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Inherited Arrhythmia Syndromes: Applying the Molecular Biology and Genetic to the Clinical Management

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Abstract

Thanks to the contribution of molecular genetics, the genetic bases, the pathogenesis and genotype–phenotype correlation of diseases such as the Long QT syndrome, the Brugada Syndrome, the Progessive cardiac conduction defect (Lenegre disease), the Catecholaminergic Polymorphic Ventricular Tachycardia and Andersen Syndrome have been progressively unveiled and show an extremely high degree of genetic heterogeneity. The evidences supporting this concept are outlined with a particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in term of the relationships between genetic defect(s) and genotype(s) as well as gene-to gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways.

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References

  1. 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 

  2. Schwartz PJ, Priori SG, Napolitano C. The Long QT Syndrome. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology. From Cell to Bedside. Philadelphia: WB Saunders Co., 2000:597–615.

    Google Scholar 

  3. Coumel P, Fidelle J, Lucet V, Attuel P, Bouvrain Y. Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: Report of four cases. Br Heart J 1978;40:28–37.

    Google Scholar 

  4. Priori SG, Napolitano C. Genetic of arrhythmogenic disorders. In: Prodrid PJ, Kowey PR, eds. Cardiac Arrhythmia: Mechanisms, Diagnosis and Management. 2nd ed. Philadelphia: Lippincott Williams and Wilkins, 2001:81–107.

    Google Scholar 

  5. Jervell A, Lange-Nielsen F. Congenital deaf mutism, functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59–61.

    Google Scholar 

  6. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare in eta' pediatrica. Clin Ped 1963;45:656–657.

    Google Scholar 

  7. Ward DC. New familial cardiac syndrome in children. J Irish Med Ass 1964;54:103.

    Google Scholar 

  8. Keating MT, 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;252:704–706.

    Google Scholar 

  9. Jiang C, Atkinson D, Towbin JA, Splawski I, Lehmann MH, Li H, Timothy K, Taggart RT, Schwartz PJ, Vincent Inherited Arrhythmia Syndromes 99 GM. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 1994;8:141–147.

    Google Scholar 

  10. Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, Donnelly P, Vergnaud G, Bachner L, Moisan JP. Mapping of a gene for long QT syndrome to chromosome 4q25–27. Am J Hum Genet 1995;57:1114–1122.

    Google Scholar 

  11. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17–23.

    Google Scholar 

  12. 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;80:795–803.

    Google Scholar 

  13. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805–811.

    Google Scholar 

  14. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997;17:338–340.

    Google Scholar 

  15. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–187.

    Google Scholar 

  16. Schott J, Mohler P, Gramolini AO, Haurognè K, Escande D, Le Marec H. Mutation in the ankyrin-b gene causes long QT syndrome and sinus node dysfunction. Circulation 2002;106(suppl II):308.

    Google Scholar 

  17. Chauhan VS, Tuvia S, Buhusi M, Bennett V, Grant AO. Abnormal cardiac Na(+) channel properties and QT heart rate adaptation in neonatal ankyrin(B) knockout mice. Circ Res 2000;86:441–447.

    Google Scholar 

  18. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178–1185.

    Google Scholar 

  19. Napolitano C, Ronchetti E, Memmi M, Nastoli J, Faggiano G, Schwartz PJ, Priori SG. Molecular Epidemiology of the Long QT Syndrome in a cohort of 267 probands. J Am Coll Cardiol 2001;37(Abs. Suppl A):87A.

    Google Scholar 

  20. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, Schwartz PJ, Towbin JA, Vincent GM, Lehmann MH. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929–2934.

    Google Scholar 

  21. Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation 2000;102:2849–2855.

    Google Scholar 

  22. Priori SG, Napolitano C, Cantu F, Brown AM, Schwartz PJ. Differential response to Na+ channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome. Circ Res 1996;78:1009–1015.

    Google Scholar 

  23. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. 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;92:3381–3386.

    Google Scholar 

  24. Moretti P, Calcaterra G, Napolitano C, Bloise R, Ronchetti E, Schwartz PJ, Priori SG. High prevalence of concealed Long QT Syndrome among carriers of KVLQT1 defects. Circulation 2001;102(Abs Suppl):II-584.

    Google Scholar 

  25. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348(19):1866–1874.

    Google Scholar 

  26. Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P. KVLQT1 C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome. Circulation 1997;96:2778–2781.

    Google Scholar 

  27. Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z. 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;19;105:794–799.

    Google Scholar 

  28. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89–95.

    Google Scholar 

  29. Wilde AM, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, van Tintelen JP, Smeets HJ, Meyer H, Geelen JL. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999;33:332.

    Google Scholar 

  30. Moss AJ, Robinson JL, Gessman L, Gillespie R, Zareba W, Schwartz PJ, Vincent GM, Benhorin J, Heilbron EL, Towbin JA, Priori SG, Napolitano C, Zhang L, Medina A, Andrews ML, Timothy K. 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;84:876–879.

    Google Scholar 

  31. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a genespecific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999;74:1088–1094.

    Google Scholar 

  32. Priori SG, Napolitano C, Grillo M. Concealed arrhythmogenic syndromes: The hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res 2001;50:218–223.

    Google Scholar 

  33. Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000;343:262–267.

    Google Scholar 

  34. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular 100 Priori, Napolitano and Vicentini analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001;286:2264–2269.

    Google Scholar 

  35. Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. 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 

  36. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–296.

    Google Scholar 

  37. Priori SG, Napolitano C, Gasparini M, Pappone C, Bella PD, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural History of Brugada Syndrome. Insights for Risk Stratification and Management. Circulation 2002;105:1342–1347.

    Google Scholar 

  38. Weiss R, Barmada MM, Nguyen T, Seibel JS, Cavlovich D, Kornblit CA, Angelilli A, Villanueva F, McNamara DM, London B. Clinical and molecular heterogeneity in the Brugada syndrome: A novel gene locus on chromosome 3. Circulation 2002;105:707–713.

    Google Scholar 

  39. Priori SG, Napolitano C, Giordano U, Collisani G, Memmi M. Brugada syndrome and sudden cardiac death in children. Lancet 2000;355:808–809.

    Google Scholar 

  40. Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited brugada and LQT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem 2001;276:30623–30630.

    Google Scholar 

  41. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510–515.

    Google Scholar 

  42. Brugada J, Brugada R, Brugada P. Brugada syndrome. Arch Mal Coeur Vaiss 1999;92:847–850.

    Google Scholar 

  43. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A. Effects of flecainide in patients with new SCN5A mutation: Mutation-specific therapy for long-QT syndrome? Circulation 2000;101:1698–1706.

    Google Scholar 

  44. 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;102:945–947.

    Google Scholar 

  45. Smits JP, Eckardt L, Probst V, Bezzina CR, Schott JJ, Remme CA, Haverkamp W, Breithardt G, Escande D, Schulze-Bahr E, LeMarec H, Wilde AA. Genotypephenotype relationship in Brugada syndrome: Electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J AmColl Cardiol 2002;40:350–356.

    Google Scholar 

  46. Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, Der Hout AH, Mannens MM, Wilde AA. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999;85:1206–1213.

    Google Scholar 

  47. Antzelevitch C. The Brugada syndrome. J Cardiovasc Electrophysiol 1998;9:513–516.

    Google Scholar 

  48. Clancy CE, Rudy Y. Na+ channel mutation that causes both brugada and long-QT syndrome phenotypes: A simulation study of mechanism. Circulation 2002;105:1208–1213.

    Google Scholar 

  49. Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori S. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 2002;110:1201–1209.

    Google Scholar 

  50. Priori SG. Foretelling the future in Brugada syndrome: Do we have the crystal ball? J Cardiovasc Electrophysiol 2001;12:1008–1009.

    Google Scholar 

  51. Brugada P, Geelen P, Brugada R, Mont L, Brugada J. Prognostic value of electrophysiologic investigations in Brugada syndrome. J Cardiovasc Electrophysiol 2001;12:1004–1007.

    Google Scholar 

  52. Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-segment elevation in leads V1 through V3: A marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998;97:457–460.

    Google Scholar 

  53. Priori SG, Napolitano C, Gasparini M, Pappone C, Della BP, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, Schwartz PJ. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families. Circulation 2000;102:2509–2515.

    Google Scholar 

  54. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and St-segment elevation in precordial leads V1 to V3. Circulation 2002;105:73–78.

    Google Scholar 

  55. Eckardt L, Kirchhof P, Schulze-Bahr E, Bruns HJ, Breithardt G, Borggrefe M, Haverkamp W. Mode of induction of ventricular tachyarrhythmias in Brugada syndrome. Pacing Clin Electrophysiol 2001;24:558.

    Google Scholar 

  56. Gasparini M, Priori SG, Mantica M, Coltorti F, Napolitano C, Galimberti P, Bloise R, Ceriotti C. Programmed electrical stimulation in Brugada syndrome: How reproducible are the results? J Cardiovasc Electrophysiol 2002;13:880–887.

    Google Scholar 

  57. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol 1996;27:1061–1070.

    Google Scholar 

  58. Wichter T, Matheja P, Eckardt L, Kies P, Schafers K, Schulze-Bahr E, Haverkamp W, Borggrefe M, Schober O, Breithardt G, Schafers M. Cardiac autonomic dysfunction in brugada syndrome. Circulation 2002;105:702–706.

    Google Scholar 

  59. Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, Yokoseki O, Kitabayashi H, Takahashi W, Yazaki Y, Watanabe N, Imamura H, Kubo K. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol 2001;24:1293–1294.

    Google Scholar 

  60. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–1519.

    Google Scholar 

  61. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, DeLogu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69–74.

    Google Scholar 

  62. Fisher JD, Krikler D, Hallidie-Smith KA. Familial polymorphic ventricular arrhythmias: A quarter century of Inherited Arrhythmia Syndromes 101 successful medical treatment based on serial exercise-pharmacologic testing. J Am Coll Cardiol 1999;34:2015–2022.

    Google Scholar 

  63. Swan H, Piippo K, Viitasalo M, Heikkila P, Paavonen T, Kainulainen K, Kere J, Keto P, Kontula K, Toivonen L. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999;34:2035–2042.

    Google Scholar 

  64. Otsu K, Fujii J, Periasamy M, Difilippantonio M, Uppender M, Ward DC, MacLennan DH. Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes. Genomics 1993;17:507–509.

    Google Scholar 

  65. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation 2001;103:196–200.

    Google Scholar 

  66. Wellens HJJ. The electrocardiogram in digitalis intoxication. In: Yu PN, Godwind JF, eds. Progress in Cardiology. Philadelphia: Lea & Fabinger, 2001:271–290.

    Google Scholar 

  67. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 1983;245:C1–14.

    Google Scholar 

  68. Priori SG, Corr PB. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am J Physiol 1990;258:H1796–H1805.

    Google Scholar 

  69. Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song LS, Rosemblit N, D'Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 2003;113(7):829–840.

    Google Scholar 

  70. Lahat H, Eldar M, Levy-Nissenbaum E, Bahan T, Friedman E, Khoury A, Lorber A, Kastner DL, Goldman B, Pras E. Autosomal recessive catecholamine-or exercise-induced polymorphic ventricular tachycardia. Circulation 2001;103:2822–2827.

    Google Scholar 

  71. Lahat H, Pras E, Olender T, Avidan N, Ben Asher E, Man O, Levy-Nissenbaum E, Khoury A, Lorber A, Goldman B, Lancet D, Eldar M. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet 2001;69:1378–1384.

    Google Scholar 

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  1. Molecular Cardiology, IRCCS Fondazione S Maugeri, University of Pavia, Pavia, Italy

    Silvia G. Priori, Carlo Napolitano & Alessandro Vicentini

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  1. Silvia G. Priori
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  2. Carlo Napolitano
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  3. Alessandro Vicentini
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Correspondence to Silvia G. Priori.

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Priori, S.G., Napolitano, C. & Vicentini, A. Inherited Arrhythmia Syndromes: Applying the Molecular Biology and Genetic to the Clinical Management. J Interv Card Electrophysiol 9, 93–101 (2003). https://doi.org/10.1023/A:1026255617913

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