Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry

Lia Crotti; Carla Spazzolini; David J. Tester; Alice Ghidoni; Alban Elouen Baruteau; Britt Maria Beckmann; Elijah R. Behr; Jeffrey S. Bennett; Connie R. Bezzina; Zahurul A. Bhuiyan; Alpay Celiker; Marina Cerrone; Federica Dagradi; Gaetano M. De Ferrari; Susan P. Etheridge; Meena Fatah; Pablo Garcia-Pavia; Saleh Al-Ghamdi; Robert M. Hamilton; Zuhair N. Al-Hassnan; Minoru Horie; Juan Jimenez-Jaimez; Ronald J. Kanter; Juan P. Kaski; Maria Christina Kotta; Najim Lahrouchi; Naomasa Makita; Gabrielle Norrish; Hans H. Odland; Seiko Ohno; John Papagiannis; Gianfranco Parati; Nicole Sekarski; Kristian Tveten; Matteo Vatta; Gregory Webster; Arthur A.M. Wilde; Julianne Wojciak; Alfred L. George; Michael J. Ackerman; Peter J. Schwartz

doi:10.1093/eurheartj/ehz311

Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry

Lia Crotti, Carla Spazzolini, David J. Tester, Alice Ghidoni, Alban Elouen Baruteau, Britt Maria Beckmann, Elijah R. Behr, Jeffrey S. Bennett, Connie R. Bezzina, Zahurul A. Bhuiyan, Alpay Celiker, Marina Cerrone, Federica Dagradi, Gaetano M. De Ferrari, Susan P. Etheridge, Meena Fatah, Pablo Garcia-Pavia, Saleh Al-Ghamdi, Robert M. Hamilton, Zuhair N. Al-HassnanMinoru Horie, Juan Jimenez-Jaimez, Ronald J. Kanter, Juan P. Kaski, Maria Christina Kotta, Najim Lahrouchi, Naomasa Makita, Gabrielle Norrish, Hans H. Odland, Seiko Ohno, John Papagiannis, Gianfranco Parati, Nicole Sekarski, Kristian Tveten, Matteo Vatta, Gregory Webster, Arthur A.M. Wilde, Julianne Wojciak, Alfred L. George, Michael J. Ackerman, Peter J. Schwartz^*

^*Corresponding author for this work

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

130 Scopus citations

Abstract

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Original language	English (US)
Pages (from-to)	2964-2975A
Journal	European heart journal
Volume	40
Issue number	35
DOIs	https://doi.org/10.1093/eurheartj/ehz311
State	Published - Sep 14 2019

Keywords

Calmodulin
Cathecolaminergic polymorphic ventricular tachycardia
Idiopathic ventricular fibrillation
Long QT syndrome
Sudden death

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1093/eurheartj/ehz311

Cite this

Crotti, L., Spazzolini, C., Tester, D. J., Ghidoni, A., Baruteau, A. E., Beckmann, B. M., Behr, E. R., Bennett, J. S., Bezzina, C. R., Bhuiyan, Z. A., Celiker, A., Cerrone, M., Dagradi, F., De Ferrari, G. M., Etheridge, S. P., Fatah, M., Garcia-Pavia, P., Al-Ghamdi, S., Hamilton, R. M., ... Schwartz, P. J. (2019). Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry. European heart journal, 40(35), 2964-2975A. https://doi.org/10.1093/eurheartj/ehz311

@article{7093a87272e140ccabc2fc751ae18f27,

title = "Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry",

abstract = "Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.",

keywords = "Calmodulin, Cathecolaminergic polymorphic ventricular tachycardia, Idiopathic ventricular fibrillation, Long QT syndrome, Sudden death",

author = "Lia Crotti and Carla Spazzolini and Tester, {David J.} and Alice Ghidoni and Baruteau, {Alban Elouen} and Beckmann, {Britt Maria} and Behr, {Elijah R.} and Bennett, {Jeffrey S.} and Bezzina, {Connie R.} and Bhuiyan, {Zahurul A.} and Alpay Celiker and Marina Cerrone and Federica Dagradi and {De Ferrari}, {Gaetano M.} and Etheridge, {Susan P.} and Meena Fatah and Pablo Garcia-Pavia and Saleh Al-Ghamdi and Hamilton, {Robert M.} and Al-Hassnan, {Zuhair N.} and Minoru Horie and Juan Jimenez-Jaimez and Kanter, {Ronald J.} and Kaski, {Juan P.} and Kotta, {Maria Christina} and Najim Lahrouchi and Naomasa Makita and Gabrielle Norrish and Odland, {Hans H.} and Seiko Ohno and John Papagiannis and Gianfranco Parati and Nicole Sekarski and Kristian Tveten and Matteo Vatta and Gregory Webster and Wilde, {Arthur A.M.} and Julianne Wojciak and George, {Alfred L.} and Ackerman, {Michael J.} and Schwartz, {Peter J.}",

note = "Publisher Copyright: {\textcopyright} 2019 Published on behalf of the European Society of Cardiology. All rights reserved. {\textcopyright} The Author(s) 2019. For permissions, please email: [email protected].",

year = "2019",

month = sep,

day = "14",

doi = "10.1093/eurheartj/ehz311",

language = "English (US)",

volume = "40",

pages = "2964--2975A",

journal = "European heart journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "35",

}

Crotti, L, Spazzolini, C, Tester, DJ, Ghidoni, A, Baruteau, AE, Beckmann, BM, Behr, ER, Bennett, JS, Bezzina, CR, Bhuiyan, ZA, Celiker, A, Cerrone, M, Dagradi, F, De Ferrari, GM, Etheridge, SP, Fatah, M, Garcia-Pavia, P, Al-Ghamdi, S, Hamilton, RM, Al-Hassnan, ZN, Horie, M, Jimenez-Jaimez, J, Kanter, RJ, Kaski, JP, Kotta, MC, Lahrouchi, N, Makita, N, Norrish, G, Odland, HH, Ohno, S, Papagiannis, J, Parati, G, Sekarski, N, Tveten, K, Vatta, M, Webster, G, Wilde, AAM, Wojciak, J, George, AL, Ackerman, MJ & Schwartz, PJ 2019, 'Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry', European heart journal, vol. 40, no. 35, pp. 2964-2975A. https://doi.org/10.1093/eurheartj/ehz311

TY - JOUR

T1 - Calmodulin mutations and life-threatening cardiac arrhythmias

T2 - Insights from the International Calmodulinopathy Registry

AU - Crotti, Lia

AU - Spazzolini, Carla

AU - Tester, David J.

AU - Ghidoni, Alice

AU - Baruteau, Alban Elouen

AU - Beckmann, Britt Maria

AU - Behr, Elijah R.

AU - Bennett, Jeffrey S.

AU - Bezzina, Connie R.

AU - Bhuiyan, Zahurul A.

AU - Celiker, Alpay

AU - Cerrone, Marina

AU - Dagradi, Federica

AU - De Ferrari, Gaetano M.

AU - Etheridge, Susan P.

AU - Fatah, Meena

AU - Garcia-Pavia, Pablo

AU - Al-Ghamdi, Saleh

AU - Hamilton, Robert M.

AU - Al-Hassnan, Zuhair N.

AU - Horie, Minoru

AU - Jimenez-Jaimez, Juan

AU - Kanter, Ronald J.

AU - Kaski, Juan P.

AU - Kotta, Maria Christina

AU - Lahrouchi, Najim

AU - Makita, Naomasa

AU - Norrish, Gabrielle

AU - Odland, Hans H.

AU - Ohno, Seiko

AU - Papagiannis, John

AU - Parati, Gianfranco

AU - Sekarski, Nicole

AU - Tveten, Kristian

AU - Vatta, Matteo

AU - Webster, Gregory

AU - Wilde, Arthur A.M.

AU - Wojciak, Julianne

AU - George, Alfred L.

AU - Ackerman, Michael J.

AU - Schwartz, Peter J.

PY - 2019/9/14

Y1 - 2019/9/14

N2 - Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

AB - Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

KW - Calmodulin

KW - Cathecolaminergic polymorphic ventricular tachycardia

KW - Idiopathic ventricular fibrillation

KW - Long QT syndrome

KW - Sudden death

UR - http://www.scopus.com/inward/record.url?scp=85072234869&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072234869&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehz311

DO - 10.1093/eurheartj/ehz311

M3 - Article

C2 - 31170290

AN - SCOPUS:85072234869

SN - 0195-668X

VL - 40

SP - 2964-2975A

JO - European heart journal

JF - European heart journal

IS - 35

ER -

Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry

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