Skip to main content
SpringerLink
Log in

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

  • Original Research
  • Published:
Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

A Correction to this article was published on 15 January 2020

This article has been updated

Abstract

Background

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.

Methods

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

Results

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).

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 15 January 2020

    The original version of this article unfortunately has a typo error. The name of the author “<Emphasis Type="Bold">Kamalan Jeeveratnam</Emphasis>” should be presented as “<Emphasis Type="Bold">Kamalan Jeevaratnam</Emphasis>” as shown above.

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(6):1391–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Osadchii OE. Role of abnormal repolarization in the mechanism of cardiac arrhythmia. Acta Physiol (Oxford). 2017;220(Suppl 712):1–71.

    Article  CAS  Google Scholar 

  10. Osadchii OE. Effects of ventricular pacing protocol on electrical restitution assessments in guinea-pig heart. Exp Physiol. 2012;97(7):807–21.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  19. Weiss JN, et al. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002;13(3):292–5.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Marshall SC, et al. Predictors of driving ability following stroke: a systematic review. Top Stroke Rehabil. 2007;14(1):98–114.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  30. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005;85(4):1205–53.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  32. Tse G, et al. Electrophysiological mechanisms of Brugada syndrome: insights from pre-clinical and clinical studies. Front Physiol. 2016;7:467.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Haanschoten DM, et al. Catheter ablation in highly symptomatic Brugada patients: a Dutch case series. Clin Res Cardiol. 2019.

  47. Aanhaanen WTJ, et al. Epicardial and subsequent endocardial ablation in a patient with Brugada syndrome. JACC Clin Electrophysiol. 2018;4(9):1268–70.

    Article  PubMed  Google Scholar 

  48. Leong KM, et al. Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts. J Cardiovasc Electrophysiol. 2017.

Download references

Author information

Authors and Affiliations

  1. Xiamen Cardiovascular Hospital Affiliated to Xiamen University, Xiamen, Fujian, People’s Republic of China

    Gary Tse & Ka Hou Christien Li

  2. Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China

    Gary Tse, Mengqi Gong, Ka Hou Christien Li & Tong Liu

  3. Laboratory of Cardiovascular Physiology, Li Ka Shing Institute of Health Sciences, Hong Kong, SAR, People’s Republic of China

    Sharen Lee

  4. Second Department of Cardiology, Laboratory of Cardiac Electrophysiology, Evangelismos General Hospital of Athens, Athens, Greece

    Panagiotis Mililis, Dimitrios Asvestas, George Bazoukis & Konstantinos P. Letsas

  5. Department of Clinical Research, Federal University of Uberlândia, Uberlândia, MG, Brazil

    Leonardo Roever

  6. Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK

    Kamalan Jeevaratnam

  7. Heart and Lung Centre, New Cross Hospital, Wolverhampton, UK

    Sandeep S. Hothi

  8. Faculty of Medicine, Newcastle University, Newcastle, UK

    Ka Hou Christien Li

Authors
  1. Gary Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengqi Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Panagiotis Mililis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dimitrios Asvestas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George Bazoukis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leonardo Roever
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kamalan Jeevaratnam
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sandeep S. Hothi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ka Hou Christien Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Konstantinos P. Letsas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gary Tse or Konstantinos P. Letsas.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original version of this article was revised: The name of the author should be written as Kamalan Jeevaratnam.

Electronic supplementary material

ESM 1

(DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tse, G., Lee, S., Gong, M. et al. Restitution metrics in Brugada syndrome: a systematic review and meta-analysis. J Interv Card Electrophysiol 57, 319–327 (2020). https://doi.org/10.1007/s10840-019-00675-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10840-019-00675-z

Keywords

Search

Navigation