Ionic Mechanisms of Cardiac Arrhythmia · excite the tissue. When additional impulses are tri-g gered by delayed afterdepolarizations (DAD) occu-r ring during the vulnerable phase,

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Introduction

Despite decisive progress in the therapy of various car-diac diseases, cardiac arrhythmia still represents amajor reason for sudden cardiac death. Pharmaco-logical therapies are often based on empirical criteriathat only partially consider the actual mechanisms ofthe particular arrhythmia [1]. However, a detailed diag-nosis of cardiac arrhythmia requires a physicallyunderpinned understanding of their generation mecha-nisms as well as systematically established electro-physiological criteria.Changes in the electrophysiological substrate con-tributing to cardiac arrhythmia can be observed at dif-ferent structural levels of the myocardium.Automaticity and triggered activity are known to bearrhythmogenic mechanisms acting at the cellularlevel, where the ion channels of the cell membrane areinvolved. In addition, the interaction between cells, thespatial orientation of muscle fibers, and the heteroge-

neous composition of the myocardium also contributeto the generation of arrhythmia [1]. As confirmed by clinical experience, the macroscopicphenomenon of reentry is the most common mechanismof cardiac arrhythmia, but the therapeutic strategies forabolishing reentry may differ according to the specificmechanism underlying the arrhythmia. Aiming at thedevelopment of antiarrhythmic therapy algorithms, asystematic analysis of cardiac reentry mechanisms andtheir determinants is an important prerequisite.In order to analyze the complex interdependencies ofthe system parameters, a mathematically well-definedmodel study is performed. The analysis focuses on themechanisms underlying the electrophysiologicalanomalies correlated with cardiac arrhythmia. Beyondverifying hypotheses suggested by electrophysiologi-cal experiments, the model also serves as a tool forplanning clinical studies.

Progress in Biomedical Research

Ionic Mechanisms of Cardiac Arrhythmia

I. WEISS, A. URBASZEK, M. SCHALDACHDepartment of Biomedical Engineering, Erlangen-Nuremberg, Germany

Summary

In order to achieve optimal therapy results, it is decisive to take into consideration the particular mechanisms ofcardiac arrhythmia. Classification and detailed understanding of the underlying mechanisms will therefore estab-lish the basis for successful management of cardiac arrhythmia. Our study focuses on reentry-based arrhythmiatriggered by early afterdepolarizations (EAD). Hypotheses concerning the mechanisms of EADs were tested andvalidated using a computer model of cardiac action potentials. We were able to demonstrate that the essentialmechanism consists in the generation of a so-called calcium window during the repolarization phase of the actionpotential. The generation of the calcium window is caused by an alteration of the calcium L-type channel prop-erties due to excessive ß-adrenergic stimulation of the cardiac tissue. The most critical consequence of EADs isa pronounced prolongation of the action potential duration. This may locally induce a unidirectional transientblock of excitation spreading, which favors reentrant circuits. As demonstrated by this study, however, the exis-tence of an excitable gap is required for the reentry to be stable and, thereby, becoming dangerous. Based on find-ings concerning the prerequisites of reentrant circuits, our study theoretically underpins the strategy of anti-tachycardia pacing, able to achieve suppression of tachycardia, as a promising alternative to drug therapy.

Key Words

Cardiac arrhythmia, early afterdepolarization, reentry, cell model

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ness favors the inducibility and persistency of cardiacfibrillation.

Arrhythmogenic MechanismsWith regard to the basic mechanisms of cardiacarrhythmia, two levels can be distinguished: a cellularand a tissue level (Figure 1). Mechanisms acting at the cellular level comprise auto-maticity and triggered activity. The latter has beenshown to be related to afterdepolarizations in the mem-brane potential. However, reentry-based arrhythmia isgenerated at the tissue level. It is observed most fre-quently and, therefore, it represents the main topic ofthis study. Yet, as found in experiments, afterdepolar-izations can be decisively involved in the reentryprocess.Understanding these mechanisms is essential for suc-cessful antitachycardia therapy management. There-fore, the main mechanisms of arrhythmogenesis willbe discussed in the following with an emphasis on trig-gered activity and reentry-based tachycardia.

AutomaticityAutomaticity is the ability to generate a spontaneousaction potential. All cardiac cells can display this prop-erty, but, in a normal heart, most do not. Depending onthe location within the heart, therefore, automaticitymay be classified as either normal or abnormal. Cardiac cells with normal automaticity are called pace-maker cells. The dominant pacemaker of the heart isnormally the sinus node, but there also exist cells capa-ble of spontaneous diastolic depolarization, such asspecialized fibers of the atria, AV junction, and theHis-Purkinje system. These secondary pacemakers liedormant (latent) until the sinus node activity isremoved, allowing the latent pacemaker's rhythm tobecome visible.A clinical example of abnormal automaticity is accel-erated idioventricular rhythm caused by Purkinje cellsin an ischemic region after a myocardial infarction. Inthis arrhythmia, normally quiet Purkinje fibers in thedamaged heart muscle suddenly assume control of theheartbeat. Loss of K and uptake of Na (Ca, H and wateraccumulate as well) within the ischemic cell result in areduced membrane potential, which can lead to auto-maticity. However, this arrhythmia caused by abnor-mal automaticity will not be visible unless the rate ofthe abnormal focus is greater than that of the dominantpacemaker.

Electrophysiological Background

To establish a systematic foundation of electrophysio-logical knowledge, mathematical modeling of cardiactissue will be based on a series of experimental find-ings, which are summarized in the following. The find-ings concern changes in the electrophysiological sub-strate and other observations revealed from experi-ments that provide an overview of the most importantarrhythmogenic mechanisms.

Electrophysiological Substrate of Cardiac Arrhythmia Early observations concerning cardiac arrhythmia havealready confirmed that dispersion of refractoriness is akey factor for arrhythmogenesis and have shown thatits increase underlies the arrhythmogenic effect of pre-mature beats [13]. Moreover, interventions such asvagal or sympathetic stimulation, quinidine intoxica-tion, hypothermia, and myocardial ischemia mightfavor reentrant activity. These can act both by increas-ing dispersion of refractory periods and by changingconduction velocity and refractory periods such thatthe minimal length of a circuit in which the impulsescan circulate is reduced. From this, the concept of"wavelength" as the product of conduction velocityand refractory period was derived, which permits thelength of the reentry circuit to be measured. Modifyingthe electrophysiological substrate alters not onlyrefractoriness but also the conduction velocity of theexcitation impulse. Therefore, a "dynamic dispersion"may exist, which could be modified by physiologicalor pathological factors favoring reentry and fibrilla-tion.Abnormalities in myocardial electrophysiology andstructure are important for the development of cardiacarrhythmia. Shortened atrial refractoriness and diminu-tion of the rate-dependent change in refractorinesshave been associated with a higher vulnerability to fib-rillation [2]. For example, changes in the atria of goatshave been found to be the result of fibrillation ratherthan being the cause of it [24]. Also, membrane poten-tial abnormalities leading to impaired conduction havebeen found in atrial fibers of patients with chronic atri-al fibrillation (AF) and extensive degenerativechanges. However, the main finding from clinical practice is that"reentry" is easily induced by increasing dispersion ofrefractoriness and slowing impulse conduction veloci-ty. In conclusion, an increased dispersion of refractori-


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Clinical Evidence of EAD-triggered ArrhythmiaTriggered rhythms are known to be caused by afterde-polarizations, which are oscillations in the membranepotential following an action potential. One mecha-nism by which triggered activity causes arrhythmia isobserved when the afterdepolarization (of either type)is large enough to reach the threshold potential. Theresulting action potential is called a triggered actionpotential. An arrhythmia is induced when impulse ini-tiation shifts from the sinus node to the triggered focus.For this to happen, the rate of triggered impulses mustbe faster than the rate of the sinus node. The importance of afterdepolarizations for arrhythmo-genesis, however, is also due to a second mechanismthat is related to electrophysiological inhomogeneitywithin the tissue. When EADs occur (predominantly alocal phenomenon), the significantly prolonged actionpotentials give rise to a pronounced dispersion ofrefractoriness. Therefore, the pathologically changedsubstrate will alter the normal impulse propagationpattern in a way that the excitation waves may re-excite the tissue. When additional impulses are trig-gered by delayed afterdepolarizations (DAD) occur-

ring during the vulnerable phase, cardiac activity islikely to become arrhythmic. Early afterdepolarizations can occur in almost any typeof cardiac cell but have been mainly studied inPurkinje fibers and ventricular muscle cells. Earlyafterdepolarizations often arise from the plateau of anaction potential but can also be observed during therapid repolarization of phase 3 (Figure 2). The relationship between EADs and cardiac arrhyth-mia was observed and experimentally proven in elec-trophysiological studies while recording endocardialand epicardial monophasic action potentials (MAP)synchronously with the ECG signal [1]. Studies havedemonstrated that arrhythmias resembling torsade depointes are induced by agents known also to induceEADs. Therefore, it was hypothesized that naturallyoccurring torsade de pointes may be caused by EADs[7]. Drugs that prolong the duration of Purkinje-fiberaction potentials, such as sotalol and quinidine, wereshown to induce EADs and triggered activity. Bothdrugs block the re-polarizing K current, so the arrhyth-mia associated with their use may also result fromEADs [20].


Figure 1. Action levels of cardiac arrhythmogenic mechanisms.

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Among several causes of slow conduction that maylead to arrhythmias, the following are of main impor-tance [21]:• changes in membrane current,• changes in the cable properties of the cell, and• changes in gap junction resistance.Normally, the action potential from the sinus node diesout after orderly depolarization of the atria, AV con-duction system, and the ventricles. Usually, theimpulse does not conduct backwards because the tissuejust stimulated is refractory.Reentry occurs when the action potential does not dieout but continues to propagate and reactivate theheart. Almost every clinically important tach-yarrhythmia is due to reentry [20]. Reentry can occuralmost anywhere in the heart and can assume manysizes and shapes. Experimentally it was first demon-strated in 1906 by Mayer in the excitable ring of a jel-lyfish [20].

Impacts of the Autonomic Nervous System on CardiacArrhythmiaThough the heart has its own control mechanisms, it isadditionally controlled by the autonomic nervous sys-

EADs and triggered activity have been producedexperimentally under a variety of conditions, mostcausing marked delays in the repolarization of cardiaccells. Slow heart rate and drug toxicity are two exam-ples [4]. Agents that increase inward current compo-nents or decrease outward currents resulted in condi-tions favorable for EAD generation [25].

Slowed Conduction, Reentry and Unidirectional BlockAside from defects in impulse formation, abnormali-ties of impulse conduction represent a second mainmechanism of arrhythmogenesis.As known from experimental studies, conductiondelay plays a large role in tachycardia caused by reen-try [21]. If extreme delay occurs, the excitation wave isgoing to be blocked. The block may be bi-directionalor unidirectional, the latter being closely tied to thephenomenon of reentry.


Figure 2. Morphologies of cardiac action potentials withEADs. Comparison of measured [1] and simulated curves[23].

Figure 3. Schematic representation of ANS regulation ofatrial electrophysiological properties. Modulation of refrac-toriness and conduction is not only a dynamic but also acontinuous process. Additionally, the vagal-sympatheticbalance changes continuously.

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tem (ANS), which constitutes a bridge closing the con-trol loop of the circulatory system.Because of a variable concentration of nerve endingsin the atrial tissue, the effects of vagal stimulation arenot uniform across the muscle [6]. Experimentsshowed that dispersion of refractoriness is increased inthe atrium by stimulating vagal nerves. On the otherhand, the influence of sympathetic nerves in the atriumis less pronounced than that of the vagus, which is dueto the opposite effects of alpha- and beta-receptors onatrial refractoriness.Summarizing the results of electrophysiological inves-tigations, it can be stated that [6]: • The ANS may induce less homogeneous behavior of

intra-atrial conduction and may change the distribu-tion of refractoriness.

• Vagus and sympathetic nerves may influence eachother.

• Vagal and sympathetic effects appear at differenttimes.

All the aforementioned findings stress that the impactsof the ANS on atrial electrophysiological propertiesare very complex in clinical settings (Figure 3). Changes in refractoriness may also be caused by othereffects that are only mediated by the ANS. It wasfound experimentally that atrial distension (stretching)is reflected by changes in refractoriness [5]. Distensioninduces a reflex increase of sympathetic tone that actsinhomogeneously as suggested by pressure measure-ments performed in both atrial chambers, thus produc-ing an increased dispersion of refractoriness.Even age should be considered when evaluating theeffects of the ANS. Age is linked not only to refrac-toriness and its dispersion but also to vagal-sympathet-ic balance [10].

Methods

In order to guarantee accurate reproducibility, thestudy is performed using a mathematical model of thephysical system that is the subject of the investigations.Compared to laboratory experiments, this procedurereveals two important advantages: • First, when running a protocol several times, the

system can be reset to absolutely the same initialconditions. This requirement can never be met dur-ing electrophysiological measurements because twoindividual cells will not necessary behave in thesame manner, and even if the same cell is re-used, it

will be differently preconditioned by the previousexperiment.

• The second and most important advantage is that theconstruction of the model helps to understand theunderlying mechanisms and furthermore, allowstracing inner system variables that are not accessibleduring electrophysiological measurements.

Model-based Investigation of Cardiac ArrhythmiaInvestigating the mechanisms of cardiac arrhythmia,the study is performed in two steps. Microscopic phe-nomena are investigated at the cellular level, whereas amodel description at tissue level is performed to ana-lyze the macroscopic processes.

Arrhythmogenic Mechanisms at the Cellular Level Since clinical investigations have shown that EADs aremainly involved in arrhythmogenic mechanisms, adetailed analysis of EAD generation was performedusing a computer model of cardiac cells. Its basicstructure is in accordance with the approaches formodeling cardiac action potentials as postulated byBeeler-Reuter [3] and Luo-Rudy [12]. Moreover, themodel is properly designed to take into account thepathological characteristics of EAD-threatened cells[22][23]. In order to validate the hypothesis of EAD generationsystematically, the model consists only of elementswhich are strictly required by the emphasized mecha-nism descriptions. Therefore, the sarcoplasmic reticu-lum (SR) is explicitly not considered in this model todemonstrate that calcium overload-induced calciumrelease from the junctional SR is not necessarilyinvolved in the generation mechanism of EADs.To induce EADs in the model, the activating and inac-tivating characteristics of the calcium L-type channeland the dynamic potassium channel were fitted toelectrophysiological measurements (Figure 4).Regarding the calcium L-type channel, the increasingconcentration of isoproterenol enhances the channelpermeability [18]. Assuming that gCa0 is the conduc-tivity of the calcium L-type channel for normal actionpotentials, the ratio gCa/gCa0 is a measure for thestrength of adrenergic stimulation. The values of thisratio differ for various cell types and are within arange of 1.5-8 [26]. Moreover, experimental findings have shown that theactivation and inactivation properties of the calcium L-type channel are also affected by isoproterenol. In [14],


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surements performed in [8] and [11], a shift by 15 mVin the negative direction of the curve is consid-ered in the model. The curve is shifted by 10 mVin the positive direction, to diminish the values of thex variable time constant for negative values of thetransmembrane potential. This fact is important to geta relatively steep repolarization course after the lastEAD, as it can also be observed in measurements (seeFigure 2).According to these findings, isoproterenol will inducefunctional changes that alter the coordination of thed-, f- and x-gates. If a certain value of the transmem-brane potential is reached during the ongoing repolar-ization, an inflection point appears in the course of thetransmembrane potential after which the action poten-tial becomes flatter. The repolarization is nearly com-pletely stopped. An intermediate plateau is formed,which has the same effect as if the transmembranepotential had been clamped on a fixed value VK.Starting from this inflection point, there will beenough time for the d-variable to settle to the asymp-totic value . This dynamic process is governedby the time constant . In the time course of thed-variable, a curve fragment appears allowing a hori-zontal tangent (Figure 5). The range between theinflection point of the transmembrane potential andthis horizontal tangent is called the 'preconditioningphase'. Given these border conditions, even a very

an isoproterenol-induced shift of the activating andinactivating characteristics is described, which isdepicted in Figure 4. However, this fact is neglected in[26], but obviously a shift in opposite directions of thecharacteristics (in negative direction of Vm) and

(in positive direction of Vm) favors the appear-ance of a calcium window. Thus, the calcium L-typechannel can be re-opened during the repolarizationphase. This fact is considered to be a major determi-nant for EAD generation and is taken into account inour model. In addition, a deceleration of the channelinactivation was observed in [17], which is consideredin the model by an increase of the inactivation timeconstant by 13%.Beside the impacts on the calcium L-type channel, thedynamic potassium channel is also affected by isopro-terenol. According to present knowledge about the car-diac potassium channels, ß-adrenergic stimulationenhances the conductivity of the dynamic potassiumchannel, whereas the non-dynamic one is not affected[16][19]. However, quantitative descriptions could notyet be found in the literature. Comparing measured andsimulated events showing EADs (see Figure 2), it wasconcluded that the conductivity of the dynamic potas-sium channel must increase by about 25% in the pres-ence of isoproterenol.An isoproterenol-induced shifting of the activatingcharacteristic was observed as well. Based on mea-


Figure 4. Impacts of isoproterenol on the activating and inactivating characteristics of the calcium L-type channel.

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small change of the transmembrane potential can tiltthe time course of the d-variable towards an increasingtrend, re-opening the calcium channel. A slight disturbance of the current equilibrium (Ca/K)towards a small net inward current will now be able totrigger a new membrane depolarization. The d-gatingvariable continues to increase, opening a so-called cal-cium window. The resulting inward calcium currentitself accelerates the depolarization process, acting as apositive feedback. The rapidly increasing transmem-brane potential makes the f-gate close again and stopsthe avalanche-like opening of calcium channels. A newrepolarization phase starts closing the calcium window.

Arrhythmogenic Mechanisms at the Tissue Level In order to investigate the impacts of EADs on the

propagation phenomenon, a model of one-dimensionalaction potential propagation was designed (Figure 6).The fiber is to be built of a chain of cylindrical mem-brane slices, each is represented by a membranemodel. These models are interconnected by resistorsrepresenting the intracellular (Ri) and the extracellular(Re) space. Gap junctions were taken into account,which were shown to reduce the propagation velocityif their resistance was increased. A detail of the equiv-alent electrical network to be analyzed is depicted inFigure 7. The transmembrane potentials for each of the mem-brane slices are computed based on a coupled differen-tial equation system (discrete cable equation):


Figure 5. The mechanism of EAD generation. Precondition-ing phase and calcium window.

Figure 6. Model of the cardiac muscle fiber. The double-out-lined rectangle represents the model of ionic channels. Rmis the myoplasm resistance.

Figure 7. Network elements of the fiber model and definitionof current flow directions.

where(1)

(2).

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Figure 8. Potential anatomic and functional reentry path-ways.

In the model study, it is assumed that the volume thatincludes the main part of the extracellular current flowis comparable to the intracellular volume, hence:


The geometrical cell dimensions are λ = 10-2 cm andr0 = 10-3 cm, whereas the electrical characteristics areg = 6.7 mS/cm for the electrolyte conductivity andcm = 1 µF/cm2 for the specific membrane capacitance.Except for diseased regions, the muscle fiber is con-sidered to be homogeneous.The propagation phenomenon was investigated forboth a model of a linear and a ring-shaped musclefiber. For normal spread of excitation (propagationvelocity 1 m/s), gap junctions were considered to befully opened (Rgap = 0 ohm). In diseased tissue, such asischemic regions, gap junctions are known to close,disconnecting the cells electrically. The model coulddemonstrate that an increase of the gap junction resis-tance reduces the velocity of action potential propaga-tion. The propagation velocity is modulated by theratio:

Frequently reentry-based arrhythmia is observed whenregions of the myocardium are temporary or persis-

(3)

(4)

Figure 9. Design of the ring model. EADs are induced with-in a small segment of the ring-shaped fiber.

tently not excitable. For example, an infarcted zone oran operation scar is considered in this study (Figure 8). The excitation wave has to pass around the damagedtissue following a ring-shaped pathway. Based on thisobservation, the reentry phenomenon is investigated ina model of a ring-shaped muscle fiber (Figure 9),according to the experimental setting used in Mayer'sexperiment.EADs were induced within a small segment of the ringmodel by modifying the model parameters of some ofthe membrane slices. The resulting, very pronounceddispersion of refractoriness favors the start-up of areentry circuit which could be initiated by two consec-utive stimuli (S1, S2).

Simulation Results

Based on the electrophysiological findings, the com-puter model for the normal action potential is modifiedand employed to simulate pathological behavior. Asdemonstrated by electrophysiological investigations,EADs are correlated to the presence of ß-adrenergicagents like isoproterenol, which act comparable to thesympathetic transmitter agent in vivo. However, EADsare known to trigger arrhythmia. Therefore, it is of par-ticular interest to investigate and elucidate these con-nections. In Figure 10, various simulated events showing EADsare presented. Depending on the strength of the adren-ergic stimulation, one or multiple EADs may appear. Inthis model study, isoproterenol is considered to be theß-adrenergic agent. Actually, isoproterenol is detectedby specific receptors of the cell membrane and has ashare in various mechanisms. The model study showed

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that EADs are generated due to the appearance of a so-called calcium window during the repolarization phaseof the action potential. The calcium window resultsbecause of an alteration of the calcium L-type channelproperties caused by ß-adrenergic stimulation of car-diac tissue.

Simulation of Cardiac ReentryIn the reentry model, EADs were generated by assum-ing that the ß-adrenergic stimulation increased the Cachannel conductivity 3.33-fold. Figure 9 indicateswhere EADs were induced. The fiber is stimulated asshown in Figure 11 a (stimulus S1 at t = 0 ms). In thecase of normal propagation, the excitation spread takesplace symmetrically in both branches of the ringmodel. The wavefronts meet at the diametrically oppo-site point of the stimulus location and extinguish eachother. Afterwards, both the left and the right branchrepolarize symmetrically (Figure 11 a). The corre-sponding time course of this process is displayed inFigure 12.In the case of diseased tissue, a region of the ring fiberremains depolarized due to the occurrence of EADs.The stimulus S2 is elicited 380 ms after S1 and propa-gates normally until the EAD region is reached (Figure11 b). As a consequence of the significantly prolongedaction potential duration, the excitation wave originat-ing from the S2-stimulus is blocked in the branch of

the ring fiber where EADs appeared (Figure 11 c). Theexcitation propagates normally in the other branch, butit has a longer way to cover and arrives at the oppositeside of the cells affected by EADs. Meanwhile thesecells have become fully or almost fully repolarized(see arrow in Figure 11 d indicating the rise in thebaseline), and, therefore, the excitation wave can passthrough this domain, reentering into the region whereit initially started. However, stable reentry is only possible if the wave-length corresponding to the refractory period of thepropagated action potential is less than the circumfer-ence of the ring fiber. It is called the recovery wave-length because it is associated to the time required bythe sodium channel to recover from inactivation. In themodel, the ring diameter was considered to be 2.55 cm(8 cm circumference), and the propagation velocitywas reduced to 0.24 m/s by setting the gap junctionresistance to Rga p= 8*Rm. The action potential wave-length corresponding to the APD90 parameter resultedas 4.6 cm. The coupling interval S2-S1 was 380 msresulting in a stable reentry tachyarrhythmia corre-sponding to a cycle length of 329 ms (182.4 min-1).

Discussion

The study presents an overview of the hypotheses stat-ed in literature concerning the generation mechanisms


Figure 10. Morphologies of simulated action potentials with EADs. The number and the shape of EADs depend on the strengthof ß-adrenergic stimulation.

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Figure 12. Time course of the simulated reentry process.


Figure 11. Simulation results of cardiac reentry. Spatial distribution of the transmembrane potential.

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of cardiac arrhythmia with an emphasis on the contri-bution of EADs to arrhythmogenesis. To test and vali-date these assumptions, a properly designed computermodel was developed and used to simulate cardiacaction potentials in isolated cells as well as in cardiactissue. The most important findings elucidating the generationmechanisms of EADs are summarized as follows:• The depolarizing charge required for EADs is car-

ried through the calcium L-type channel.• The decisive mechanism of EADs consists in the

reactivation of the calcium current through the cellmembrane as a result of the development of a calci-um window. The reactivation mechanism of the cal-cium channel does not depend on the type of agentcausing the EAD.

• EAD generation neither requires an increased intra-cellular calcium concentration nor a calcium releasefrom the SR.

• EADs are favored by low stimulation rates and areabolished by high stimulation rates.

The initiation of the reentrant circuit depends on therelationship between the propagation velocity, thelongest way between the stimulus location and theEAD zone, and the coupling interval S2-S1. In gener-al, the following prerequisites have to be satisfied [21]:• Reentry requires a suitable region of heart with elec-

trical characteristics capable of supporting reentry.Additionally, for random reentry, the path must con-tain a critical mass of cardiac tissue to sustain theseveral simultaneously circulating reentrant wave-fronts.

• The excitation wavefront must encounter unidirec-tional block. In order for the unidirectional block tooccur, a premature impulse must arise in a regionwith a short effective refractory period so that itoccurs before the action potentials in one of thepathways have repolarized.

• The activation wave must be able to circulate arounda central area of block.

• Tissue initially activated must have sufficient timeto recover excitability. There must always be a gapof excitable (either fully or partially) tissue ahead ofthe circulating wave.

• Reentry requires an initiating trigger which bringsone or more of the conditions to a critical state. Thetrigger beat may be unrelated to the reentrant tachy-cardia and may occur by any mechanism (e.g. due toDADs).

• Regional differences in refractory period may causeconduction of an appropriately timed prematureimpulse to be blocked in the region with the longestrefractory period.

Stable reentry, however, is achieved only if the recov-ery wavelength is less than the circumference of thering. This fundamental finding revealed by both exper-imental and model studies led to the so-called wave-length concept underlying the theory of cardiac fibril-lation.

Outcomes for Antitachycardia ElectrotherapyRecent observations of AF demonstrated that such anexcitable gap actually does exist while the model studyhas revealed its importance for the stability of reentrantcircuits. These findings give evidence that if reentrypersists, an excitable gap has also to exist. That meansthat antitachycardia pacing within this gap enablescontrol of reentry. The discussion of tachycardia theo-ry pertains to the underlying mechanisms of thosearrhythmia deemed treatable by antitachycardia pac-ing. Factors influencing termination success by anti-tachycardia pacing include [15]: • the refractory period and conduction velocity of the

stimulation site, reentrant circuit, and interveningmyocardium,

• the number of entry routes into the reentrant circuit, • the relative locations of the stimulation site and the

circuit,• the rate of the tachycardia,• stimulus pulse timing and number,• pharmacological factors, and• the disease process or substrate.Among these influencing factors, clinical studies haveestablished three antitachycardia pacemaker parame-ters as being most important for successful termina-tion. These are:• the number of stimulation pulses, • the stimulation pulse timing, and • the site of stimulation.Determining the optimal number of pulse stimuli is thefirst step towards termination success. In some tachy-cardias, two or more stimuli are often more effectivethan a single stimulus. The first pulse compresses thelength of the refractory tissue in the reentrant circuitwhen it collides with and slows the encircling wavemomentarily. The resultant wider excitable gap allowsthe second pulsed wave to reach the reentrant circuitearly enough to fully interrupt the circulating wave.


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[21] Weinberg GM. Mechanisms of Cardiac Arrhythmia in Designof Cardiac Pacemakers. In: Webster JG. Design of cardiacpacemakers, IEEE Press 1995: 34.

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[23 Weiss I, Urbaszek A, Schaldach M. A Model Study ofCardiac Early Afterdepolarizations. Prog Biomed Res.December 1996: 84-94.

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The most important clinical parameter for determiningtachycardia termination success is the site of stimula-tion. Studies have shown that reentrant circuits can beterminated by fewer pulses when the stimulation site islocated in the normal myocardial tissue proximal to theslow conduction zone [9]. The optimal site for successwould be the ischemic zone itself, close to the proximalside of the slow zone. However, here the tissueexcitability may be reduced due to the ischemia and,thus, a higher stimulation current would be required.Noninvasive techniques for determining the preciselocation of a reentrant circuit, particularly its slow zoneof reentry and the direction of the wave front in thiszone, are topics of future research. Though restrictionson mapping reentrant circuits currently still exist inclinical practice, the outcomes of both experimentaland model studies should be emphasized because theyare yielding strategies to be pursued for successfulantiarrhythmic therapy.

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Documents

Ionic Mechanisms of Cardiac Arrhythmia · excite the tissue. When additional impulses are tri-g gered by delayed afterdepolarizations (DAD) occu-r ring during the vulnerable phase,