Biomedical subjects

L Joshua Leon

Publications and source records attributed to L Joshua Leon.

7 recordsLinked to original sources

PubMed2005

Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium.

Tissue size has been considered an important determinant of atrial fibrillation (AF), but recent work has questioned the critical size hypothesis. Here, we use a previously developed mathematical model of the two-dimensional canine atrium with realistic action potential, ionic, and conduction properties to address substrate size effects on the maintenance of fibrillatory activity. Cholinergic AF was simulated at different acetylcholine (ACh) concentrations ([ACh]) and distributions, with substrate area varied 11.1-fold. Automated phase singularity detection was used to facilitate the analysis of arrhythmic activity. The duration of activity induced by a single extrastimulus increased with increasing substrate dimensions. Two general mechanisms underlying activity were observed and were differentially affected by substrate size. For large mean [ACh], single primary rotors anchored in low-[ACh] zones maintained activity and substrate dimensions were not critical. At lower mean [ACh], extensive spiral wave meander prevented the emergence of single stable rotors. Prolonged activity was favored when substrate size permitted a sufficiently large number of simultaneous longer-lasting rotors that extinction of all was unlikely. Thus either single dominant rotor or multiple reentrant spiral generator mechanisms could maintain fibrillatory activity in this model and were differentially dependent on substrate size. These results speak to recent debates about the role in AF of single driver rotors versus multiple reentrant circuit mechanisms by suggesting that either may maintain fibrillatory atrial activity depending on atrial size and electrophysiological properties.

Action Potentials↗

PubMed2005

Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model.

The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I(Na)) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I(Na) inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I(Na) inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I(Na) inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I(Na) inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I(Na) block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I(Na) inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org

Algorithms↗

PubMed2005

Defibrillation depends on conductivity fluctuations and the degree of disorganization in reentry patterns.

UNLABELLED: Defibrillation depends on conductivity and disorganization. INTRODUCTION: Cardiac fibrillation is the deterioration of the heart's normally well-organized activity into one or more meandering spiral waves, which subsequently break up into many meandering wave fronts. Delivery of an electric shock (defibrillation) is the only effective way of restoring the normal rhythm. This study focuses on examining whether higher degrees of disorganization requires higher shock strengths to defibrillate and whether microscopic conductivity fluctuations favor shock success. METHODS AND RESULTS: We developed a three-dimensional computer bidomain model of a block of cardiac tissue with straight fibers immersed in a conductive bath. The membrane behavior was described by the Courtemanche human atrial action potential model incorporating electroporation and an acetylcholine- (ACh) dependent potassium current. Intracellular conductivities were varied stochastically around nominal values with variations of up to 50%. A single rotor reentry was initiated and, by adjusting the spatial ACh variation, the level of organization could be controlled. The single rotor could be stabilized or spiral wave breakup could be provoked leading to fibrillatory-like activity. For each level of organization, multiple shock timings and strengths were applied to compute the probability of shock success as a function of shock strength. CONCLUSIONS: Our results suggest that the level of the small-scale conductivity fluctuations is a very important factor in defibrillation. A higher variation significantly lowers the required shock strength. Further, we demonstrated that success also heavily depends on the level of organization of the fibrillatory episode. In general, higher levels of disorganization require higher shock strengths to defibrillate.

Acetylcholine↗

PubMed2004

Simulation of QRST integral maps with a membrane-based computer heart model employing parallel processing.

The simulation of the propagation of electrical activity in a membrane-based realistic-geometry computer model of the ventricles of the human heart, using the governing monodomain reaction-diffusion equation, is described. Each model point is represented by the phase 1 Luo-Rudy membrane model, modified to represent human action potentials. A separate longer duration action potential was used for the M cells found in the ventricular midwall. Cardiac fiber rotation across the ventricular wall was implemented via an analytic equation, resulting in a spatially varying anisotropic conductivity tensor and, consequently, anisotropic propagation. Since the model comprises approximately 12.5 million points, parallel processing on a multiprocessor computer was used to cut down on simulation time. The simulation of normal activation as well as that of ectopic beats is described. The hypothesis that in situ electrotonic coupling in the myocardium can diminish the gradients of action-potential duration across the ventricular wall was also verified in the model simulations. Finally, the sensitivity of QRST integral maps to local alterations in action-potential duration was investigated.

Action Potentials↗

PubMed2003

Computational tools for modeling electrical activity in cardiac tissue.

Computer models offer many attractive benefits. However, the modeling of cardiac tissue is computationally expensive due to several physical constraints which result in fine spatiotemporal discretization over large spatiotemporal regions. Our laboratory has been actively trying to develop new techniques to make large scale cardiac simulations tractable over the past 15 years. This paper describes the latest modeling software that our group has developed, called Carp (Cardiac arrhythmias research package). It is designed to run in both shared memory and clustered computing environments. Carp aims to be modular and flexible by following a plug-in framework. This allows the latest models and most efficient solvers to be incorporated as well as enabling run-time selection of techniques. Performance results are given for a large-scale simulation which utilized a comprehensive membrane ionic current description.

Action Potentials↗

PubMed2003

Mechanisms of termination of atrial fibrillation by Class I antiarrhythmic drugs: evidence from clinical, experimental, and mathematical modeling studies.

Sodium channel blocking drugs (Class I antiarrhythmic agents) have been used for the termination of atrial fibrillation (AF) and for sinus rhythm maintenance for almost 100 years. Despite this long history, the mechanisms that underlie their efficacy in AF remain poorly understood. Classic notions about the determinants of cardiac reentry, as embodied in leading circle theory, and of AF, as reflected in the multiple wavelet hypothesis, suggest that cardiac conduction slowing should promote, rather than prevent, AF. This article reviews the evidence (both clinical and experimental) for the efficacy and mechanisms of action of Class I antiarrhythmic agents in AF. Application of mathematical models of AF to the evaluation of Class I mechanisms is discussed, and recent insights into the latter are presented. A better understanding of the ways in which Na+ channel blockers affect AF will be useful, not only for new antiarrhythmic drug development but also for gaining insight into the mechanisms of the arrhythmia.

Anti-Arrhythmia Agents↗

PubMed2002

Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties.

Classical concepts of atrial fibrillation (AF) have been rooted in Moe's multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete "driver region" underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5x10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by approximately 70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0+/-1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response. The full text of this article is available at http://www.circresaha.org.

Acetylcholine↗