177 research outputs found
Systematic Analysis of Gene Expression Differences between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue
Background: Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (paired-like homeodomain transcription factor 2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. We therefore systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.
Methods: We compared left and right atrial gene expression in healthy, adult mice of different strains and ages by
employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in either atrium were validated by RT-qPCR and Western blot in further animals and in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.
Results: We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10, a member of the TGFb family, showed highest enrichment in right atrium. These differences were validated by RT-qPCR in murine and human tissue. Western blot showed a 2-fold left-right concentration gradient in PITX2 protein in adult human atria. Several of the genes and gene groups enriched in left atria have a known biological role for maintenance of healthy physiology, specifically the prevention of atrial pathologies involved in atrial fibrillation, including membrane electrophysiology, metabolic cellular function, and regulation of inflammatory processes. Comparison of the array datasets with published array analyses in heterozygous Pitx2c+/2 atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.
Conclusions: Our study reveals systematic differences between left and right atrial gene expression and supports the hypothesis that Pitx2c has a functional role in maintaining āāleftnessāā in the atrium in adult murine and human hearts
The U.S. Law of Client Confidentiality: Framework for an International Perspective
In this Article, I will consider two general areas of the U.S. law of confidentiality. In Part I, I will reflect briefly upon what I call āthe U.S. culture of lawyer-client confidentiality.ā I say ācultureā rather than ācult,ā and one must guard against temptations to confuse those concepts. Those reflections will serve as backgroundāby way of both match and contrastāto my sketch of the U.S. law of confidentiality in Part II
Social and individual features affecting natal dispersal in the colonial Lesser Kestrel
Causes of natal dispersal were studied in an isolated population of the migratory, facultatively colonial Lesser Kestrel (Falco naumanni) in northeastern Spain. During a seven-year study, we gathered information on natal dispersal of 751 individuals and on 24 explanatory variables that evaluated individual traits, conspecific cues in terms of colony size, and different ecological and populational features. We examined separately whether or not individuals changed colonies and how far they moved. Dispersal from the natal colony was high (83%), and dispersers covered a median distance of 7225 m (range 112-136 500 m). The probability of natal dispersal decreased with the size of the natal colony and with the distance to the nearest colony, but not with the distance to unoccupied buildings, in the year of recruitment. Moreover, the shorter the distance to the nearest colony, the shorter the distances that individuals dispersed, particularly to large colonies (>10 pairs). These results support the conspecific attraction hypothesis. Accordingly, the probability of recruiting in the natal colony increased with the proportion of philopatric adults, although beyond a threshold individuals were prevented from recruiting by the more dominant adults in a despotic way. The timing of arrival from the wintering grounds was positively related to the probability of colony change, especially in males. To the extent that this variable is related to the phenotypic quality of individuals, it reinforces the idea that natal dispersal is shaped by intraspecific competition in crowded colonies. Males showed lower frequencies of colony change and dispersed shorter distances than did females, as explained by the different role of the sexes in nest acquisition and defense. Our results indicate that natal dispersal is an evolutionarily labile trait simultaneously influenced by ecological, social, and individual features both within and between populations.Peer Reviewe
The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results.
Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network
Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in ĪKPQ Scn5a murine hearts modelling human long QT 3 syndrome
Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide
Aims
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the Ī±-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients.
Methods and results
We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/ā mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/ā compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/ā mice could be excluded.
Conclusion
The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability
Development and external validation of predictive models for prevalent and recurrent atrial fibrillation: a protocol for the analysis of the CATCH ME combined dataset
Background: Atrial fibrillation (AF) is caused by different mechanisms but current treatment strategies do not target these mechanisms. Stratified therapy based on mechanistic drivers and biomarkers of AF have the potential to improve AF prevention and management outcomes. We will integrate mechanistic insights with known pathophysiological drivers of AF in models predicting recurrent AF and prevalent AF to test hypotheses related to AF mechanisms and response to rhythm control therapy. Methods: We will harmonise and combine baseline and outcome data from 12 studies collected by six centres from the United Kingdom, Germany, France, Spain, and the Netherlands which assess prevalent AF or recurrent AF. A Delphi process and statistical selection will be used to identify candidate clinical predictors. Prediction models will be developed in patients with AF for AF recurrence and AF-related outcomes, and in patients with or without AF at baseline for prevalent AF. Models will be used to test mechanistic hypotheses and investigate the predictive value of plasma biomarkers. Discussion: This retrospective, harmonised, individual patient data analysis will use information from 12 datasets collected in five European countries. It is envisioned that the outcome of this analysis would provide a greater understanding of the factors associated with recurrent and prevalent AF, potentially allowing development of stratified approaches to prevention and therapy management
An automated system using spatial oversampling for optical mapping in murine atria. Development and validation with monophasic and transmembrane action potentials
AbstractWe developed and validated a new optical mapping system for quantification of electrical activation and repolarisation in murine atria. The system makes use of a novel 2nd generation complementary metal-oxide-semiconductor (CMOS) camera with deliberate oversampling to allow both assessment of electrical activation with high spatial and temporal resolution (128Ā ĆĀ 2048 pixels) and reliable assessment of atrial murine repolarisation using post-processing of signals. Optical recordings were taken from isolated, superfused and electrically stimulated murine left atria. The system reliably describes activation sequences, identifies areas of functional block, and allows quantification of conduction velocities and vectors. Furthermore, the system records murine atrial action potentials with comparable duration to both monophasic and transmembrane action potentials in murine atria
Smartphone and wearable detected atrial arrhythmias in Older Adults: Results of a fully digital European Case finding study
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