The contribution of channelopathy to the non-ischemic ventricular arrhythmias development

Authors: Bockeria L.A., Serguladze S.Yu., Kotanova E.S.

Company: Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, Russian Federation

For correspondence:  Sign in or register.

Type:  Reviews


For citation: Bockeria L.A., Serguladze S.Yu., Kotanova E.S. The contribution of channelopathy to the non-ischemic ventricular arrhythmias development. Creative Cardiology. 2022; 16 (1): 49–60 (in Russ.). DOI: 10.24022/1997-3187-2022-16-1-49-60

Received / Accepted:  21.11.2021 / 23.03.2022

Keywords: ventricular arrhythmias channelopathy non-ischemic genesis risk stratification

Subscribe 🔒



About 40% of patients died suddenly at the age of under 35, have no structural pathology of the heart according to autopsy data. Channelopathies are rare heterogeneous congenital heart rhythm disorders caused by mutations in genes encoding defective ion channel proteins and making up 50% cases of primary non-ischemic cardiomyopathies. Channelopathies include long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. These conditions may be detected by genetic testing, which is especially important in asymptomatic persons younger than 40 years. The cardiomyocyte action potential is formed by a certain series of depolarizing and repolarizing ion currents mediated by ion channels. Changes in any of these currents and the appearance of free intracellular calcium make the myocardium vulnerable to polymorphic ventricular tachycardia or ventricular fibrillation. Each of the channelopathies has its own signature of an electrocardiogram, typical forms of manifestation, and a pathognomonically mutating gene. The risk stratification of the channelopathies has specific features, as well as different scales. This review will highlight the mechanisms of development, clinical manifestations and the risk stratification of ventricular arrhythmias associated with cardiac channelopathies.


  1. Bockeria L.A., Revishvili A.Sh., Ardashev A.A. Ventricular arrhythmias. Moscow; 2002 (in Russ.).
  2. John R., Tedrow U., Koplan B., Albert C., Epstein L., Sweeney M. et al. Ventricular arrhythmias and sudden cardiac death. Lancet. 2012; 380 (9852): 1520–9. DOI: 10.1016/S0140-6736(12)61413-5
  3. Marsman R., Tan H., Bezzina C. Genetics of sudden cardiac death caused by ventricular arrhythmias. Nat. Rev. Cardiol. 2014; 11: 96–111. DOI: 10.1038/nrcardio.2013.186
  4. Tung P., Albert C. Causes and prevention of sudden cardiac death in the elderly. Nat. Rev. Cardiol. 2013; 10: 135–42. DOI: 10.1038/nrcardio.2012.201
  5. Al-Khatib S.M., Stevenson W.G., Ackerman M.J., Bryant W.J., Callans D.J., Curtis A.B. et al. 2017 AHA/ACC/HRS Guideline for management of patients with ventricular arrhythmias and the pre vention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. J. Am. Coll. Cardiol. 2018; 72 (14): e91–220. DOI: 10.1016/j.jacc.2017.10.054
  6. Shah S.R., Park K., Alweis R. Long QT syndrome: a comprehensive review of the literature and current evidence. Curr. Probl. Cardiol. 2019; 44 (3): 92–106. DOI: 10.1016/j.cpcardiol.2018.04.002
  7. Priori S.G., Blomström-Lundqvist C., Mazzanti A. et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J. 2015; 36: 2793–867.
  8. Kass R.S., Moss A.J. Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias. J. Clin. Invest. 2003; 112 (6): 810–5. DOI: 10.1172/JCI19844
  9. Bohnen M.S., Peng G., Robey S.H., Terrenoire C., Iyer V., Sampson K.J. et al. Molecular pathophysiology of congenital long QT syndrome. Physiol Rev. 2017; 97 (1): 89–134. DOI: 10.1152/physrev.00008.2016
  10. Fozzard H.A. Afterdepolarizations and triggered activity. Basic. Res. Cardiol. 1992; 87 (2): 105–13. DOI: 10.1007/978-3-642-72477-0_10
  11. Nerbonne J.M., Kass R.S. Molecular physiology of cardiac repolarization. Physiol. Rev. 2005; 85 (4): 1205–53. DOI: 10.1152/physrev.00002.2005
  12. Newton-Cheh C., Eijgelsheim M., Rice K.M., de Bakker P.I., Yin X., Estrada K. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 2009; 41 (4): 399–406. DOI: 10.1038/ng.364
  13. Alabdulgader A. Inherited ventricular arrhythmias, the channelopathies and scd: current knowledge and future speculations – risk stratification., management plans and future speculations. In: Sudden Cardiac Death. 2020. DOI: 10.5772/intechopen. 92131
  14. Schwartz P.J., Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011; 124 (20): 2181–4.
  15. Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ. J. 2012; 76 (5): 1054–65.
  16. Priori S.G. Association of long QT syndrome loci and cardiac events among patients treated with β-blockers. J. Am. Med. Assoc. 2004; 292 (11): 1341.
  17. Rudic B., Schimpf R., Borggrefe M. Short QT syndrome – review of diagnosis and treatment. Arrhythm. Electrophysiol. Rev. 2014; 3 (2): 76–9. DOI: 10.15420/aer.2014.3.2.76
  18. Gussak I., Brugada P., Brugada J., Wright R.S., Kopecky S.L., Chaitman B.R. et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000; 94 (2): 99–102. DOI: 10.1159/000047299
  19. Nielsen J.B., Graff C., Rasmussen P.V., Pietersen A., Lind B., Olesen M.S. et al. Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population. Eur. Heart J. 2014; 35 (20): 1335–44. DOI: 10.1093/eurheartj/ehu081
  20. Kobza R., Roos M., Niggli B., Abächerli R., Lupi G.A., Frey F. et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm. 2009; 6 (5): 652–7. DOI: 10.1016/j.hrthm.2009.01.009
  21. Viskin S. The QT interval: too long., too short or just right. Heart Rhythm. 2009; 6 (5): 711–5. DOI: 10.1016/j.hrthm.2009.02.044
  22. Borggrefe M., Wolpert C., Antzelevitch C., Veltmann C., Giustetto C., Gaita F. et al. Short QT syndrome. Genotype-phenotype correlations. J. Electrocardiol. 2005; 38 (4): 75–80. DOI: 10.1016/j.jelectrocard.2005.06.009
  23. Tülümen E., Giustetto C., Wolpert C., Maury P., Anttonen O., Probst V. et al. PQ segment depression in patients with short QT syndrome: a novel marker for diagnosing short QT syndrome? Heart Rhythm. 2014; 11 (6): 1024–30. DOI: 10.1016/j.hrthm.2014.02.024
  24. Templin C., Ghadri J.R., Rougier J.S., Baumer A., Kaplan V., Albesa M. et al. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur. Heart J. 2011; 32 (9): 1077–88. DOI: 10.1093/eurheartj/ehr076
  25. Brugada R., Hong K., Dumaine R., Cordeiro J., Gaita F., Borggrefe M. et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004; 109 (1): 30–5. DOI: 10.1161/01.CIR.0000109482.92774.3A
  26. Bellocq C., van Ginneken A.C., Bezzina C.R., Alders M., Escande D., Mannens M. et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004; 109 (20): 2394–7. DOI: 10.1161/01.CIR. 0000130409.72142.FE
  27. Priori S.G., Pandit S.V., Rivolta I., Berenfeld O., Ronchetti E., Dhamoon A. et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ. Res. 2005; 96 (7): 800–7. DOI: 10.1161/01.RES.0000162101.76263.8c
  28. Gollob M.H., Redpath C.J., Roberts J.D. The short QT syndrome: proposed diagnostic criteria. J. Am. Coll. Cardiol. 2011; 57 (7): 802–12. DOI: 10.1016/j.jacc.2010.09.048
  29. Villafan~e J., Atallah J., Gollob M.H., Maury P., Wolpert C., Gebauer R. et al. Long-term follow-up of a pediatric cohort with short QT syndrome. J. Am. Coll. Cardiol. 2013; 61 (11): 1183–91. DOI: 10.1016/j.jacc.2012.12.025
  30. Mazzanti A., Kanthan A., Monteforte N., Memmi M., Bloise R., Novelli V. et al. Novel insight into the natural history of short QT syndrome. J. Am. Coll. Cardiol. 2014; 63 (13): 1300–8. DOI: 10.1016/j.jacc.2013.09.078
  31. Kobayashi T., Shintani U., Yamamoto T., Shida S., Isshiki N., Tanaka T. et al. Familial occurrence of electrocardiographic abnormalities of the Brugadatype. Intern. Med. 1996; 35 (8): 637–40. DOI: 10.2169/internalmedicine.35.637
  32. Yan G.X., Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996; 93 (2): 372–9. DOI: 10.1161/01.cir.93.2.372
  33. Li K.H.C., Lee S., Yin C., Liu T., Ngarmukos T., Conte G. et al. Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies. Int. J. Cardiol. Heart Vasc. 2020; 26: 100468. DOI: 10.1016/j.ijcha.2020.100468
  34. Letsas K.P., Korantzopoulos P., Efremidis M., Weber R., Lioni L., Bakosis G. et al. Sinus node disease in subjects with type 1 ECG pattern of Brugada syndrome. J. Cardiol. 2013; 61 (3): 227–31. DOI: 10.1016/j.jjcc.2012.12.006
  35. Bockeria L.A., Serguladze S.Yu., Pronicheva I.V., Golukhova E.Z., Bockeria O.L., Kovalev S.A. Brugada syndrome. Clinical guidelines. Russian Cardiovascular Surgeons Association. 2020; 14–5. Available at: 85c6b90a6a934f90e3c5.pdf (accessed March 01, 2022) (in Russ.).
  36. Priori S.G., Wilde A.A., Horie M., Cho Y., Behr E.R., 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; 10 (12): e85–108. DOI: 10.1016/j.hrthm.2013.07.021
  37. 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 (6): 1391–6. DOI: 10.1016/0735- 1097 (92)90253-j
  38. Vutthikraivit W., Rattanawong P., Putthapiban P., Sukhumthammarat W., Vathesatogkit P., Ngarmukos T. et al. Worldwide prevalence of Brugada syndrome: a systematic review and meta-analysis. Acta Cardiol. Sin. 2018; 34 (3): 267–77. DOI: 10.6515/ACS.201805_34(3).20180302B
  39. Holst A.G., Jensen H.K., Eschen O., Henriksen F.L., Kanters J., Bundgaard H. et al. Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study. Europace. 2012; 14 (7): 1025–9. DOI: 10.1093/europace/eus002
  40. Roden D.M. Brugada syndrome: lots of questions, some answers. Heart Rhythm. 2010; 7 (1): 47–9. DOI: 10.1016/j.hrthm.2009.10.016
  41. Dolz-Gaitón P., Nún ~ez M., Nún ~ez L., Barana A., Amorós I., Matamoros M. et al. Functional characterization of a novel frameshift mutation in the C-terminus of the Nav1.5 channel underlying a Brugada syndrome with variable expression in a Spanish family. PLoS One. 2013; 8 (11): e81493. DOI: 10.1371/journal.pone.0081493
  42. Gray M.P., Saba S., Zhang Y., Hernandez I. Outcomes of patients with atrial fibrillation newly recommended for oral anticoagulation under the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society Guideline. J. Am. Heart Assoc. 2018; 7 (1): e007881. DOI: 10.1161/JAHA.117.007881
  43. Antzelevitch C., Pollevick G.D., Cordeiro J.M., Casis O., Sanguinetti M.C. 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 (4): 442–9. DOI: 10.1161/CIRCULATIONAHA.106.668392
  44. Portero V., Le Scouarnec S., Es-Salah-Lamoureux Z., Burel S., Gourraud J.B., Bonnaud S. et al. Dysfunction of the voltage-gated K+ channel β2 subunit in a familial case of Brugada syndrome. J. Am. Heart Assoc. 2016; 5 (6): e003122. DOI: 10.1161/JAHA.115.003122
  45. Wilde A.A., Postema P.G., Di Diego J.M., Viskin S., Morita H., Fish J.M. et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J. Mol. Cell. Cardiol. 2010; 49 (4): 543–53. DOI: 10.1016/j.yjmcc.2010.07.012
  46. Hoogendijk M.G., Potse M., Linnenbank A.C., Verkerk A.O., den Ruijter H.M., van Amersfoorth S.C. et al. Mechanism of right precordial ST-segment elevation in structural heart disease: excitation failure by current-to-load mismatch. Heart Rhythm. 2010; 7 (2): 238–48. DOI: 10.1016/j.hrthm.2009.10.007
  47. Morita H., Watanabe A., Kawada S., Miyamoto M., Morimoto Y., Nakagawa K. et al. Identification of electrocardiographic risk markers for the initial and recurrent episodes of ventricular fibrillation in patients with Brugada syndrome. J. Cardiovasc. Electrophysiol. 2018; 29 (1): 107–14. DOI: 10.1111/jce.13349
  48. Tse G. (Tpeak – Tend)/QRS and (Tpeak – Tend)/(QT × QRS): novel markers for predicting arrhythmic risk in the Brugada syndrome. Europace. 2017; 19 (4): 696. DOI: 10.1093/europace/euw194
  49. Castro Hevia J., Dorantes Sanchez M., Martinez Lopez F., Castan~eda Chirino O., Falcon Rodrigu ez R., Puga Bravo M. et al. Multiple serial ECGs aid with the diagnosis and prognosis of Brugada syndrome. Int J. Cardiol. 2019; 277: 130–5. DOI: 10.1016/j.ijcard.2018.08.089
  50. Aizawa Y., Takatsuki S., Kaneko Y., Noda T., Katsumata Y., Nishiyama T. et al. Comparison of circadian, weekly, and seasonal variations of electrical storms and single events of ventricular fibrillation in patients with Brugada syndrome. Int. J. Cardiol. Heart Vasc. 2016; 11: 104–10. DOI: 10.1016/j.ijcha.2016.05.008
  51. Coumel P., Fidelle J., Lucet V., Attuel P., Bouvrain Y. Catecholamine-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases. Br. Heart J. 1978; 40 (suppl.): 28–37
  52. Lieve K.V., van der Werf C., Wilde A.A. Catecholaminergic polymorphic ventricular tachycardia. Circ. J. 2016; 80 (6): 1285–91. DOI: 10.1253/circj.CJ-16-0326
  53. Lahat H., Pras E., Olender T., Avidan N., BenAsher E., Man O. et al. 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 (6): 1378–84. DOI: 10.1086/324565
  54. Roston T.M., Vinocur J.M., Maginot K.R., Mohammed S., Salerno J.C., Etheridge S.P. et al. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ. Arrhythm. Electrophysiol. 2015; 8 (3): 633–42. DOI: 10.1161/CIRCEP.114.002217
  55. Tülümen E., Schulze-Bahr E., Zumhagen S., Stallmeyer B., Seebohm G., Beckmann B.M. et al. Early repolarization pattern: a marker of increased risk in patients with catecholaminergic polymorphic ventricular tachycardia. Europace. 2016; 18 (10): 1587–92. DOI: 10.1093/europace/euv357

About Authors

  • Leo A. Bockeria, Academician of RAS and RAMS, President, ORCID
  • Sergey Yu. Serguladze, Dr. Med. Sci., Senior Researcher, Head of Department, ORCID
  • Evgeniya S. Kotanova, Cand. Med. Sci., Cardiologist, ORCID

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery