The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and ...is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial.
We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier.
In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.
Endocrine disrupting chemicals (EDCs) set a public health risk through disruption of normal physiological processes. The toxicoepigenetic mechanisms of developmental exposure to common EDCs, such as ...bisphenol A (BPA), are poorly known. The present study aimed to evaluate associations between perinatal maternal urinary concentrations of BPA, bisphenol S (BPS) and bisphenol F (BPF) and LINE-1 (long interspersed nuclear elements) and Alu (short interspersed nuclear elements, SINEs) DNA methylation levels in newborns, as surrogate markers of global DNA methylation. Data come from 318 mother-child pairs of the `Nutrition in Early Life and Asthma´ (NELA) birth cohort. Urinary bisphenol concentration was measured by dispersive liquid–liquid microextraction and ultrahigh performance liquid chromatography with tandem mass spectrometry detection. DNA methylation was quantitatively assessed by bisulphite pyrosequencing on 3 LINEs and 5 SINEs. Unadjusted linear regression analyses showed that higher concentration of maternal urinary BPA in 24th week's pregnancy was associated with an increase in LINE-1 methylation in all newborns (p = 0.01) and, particularly, in male newborns (p = 0.03). These associations remained in full adjusted models beta = 0.09 (95 % CI = 0.03; 0.14) for all newborns; and beta = 0.10 (95 % CI = 0.03; 0.17) for males, including a non-linear association for female newborns as well (p-trend = 0.003). No associations were found between maternal concentrations of bisphenol and Alu sequences. Our results suggest that exposure to environmental levels of BPA may be associated with a modest increase in LINE-1 methylation -as a relevant marker of epigenomic stability- during human fetal development. However, any effects on global DNA methylation are likely to be small, and of uncertain biological significance.
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•Early exposure to bisphenols may have potential toxicoepigenetic effects.•Global DNA methylation of LINE-1 and Alu in cord blood samples were analyzed.•Maternal urinary Bisphenol A was associated with an increase of LINE-1 methylation.•No associations between bisphenols and percentage of Alu methylation were found.
Rule‐based methods are often used for assigning fiber orientation to cardiac anatomical models. However, existing methods have been developed using data mostly from the left ventricle. As a ...consequence, fiber information obtained from rule‐based methods often does not match histological data in other areas of the heart such as the right ventricle, having a negative impact in cardiac simulations beyond the left ventricle. In this work, we present a rule‐based method where fiber orientation is separately modeled in each ventricle following observations from histology. This allows to create detailed fiber orientation in specific regions such as the endocardium of the right ventricle, the interventricular septum, and the outflow tracts. We also carried out electrophysiological simulations involving these structures and with different fiber configurations. In particular, we built a modeling pipeline for creating patient‐specific volumetric meshes of biventricular geometries, including the outflow tracts, and subsequently simulate the electrical wavefront propagation in outflow tract ventricular arrhythmias with different origins for the ectopic focus. The resulting simulations with the proposed rule‐based method showed a very good agreement with clinical parameters such as the 10 ms isochrone ratio in a cohort of nine patients suffering from this type of arrhythmia. The developed modeling pipeline confirms its potential for an in silico identification of the site of origin in outflow tract ventricular arrhythmias before clinical intervention.
We have developed a rule‐based method (RBM) that includes specific fiber orientation in different cardiac regions such as the right ventricle endocardium, the interventricular septum, and the outflow tracts, following observations from histological data. This adapted RBM allows running in silico simulations aimed to model pathologies where these regions are relevant such as outflow tract ventricular arrhythmias. The resulting simulations with the proposed RBM showed a very good agreement with clinical parameters.
Identification of left atrial (LA) fibrosis through late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) remains controversial due to the heterogeneity and lack of reproducibility of ...proposed methods. Our aim is to describe a normalized, reproducible, standardized method to evaluate LA fibrosis through LGE-CMR.
Electrocardiogram- and respiratory-gated 3-Tesla LGE-CMR was performed in 10 healthy young volunteers and 30 patients with atrial fibrillation (AF): 10 with paroxysmal AF, 10 with persistent AF, and 10 with a previous AF ablation procedure. Local image intensity ratio (IIR) of the LA was calculated as the absolute pixel intensity to mean blood pool intensity ratio. The healthy atrial tissue threshold was defined in young healthy volunteers (upper limit of normality set at IIR tissue mean plus 2 SDs). Dense atrial scarring was characterized in patients with previous radiofrequency-induced scarring (post-AF ablation patients). Validation groups consisted of patients with paroxysmal and persistent AFs. The upper limit of normal IIR was 1.20; IIR values higher than 1.32 (60% of mean maximum pixel intensity in post-ablation patients) were considered dense scar. Image intensity ratio values between 1.2 and 1.32 identified interstitial fibrosis. Patients with paroxysmal and persistent AFs had less atrial fibrotic tissue compared with post-ablation patients. Endocardial bipolar voltage was correlated to IIR values.
An IIR of 1.2 identifies the upper limit of normality in healthy young individuals. An IIR of >1.32 defines dense atrial fibrosis in post-ablation patients. Our results provide a consistent, comparable, and normalized tool to assess atrial arrhythmogenic substrate.
Introduction:
Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V
1
to V
3
of patients with structurally normal ...hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in
SCN5A.
Methods and Results:
We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the
SCN5A
locus. Sequencing of
SCN5A
identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in
SCN5A.
The R367H mutation failed to generate any current when heterologously expressed in HEK cells.
Conclusion:
Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false‐positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.
(J Cardiovasc Electrophysiol, Vol. 15, pp. 64‐69, January 2004)
The role of high-intensity exercise and other emerging risk factors in lone atrial fibrillation (Ln-AF) epidemiology is still under debate. The aim of this study was to analyse the contribution of ...each of the emerging risk factors and the impact of physical activity dose in patients with Ln-AF.
Patients with Ln-AF and age- and sex-matched healthy controls were included in a 2:1 prospective case-control study. We obtained clinical and anthropometric data transthoracic echocardiography, lifetime physical activity questionnaire, 24-h ambulatory blood pressure monitoring, Berlin questionnaire score, and, in patients at high risk for obstructive sleep apnoea (OSA) syndrome, a polysomnography. A total of 115 cases and 57 controls were enrolled. Conditional logistic regression analysis associated height odds ratio (OR) 1.06 1.01-1.11, waist circumference (OR 1.06 1.02-1.11), OSA (OR 5.04 1.44-17.45), and 2000 or more hours of cumulative high-intensity endurance training to a higher AF risk. Our data indicated a U-shaped association between the extent of high-intensity training and AF risk. The risk of AF increased with an accumulated lifetime endurance sport activity ≥ 2,000 h compared with sedentary individuals (OR 3.88 1.55-9.73). Nevertheless, a history of <2000 h of high-intensity training protected against AF when compared with sedentary individuals (OR 0.38 0.12-0.98).
A history of ≥ 2,000 h of vigorous endurance training, tall stature, abdominal obesity, and OSA are frequently encountered as risk factors in patients with Ln-AF. Fewer than 2000 total hours of high-intensity endurance training associates with reduced Ln-AF risk.
The left atrium (LA) can change in size and shape due to atrial fibrillation (AF)-induced remodeling. These alterations can be linked to poorer outcomes of AF ablation. In this study, we propose a ...novel comprehensive computational analysis of LA anatomy to identify what features of LA shape can optimally predict post-ablation AF recurrence. To this end, we construct smooth 3D geometrical models from the segmentation of the LA blood pool captured in pre-procedural MR images. We first apply this methodology to characterize the LA anatomy of 144 AF patients and build a statistical shape model that includes the most salient variations in shape across this cohort. We then perform a discriminant analysis to optimally distinguish between recurrent and non-recurrent patients. From this analysis, we propose a new shape metric called vertical asymmetry, which measures the imbalance of size along the anterior to posterior direction between the superior and inferior left atrial hemispheres. Vertical asymmetry was found, in combination with LA sphericity, to be the best predictor of post-ablation recurrence at both 12 and 24 months (area under the ROC curve: 0.71 and 0.68, respectively) outperforming other shape markers and any of their combinations. We also found that model-derived shape metrics, such as the anterior-posterior radius, were better predictors than equivalent metrics taken directly from MRI or echocardiography, suggesting that the proposed approach leads to a reduction of the impact of data artifacts and noise. This novel methodology contributes to an improved characterization of LA organ remodeling and the reported findings have the potential to improve patient selection and risk stratification for catheter ablations in AF.
Introduction
To investigate the relation between left atrial (LA) volume, sphericity, and fibrotic content derived from contrast‐enhanced cardiac magnetic resonance imaging (CE‐CMR) and their impact ...on the outcome of catheter ablation for atrial fibrillation (AF).
Methods and results
In 83 patients undergoing catheter ablation for AF, CE‐CMR was used to assess LA volume, sphericity, and fibrosis. There was a significant correlation between LA volume and sphericity (R = 0.535, P < 0.001) and between LA volume and fibrosis (R = 0.241, P = 0.029). Multivariate analyses demonstrated that LA volume was the strongest independent predictor of AF recurrence after catheter ablation (1.019, P = 0.018).
Conclusion
LA volume, sphericity, and fibrosis were closely related; however, LA volume was the strongest predictor of AF recurrence after catheter ablation.
Insertable cardiac monitors (ICMs) require an invasive procedure and are used for purely diagnostic purposes. Therefore, simplicity of the insertion procedure, low complication rate, long-term ...patient acceptance, sensing quality, and reliable remote monitoring are of great importance.
To evaluate a novel ICM (BIOMONITOR III) regarding all these aspects.
BIOMONITOR III has a miniaturized profile, long sensing vector (≈70 mm), a fast insertion tool for pocket formation and ICM placement in 1 step, and daily automatic Home Monitoring (HM) function. We evaluated the insertion procedure, complication rate, patient acceptance, sensing quality, and HM performance in 653 patients with BIOMONITOR III inserted for any ICM indication within 2 ongoing studies involving 51 sites in 11 countries.
The median time from skin incision to wound closure was 4.0 minutes (interquartile range, 2.3–6.2 minutes). Median follow-up period was 274 days (interquartile range, 175–342 days). Serious adverse device-related events occurred in 6 patients (0.9%). No deep infections were reported in 334 patients without antibiotic prophylaxis. The wearing comfort was good or excellent in ≈95%. The mean R-wave amplitude (0.73 mV) and HM transmission rate (≈94% of days) were stable over 1.5 years. R-wave amplitudes were larger (mean 0.80 vs 0.62 mV, P < .001) and noise burden was lower (median 3.7 vs 14.5 minutes/day, P < .001) for ICM insertions parallel to the heart’s long axis (54.2%) vs parasternal (41.3%). A gross visibility of P waves was 95.1%.
The study demonstrated fast insertion times, low complication rate, high patient acceptance, and favorable long-term sensing and HM performance of the ICM.
Left atrial (LA) fibrosis can be identified by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) in patients with atrial fibrillation (AF). However, there is limited information about ...anatomical fibrosis distribution in the left atrium. The aim is to determine whether there is a preferential spatial distribution of fibrosis in the left atrium in patients with AF.
A 3-Tesla LGE-CMR was performed in 113 consecutive patients referred for AF ablation. Images were post-processed and analysed using ADAS-AF software (Galgo Medical), which allows fibrosis identification in 3D colour-coded shells. A regional semiautomatic LA parcellation software was used to divide the atrial wall into 12 segments: 1-4, posterior wall; 5-6, floor; 7, septal wall; 8-11, anterior wall; 12, lateral wall. The presence and amount of fibrosis in each segment was obtained for analysis. After exclusions for artefacts and insufficient image quality, 76 LGE-MRI images (68%) were suitable for fibrosis analysis. Segments 3 and 5, closest to the left inferior pulmonary vein, had significantly higher fibrosis (40.42% ± 23.96 and 25.82% ± 21.24, respectively; P < 0.001), compared with other segments. Segments 8 and 10 in the anterior wall contained the lowest fibrosis (2.54% ± 5.78 and 3.82% ± 11.59, respectively; P < 0.001). Age >60 years was significantly associated with increased LA fibrosis 95% confidence interval (CI) 0.19-8.39, P = 0.04 and persistent AF approached significance (95% CI -0.19% to 7.83%, P = 0.08).
In patients with AF, the fibrotic area is preferentially located at the posterior wall and floor around the antrum of the left inferior pulmonary vein. Age >60 years was associated with increased fibrosis.
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