Effect of Ibutilide on the Canine Cardiac Conduction System

The objective of the study was to evaluate the effect of ibutilide on canine cardiac sinoatrial and atrioventricular nodes (AVNs). For this purpose, 18 mongrel dogs were injected intravenously with ibutilide and the changes in heart rate, sinus node recovery time, and AVN were measured. Our data show that ibutilide administration caused significant suppression of the sinus atrial node, the peak response time was 20?C30?min, and the heart rate was restored to pre-drug administration level. After receiving ibutilide, 1 animal had a 5?s sinus pause, and after 5?min of ibutilide administration, 1 dog showed 2:1 atrioventricular conduction. Therefore, it was concluded that ibutilide had a suppressive effect on the sinoatrial node and AVN.     

Theoretical Study of Cardiac Transient Conduction Blocks on Reentries Induction. Applications to Antiarrhythmic Drugs

Limitations of antiarrhythmic drugs on cardiac sudden death prevention appeared since the early 80's. The "Cardiac Arrhythmia Suppression Trial"(CAST) showed more recently that mortality was significantly higher inpatients treated with some particular antiarrhythmic drugs than in non-treated patients. In this field, our group recently demonstrated that a bolus of a Class 1B antiarrhythmic drug was able to trigger a ventricular fibrillation due to transient blocks induction. The aim of the present work was to systematically study, by use of the van Capelle and Durrer (VCD) model which allows to simulate ventricular activation wave propagation, the link between arrhythmogenic effects and the ability of transient blocks to possibly degenerate in severe arrhythmias. A fragment of the ventricular wall is represented by an array of 16384elements electrically coupled. Effects of induction of one or several transient blocks, as the effects of their size and duration on possible induction of reentries have been studied. Results obtained show that various combinations between these different parameters may trigger reentries, ventricular tachycardia and/or more complex patterns assimilable to ventricular fibrillation. These results clearly evidence the fact that possible induction of transient blocks may directly be related to risk factor associated to arrhythmogenic effects of antiarrhythmic drugs. This revised version was published online in June 2006 with corrections to the Cover Date.     

Modeling the Building Blocks of Biodiversity

Background

Networks of single interaction types, such as plant-pollinator mutualisms, are biodiversity’s “building blocks”. Yet, the structure of mutualistic and antagonistic networks differs, leaving no unified modeling framework across biodiversity’s component pieces.

Methods/Principal Findings

We use a one-dimensional “niche model” to predict antagonistic and mutualistic species interactions, finding that accuracy decreases with the size of the network. We show that properties of the modeled network structure closely approximate empirical properties even where individual interactions are poorly predicted. Further, some aspects of the structure of the niche space were consistently different between network classes.

Conclusions/Significance

These novel results reveal fundamental differences between the ability to predict ecologically important features of the overall structure of a network and the ability to predict pair-wise species interactions.     

Cardiac Conduction System: Delineation of Anatomic Landmarks With Multidetector CT

Major components of the cardiac conduction system including the sinoatrial node (SAN), atrioventricular node (AVN), the His Bundle, and the right and left bundle branches are too small to be directly visualized by multidetector CT (MDCT) given the limited spatial resolution of current scanners. However, the related anatomic landmarks and variants of this system a well as the areas with special interest to electrophysiologists can be reliably demonstrated by MDCT. Some of these structures and landmarks include the right SAN artery, right atrial cavotricuspid isthmus, Koch triangle, AVN artery, interatrial muscle bundles, and pulmonary veins. In addition, MDCT has an imperative role in demarcating potential arrhythmogenic structures. The aim of this review will be to assess the extent at which MDCT can outline the described anatomic landmarks and therefore provide crucial information used in clinical practice.     

Suppression of Rap1 Impairs Cardiac Myofibrils and Conduction System in Zebrafish

Numerous studies have revealed that Rap1 (Ras-proximate-1 or Ras-related protein 1), a small GTPase protein, plays a crucial role in mediating cAMP signaling in isolated cardiac tissues and cell lines. However, the involvement of Rap1 in the cardiac development in vivo is largely unknown. By injecting anti-sense morpholino oligonucleotides to knock down Rap1a and Rap1b in zebrafish embryos, and in combination with time-lapsed imaging, in situ hybridization, immunohistochemistry and transmission electron microscope techniques, we seek to understand the role of Rap1 in cardiac development and functions. At an optimized low dose of mixed rap1a and rap1b morpholino oligonucleotides, the heart developed essentially normally until cardiac contraction occurred. Morphant hearts showed the myocardium defect phenotypes, most likely due to disrupted myofibril assembly and alignment. In vivo heart electrocardiography revealed prolonged P-R interval and QRS duration, consistent with an adherens junction defect and reduced Connexons in cardiac myocytes of morphants. We conclude that a proper level of Rap1 is crucial for heart morphogenesis and function, and suggest that Rap1 and/or their downstream factor genes are potential candidates for genetic screening for human heart diseases.     

DNA Building Blocks at the Foundation of Better Survival

No abstract available.     

New Building Blocks for the Preparation of Branched Oligonucleotides

Abstract

New building blocks 2 and 3 were prepared and successfully employed for the synthesis of branched oligonucleotides 5 and 6. The structure of oligomers obtained was confirmed by electrospray ionisation mass spectrometry.     

An mRNA Encoding a Putative GABA-Gated Chloride Channel Is Expressed in the Human Cardiac Conduction System

Abstract: GABA-gated chloride channels are the main inhibitory neurotransmitter receptors in the CNS. Conserved domains among members of previously described GABA_A receptor subunits were used to design degenerate sense and antisense oligonucleotides. A PCR product from this amplification was used to isolate a full-length cDNA. The predicted protein has many of the features shared by other members of the ligand-gated ion channel family. This channel subunit has significant amino acid identity (25–40%) with members of GABA_A and GABA_C receptor subunits and thus may represent a new subfamily of the GABA receptor channel. Although we cannot rule out that this clone encodes a receptor for an unidentified ligand, it was termed GABA _χ. This gene is mainly expressed in placenta and in heart; however, placenta appears to express only an unspliced mRNA. In situ hybridization reveals that the GABA _χ subunit mRNA is present in the electrical conduction system of the human heart. Our results suggest that novel GABA receptors expressed outside of the CNS may regulate cardiac function.     

Building Blocks of Temporal Filters in Retinal Synapses

Sensory systems must be able to extract features of a stimulus to detect and represent properties of the world. Because sensory signals are constantly changing, a critical aspect of this transformation relates to the timing of signals and the ability to filter those signals to select dynamic properties, such as visual motion. At first assessment, one might think that the primary biophysical properties that construct a temporal filter would be dynamic mechanisms such as molecular concentration or membrane electrical properties. However, in the current issue of PLOS Biology, Baden et al. identify a mechanism of temporal filtering in the zebrafish and goldfish retina that is not dynamic but is in fact a structural building block—the physical size of a synapse itself. The authors observe that small, bipolar cell synaptic terminals are fast and highly adaptive, whereas large ones are slower and adapt less. Using a computational model, they conclude that the volume of the synaptic terminal influences the calcium concentration and the number of available vesicles. These results indicate that the size of the presynaptic terminal is an independent control for the dynamics of a synapse and may reveal aspects of synaptic function that can be inferred from anatomical structure.     

Slow Conduction in Cardiac Muscle: A Biophysical Model

Mechanisms of slow conduction in cardiac muscle are categorized and the most likely identified. Propagating action potentials were obtained experimentally from a synthetically grown strand of cardiac muscle (around 50 μm by 30 mm) and theoretically from a one-dimensional cable model that incorporated varying axial resistance and membrane properties along its length. Action potentials propagated at about 0.3 m/s, but in some synthetic strands there were regions (approximately 100 μm in length) where the velocity decreased to 0.002 m/s. The electrophysiological behavior associated with this slow conduction was similar to that associated with slow conduction in naturally occurring cardiac muscle (notches, Wenckebach phenomena, and block). Theoretically, reasonable changes in specific membrane capacitance, membrane activity, and various changes in geometry were insufficient to account for the observed slow conduction velocities. Conduction velocities as low as 0.009 m/s, however, could be obtained by increasing the resistance (r_i) of connections between the cells in the cable; velocities as low as 0.0005 m/s could be obtained by a further increase in r_i made possible by a reduction in membrane activity by one-fourth, which in itself decreased conduction velocity by only a factor of 1/1.4. As a result of these findings, several of the mechanisms that have been postulated, previously, are shown to be incapable of accounting for delays such as those which occur in the synthetic strand as well as in the atrioventricular (VA) node.     

Synthesis of Triamino Acid Building Blocks with Different Lipophilicities

To obtain different amino acids with varying lipophilicity and that can carry up to three positive charges we have developed a number of new triamino acid building blocks. One set of building blocks was achieved by aminoethyl extension, via reductive amination, of the side chain of ortnithine, diaminopropanoic and diaminobutanoic acid. A second set of triamino acids with the aminoethyl extension having hydrocarbon side chains was synthesized from diaminobutanoic acid. The aldehydes needed for the extension by reductive amination were synthesized from the corresponding Fmoc-L-2-amino fatty acids in two steps. Reductive amination of these compounds with Boc-L-Dab-OH gave the C4-C8 alkyl-branched triamino acids. All triamino acids were subsequently Boc-protected at the formed secondary amine to make the monomers appropriate for the N-terminus position when performing Fmoc-based solid-phase peptide synthesis.     

Building Blocks,Hinge-Bending Motions and Protein Topology

Abstract

Here we show that the locations of molecular hinges in protein structures fall between building block elements. Building blocks are fragments of the protein chain which constitute local minima. These elements fold first. In the next step they associate through a combinatorial assembly process. While chain-linked building blocks may be expected to trial-associate first, if unstable, alternate more stable associations will take place. Hence, we would expect that molecular hinges will be at such inter-building block locations, or at the less stable, ‘unassigned’ regions.

On the other hand, hinge-bending motions are well known to be critical for protein function. Hence, protein folding and protein function are evolutionarily related. Further, the pathways through which proteins attain their three dimensional folds are determined by protein topology. However, at the same time the locations of the hinges, and hinge-bending motions are also an outcome of protein topology. Thus, protein folding and function appear coupled, and relate to protein topology. Here we provide some results illustrating such a relationship.     

Binets: Fundamental Building Blocks for Phylogenetic Networks

Phylogenetic networks are a generalization of evolutionary trees that are used by biologists to represent the evolution of organisms which have undergone reticulate evolution. Essentially, a phylogenetic network is a directed acyclic graph having a unique root in which the leaves are labelled by a given set of species. Recently, some approaches have been developed to construct phylogenetic networks from collections of networks on 2- and 3-leaved networks, which are known as binets and trinets, respectively. Here we study in more depth properties of collections of binets, one of the simplest possible types of networks into which a phylogenetic network can be decomposed. More specifically, we show that if a collection of level-1 binets is compatible with some binary network, then it is also compatible with a binary level-1 network. Our proofs are based on useful structural results concerning lowest stable ancestors in networks. In addition, we show that, although the binets do not determine the topology of the network, they do determine the number of reticulations in the network, which is one of its most important parameters. We also consider algorithmic questions concerning binets. We show that deciding whether an arbitrary set of binets is compatible with some network is at least as hard as the well-known graph isomorphism problem. However, if we restrict to level-1 binets, it is possible to decide in polynomial time whether there exists a binary network that displays all the binets. We also show that to find a network that displays a maximum number of the binets is NP-hard, but that there exists a simple polynomial-time 1/3-approximation algorithm for this problem. It is hoped that these results will eventually assist in the development of new methods for constructing phylogenetic networks from collections of smaller networks.     

脊椎动物心传导系统的发生

在成熟的心脏中,人们一般将心脏的工作肌与传导系统区分开来.成熟的传导系统由窦房结、房室结、房室束、束分支以及浦肯野纤维组成.每一部分都有不同的功能并有不同的基因表达.主要对心传导系统的主要组成结构和各部分的发生发育模式进行了综述.     

Embryology of the Conduction System for the Electrophysiologist

It is critical for interventional electrophysiologists to thoroughly appreciate the topographic and developmental anatomy of the heart and its conduction system. Not only is understanding cardiac anatomy important to prevent complications from collateral damage and to help guide catheter placement, but developmental anatomy allows a deeper appreciation of the arrhythmogenic substrate. In this article, we briefly review the relevant stages of cardiac development for electrophysiologists. The potential location of normal and abnormal conduction patterns resulting from heterogeneous developmental origin is discussed.     

Reduced Heart Rate Variability and Altered Cardiac Conduction after Pre-Eclampsia

Pre-eclampsia is a hypertensive disorder of pregnancy that is associated with elevated maternal risk for cardiovascular disease. The aims of this study were to determine the effect of normal pregnancy on postpartum parameters of the electrocardiogram, and furthermore to determine how a history of pre-eclampsia may affect these parameters. Ten-minute high-resolution (1000 Hz) orthogonal Holter electrocardiogram (ECG) recordings were used to measure heart rate variability (HRV). Signal-averaged P-wave and QRS complex durations were determined. Participants included non-pregnant controls, normotensive parous controls and women with a recent history of PE. While reductions in HRV induced by uncomplicated pregnancy returned to non-pregnant levels by 6–8 months postpartum HRV remained reduced in women with a history of PE compared to control groups. In addition, P-Wave and QRS complex durations were prolonged in PE subjects at 6–8 months postpartum compared to control groups. Only QRS duration was independent of differences in blood pressure. These results suggest increased sympathetic cardiac activity, and delayed myocardial conduction in women after PE; alterations consistent with cardiac remodeling and increased risk for arrhythmia. In examining the association between PE and cardiovascular disease, identification of ECG abnormalities soon after pregnancy in women with a history of PE highlights a unique opportunity for early identification and screening in this population before other risk factors become apparent.