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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. (2019): Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry. In: European Heart Journal, Vol. 40, No. 35
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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.