tsuda, E, Kurosaki, K, et al. Electrocardiographic and clinical characteristics of idiopathic restrictive cardiomyopathy in children. Circ J 2007; 71: 1534–1539.CrossRefGoogle ScholarPubMed
58. Sen-Chowdhry, S, Syrris, P, McKenna, WJ. Genetics of restrictive cardiomyopathy. Heart Fail Clin 2011; 6: 179–186.Google Scholar
59. McKenna, WJ, Thiene, G, Nava, A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994; 71: 215–218.Google Scholar
60. Marcus, FI, McKenna, WJ, Sherrill, D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010; 121: 1533–1541.Google Scholar
61. Tiso, N, Stephan, DA, Nava, A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001; 10: 189–194.Google Scholar
62. Thiene, G, Corrado, D, Basso, C. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Orphanet J Rare Dis 2007; 2: 45.Google Scholar
63. Deyell, MW, Andrade, JG, McManus, BM, et al. The other side of arrhythmogenic right ventricular cardiomyopathy. Can J Cardiol 2011; 27263: e213–e266.Google Scholar
64. Bauce, B, Nava, A, Beffagna, G, et al. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 2010; 7: 22–29.Google Scholar
65. Hamilton, RM. Arrhythmogenic right ventricular cardiomyopathy. Pacing Clin Electrophysiol 2009; 32 (Suppl 2): S44–S51.Google Scholar
66. Douglas, PS, O'Toole, ML, Hiller, WD, et al. Different effects of prolonged exercise on the right and left ventricles. J Am Coll Cardiol 1990; 15: 64–69.Google Scholar
67. Pinamonti, B, Dragos, AM, Pyxaras, SA, et al. Prognostic predictors in arrhythmogenic right ventricular cardiomyopathy: results from a 10-year registry. Eur Heart J 2011; 32: 1105–1113.Google Scholar
68. Maron, BJ. Sudden death in young athletes. N Engl J Med 2003; 349: 1064–1075.Google Scholar
69. Maron, BJ. Risk profiles and cardiovascular preparticipation screening of competitive athletes. Cardiol Clin 1997; 15: 473–483.Google Scholar
70. Zeppilli, P, dello Russo, A, Santini, C, et al. In vivo detection of coronary artery anomalies in asymptomatic athletes by echocardiographic screening. Chest 1998; 114: 89–93.Google Scholar
71. Frommelt, PC. Congenital coronary artery abnormalities predisposing to sudden cardiac death. Pacing Clin Electrophysiol 2009; 32 2 Suppl: S63–S66.Google Scholar
72. Kinoshita, N, Mimura, J, Obayashi, C, et al. Aortic root dilatation among young competitive athletes: echocardiographic screening of 1929 athletes between 15 and 34 years of age. Am Heart J 2000; 139: 723–728.Google Scholar
73. Bader, RS, Goldberg, L, Sahn, DJ. Risk of sudden cardiac death in young athletes: which screening strategies are appropriate? Pediatr Clin North Am 2004; 51: 1421–1441.Google Scholar
74. Tan, HL, Hofman, N, van Langen, IM, et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005; 112: 207–213.Google Scholar
75. Denjoy, I, Lupoglazoff, JM, Guicheney, P, et al. Arrhythmic sudden death in children. Arch Cardiovasc Dis 2008; 101: 121–125.Google Scholar
76. Corrado, D, Basso, C, Pavei, A, et al. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA 2006; 296: 1593–1601.Google Scholar
77. Drezner, JA, Chun, JS, Harmon, KG, et al. Survival trends in the United States following exercise-related sudden cardiac arrest in the youth: 2000–2006. Heart Rhythm 2008; 5: 794–799.Google Scholar
78. Corrado, D, Schmied, C, Basso, C, et al. Risk of sports: do we need a pre-participation screening for competitive and leisure athletes? Eur Heart J 2011; 32: 934–944.Google Scholar
79. Maron, BJ. Hypertrophic cardiomyopathy in childhood. Pediatr Clin North Am 2004; 51: 1305–1346.Google Scholar
80. Munoz, L, Norgan, G, Rauschhuber, M, et al. An exploratory study of cardiac health in college athletes. Appl Nurs Res 2009; 22: 228–235.Google Scholar
81. Kramer, MR, Drori, Y, Lev, B. Sudden death in young soldiers. High incidence of syncope prior to death. Chest 1988; 93: 345–347.Google Scholar
82. Link, MS, Mark Estes, NA 3rd. Sudden cardiac death in athletes. Prog Cardiovasc Dis 2008; 51: 44–57.Google Scholar
83. Balady, GJ, Cadigan, JB, Ryan, TJ. Electrocardiogram of the athlete: an analysis of 289 professional football players. Am J Cardiol 1984; 53: 1339–1343.Google Scholar
84. Gersh, BJ, Maron, BJ, Bonow, RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 58: e212–e260.Google Scholar