Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.
Calmodulin
Cathecolaminergic polymorphic ventricular tachycardia
Idiopathic ventricular fibrillation
Long QT syndrome
Sudden death
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
14 09 2019
14 09 2019
Historique:
received:
30
10
2018
revised:
06
02
2019
accepted:
29
04
2019
pubmed:
7
6
2019
medline:
6
11
2020
entrez:
7
6
2019
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 31170290
pii: 5512097
doi: 10.1093/eurheartj/ehz311
pmc: PMC6748747
doi:
Substances chimiques
CALM1 protein, human
0
CALM2 protein, human
0
CALM3 protein, human
0
Calmodulin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2964-2975Subventions
Organisme : NHLBI NIH HHS
ID : K23 HL130554
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL083374
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL131914
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
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