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

Eur Heart J. 2019 Sep 14;40(35):2964-2975. doi: 10.1093/eurheartj/ehz311.


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.

Keywords: Calmodulin; Cathecolaminergic polymorphic ventricular tachycardia; Idiopathic ventricular fibrillation; Long QT syndrome; Sudden death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / mortality
  • Calmodulin / genetics
  • Child
  • Child, Preschool
  • DNA Mutational Analysis*
  • Death, Sudden, Cardiac / etiology
  • Female
  • Genetic Variation / genetics*
  • Humans
  • Long QT Syndrome / genetics
  • Phenotype
  • Registries*
  • Survival Rate
  • Tachycardia, Ventricular / genetics


  • CALM1 protein, human
  • CALM2 protein, human
  • CALM3 protein, human
  • Calmodulin

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia