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.
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•High dietary and plasma proline significantly associate with depression severity•Circulating proline is dependent on microbiome composition and functionality•With FMT, depression phenocopies to mice and increases a proline transporter gene•Slc6a20 knockdown and L. plantarum supplementation protect flies from depression
Mayneris-Perxachs et al. apply a multi-omics approach to study the microbiota-gut-brain axis in depression and demonstrate that microbiome-dependent elevations in plasma proline are significantly associated with depression severity in humans. Proline supplementation exacerbated depression in mice, and knockdown of proline and GABA transporters or mono-association with L. plantarum conferred protection against depression-like states in Drosophila.
Diagnosis of Type-2 Brugada pattern remains challenging and it could be confused with other electrocardiogram (ECG) patterns presenting an r'-wave in leads V1-V2 like in healthy athletes. This could ...impact their ability to perform competitive sports. The aim of the study was to evaluate, as a proof of concept, the new ECG criteria to differentiate the Type-2 Brugada pattern from the ECG pattern of healthy athletes depicting an r'-wave in leads V1-V2.
Surface ECGs from 50 patients with Brugada syndrome and type-2 Brugada pattern and 58 healthy athletes with an r'-wave in leads V1-V2 were analysed. Different criteria based on the characteristics of the triangle formed by the ascendant and descendant arms of the r'-wave in leads V1-V2 were compared. The duration of the base of the triangle at 0.5 mV (5 mm) from high take-off ≥160 ms (4 mm) has a specificity (SP) of 95.6%, sensitivity (SE) 85%, positive predictive value (PPV) 94.4%, and negative predictive value (NPV) 87.9%. The duration of the base of the triangle at the isoelectric line ≥60 ms (1.5 mm) in leads V1-V2 has an SP of 78%, SE 94.8%, PPV 79.3%, and NPV 93.5%. The ratio of the base at isoelectric line/height from the baseline to peak of r'-wave in leads V1-V2 has an SP of 92.1%, SE 82%, PPV 90.1%, and NPV 83.3%.
The three new ECG criteria were accurate to distinguish the Type-2 Brugada pattern from the ECG pattern with an r'-wave in healthy athletes. The duration of the base of the triangle at 0.5 mV from the high take-off is the easiest to measure and may be used in clinical practice.
Lafora Disease Is an Inherited Metabolic Cardiomyopathy Villalba-Orero, María, DVM, PhD; Sánchez-Elexpuru, Gentzane, MSc; López-Olañeta, Marina, MLT ...
Journal of the American College of Cardiology,
06/2017, Volume:
69, Issue:
24
Journal Article
Peer reviewed
Open access
Typical pathologic vacuoles containing glycogen or intermediary metabolites altering cardiac structure and function are usually described in Pompe, Danon, and Fabry diseases as well as in patients ...with mutations in PRKAG2, the regulatory γ subunit of AMP-activated protein kinase. Echocardiography analysis, performed in 2 separate groups of mice at 8 to 10 months of age and at 14 to 16 months of age under light anesthesia, revealed that laforin and malin knockout mice develop cardiac hypertrophy and marked systolic dysfunction by 14 to 16 months of age, as indicated by an increased end-diastolic left ventricular wall thickness and normalized cardiac mass, and a decreased left ventricular ejection fraction (Table 1). Values in bold are statistically significant.2D = 2-dimensional; BNP = B-type natriuretic peptide; HW = heart weight; LAX = long axis view; LV = left ventricular; LVEF = left ventricular ejection fraction; LVVold = end-diastolic left ventricular volume; MM =...
Abstract
Aims
Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according ...to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns.
Methods and results
Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE.
Conclusion
LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.
Graphical Abstract
Graphical Abstract
A cohort of 577 individuals with DCM phenotyped with genetic testing and CMR was analysed. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. LGE patterns in genetic DCM have a specific distribution. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. Abbreviations: CMR, cardiovascular magnetic resonance; DCM, dilated cardiomyopathy; HR, hazard ratio; IQR, interquartile range; LGE, late gadolinium enhancement; L.Midwall, lineal midwall; LVEF, left ventricular ejection fraction; MVA, major ventricular arrhythmias; RV, right ventricle.
Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an ...autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the
gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.
AbstractIntroduction and objectivesDanon disease (DD) is caused by mutations in the LAMP2 gene. It is considered a multisystemic disease characterized by hypertrophic cardiomyopathy with ...pre-excitation and extreme hypertrophy, intellectual disability, myopathy, childhood presentation, and worse prognosis in men. There are scarce data on the clinical characteristics and prognosis of DD. MethodsWe analyzed the clinical records of patients with DD from 10 Spanish hospitals.ResultsTwenty-seven patients were included (mean age, 31 ± 19 years; 78% women). Male patients showed a high prevalence of extracardiac manifestations: myopathy (80%), learning disorders (83%), and visual alterations (60%), which were uncommon findings in women (5%, 0%, and 27%, respectively). Although hypertrophic cardiomyopathy was the most common form of heart disease (61%), the mean maximum wall thickness was 15 ± 7 mm and dilated cardiomyopathy was present in 12 patients (10 women). Pre-excitation was found in only 11 patients (49%). Age at presentation was older than 20 years in 16 patients (65%). After a median follow-up of 4 years (interquartile range, 2-9), 4 men (67%) and 9 women (43%) died or required a transplant. Cardiac disease and adverse events occurred later in women (37 ± 9 vs 23 ± 16 and 36 ± 20 vs 20 ± 11 years, respectively).ConclusionsThe clinical characteristics of DD differ substantially from traditional descriptions: age at presentation of DD is older, the disease is not multisystemic in women, and pre-excitation is infrequent.
Abstract Brugada syndrome is an inherited heart disease without structural abnormalities that is thought to arise as a result of accelerated inactivation of Na channels and predominance of transient ...outward K current ( Ito ) to generate a voltage gradient in the right ventricular layers. This gradient triggers ventricular tachycardia/ventricular fibrillation possibly through a phase 2 reentrant mechanism. The Brugada electrocardiographic (ECG) pattern, which can be dynamic and is sometimes concealed, being only recorded in upper precordial leads, is the hallmark of Brugada syndrome. Because of limitations of previous consensus documents describing the Brugada ECG pattern, especially in relation to the differences between types 2 and 3, a new consensus report to establish a set of new ECG criteria with higher accuracy has been considered necessary. In the new ECG criteria, only 2 ECG patterns are considered: pattern 1 identical to classic type 1 of other consensus (coved pattern) and pattern 2 that joins patterns 2 and 3 of previous consensus (saddle-back pattern). This consensus document describes the most important characteristics of 2 patterns and also the key points of differential diagnosis with different conditions that lead to Brugada-like pattern in the right precordial leads, especially right bundle-branch block, athletes, pectus excavatum, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Also discussed is the concept of Brugada phenocopies that are ECG patterns characteristic of Brugada pattern that may appear and disappear in relation with multiple causes but are not related with Brugada syndrome.
Brugada syndrome Benito, Begoña; Brugada, Josep; Brugada, Ramón ...
Revista española de cardiologia
62, Issue:
11
Journal Article
Peer reviewed
First described in 1992, Brugada syndrome is characterized by a specific electrocardiographic pattern in the right precordial leads and susceptibility to ventricular arrhythmias and sudden death. ...Brugada syndrome is included among the channelopathies, primary electrical disorders that, characteristically, are not associated with concomitant structural cardiac abnormalities. In recent years, substantial preclinical and clinical research has led to the identification of multiple causative mutations and to understanding of the mechanisms underlying the development of the characteristic phenotype and of the factors that determine clinical prognosis in patients. Nevertheless, there remain numerous unresolved questions which provide an impetus for ongoing active research into the condition. This article provides a summary of what is currently known about Brugada syndrome and an overview of the principal preclinical and clinical studies that have made the most significant contributions to our understanding of the condition.
Electrocardiographic (ECG) fusion with intrinsic QRS could reduce the benefit of atrial synchronous biventricular pacing (AS-BiVP) in patients with hypertrophic obstructive cardiomyopathy (HOCM).
The ...purpose of this study was to assess the benefit of AS-BiVP and the influence of ECG fusion for reduction of left ventricular outflow tract gradient (LVOTG) in these patients.
Twenty-one symptomatic HOCM patients with severe LVOTG were included. Twelve patients were evaluated retrospectively for the prevalence of fusion and its influence on outcomes after AS-BiVP. Eleven patients (2 of the first population were also evaluated retrospectively) were prospectively included to evaluate the benefit of performing atrioventricular node ablation (AVNA) to achieve full ventricular capture if fusion was present during AS-BiVP.
Seven of the first 12 patients (58%) had ECG fusion. After 54 ± 24 months of AS-BiVP, the presence of fusion was associated with lower values for reduction of resting, dynamic LVOTG and New York Heart Association (NYHA) class. In the prospectively evaluated patients, after 12 months of follow-up, resting LVOTG decreased from 98 ± 39 to 39 ± 24 mm Hg (P = .008); dynamic LVOTG decreased from 112 ± 38 to 60 ± 24 mm Hg (P = .013); NYHA class decreased from 2.8 ± 0.4 to 1.7 ± 0.6 (P = .014); endurance time during constant work rate cycling exercise (80% of peak oxygen consumption) increased from 399 ± 148 to 691 ± 249 seconds (P = .046); quality of life improved from 46 ± 22 to 22 ± 20 points (P = .02); and brain natriuretic peptide levels decreased from 318 ± 238 to 152 ± 118 pg/mL (P = .09). Eight of the 11 prospectively evaluated patients (73%) needed AVNA, which further decreased LVOTG from 108 ± 40 mm Hg at baseline to 89 ± 29 mm Hg after BiVP to 54 ± 22 mm Hg after AVNA (P = .003).
As-BiVP that ensures no ECG fusion, by means of AVNA when needed, appears to be the optimal pacing mode in HOCM patients.
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