Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. (6th June 2019)

• Record Type: Journal Article
• Authors: Crotti, Lia; Spazzolini, Carla; Tester, David J; Ghidoni, Alice; Baruteau, Alban-Elouen; Beckmann, Britt-Maria; Behr, Elijah R; Bennett, Jeffrey S; Bezzina, Connie R; Bhuiyan, Zahurul A; Celiker, Alpay; Cerrone, Marina; Dagradi, Federica; De Ferrari, Gaetano M; Etheridge, Susan P; Fatah, Meena; Garcia-Pavia, Pablo; Al-Ghamdi, Saleh; Hamilton, Robert M; Al-Hassnan, Zuhair N; Horie, Minoru; Jimenez-Jaimez, Juan; Kanter, Ronald J; Kaski, Juan P; Kotta, Maria-Christina; Lahrouchi, Najim; Makita, Naomasa; Norrish, Gabrielle; Odland, Hans H; Ohno, Seiko; Papagiannis, John; Parati, Gianfranco; Sekarski, Nicole; Tveten, Kristian; Vatta, Matteo; Webster, Gregory; Wilde, Arthur A M; Wojciak, Julianne; George, Alfred L; Ackerman, Michael J; Schwartz, Peter J;
• Is Part Of: European heart journal. Volume 40:Number 35(2019)
• Page Start: 2964
• Page End: 2975
• Publication Date: 2019-06-06
• Subjects: Calmodulin -- Cathecolaminergic polymorphic ventricular tachycardia -- Idiopathic ventricular fibrillation -- Long QT syndrome -- Sudden death; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehz311
• Languages: English
• ISSNs: 0195-668X

Abstract

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.