Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator

Clinical management of catecholaminergic polymorphic ventricular tachycardia: The role of left cardiac sympathetic denervation.

BACKGROUND: -Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. Β-blockers are the mainstay of therapy; when they fail, implantable cardioverter defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. METHODS AND RESULTS: -We report on 63 CPVT patients who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events (MCEs). Of the 54 patients with prior MCEs either on (n=38) or off (n=16) optimal medical therapy (OMT), 13 (24%) had at least 1 recurrence: none had an aborted cardiac arrest, 2 had syncope only, 10 had ≥1 appropriate ICD discharge and one died suddenly. The 1- and 2-year cumulative event-free survivals were 87% and 81%. The percentage of patients with MCEs despite OMT (n=38) was reduced from 100% to 32% (p<0.001) following LCSD and, among 29 patients with a pre-surgical ICD, the rate of shocks dropped by 93%, from 3.6 to 0.6 shocks/person/year (p<0.001). Patients with an incomplete LCSD (n=7) were more likely to suffer MCEs post-LCSD (71% vs 17%, p<0.01) than those with a complete LCSD. CONCLUSIONS: -LCSD is an effective anti-fibrillatory intervention for patients with CPVT. Whenever syncope occurs despite OMT, LCSD could be considered as the next step rather than an ICD and could complement ICDs in patients with recurrent shocks