An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function

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

Rat experimental model of myocardial ischemia/reperfusion injury: an ethical approach to set up the analgesic management of acute post-surgical pain

RATIONALE: During the past 30 years, myocardial ischemia/reperfusion injury in rodents became one of the most commonly used model in cardiovascular research. Appropriate pain-prevention appears critical since it may influence the outcome and the results obtained with this model. However, there are no proper guidelines for pain management in rats undergoing thoracic surgery. Accordingly, we evaluated three analgesic regimens in cardiac ischemia/reperfusion injury. This study was strongly focused on 3R's ethic principles, in particular the principle of Reduction. METHODS: Rats undergoing surgery were treated with pre-surgical tramadol (45 mg/kg intra-peritoneal), or carprofen (5 mg/kg sub-cutaneous), or with pre-surgical administration of carprofen followed by 2 post-surgery tramadol injections (multi-modal group). We assessed behavioral signs of pain and made a subjective evaluation of stress and suffering one and two hours after surgery. RESULTS: Multi-modal treatment significantly reduced the number of signs of pain compared to carprofen alone at both the first hour (61±42 vs 123±47; p<0.05) and the second hour (43±21 vs 74±24; p<0.05) post-surgery. Tramadol alone appeared as effective as multi-modal treatment during the first hour, but signs of pain significantly increased one hour later (from 66±72 to 151±86, p<0.05). Carprofen alone was more effective at the second hour post-surgery when signs of pain reduced to 74±24 from 113±40 in the first hour (p<0.05). Stress behaviors during the second hour were observed in only 20% of rats in the multimodal group compared to 75% and 86% in the carprofen and tramadol groups, respectively (p<0.05). CONCLUSIONS: Multi-modal treatment with carprofen and tramadol was more effective in preventing pain during the second hour after surgery compared with both tramadol or carprofen. Our results suggest that the combination of carprofen and tramadol represent the best therapy to prevent animal pain after myocardial ischemia/reperfusion. We obtained our results accordingly with the ethical principle of Reduction