Observational Study

. 2021 Jan;14(1):e008509.

doi: 10.1161/CIRCEP.120.008509. Epub 2020 Dec 9.

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Julia Cadrin-Tourigny^{1

2}, Laurens P Bosman^{3

4}, Weijia Wang¹, Rafik Tadros², Aditya Bhonsale¹, Mimount Bourfiss⁴, Øyvind H Lie⁵, Ardan M Saguner⁶, Anneli Svensson⁷, Antoine Andorin², Crystal Tichnell¹, Brittney Murray¹, Katja Zeppenfeld⁸, Maarten P van den Berg⁹, Folkert W Asselbergs^{3

4

10}, Arthur A M Wilde^{11

12}, Andrew D Krahn¹³, Mario Talajic², Lena Rivard², Stephen Chelko^{1

14}, Stefan L Zimmerman¹⁵, Ihab R Kamel¹⁵, Jane E Crosson¹, Daniel P Judge¹, Sing-Chien Yap¹⁶, Jeroen F Van der Heijden⁴, Harikrishna Tandri¹, Jan D H Jongbloed¹⁷, J Peter van Tintelen^{3

18

19}, Pyotr G Platonov¹, Firat Duru¹, Kristina H Haugaa¹, Paul Khairy¹, Richard N W Hauer¹, Hugh Calkins¹, Anneline S J M Te Riele¹, Cynthia A James¹

Affiliations

¹ Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.
² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Canada (J.C.-T., R.T., A.A., M.T., L.R., P.K.).
³ Netherlands Heart Institute (L.P.B., F.W.A., J.P.v.T., R.N.W.H., A.S.J.M.t.R.).
⁴ Department of Cardiology (L.P.B., M.B., F.W.A., J.F.V.d.H., A.S.J.M.t.R.), University Medical Center Utrecht, Utrecht University, the Netherlands.
⁵ Department of Cardiology and Research group for Cardiogenetics and Sudden Cardiac Death, Oslo University Hospital, Rikshospitalet, Norway (Ø.H.L., K.H.H.).
⁶ Department of Cardiology, University Heart Center Zurich, Switzerland (A.M.S., F.D.).
⁷ Department of Cardiology and Department of Medical & Health Sciences, Linköping University, Swede (A.S.).
⁸ Department of Cardiology, Leiden University Medical Center (K.Z.).
⁹ Department of Cardiology (M.P.v.d.B.), University Medical Center Groningen, University of Groningen, the Netherlands.
¹⁰ Institute of Cardiovascular Science & Institute of Health Informatics, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
¹¹ Amsterdam UMC, University of Amsterdam, Heart Center (A.A.M.W.).
¹² Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, the Netherlands (A.A.M.W.).
¹³ Division of Cardiology, University of British Columbia, Vancouver, Canada (A.D.K.).
¹⁴ Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee (S.C.).
¹⁵ The Russell H. Morgan Department of Radiology and Radiological Science (S.L.Z., I.R.K.), Johns Hopkins Hospital, Baltimore, MD.
¹⁶ Department of Cardiology, Erasmus Medical Center, Rotterdam (S.-C.Y.).
¹⁷ Department of Genetics (J.D.H.J.), University Medical Center Groningen, University of Groningen, the Netherlands.
¹⁸ Department of Genetics (J.P.v.T.), University Medical Center Utrecht, Utrecht University, the Netherlands.
¹⁹ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (J.P.v.T.).

PMID: 33296238
PMCID: PMC7834666
DOI: 10.1161/CIRCEP.120.008509

Observational Study

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Julia Cadrin-Tourigny et al. Circ Arrhythm Electrophysiol. 2021 Jan.

. 2021 Jan;14(1):e008509.

doi: 10.1161/CIRCEP.120.008509. Epub 2020 Dec 9.

Authors

Affiliations

¹ Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.
² Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Canada (J.C.-T., R.T., A.A., M.T., L.R., P.K.).
³ Netherlands Heart Institute (L.P.B., F.W.A., J.P.v.T., R.N.W.H., A.S.J.M.t.R.).
⁴ Department of Cardiology (L.P.B., M.B., F.W.A., J.F.V.d.H., A.S.J.M.t.R.), University Medical Center Utrecht, Utrecht University, the Netherlands.
⁵ Department of Cardiology and Research group for Cardiogenetics and Sudden Cardiac Death, Oslo University Hospital, Rikshospitalet, Norway (Ø.H.L., K.H.H.).
⁶ Department of Cardiology, University Heart Center Zurich, Switzerland (A.M.S., F.D.).
⁷ Department of Cardiology and Department of Medical & Health Sciences, Linköping University, Swede (A.S.).
⁸ Department of Cardiology, Leiden University Medical Center (K.Z.).
⁹ Department of Cardiology (M.P.v.d.B.), University Medical Center Groningen, University of Groningen, the Netherlands.
¹⁰ Institute of Cardiovascular Science & Institute of Health Informatics, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
¹¹ Amsterdam UMC, University of Amsterdam, Heart Center (A.A.M.W.).
¹² Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, the Netherlands (A.A.M.W.).
¹³ Division of Cardiology, University of British Columbia, Vancouver, Canada (A.D.K.).
¹⁴ Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee (S.C.).
¹⁵ The Russell H. Morgan Department of Radiology and Radiological Science (S.L.Z., I.R.K.), Johns Hopkins Hospital, Baltimore, MD.
¹⁶ Department of Cardiology, Erasmus Medical Center, Rotterdam (S.-C.Y.).
¹⁷ Department of Genetics (J.D.H.J.), University Medical Center Groningen, University of Groningen, the Netherlands.
¹⁸ Department of Genetics (J.P.v.T.), University Medical Center Utrecht, Utrecht University, the Netherlands.
¹⁹ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (J.P.v.T.).

PMID: 33296238
PMCID: PMC7834666
DOI: 10.1161/CIRCEP.120.008509

Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD.

Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping.

Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism.

Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

Keywords: arrhythmogenic right ventricular dysplasia; calibration; sudden cardiac death; syncope; ventricular tachycardia.

PubMed Disclaimer

Conflict of interest statement

Dr Calkins is a consultant for Medtronic Inc and St. Jude Medical/Abbott. Dr Calkins receives research support from Boston Scientific Corp. C. Tichnell and Dr James receive salary support from this grant. Dr James has received funding for an invited lecture from Abbott. Dr Tandri receives research support from Abbott. Dr Saguner received lecture honoraria from Boston Scientific Corp. Dr Zimmerman receives salary support from Siemens Healthcare. Dr Yap has research grants from Medtronic and Biotronik and is consultant for Boston Scientific. Dr Judge is a consultant for 4D Molecular Therapeutics, ADRx, Pfizer, and Blade Therapeutics and receives research support from Eidos Therapeutics and Array Biopharma. Dr Chelko receives laboratory supplies from Novartis. Dr Krahn receives research and consulting fees from Medtronic. The other authors report no conflicts.

Figures

**Figure 1.**
**Survival free from life-threatening ventricular arrhythmia (LTVA) and any sustained ventricular arrhythmia (VA).** The cumulative event-free survival for LTVA is plotted in A. LTVA events occurred in follow-up in 52 patients with no prior sustained VA event at baseline, 19 with prior LTVA/unstable ventricular tachycardia (VT) a and 23 with prior stable VT. The cumulative event-free survival for any VA is plotted in B. Sustained VA events occurred in follow-up in 147 patients with no prior sustained VA event at baseline, 91 with prior LTVA/unstable VT a and 137 with prior stable VT. For both parts, 95% CIs are provided (shaded area).

**Figure 2.**
**Calibration plot showing the agreement between predicted (x axis) and observed (y axis) 5-year risk of the primary outcome of life-threatening ventricular arrhythmia (LTVA).** Triangles represent binned Kaplan-Meier estimates with 95% CIs for quintiles of predicted risk. Straight line is the continuous calibration hazard regression. Dotted line represents perfect calibration. Spike histogram on the x axis reflects the number of patients with a predicted risk corresponding to the x axis value.

**Figure 3.**
**Outcomes of patients associated with model-based implantable cardioverter-defibrillator use thresholds.** The implications of using implantable cardioverter-defibrillators (ICD) in all (**left** bar) or none (**right** bar) of the patients are shown. The bars show the impact of using different ICD placement thresholds based on the 5-year risk calculated by our model. Each bar represents the complete cohort (n=864) and color coding represents the proportion of patients experiencing life-threatening ventricular arrhythmia (LTVA; red) or absence thereof (blue) as well as the placement (solid colors) vs the nonplacement (striped colors) of an ICD. The number of patients in each of the four categories is presented in the table below.

See this image and copyright information in PMC

References

1. Finocchiaro G, Papadakis M, Robertus JL, Dhutia H, Steriotis AK, Tome M, Mellor G, Merghani A, Malhotra A, Behr E, et al. Etiology of sudden death in sports: insights from a United Kingdom Regional Registry. J Am Coll Cardiol. 2016;67:2108–2115. doi: 10.1016/j.jacc.2016.02.062 - PubMed
1. Cadrin-Tourigny J, Bosman LP, Nozza A, Wang W, Tadros R, Bhonsale A, Bourfiss M, Fortier A, Lie ØH, Saguner AM, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2019;40:1850–1858. doi: 10.1093/eurheartj/ehz103 - PMC - PubMed
1. Ellenbogen KA, Levine JH, Berger RD, Daubert JP, Winters SL, Greenstein E, Shalaby A, Schaechter A, Subacius H, Kadish A; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation. 2006;113:776–782. doi: 10.1161/CIRCULATIONAHA.105.561571 - PubMed
1. Ingles J, Bagnall RD, Yeates L, McGrady M, Berman Y, Whalley D, Duflou J, Semsarian C. Concealed arrhythmogenic right ventricular cardiomyopathy in sudden unexplained cardiac death events. Circ Genom Precis Med. 2018;11:e002355 doi: 10.1161/CIRCGEN.118.002355 - PubMed
1. Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, Quarta G, Nobles M, Syrris P, Chaubey S, 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;33:1942–1953. doi: 10.1093/eurheartj/ehr472 - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

RN380020-406814/CIHR/Canada

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Affiliations

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources