Isoelectric Window Research Articles

Tunnel propagation following defibrillation with ICD shocks: Hidden postshock activations in the left ventricular wall underlie isoelectric window

After near-defibrillation threshold (DFT) shocks from an implantable cardioverter-defibrillator (ICD), the first postshock activation that leads to defibrillation failure arises focally after an isoelectric window (IW). The mechanisms underlying the IW remain incompletely understood. The goal of this study was to provide mechanistic insight into the origins of postshock activations and IW after ICD shocks, and to link shock outcome to the preshock state of the ventricles. We hypothesized that the nonuniform ICD field results in the formation of an intramural excitable area (tunnel) only in the left ventricular (LV) free wall, through which both pre-existing and new shock-induced wavefronts propagate during the IW. Simulations were conducted using a realistic three dimensional (3D) model of defibrillation in the rabbit ventricles. Biphasic ICD shocks of varying strengths were delivered to 27 different fibrillatory states. After near-DFT shocks, regardless of preshock state, the main postshock excitable area was always located within LV free wall, creating an intramural tunnel. Either pre-existing fibrillatory or shock-induced wavefronts propagated during the IW (duration of up to 74 ms) in this tunnel and emerged as breakthroughs on LV epicardium. Preshock activity within the LV played a significant role in shock outcome: a large number of preshock filaments resulted in an IW associated with tunnel propagation of pre-existing rather than shock-induced wavefronts. Furthermore, shocks were more likely to succeed if the LV excitable area was smaller. The LV intramural excitable area is the primary reason for near-DFT failure. Any intervention that decreases the extent of this area will improve the likelihood of defibrillation success.

Tunnel Propagation of Postshock Activations as a Hypothesis for Fibrillation Induction and Isoelectric Window

Comprehensive understanding of the ventricular response to shocks is the approach most likely to succeed in reducing defibrillation threshold. We propose a new theory of shock-induced arrhythmogenesis that unifies all known aspects of the response of the heart to monophasic (MS) and biphasic (BS) shocks. The central hypothesis is that submerged "tunnel" propagation of postshock activations through shock-induced intramural excitable areas underlies fibrillation induction and the existence of isoelectric window. We conducted simulations of fibrillation induction using a realistic bidomain model of rabbit ventricles. Following pacing, MS and BS of various strengths/timings were delivered. The results demonstrated that, during the isoelectric window, an activation originated deep within the ventricular wall, arising from virtual electrodes; it then propagated fully intramurally through an excitable tunnel induced by the shock, until it emerged onto the epicardium, becoming the earliest-propagated postshock activation. Differences in shock outcomes for MS and BS were found to stem from the narrower BS intramural postshock excitable area, often resulting in conduction block, and the difference in the mechanisms of origin of the postshock activations, namely intramural virtual electrode-induced phase singularity for MS and virtual electrode-induced propagated graded response for BS. This study provides a novel analysis of the 3D mechanisms underlying the origin of postshock activations in the process of fibrillation induction by MS and BS and the existence of isoelectric window. The tunnel propagation hypothesis could open a new avenue for interventions exploration to achieve significantly lower defibrillation threshold.

Post‐Shock Synchronized Pacing in Isolated Rabbit Left Ventricle: Evaluation of a Novel Defibrillation Strategy

A failed near-threshold defibrillation shock is followed by an isoelectric window (IEW) and rapid repetitive responses that reinitiate ventricular fibrillation (VF). We hypothesized that properly timed (synchronized) postshock pacing stimuli (SyncP) may capture the recovered tissues during the repetitive responses and prevent postshock reinitiation of VF, resulting in improved defibrillation efficacy. We explored the effect of postshock SyncP on defibrillation efficacy in isolated rabbit hearts (n = 12). Optical recording-guided real-time detection and electrical stimulation (5 mA) of recovered tissues in anterior/posterior left ventricle (LV) were performed following IEW. The IEW duration was found to be 69 +/- 13 ms. With the same shock strength, successful and failed defibrillation episodes were associated with 50% and 15% of the myocardium, respectively, captured by the SyncP (P < 0.001). Electrical stimulation from the posterior LV resulted in 75% of episodes capturing myocardium, as compared with anterior LV stimulation (55%; P < 0.01) and higher successful defibrillation rate (14%, posterior vs. 3%, anterior LV). The overall success in terminating VF by postshock SyncP was approximately 10%. The causes for failed myocardium capture by postshock SyncP included lack of IEW after low-strength shock (42.9%), incorrect locations of reference site (25.7%) and pacing electrodes (17.9%), and others, such as wave breakthroughs (13.5%). Postshock SyncP was feasible and the larger the myocardium captured area, the more likely was the successful defibrillation. Postshock SyncP delivered to the posterior LV was more effective than anterior LV to terminate VF.

Mechanistic enquiry into the effect of increased pacing rate on the upper limit of vulnerability

The goal of this study is to investigate the mechanisms responsible for the increase in the upper limit of vulnerability (ULV; highest shock strength that induces arrhythmia) following the increase in pacing rate. To accomplish this goal, the study employs a three-dimensional bidomain finite element model of a slice through the canine ventricles. The preparation was paced eight times at a basic cycle length (BCL) of either 80 or 150ms followed by delivery of shocks of various strengths and timings. Our results demonstrate that the shock strength, which induced an arrhythmia 50% of the time, increased 20% for the faster pacing compared to the slower pacing. Analysis of the mechanisms underlying the increased vulnerability revealed that delayed post-shock activations originating in the tissue depths appear as breakthrough activations on the surfaces of the preparation following an isoelectric window (IW). However, the IW duration was consistently shorter in the faster-paced preparation. Consequently, breakthrough activations appeared on the surfaces of this preparation earlier, when the tissue was less recovered, resulting in higher probability of unidirectional block and reentry. This explains why shocks of the same strength were more likely to result in arrhythmia induction when delivered to a preparation that was rapidly paced.

Characterization of the relationship between preshock state and virtual electrode polarization-induced propagated graded responses resulting in arrhythmia induction

Studies have demonstrated that failed defibrillation shocks often are followed by an electrically quiescent period (isoelectric window); however, the underlying mechanisms remain incompletely understood. We recently suggested a new mechanism termed "virtual electrode polarization-induced propagated graded responses" (VEPiPGRs) that might play a role in the origin of the global postshock activation following the isoelectric window. The purpose of this study to elucidate the circumstances under which VEPiPGR activations originate for shocks given to paced right ventricular preparations. Specifically, we examined the dependence of VEPiPGRs on coupling interval (CI) and shock polarity and whether VEPiPGRs emerge preferentially on the epicardium or the endocardium. Simultaneous endocardial and epicardial activity in isolated right ventricular preparations (n = 4) was imaged optically following shocks of strength +/-5A. All VEPiPGRs were analyzed, and the time T from shock end to activation onset was recorded (isoelectric window is the smallest T among activations that propagated globally). VEPiPGR activations occurred for CIs in the range from 80 to 150 ms. Average duration of T was 64.5 +/- 18.15 ms, with T decreasing as CI increased (Tmax = 82 ms, Tmin = 46 ms, linear-fit slope = -0.675). The average earliest CI at which cathodal (+5A) shocks resulted in VEPiPGRs was 87 ms compared with 116 ms for anodal (-5A) shocks. All VEPiPGR activations emerged first on the epicardium in a focal pattern, and all induced ventricular fibrillation. The global activation that terminates the isoelectric window could result from VEPiPGRs that find an exit pathway. VEPiPGRs originate at the sites of maximum action potential abbreviation by the shock, always on the epicardium for the preparation used here.

The Puzzle of Defibrillation: Putting the Pieces Together

Try the following: induce fibrillation in a pig heart, shock it using a strength just below the defibrillation threshold, and then watch what happens. When Chattipakorn et al.1 performed this experiment, they observed nothing at all for about 60 msec after the shock (the “isoelectric window”). Then, a postshock response “arose on the epicardium from a single region in the anteroapical [left ventricle].”1 In other words, a wave front originated focally after a delay. Why? Perhaps early or delayed afterdepolarizations caused this behavior. Chattipakorn and Ideker2 tested this hypothesis, and found that the drug Flunarizine—a delayed afterdepolarization inhibitor—lowered the defibrillation threshold, suggesting that indeed afterdepolarizations induced the postshock response. In this issue of the Journal, Zheng et al.3 reexamine the same hypothesis and draw the opposite conclusion: neither flunarizine nor pinacidil—an early afterdepolarization inhibitor—lower the defibrillation threshold, nor do they influence the location and timing of the postshock focus, implying that “these foci are not caused by triggered activity.”3 What do we make of this inconsistency? Zheng et al. honestly admit “it is unclear why the results in the two studies differ.”3 The discrepancy makes me wish they had used more pigs (only 6 received flunarizine in each study). However, in this editorial, I will assume Zheng et al. are correct: Flunarizine and pinacidil do not influence their results, implying that afterdepolarizations do not trigger foci. If not afterdepolarizations, then what is the reason for the isoelectric window and the focal postshock response? This question is significant, because it bears upon the mechanism of defibrillation, which is notoriously difficult to understand. Like those blind Indostanians, different researchers using different techniques have come to different conclusions about how defibrillation works.4 Currently, scientists study defibrillation using three methods: epicardial mapping of the extracellular voltage (the technique employed by Zheng et al.), optical mapping of the transmembrane voltage, and numerical simulation. Let us see what each tells us. During epicardial mapping, the heart is covered by an elastic sock containing hundreds of electrodes that record the extracellular voltage. These recordings contain information about the location and timing of depolarization wave fronts. Chattipakorn et al.5 examined the isoelectric window using epicardial mapping, and found that it “was not electrically silent.” Locally propagated activations appeared earlier

Shock-induced epicardial and endocardial virtual electrodes leading to ventricular fibrillation via reentry, graded responses, and transmural activation.

The mechanism of ventricular fibrillation (VF) induction by T wave shocks has been attributed to reentry, propagated graded responses (PGR), and triggered activity. The limitation of recording transmembrane potential (V(m)) from only a single surface has hampered efforts to elucidate the relative role of these phenomena and their relationship to shock-induced virtual electrodes. V(m) patterns from epicardial and endocardial surfaces of isolated sheep right ventricles were recorded with two CCD cameras for monophasic (M) and biphasic (B) shocks delivered at various coupling intervals (CI) from a unipolar mesh electrode on the epicardium. VF was induced via (1) the formation of reentry following make or break excitation; (2) propagated graded responses during apparent isoelectric window; and (3) breakthrough activation patterns coincident with endocardial-to-epicardial gradients in V(m). M shocks depolarized both surfaces at long CIs and polarized epicardial and endocardial surfaces oppositely at short CIs. At intermediate CIs, postshock V(m) patterns could lead to reentry on one surface or endocardial-to-epicardial gradients resulting in breakthrough. B induced VF less than M for short and intermediate CIs due to more homogeneous end-shock V(m) patterns. However, at long CIs these homogeneous patterns resulted in more VF induction because B left the tissue closer to the V(m) threshold for propagation. Postshock activity occurred either immediately via epicardial or endocardial reentry, or after a delay caused by transmural propagation or propagated graded responses. These findings could explain the isoelectric window and focal activation patterns observed on the epicardium following VF induction shocks.

Mechanistic inquiry into decrease in probability of defibrillation success with increase in complexity of preshock reentrant activity.

Energy requirements for successful antiarrhythmia shocks are arrhythmia specific. However, it remains unclear why the probability of shock success decreases with increasing arrhythmia complexity. The goal of this research was to determine whether a diminished probability of shock success results from an increased number of functional reentrant circuits in the myocardium, and if so, to identify the responsible mechanisms. To achieve this goal, we assessed shock efficacy in a bidomain defibrillation model of a 4-mm-thick slice of canine ventricles. Shocks were applied between a right ventricular cathode and a distant anode to terminate either a single scroll wave (SSW) or multiple scroll waves (MSWs). From the 160 simulations conducted, dose-response curves were constructed for shocks given to SSWs and MSWs. The shock strength that yielded a 50% probability of success (ED(50)) for SSWs was found to be 13% less than that for MSWs, which indicates that a larger number of functional reentries results in an increased defibrillation threshold. The results also demonstrate that an isoelectric window exists after both failed and successful shocks; however, shocks of strength near the ED(50) value that were given to SSWs resulted in 16.3% longer isoelectric window durations than the same shocks delivered to MSWs. Mechanistic inquiry into these findings reveals that the two main factors underlying the observed relationships are 1) smaller virtual electrode polarizations in the tissue depth, and 2) differences in preshock tissue state. As a result of these factors, intramural excitable pathways leading to delayed breakthrough on the surface were formed earlier after shocks given to MSWs compared with SSWs and thus resulted in a lower defibrillation threshold for shocks given to SSWs.

Mechanisms of shock-induced arrhythmogenesis during acute global ischemia.

Little is known about the mechanisms of vulnerability and defibrillation under ischemic conditions. We investigated these mechanisms in 18 Langendorff-perfused rabbit hearts during 75% reduced-flow ischemia. Electrical activity was optically mapped from the anterior epicardium during right ventricular shocks applied at various phases of the cardiac cycle while the excitation-contraction decoupler 2,3-butanedione monoxime (BDM; 15 mM) was used to suppress motion artifacts caused by contraction of the heart. During ischemia, vulnerable window width increased [from 30-90% of the action potential duration (APD) in the control to -10 to 100% of the APD in ischemia]. Moreover, arrhythmia severity increased along with the reduction of APD (176 +/- 9 ms in control and 129 +/- 26 ms in ischemia, P < 0.01) and increased dispersion of repolarization (45 +/- 17 ms in control and 73 +/- 28 ms in ischemia, P < 0.01). Shock-induced virtual electrode polarization was preserved. Depolarizing (contrary to hyperpolarizing) response time constants increased. Virtual electrode-induced wavefronts of excitation had much more tortuous pathways leading to wavefront fractionation. Defibrillation failure at all shock strengths was observed in four hearts. Optical mapping revealed that the shock extinguished the arrhythmia; however, the arrhythmia self-originated after an isoelectric window of 339 +/- 189 ms. In conclusion, in most cases, virtual electrode-induced phase singularity (VEIPS) was responsible for shock-induced arrhythmogenesis during acute global ischemia. Enhancement of arrhythmogenesis was associated with an increased dispersion of repolarization and altered deexcitation. In four hearts, arrhythmogenesis could not be explained by VEIPS.

Optical Mapping of Ventricular Defibrillation in Isolated Swine Right Ventricles

Investigators who studied ventricular defibrillation by use of optical mapping techniques failed to observe an initial defibrillation event (isoelectric window or quiescent period) shown by electrode mapping studies. This discrepancy has important implications for the mechanisms of defibrillation. The purpose of the present study was to demonstrate an optical equivalent of an isoelectric window after a near-threshold defibrillation shock. Methods and Results-- We studied 10 isolated, perfused swine right ventricles. Upper limit of vulnerability was determined by shocks on T waves. A 50% probability of successful defibrillation (DFT50) was determined with an up-down algorithm. Immediately after unsuccessful defibrillation shock, new wavefronts were generated. When the shock strength was low, immediate reinitiation of reentry and ventricular fibrillation might occur without a postshock isoelectric window. However, if the shock strength was within 50 V of DFT50 (near-threshold), a synchronized activation occurred, followed by organized repolarization that ended 64+/-18 ms after shock. After a period of quiescence (18+/-24 ms), activation recurred 83+/-33 ms after shock and reinitiated ventricular fibrillation. Similar patterns of activation, including a quiescent period, were observed after shock was applied on the T wave of the paced beat that induced ventricular fibrillation. Upper limit of vulnerability correlated well with DFT50. In isolated swine right ventricles, an optical equivalent of an isoelectric window exists after near-threshold defibrillation shocks. These findings support the idea that a near-threshold defibrillation shock terminates all activation wavefronts but fails to halt ventricular fibrillation because the same shock reinitiates ventricular fibrillation after an isoelectric window.

Comparison of activation during ventricular fibrillation and following unsuccessful defibrillation shocks in open-chest dogs.

The purpose of this study was to map in detail the spread of activation away from sites of early postshock excitation following unsuccessful defibrillation to determine whether these activation fronts are the unaltered continuation of activation fronts present just before the shock. We recorded simultaneously from 120 bipolar electrodes on 40 plunge needles in a 20 x 35 x 5-mm volume of tissue of the right ventricular outflow tract immediately before and after shocks of 190-350 V were given via electrodes on the right atrium and left ventricular apex to six open-chest dogs with electrically induced ventricular fibrillation. For 20 shocks approximately 100 V below the defibrillation threshold, the site of earliest recorded activation following the shock was near the center of the mapped region. At the earliest recorded activation sites, there was an isoelectric window in the immediate postshock period lasting 42 +/- 15 msec after which activation fronts either spread away from a site in all directions in a focal pattern (12 episodes) or else spread away in only one direction (eight episodes). Comparison of activation patterns immediately before and after the shock revealed that in 18 of the 20 episodes, the location and pathway of activation fronts after the shock were markedly different from those before the shock. The preshock intervals at the sites of earliest activation following the shock, that is, the interval between the last activation at the site and the time of the shock, were not randomly distributed but were similar, averaging 64 +/- 11 msec, and were negatively correlated with the isoelectric postshock window (r = -0.70, p = 0.0001). These findings indicate that the presence and the site of origin of activation fronts after the shock are influenced by at least two factors: the shock itself and the electrophysiological state of the myocardium at the time of the shock. Thus, epicardial shocks approximately 100 V below the defibrillation threshold markedly alter the activation sequences of fibrillation but are unsuccessful because the activation fronts following the shock reinitiate fibrillation.

Activation during ventricular defibrillation in open-chest dogs. Evidence of complete cessation and regeneration of ventricular fibrillation after unsuccessful shocks.

To test the hypothesis that a defibrillation shock is unsuccessful because it fails to annihilate activation fronts within a critical mass of myocardium, we recorded epicardial and transmural activation in 11 open-chest dogs during electrically induced ventricular fibrillation (VF). Shocks of 1-30 J were delivered through defibrillation electrodes on the left ventricular apex and right atrium. Simultaneous recordings were made from septal, intramural, and epicardial electrodes in various combinations. Immediately after all 104 unsuccessful and 116 successful defibrillation shocks, an isoelectric interval much longer than that observed during preshock VF occurred. During this time no epicardial, septal, or intramural activations were observed. This isoelectric window averaged 64 +/- 22 ms after unsuccessful defibrillation and 339 +/- 292 ms after successful defibrillation (P less than 0.02). After the isoelectric window of unsuccessful shocks, earliest activation was recorded from the base of the ventricles, which was the area farthest from the apical defibrillation electrode. Activation was synchronized for one or two cycles following unsuccessful shocks, after which VF regenerated. Thus, after both successful and unsuccessful defibrillation with epicardial shocks of greater than or equal to 1 J, an isoelectric window occurs during which no activation fronts are present; the postshock isoelectric window is shorter for unsuccessful than for successful defibrillation; unsuccessful shocks transiently synchronize activation before fibrillation regenerates; activation leading to the regeneration of VF after the isoelectric window for unsuccessful shocks originates in areas away from the defibrillation electrodes. The isoelectric window does not support the hypothesis that defibrillation fails solely because activation fronts are not halted within a critical mass of myocardium. Rather, unsuccessful epicardial shocks of greater than or equal to 1 J halt all activation fronts after which VF regenerates.