Biomedical subjects

Renqiang Zou

Publications and source records attributed to Renqiang Zou.

5 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↗

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↗

PubMed2002

Development of a computer algorithm for the detection of phase singularities and initial application to analyze simulations of atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia, but its mechanisms are incompletely understood. The identification of phase singularities (PSs) has been used to define spiral waves involved in maintaining the arrhythmia, as well as daughter wavelets. In the past, PSs have often been identified manually. Automated PS detection algorithms have been described previously, but when we attempted to apply a previously developed algorithm we experienced problems with false positives that made the results difficult to use directly. We therefore developed a tool for PS identification that uses multiple strategies incorporating both image analysis and mathematical convolution for automated detection with optimized sensitivity and specificity, followed by manual verification. The tool was then applied to analyze PS behavior in simulations of AF maintained in the presence of spatially distributed acetylcholine effects in cell grids of varying size. These analyses indicated that in almost all cases, a single PS lasted throughout the simulation, corresponding to the central-core tip of a single spiral wave that maintained AF. The sustained PS always localized to an area of low acetylcholine concentration. When the grid became very small and no area of low acetylcholine concentration was surrounded by zones of higher concentration, AF could not be sustained. The behavior of PSs and the mechanisms of AF were qualitatively constant over an 11.1-fold range of atrial grid size, suggesting that the classical emphasis on tissue size as a primary determinant of fibrillatory behavior may be overstated. (c) 2002 American Institute of Physics.

Journal Article↗