F.J.L. van Capelle

Flow of "injury" current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms.

We recorded 60 DC-extracellular electrograms simultaneously from epicardial and intra- mural sites of the left ventricle of isolated perfused porcine and canine hearts during the first 15 minutes after occlusion of the left anterior descending coronary artery. During coronary occlusion, maximal current flow across the ischemic border occurred when normal cells had repolarized and ischemic cells had not. At that moment, maximal current sources at the normal side of the ischemic border were in the order of 2 μA/mm3 and maximal current sinks were -5 μA/mm3. During propagation of a broad wavefront in nonischemic myocardium, current sources in the wake of the wavefront were about twice as large. Ventricular premature beats usually followed deep negative T waves in ischemic myocardium, when “injury” currents were maximal. Earliest activity always occurred at the normal side of the ischemic border, and whenever Purkinje activity was recorded it preceded myocardial activity in both single premature beats and the initial beats of ventricular tachycardia (VT) or ventricular fibrillation (VF). For later beats of VT, circus movements with a diameter of 1-2 cm were responsible for continuation of the arrhythmia. Dimension and position of the reentrant circuit changed from beat to beat. In VF, fragmentation of wavefronts occurred, and multiple wavelets followed tortuous paths. Circus movements were seldom completed; when they were, their diameter was 0.5 cm. It is concluded that two mechanisms are responsible for the very early ischemic arrhythmias: one, a μfocalμ mechanism located at the normal side of the ischemic border, possibly induced by injury currents in normal Purkinje fibers and, two, macro- and micro-reentry in ischemic myocardium. Circ Res 47:151-165, 1980

Mechanism and time course of S-T and T-Q segment changes during acute regional myocardial ischemia in the pig heart determined by extracellular and intracellular recordings.

We recorded transmembrane potentials from subepicardial ventricular cells and local extracellular DC electrograms in isolated perfused pig hearts before and after occlusion of the left anterior descending artery. The first change was a decrease in the resting membrane potential, reflected by T-Q depression in the electrogram. After 3 minutes, action potentials shortened and their amplitude decreased, resulting in S-T elevation until, finally, cells in the center of the ischemic zone became totally unresponsive at resting potentials of about −65 mV. This rendered the extracellular complex monophasic. Determination of extracellular potential distribution at 150-250 epicardial sites after 15-30 minutes of occlusion showed an increase of T-Q depression and S-T elevation toward a central area, with maximum values of −15 and +35 mV, respectively. Comparison of amplitude and configuration of intramural and epicardial potential profiles revealed that the potential distribution was homogeneous throughout ischemic parts of the wall. Extracellular epicardial current originated, therefore, from the epicardial intracellular compartment. Maximal current density during late systole was 1 μA/mm 2, flowing in the border zone towards normal myocardium. After 1 hour of occlusion, there was a marked decrease of extracellular DC potentials which could be attributed to transient recovery of electrical activity in the ischemic zone. After 2 hours, the zone of unresponsiveness was larger than after 15 minutes of occlusion, and the overall amplitude of DC potentials had decreased further, possibly because of healing over.

Dispersion of refractoriness in canine ventricular myocardium. Effects of sympathetic stimulation.

In 18 dogs on total cardiopulmonary bypass, the average interval between local activations during artificially induced ventricular fibrillation (VF interval) was measured from extracellular electrograms, simultaneously recorded from up to 32 ventricular sites. VF intervals were used as an index of local refractoriness, based on the assumption that during ventricular fibrillation, cells are reexcited as soon as they have recovered their excitability. In support of this, microelectrode recordings in two hearts during ventricular fibrillation did not show a diastolic interval between successive action potentials. Refractory periods determined at a basic cycle length of 300 msec with the extrastimulus method correlated well with VF intervals measured at the same sites. Thus, this technique allows assessment of spatial dispersion of refractoriness during brief interventions such as sympathetic stimulation. The responses to left, right, and combined stellate ganglion stimulation varied substantially among individual hearts. This was observed both in dogs with an intact (n = 12) and decentralized (n = 6) autonomic nervous system. Individual ventricular sites could show effects of both left and right stellate ganglion stimulation (42% of tested sites) or show effects of left-sided stimulation only (31%) or right-sided stimulation only (14%). In 13% of sites, no effects of stellate stimulation were observed. Apart from these regional effects, the responses could be qualitatively different; that is, within the same heart, the VF interval prolonged at one site but shortened at another in response to the same intervention, although shortening was the general effect and prolongation the exception. Whenever sites responded to stellate ganglion stimulation with a shortening of VF interval, this shortening was approximately 10% for left, right, or combined stimulation, whether the autonomic nervous system was intact or decentralized. In six of 12 hearts in the intact group, there was a distinct regional effect of left stellate ganglion stimulation; in the other six hearts, the effects were distributed homogeneously over the ventricles. In three hearts, the effect of left stellate ganglion stimulation was strongest in the posterior wall, and in the other three hearts, in the anterior wall. The effects of right stellate ganglion stimulation were restricted to the anterior or lateral part of the left ventricle. Dispersion of VF intervals increased after left and combined stellate ganglion stimulation in the intact group and after right stellate ganglion stimulation in the decentralized group, but not significantly in every heart. This points to a marked individual variation with regard to the effects of sympathetic stimulation on electrophysiological properties of the heart.

Computer simulation of arrhythmias in a network of coupled excitable elements.

Arrhythmias were simulated in sheets or cables, consisting of coupled excitable elements, which were characterized by a simple regenerative mechanism. The geometry of the network, the amount of coupling among individual elements, and the properties of the elements relating to excita-bility, automaticity, and duration of the refractory period could be adjusted arbitrarily in an interactive computer program. When a critical amount of coupling was present between automatic and non-automatic cells, sustained repetitive activity could be initiated and stopped by stimulation of the elements. Using this mechanism, it also was possible to evoke reciprocal activity in a one-dimensional cable. In uniform sheets of coupled elements, circus movement of the activation front could be evoked. The presence of an obstacle or dispersion of the refractory periods of the elements was not a prerequisite for the initiation of circus movements. The vortex of circus movements in the homogeneous sheets consisted of elements which were inactivated by depolarizing currents from the circulating wavefront. In sheets of sufficient size, multiple vortices could be present. Circ Res 47: 454-466, 1980

Circus movement within the AV node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart.

Supraventricular tachycardia in an isolated rabbit heart preparation was repeatedly initiated and terminated by carefully timed atrial premature beats. Transmembrane action potentials of AV nodal cells were recorded simultaneously by a “brush electrode” consisting of 10 microelectrodes. Surface electrograms of atrium and His bundle were also recorded. The moments of activation of 54 different AV nodal cells, both during regular driving of the atrium and during tachycardia were ascertained. Premature atrial beats introduced during tachycardia would either “reset” the tachycardia or terminate it. The sequence of activation of the AV nodal cells when initiating tachycardia, during tachycardia itself, and when premature beats were interpolated during tachycardia warrant the conclusion that a circus movement in the AV node, based on functional longitudinal dissociation of the upper AV node, was the underlying mechanism of the arrhythmia.

Electrotonic interactions across an inexcitable region as a cause of ectopic activity in acute regional myocardial ischemia. A study in intact porcine and canine hearts and computer models.

We recorded 60 DC simultaneous electrograms from isolated porcine and canine hearts in the first minutes after coronary occlusion. Ventricular premature beats (VPB) originated from the normal side of the ischemic border, which was frequently separated from the central ischemic area showing delayed activity by a small zone of inexcitable tissue. We attempted in a computer model to generate VPBs at one side of an area showing conduction block. In computer simulations, the presence of elements capable of automatic activity greatly facilitated the induction of VPBs. By coupling automatic elements to nonautomatic elements, overt pacemaking activity could be suppressed. Subthreshold depolarizations transmitted through a zone of conduction block could, when properly timed, trigger the latent automatic elements into overt automatic activity, resulting in single or repetitive VPBs. The ventricular premature beats in the intact hearts with acute regional ischemia may be caused by “triggered automaticity” in which the trigger is provided by the “injury current” flowing from ischemic cells showing delayed repolarization via a segment of inexcitable ischemic cells in the border zone to normally perfused cells with suppressed automaticity.

Wave propagation simulation in normal and infarcted myocardium: Computational and modelling issues

Simulation of propagating action potentials (PAP) in normal and abnormal myocardium is used for the understanding of mechanisms responsible for eliciting dangerous arrhythmias. One- and two-dimensional models dealing with PAP properties are reviewed in this paper viewed both from the computational and mathematical aspects. These models are used for linking theoretical and experimental results. The discontinuous nature of the PAP is demonstrated through the combination of experimental and theoretically derived results. In particular it can be shown that for increased intracellular coupling resistance the PAP upstroke phase properties (Vmax, dV/dtmax and tau foot) change considerably, and in some cases non-monotonically with increased coupling resistance. It is shown that tau foot) is a parameter that is very sensitive to the cells distance to the stimulus site, the stimulus strength and the coupling resistance. In particular it can be shown that in a one-dimensional structure the tau foot value can increase dramatically for lower coupling resistance values near the stimulus site and subsequently can be reduced as we move to distances larger than five resting length constants from the stimulus site. The tau foot variability is reduced with increased coupling resistance, rendering the lower coupling resistance structures, under abnormal excitation sequences, more vulnerable to conduction block and arrhythmias. Using the theory of discontinuous propagation of the PAP in the myocardium it is demonstrated that for specific abnormal situations in the myocardium, such as infarcted tissue, one- and two-dimensional models can reliably simulate propagation characteristics and explain complex phenomena such as propagation at bifurcation sites and mechanisms of block and re-entry. In conclusion it is shown that applied mathematics and informatics can help in elucidating electrophysiologically complex mechanisms such as arrhythmias and conduction disturbances in the myocardium.

Deconvolution and wavelet-based methods for membrane current estimation from simulated fractionated electrograms

In infarcted myocardium, extracellular recordings exhibit multiple deflections due to irregular pathway of the electric impulse. In this work the problem of distinguishing local from distant deflections is tackled. In order to evaluate the proposed methods in a controlled setting, simulated data are used, following both Reeler-Reuter and Luo-Rudy kinetics. The input is an array of electrograms positioned on grid-points of a rectangular grid and the output is an array of estimates of the membrane current. First, deconvolution techniques are used in the form of spatial filtering for membrane current estimation from the extracellular recordings. Second, the extracellular recordings undergo wavelet based transformation, followed by a spatial filter which enhances local activity deflections and suppresses distant activity deflections. It is shown that wavelet filtering of the extracellular recordings acts as an evaluator of the efficiency of the deconvolution techniques for the membrane current estimation. Subsequently, activation times based on the results from the two methods are used for the reconstruction of the propagation pattern in a zig-zag case in two-dimensional grids. It is shown that the wavelet-based method is more robust, and can work well even in cases where the grid interval in the y direction is four times larger than the single cell size.

Estimation of Distance Between a Unipolar Recording Electrode and a Myocardial Bundle Based on Signal Characteristics

The aim of the present paper, is the estimation of the distance between an electrode used as a recording site of the extracellular potential field and a surviving myocardial bundle. The importance of the reliable solution of this problem lies among others in controlling ablation. For our purposes one-dimensional propagation is considered and current sources are activated along a cable simulating the propagating waves with constant velocity. Different models of current sources are explored. By use of these models, the corresponding functions expressing extracellular potentials are calculated, using the volume conductor equation. This way, extracellular potentials are modeled as parametric functions of longitudinal distance, while perpendicular distance, current source strength, and other factors related to the propagated wave are parameters of the functions. Simulated annealing is applied for model parameter estimation and appropriate Time Domain and Wavelet Domain cost functions are investigated. Different combinations of model and cost function are evaluated regarding the accuracy of distance estimation. A continuous source model function with a wavelet cost function was found to be the most accurate combination. The accuracy of distance estimation is related to the selected source model and to the actual distance of recording in a nonmonotonic way.

Comparison of time and frequency based methods for electrode distance estimation from surviving tissue

In this work, time, frequency and time-frequency methods for distance estimation are presented and compared for the electrode distance estimation one-dimensional case, under a constant velocity assumption. Electrical sources are modelled as multipoles or sources with triangular distribution. The estimation is based on these spatial models of the electrical sources and the corresponding electrical fields. Among the methods used, non-linear distance estimation seems to be a robust method. Specific characteristics of the signals (in time domain or frequency domain) are not sufficient for successful estimation. On the other hand, wavelet analysis may describe signal behavior in more detail and thus help improve ones models.