Journal article
Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.
- Crotti L Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- Spazzolini C Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- Tester DJ Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
- Ghidoni A Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- Baruteau AE Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Beckmann BM Department of Medicine I, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
- Behr ER Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Bennett JS The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA.
- Bezzina CR Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Bhuiyan ZA Unité de Recherche Cardiogénétique, Service de Médecine Génétique, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Celiker A Department of Pediatric Cardiology, Koc University School of Medicine, Istanbul, Turkey.
- Cerrone M Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
- Dagradi F Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- De Ferrari GM Division of Cardiology, "Città della Salute e della Scienza di Torino" Hospital, Department of Medical Sciences, University of Turin, Italy.
- Etheridge SP Division of Pediatric Cardiology, Department of Pediatrics, University of Utah and Primary Children's Hospital, Salt Lake City, UT, USA.
- Fatah M The Labatt Family Heart Centre and Pediatrics (Cardiology), The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
- Garcia-Pavia P Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Al-Ghamdi S Cardiac Sciences Department, Section of Pediatric Cardiology, King Abdulaziz Cardiac Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
- Hamilton RM The Labatt Family Heart Centre and Pediatrics (Cardiology), The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
- Al-Hassnan ZN Cardiovascular Genetic Program, Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
- Horie M Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
- Jimenez-Jaimez J Cardiology Department, Virgen de las Nieves University Hospital, Granada, Spain.
- Kanter RJ Nicklaus Children's Hospital Miami, Miami, FL, USA.
- Kaski JP Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Kotta MC Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- Lahrouchi N Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Makita N National Cerebral and Cardiovascular Center, Research Institute and Omics Research Center, Osaka, Japan.
- Norrish G Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK.
- Odland HH Department of Pediatric Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
- Ohno S Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
- Papagiannis J Division of Cardiology, Children's Mercy Hospital, Kansas City, MO, USA.
- Parati G Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.
- Sekarski N Paediatric Cardiology Unit, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Tveten K Department of Medical Genetics, Telemark Hospital Trust, Skien, Norway.
- Vatta M Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
- Webster G Division of Cardiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Wilde AAM Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart.
- Wojciak J Department of Genomic Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA.
- George AL Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Ackerman MJ Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
- Schwartz PJ Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.
- 2019-06-07
Published in:
- European heart journal. - 2019
Calmodulin
Cathecolaminergic polymorphic ventricular tachycardia
Idiopathic ventricular fibrillation
Long QT syndrome
Sudden death
Age of Onset
Arrhythmias, Cardiac
Calmodulin
Child
Child, Preschool
DNA Mutational Analysis
Death, Sudden, Cardiac
Female
Genetic Variation
Humans
Long QT Syndrome
Phenotype
Registries
Survival Rate
Tachycardia, Ventricular
English
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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1093/eurheartj/ehz311
- PMID 31170290
- Persistent URL
- https://sonar.ch/global/documents/7715
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