Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

Krystien V.V. Lieve, Judith M.A. Verhagen, Jinhong Wei, J. Martijn Bos, Christian van der Werf, Ferran Rosés i Noguer, Grazia M.S. Mancini, Wenting Guo, Ruiwu Wang, Freek van den Heuvel, Ingrid M.E. Frohn-Mulder, Wataru Shimizu, Akihiko Nogami, Hitoshi Horigome, Jason D. Roberts, Antoine Leenhardt, Harry J.G. Crijns, Andreas C. Blank, Takeshi Aiba, Ans C.P. WiesfeldNico A. Blom, Naokata Sumitomo, Jan Till, Michael John Ackerman, S. R.Wayne Chen, Ingrid M.B.H. van de Laar, Arthur A.M. Wilde

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. Objective: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. Methods: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. Results: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%–11%). Median age at diagnosis was 9.3 years (interquartile range 7.0–14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8–12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. Conclusion: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%–3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Original languageEnglish (US)
Pages (from-to)220-228
Number of pages9
JournalHeart Rhythm
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Brain Diseases
Intellectual Disability
Ryanodine Receptor Calcium Release Channel
Cardiac Arrhythmias
Mutation
Caffeine
Polymorphic catecholergic ventricular tachycardia
Neurodevelopmental Disorders
Genetic Testing
Medical Records
Protein Isoforms
Parents
Confidence Intervals
Phenotype

Keywords

  • Catecholaminergic polymorphic ventricular tachycardia
  • RYR2
  • Supraventricular arrhythmia
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lieve, K. V. V., Verhagen, J. M. A., Wei, J., Bos, J. M., van der Werf, C., Rosés i Noguer, F., ... Wilde, A. A. M. (2019). Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm, 16(2), 220-228. https://doi.org/10.1016/j.hrthm.2018.08.025

Linking the heart and the brain : Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia. / Lieve, Krystien V.V.; Verhagen, Judith M.A.; Wei, Jinhong; Bos, J. Martijn; van der Werf, Christian; Rosés i Noguer, Ferran; Mancini, Grazia M.S.; Guo, Wenting; Wang, Ruiwu; van den Heuvel, Freek; Frohn-Mulder, Ingrid M.E.; Shimizu, Wataru; Nogami, Akihiko; Horigome, Hitoshi; Roberts, Jason D.; Leenhardt, Antoine; Crijns, Harry J.G.; Blank, Andreas C.; Aiba, Takeshi; Wiesfeld, Ans C.P.; Blom, Nico A.; Sumitomo, Naokata; Till, Jan; Ackerman, Michael John; Chen, S. R.Wayne; van de Laar, Ingrid M.B.H.; Wilde, Arthur A.M.

In: Heart Rhythm, Vol. 16, No. 2, 01.02.2019, p. 220-228.

Research output: Contribution to journalArticle

Lieve, KVV, Verhagen, JMA, Wei, J, Bos, JM, van der Werf, C, Rosés i Noguer, F, Mancini, GMS, Guo, W, Wang, R, van den Heuvel, F, Frohn-Mulder, IME, Shimizu, W, Nogami, A, Horigome, H, Roberts, JD, Leenhardt, A, Crijns, HJG, Blank, AC, Aiba, T, Wiesfeld, ACP, Blom, NA, Sumitomo, N, Till, J, Ackerman, MJ, Chen, SRW, van de Laar, IMBH & Wilde, AAM 2019, 'Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia', Heart Rhythm, vol. 16, no. 2, pp. 220-228. https://doi.org/10.1016/j.hrthm.2018.08.025
Lieve, Krystien V.V. ; Verhagen, Judith M.A. ; Wei, Jinhong ; Bos, J. Martijn ; van der Werf, Christian ; Rosés i Noguer, Ferran ; Mancini, Grazia M.S. ; Guo, Wenting ; Wang, Ruiwu ; van den Heuvel, Freek ; Frohn-Mulder, Ingrid M.E. ; Shimizu, Wataru ; Nogami, Akihiko ; Horigome, Hitoshi ; Roberts, Jason D. ; Leenhardt, Antoine ; Crijns, Harry J.G. ; Blank, Andreas C. ; Aiba, Takeshi ; Wiesfeld, Ans C.P. ; Blom, Nico A. ; Sumitomo, Naokata ; Till, Jan ; Ackerman, Michael John ; Chen, S. R.Wayne ; van de Laar, Ingrid M.B.H. ; Wilde, Arthur A.M. / Linking the heart and the brain : Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia. In: Heart Rhythm. 2019 ; Vol. 16, No. 2. pp. 220-228.
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abstract = "Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. Objective: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. Methods: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. Results: Among 421 CPVT1 patients, we identified 34 patients with ID (8{\%}; 95{\%} confidence interval 6{\%}–11{\%}). Median age at diagnosis was 9.3 years (interquartile range 7.0–14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54{\%}) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26{\%}). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50{\%}) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8–12.4), 15 patients (45{\%}) experienced an arrhythmic event despite adequate therapy. Conclusion: Our study indicates that ID is more prevalent among CPVT1 patients (8{\%}) than in the general population (1{\%}–3{\%}). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.",
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T2 - Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

AU - Lieve, Krystien V.V.

AU - Verhagen, Judith M.A.

AU - Wei, Jinhong

AU - Bos, J. Martijn

AU - van der Werf, Christian

AU - Rosés i Noguer, Ferran

AU - Mancini, Grazia M.S.

AU - Guo, Wenting

AU - Wang, Ruiwu

AU - van den Heuvel, Freek

AU - Frohn-Mulder, Ingrid M.E.

AU - Shimizu, Wataru

AU - Nogami, Akihiko

AU - Horigome, Hitoshi

AU - Roberts, Jason D.

AU - Leenhardt, Antoine

AU - Crijns, Harry J.G.

AU - Blank, Andreas C.

AU - Aiba, Takeshi

AU - Wiesfeld, Ans C.P.

AU - Blom, Nico A.

AU - Sumitomo, Naokata

AU - Till, Jan

AU - Ackerman, Michael John

AU - Chen, S. R.Wayne

AU - van de Laar, Ingrid M.B.H.

AU - Wilde, Arthur A.M.

PY - 2019/2/1

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N2 - Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. Objective: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. Methods: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. Results: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%–11%). Median age at diagnosis was 9.3 years (interquartile range 7.0–14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8–12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. Conclusion: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%–3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

AB - Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. Objective: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. Methods: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. Results: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%–11%). Median age at diagnosis was 9.3 years (interquartile range 7.0–14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8–12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. Conclusion: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%–3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

KW - Catecholaminergic polymorphic ventricular tachycardia

KW - RYR2

KW - Supraventricular arrhythmia

KW - Ventricular arrhythmia

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