Fagen Xie

Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias

The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple hat propagate “shifting” foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H2O2) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.

Role of Papillary Muscle in the Generation and Maintenance of Reentry During Ventricular Tachycardia and Fibrillation in Isolated Swine Right Ventricle

BACKGROUND The role of papillary muscle (PM) in the generation and maintenance of reentry is unclear. METHODS AND RESULTS Computerized mapping (477 bipolar electrodes, 1.6-mm resolution) was performed in fibrillating right ventricles (RVs) of swine in vitro. During ventricular fibrillation (VF), reentrant wave fronts often transiently anchored to the PM. Tissue mass reduction was then performed in 10 RVs until VF converted to ventricular tachycardia (VT). In an additional 6 RVs, procainamide infusion converted VF to VT. Maps showed that 77% (34 of 44) of all VT episodes were associated with a single reentrant wave front anchored to the PM. Purkinje fiber potentials preceded the local myocardial activation, and these potentials were recorded mostly around the PM. When PM was trimmed to the level of endocardium (n = 4), sustained VT was no longer inducible. Transmembrane potential recordings (n = 5) at the PM revealed full action potential during pacing, without evidence of ischemia. Computer simulation studies confirmed the role of PM as a spiral wave anchoring site that stabilized wave conduction. CONCLUSIONS We conclude that PM is important in the generation and maintenance of reentry during VT and VF.

A simulation study of the effects of cardiac anatomy in ventricular fibrillation

In ventricular fibrillation (VF), the principal cause of sudden cardiac death, waves of electrical excitation break up into turbulent and incoherent fragments. The causes of this breakup have been intensely debated. Breakup can be caused by fixed anatomical properties of the tissue, such as the biventricular geometry and the inherent anisotropy of cardiac conduction. However, wavebreak can also be caused purely by instabilities in wave conduction that arise from ion channel dynamics, which represent potential targets for drug action. To study the interaction between these two wave-breaking mechanisms, we used a physiologically based mathematical model of the ventricular cell, together with a realistic three-dimensional computer model of cardiac anatomy, including the distribution of fiber angles throughout the myocardium. We find that dynamical instabilities remain a major cause of the wavebreak that drives VF, even in an anatomically realistic heart. With cell physiology in its usual operating regime, dynamics and anatomical features interact to promote wavebreak and VF. However, if dynamical instability is reduced, for example by modeling of certain pharmacologic interventions, electrical waves do not break up into fibrillation, despite anatomical complexity. Thus, interventions that promote dynamical wave stability show promise as an antifibrillatory strategy in this more realistic setting.

Origins of Spiral Wave Meander and Breakup in a Two-Dimensional Cardiac Tissue Model

AbstractWe studied the stability of spiral waves in homogeneous two-dimensional cardiac tissue using phase I of the Luo–Rudy ventricular action potential model. By changing the conductance and the relaxation time constants of the ion channels, various spiral wave phenotypes, including stable, quasiperiodically meandering, chaotically meandering, and breakup were observed. Stable and quasiperiodically meandering spiral waves occurred when the slope of action potential duration (APD) restitution was <1 over all diastolic intervals visited during reentry; chaotic meander and spiral wave breakup occurred when the slope of APD restitution exceeded 1. Curvature of the wave changes both conduction velocity and APD, and their restitution properties, thereby modulating local stability in a spiral wave, resulting in distinct spiral wave phenotypes. In the LR1 model, quasiperiodic meander is most sensitive to the Na+ current, whereas chaotic meander and breakup are more dependent on the Ca2+ and K+ currents.

Mechanism Underlying Initiation of Paroxysmal Atrial Flutter/Atrial Fibrillation by Ectopic Foci A Simulation Study

Background— The mechanisms underlying paroxysmal atrial flutter/atrial fibrillation initiation by ectopic foci from various locations are unclear. Methods and Results— We used parallel computational techniques to study an anatomically accurate 3-dimensional atrial structure incorporating a detailed ionic-current model of an atrial myocyte. At the single-cell level, upregulation of the L-type Ca2+ current ICa,L steepened restitution curves of action potential duration and conduction velocity compared with the control. Spontaneous firings of ectopic foci, coupled with sinus activity, produced dynamic spatial dispersions of repolarization, including discordant alternans, which caused conduction block and reentry only for the elevated ICa,L case. For each foci location, a vulnerable window for atrial flutter/atrial fibrillation induction was identified as a function of the coupling interval and focus cycle length. For ectopic foci in the pulmonary veins and left atrium, the site of conduction block and reentry gradually shifted, as a function of coupling interval, from the right atrium to the interatrial area and finally to the left atrium. The size of the vulnerable window was largest for pulmonary vein foci, becoming markedly smaller for right atrial foci, especially those near the sinoatrial node. Conclusions— These findings suggest that a mechanism of dynamically induced repolarization dispersion, especially discordant alternans, underlies the induction of atrial flutter/atrial fibrillation by atrial ectopic foci. The sites and likelihood of reentry induction varied according to ectopic focus location and timing, with the largest vulnerable window corresponding to the pulmonary vein region.

Computer Modeling of Atrial Fibrillation

The recent development of models of atrial cellular dynamics and of realistic atrial anatomic structures has enabled modeling and computer simulation to become important investigative tools in the analysis of atrial arrhythmias. The cell model includes membrane potential, transmembrane ionic currents and ion concentrations. The tissue model describes the overall geometric structure of the tissue as well as how cells are interconnected. For these studies, the mechanical properties of the heart are decoupled and only the electrical properties are considered. The most important use of computer simulation is in enabling “clean” experiments, in which exactly one parameter of interest is varied. This may be difficult or impossible to do in tissue experiments. Modeling provides other advantages when used to complement traditional experiments and clinical work. Computer simulations can guide experiments by providing hypotheses to test in vivo that have been verified already in silico. In addition, simulations can be used to investigate and to explain experimental and clinical observations. This continual feedback between simulation and experiment can reduce time and money spent on animal experiments and can generate valuable information about human arrhythmias while avoiding issues of patient safety.