THE ANATOMICAL RECORD 201:179-188 (1981) The Mechanism of AV Junctional Reentry: Role of the AtrioNodal Junction TODOR MAZGALEV, LEONARD S. DREIFUS, JOHN BIANCHI, AND ERIC L. MICHELSON Departments of Medicine and Physiology of the Jefferson Medical College of the Thomas Jefferson University and the Lankenav-Hospital, Philadelphia, Pennsyfvania ABSTRACT Mapping of atrial-AV nodal (AVN)activation patterns was performed in 10 superfused rabbit AVN preparations utilizing 3 bipolar electrodes placed simultaneously a t the crista terminalis (CT),interatrial septum (IAS) and His bundle (H) regions in close proximity to the AVN, along with two or three microelectrodes in the AN, N and NH regions of the AVN. Basic and premature stimuli were introduced a t either or both the CT and IAS regions of the AVN. The timing of the premature stimuli was varied to induce close interaction of inputs to the AVN. Summation andlor cancellation, as evidenced by changes in the morphology of the action potentials and alteration of Hl-HZ intervals, were observed. Apparent reentry phenomena could be induced or terminated by appropriately timed stimulation a t the CT and IAS inputs. Reentry was critically related to both the patterns and timing of the spread of excitation within AVN and surrounding atrial tissue. Slow conduction and unidirectional block were observed in various portions of the reentry circuit. It is concluded that 1) interaction between input waves engaging the AVN produced either summation or fragmentation; 2 ) slow conduction and reentry resulted from a critical collision of wavefronts; 3) in this preparation, AVN reentry circuits always appeared to involve conduction through atrial tissue immediately surrounding AVN; and 4) remarkably, reentry confined to the intranodal region was never observed. Recently, the factors controlling impulse transmission within the atrioventricular (AV) junctional tissues have been extensively reviewed (Watanabe and Dreifus, '77). Delay in conduction of the cardiac excitatory wave is thought to occur predominantly within the N region of the AV node, as originally suggested by Paes de Carvalho and de Almeida ('60) and others (Billette et al., '76). Early evidence for a dual AV transmission system was suggested by Mendez and Moe ('66). This concept was used to explain sudden, marked alterations in AV conduction intervals, which were attributed to either anatomically or functionally independent AV nodal pathways (Mendez and Moe, '66; Hoffman et al., '63; Denes, '73; Ogawa and Dreifus, '77). Alternatively, these observations were also explained by different degrees of fragmentation and inhomogeneous conduction at several levels within the AV node (Watanabe and Dreifus, '65; Janse et al., '71). Janse et al. ('71) presented experimental evidence that possible reentry circuits could occur within the AV node, whereas Watanabe and Dreifus ('65) demonstrated concealed reentry within the AV node resulting from inhomogeneous conduction, particularly within the N fibers. Later experimental work by Janse et al. ('76) and Zipes et al. ('73) indicated that AV nodal transmission was also dependent on the pattern of AV nodal input. For example, although the crista terminalis (CT)was the dominant nodal input, AV nodal activation changed when the interatrial septum was stimulated. These authors concluded that the site of the atrial pacemaker could be a decisive factor in AV nodal transmission. It became clear that, using the concept of a dual AV nodal input, the presence of unidirectional block in one of the inputs could predispose to a reentry movement as the wavefront from the other input invaded the blocked route retrogradely and engendered a circus movement. The present studies confirm the importance of a dual input into the AV node and the imReceived January 26, 1981; accepted April 30, 1981 Address reprint requests to Dr. Leonard M. Dreifus. Lankenau Hospital, Lancaster and City Line, Philadelphia, PA 19151. 180 TODOR MAZGALEV ET AL. portance of the perinodal fibers of the atrium, which surround the AV node and could participate in AV junctional reentry mechanisms. METHODS We studied in vitro preparations from the hearts of 10 young adult New Zealand white rabbits (weight 2.5-3.5 kg), and successful experiments were completed in 6 preparations. Figures 1-5 are representative of the electrophysiological responses resulting from the various interventions. The preparution Each rabbit was anesthetized with sodium pentobarbital (30 mglkg, intravenously) and heparinized (1,000 units, intravenously). The chest was opened by a midsternal incision, and the heart was rapidly excised. After quick removal of apical tissue to ensure more thorough superfusion of the ventricular cavities, the heart was placed in a room temperature modified Tyrode's solution of the following composition (concentrations are in units of mM1 liter: NaCL 128.2; KC1 4.7; CaC1, 1.3; MgCl, 1.05; NaHCO, 20.1; NaHPO, 4.7; and glucose 11.1).The solution was constantly gassed with a mixture of 95% 02/5% C02. After the tissue was fixed to a paraffin block, a probe was passed through the apical end of the right ventricle (RV), through the tricuspid valve (TCV), into the right atrium (RA) and out through the superior vena cava (SVC). Using the probe as a guide, the right heart was opened by an incision through the RV and RA margin to the interatrial septum (IAS), to expose the endocardia1 surface. Following resection of the RV, LV and LA, the preparation consisting of the right atrial appendage, sinus node (SN) and atrioventricular node (AVN) was fixed to the bottom of a tissue bath (volume 45 ml) and superfused with a constantly oxygenated solution at a rate of 10 mllmin. A temperature of 37 '.1" C was maintained by means of a Hakke circulating water bath with thermostat. Electrical recordings Surface electrograms were obtained from Teflon-insulated silver bipolar electrodes placed in the CT, the interatrial septum (IAS) and the bundle of His (H). Bipolar stimulating electrodes were placed at SN, CT and IAS. Rectangular pulses twice diastolic threshold and 1 msec in duration were delivered by a programmable digital stimulator (Bloom As- sociates, Narberth, PA). Tissue response was amplified by using either a differential amplifier (Bloom Associates) or a Hewlett-Packard bioelectric amplifier (model 8811A) prior to being displayed on a Tektronix memory oscilloscope (model D15). Standard glass microelectrodes (1.0 mm outside diameter) were filled with 3.0 m KCl and were used to monitor cellular responses within the preparations. Tissue and cellular responses were recorded on Kodak Ortho paper at a paper speed of 500 m d s e c using either a Grass Kymographic camera or a Polaroid camera after being displayed on the oscilloscope screen. The stimulating and recording electrodes were placed close to the CT and IAS input regions to the AV node and arranged in a manner that would record both spontaneous and electrically induced impulses a t their respective input regions. The recording electrodes were always placed most proximal at each input region (Figs. 1-5). Simultaneous transmembrane potentials were recorded from 3 microelectrodes in each preparation. At least one microelectrode was used as a reference, and the others were moved to the various areas of the AN, N and NH regions to map the course of impulse transmission through the AV node. Microelectrodes were mounted on micromanipulators (Stoelting-Prior) for precise impalements into the various regions of the AV node. Several coordinates drawn from the superior-anterior and right and left portions of the AV node were noted to localize the area of recording of the impaled cells. The terminology of Paes de Carvalho ('60) as applied to the zones of the AV node was used throughout the study, but the location of the N region was more closely identified with the findings of Janse et al. ('76). Perinodal fibers were identified by typical atrial action potential configuration and their location at the border of the AV node. The location and timing of a particular fiber was identified both by the initial inscription and contour of the action potential (e.g. AN, N or NH). The basic drive was from either the CT or IAS. Several types of premature and/or conditioning stimuli were applied at the inputs of the CT or IAS to preexcite or induce block at a particular site, as indicated in the figures. Block and reentry could then be reproduced in order to carry out the mapping techniques. In 4 experiments, precisely reproducible intervals could not be achieved, and these 4 rabbit heart preparations were eliminated from further study. 181 AV JUNCTIONAL REENTRY V 1 r r ”. CT IAS N Fig. l.A. AV junctional reentry utilizing perinodal atrial fibers. B. concealed reentry is rnonstrated. See text for details. Analog records are organized from top to bottom as follows: CT and IAS = bipolar electrograms from the crista terminalis and interatrial septum, respectively; AN1, N2 and NH3 are microelectroderecordings from cells in the atrionodal, nodal and nodal-His regions, respectively, of the atrioventricular node. Subscripts 1-3 refer to sites identified in the schematic diagrams. H = bipolar His bundle recordings. SCtand S,, indicate the timing of stimuli introduced at the indicated intervals (in milliseconds) at each of these input regions. In the accompanying schematic diagrams of the atrioventricular junction, the relative positions of the bipolar recording electrodes I., stimulating electrodes (00)and microelectrode impalements 1-3 (*) are indicated. Subsequent figures (2-5)are organized and labelled similarly. (m RESULTS A V atrial reentry In Figure lA, AV junctional conduction utilizing the perinodal atrial fibers is demonstrated. Basic stimulation of the crista terminalis (CT) produced activation of the atrio-nodal (ANl), nodal (N2) and nodal-His (NH3) fibers, with subsequent activation of the His bundle. Premature stimulation of the CT 120 msec after the basic drive engendered conduction to the level of the AN1 fiber, and only a local response (arrow) was seen at the level of the N2 fiber. Subsequent but delayed activation from the septum activated fiber N2 with retrograde activation of fiber AN1 and CT (Fig. 1, triangle). Activation after the extrastimulus via IAS (multiple arrowheads) to N2, fiber NH3 and then to the His bundle was noted. Alternatively, fiber N2 could have been activated by a slowly conducting wavefront in a contiguous pathway but manifest intranodal reentry was never observed in this preparation. Furthermore, local responses or hump formation were not observed in AN and NH regions to indicate fractionation or continguous pathways in this instance. Subsequent IAS activation occurred via the perinodal fibers. In Figure l B , recorded from different AN fibers, as indicated in the schematic, there was a similar activation pattern from the CT. The premature stimulus altered the morphology of the action potential in fibers AN1 and AN2 and only concealed retrograde conduction to these fibers (arrows) without manifest retro- 182 TODOR MAZGALEV ET AL. A I\ Il I 200 li I H sct 1 SBS 5 Y CT Fig. 2.A. Both concealed and manifest reentry is seen following premature stimulation a t the IAS. Multiple reentries, probably within the N region, are apparent (small arrows). B. An additional stimulus a t the crista terminalis (CT) prevented perinodal reentry. grade activation of the CT or subsequent perinodal activation of the IAS, as seen in Figure 1A. Mechanism of initiation and termination of the reentry mechanism In Figure 2A, following the last basic stimulus from the CT, a pair of stimuli was given to the CT and IAS (at 200 and 220 msec, respectively), and the septum was then stimulated 130 msec later. Notably, the CT was not activated via the perinodal fibers after the last stimulation of IAS. Activation of the IAS, N2 and AN1 proceeded in that order, with retrograde conduction to the CT (triangle) and presumably subsequent conduction to the IAS via perinodal atrial fibers. It is possible that local reentries in the region of the N2 fiber could have emerged to depolarize the IAS. These analog records present presumptive evidence that reentry via the perinodal tissue activated the IAS, N2 and AN1 but failed to exit at the CT. Multiple AN1 and N2 activations presumably resulted from fragmentation or local reentries (small arrows) within this area. In contrast, when the identical stimulation sequence was repeated (Fig. 2B) but a n additional premature stimulation a t the CT input (curved arrow) was introduced, earlier activation of fiber AN1 occurred than was seen in Figure 1A. Presumably, Figure lB, retrograde activation of AN1 did not occur because of the earlier stimulation of the CT region. This prevented the retrograde wavefront from exiting at the CT atrio-nodaI region and thereby prevented perinodal activation and AV junctional reentry. An example of the initiation of another pattern of AV junctional reentry is shown in Figure 3A. After the last basic drive from CT, a 183 AV JUNCTIONAL REENTRY I 220 ' 1 175 5 II I 2ooy 220 j Sct Sias I I 175 '5 H t= , s,as Fig. 3.A. In this case, repetitive reentry was produced by stimulation a t the crista and interatrial septum. The IAS was stimulated 220 msec after the last basic drive at the CT. The conditioning stimuli 5 msec apart engenedered the reentry movement with activation sequences indicated by the arrows. B. The strength of the stimulus was increased a t the CT (2 x to 2.5 x 1, which produced depolarization in this region. Earlier activation of the area of the crista prevented repetitive reentries, and the mechanism terminated. C. The crista terminalis was depolarized 200 msec after the last basic stimulus, and because of the altered refractoriness, reentry could not be produced. conditioning premature stimulus was given at the IAS (220 msec). Late activation of CT from the IAS via perinodal fibers was seen (arrow), although slow intranodal conduction not involving fiber AN1 could have activated the CT in this instance. In Figure 3A, 175 msec after the last IAS conditioning stimulation, the IAS and CT were stimulated within 5 msec. An electrogram was seen a t the IAS, but only a stimulus artifact was observed at CT due to refractoriness in this region. The activation sequence following IAS stimulation was antegrade through the AV node to His. Fiber AN1 and CT were subsequently to be activated. 184 TODOR MAZGALEV ET AL. Activation of the IAS was via the perinodal fibers, with subsequent reentry movements, for a total of 10 cycles. Finally, progressive delay and block occurred between AN1 and CT, and the reentry was terminated (not shown). In Figure 3B, a stimulation pattern similar to A was used, but the stimulation strength was increased from twice to two and one-half times threshold. The IAS conditioning stimulus was conducted via perinodal fibers to the CT somewhat earlier (Fig. 3B, arrow and dotted line). The last stimulation of the CT then elicited a local response but was not sufficient to prevent retrograde reentrant activation of AN1 and N2. However, this local response at CT was sufficient to delay the subsequent echo activation of CT (triangle), but it failed to activate the IAS, and the reentry loop was terminated. In Figure 3A and B, the premature activation of CT was via perinodal conduction. In Figure 3C, CT depolarization was earlier due to active stimulation (curved arrow) at the CT site in addition to the conditioning activiation at the IAS (straight arrow). A more uniform engagegment of AN1 and N2 with conduction to H was seen. Thus, retrograde conduction to the CT, as shown in Figure 3A and B, could not occur to initiate the reentry movement. In Figure 3C, the earlier activation of CT (curved arrow) permitted depolarization of the CT during the last set of stimuli, and thus reentry did not occur. The earlier stimulation of the CT altered refractoriness such that the second extrastimulus was successful and subsequent reentry could not emerge. The last activation of IAS and CT within 5 msec resulted i n antegrade AV conduction to His. Further variations in the patterns of reentry, dependent on the time relationship of the CT and IAS activation, are shown in Figure 4. In Figure 4A the time differential between the two last stimuli was 20 msec. Initial activation occurred a t the IAS input, with subsequent activation of fiber N2 and retrograde activation of fiber N1 and CT (triangle). Since there was no further activation of the IAS, the second depolarization of fiber N2 (arrow) occurred from a local reentry, but subsequent conduction to His was absent. Alternatively, the activation of N1 could also be explained by collision of the antegrade impulse from the CT depolarization, with the retrograde waveform from N2 producing slow conduction and a reentry from N1 back to the CT. If this were the case then the second N2 depolarization would occur in a n antegrade fashion but block to His. In Figure 4B, the reentry was somewhat sim- ilar to that shown in Figure 4A, but in this instance the IAS was activated 11msec earlier (i.e., 31 msec before CT, vs. 20 msec) and the following pattern of activation resulted. Fiber N2 was initially activated from the IAS. Fiber N1 activation followed either from continuation of the wavefront from N2 in a retrograde manner or from reentry above fiber N1 and subsequent retrograde activation of the CT (Fig. 4B, triangle). The second hump (curved arrow) at fiber N2 probably was a result of antegrade conduction from the reentry loop with subsequent conduction to the His. The last group of complexes most likely occcurred from a spontaneous antegrade conduction sequence from CT, but the reentry movement terminated. In Figure 4C, stimulation of IAS 13 msec earlier than that shown in Figure 4B produced a pattern of reentry movement similar to the one in Figure 4B. Reentry to the CT (Fig. 4C, triangle) allowed perinodal conduction to occur and enter the AV node via the IAS (circle). However, in this case a second reentry loop also occurred via fibers N1 and N2 (star) and may have influenced CT activation before the reentry terminated. An additional reentry mechanism dependent upon the interrelationship of both CT and IAS inputs is shown in Figure 5. In Figure 5A, premature activation of the CT 155 msec after the last basic CT depolarization produced activation of fiber AN1, but only a small hump at the level of fiber N1 (curved arrow). Subsequent activation of Fiber N2, indicated by a larger and fuller action potential, probably resulted from a second input from the region of the IAS. This second impulse presumably resulted from perinodal conduction of the initial stimulus from the CT. Reentry did not occur, but subsequent His bundle activation was seen. As shown in Figure 5B, when the IAS was additionally activated 10 msec earlier than the CT, several graded responses or humps were seen in fiber N2 (small arrows). Subsequently, reentry to the IAS and CT was seen. Antegrade conduction then penetrated as far as fiber AN1 without subsequent conduction, and the reentry loop was terminated. As shown in Figure 5C, a similar sequence of reentry movement was reproduced merely by moving the stimulation time at the CT 10 msec earlier (i.e., 145 msec) than in Figure 5A. Activation of fiber AN1 occurred with a small hump formation at the level of fiber N2. Septa1 activation probably occurred via the perinodal tissue and was responsible for activation of fiber N2 (larger hump, curved arrow), with reen- 185 AV JUNCTIONAL REENTRY V CT IAS Figure 4.A. Initial activation a t the IAS input by the conditioning stimuli which were 20 msec apart with subsequent antegrade activation of fiber N2 antegrade and retrograde activation of fiber N1 and CT (triangle).The second depolarization following this pair of stimuli a t N2 (arrow) resulted from retrograde activation from local reentry without conduction to His. B. The IAS was activated 31 msec before the CT, which resulted in sustained reentry movements with subsequent activation of His. C. Stimulation of IAS 13 msec earlier than in B produced a pattern of reentry movement; however, in this instance perinodal conduction occurred and activated the IAS (circle). try to the IAS and CT, and with subsequent activation of fiber AN1. The reentry mechanism then terminated spontaneously. to be operative in the presence of reentry tachycardias associated with the Wolff-ParkinsonWhite syndrome, the mechanism of reentry within the AV nodal junction is less obvious. DISCUSSION Janse et al. ('76) clearly demonstrated that While two anatomically distinct atrioventri- during a regular sinus rhythm the AV node cular conducting pathways have been shown receives dual input from the CT and IAS. How- 186 TODOR MAZGALEV ET AL. CT I AS Fig. 5. A. Premature activation of the CT 155 msec after the last basic CT depolarization produced activation of fiber ANI, with only a small hump at the level of fiber AN2. The second input from the region of the IAS produced a larger fuller action potential a t fiber N2. B. When the IAS was activated in addition, 10 msec earlier than in A, several graded responses were seen (small arrows) a t fiber N2, with subsequent reentry to the CT and IAS. C. A similar sequence of reentry movement was reproduced merely by moving the stimulation time a t the CT alone 10 msec earlier. ever, premature stimulation of the atria resulted in block of the impulse to the posterior input, with the AV node then exclusively activated via the interatrial septum. Then, after a considerable interatrial conduction delay, the wavefront reached the AV node and was able to reexcite the posterior input travelling along the CT in a retrograde direction. Al- in Janse's ('76) experiments, the exact course of the circuit with respect t o the perinodal atrial tissue remained somewhat unclear. Janse et al. ('76) further demonstrated that both summation and fragmentation of impulses affected AV transmission and the ability to produce echo beats. In the present study, AV junctional reentry 187 AV JUNCTIONAL REENTRY demonstrated (Fig. 1).Premature stimulation a t the area of the CT resulted in antegrade block in the region of the N fibers. An impulse could travel through the perinodal fibers and enter the interatrial septum, and it could conduct retrogradely t o the CT and atrium, and antegradely to the ventricles. To verify that the echo actually used a perinodal pathway, programmed stimulation was applied first to initiate the reentry mechanism. This was done by introducing a properly timed premature stimulus in the region of the interatrial septum (Fig. 2A). This impulse travelled retrogradely through the AV node and returned via the perinodal atrial fibers to the interatrial septa1 input and then to the His, with multiple fragmentary waves within the N region. However, an additional stimulus placed at the CT could block the retrograde impulse to the atria and thus interrupt the perinodal reentry pathway (Fig. 2B). In Figure 3 premature stimulation in the region of the CT input either aborted the reentry mechanism or prevented it entirely. This was dependent on the ability of the premature stimulation to depolarize the CT and prevent the retrograde reentry mechanism to the atria, thereby blocking the perinodal input to the IAS. The patterns of AV junctional reentry varied in any given preparation dependent on the time relationship of activation of CT versus IAS. Further evidence for the role of appropriately timed stimuli a t the CT and IAS in the initiation of reentry is shown in Figure 4. Here both concealed local reentry, as well as manifest reentry utilizing the perinodal fibers of the atria, were apparently operative. A reentry mechanism dependent upon the interrelationship of the inputs to both the CT and IAS was also demonstrated (Fig. 5). This occurred as a result of fragmentation of wavefronts in an antegrade fashion. When there was sufficient conduction delay the impulse could then converge to activate the perinodal fibers of the atria. Such impulses could then reenter the AV node. In Figure 5A, the initial hump in fiber N1 (arrow) may have resulted from electrotonic spread in an antegrade direction. The fuller action potential a t N2 could then have resulted from a subsequent antegrade wavefront via the CT, but more likely entered via the IAS input since the CT electrogram was inscribed prior to fiber N2. When the premature stimulus was further conditioned by a 10 msec earlier stimulation a t the IAS (Fig. 5B) multiple humps (small arrows) appeared at N2, the wavefront exited via N2, and the IAS and returned via the CT and AN1. A reentry activation sequence was also produced merely by delivering a n earlier premature stimulus to the CT (e.g., 145 msec rather than 155 msec) as shown in Figure 5C. In this instance fragmentation of the antegrade wave produced an initial hump a t N2, followed by a large action potential. Perinodal conduction then occurred to both the CT and the IAS with subsequent activation of AN1 before the reentry terminated. Thus, the present study has demonstrated that dual input to the AV node from the CT and IAS could result in either fragmentation, cancellation, or, alternatively, summation of wavefronts. Hence, there was evidence of an interaction between the two inputs of the AV node shown clearly by varying the timing of stimulation of the CT and IAS. Mapping of activation patterns suggested that delayed conduction within the AV node itself allowed an impulse to enter one atrio-nodal input region, emerge from the other atrio-nodal “input” region and conduct via the perinodal fibers to reenter the AV node from the initial input area. The use of programmed stimulation to induce block in one or the other of the atrio-nodal input regions could then interrupt the reentry mechanism, proving that the perinodal atrial tissue was a necessary link in the reentry circuit. Finally, although concealed intranodal reentry was identified by intranodal mapping techniques, manifest reentry confined strictly to within the AV node and not using the perinodal atrial tissues as a necessary link €or the reentry mechanism was not observed. ACKNOWLEDGMENTS This work was done during Dr. Mazgalev’s tenure as a Visiting Scientist from BAN Institute of Physiology in Sofia, Bulgaria under the sponsorship of the Bulgarian Academy of Sciences and the National Academy of Sciences, Washington, D.C. Dr. Michelson is the recipient of Clinical Investigatorship Award 1KO8 HL00709-01 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. LITERATURE CITED Billette, J.,Janse, M.J., vancapelle, F.J.L., Anderson, R.H., Touboul P., Durrer D. (1976) Cycle-length-dependent properties of AV nodal activation in rabbit hearts. Am. J. Physiol., 231:1129-1139 188 TODORMAZGALEVETAL. Denes, P., Dhingra, R.C., Chuquimia,R., Rosen, K.M. 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