Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification

Krystien V Lieve; Christian van der Werf; Dania Kallas; Isabelle Denjoy; J Martijn Bos; Takeshi Aiba; Elijah R Behr; Maarten P van den Berg; Auke T Bergeman; Nico A Blom; Martin Borggrefe; Ramon Brugada; Lidia María Carrillo Mora; Ehud Chorin; Lia Crotti; Andrew Davis; Fabrizio Drago; Veronica Dusi; Fabrice Extramiana; Sonia Franciosi; John R Giudicessi; Francisco Ángel González Llopis; Kristina H Haugaa; Freek van den Heuvel; Minoru Horie; Jodie Ingles; Janneke Kammeraad; Prince J Kannankeril; Habib R Khan; Andrew D Krahn; Ciorsti MacIntyre; Alice Maltret; Annukka Marjamaa; Seiko Ohno; Puck J Peltenburg; Guillermo J Perez; Vincent Probst; Jason D Roberts; Tomas Robyns; Christine Rootwelt-Norberg; Ferran Roses I Noguer; Thomas M Roston; Annika Rydberg; Frederic Sacher; Georgia Sarquella-Brugada; Peter J Schwartz; Christopher Semsarian; Wataru Shimizu; Luke Starling; Naokata Sumitomo; Jonathan R Skinner; Terezia Tavacova; Jacob Tfelt-Hansen; Janice A Till; Sing-Chien Yap; Yuko Wada; Fernando Wangüemert; Esther Zorio; Michael J Ackerman; Antoine Leenhardt; Shubhayan Sanatani; Michael W Tanck; Arthur A Wilde

doi:10.1093/eurheartj/ehaf965

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification

Krystien V Lieve
, Christian van der Werf^*
, Dania Kallas
, Isabelle Denjoy
, J Martijn Bos
, Takeshi Aiba
, Elijah R Behr
, Maarten P van den Berg
, Auke T Bergeman
, Nico A Blom
, Martin Borggrefe
, Ramon Brugada
, Lidia María Carrillo Mora
, Ehud Chorin
, Lia Crotti
, Andrew Davis
, Fabrizio Drago
, Veronica Dusi
, Fabrice Extramiana
, Sonia Franciosi

John R Giudicessi, Francisco Ángel González Llopis, Kristina H Haugaa, Freek van den Heuvel, Minoru Horie, Jodie Ingles, Janneke Kammeraad, Prince J Kannankeril, Habib R Khan, Andrew D Krahn, Ciorsti MacIntyre, Alice Maltret, Annukka Marjamaa, Seiko Ohno, Puck J Peltenburg, Guillermo J Perez, Vincent Probst, Jason D Roberts, Tomas Robyns, Christine Rootwelt-Norberg, Ferran Roses I Noguer, Thomas M Roston, Annika Rydberg, Frederic Sacher, Georgia Sarquella-Brugada, Peter J Schwartz, Christopher Semsarian, Wataru Shimizu, Luke Starling, Naokata Sumitomo, Jonathan R Skinner, Terezia Tavacova, Jacob Tfelt-Hansen, Janice A Till, Sing-Chien Yap, Yuko Wada, Fernando Wangüemert, Esther Zorio, Michael J Ackerman, Antoine Leenhardt, Shubhayan Sanatani, Michael W Tanck, Arthur A Wilde^*

^*Corresponding author for this work

Amsterdam UMC, Locatie UvA/AMC
BC Children's Hospital
Member of the European Reference Network for Rare
Department of Cardiovascular Medicine
National Cerebral and Cardiovascular Center
University of London
University of Groningen
Heidelberg University
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV)
Tel Aviv University
Center for Cardiac Arrhythmias of Genetic Origin
The Royal Children's Hospital
University of Turin
General University Hospital of Elda
University of Oslo
University Medical Centre Groningen
Shiga University of Medical Science
University of New South Wales
Vanderbilt University Medical Centre
Western University
University of British Columbia
Royal Brompton Hospital
The University of Sydney
University College London
Saitama Medical University International Medical Center
Starship Children’s Hospital
Cardiavant
Hospital Universitario y Politécnico La Fe
University of Amsterdam

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND AND AIMS:

Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy.

METHODS:

The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated.

RESULTS:

A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE.

CONCLUSIONS:

These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Original language	English
Journal	European Heart Journal
Early online date	19 Dec 2025
DOIs	https://doi.org/10.1093/eurheartj/ehaf965
Publication status	Published - 19 Dec 2025

Bibliographical note

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

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Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2
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Lieve, K. V., van der Werf, C., Kallas, D., Denjoy, I., Bos, J. M., Aiba, T., Behr, E. R., van den Berg, M. P., Bergeman, A. T., Blom, N. A., Borggrefe, M., Brugada, R., Carrillo Mora, L. M., Chorin, E., Crotti, L., Davis, A., Drago, F., Dusi, V., Extramiana, F., ... Wilde, A. A. (2025). Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification. European Heart Journal. https://doi.org/10.1093/eurheartj/ehaf965

@article{542311b4a5224a838215317da4c5080c,

title = "Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification",

abstract = "BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy.METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated.RESULTS: A total of 102 (13.7\%) patients in the derivation cohort and 24 (18.6\%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95\% confidence interval (CI) 0.62-0.72] and 0.59 (95\% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95\% CI 0.68-0.80) and 0.60 (95\% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95\% CI 0.59-1.41) for AE and 1.00 (95\% CI 0.69-1.32) for nf/fAE.CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.",

author = "Lieve, \{Krystien V\} and \{van der Werf\}, Christian and Dania Kallas and Isabelle Denjoy and Bos, \{J Martijn\} and Takeshi Aiba and Behr, \{Elijah R\} and \{van den Berg\}, \{Maarten P\} and Bergeman, \{Auke T\} and Blom, \{Nico A\} and Martin Borggrefe and Ramon Brugada and \{Carrillo Mora\}, \{Lidia Mar{\'i}a\} and Ehud Chorin and Lia Crotti and Andrew Davis and Fabrizio Drago and Veronica Dusi and Fabrice Extramiana and Sonia Franciosi and Giudicessi, \{John R\} and \{Gonz{\'a}lez Llopis\}, \{Francisco {\'A}ngel\} and Haugaa, \{Kristina H\} and \{van den Heuvel\}, Freek and Minoru Horie and Jodie Ingles and Janneke Kammeraad and Kannankeril, \{Prince J\} and Khan, \{Habib R\} and Krahn, \{Andrew D\} and Ciorsti MacIntyre and Alice Maltret and Annukka Marjamaa and Seiko Ohno and Peltenburg, \{Puck J\} and Perez, \{Guillermo J\} and Vincent Probst and Roberts, \{Jason D\} and Tomas Robyns and Christine Rootwelt-Norberg and \{Roses I Noguer\}, Ferran and Roston, \{Thomas M\} and Annika Rydberg and Frederic Sacher and Georgia Sarquella-Brugada and Schwartz, \{Peter J\} and Christopher Semsarian and Wataru Shimizu and Luke Starling and Naokata Sumitomo and Skinner, \{Jonathan R\} and Terezia Tavacova and Jacob Tfelt-Hansen and Till, \{Janice A\} and Sing-Chien Yap and Yuko Wada and Fernando Wang{\"u}emert and Esther Zorio and Ackerman, \{Michael J\} and Antoine Leenhardt and Shubhayan Sanatani and Tanck, \{Michael W\} and Wilde, \{Arthur A\}",

note = "{\textcopyright} The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].",

year = "2025",

month = dec,

day = "19",

doi = "10.1093/eurheartj/ehaf965",

language = "English",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

}

Lieve, KV, van der Werf, C, Kallas, D, Denjoy, I, Bos, JM, Aiba, T, Behr, ER, van den Berg, MP, Bergeman, AT, Blom, NA, Borggrefe, M, Brugada, R, Carrillo Mora, LM, Chorin, E, Crotti, L, Davis, A, Drago, F, Dusi, V, Extramiana, F, Franciosi, S, Giudicessi, JR, González Llopis, FÁ, Haugaa, KH, van den Heuvel, F, Horie, M, Ingles, J, Kammeraad, J, Kannankeril, PJ, Khan, HR, Krahn, AD, MacIntyre, C, Maltret, A, Marjamaa, A, Ohno, S, Peltenburg, PJ, Perez, GJ, Probst, V, Roberts, JD, Robyns, T, Rootwelt-Norberg, C, Roses I Noguer, F, Roston, TM, Rydberg, A, Sacher, F, Sarquella-Brugada, G, Schwartz, PJ, Semsarian, C, Shimizu, W, Starling, L, Sumitomo, N, Skinner, JR, Tavacova, T, Tfelt-Hansen, J, Till, JA, Yap, S-C, Wada, Y, Wangüemert, F, Zorio, E, Ackerman, MJ, Leenhardt, A, Sanatani, S, Tanck, MW & Wilde, AA 2025, 'Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification', European Heart Journal. https://doi.org/10.1093/eurheartj/ehaf965

TY - JOUR

T1 - Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2

T2 - a validated risk stratification

AU - Lieve, Krystien V

AU - van der Werf, Christian

AU - Kallas, Dania

AU - Denjoy, Isabelle

AU - Bos, J Martijn

AU - Aiba, Takeshi

AU - Behr, Elijah R

AU - van den Berg, Maarten P

AU - Bergeman, Auke T

AU - Blom, Nico A

AU - Borggrefe, Martin

AU - Brugada, Ramon

AU - Carrillo Mora, Lidia María

AU - Chorin, Ehud

AU - Crotti, Lia

AU - Davis, Andrew

AU - Drago, Fabrizio

AU - Dusi, Veronica

AU - Extramiana, Fabrice

AU - Franciosi, Sonia

AU - Giudicessi, John R

AU - González Llopis, Francisco Ángel

AU - Haugaa, Kristina H

AU - van den Heuvel, Freek

AU - Horie, Minoru

AU - Ingles, Jodie

AU - Kammeraad, Janneke

AU - Kannankeril, Prince J

AU - Khan, Habib R

AU - Krahn, Andrew D

AU - MacIntyre, Ciorsti

AU - Maltret, Alice

AU - Marjamaa, Annukka

AU - Ohno, Seiko

AU - Peltenburg, Puck J

AU - Perez, Guillermo J

AU - Probst, Vincent

AU - Roberts, Jason D

AU - Robyns, Tomas

AU - Rootwelt-Norberg, Christine

AU - Roses I Noguer, Ferran

AU - Roston, Thomas M

AU - Rydberg, Annika

AU - Sacher, Frederic

AU - Sarquella-Brugada, Georgia

AU - Schwartz, Peter J

AU - Semsarian, Christopher

AU - Shimizu, Wataru

AU - Starling, Luke

AU - Sumitomo, Naokata

AU - Skinner, Jonathan R

AU - Tavacova, Terezia

AU - Tfelt-Hansen, Jacob

AU - Till, Janice A

AU - Yap, Sing-Chien

AU - Wada, Yuko

AU - Wangüemert, Fernando

AU - Zorio, Esther

AU - Ackerman, Michael J

AU - Leenhardt, Antoine

AU - Sanatani, Shubhayan

AU - Tanck, Michael W

AU - Wilde, Arthur A

N1 - © The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

PY - 2025/12/19

Y1 - 2025/12/19

N2 - BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy.METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated.RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE.CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

AB - BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy.METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated.RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE.CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

U2 - 10.1093/eurheartj/ehaf965

DO - 10.1093/eurheartj/ehaf965

M3 - Article

C2 - 41416846

SN - 0195-668X

JO - European Heart Journal

JF - European Heart Journal

ER -

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification

Abstract

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