Genetics, Molecular Biology, and Emerging Concepts of Early Repolarization Syndrome

  • Charles Antzelevitch
  • Gregory Dendramis


Early repolarization pattern (ERP) has traditionally been regarded as benign and is often encountered in apparently healthy individuals. In the absence of organic heart disease and when associated with ventricular tachycardia (VT) or fibrillation (VF), ERP is referred to as early repolarization syndrome (ERS) and is considered to be one of the J wave syndromes (JWS). To date, ERS has been associated with variants in seven different genes but a large number of variants remain in “genetic purgatory.” In ERS, an outward shift in the balance of current during the early phase of the left ventricular (LV) epicardial action potential (AP) secondary to genetic defects in either inward or outward currents is thought to lead to accentuation of the Ito-mediated action potential (AP) notch in ventricular epicardium but not endocardium, giving rise to a J wave in the ECG, particularly in the inferior LV. Loss of the AP dome at some epicardial sites but not others creates an epicardial dispersion of repolarization giving rise to phase 2 reentrant extrasystole. Loss of the epicardial AP dome also creates a transmural dispersion of repolarization giving rise to a vulnerable window across the ventricular wall which when captured by the closely coupled phase 2 reentrant extrasystole can induce VT/VF. Recent consensus statements and guidelines provide recommendations for therapy of ERS. The most effective therapy for the prevention of SCD in high-risk ERS patients is an implantable cardioverter defibrillator (ICD). The pharmacologic approach to therapy involves inhibition of Ito, augmentation of ICa or slowing of inactivation of INa. Experimental evidence has been advanced showing an ameliorative effect of radiofrequency ablation of the inferior LV epicardium; however clinical data are lacking at this time.


Sudden cardiac death Cardiac electrophysiology  J wave syndrome  Cardiac arrhythmias  Sudden cardiac death 

Abbreviations and Acronyms


action potential






early repolarization syndrome


Brugada syndrome


J wave syndromes


left ventricle




radiofrequency ablation


right ventricular outflow tract


ventricular fibrillation


ventricular tachycardia



We acknowledge support from NIH-NHLBI Grant #HL47678, the W.W. Smith Charitable Trust Grant #1820 and from the Martha and Wistar Morris Fund.


  1. 1.
    Wasserburger RH, Alt WJ. The normal RS-T segment elevation variant. Am J Cardiol. 1961;8:184–92.CrossRefGoogle Scholar
  2. 2.
    Mehta MC, Jain AC. Early repolarization on scalar electrocardiogram. Am J Med Sci. 1995;309(6):305–11.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Clements SD, Hurst JW. Diagnostic value of ECG abnormalities observed in subjects accidentally exposed to cold. Am J Cardiol. 1972;29:729–34.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Thompson R, Rich J, Chmelik F, Nelson WL. Evolutionary changes in the electrocardiogram of severe progressive hypothermia. J Electrocardiol. 1977;10:67–70.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Eagle K. Images in clinical medicine. Osborn waves of hypothermia. N Engl J Med. 1994;10:680.CrossRefGoogle Scholar
  6. 6.
    Kraus F. Ueber die wirkung des kalziums auf den kreislauf 1. Dtsch Med Wochenschr. 1920;46(8):201–3.CrossRefGoogle Scholar
  7. 7.
    Sridharan MR, Horan LG. Electrocardiographic J wave of hypercalcemia. Am J Cardiol. 1984;54:672–3.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Sato A, Tanabe Y, Chinushi M, Hayashi Y, Yoshida T, Ito E, et al. Analysis of J waves during myocardial ischaemia. Europace. 2012;14(5):715–23.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol. 2000;33(4):299–309.CrossRefGoogle Scholar
  10. 10.
    Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm. 2010;7(4):549–58.CrossRefGoogle Scholar
  11. 11.
    Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation. 1999;100(15):1660–6.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Shu J, Zhu T, Yang L, Cui C, Yan GX. ST-segment elevation in the early repolarization syndrome, idiopathic ventricular fibrillation, and the Brugada syndrome: cellular and clinical linkage. J Electrocardiol. 2005;38(4 Suppl):26–32.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Haissaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, De Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med. 2008;358(19):2016–23.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Nam GB, Kim YH, Antzelevitch C. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med. 2008;358(19):2078–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Rosso R, Kogan E, Belhassen B, Rozovski U, Scheinman MM, Zeltser D, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol. 2008;52(15):1231–8.CrossRefGoogle Scholar
  16. 16.
    Macfarlane P, Antzelevitch C, Haissaguerre M, Huikuri HPMRR, Sacher F, Tikkanen J, Wellens H, Yan G-X. Consensus paper- early repolarization pattern. J Am Coll Cardiol. 2015; In Press.Google Scholar
  17. 17.
    Kawata H, Noda T, Yamada Y, Okamura H, Satomi K, Aiba T, et al. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome. Heart Rhythm. 2012;9(1):77–83.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Nakagawa K, Nagase S, Morita H, Ito H. Left ventricular epicardial electrogram recordings in idiopathic ventricular fibrillation with inferior and lateral early repolarization. Heart Rhythm. 2013;11(2):314–7.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    McIntyre WF, Perez-Riera AR, Femenia F, Baranchuk A. Coexisting early repolarization pattern and Brugada syndrome: recognition of potentially overlapping entities. J Electrocardiol. 2012;45(3):195–8.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Nam GB, Ko KH, Kim J, Park KM, Rhee KS, Choi KJ, et al. Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome. Eur Heart J. 2010;31(3):330–9.CrossRefGoogle Scholar
  21. 21.
    Antzelevitch C, Yan GX, Ackerman MJ, Borggrefe M, Corrado D, Guo J, et al. J-Wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. Heart Rhythm. 2016;32(5):315–39.Google Scholar
  22. 22.
    Kawada SMH, Antzelevitch C, Morimoto Y, Nakagawa K, Atsuyuki W, Nishii N, Nakamura K, Ito H. The Shanghai score system for diagnosis of Brugada syndrome. JACC Clin Electrophysiol. In press, 2018.Google Scholar
  23. 23.
    Rosso R, Adler A, Halkin A, Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective. Heart Rhythm. 2011;8(6):923–9.CrossRefGoogle Scholar
  24. 24.
    Tikkanen JT, Junttila MJ, Anttonen O, Aro AL, Luttinen S, Kerola T, et al. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome. Circulation. 2011;123(23):2666–73.CrossRefGoogle Scholar
  25. 25.
    Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med. 2009;361(26):2529–37.CrossRefGoogle Scholar
  26. 26.
    Sinner MF, Reinhard W, Muller M, Beckmann BM, Martens E, Perz S, et al. Association of early repolarization pattern on ecg with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA). PLoS Med. 2010;7(7):e1000314.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Haruta D, Matsuo K, Tsuneto A, Ichimaru S, Hida A, Sera N, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation. 2011;123:2931–7.CrossRefGoogle Scholar
  28. 28.
    Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116(12):1887–906.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Nam GB. Idiopathic ventricular fibrillation, early repolarization and other J wave-related ventricular fibrillation syndromes. Circ J. 2012;76(12):2723–31.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Antzelevitch C. J wave syndromes: molecular and cellular mechanisms. J Electrocardiol. 2013;46(6):510–8.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996;93(2):372–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52(19):1567–73.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Kamakura T, Kawata H, Nakajima I, Yamada Y, Miyamoto K, Okamura H, et al. Significance of non-type 1 anterior early repolarization in patients with inferolateral early repolarization syndrome. J Am Coll Cardiol. 2013;62(17):1610–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Kalla H, Yan GX, Marinchak R. Ventricular fibrillation in a patient with prominent J (Osborn) waves and ST segment elevation in the inferior electrocardiographic leads: a Brugada syndrome variant? J Cardiovasc Electrophysiol. 2000;11(1):95–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Aizawa Y, Sato A, Watanabe H, Chinushi M, Furushima H, Horie M, et al. Dynamicity of the J-wave in idiopathic ventricular fibrillation with a special reference to pause-dependent augmentation of the J-wave. J Am Coll Cardiol. 2012;59(22):1948–53.CrossRefGoogle Scholar
  36. 36.
    Nademanee K. Sudden unexplained death syndrome in Southeast Asia. Am J Cardiol. 1997;79(6A):10–1.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Matsumoto AM. Fundamental aspects of hypogonadism in the aging male. Rev Urol. 2003;5(Suppl 1):S3–s10.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Shimizu W, Kamakura S. Catecholamines in children with congenital long QT syndrome and Brugada syndrome. J Electrocardiol. 2001;34(Suppl):173–5.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Suzuki H, Torigoe K, Numata O, Yazaki S. Infant case with a malignant form of Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1277–80.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Ohgo T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T, et al. Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm. 2007;4(6):695–700.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Watanabe A, Fukushima KK, Morita H, Miura D, Sumida W, Hiramatsu S, et al. Low-dose isoproterenol for repetitive ventricular arrhythmia in patients with Brugada syndrome. Eur Heart J. 2006;27(13):1579–83.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Hermida JS, Denjoy I, Clerc J, Extramiana F, Jarry G, Milliez P, et al. Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. 2004;43(10):1853–60.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731–7.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Tsuchiya T, Ashikaga K, Honda T, Arita M. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2002;13(7):698–701.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Iguchi K, Noda T, Kamakura S, Shimizu W. Beneficial effects of cilostazol in a patient with recurrent ventricular fibrillation associated with early repolarization syndrome. Heart Rhythm. 2013;10(4):604–6.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Agac MT, Erkan H, Korkmaz L. Conversion of Brugada type I to type III and successful control of recurrent ventricular arrhythmia with cilostazol. Arch Cardiovasc Dis. 2013.Google Scholar
  47. 47.
    Hasegawa K, Ashihara T, Kimura H, Jo H, Itoh H, Yamamoto T, et al. Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy? Intern Med. 2014;53(14):1523–6.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Shinohara T, Ebata Y, Ayabe R, Fukui A, Okada N, Yufu K, et al. Combination therapy of cilostazol and bepridil suppresses recurrent ventricular fibrillation related to J-wave syndromes. Heart Rhythm. 2014;11(8):1441–5.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Haissaguerre M, Sacher F, Nogami A, Komiya N, Bernard A, Probst V, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy. J Am Coll Cardiol. 2009;53(7):612–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Junttila MJ, Tikkanen JT, Kentta T, Anttonen O, Aro AL, Porthan K, et al. Early repolarization as a predictor of arrhythmic and nonarrhythmic cardiac events in middle-aged subjects. Heart Rhythm. 2014;11(10):1701–6.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L, Rothery S, et al. Fibrosis, Connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol. 2015;66(18):1976–86.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ghosh S, Cooper DH, Vijayakumar R, Zhang J, Pollak S, Haissaguerre M, et al. Early repolarization associated with sudden death: insights from noninvasive electrocardiographic imaging. Heart Rhythm. 2010;7(4):534–7.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Zhang J, Sacher F, Hoffmayer K, O'Hara T, Strom M, Cuculich P, et al. Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients. Circulation. 2015;131(22):1950–9.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Noda T, Shimizu W, Tanaka K, Chayama K. Prominent J wave and ST segment elevation: serial electrocardiographic changes in accidental hypothermia. J Cardiovasc Electrophysiol. 2003;14(2):223.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bastiaenen R, Hedley PL, Christiansen M, Behr ER. Therapeutic hypothermia and ventricular fibrillation storm in early repolarization syndrome. Heart Rhythm. 2010;7(6):832–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Federman NJ, Mechulan A, Klein GJ, Krahn AD. Ventricular fibrillation induced by spontaneous hypothermia in a patient with early repolarization syndrome. J Cardiovasc Electrophysiol. 2013;24:586–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Kowalczyk E, Kasprzak JD, Lipiec P. Giant J-wave and Brugada-like pattern in a patient with severe hypothermia. Acta Cardiol. 2014;69(1):66–7.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    RuDusky BM. The electrocardiogram in hypothermia-the J wave and the Brugada syndrome. Am J Cardiol. 2004;93(5):671–2.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Patel RB, Ng J, Reddy V, Chokshi M, Parikh K, Subacius H, et al. Early repolarization associated with ventricular arrhythmias in patients with chronic coronary artery disease. Circ Arrhythm Electrophysiol. 2010;3(5):489–95.CrossRefGoogle Scholar
  60. 60.
    Amin AS, Meregalli PG, Bardai A, Wilde AA, Tan HL. Fever increases the risk for cardiac arrest in the Brugada syndrome. Ann Intern Med. 2008;149(3):216–8.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Rattanawong P, Vutthikraivit W, Charoensri A, Jongraksak T, Prombandankul A, Kanjanahattakij N, et al. Fever-induced Brugada syndrome is more common than previously suspected: a cross-sectional study from an endemic area. Ann Noninvasive Electrocardiol. 2015.Google Scholar
  62. 62.
    Kawata H, Morita H, Yamada Y, Noda T, Satomi K, Aiba T, et al. Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: a novel risk factor for Brugada syndrome with ventricular fibrillation. Heart Rhythm. 2013;10(8):1161–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Noseworthy PA, Tikkanen JT, Porthan K, Oikarinen L, Pietila A, Harald K, et al. The early repolarization pattern in the general population clinical correlates and heritability. J Am Coll Cardiol. 2011;57(22):2284–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Reinhard W, Kaess BM, Debiec R, Nelson CP, Stark K, Tobin MD, et al. Heritability of early repolarization: a population-based study. Circ Cardiovasc Genet. 2011;4(2):134–8.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Nunn LM, Bhar-Amato J, Lowe MD, Macfarlane PW, Rogers P, McKenna WJ, et al. Prevalence of J-point elevation in sudden arrhythmic death syndrome families. J Am Coll Cardiol. 2011;58(3):286–90.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Haissaguerre M, Chatel S, Sacher F, Weerasooriya R, Probst V, Loussouarn G, et al. Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol. 2009;20(1):93–8.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Medeiros-Domingo A, Tan BH, Crotti L, Tester DJ, Eckhardt L, Cuoretti A, et al. Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart Rhythm. 2010;7(10):1466–71.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Barajas-Martinez H, Hu D, Ferrer T, Onetti CG, Wu Y, Burashnikov E, et al. Molecular genetic and functional association of Bugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart Rhythm. 2012;9(4):548–55.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Burashnikov E, Pfeiffer R, Barajas-Martinez H, Delpon E, Hu D, Desai M, et al. Mutations in the cardiac L-type calcium channel associated J wave syndrome and sudden cardiac death. Heart Rhythm. 2010;7(12):1872–82.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Watanabe H, Nogami A, Ohkubo K, Kawata H, Hayashi Y, Ishikawa T, et al. Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization. Circ Arrhythm Electrophysiol. 2011;4(6):874–81.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Hu D, Barajas-Martinez H, Pfeiffer R, Dezi F, Pfeiffer J, Buch T, et al. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol. 2014;64(1):66–79.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AA. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol. 2013;62(3):169–80.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Osborn JJ. Experimental hypothermia: respiratory and blood pH changes in relation to cardiac function. Am J Phys. 1953;175:389–98.CrossRefGoogle Scholar
  74. 74.
    Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res. 1988;62(1):116–26.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Litovsky SH, Antzelevitch C. Differences in the electrophysiology of ventricular epicardium and endocardium as the basis for the Osborne wave. Circulation. 1989;80:II–129.Google Scholar
  76. 76.
    Di Diego JM, Sun ZQ, Antzelevitch C. Ito and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Phys. 1996;271:H548–H61.Google Scholar
  77. 77.
    Antzelevitch C, Yan GX. J-wave syndromes: Brugada and early repolarization syndromes. Heart Rhythm. 2015;12(8):1852–66.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Koncz I, Gurabi Z, Patocskai B, Panama BK, Szel T, Hu D, et al. Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome. J Mol Cell Cardiol. 2014;68C:20–8.CrossRefGoogle Scholar
  79. 79.
    Wilhelm M, Brem MH, Rost C, Klinghammer L, Hennig FF, Daniel WG, et al. Early repolarization, left ventricular diastolic function, and left atrial size in professional soccer players. Am J Cardiol. 2010;106(4):569–74.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Marcus RR, Kalisetti D, Raxwal V, Kiratli BJ, Myers J, Perkash I, et al. Early repolarization in patients with spinal cord injury: prevalence and clinical significance. J Spinal Cord Med. 2002;25(1):33–8.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Mizumaki K, Nishida K, Iwamoto J, Nakatani Y, Yamaguchi Y, Sakamoto T, et al. Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation. Heart Rhythm. 2012;9(2):249–55.CrossRefGoogle Scholar
  82. 82.
    Koutbi L, Roussel M, Haissaguerre M, Deharo JC. Hyperpnea test triggering malignant ventricular arrhythmia in a child with early repolarization. Heart Rhythm. 2012;9(7):1153–6.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Brugada J, Brugada R, Brugada P. Pharmacological and device approach to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death. J Electrocardiol. 2000;33(Suppl):41–7.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Nademanee K, Veerakul G, Mower M, Likittanasombat K, Krittayapong R, Bhuripanyo K, et al. Defibrillator versus beta-blockers for unexplained death in Thailand (DEBUT): a randomized clinical trial. Circulation. 2003;107(17):2221–6.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y, et al. Outcome after implantation of cardioverter-defibrillator in patients with Brugada syndrome: a Multicenter Study - Part 2. Circulation. 2013;128(16):1739–47.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, et al. Implantable cardioverter-defibrillator therapy in brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol. 2015;65(9):879–88.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Sacher F, Probst V, Bessouet M, Wright M, Maluski A, Abbey S, et al. Remote implantable cardioverter defibrillator monitoring in a Brugada syndrome population. Europace. 2009;11(4):489–94.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    De Maria E, Olaru A, Cappelli S. The entirely subcutaneous defibrillator (s-icd): state of the art and selection of the ideal candidate. Curr Cardiol Rev. 2015;11(2):180–6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    van Den Berg MP, Wilde AA, Viersma TJW, Brouwer J, Haaksma J, van der Hout AH, et al. Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. J Cardiovasc Electrophysiol. 2001;12(6):630–6.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Bertomeu-Gonzalez V, Ruiz-Granell R, Garcia-Civera R, Morell-Cabedo S, Ferrero A. Syncopal monomorphic ventricular tachycardia with pleomorphism, sensitive to antitachycardia pacing in a patient with Brugada syndrome. Europace. 2006;8(12):1048–50.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Lee KL, Lau C, Tse H, Wan S, Fan K. Prevention of ventricular fibrillation by pacing in a man with Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11(8):935–7.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Haissaguerre M, SFDNJLDIdRLPJLNABDY-MSAFA. Early repolarization in the inferolateral leads: a new syndrome associated with sudden cardiac death. J Interv Card Electrophysiol. 2007;18:281.CrossRefGoogle Scholar
  93. 93.
    Chatzidou S, Repasos E, Plastiras S, Kontogiannis C, Kosmopoulos M, Tsilimigras DI, et al. Repetitive-incessant electrical storm triggered by early repolarization. Ann Noninvasive Electrocardiol. 2017.Google Scholar
  94. 94.
    Latcu DG, Bun SS, Zarqane N, Saoudi N. Ablation of left ventricular substrate in early repolarization syndrome. J Cardiovasc Electrophysiol. 2016;27(4):490–1.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Kakihara J, Takagi M, Hayashi Y, Tatsumi H, Doi A, Yoshiyama M. Radiofrequency catheter ablation for treatment of premature ventricular contractions triggering ventricular fibrillation from the right ventricular outflow tract in a patient with early repolarization syndrome. HeartRhythm Case Rep. 2016;2(4):342–6.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123(12):1270–9.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cortez-Dias N, Placido R, Marta L, Bernardes A, Sobral S, Carpinteiro L, et al. Epicardial ablation for prevention of ventricular fibrillation in a patient with Brugada syndrome. Rev Port Cardiol. 2014;33(5):305.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Shah AJ, Hocini M, Lamaison D, Sacher F, Derval N, Haissaguerre M. Regional substrate ablation abolishes Brugada syndrome. J Cardiovasc Electrophysiol. 2011;22(11):1290–1.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Sacher F, Jesel L, Jais P, Haissaguerre M. Insight into the mechanism of Brugada syndrome: epicardial substrate and modification during ajmaline testing. Heart Rhythm. 2014;11(4):732–4.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Brugada J, Pappone C, Berruezo A, Vicedomini G, Manguso F, Ciconte G, et al. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol. 2015;8:1373.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;15(10):1389–406.Google Scholar
  102. 102.
    Yoon N, Patocskai B, Antzelevitch C. Epicardial substrate as a target for radiofrequency ablation in an experimental model of early repolarization syndrome. Circ Arrhythm Electrophysiol. 2018; In press.Google Scholar
  103. 103.
    Antzelevitch C, Brugada P, Brugada J, Brugada R, Nademanee K, Towbin JA. Clinical approaches to tachyarrhythmias. The Brugada syndrome, vol. 1999. Armonk: Futura Publishing Company, Inc.; 1999.Google Scholar
  104. 104.
    Minoura Y, Di Diego JM, Barajas-Martinez H, Zygmunt AC, Hu D, Sicouri S, et al. Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants. J Cardiovasc Electrophysiol. 2012;23(4):423–32.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Minoura Y, Panama BK, Nesterenko VV, Betzenhauser M, Barajas-Martinez H, Hu D, et al. Effect of Wenxin Keli and quinidine to suppress arrhythmogenesis in an experimental model of Brugada syndrome. Heart Rhythm. 2013;10(7):1054–62.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Szel T, Antzelevitch C. Abnormal repolarization as the basis for late potentials and fractionated electrograms recorded from epicardium in experimental models of brugada syndrome. J Am Coll Cardiol. 2014;63(19):2037–45.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Johson P, Lesage A, Floyd WL, Young WG Jr, Sealy WC. Prevention of ventricular fibrillation during profound hypothermia by quinidine. Ann Surg. 1960;151:490–5.Google Scholar
  108. 108.
    Belhassen B, Shapira I, Shoshani D, Paredes A, Miller H, Laniado S. Idiopathic ventricular fibrillation: inducibility and beneficial effects of class I antiarrhythmic agents. Circulation. 1987;75(4):809–16.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Belhassen B, Viskin S, Antzelevitch C. The Brugada syndrome: is an implantable cardioverter defibrillator the only therapeutic option? Pacing Clin Electrophysiol. 2002;25(11):1634–40.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Alings M, Dekker L, Sadee A, Wilde A. Quinidine induced electrocardiographic normalization in two patients with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24(9 Pt 1):1420–2.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Belhassen B, Viskin S. Pharmacologic approach to therapy of Brugada syndrome: quinidine as an alternative to ICD therapy? In: Antzelevitch C, Brugada P, Brugada J, Brugada R, editors. The Brugada syndrome: from bench to bedside. Oxford: Blackwell Futura; 2004. p. 202–11.Google Scholar
  112. 112.
    Viskin S, Wilde AA, Tan HL, Antzelevitch C, Shimizu W, Belhassen B. Empiric quinidine therapy for asymptomatic Brugada syndrome: time for a prospective registry. Heart Rhythm. 2009;6(3):401–4.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Belhassen B, Glick A, Viskin S. Excellent long-term reproducibility of the electrophysiologic efficacy of quinidine in patients with idiopathic ventricular fibrillation and Brugada syndrome. Pacing Clin Electrophysiol. 2009;32(3):294–301.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Marquez MF, Bonny A, Hernandez-Castillo E, De SA, Gomez-Flores J, Nava S, et al. Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverter-defibrillator: a case series and literature review. Heart Rhythm. 2013;9(12):1995–2000.CrossRefGoogle Scholar
  115. 115.
    Pellegrino PL, Di BM, Brunetti ND. Quinidine for the management of electrical storm in an old patient with Brugada syndrome and syncope. Acta Cardiol. 2013;68(2):201–3.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Probst V, Evain S, Gournay V, Marie A, Schott JJ, Boisseau P, et al. Monomorphic ventricular tachycardia due to brugada syndrome successfully treated by hydroquinidine therapy in a 3-year-old child. J Cardiovasc Electrophysiol. 2006;17(1):97–100.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Schweizer PA, Becker R, Katus HA, Thomas D. Successful acute and long-term management of electrical storm in Brugada syndrome using orciprenaline and quinine/quinidine. Clin Res Cardiol. 2010;99(7):467–70.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Marquez MF, Rivera J, Hermosillo AG, Iturralde P, Colin L, Moragrega JL, et al. Arrhythmic storm responsive to quinidine in a patient with Brugada syndrome and vasovagal syncope. Pacing Clin Electrophysiol. 2005;28(8):870–3.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Viskin S, Antzelevitch C, Marquez MF, Belhassen B. Quinidine: a valuable medication joins the list of 'endangered species'. Europace. 2007;12(12):1105–6.CrossRefGoogle Scholar
  120. 120.
    Rosso R, Glick A, Glikson M, Wagshal A, Swissa M, Rosenhek S, et al. Outcome after implantation of cardioverter defribrillator in patients with Brugada syndrome: a multicenter Israeli study (ISRABRU). Isr Med Assoc J. 2008;10(6):435–9.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Belhassen B, Rahkovich M, Michowitz Y, Glick A, Viskin S. Management of Brugada Syndrome: a 33-year experience using electrophysiologically-guided therapy with class 1A antiarrhythmic drugs. Circ Arrhythm Electrophysiol. 2015;8:1393.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Sacher F, Derval N, Horlitz M, Haissaguerre M. J wave elevation to monitor quinidine efficacy in early repolarization syndrome. J Electrocardiol. 2014;47(2):223–5.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol. 2001;12(2):268–72.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Kyriazis K, Bahlmann E, van der SH, Kuck KH. Electrical storm in Brugada syndrome successfully treated with orciprenaline; effect of low-dose quinidine on the electrocardiogram. Europace. 2009;11(5):665–6.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Gurabi Z, Koncz I, Patocskai B, Nesterenko VV, Antzelevitch C. Cellular mechanism underlying hypothermia-induced VT/VF in the setting of early repolarization and the protective effect of quinidine, cilostazol and milrinone. Circ Arrhythm Electrophysiol. 2014;7(1):134–42.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Szel T, Koncz I, Antzelevitch C. Cellular mechanisms underlying the effects of milrinone and cilostazol to suppress arrhythmogenesis associated with Brugada syndrome. Heart Rhythm. 2013;10(11):1720–7.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Shimizu W, Matsuo K, Takagi M, Tanabe Y, Aiba T, Taguchi A, et al. Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol. 2000;11(4):396–404.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A, et al. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24(8 Pt 1):1293–4.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Mok NS, Chan NY, Chi-Suen CA. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004;27(6P1):821–3.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    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;27:1061–70.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Maury P, Couderc P, Delay M, Boveda S, Brugada J. Electrical storm in Brugada syndrome successfully treated using isoprenaline. Europace. 2004;6(2):130–3.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Maury P, Hocini M, Haissaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. Indian Pacing Electrophysiol J. 2005;5(1):25–34.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Jongman JK, Jepkes-Bruin N, Ramdat Misier AR, Beukema WP, Delnoy PP, Oude LH, et al. Electrical storms in Brugada syndrome successfully treated with isoproterenol infusion and quinidine orally. Neth Heart J. 2007;15(4):151–5.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Sharif-Kazemi MB, Emkanjoo Z, Tavoosi A, Kafi M, Kheirkhah J, Alizadeh A, et al. Electrical storm in Brugada syndrome during pregnancy. Pacing Clin Electrophysiol. 2011;34(2):e18–21.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Furniss G. Isoprenaline and quinidine to calm Brugada VF storm. BMJ Case Rep. 2012.Google Scholar
  136. 136.
    Roten L, Derval N, Sacher F, Pascale P, Scherr D, Komatsu Y, et al. Heterogeneous response of J wave syndromes to beta-adrenergic stimulation. Heart Rhythm. 2012;9(12):1970–6.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Kaneko Y, Horie M, Niwano S, Kusano K, Takatsuki S, Kurita T, et al. Electrical storm in patients with Brugada syndrome is associated with early repolarization. Circ Arrhythm Electrophysiol. 2014;7:1122.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Kanlop N, Chattipakorn S, Chattipakorn N. Effects of cilostazol in the heart. J Cardiovasc Med (Hagerstown). 2011;12(2):88–95.CrossRefGoogle Scholar
  139. 139.
    Patocskai B, Barajas-Martinez H, Hu D, Gurabi Z, Koncz I, Antzelevitch C. Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome. Heart Rhythm. 2016;13(6):1326–34.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Sugao M, Fujiki A, Nishida K, Sakabe M, Tsuneda T, Iwamoto J, et al. Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide. J Cardiovasc Pharmacol. 2005;45(6):545–9.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Murakami M, Nakamura K, Kusano KF, Morita H, Nakagawa K, Tanaka M, et al. Efficacy of low-dose bepridil for prevention of ventricular fibrillation in patients with Brugada syndrome with and without SCN5A mutation. J Cardiovasc Pharmacol. 2010;56(4):389–95.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Aizawa Y, Yamakawa H, Takatsuki S, Katsumata Y, Nishiyama T, Kimura T, et al. Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation. Int J Cardiol. 2013;168(5):5083–5.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Aizawa Y, Chinushi M, Hasegawa K, Naiki N, Horie M, Kaneko Y, et al. Electrical storm in idiopathic ventricular fibrillation is associated with early repolarization. J Am Coll Cardiol. 2013;62(11):1015–9.CrossRefGoogle Scholar
  144. 144.
    Kang L, Zheng MQ, Morishima M, Wang Y, Kaku T, Ono K. Bepridil up-regulates cardiac Na+ channels as a long-term effect by blunting proteasome signals through inhibition of calmodulin activity. Br J Pharmacol. 2009;157(3):404–14.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK, Antzelevitch C. Dimethyl lithospermate B, an extract of danshen, suppresses arrhythmogenesis associated with the Brugada syndrome. Circulation. 2006;113(11):1393–400.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Li GR, Wang HB, Qin GW, Jin MW, Tang Q, Sun HY, et al. Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs. Circulation. 2008;117(19):2449–57.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, 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.CrossRefGoogle Scholar
  148. 148.
    Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, 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 European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2793.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Charles Antzelevitch
    • 1
    • 2
    • 3
  • Gregory Dendramis
    • 4
  1. 1.Department of Cardiovascular ResearchLankenau Institute for Medical ResearchWynnewoodUSA
  2. 2.Lankenau Heart InstituteWynnewoodUSA
  3. 3.Sidney Kimmel Medical School, Thomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Cardiovascular DivisionPietro Cosma HospitalPadovaItaly

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