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Eur Heart J. 2019 Jun 6. pii: ehz311. doi: 10.1093/eurheartj/ehz311. [Epub ahead of print]

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

Author information

1
Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
2
Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, Milan, Italy.
3
Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.
4
Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
5
Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
6
Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
7
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
8
Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
9
L'Institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.
10
Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK.
11
Department of Medicine I, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
12
The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA.
13
Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
14
Unité de Recherche Cardiogénétique, Service de Médecine Génétique, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
15
Department of Pediatric Cardiology, Koc University School of Medicine, Istanbul, Turkey.
16
Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
17
Division of Cardiology, "Città della Salute e della Scienza di Torino" Hospital, Department of Medical Sciences, University of Turin, Italy.
18
PhD Program in Translational Medicine, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
19
Division of Pediatric Cardiology, Department of Pediatrics, University of Utah and Primary Children's Hospital, Salt Lake City, UT, USA.
20
The Labatt Family Heart Centre and Pediatrics (Cardiology), The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
21
Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain.
22
University Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain.
23
Cardiac Sciences Department, Section of Pediatric Cardiology, King Abdulaziz Cardiac Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
24
Cardiovascular Genetic Program, Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
25
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
26
Cardiology Department, Virgen de las Nieves University Hospital, Granada, Spain.
27
Nicklaus Children's Hospital Miami, Miami, FL, USA.
28
Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK.
29
Institute of Cardiovascular Science, University College London, London, UK.
30
National Cerebral and Cardiovascular Center, Research Institute and Omics Research Center, Osaka, Japan.
31
Department of Pediatric Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
32
Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan.
33
Division of Cardiology, Children's Mercy Hospital, Kansas City, MO, USA.
34
Paediatric Cardiology Unit, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
35
Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
36
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
37
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
38
Invitae Corporation, San Francisco, CA, USA.
39
Division of Cardiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
40
Department of Genomic Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA.
41
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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

PMID:
31170290
DOI:
10.1093/eurheartj/ehz311

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