© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Cellular mechanism of reentry induced by a strong electrical stimulus
Implications for fibrillation and defibrillation
Division of Cardiology, Department of Medicine, Cedars—Sinai Medical Center, Davis Research Bldg., Room 6066, 8700 Beverly Boulevard and the UCLA School of Medicine, Los Angeles, CA 90048, USA
* Corresponding author. Tel.: +1-310-423-7768; fax: +1-310-423-0291 karagueuzian{at}csmc.edu
Received 4 August 2000; accepted 12 November 2000
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Abstract |
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 Top Abstract 1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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The objective of this review article is to describe the graded response hypothesis of reentry induced by a strong single electrical stimulus in the normal canine ventricular myocardium. It is shown that the graded responses (subthreshold depolarization during phase 3 of the action potential) induced at a site distant (S2) from the regular S1–S1 pacing site, propagate slowly over short distances (
5 mm) and initiate a regenerative action potentials in recovered cells near the S1 site. Activation wave then blocks near the S2 site (unidirectional block) but reenters when the S2 site recovers it excitability. Super strong S2 currents do not induce reentry (upper limit of vulnerability). Since similar activation sequence and properties are shown to exist in intact canine hearts during induction of ventricular fibrillation with a similar S2 stimulus, the graded response hypothesis may have relevance to vulnerability to fibrillation. Furthermore, since the upper limit of vulnerability is closely related to defibrillation threshold, the graded response hypothesis might also be relevant to defibrillation mechanism. Other proposed mechanisms of fibrillation and defibrillation (critical point hypothesis, the progressive depolarization hypothesis and the hypothesis of phase singularity of defibrillation failure) are also discussed in this review paper and compared to the graded response hypothesis.
KEYWORDS Arrhythmia (mechanisms); Defibrillation; Sudden death; Ventricular arrhythmias
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1 Background and introduction |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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Ventricular fibrillation (VF) has been shown to be induced repeatedly in normal ventricles by a single, critically-timed electrical stimulus of an appropriate strength [1–4]. While extremely strong shocks may induce VF during any period of the cardiac cycle [5], criticality of the shock, both in terms of timing and strength, is crucial for VF induction. Shocks outside a well-defined time interval of the cardiac cycle (the vulnerable period) or shock, below or above certain electrical stimulus strengths known as the lower and upper limits of vulnerability (LLV and ULV, respectively) cannot induce VF. Three-dimensional computerized mapping studies in intact canine ventricles have shown that shock-induced VF in the normal ventricles is initiated by the immediate formation of a single functional reentrant wave front of excitation (scroll wave in 3-D or spiral wave in 2-D) which after two to four rotations, in the case of a point S2 stimulus, or up to ten rotations, in the case of a multiple linear array of S2 electrodes, breaks down into irregular wave fronts that signal the onset of VF [4,6]. While KCl solution was once used to transiently arrest fibrillation during surgery, defibrillation by means of electrical shocks, often delivered through an implantable cardioverter defibrillator (ICD), remains the most effective form of therapy today [7,8]. Computerized activation maps show that shocks otherwise successful often fail to terminate fibrillation on repeat trials. Detailed computerized studies suggest that failed defibrillation shocks, while terminating many of the reentrant and non-reentrant wave fronts of the VF, induce reentry (phase singularity) [9] at one or more ‘vulnerable’ sites which upon several rotations, could degenerate(s) to VF, causing the defibrillation to fail [10]. This phenomenon might appear counterintuitive. How is it possible to induce VF when in VF? The answer lies in the criticality of the timing and the strength of the shock relative to the recovery (i.e. relative refractory period) at one or more site(s) of the fibrillating ventricles. Should a shock of a critical strength (i.e. between the LLV and ULV) find a site or sites in the fibrillating ventricle in its or their relative refractory period (vulnerable period), reentry may be induced (phase singularity) [9]. During the ensuing rotations, the induced reentry undergoes an enhanced likelihood for breakup in the heterogeneously recovering ventricles leading to VF and failure of defibrillation. The phraseology used to describe the shock outcome clearly depends on the nature of the pre-shock rhythm. If the shock induces reentry during VF, then the phenomenon is described as ‘failed defibrillation shock,’ because VF will still be present after the shock. However, when reentry and VF are induced during sinus or regularly paced rhythm, the phenomenon is described as ‘vulnerability to VF.’ It is clear that a relationship, however implicit, does exist between a shock that fails to defibrillate a fibrillating ventricle and a shock that induces reentry and VF during a regular rhythm. The common link between failed defibrillation and induction of VF by a strong electrical stimulus in normal ventricles is then reduced to a precise mechanistic understanding as to how an electrical stimulus induces reentry in recovering normal ventricular cells. It could therefore be inferred from these paradigms that the mechanism of reentry formation by an electrical stimulus might be the same, whether the cells are recovering during VF or during normal sinus or regularly paced rhythm.
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2 Electrical shock, virtual electrode, fibrillation and defibrillation |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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A uniform finding in the defibrillation studies is the occurrence of an increased rate of successful defibrillation with increasing shock strengths [11,12]. According to the paradigms mentioned above, it is therefore not surprising that increasing shock strengths applied during regular rhythms should also decrease the vulnerability to reentry and VF. This inferred paradigm has not only been observed experimentally, but it also has been shown that a relatively close numerical similarity exists between the defibrillation threshold (DFT) and the ULV in animals [5,13], and man [14,15]. A shock strength just above the ULV (i.e. shock that can no longer induce reentry even if applied during the vulnerable period) is numerically similar to the DFT. The inference made from these studies is that successful defibrillation is analogous to a failure to induce reentry. Conversely, failed defibrillation is analogous to successful formation of reentry (phase singularity) [9,10,13]. Many insightful observations have been made using electrode and optical mapping techniques to explain how a critical shock induces reentry during regular rhythm or during VF. Taking advantage of the immunity of optical signals to shock-induced artifacts, it was shown that cathodal and anodal defibrillation shocks produce hitherto unrecognized patterns of cardiac polarization (virtual electrode effect), often characterized by the juxtaposition of depolarized and hyperpolarized regions on the surface of the ventricles [16–18]. It is therefore essential that the interaction of different cardiac polarizations induced by the S2 electrical stimulus with the recovering ventricular cells be taken into account in a hypothesis that seeks to elucidate the mechanism of reentry (phase singularity) formation [19,20]. It is apparent that an understanding of the cellular basis of shock-induced reentry in the normal ventricular myocardium could not only be useful in understanding vulnerability to VF but also could provide an insight into the cellular basis of defibrillation [21].
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3 Different proposed hypotheses for fibrillation and defibrillation |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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There are four proposed hypotheses for the fibrillation/defibrillation mechanism that while seemingly different from each other, are actually complimentary to each other. The first hypothesis, the ‘critical point hypothesis,’ was proposed by Frazier et al. [6] in Dr Ideker's laboratory, which showed that reentry by a strong electrical stimulus occurs at the intersection of a critical tissue refractoriness with a critical electrical field strength. The second hypothesis was proposed by Witkowsky et al. [22] who suggested that defibrillation shocks fail because certain regions of the fibrillating ventricles remain unaffected by the shock. Fibrillation will thus continue, provided the unaffected fibrillating region is of a critical mass. The third hypothesis was proposed by Kwaku and Dillon [23], who suggested that defibrillation success is related to the ability of the shock to increase refractoriness at the border of shock-depolarized areas so as to prevent wave front propagation from these areas after the shock. The fourth hypothesis was proposed by Efimov et al. [9], who showed that failed defibrillation results from the formation of post-shock reentry (phase singularity) induced by the combined interaction of virtual and real electrode polarization. Successful defibrillation results when shocks fail to induce reentry [9].
3.1 Discussion of these four proposed hypotheses
Since the seminal work of Zipes et al. [24], who for the first time extended Garrey's in vitro observations of the ‘critical mass’ hypothesis of fibrillation [25] to in situ ventricles, variants of the critical mass hypothesis of defibrillation have been formulated. Upon induction of progressively larger mass of myocardial tissue inexcitability by regional hyperkalemic depolarization, Zipes et al. [24] concluded that VF could be terminated when ‘the remaining number of excitable cells represented a critical mass insufficient to maintain fibrillation’. The concept of critical mass was extended to explain electrical defibrillation. Witkowsky et al. [22] maintained that for a shock to be successful, it must extinguish wave fronts only in a portion of the fibrillating ventricles, as post-shock ‘residual fibrillating activity’ in a mass smaller then the critical mass ‘can either go on to reinitiate global VF or not,’ depending on the surrounding tissue excitability. The probabilistic nature of defibrillation success argues against this tenet. The fact that a successful shock may fail to defibrillate on a subsequent trial in the same heart argues against the failed shock being unable to interact with more than a critical mass of myocardium. This is so because similar shock strengths, when successful, are claimed to interfere with all wave fronts in both ventricles without leaving out regions of the ventricle (i.e. ‘critical mass’) that remain unaffected by the shock. A variant of the critical mass hypothesis, the ‘progressive depolarization hypothesis’ was advanced by Dillon and Kwaku [26]. This hypothesis suggests that ‘the shock always produces a propagating impulse’ and that the likelihood of the induced propagating wave front ‘to run the risk of breaking down into fibrillation’ (failed defibrillation) will depend on how much myocardium is depolarized by the shock. Stronger shocks, it is argued, are less likely to be followed by fibrillation because the stronger shocks ‘progressively prolong and synchronize repolarization in an increasing fashion of the ventricle to antagonize the arrhythmic propagation of wave fronts present after the shock’ [26]. Stronger shocks, however, also increase the probability of inducing activation from partially recovered sites according to the strength—interval relationship that otherwise could not have been initiated with weaker shocks. The increased number of wave fronts in a setting with increased prolongation and synchronization of refractoriness increase the probability of wavebreaks and cause electrical defibrillation to fail. A third hypothesis of defibrillation, the ‘critical point,’ was proposed by Frazier et al. [6]. According to this hypothesis, for a shock to be successful, the shock must not create a critical point, where a critical extracellular voltage gradient (5 V/cm) intersects with critical tissue refractoriness [27]. Such states are presumed to underlie the mechanism of defibrillation failure because critical points lead to the formation of reentry and subsequent regeneration of fibrillation [6]. The ‘critical point’ hypothesis explains the mechanisms by which, the coupling interval and increasing shock strength move the location where reentry is formed (away from the shock electrode and pacing electrode, respectively) [28]. With a sufficiently high shock strength, the critical point is pushed outside of the heart, resulting in failure of reinducing VF (successful defibrillation). The fourth hypothesis, virtual electrode-induced phase singularity, was proposed by Efimov and co-workers [9,29]. According to this hypothesis, defibrillation fails when shock-induced virtual electrode polarization leads to reentry (phase singularity). Consequently, successful shock should not produce any phase singularities through the virtual electrode cardiac polarization phenomenon. Kwaku and Dillon [23], however, failed to observe phase singularities or critical points in more than 95% of the failed defibrillation shocks. It needs to be mentioned that none of the proposed hypotheses of fibrillation/defibrillation provides a quantitative or specific cellular descriptor of vulnerability to reentry by an electrical shock.
Our proposed propagated graded response hypothesis of vulnerability (fifth hypothesis) is not only compatible with the proposed four hypotheses but also offers a concise cellular basis (the missing link) [30] for the formation and prevention of functional reentry induced by an electrical stimulus. The graded response hypothesis of origination of earliest activation away from the stimulating electrode gained renewed interest as it offered a satisfactory explanation to older and newer findings on shock outcomes. First described by van Dam et al. [31] in Dr Hoffman's laboratory, the propagated graded response hypothesis explains how the earliest site of activation might arise distant from the stimulating electrode [6,32], and is compatible with the presence of an isoelectric interval preceding activation after a failed defibrillation shock [10]. Lastly but not least, the graded response hypothesis explains the presence of a vulnerable period and the ULV for reentry formation, which cannot be explained exclusively by the virtual electrode phenomenon because of the independence of virtual electrode polarization from the underlying vulnerable period (cardiac cycle) [16,18].
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4 The graded response hypothesis vs. fibrillation/defibrillation mechanisms |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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The graded response hypothesis is compatible with the following eight reported major characteristics and observations relative to the vulnerability of the normal ventricular myocardium to shock-induced reentry. All studies on the graded response hypothesis were conducted in dogs in conformity with the Guide for the Care and Use and Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The graded response hypothesis:
- 1. Describes the sequence of cellular events through which a critical electrical shock leads to reentry.
- 2. Elucidates the need for critical shock amplitude (i.e. between LLV and ULV).
- 3. Explains the need for critical shock timing (i.e. the vulnerable period).
- 4. Provides a mechanism for break excitation, a phenomenon commonly associated with shock-induced reentry in the normal myocardium.
- 5. Elucidates the mechanism by which the earliest activation after a stimulus arises from a low voltage gradient area away from the stimulating electrode.
- 6. Describes the vulnerability mechanism by incorporating virtual electrode cardiac polarization.
- 7. Provides an insight to why the ULV and the DFT are numerically close to each other.
- 8. Suggests a plausible scenario as to why biphasic shocks are more effective than monophasic shocks in terminating VF.
- 2. Elucidates the need for critical shock amplitude (i.e. between LLV and ULV).
4.1 Sequence of cellular events through which a critical electrical shock leads to reentry
4.1.1 Graded response characteristics
Graded response or progressive cellular depolarization is a property of cardiac cells that is manifested when a strong electrical stimulus is applied during the relative refractory period [33,34]. The term ‘graded’ [33] or ‘progressive’ indicates that the response is not an all-or-none phenomenon. The graded response differs from an action potential by its low amplitude and slow rate of rise. The properties of the graded responses vary as a function of the stimulus characteristics [33,34] and to some degree of transmembrane voltage as well [35]. For a given coupling interval, a progressive increase in the strength of the current progressively increases the amplitude and duration of the depolarizing responses [35]. Fig. 1 illustrates an example. Similarly, for a given stimulus current intensity, the more negative the transmembrane potential the higher the amplitude and duration of the graded response [35]. Graded responses lengthen the refractory period by a duration equal to the additional repolarization time caused by the depolarizing graded response. Fig. 2 illustrates an example of graded-response induced prolongation of the refractory period. Depolarizing graded responses have the ability to propagate, albeit slowly and poorly (decremental propagation) [31,34,35]. In addition, the propagation appears anisotropic as the wave of graded response depolarization reaches longer distances along than across the fiber [35]. An important consequence of propagating graded responses is the initiation of a regenerative response in recovered cells when the propagated depolarizing graded response amplitude reaches threshold in the recovered cells [31,35,36]. Fig. 3 illustrates an example of graded response-induced action potential in a recovered cell some 5 mm away from the S2 source. Two simultaneous cell recordings are shown with a strong electrical point stimulus (S2) applied near Cell 1 evoking a graded response in Cell 1 and an action potential in the more recovered Cell 2 (located near the S1–S1 pacing site and 5 mm away from Cell 1). The action potential induced away from the point stimulus site (break excitation) propagates in all directions but blocks at the S2 site where the refractory period is most prolonged by virtue of the longer duration graded response at the S2 site (source). However, the wave front propagates around the site of block to reenter from this very site as it recovers its excitability, forming the first reentrant activation. Fig. 4 shows this sequence of events with two simultaneous microelectrode recordings and Fig. 5 uses electrode activation maps to show how an S2 initiates activation distal to the stimulus site with unidirectional block developing at the S2 site and subsequent reentry through the original site of block (site of unidirectional block). Reentry in this model could be single or double arm (figure eight) depending on tissue geometry and size.
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This sequence of events recorded in isolated canine epicardial slices demonstrates step by step how an S2 stimulus induces reentry by the propagating ‘wave’ of graded responses. Since similar stimulation protocols, stimulation sites and electrode configurations also induce similar functional reentrant activations (which precede VF) in the in situ normal canine hearts, the graded response hypothesis of vulnerability to reentry (precursor of VF) is therefore also operative in the intact heart [4,32].
4.2 Criticality of the electrical stimulus strength
Reentry could be induced only when the current strength of the S2 was above (LLV) and below (ULV) two well-defined values. Current strengths falling outside this range could not induce reentry even if the current was applied during the vulnerable period. These findings are compatible with earlier reports of reentry induction by an S2 in isolated tissues [35,37], in in situ ventricles at the onset of VF [3,4], and in humans [15].
4.3 Criticality of the electrical stimulus timing
Vulnerability to reentry using similar electrode configurations and stimulation protocols as those used during cellular graded response measurements showed that the vulnerability to VF was critically dependent on the timing of the S2 stimulus. The S1–S2 coupling intervals that initiated reentry (‘vulnerable period’) both in vitro [35] and in vivo [4] are confined to the period that precede the refractory period by up to 50 ms (the relative refractory period). An S2 applied outside the vulnerable period fails to induce reentry.
4.4 Break excitation
The graded response hypothesis of vulnerability to reentry formation by an S2 is based on the slowly propagating graded response initiating (after a delay) activation in the recovered cells located away from the physical dimensions of the S2 electrode. The conduction time needed for the depolarizing wave of the graded responses to travel from the S2 electrode site to recovered cells and evoke a regenerative action potential unambiguously explains this delay in excitation after a critical S2 [35]. This delay forms the basis of break excitation that is often present after a critical S2 induces reentry in normal myocardium [30,38]. A delay observed in post-shock activation for the induction of reentry during regular rhythm is also present after a failed defibrillation shock [10]. Three-dimensional mapping studies showed that following an unsuccessful shock a period of about 60 ms electrical quiescence (‘isoelectric window’), never recorded during free-running VF, ensues [10]. After this transient period of quiescence, an activation wave front (break excitation) that may lead to reentry [9] and reinitiation of VF [10] is initiated. However, it is not clear if this quiescent period is caused by propagating graded responses as no multisite microelectrode data are available (see Limitation below).
4.5 Earliest site of activation arises in low voltage gradient areas
In our in vitro model of reentry the earliest activation after a premature S2 stimulus arises away from the S2 stimulus site and close to more recovered cells [35]. Since the voltage gradient at the source of the stimulating electrical current is the highest and diminishes at distances away from the S2 source [39], the graded response hypothesis of vulnerability to reentry is therefore compatible with the reported findings that the earliest post-shock activation in normal in situ canine hearts arises away from current source [4,10,32].
4.6 Virtual electrode effect and vulnerability to reentry
Unipolar stimulation in bidomain models [17,40] showed that under a cathode, the contours of transmembrane potential form a ‘dog bone’ of depolarization with two areas of hyperpolarization on both sides of the dog-bone. These areas of hyperpolarization are called virtual electrodes [17,40]. During unipolar anodal stimulation, a dog-bone of hyperpolarization forms with two virtual electrodes of depolarization on both sides of the dog-bone [17,40]. More recently, it was found using optical mapping that bipolar stimulation, as was done in studies designed to characterize the graded responses, also induces virtual electrode polarization that is quite analogous to the virtual electrode polarization observed during unipolar stimulation [41]. Adjacent to each real electrode polarization (depolarization at the cathode side of the bipole and hyperpolarization at the anode side of the bipole), virtual electrode polarization of opposite polarity develops [41]. A question may then arise if the proposed graded response hypothesis of reentry formation is compatible with the presence of the virtual electrode polarization effect. The answer to this question is yes. The virtual anode that develops near the real cathode of the bipole used in our graded response studies accelerates cellular repolarization and provides a greater opportunity for the depolarizing wave of graded responses induced by the real cathode to encounter recovered cells and initiate an activation. Recent simulation studies using a two-dimensional bidomain model and unipolar stimulation with juxtaposition of real electrode depolarization and virtual electrode hyperpolarization replicated the figure eight reentry that was observed with bipolar stimulation in isolated canine epicardial tissue slices [38]. Consequently, the presence of an adjacent hyperpolarized zone (virtual anode) near the depolarizing cathode (real cathode) of the bipole (side at which the earliest activation occurs) is highly compatible with the graded response hypothesis of vulnerability to reentry and fully takes into account the phenomenon of virtual electrode polarization [38]. Furthermore, these findings demonstrate that the graded response hypothesis of reentry, first formulated using bipolar stimulation, is also operative for unipolar stimulation as well [38].
4.7 ULV and DFT numeric similarities
Based upon the observation that defibrillation shocks fail because shock induces reentry formation [9], it could then be inferred that for a defibrillation shock to be successful, the shock must fail to produce reentry. Our in vitro mapping studies show that shock strengths just above the ULV fail to produce reentry during regular pacing and that the graded response hypothesis of vulnerability to reentry [35] can adequately explain the failure to produce reentry. Super-strong S2 electrical currents associated with the longer graded response duration and refractoriness become so excessive that the distally originated activation wave front cannot reenter while undergoing block (wavebreak) at the S2 site. This is because the rotating wavebreak undergoes block in the retrograde direction due to excessive prolongation of the refractory period at the S2 site, which converts the unidirectional block to bidirectional block, causing failure of reentry [35]. Fig. 6 shows two simultaneous cell recordings with an S2 below the ULV causing reentry and a super-strong (above the ULV) S2 that fails to induce reentry because of the conversion of unidirectional block to bidirectional block. A high resolution electrode activation map verified the presence of bidirectional block with super-strong S2 current strength [35].
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The stronger current that converts unidirectional block to bidirectional block can prevent the formation of reentry during regular rhythm (ULV) or during VF (successful defibrillation). It is apparent then how the ULV is similar to the defibrillation threshold.
4.8 Monophasic vs. biphasic shocks
It is now common knowledge that biphasic shocks are more effective than monophasic shocks in terminating VF [42–46]. While the precise mechanism of such an effect still remains somewhat elusive, the graded response hypothesis might tentatively provide a plausible explanation for such an effect. Focusing on the phenomenon of conversion from unidirectional to bidirectional block by super-strong currents, the hyperpolarizing effect induced by the real electrode effect of the biphasic shock accelerates repolarization of cells in their plateau phase where no graded or only a short duration graded response could be induced. The induced acceleration of repolarization by the hyperpolarizing phase of the biphasic shock can then be followed by depolarizing graded responses from adjoining real and virtual depolarized areas, causing lengthening of the total repolarization time and a net increase in refractoriness. This net increase in refractoriness that otherwise might be absent with a monophasic shock might prevent propagation of an induced reentrant wave front or else convert unidirectional block to bidirectional block, preventing reentry formation. This scenario, however plausible, still remains speculative as the greater efficacy of biphasic shocks may not necessarily be associated with ERP lengthening [46] (see Limitations).
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5 Ionic mechanisms, channel block and defibrillation threshold |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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The ionic mechanism(s) of the graded response remain(s) undefined. It is possible that both passive and active ionic mechanisms may participate in the depolarizing process after a strong premature electrical stimulus [34]. Passive capacitative currents may be present during the slowly rising phase of the graded response because it is unlikely that the impedance during such slow dV/dt is purely ohmic. However, two properties of the graded responses argue against an exclusively passive mechanism. One is the voltage dependence of the graded response amplitude and duration, i.e. the increase in amplitude and duration with increasing voltage negativity and the decrease at positive transmembrane voltages [16,35]. The second property is the incompatibility of the voltage decay pattern of the graded response amplitude along the fiber with the measured space constants (0.9–1.2 mm) [47]. Although the nature of the active currents involved in the generation of the graded response remains undefined, it is possible that some sodium channels and/or calcium channels may be ‘forced’ to be reactivated by the strong S2 depolarizing currents. Block of such cationic channels may decrease the amplitude and the duration of the graded responses; however, such channel blockade may also influence refractoriness, making prediction of drug action on the vulnerability to reentry by an electrical stimulus and by inference on the DFT a difficult task. It is now the norm to evaluate the concomitant use of antiarrhythmic drugs and ICDs in each patient individually to determine the effect of the selected drug on the DFT.
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6 Limitations |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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There are two limitations to the graded response hypothesis of vulnerability.
The lack of greater ERP prolongation with biphasic shocks over monophasic shocks while increasing the success rate of defibrillation is not compatible with the graded response hypothesis [46]. The graded response hypothesis of the ULV proposes induction of bidirectional block to prevent reentry. While there may be in absolute terms greater ERP prolongation with monophasic shocks, areas that were not prolonged or only minimally prolonged with monophasic shocks may manifest a net increase in their ERP with biphasic shocks leading to bidirectional block and prevention of reentry. More studies are needed to clarify this issue. The second limitation is the difficulty in using optical action potentials if graded response propagation was present during the post-shock isoelectric interval in cases of failed defibrillation. Optical action potentials representing space averaged multicellular signals may not correctly identify single cell graded responses from a regenerative response especially during fibrillation when the amplitude of the regenerative action potential is relatively small. Perhaps multiple simultaneous microelectrode recordings would be necessary to conclusively demonstrate the presence of graded responses. Finally in cases where very strong electrical stimuli induce VF or fail to terminate VF by inducing an automatic mechanism, then the graded response hypothesis of vulnerability would fail.
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7 Conclusions |
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TopAbstract1 Background and introduction2 Electrical shock, virtual...3 Different proposed hypotheses...4 The graded response...5 Ionic mechanisms, channel...6 Limitations7 ConclusionsReferences |
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The graded response hypothesis of vulnerability to reentry explains step-by-step how a critical electrical stimulus interacts with an activation wave to either succeed or fail in inducing reentry. The outcome of the interaction between a given shock and an activation wave appears to be independent of the origin of the activation wave. The demonstration that reentry can be induced by a critical shock during regular pacing and during VF supports this contention. Given the ability of the graded response hypothesis to adequately explain the cellular basis of reentry formation for both in vitro and in vivo settings, it is highly likely that reentry (phase singularity) formation by a failed defibrillation shock may also be explained by graded responses. That failed shocks may induce propagating graded responses that find recovered cells and induce activation leading to reentry and VF is strongly suggested by the presence of a period of quiescence after the failed shock and before VF resumes [10]. Our recent optical mapping studies confirmed that the period of quiescence after a failed shock is unrelated to amplifier saturation and reflects a true tissue characteristic [48]. This period of quiescence is compatible with the subthreshold wave of propagating graded responses. More work is needed to verify this claim.
The ability of post-shock activation wave fronts to either evolve to more complex patterns (breakup) or undergo block and extinction signals failure or success of defibrillation, respectively. A word must be mentioned on type-B successful defibrillation, where two to three post-shock activation cycles precede VF termination. Here, the post-shock rotation period is significantly slower than the post shock period of failed defibrillation [10]. Slower rotation period is less likely to undergo breakup according to the action potential duration restitution hypothesis [49] and thus may not induce VF [50]. It is highly likely that shocks causing type B successful defibrillation may induce larger areas of block because the stimulus causes the formation of a larger reentry core size and thus longer periods [51,52].
Time for primary review 28 days.
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Acknowledgements |
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We greatly appreciate Nina Wang for the final editing of the manuscript and Elaine Lebowitz for secretarial assistance. Supported in part by AHA National Center Grant-in-Aid 9750623N and 9950464N; the Cedars—Sinai ECHO Foundation and Grand Sweepstakes, UC Tobacco Related Disease Research Program (9RT-0041), NIH Specialized Center of Research (SCOR) Grant in Sudden Death (HL52319), RO1 HL 66389 and the Pauline and Harold Price Endowment.
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