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

Krystien 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 Maria Carrillo Mora; Ehud Chorin; Lia Crotti; Andrew Davis; Fabrizio Drago; Veronica Dusi; Fabrice Extramiana; Sonia Franciosi; John R. Giudicessi; Francisco Angel Gonzalez 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 Wanguemert; 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 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 Maria Carrillo Mora, Ehud Chorin, Lia Crotti, Andrew Davis, Fabrizio Drago, Veronica Dusi, Fabrice Extramiana, Sonia FranciosiJohn R. Giudicessi, Francisco Angel Gonzalez 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 Wanguemert, Esther Zorio, Michael J. Ackerman, Antoine Leenhardt, Shubhayan Sanatani, Michael W. Tanck, Arthur A. Wilde^*

^*Corresponding author af dette arbejde

Afdeling for Retsgenetik

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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 beta-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on beta-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 beta-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 beta-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 beta-blocker monotherapy at low and high risk for future AEs while treated with beta-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Originalsprog	Engelsk
Artikelnummer	ehaf965
Tidsskrift	European Heart Journal
Antal sider	12
ISSN	0195-668X
DOI	https://doi.org/10.1093/eurheartj/ehaf965
Status	E-pub ahead of print - 2025

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10.1093/eurheartj/ehaf965

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Lieve, K., 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, Artikel ehaf965. Advance online publication. https://doi.org/10.1093/eurheartj/ehaf965

Lieve, K, 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, Gonzalez Llopis, FA, 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, Wanguemert, 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

@article{c260490eb36a4710a1f4ab8834fc14b8,

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 beta-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on beta-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 beta-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 beta-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 beta-blocker monotherapy at low and high risk for future AEs while treated with beta-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.",

keywords = "Catecholaminergic polymorphic ventricular tachycardia, Risk stratification, Sudden cardiac death, Ventricular arrhythmias, beta-Blockers",

author = "Krystien Lieve 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 Maria} 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 {Gonzalez Llopis}, {Francisco Angel} 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 Wanguemert and Esther Zorio and Ackerman, {Michael J.} and Antoine Leenhardt and Shubhayan Sanatani and Tanck, {Michael W.} and Wilde, {Arthur A.}",

year = "2025",

doi = "10.1093/eurheartj/ehaf965",

language = "English",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

}

TY - JOUR

T1 - Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2

T2 - a validated risk stratification

AU - Lieve, Krystien

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 Maria

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 - Gonzalez Llopis, Francisco Angel

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 - Wanguemert, Fernando

AU - Zorio, Esther

AU - Ackerman, Michael J.

AU - Leenhardt, Antoine

AU - Sanatani, Shubhayan

AU - Tanck, Michael W.

AU - Wilde, Arthur A.

PY - 2025

Y1 - 2025

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 beta-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on beta-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 beta-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 beta-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 beta-blocker monotherapy at low and high risk for future AEs while treated with beta-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 beta-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on beta-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 beta-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 beta-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 beta-blocker monotherapy at low and high risk for future AEs while treated with beta-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

KW - Catecholaminergic polymorphic ventricular tachycardia

KW - Risk stratification

KW - Sudden cardiac death

KW - Ventricular arrhythmias

KW - beta-Blockers

U2 - 10.1093/eurheartj/ehaf965

DO - 10.1093/eurheartj/ehaf965

M3 - Journal article

C2 - 41416846

SN - 0195-668X

JO - European Heart Journal

JF - European Heart Journal

M1 - ehaf965

ER -