Mechanisms of unpinning and termination of ventricular tachycardia

High-energy defibrillation shock is the only therapy for ventricular tachyarrhythmias. However, because of adverse side effects, lowering defibrillation energy is desirable. We investigated mechanisms of unpinning, destabilization, and termination of ventricular tachycardia (VT) by low-energy shocks in isolated rabbit right ventricular preparations (n = 22). Stable VT was initiated with burst pacing and was optically mapped. Monophasic "unpinning" shocks (10 ms) of different strengths were applied at various phases throughout the reentry cycle. In 8 of 22 preparations, antitachycardia pacing (ATP: 8-20 pulses, 50-105% of period, 0.8-10 mA) was also applied. Termination of reentry by ATP was achieved in only 5 of 8 preparations. Termination by unpinning occurred in all 22 preparations. Rayleigh's test showed a statistically significant unpinning phase window, during which reentry could be unpinned and subsequently terminated with E80 (magnitude at which 80% of reentries were unpinned) = 1.2 V/cm. All reentries were unpinned with field strengths < or = 2.4 V/cm. Unpinning was achieved by inducing virtual electrode polarization and secondary sources of excitation at the core of reentry. Optical mapping revealed the mechanisms of phase-dependent unpinning of reentry. These results suggest that a 20-fold reduction in energy could be achieved compared with conventional high-energy defibrillation and that the unpinning method may be more effective than ATP for terminating stable, pinned reentry in this experimental model.     

Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength--electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely.     

Effect of myocardial infarction and ischemia on induction of cardiac reentries and ventricular fibrillation

The present work is aimed at investigating the effects of myocardial infarction and ischemia on induction of ventricular fibrillation. Electrophysiologic effects of global and local ischemia (variation of the dispersion of refractory periods as well as conduction velocity) on initiation of reentry mechanisms was studied by means of computer simulations based on a cellular automata model of propagation of activation wave through a ventricular surface element. A local area of ischemia where effects of the dispersion of refractory periods are investigated is then simulated. This is made using a Gaussian distribution characterized by its mean and standard deviation. These simulations show that ischemia is capable of initiating reentry phenomena which propagate through the whole ventricle; they are responsible for ventricular fibrillation which causes sudden cardiac death, even when ischemia only involves limited parts of the myocardium. Statistical study of the probability of reentries as a function of both of the size of ischemic zones and the rate of dispersion of refractory periods shows that the latter parameter is of primary importance in triggering cardiac reentries.     

The topology of defibrillation

We describe how Art Winfree's ideas about phase singularities can be used to understand the response of cardiac tissue with a random preexisting pattern of reentrant waves (fibrillation) to a large brief current stimulus. This discussion is organized around spatial dimension, beginning with a discussion of reentry on a periodic ring, followed by reentry in a two-dimensional planar domain (spiral waves), and ending with consideration of three-dimensional reentrant patterns (scroll waves). In all cases, we show how reentrant activity is changed by the application of a shock, describing conditions under which defibrillation is successful or not. Using topological arguments we draw the general conclusion that with a generic placement of stimulating electrodes, large-scale virtual electrodes do not give an adequate explanation for the mechanism of defibrillation.     

Spiral reentry waves in confluent layer of HL-1 cardiomyocyte cell lines

Cardiac excitation waves that arise in heart tissues have long been an important research topic because they are related to various cardiac arrhythmia. Investigating their properties based on intact animal whole hearts is important but quite demanding and expensive. Subsequently, dissociated cardiac cell cultures have been used as an alternative. Here, we access the usefulness of cardiomyocyte cell line HL-1 in studying generic properties of cardiac waves. Spontaneous wave activities in confluent populations of HL-1 cells are monitored using a phase-contrast optical mapping system and a microelectrode array recording device. We find that high-density cultures of HL-1 cells can support well-defined reentries. Their conduction velocity and rotation period both increase over few days. The increasing trend of rotation period is opposite to the case of control experiments using primary cultures of mouse atrial cells. The progressive myolysis of HL-1 seems responsible for this difference.     

Functional reentry and circus movement arrhythmias in the small intestine of normal and diabetic rats

In a few recent studies, the presence of arrhythmias based on reentry and circus movement of the slow wave have been shown to occur in normal and diseased stomachs. To date, however, reentry has not been demonstrated before in any other part of the gastrointestinal system. No animals had to be killed for this study. Use was made of materials obtained during the course of another study in which 11 rats were treated with streptozotocin and housed with age-matched controls. After 3 and 7 mo, segments of duodenum, jejunum, and ileum were isolated and positioned in a tissue bath. Slow wave propagation was recorded with 121 extracellular electrodes. After the experiment, the propagation of the slow waves was reconstructed. In 10 of a total of 66 intestinal segments (15%), a circus movement of the slow wave was detected. These reentries were seen in control (n = 2) as well as in 3-mo (n = 2) and 7-mo (n = 6) diabetic rats. Local conduction velocities and beat-to-beat intervals during the reentries were measured (0.42 ± 0.15 and 3.03 ± 0.67 cm/s, respectively) leading to a wavelength of 1.3 ± 0.5 cm and a circuit diameter of 4.1 ± 1.5 mm. This is the first demonstration of a reentrant arrhythmia in the small intestine of control and diabetic rats. Calculations of the size of the circuits indicate that they are small enough to fit inside the intestinal wall. Extrapolation based on measured velocities and rates indicate that reentrant arrhythmias are also possible in the distal small intestine of larger animals including humans.     

Incidence of Dispersion of Refractoriness and Cellular Coupling Resistance on Cardiac Reentries and Ventricular Fibrillation

We used computer simulations to study the possible role of the dispersion of cellular coupling, refractoriness or both, in the mechanisms underlying cardiac arrhythmias. Local ischemia was first assumed to induce cell to cell dispersion of the coupling resistance (Case 1), refractory period (Case 2), or both of them (Case 3). Our numerical experiments based on the van Capelle and Durrer model showed that vortices could not be induced by cell to cell variations. With cellular properties dispersed in a patchy way within the ischemic zone, a single activation wave could give rise to abnormal activities. This demonstrates the stability of the wave front under small inhomogeneities. Probabilities of reentry, estimated for the three cases cited above showed that a severe alteration of the coupling resistance may be an important factor in the genesis of reentry. Moreover, use of isochronal maps revealed that vortices were both stable and sustained with an alteration of the coupling alone or combined with a reduction of the action potential duration. Conversely, simulations with reduction of the refractoriness alone, inducing only transient patterns, could exhibit functionally determined reentries.     

Reentrant waves in a ring of embryonic chick ventricular cells imaged with a Ca2+ sensitive dye

According to the classic model initially formulated by Mines, reentrant cardiac arrhythmias may be associated with waves circulating in a ring geometry. This study was designed to study the dynamics of reentry in a ring geometry of cardiac tissue culture. Reentrant calcium waves in rings of cultured embryonic chick cardiac myocytes were imaged using a macroscope to monitor the fluorescence of intracellular Calcium Green-1 dye. The rings displayed a variety of stable rhythms including pacemaker activity and spontaneous reentry. Waves originating from a localized pacemaker could lead to reentry as a consequence of unidirectional block. In addition, more complex patterns were observed due to the interactions between reentrant and pacemaker rhythms. These rhythms included instances in which pacemakers accelerated the reentrant rhythm, and instances in which the excitation was blocked in the vicinity of pacemakers. During reentrant activity an appropriately timed electrical stimulus could induce resetting of activity or cause complete annihilation of the propagating waves. This experimental preparation reveals many spontaneously occuring complex rhythms. These complex rhythms are hypothesized to reflect interactions between spontaneous pacemakers, wave propagation, refractory period, and overdrive suppression. This preparation may serve as a useful model system to further investigate complex dynamics arising during reentrant rhythms in cardiac tissue.     

Role of the dispersion of refractoriness on cardiac reentries

We used computer simulation to study the possible role of the dispersion of cellular coupling, refractoriness or both, in the mechanisms underlying cardiac arrhythmias. Local ischemia was first assumed to induce cell to cell dispersion of the coupling resistance (case 1), refractory period (case 2), or both (case 3). Our numerical experiments based on the van Capelle and Durrer model showed that vortices could not be induced. On the other hand, with cellular properties dispersed in a patchy way within the ischemic zone, a single activation wave could give rise to abnormal activities. This demonstrates the stability of the wave front under small inhomogeneities. Probabilities of reentry, estimated for the three cases cited above showed that a severe alteration of the coupling resistance may be an important factor in the genesis of reentry. Moreover, use of isochronal maps revealed that vortices were both stable and sustained with an alteration of the coupling alone or along with a reduction of the action potential duration. Conversely, simulations with reduction of the refractoriness alone, inducing only transient patterns, could exhibit functionally determined reentries.     

Theoretical analysis of the magnetocardiographic pattern for reentry wave propagation in a three-dimensional human heart model

We present a computational study of reentry wave propagation using electrophysiological models of human cardiac cells and the associated magnetic field map of a human heart. We examined the details of magnetic field variation and related physiological parameters for reentry waves in two-dimensional (2-D) human atrial tissue and a three-dimensional (3-D) human ventricle model. A 3-D mesh system representing the human ventricle was reconstructed from the surface geometry of a human heart. We used existing human cardiac cell models to simulate action potential (AP) propagation in atrial tissue and 3-D ventricular geometry, and a finite element method and the Galerkin approximation to discretize the 3-D domain spatially. The reentry wave was generated using an S1-S2 protocol. The calculations of the magnetic field pattern assumed a horizontally layered conductor for reentry wave propagation in the 3-D ventricle. We also compared the AP and magnetocardiograph (MCG) magnitudes during reentry wave propagation to those during normal wave propagation. The temporal changes in the reentry wave motion and magnetic field map patterns were also analyzed using two well-known MCG parameters: the current dipole direction and strength. The current vector in a reentry wave forms a rotating spiral. We delineated the magnetic field using the changes in the vector angle during a reentry wave, demonstrating that the MCG pattern can be helpful for theoretical analysis of reentry waves.     

Dynamics of virtual electrode-induced scroll-wave reentry in a 3D bidomain model

Functional reentry in the heart can be caused by a wave front of excitation rotating around its edge. Previous simulations on the basis of monodomain cable equations predicted the existence of self-sustained, vortex-like wave fronts (scroll waves) rotating around a filament in three dimensions. In our simulations, we used the more accurate bidomain model with modified Beeler-Reuter ionic kinetics to study the dynamics of scroll-wave filaments in a 16 x 8 x 1.5-mm slab of ventricular tissue with straight fibers. Wave fronts were identified as the areas with inward current. Their edges represented the filaments. Both transmural and intramural reentries with I- and U-shaped filaments, respectively, were obtained by the S1-S2 point stimulation protocol through the virtual electrode-induced phase singularity mechanism. The filaments meandered along elongated trajectories and tended to attach to the tissue boundaries exposed to air (no current flow) rather than to the bath (zero extracellular potential). They completely detached from electroporated (zero transmembrane potential) boundaries. In our simulations, the presence of the bath led to generation of only U-shaped filaments, which survived for the 1.5-mm-thick slab but not for the slabs of 0.5- or 3-mm thicknesses. Thus boundary conditions may be another determinant of the type and dynamics of reentry.     

Role of AMP-activated protein kinase in healthy and diseased hearts

The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed.     

Directional sensitivity of tuberous electroreceptors: polarity preferences and frequency tuning

This paper examines the directionality of tuberous electroreceptor responses and relates them to a polarity bias seen for passive electrolocation by electric fish (Hypopomus). We recorded from Burst Duration Coders (BDCs) while stimulating with 1 kHz single period sine waves with electric fields oriented horizontally in different directions. Electroreceptors have figure-8 directional sensitivity profiles with two, usually unequal lobes of sensitivity separated by 180°. For most units the larger lobe points inward, while for a few, the lobes are symmetrical or the larger lobe points outward. The differences correlate with differences in frequency tuning of the receptors. We can alter, and even reverse, the directional asymmetry of a single unit by changing the frequency of the stimulus. Two general response profiles result, with two corresponding classes of tuning curves. The degree of asymmetry varies with position on the body surface. The asymmetries and the effects of stimulus frequency and of tuning can be modeled with a linear/non-linear/linear cascade filter. The behavioral preference for approaching the head end ( + ) of an electrode is difficult to understand in light of the asymmetry of responses we report for amplitude-coding BDCs but can be understood by reference to the time-coding Pulse Marker (PM) receptors.Abbreviations BDC Burst Duration Coder - EOD electric organ discharge - nALL anterior lateral line nerve - PM Pulse Marker     

The effect of spatial scale of resistive inhomogeneity on defibrillation of cardiac tissue

Defibrillation of cardiac tissue can be viewed in the context of dynamical systems theory as the attempt to move a dynamical system from the basin of attraction of one attractor (fibrillation) to another (the uniform rest state) by applying a stimulus whose form is physically constrained. Here we give an introduction to the physical mechanism of cardiac defibrillation from this dynamical perspective and examine the role of resistive inhomogeneity on defibrillation efficacy. Using numerical simulations with rotating waves on a one-dimensional periodic ring, we study the role of the spatial scale of resistive inhomogeneity on defibrillation. For a rotating wave on a periodic ring there are three stable attractors, namely the uniform rest state, a wave traveling clockwise and a wave traveling counterclockwise. As a result, the application of a stimulus has the potential for three different outcomes, namely elimination of the wave, phase resetting of the wave, and reversal of the wave. The results presented here show that with resistive inhomogeneities of large spatial scale, all three of these transitions are possible with large amplitude shocks, so that the probability of defibrillation is bounded well below one, independent of stimulus amplitude. On the other hand, resistive inhomogeneities of small spatial scale produce a defibrillation threshold that is qualitatively consistent with that found experimentally, namely the probability of defibrillation success is an increasing function that approaches one for large enough stimulus amplitude. Extending these results to higher dimensions, we describe conditions for successful defibrillation of functional reentry with large scale spatial inhomogeneity, but find that elimination of anatomical reentry is quite difficult. With small spatial scale inhomogeneity, there are no similar restrictions.     

Unpinning of a rotating wave in cardiac muscle by an electric field.

The possibility of terminating cardiac arrhythmias with electric fields of moderate intensity is a challenging problem from a fundamental point of view and an important issue for clinical applications. In an effort to understand how anatomical re-entries are affected by electric fields, we found that a weak shock, with an amplitude of an order of magnitude less than the defibrillating shock, may unpin the vortices rotating around the defects (obstacles). The unpinning results from a depolarization of the tissue near the obstacle, induced by an external electric field within a distance of order lambda approximately 1 mm. Unpinning was observed both in the FitzHugh model of excitable tissue, and in a specific Beeler-Reuter model of cardiac tissue. This theoretical observation suggests that anatomical re-entries can be transformed into functional re-entries, an effect that can be tested in experiments with cardiac muscle.     

Interpretation of epicardial mapping by means of computer simulations: Applications to calcium,lidocaine and to BRL 34915

The aim of this work was to compare experimental investigations on effects of lidocaine, calcium and, BRL 34915 on reentries to simulated data obtained by use of a model of propagation based on the Huygens' constriction method already described in previous works. Calcium and lidocaine effects are investigated on anisotropic conduction conditions. In both cases, reduction in conduction velocities are observed. In lidocaine case, a refractory area is located along the longitudinal axis. In agreement with experimental electrical mapping, the simulations show that the stabilization of reentrant excitation is mainly due to the existence of this refractory area around which the reentrant circuit can develop. The experimental study shows that BRL 34915 has both arrhythmogenic and antiarrhythmic effects. A detailed electrophysiological analysis has shown that drug infusion act on normal cardiac cells by decreasing the relative and absolute refractory period. BRL 34915 action is simulated by a decrease in the refractory period showing that the time frequency of the reentrant activity is increased and that the spatial size where the reentry is developing is becoming smaller. These two effects are arrhythmogenic, the simulated data being so in good agreement with the experimental ones.     

Control of wave propagation in a biological excitable medium by an external electric field

We present an experimental evidence of effects of external electric fields (EFs) on the velocity of pulse waves propagating in a biological excitable medium. The excitable medium used is formed by a layer of starving cells of Dictyostelium discoideum through which the waves of increased concentration of cAMP propagate by reaction-diffusion mechanism. External dc EFs of low intensities (up to 5 V/cm) are shown to speed up the propagation of cAMP waves towards the positive electrode and slow it down towards the negative electrode. Electric fields were also found to support an emergence of new centers, emitting cAMP waves, in front of cAMP waves propagating towards the negative electrode.     

Differences between left and right ventricular anatomy determine the types of reentrant circuits induced by an external electric shock. A rabbit heart simulation study

Despite the fact that elucidating the mechanisms of cardiac vulnerability to electric shocks is crucial to understanding why defibrillation shocks fail, important aspects of cardiac vulnerability remain unknown. This research utilizes a novel anatomically based bidomain finite-element model of the rabbit ventricles to investigate the effect of shock polarity reversal on the reentrant activity induced by an external defibrillation-strength shock in the paced ventricles. The specific goal of the study is to examine how differences between left and right ventricular chamber anatomy result in differences in the types of reentrant circuits established by the shock. Truncated exponential monophasic shocks of duration 8 ms were delivered via two external electrodes at various timings. Vulnerability grids were constructed for shocks of reversed polarity (referred to as RV- or LV- when either the RV or the LV electrode is a cathode). Our results demonstrate that reversing electrode polarity from RV- to LV- changes the dominant type of post-shock reentry: it is figure-of-eight for RV- and quatrefoil for LV- shocks. Differences in secondary types of post-shock arrhythmia also occur following shock polarity reversal. These effects of polarity reversal are primarily due to the fact that the LV wall is thicker than the RV, resulting in a post-shock excitable gap that is predominantly within the LV wall for RV- shocks and in the septum for LV- shocks.     

Energy-storage capacity of the mitochondrial proton-motive force

Resting state respiration of rat-liver mitochondria in the presence of oligomycin was rapidly blocked with cyanide and the dissipation of the membrane potential was followed with a tetraphenylphosphonium-sensitive electrode. From the rate of this dissipation and the electric capacitance of the mitochondrial membrane the energy stored in form of the membrane potential was calculated as about 7 microJ/mg protein. In the absence of oligomycin, dissipation of the membrane potential was slower, as it was partly compensated by proton ejection by mitochondrial ATPase hydrolyzing endogenous ATP. This allowed to calculate the total energy storage capacity of the proton-motive force. It amounted to the equivalence of 3.3 nmol ATP/mg protein or about 130 microJ/mg protein. The stoichiometry of proton-pumping ATPase utilizing endogenous ATP was estimated as three protons per molecule ATP.     

Electric field induced desorption of bacteria from a conditioning film covered substratum.

Desorption of three oral bacterial strains from a salivary conditioning film on an indium tin oxide electrode during application of a positive (bacterial adhesion to the anode) or a negative electric current was studied in a parallel plate flow chamber. Bacterial adhesion was from a flowing suspension of high ionic strength, after which the bacterial suspension was replaced by a low ionic strength solution without bacteria and currents ranging from -800 to +800 microA were applied. Streptococcus oralis J22 desorbed during application of a positive and negative electric current with a desorption probability that increased with increasing electric current. Two actinomyces strains, however, could not be stimulated to desorb by the electric currents applied. The desorption forces acting on adhering bacteria are electroosmotic in origin and working parallel to the electrode surface in case of a positive current, whereas they are electrophoretic and electrostatic in origin and working perpendicular to the surface in case of a negative current. By comparison of the effect of positive and negative electric currents, it can be concluded that parallel forces are more effective in stimulating bacterial desorption than perpendicular forces. The results of this study point to a new pathway of cleaning industrial and biomedical surfaces without the use of detergents or biocides.