SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.

International audienceBACKGROUND: Mutations in SCN5A are identified in approximately 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. METHODS AND RESULTS: Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. CONCLUSIONS: Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Brugada syndrome: Diagnosis, risk stratification and management

International audienceBrugada syndrome is a rare inherited arrhythmia syndrome leading to an increased risk of sudden cardiac death, despite a structurally normal heart. Diagnosis is based on a specific electrocardiogram pattern, observed either spontaneously or during a sodium channel blocker test. Among affected patients, risk stratification remains a challenge, despite recent insights from large population cohorts. As implantable cardiac defibrillators - the main therapy in Brugada syndrome - are associated with a high rate of complications in this population, the main challenge is risk stratification of patients with Brugada syndrome. Aside from the two main predictors of arrhythmia (symptoms and spontaneous electrocardiogram pattern), many risk factors have been recently suggested for stratifying risk of sudden cardiac death in Brugada syndrome. We have reviewed these data and discuss current guidelines in light of recent progress in this complex field

The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance

International audienceFor the last 10 years, applying new sequencing technologies to thousands of whole exomes has revealed the high variability of the human genome. Extreme caution should thus be taken to avoid misinterpretation when associating rare genetic variants to disease susceptibility. The Brugada syndrome (BrS) is a rare inherited arrhythmia disease associated with high risk of sudden cardiac death in the young adult. Familial inheritance has long been described as Mendelian, with autosomal dominant mode of transmission and incomplete penetrance. However, all except 1 of the 23 genes previously associated with the disease have been identified through a candidate gene approach. To date, only rare coding variants in the SCN5A gene have been significantly associated with the syndrome. However, the genotype/phenotype studies conducted in families with SCN5A mutations illustrate the complex mode of inheritance of BrS. This genetic complexity has recently been confirmed by the identification of common polymorphic alleles strongly associated with disease risk. The implication of both rare and common variants in BrS susceptibility implies that one should first define a proper genetic model for BrS predisposition prior to applying molecular diagnosis. Although long remains the way to personalized medicine against BrS, the high phenotype variability encountered in familial forms of the disease may partly find an explanation into this specific genetic architecture

Severe infections due to Francisella tularensis ssp. holarctica in solid organ transplant recipient: report of two cases and review of literature

Abstract Background Tularemia is a rare zoonotic infection caused by bacterium Francisella tularensis. It has been well described in immunocompetent patients but poorly described in immunocompromised patients notably in solid organ transplant recipients. Case presentations We report here two cases of tularemia in solid organ transplant recipients including first case after heart transplant. We also carried out an exhaustive review of literature describing characteristics of this infection in solid organ transplant recipients

Acute kidney injury in SARS-CoV2-related pneumonia ICU patients: a retrospective multicenter study

International audienceBackground: While acute kidney injury (AKI) is frequent in severe SARS-CoV2-related pneumonia ICU patients, few data are still available about its risk factors.Methods: Retrospective observational study performed in four university affiliated hospitals in Paris. AKI was defined according to the KIDGO guidelines. Factors associated with AKI were picked up using multivariable mixed-effects logistic regression. Independent risk factors of day 28 mortality were assessed using Cox model.Results: 379 patients (median age 62 [53,69], 77% of male) were included. Half of the patients had AKI (n = 195, 52%) including 58 patients (15%) with AKI stage 1, 44 patients (12%) with AKI stage 2, and 93 patients (25% with AKI stage 3). Chronic kidney disease (OR 7.41; 95% CI 2.98-18.4), need for invasive mechanical ventilation at day 1 (OR 4.83; 95% CI 2.26-10.3), need for vasopressors at day 1 (OR 2.1; 95% CI 1.05-4.21) were associated with increased risk of AKI. Day 28 mortality in the cohort was 26.4% and was higher in patients with AKI (37.4 vs. 14.7%, P < 0.001). Neither AKI (HR 1.35; 95% CI 0.78-2.32) nor AKI stage were associated with mortality (HR [95% CI] for stage 1, 2 and 3 when compared to no AKI of, respectively, 1.02 [0.49-2.10], 1.73 [0.81-3.68] and 1.42 [0.78-2.58]).Conclusion: In this large cohort of SARS-CoV2-related pneumonia patients admitted to the ICU, AKI was frequent, mostly driven by preexisting chronic kidney disease and life sustaining therapies, with unclear adjusted relationship with day 28 outcome

Overview of Development of Laser Driven Secondary Sources at PALS and ELI

International audienceIn this paper we report on development of the secondary X-ray sources at the PALS Centre and discuss the plan for the ELI Beamlines project. The spatial and temporal coherence of the most energetic quasi-steady state Ne-like Zn X-ray laser, which is operated at PALS Centre as standard user beamline, was examined proving that amplification of coherent EUV pulses with duration below 1 ps will be possible. Meanwhile, the first transient lasing at PALS Center was achieved using 10 Hz Ti: Sapphire laser chain with peak power of 20 TW as a driver. Finally, we discuss the recent design of laser driven secondary sources generating short coherent or incoherent EUV/X-ray pulses within the ELI Beamlines project

0224 : Mental stress unmasked new phenotype of sudden cardiac death related to adrenalin dependent prolongation of the QT interval

IntroductionCongenital long QT syndrome (LQTS) is a hereditary disease characterized by prolonged QTc and associated with sudden cardiac death (SCD).MethodsRelatives of 4 large families in which case of (aborted) SCD occurred have been clinically investigated. Twelve-lead ECG, adrenaline provocation test, exercise test and mental stress (rapid mental calculation) test were performed. Patients were considered as affected by LQTS in case of QTc>480ms at rest or during the tests. Genetic screening of the major and minor genes previously associated with LQTS identified no causal variant.ResultsAmong the 4 pedigrees, 62 relatives were screened: 8, 12, 17 and 25 respectively. At rest, mean HR was 70±13 bpm and QTc was 415±29ms. Only 1 patient was considered affected. A mental stress was performed in 49 family members: HR increased from 71±13 bpm to 94±17 bpm. QTc increased from 414±26ms to 462±42ms. This test unmasked LQTS in 18 patients including one patient resuscitated from cardiac arrest (mean QTc=509±26ms). For 8 of them an adrenalin test was performed and turned positive in all. One patient had a positive adrenalin test while the mental stress was negative. However exercise test was performed in 14 and none present a positive test. During the different tests no arrhythmia was recorded.QTc prolongation in patients considered as affected was characterized by a prolonged and depressed ST segment with a normal T wave. This aspect does not fit with any classical aspect of LQTS.Conclusion-Future PlanWe described a new phenotype of SCD related to adrenalin dependent prolongation of the QT interval that is not related to the already known LQTS genes. Whole exome sequencing will be carried out in 2 distantly related individuals presenting the most severe phenotype from each of the 4 pedigrees. From the shared variants we shall filter out variants that are common in the general population (MAF >1%) and not segregating in the rest of the affected family members