Anchoring of Drifting Spiral and Scroll Waves to Impermeable Inclusions in Excitable Media

Anchoring of spiral and scroll waves in excitable media has attracted considerable interest in the context of cardiac arrhythmias. Here, by bombarding inclusions with drifting spiral and scroll waves, we explore the forces exerted by inclusions onto an approaching spiral and derive the equations of motion governing spiral dynamics in the vicinity of inclusion. We demonstrate that these forces nonmonotonically depend on distance and can lead to complex behavior: (a) anchoring to small but circumnavigating larger inclusions; (b) chirality-dependent anchoring

Frustrated Drift of an Anchored Scroll-Wave Filament and the Geodesic Principle

We investigate anchored scroll-wave filaments in an excitable medium whose diffusivity matrix, including its determinant, is spatially nonuniform. The study is motivated by cardiological applications where scroll-wave behavior in the presence of diffusivity gradients is believed to play an important role in the development of severe arrhythmias. A diffusivity gradient is expected to make the filament drift, unless drift is prevented ( frustrated ) by anchoring to localized defects in the propagation medium. The resulting stationary filament is a geodesic curve, as demonstrated here in the case of a nonzero but constant gradient. That is, the diffusivity matrix has a determinant that varies in space, in contrast to what was assumed in earlier work. Here, we show that the filament shape results from a metric tensor of the form (det D)D{-1} , where D is the diffusivity tensor. The filament\u27s shape is solely determined by the diffusivity tensor and is independent of the equation\u27s reaction terms. We derive the analytic solution for the filament and determine conditions for the existence of that solution. The theory is in excellent agreement with numerical simulations

Refraction of Scroll-Wave Filaments at the Boundary between Two Reaction-Diffusion Media

We explore the shape and the dynamics of scroll-wave filaments in excitable media with an abruptly changing diffusion tensor, important for cardiac applications. We show that, similar to a beam of light, the filament refracts at the boundary separating domains with different diffusion. We derive the laws of filament refraction and test their validity in computational experiments. We discovered that at small angles to the interface, the filament can become unstable and develop oscillations. The nature of the observed instabilities, as well as overall theoretical and experimental significance of the findings, is discussed

Scroll Wave Unpinning with External Field is Impeded by Filament Alignment with Field

Scroll waves in excitable media can anchor to non-excitable inclusions

Bioinformatic identification of novel putative photoreceptor specific cis-elements

<p>Abstract</p> <p>Background</p> <p>Cell specific gene expression is largely regulated by different combinations of transcription factors that bind <it>cis</it>-elements in the upstream promoter sequence. However, experimental detection of <it>cis</it>-elements is difficult, expensive, and time-consuming. This provides a motivation for developing bioinformatic methods to identify <it>cis</it>-elements that could prioritize future experimental studies. Here, we use motif discovery algorithms to predict transcription factor binding sites involved in regulating the differences between murine rod and cone photoreceptor populations.</p> <p>Results</p> <p>To identify highly conserved motifs enriched in promoters that drive expression in either rod or cone photoreceptors, we assembled a set of murine rod-specific, cone-specific, and non-photoreceptor background promoter sequences. These sets were used as input to a newly devised motif discovery algorithm called Iterative Alignment/Modular Motif Selection (IAMMS). Using IAMMS, we predicted 34 motifs that may contribute to rod-specific (19 motifs) or cone-specific (15 motifs) expression patterns. Of these, 16 rod- and 12 cone-specific motifs were found in clusters near the transcription start site. New findings include the observation that cone promoters tend to contain TATA boxes, while rod promoters tend to be TATA-less (exempting <it>Rho </it>and <it>Cnga1</it>). Additionally, we identify putative sites for IL-6 effectors (in rods) and RXR family members (in cones) that can explain experimental data showing changes to cell-fate by activating these signaling pathways during rod/cone development. Two of the predicted motifs (NRE and ROP2) have been confirmed experimentally to be involved in cell-specific expression patterns. We provide a full database of predictions as additional data that may contain further valuable information. IAMMS predictions are compared with existing motif discovery algorithms, DME and BioProspector. We find that over 60% of IAMMS predictions are confirmed by at least one other motif discovery algorithm.</p> <p>Conclusion</p> <p>We predict novel, putative <it>cis-</it>elements enriched in the promoter of rod-specific or cone-specific genes. These are candidate binding sites for transcription factors involved in maintaining functional differences between rod and cone photoreceptor populations.</p

Fiber Organization has Little Effect on Electrical Activation Patterns during Focal Arrhythmias in the Left Atrium

Over the past two decades there has been a steady trend towards the development of realistic models of cardiac conduction with increasing levels of detail. However, making models more realistic complicates their personalization and use in clinical practice due to limited availability of tissue and cellular scale data. One such limitation is obtaining information about myocardial fiber organization in the clinical setting. In this study, we investigated a chimeric model of the left atrium utilizing clinically derived patient-specific atrial geometry and a realistic, yet foreign for a given patient fiber organization. We discovered that even significant variability of fiber organization had a relatively small effect on the spatio-temporal activation pattern during regular pacing. For a given pacing site, the activation maps were very similar across all fiber organizations tested

Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease

<p>Abstract</p> <p>Background</p> <p>Cardiomyopathies, degenerative diseases of cardiac muscle, are among the leading causes of death in the developed world. Microarray studies of cardiomyopathies have identified up to several hundred genes that significantly alter their expression patterns as the disease progresses. However, the regulatory mechanisms driving these changes, in particular the networks of transcription factors involved, remain poorly understood. Our goals are (A) to identify modules of co-regulated genes that undergo similar changes in expression in various types of cardiomyopathies, and (B) to reveal the specific pattern of transcription factor binding sites, <it>cis</it>-elements, in the proximal promoter region of genes comprising such modules.</p> <p>Methods</p> <p>We analyzed 149 microarray samples from human hypertrophic and dilated cardiomyopathies of various etiologies. Hierarchical clustering and Gene Ontology annotations were applied to identify modules enriched in genes with highly correlated expression and a similar physiological function. To discover motifs that may underly changes in expression, we used the promoter regions for genes in three of the most interesting modules as input to motif discovery algorithms. The resulting motifs were used to construct a probabilistic model predictive of changes in expression across different cardiomyopathies.</p> <p>Results</p> <p>We found that three modules with the highest degree of functional enrichment contain genes involved in myocardial contraction (n = 9), energy generation (n = 20), or protein translation (n = 20). Using motif discovery tools revealed that genes in the contractile module were found to contain a TATA-box followed by a CACC-box, and are depleted in other GC-rich motifs; whereas genes in the translation module contain a pyrimidine-rich initiator, Elk-1, SP-1, and a novel motif with a GCGC core. Using a naïve Bayes classifier revealed that patterns of motifs are statistically predictive of expression patterns, with odds ratios of 2.7 (contractile), 1.9 (energy generation), and 5.5 (protein translation).</p> <p>Conclusion</p> <p>We identified patterns comprised of putative <it>cis</it>-regulatory motifs enriched in the upstream promoter sequence of genes that undergo similar changes in expression secondary to cardiomyopathies of various etiologies. Our analysis is a first step towards understanding transcription factor networks that are active in regulating gene expression during degenerative heart disease.</p

Detection of intramyocardial scroll waves using absorptive transillumination imaging

Optical imaging using voltage-sensitive dyes has become an important tool for studying vortex-like electrical waves in the heart. Such waves, known as spiral or scroll waves, can spontaneously form in pathological ventricular myocardium, causing ventricular fibrillation and sudden death. Until recently, observations of scroll waves were limited to their surface manifestations, thus providing little information about the shape and location of their organizing center, the filament. We use computer modeling to assess the feasibility of visualizing filaments using dynamic transillumination imaging in conjunction with near-IR voltage-sensitive absorptive dyes (absorptive transillumination). We simulate transillumination signals produced by the intramural scroll waves in a realistic slab of ventricular tissue with trabeculated endocardial surface. The computations use a detailed ionic model of electrical excitation (LRd) coupled to a photon transport model for cardiac tissue. Our simulations show that dynamic absorptive transillumination data, with subsequent processing involving either amplitude maps, time-space plots, or power-of-the-dominant-frequency maps, can be used to reliably detect intramural scroll waves through the whole thickness (similar to 10 mm) of the ventricular wall. Neither variations in the thickness of the myocardial wall nor noise impeded the detection of intramural filaments