Microbiota alterations in proline metabolism impact depression.

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

BACKGROUND: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited. OBJECTIVES: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence. METHODS: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31). RESULTS: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents. CONCLUSIONS: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.

Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome.

BACKGROUND: There is emerging evidence that localization and elimination of abnormal electric activity in the epicardial right ventricular outflow tract may be beneficial in patients with Brugada syndrome. METHODS AND RESULTS: A total of 135 symptomatic Brugada syndrome patients having implantable cardiac defibrillator were enrolled: 63 (group 1) having documented ventricular tachycardia (VT)/ventricular fibrillation (VF) and Brugada syndrome-related symptoms, and 72 (group 2) having inducible VT/VF without ECG documentation at the time of symptoms. About 27 patients of group 1 experienced multiple implantable cardiac defibrillator shocks for recurrent VT/VF episodes. Three-dimensional maps before and after ajmaline determined the arrhythmogenic electrophysiological substrate (AES) as characterized by prolonged fragmented ventricular potentials. Primary end point was identification and elimination of AES leading to ECG pattern normalization and VT/VF noninducibility. Extensive areas of AES were found in the right ventricle epicardium, which were wider in group 1 (P=0.007). AES increased after ajmaline in both groups (P<0.001) and was larger in men (P=0.008). The increase of type-1 ST-segment elevation correlated with AES expansion (r=0.682, P<0.001). Radiofrequency ablation eliminated AES leading to ECG normalization and VT/VF noninducibility in all patients. During a median follow-up of 10 months, the ECG remained normal even after ajmaline in all except 2 patients who underwent a repeated effective procedure for recurrent VF. CONCLUSIONS: In Brugada syndrome, AES is commonly located in the right ventricle epicardium and ajmaline exposes its extent and distribution, which is correlated with the degree of coved ST-elevation. AES elimination by radiofrequency ablation results in ECG normalization and VT/VF noninducibility. Substrate-based ablation is effective in potentially eliminating the arrhythmic consequences of this genetic disease. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02641431.

A missense mutation in the sodium channel ß1b subunit reveals SCN1B as a susceptibility gene underlying long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is associated with sudden cardiac death and the prolongation of the QT interval on the electrocardiogram. A comprehensive screening of all genes previously associated with this disease leaves 30% of the patients without a genetic diagnosis. Pathogenic mutations in the sodium channel ß subunits have been associated with cardiac channelopathies, including SCN4B mutations in LQTS. OBJECTIVE: To evaluate the role of mutations in the sodium channel ß subunits in LQTS. METHODS: We screened for mutations in the genes encoding the 5 sodium ß subunits (SCN1B isoforms a and b, SCN2B, SCN3B, and SCN4B) from 30 nonrelated patients who were clinically diagnosed with LQTS without mutations in common LQTS-related genes. We used the patch-clamp technique to study the properties of sodium currents and the action potential duration in human embryonic kidney and HL-1 cells, respectively, in the presence of ß1b subunits. RESULTS: The genetic screening revealed a novel mutation in the SCN1Bb gene (ß1bP213T) in an 8-year-old boy. Our electrophysiological analysis revealed that ß1bP213T increases late sodium current. In addition, ß1bP213T subtly altered Nav1.5 function by shifting the window current, accelerating recovery from inactivation, and decreasing the slow inactivation rate. Moreover, experiments using HL-1 cells revealed that the action potential duration significantly increases when the mutant ß1b was overexpressed compared with ß1bWT. CONCLUSION: These data revealed SCN1Bb as a susceptibility gene responsible for LQTS, highlighting the importance of continuing the search for new genes and mechanisms to decrease the percentage of patients with LQTS remaining without genetic diagnosis.

Innovations in heart rhythm disturbances: cardiac electrophysiology, arrhythmias, and cardiac pacing.

This article reviews the most relevant articles published in 2012 in the field of arrhythmias, on subjects that include clinical arrhythmology, ablation, cardiac pacing, and the genetics of sudden cardiac death.

Serum 25-hydroxyvitamin D, calcium, phosphorus, and electrocardiographic QT interval duration: findings from NHANES III and ARIC.

CONTEXT: Disturbances in 25-hydroxyvitamin D, calcium, and phosphorus concentrations have been associated with increased risks of total and cardiovascular mortality. It is possible that changes in electrocardiographic QT interval duration may mediate these effects, but the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration has not been evaluated in general population samples. OBJECTIVE: The objective of the study was to evaluate the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration in two large samples of the U.S. general population. DESIGN: This study included cross-sectional analyses the Third National Health and Nutrition Survey (NHANES III) and the Atherosclerosis Risk in Communities (ARIC) study. SETTING: The study was conducted in the general community. PATIENTS OR OTHER PARTICIPANTS: Patients included 7,312 men and women from NHANES III and 14,825 men and women from the ARIC study. INTERVENTIONS: Serum 25-hydroxyvitamin D, total and ionized calcium, and inorganic phosphorus were measured in NHANES III, and serum total calcium and inorganic phosphorus were measured in ARIC. MAIN OUTCOME MEASURE: QT interval duration was obtained from standard 12-lead electrocardiograms. RESULTS: In NHANES III, the multivariate adjusted differences in average QT interval duration comparing the highest vs. the lowest quartiles of serum total calcium, ionized calcium, and phosphorus were -3.6 msec (-5.8 to -1.3; P for trend = 0.005), -5.4 msec (-7.4 to -3.5; P for trend <0.001), and 3.9 msec (2.0-5.9; P for trend <0.001), respectively. The corresponding differences in ARIC were -3.1 msec (-4.3 to -2.0; P for trend <0.001), -2.9 msec (-3.8 to -1.9; P for trend <0.001), and 2.3 msec (1.3-3.3; P for trend <0.001). No association was found between 25-hydroxyvitamin D concentrations and QT interval duration. CONCLUSIONS: In two large samples of the general population, QT interval duration was inversely associated with the serum total and ionized calcium and positively associated with serum phosphorus.

Clinical, electrocardiographic, and electrophysiologic characteristics of patients with a fasciculoventricular pathway: the role of PRKAG2 mutation.

BACKGROUND: The ECG, clinical, and electrophysiologic profiles of patients with a fasciculoventricular pathway are well described. Fasciculoventricular pathways occurring in the setting of glycogen storage cardiomyopathy possess unique features. OBJECTIVE: The purpose of this study was to compare the clinical, ECG, and electrophysiologic characteristics of patients with a fasciculoventricular pathway, with or without glycogen storage cardiomyopathy. METHODS: Two groups of patients with a fasciculoventricular pathway were compared: group A consisted of 10 patients with the PRKAG2 mutation (Arg302gln), and group B consisted of 9 patients without the mutation. RESULTS: Thirty percent of group A patients had left ventricular hypertrophy, and none had an additional accessory pathway. Group B patients had no structural heart disease, and 33% had an additional accessory pathway. Group A patients had a slower resting heart rate (56 ± 7 vs 75 ± 10 bpm, P <0.0001), a wider QRS complex (0.15 ± 0.01 vs 0.11 ± 0.02 ms, P = .0004), and a longer HV interval (34 ± 1 vs 25 ± 3 ms, P = .0003). During long-term follow-up, 50% of group A patients developed complete AV block versus none in group B. Eighty percent of group A patients developed atrial flutter and/or atrial fibrillation. No Group B patient had any arrhythmia during follow-up after successful ablation of additional arrhythmia circuits. No sustained ventricular arrhythmia was induced in any patient from either group. CONCLUSION: Patients with a fasciculoventricular pathway associated with the PRKAG2 mutation have distinct clinical, ECG, and electrophysiologic profiles and should be correctly identified because of their ominous long-term prognosis. Patients without the mutation have an excellent arrhythmia-free prognosis after treatment of additional circuits.

Conduction abnormalities in the right ventricular outflow tract in Brugada syndrome detected body surface potential mapping.

Brugada syndrome (BrS) causes sudden death in patients with structurally normal hearts. Manifestation of BrS in the ECG is dynamical and most patients do not show unequivocal signs of the syndrome during ECG screening. We have obtained 67-lead body surface potential mapping recordings of 25 patients with BrS and analyzed their spatial distribution of surface potentials during ventricular activation. Six patients presented spontaneous type I ECGs during the recording. These patients showed non-dipolarities in isopotential maps at the right ventricular outflow tract (RVOT) region during the development of terminal R waves in right precordial leads. Same finding was observed in 95% of BrS patients not presenting a type I ECG. Conduction delay in the RVOT may be a consistent finding in BrS patients that can be identified by Body Surface Potential Mapping.

Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada syndrome: a diagnostic consensus criterion to be revised.

AIMS: According to the diagnostic consensus criteria, the electrocardiographic (ECG) diagnosis of Brugada syndrome requires coved-type > or =2 mm ST-segment elevation in >1 right precordial lead (RPL) V1-V3 in the presence or absence of a sodium-channel blocker. However, this consensus has not been evaluated. We aimed to assess the distribution of coved-type ST-segment elevation on RPLs in a large patient cohort to reevaluate the appropriateness of the diagnostic consensus criteria. METHODS AND RESULTS: We included 186 individuals with spontaneous and/or drug-induced ECGs of coved-type > or =2 mm ST-segment elevation in at least one RPL. A total of 376 ECGs were analysed for the number, distribution and maximal J-point elevation of diagnostic RPLs. Among all ECGs, 27 (7%) showed a coved-type pattern in 3 RPLs, 205 (55%) in 2 RPLs, and 144 (38%) in only 1 RPL. Leads V1 and V2 were diagnostic in 99% of all ECGs with two diagnostic RPLs. Lead V3 alone was not diagnostic in any ECG. Maximal J-point elevation was significantly higher in lead V2 than V1. Sixty case subjects (32%) had only ECGs with one RPL displaying a coved-type ST-segment elevation. There was no significant difference in clinical presentation and outcome compared with the 126 Brugada patients with ECGs displaying >1 diagnostic RPL. Major arrhythmic events occurred with the same rate (8%) in both groups during a follow-up >5 years. CONCLUSION: Lead V3 does not yield diagnostic information in Brugada syndrome. Individuals with ECGs displaying only one diagnostic RPL have a similar clinical profile and arrhythmic risk as Brugada patients with ECGs displaying >1 diagnostic RPL. Revision of the consensus criteria should be considered.

Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction.

BACKGROUND: Ventricular tachycardia (VT) and ventricular fibrillation (VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) both have been linked to phase 2 reentry. OBJECTIVE: Given the mechanistic similarities in arrhythmogenesis, the purpose of this study was to examine the contribution of SCN5A mutations to VT/VF complicating AMI. METHODS: Nineteen consecutive patients developing VF during AMI were enrolled in the study. Wild-type (WT) and mutant SCN5A genes were coexpressed with SCN1B in TSA201 cells and studied using whole-cell patch clamp techniques. RESULTS: Among the cohort of 19 patients, one missense mutation (G400A) in SCN5A was detected in a conserved region. An H558R polymorphism was detected on the same allele. Unlike the other 18 patients, who each developed 1-2 VF episodes during AMI, the mutation carrier developed six episodes of VT/VF within the first 12 hours. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. Flecainide and adenosine challenge performed to unmask Brugada and long QT syndromes both were negative. Peak G400A and G400A+H558R current were 70.7% and 88.4% less than WT current at -35 mV (P

Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart.

INTRODUCTION: The prognostic value of electrophysiologic studies in individuals with the syndrome of right bundle branch block and ST segment elevation in precordial leads V1 to V3 (Brugada syndrome) remains controversial. Our previous data from 252 individuals with the syndrome suggested that programmed ventricular stimulation had a good overall accuracy to predict events. However, studies from independent investigators questioned our results. We report here the largest population with Brugada syndrome ever studied by programmed electrical stimulation of the heart. METHODS AND RESULTS: Four hundred forty-three individuals with an ECG diagnostic of Brugada syndrome were studied by programmed electrical stimulation of the heart. The diagnosis was made because of the classic ECG showing a coved-type ST segment elevation in precordial leads V1 to V3. Of the 443 individuals, 180 had developed spontaneous symptoms (syncope or aborted sudden cardiac death) and 263 were asymptomatic at the time the diagnosis was made. The ventricular stimulation protocol included a minimum of two basic pacing cycle lengths with two ventricular premature beats from the right ventricular apex. A sustained ventricular arrhythmia was induced in 217 cases (49%). Symptomatic patients were more frequently inducible [126/180 (70%)] than asymptomatic individuals [91/263 (34%); P = 0.0001]. Males were more frequently inducible than females (54% vs 32%, P < 0.0001). Inducible individuals had a longer HV interval than noninducible patients (50 +/- 12 msec vs 46 +/- 10 msec, P < 0.002). HV interval and number of premature beats needed to induce VF were not related to outcome. Inducibility was statistically a powerful predictor of arrhythmic events during follow-up. Sixty of 217 inducible patients (28%) had spontaneous ventricular fibrillation compared with 5 of 221 noninducible patients (2%; P = 0.0001). CONCLUSION: Inducibility of sustained ventricular arrhythmias during programmed ventricular stimulation of the heart is a good predictor of outcome in Brugada syndrome.