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

Crotti, L.; Spazzolini, C.; Tester, D. J.; Ghidoni, A.; Baruteau, A. E.; Beckmann, B. M.; Behr, E. R.; Bennett, J. S.; Bezzina, C. R.; Bhuiyan, Z. A.; Celiker, A.; Cerrone, M.; Dagradi, F.; De Ferrari, G. M.; Etheridge, S. P.; Fatah, M.; Garcia-Pavia, P.; Al-Ghamdi, S.; Hamilton, R. M.; Al-Hassnan, Z. N.; Horie, M.; Jimenez-Jaimez, J.; Kanter, R. J.; Kaski, J. P.; Kotta, M. C.; Lahrouchi, N.; Makita, N.; Norrish, G.; Odland, H. H.; Ohno, S.; Papagiannis, J.; Parati, G.; Sekarski, N.; Tveten, K.; Vatta, M.; Webster, G.; Wilde, A. A. M.; Wojciak, J.; George, A. L.; Ackerman, M. J.; Schwartz, P. J.

Eur Heart J. 2019 Jun 7; 40(35):2964-2975


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.

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