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

Lia Crotti, Carla Spazzolini, David J. Tester, Alice Ghidoni, Alban Elouen Baruteau, Britt Maria Beckmann, Elijah R. Behr, Jeffrey S. Bennett, Connie R. Bezzina, Zahurul A. Bhuiyan, Alpay Celiker, Marina Cerrone, Federica Dagradi, Gaetano M. De Ferrari, Susan P. Etheridge, Meena Fatah, Pablo Garcia-Pavia, Saleh Al-Ghamdi, Robert M. Hamilton, Zuhair N. Al-HassnanMinoru Horie, Juan Jimenez-Jaimez, Ronald J. Kanter, Juan P. Kaski, Maria Christina Kotta, Najim Lahrouchi, Naomasa Makita, Gabrielle Norrish, Hans H. Odland, Seiko Ohno, John Papagiannis, Gianfranco Parati, Nicole Sekarski, Kristian Tveten, Matteo Vatta, Gregory Webster, Arthur A.M. Wilde, Julianne Wojciak, Alfred L. George, Michael J. Ackerman, Peter J. Schwartz

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2964-2975A
JournalEuropean heart journal
Issue number35
StatePublished - Sep 14 2019


  • Calmodulin
  • Cathecolaminergic polymorphic ventricular tachycardia
  • Idiopathic ventricular fibrillation
  • Long QT syndrome
  • Sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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