TY - JOUR
T1 - Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry
AU - Crotti, Lia
AU - Spazzolini, Carla
AU - Tester, David J.
AU - Ghidoni, Alice
AU - Baruteau, Alban-Elouen
AU - Beckmann, Britt-Maria
AU - Behr, Elijah R.
AU - Bennett, Jeffrey S.
AU - Bezzina, Connie R.
AU - Bhuiyan, Zahurul A.
AU - Celiker, Alpay
AU - Cerrone, Marina
AU - Dagradi, Federica
AU - de Ferrari, Gaetano M.
AU - Etheridge, Susan P.
AU - Fatah, Meena
AU - Garcia-Pavia, Pablo
AU - Al-Ghamdi, Saleh
AU - Hamilton, Robert M.
AU - Al-Hassnan, Zuhair N.
AU - Horie, Minoru
AU - Jimenez-Jaimez, Juan
AU - Kanter, Ronald J.
AU - Kaski, Juan P.
AU - Kotta, Maria-Christina
AU - Lahrouchi, Najim
AU - Makita, Naomasa
AU - Norrish, Gabrielle
AU - Odland, Hans H.
AU - Ohno, Seiko
AU - Papagiannis, John
AU - Parati, Gianfranco
AU - Sekarski, Nicole
AU - Tveten, Kristian
AU - Vatta, Matteo
AU - Webster, Gregory
AU - Wilde, Arthur A. M.
AU - Wojciak, Julianne
AU - George, Alfred L.
AU - Ackerman, Michael J.
AU - Schwartz, Peter J.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072234869&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31170290
U2 - https://doi.org/10.1093/eurheartj/ehz311
DO - https://doi.org/10.1093/eurheartj/ehz311
M3 - Article
C2 - 31170290
SN - 0195-668X
VL - 40
SP - 2964
EP - 2975
JO - European Heart journal
JF - European Heart journal
IS - 35
ER -