Restitution metrics in Brugada syndrome: a systematic review and meta-analysis

  • Gary TseEmail author
  • Sharen Lee
  • Mengqi Gong
  • Panagiotis Mililis
  • Dimitrios Asvestas
  • George Bazoukis
  • Leonardo Roever
  • Kamalan Jeevaratnam
  • Sandeep S. Hothi
  • Ka Hou Christien Li
  • Tong Liu
  • Konstantinos P. LetsasEmail author
Original Research



Brugada syndrome (BrS) is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death. Restitution analysis has been examined in BrS patients but not all studies have reported significant differences between BrS patients and controls. Therefore, we conducted a systematic review and meta-analysis to investigate the different restitution indices used in BrS.


PubMed and Embase were searched until April 7, 2019, identifying 20 and 27 studies.


A total of ten studies involving 178 BrS (mean age 38 years old, 63% male) and 102 controls (mean age 31 years old, 42% male) were included in this systematic review. Pacing was carried out at the right ventricular outflow tract (RVOT)/right ventricular apex (RPA) (n = 4), RPA (n = 4), or right atrium (RA) (n = 1). Basic cycle lengths of 400 (n = 4), 500 (n = 2), 600 (n = 6) and 750 ms (n = 1) were used. Recording methods include electrograms (n = 4), monophasic action potentials (n = 5), and electrocardiograms (n = 1). Signals were obtained from the RVOT (n = 8), RVA (n = 3), RA (n = 1), or the body surface (n = 1). The maximum restitution slope for endocardial repolarization at the RVOT was 0.87 for BrS patients (n = 5; 95% confidence interval [CI] 0.68–1.07) compared with 0.74 in control subjects (n = 4; 95% CI 0.42–1.06), with a significant mean difference of 0.40 (n = 4; 95% CI 0.11–0.69; P = 0.007).


Steeper endocardial repolarization restitution slopes are found in BrS patients compared with controls at baseline. Restitution analysis can provide important information for risk stratification in BrS.


Restitution Repolarization Conduction Brugada syndrome 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

10840_2019_675_MOESM1_ESM.docx (18 kb)
ESM 1 (DOCX 18 kb)


  1. 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(6):1391–6.PubMedGoogle Scholar
  2. 2.
    Sakamoto S, Takagi M, Tatsumi H, Doi A, Sugioka K, Hanatani A, et al. Utility of T-wave alternans during night time as a predictor for ventricular fibrillation in patients with Brugada syndrome. Heart Vessel. 2016;31(6):947–56.Google Scholar
  3. 3.
    Kawazoe H, Nakano Y, Ochi H, Takagi M, Hayashi Y, Uchimura Y, et al. Risk stratification of ventricular fibrillation in Brugada syndrome using noninvasive scoring methods. Heart Rhythm. 2016;13(10):1947–54.PubMedGoogle Scholar
  4. 4.
    Uchimura-Makita Y, Nakano Y, Tokuyama T, Fujiwara M, Watanabe Y, Sairaku A, et al. Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2014;25(9):1021–7.PubMedGoogle Scholar
  5. 5.
    Tse G, Wong ST, Tse V, Yeo JM. Determination of action potential wavelength restitution in Scn5a(+/−) mouse hearts modelling human Brugada syndrome. J Geriatr Cardiol. 2017;14(9):595–6.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Tse G, Wong ST, Tse V, Yeo JM. Variability in local action potential durations, dispersion of repolarization and wavelength restitution in aged wild-type and Scn5a+/− mouse hearts modeling human Brugada syndrome. J Geriatr Cardiol. 2016;13(11):930–1.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Franz MR, Schaefer J, Schöttler M, Seed WA, Noble MI. Electrical and mechanical restitution of the human heart at different rates of stimulation. Circ Res. 1983;53(6):815–22.PubMedGoogle Scholar
  8. 8.
    Zaniboni M. Short-term action potential memory and electrical restitution: a cellular computational study on the stability of cardiac repolarization under dynamic pacing. PLoS One. 2018;13(3):e0193416.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Osadchii OE. Role of abnormal repolarization in the mechanism of cardiac arrhythmia. Acta Physiol (Oxford). 2017;220(Suppl 712):1–71.Google Scholar
  10. 10.
    Osadchii OE. Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart. Exp Physiol. 2012;97(7):807–21.PubMedGoogle Scholar
  11. 11.
    Tse G, Liu T, Li G, Keung W, Yeo JM, Fiona Chan YW, et al. Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts. Oncotarget. 2017;8(49):85341–52.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Tse G, Wong ST, Tse V, Yeo JM. Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts. Biomed Rep. 2016;4(6):673–80.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Srinivasan NT, Orini M, Providencia R, Dhinoja MB, Lowe MD, Ahsan SY, et al. Prolonged action potential duration and dynamic transmural action potential duration heterogeneity underlie vulnerability to ventricular tachycardia in patients undergoing ventricular tachycardia ablation. Europace. 2019;21(4):616–25.PubMedGoogle Scholar
  14. 14.
    Orini M, Taggart P, Srinivasan N, Hayward M, Lambiase PD. Interactions between activation and repolarization restitution properties in the intact human heart: in-vivo whole-heart data and mathematical description. PLoS One. 2016;11(9):e0161765.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Orini M, et al. Analytical description of the slope of the APD-restitution curve to assess the interacting contribution of conduction and repolarization dynamics. Conf Proc IEEE Eng Med Biol Soc. 2015;2015:5672–5.PubMedGoogle Scholar
  16. 16.
    Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, et al. Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-a combined murine and human study. Eur Heart J. 2012;33(15):1942–53.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Nolasco JB, Dahlen RW. A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol. 1968;25(2):191–6.PubMedGoogle Scholar
  18. 18.
    Banville I, Gray RA. Effect of action potential duration and conduction velocity restitution and their spatial dispersion on alternans and the stability of arrhythmias. J Cardiovasc Electrophysiol. 2002;13(11):1141–9.PubMedGoogle Scholar
  19. 19.
    Weiss JN, et al. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002;13(3):292–5.PubMedGoogle Scholar
  20. 20.
    Postema PG, van Dessel P, de Bakker JM, Dekker LR, Linnenbank AC, Hoogendijk MG, et al. Slow and discontinuous conduction conspire in Brugada syndrome: a right ventricular mapping and stimulation study. Circ Arrhythm Electrophysiol. 2008;1(5):379–86.PubMedGoogle Scholar
  21. 21.
    Bhar-Amato J, Finlay M, Santos D, Orini M, Chaubey S, Vyas V, et al. Pharmacological modulation of right ventricular endocardial-epicardial gradients in Brugada syndrome. Circ Arrhythm Electrophysiol. 2018;11(9):e006330.PubMedGoogle Scholar
  22. 22.
    S S, et al. Risk stratification of sudden cardiac death: positive evaluation of novel surface electrocardiogram biomarkers in a Brugada syndrome cohort. EP Europace. 2016;17(suppl_5):v10–3.Google Scholar
  23. 23.
    Marshall SC, et al. Predictors of driving ability following stroke: a systematic review. Top Stroke Rehabil. 2007;14(1):98–114.PubMedGoogle Scholar
  24. 24.
    Ashino S, et al. Effects of quinidine on the action potential duration restitution property in the right ventricular outflow tract in patients with brugada syndrome. Circ J. 2011;75(9):2080–6.PubMedGoogle Scholar
  25. 25.
    Kofune M, Watanabe I, Ohkubo K, Ashino S, Okumura Y, Nagashima K, et al. Abnormal atrial repolarization and depolarization contribute to the inducibility of atrial fibrillation in Brugada syndrome. Int Heart J. 2010;51(3):159–65.PubMedGoogle Scholar
  26. 26.
    Hayashi M, Takatsuki S, Maison-Blanche P, Messali A, Haggui A, Milliez P, et al. Ventricular repolarization restitution properties in patients exhibiting type 1 Brugada electrocardiogram with and without inducible ventricular fibrillation. J Am Coll Cardiol. 2008;51(12):1162–8.PubMedGoogle Scholar
  27. 27.
    Lambiase PD, et al. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation. 2009;120(2):106–17 1-4.PubMedGoogle Scholar
  28. 28.
    Nishii N, Nagase S, Morita H, Kusano KF, Namba T, Miura D, et al. Abnormal restitution property of action potential duration and conduction delay in Brugada syndrome: both repolarization and depolarization abnormalities. Europace. 2010;12(4):544–52.PubMedGoogle Scholar
  29. 29.
    Sang Weon P, et al. Relation between action potential duration restitution kinetics and inducibility of ventricular fibrillation in brugada syndrome. J Am Coll Cardiol. 2003;41(6, Supplement 1):105.Google Scholar
  30. 30.
    Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005;85(4):1205–53.PubMedGoogle Scholar
  31. 31.
    Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392(6673):293–6.PubMedGoogle Scholar
  32. 32.
    Tse G, et al. Electrophysiological mechanisms of Brugada syndrome: insights from pre-clinical and clinical studies. Front Physiol. 2016;7:467.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Shimizu W, Aiba T, Kamakura S. Mechanisms of disease: current understanding and future challenges in Brugada syndrome. Nat Clin Pract Cardiovasc Med. 2005;2(8):408–14.PubMedGoogle Scholar
  34. 34.
    Rodriguez-Manero M, et al. Monomorphic ventricular tachycardia in patients with Brugada syndrome: a multicenter retrospective study. Heart Rhythm. 2016;13(3):669–82.PubMedGoogle Scholar
  35. 35.
    Robyns T, et al. Evaluation of index of cardio-electrophysiological balance (iCEB) as a new biomarker for the identification of patients at increased arrhythmic risk. Ann Noninvasive Electrocardiol. 2016;21(3):294–304.PubMedGoogle Scholar
  36. 36.
    Tse G. Both transmural dispersion of repolarization and of refractoriness are poor predictors of arrhythmogenicity: a role for iCEB (QT/QRS)? J Geriatr Cardiol. 2016;13(9):813–4.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Trethewey SP, Nicolson WB, Ng GA. Investigation of the relationship between two novel electrocardiogram-based sudden cardiac death risk markers and autonomic function. J Electrocardiol. 2018;51(5):889–94.PubMedGoogle Scholar
  38. 38.
    Nicolson WB, McCann G, Smith MI, Sandilands AJ, Stafford PJ, Schlindwein FS, et al. Prospective evaluation of two novel ECG-based restitution biomarkers for prediction of sudden cardiac death risk in ischaemic cardiomyopathy. Heart. 2014;100(23):1878–85.PubMedGoogle Scholar
  39. 39.
    Nicolson WB, et al. A novel surface electrocardiogram-based marker of ventricular arrhythmia risk in patients with ischemic cardiomyopathy. J Am Heart Assoc. 2012;1(4):e001552.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Mironov S, Jalife J, Tolkacheva EG. Role of conduction velocity restitution and short-term memory in the development of action potential duration alternans in isolated rabbit hearts. Circulation. 2008;118(1):17–25.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Sabir IN, Li LM, Jones VJ, Goddard CA, Grace AA, Huang CL. Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome. Pflugers Arch. 2008;455(4):637–51.PubMedGoogle Scholar
  42. 42.
    Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, et al. Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol. 2006;47(10):2074–85.PubMedGoogle Scholar
  43. 43.
    Clayton RH, Taggart P. Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: a computational study. Biomed Eng Online. 2005;4(1):54.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Tse G, Wong ST, Tse V, Lee YT, Lin HY, Yeo JM. Cardiac dynamics: Alternans and arrhythmogenesis. J Arrhythm. 2016;32(5):411–7.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Glynn P, Onal B, Hund TJ. Cycle length restitution in Sinoatrial node cells: a theory for understanding spontaneous action potential dynamics. PLoS One. 2014;9(2):e89049.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Haanschoten DM, et al. Catheter ablation in highly symptomatic Brugada patients: a Dutch case series. Clin Res Cardiol. 2019.Google Scholar
  47. 47.
    Aanhaanen WTJ, et al. Epicardial and subsequent endocardial ablation in a patient with Brugada syndrome. JACC Clin Electrophysiol. 2018;4(9):1268–70.PubMedGoogle Scholar
  48. 48.
    Leong KM, et al. Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts. J Cardiovasc Electrophysiol. 2017.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020
corrected publication 2020

Authors and Affiliations

  • Gary Tse
    • 1
    • 2
    Email author
  • Sharen Lee
    • 3
  • Mengqi Gong
    • 2
  • Panagiotis Mililis
    • 4
  • Dimitrios Asvestas
    • 4
  • George Bazoukis
    • 4
  • Leonardo Roever
    • 5
  • Kamalan Jeevaratnam
    • 6
  • Sandeep S. Hothi
    • 7
  • Ka Hou Christien Li
    • 1
    • 2
    • 8
  • Tong Liu
    • 2
  • Konstantinos P. Letsas
    • 4
    Email author
  1. 1.Xiamen Cardiovascular Hospital Affiliated to Xiamen UniversityXiamenPeople’s Republic of China
  2. 2.Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinPeople’s Republic of China
  3. 3.Laboratory of Cardiovascular PhysiologyLi Ka Shing Institute of Health SciencesHong KongPeople’s Republic of China
  4. 4.Second Department of Cardiology, Laboratory of Cardiac ElectrophysiologyEvangelismos General Hospital of AthensAthensGreece
  5. 5.Department of Clinical ResearchFederal University of UberlândiaUberlândiaBrazil
  6. 6.Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
  7. 7.Heart and Lung CentreNew Cross HospitalWolverhamptonUK
  8. 8.Faculty of MedicineNewcastle UniversityNewcastleUK

Personalised recommendations