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.

SummaryLong-QT syndrome mutations can cause syncope and sudden death by prolonging the cardiac action potential (AP). Ion channels affected by mutations are various, and the influences of cellular calcium cycling on LQTS cardiac events are unknown. To better understand LQTS arrhythmias, we performed current-clamp and intracellular calcium ([Ca2+]i) measurements on cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPS-CM). In myocytes carrying an LQT2 mutation (HERG-A422T), APs and [Ca2+]i transients were prolonged in parallel. APs were abbreviated by nifedipine exposure and further lengthened upon releasing intracellularly stored Ca2+. Validating this model, control iPS-CM treated with HERG-blocking drugs recapitulated the LQT2 phenotype. In LQT3 iPS-CM, expressing NaV1.5-N406K, APs and [Ca2+]i transients were markedly prolonged. AP prolongation was sensitive to tetrodotoxin and to inhibiting Na+-Ca2+ exchange. These results suggest that LQTS mutations act partly on cytosolic Ca2+ cycling, potentially providing a basis for functionally targeted interventions regardless of the specific mutation site.

Rationale Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during beta-adrenergic stimulation. Objective This study sought to determine the effects of a novel identified RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca2+). Methods Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2 (FKBP12.6). RyR2 channels were measured in order to examine the regulation of the channels by cytosolic vs. luminal SR Ca2+. Results A 50 year-old Caucasian male with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. PKA-phosphorylated RyR2-G230C channels exhibited a significantly higher open probability (Po) at diastolic Ca2+ concentrations, associated with a depletion of calstabin2. The luminal Ca2+ sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like. Conclusions The RyR2-G230C mutant exhibits similar biophysical defects compared to previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca2+-dependence for activation under conditions that simulate exercise, consistent with a “leaky” channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca2+ activation. Thus, diastolic SR Ca2+ leak caused by reduced calstabin2 binding and a leftward shift in the Ca2+-dependence for activation by diastolic levels of cytosolic Ca2+ is a common mechanism underlying CPVT.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. BIN1 is a membrane associated protein important to cardiomyocyte homeostasis and is down regulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing due to ARVC. Objective To determine whether plasma BIN1 can measure disease severity in patients with ARVC. Methods We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to predict cardiac functional status and ventricular arrhythmias. Results Mean plasma BIN1 levels were decreased in ARVC patients with heart failure (15 ± 7 vs. 60 ± 17 in patients without heart failure, p<0.05; plasma BIN1 is 60±10 in non-ARVC normal controls). BIN1 levels correlated inversely with ventricular arrhythmia (R=−0.47, p<0.05), and low BIN1 correctly classified patients with advanced heart failure or ventricular arrhythmia (ROC Area under the curve, AUC, of 0.88±0.07). Low BIN1 also predicted future ventricular arrhythmias (ROC AUC of 0.89±0.09). In a stratified analysis, BIN1 could predict future arrhythmias in patients without severe heart failure (n=20) with an accuracy of 82 %. In the seven ARVC patients with serial blood samples, all of whom had evidence of disease progression during follow up, plasma BIN1 decreased significantly (decrease of 63 %, p<0.05). Conclusions Plasma BIN1 seems to correlate with cardiac functional status and presence or absence of sustained ventricular arrhythmias in a small cohort of ARVC patients and can predict future ventricular arrhythmias.