Sinus Node Reentry AN IN VIVO DEMONSTRATION IN THE DOG. By Karlen L Paulay, P. Jacob Varghese, and Anthony N. Da ma to

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1 Sinus Node Reentry N IN VIVO DEMONSTRTION IN THE DOG By Karlen L Paulay, P. Jacob Varghese, and nthony N. Da ma to BSTRCT The phenomenon of sinus node reentry was investigated in 20 dogs by programed atrial stimulation during sinus rhythm and atrial pacing. Recordings were made simultaneously at multiple atrial sites. In 18 dogs, a closely coupled premature atrial beat ( 2 ) introduced into the region of the coronary sinus, the right or the left atrial appendage, or the Bachmann bundle was followed msec later by an accelerated beat ( 3 ) consistent with sinus node reentry. The atrial activation sequence and the P-wave morphology of 3 and of the spontaneous sinus beats were similar. The occurrence of 3 during sinus rhythm and atrial pacing was dependent on the coupling interval of 2 and the arrival time of excitation in the region of the sinus node but was independent of the atrial site at which 2 was introduced; 3 could be clearly distinguished from local or atrioventricular node reentry and sinus node entrance block. Moreover, crushing of the sinus node (10 dogs) or vagal stimulation (7 dogs) prevented the appearance of 3 in all dogs, presumably by blocking the sinus node reentry pathway. During graded vagal stimulation a progressive increase in the 2-3 interval occurred. Sinus node reentry was sustained for three cycles in 1 dog. Sinus node reentry may be one mechanism for interpolated atrial premature depolarization and some atrial tachyarrhythmias seen clinically. KEY WORDS atrial fibrillation vagal stimulation atrial pacing atrial premature depolarization atrial reentry atrial arrhythmia sinus node entrance block crushing of sinus node Sinus node reentry was investigated using microelectrode techniques in isolated preparations of rabbit heart tissue by Han and co-workers (1). These authors suggested that sinus node reentry might occur when the excitation wave of a propagated atrial premature depolarization arrives in the region of the sinus node but fails "to engage one margin of the node" because of refractoriness at that site. ccording to this concept, the impulse entering at another site slowly traverses the nodal tissue and then emerges as a reentrant beat. Fundamental to this concept of reentry is the known disparity in refractory periods between sinus nodal and atrial tissues (2, 3). Recently, we reported (4) that sinus node reentry might be a mechanism involved in the observed response to an early atrial premature depolarization in man. The present study was From the Cardiopulmonary Laboratory, U. S. Public Health Service Hospital, Staten Island, New York This work was supported in part by the Federal Health Program Service, by U. S. Public Health Service Project Py 72-1, and by U. S. Public Health Service Grants HE and HE from the National Heart and Lung Institute. Received September 11, ccepted for publication January 29, designed to investigate this phenomenon in more detail in the intact heart of the dog. Methods Twenty mongrel dogs (10 25 kg) were anesthetized with sodium pentobarbital (30 mg/kg, iv). The trachea was cannulated, and the dogs were mechanically ventilated with room air. The heart was exposed by a midsternal incision and pericardiotomy; it was then cradled in the pericardial sac. Both vagi were sectioned in the neck, and the stellate ganglia and the sympathetic chains (Tj-T 4 ) were excised so that sinus arrhythmia was essentially eliminated (see Results). Body temperature was monitored by a rectal temperature probe and maintained at 37 ± 1 C by an electric heating pad. Teflon-coated bipolar plunge wire electrodes (5) were inserted into the regions of the sinus node, the Bachmann bundle, the coronary sinus, the right atrial appendage, the left atrial appendage, and the low atrial septum for recording and stimulation purposes. RECORDING TECHNIQUE Electrograms from several atrial recording sites, a lead II electrocardiogram, the stimulus artifact, and accurately generated time marks at 10- and 100-msec intervals (Tektronix 184) were simultaneously viewed on a multichannel switched-beam oscilloscope (Electronics for Medicine) and recorded on magnetic tape. The electrograms were displayed at frequency settings of Hz. nalog tracings were subsequently Circulation Research, Vol. XXXII, pril

2 456 PULY, VRGHESE, DMTO transferred from the tape to photographic paper (150 mm/sec) for analysis. STIMULTION TECHNIQUE trial Premature Stimulation during Sinus Rhythm. The sinus node electrogram triggered the sweep of an oscilloscope (Tektronix 565) which in turn activated a specially designed pulse generator capable of delivering stimuli with an accuracy of ±1 msec. The pulse generator was programed to deliver rectangular stimuli 1.5 msec in duration at twice diastolic threshold to a selected atrial stimulation site after every tenth sinus beat ( a ) via a stimulus isolation unit. These stimuli evoked atrial premature depolarizations ( 2 ) at progressively decreasing coupling intervals (10-20-msec decrements in r 2 ) throughout the sinus cycle until the atrial effective refractory period was reached. trial Premature Stimulation during trial Pacing. Basic pacing pulses having the characteristics described above were delivered to a selected atrial stimulation site at a rate of /min. fter every tenth paced beat (,), 2 was introduced through the stimulating electrodes used to introduce,, and the atrial cycle was scanned as previously described. Basic pacing pulses were omitted for several spontaneous atrial cycles after 2. DEFINITION OF TERMS j = trial depolarization of either a spontaneous sinus beat or a paced atrial beat. 2 = trial depolarization of an induced atrial premature beat. 3, 4, 5, etc. = Subsequent atrial beats. j-i = trial interval measured during sinus rhythm or atrial pacing. 1-2 = Coupling interval measured from the last sinus or paced beat (j) to the atrial premature depolarization ( 2 ). 2-3 = Interval measured from the induced atrial premature depolarization ( 2 ) to the subsequent atrial beat (3). i- 3 = Sum of the j- 2 and 2-3 intervals. 3-4, 4-5, etc. = Intervals between atrial depolarizations subsequent to 3. S = Stimulus. Sj = Basic pacing stimulus. = Premature stimulus. S 2 ll atrial intervals were measured from the electrogram recorded in the region of the sinus node unless stated otherwise. DDITIONL STUDIES Vagal Stimulation. With a bipolar plunge wire electrode the distal end of the sectioned cervical right vagus nerve was stimulated with a Grass stimulator (S8) in nine dogs during premature atrial stimulation. Vagal stimulation consisted of a second train of impulses; each impulse was 5.0 msec in duration, and the frequency was 20 cps. The train was triggered by the last spontaneous beat (tenth beat) during sinus rhythm or by the last paced beat during atrial pacing. Voltage varied from 0-40 v and was measured using a differential amplifier (Tektronix 33) and oscilloscope (Tektronix 565). Crushing of the Sinus Node. The effect of premature atrial stimulation was assessed in ten dogs after the sinus node was crushed by a clamp applied to its upper third (two dogs), to its upper and middle thirds (two dogs), or to its entire length (six dogs). In the last group of dogs sinus arrest was consistently observed. The clamp remained in place during atrial stimulation. Results Variability in Spontaneous Cycle Length. The absence of sinus arrhythmia was necessary for the accurate analysis of the response to premature atrial stimulation. Variability in the spontaneous cycle length in these extrinsically denervated dogs was minimal and averaged 5 msec (range 0 to 10 msec). This degree of variability was assessed during an average of 15 consecutive cycles during sinus rhythm. lso, following atrial pacing for ten beats, the escape time (measured from the last paced i to the first sinus beat) and the subsequent sinus cycle showed a similar degree of variability on repeated testing (average 15 consecutive tests). Premature trial Stimulation during Sinus Rhythm. Every dog demonstrated sinus suppression when 2 was introduced relatively late in the atrial cycle. However, in seven dogs, at close coupling intervals of 2 (39-45% of the basic cycle length), the subsequent beat, 3, occurred early ( msec after 2 ) and appeared to originate from the region of the sinus node. Figure 1 illustrates the typical response to early premature stimuli introduced during sinus rhythm. In Figure 1, the stimulus was introduced at the tip of the right atrial appendage 130 msec after activation of this region by the sinus impulse ( t on the right atrial appendage electrogram). ctivation of the sinus node region followed at an i- 2 interval of 220 msec, and a slight degree of postextrasystolic sinus suppression was observed ( msec). The difference between the 1-0 intervals measured at the right atrial appendage site and those measured in the region of the sinus node was a function of the conduction times between these two sites. In Figure IB, the stimulus was introduced 10 msec earlier (^S 120 msec) and fell within the atrial effective refractory period. Therefore, the coupling interval of 220 msec shown in Figure 1 was the shortest possible coupling interval in the sinus node region when the stimulus was applied to Circulation Research, Vol. XXXII, pril 1973

3 SINUS NODE REENTRY IN THE DOG 457 FPfi LS S TL 1 1 ft J J, P _ S130 S R TIP?200* 2 23C -S p T S R BSE p 3 I - -.>J\ F L 1 I 1 I I S R BSE appendage. In these seven dogs the zone ranged from 170 msec to 220 msec and had an average duration of 17 msec. No consistent relationship, either direct or reciprocal, was observed between the i- 2 and the 2-3 (SN) intervals for the different dogs within this zone. Premature trial Stimulation during trial Pacing. t close coupling intervals of 2 in 2 dogs, only sinus suppression was seen, and an early 3 (SN) was not elicited. Figure 2 illustrates the type of response seen in the remaining 18 dogs. Basic (Si) and premature (S 2 ) stimuli were applied to the region of the coronary sinus. In FIGURE 1 Effect of early atrial premature stimulation during sinus rhythm in a dog. In and B the stimulus (S) is applied to the tip of the right atrial appendage (R), and in C and D to the base of the R. ECG = standard lead II electrocardiogram, SN = sinus node electrogram, BB = Bachmann's bundle electrogram, LS = low atrial septum electrogram, and TL = time lines at 10- and 100-msec intervals. The rapid deflections were retouched in this and subsequent figures for the purpose of reproduction. See text for details. ECG SN BB R ! 545 the tip of the right atrial appendage. In contrast, when the stimulus was applied to the base of the right atrial appendage (Fig. 1C), the conduction time to the adjacent sinus node region was short, and, at an i- 2 interval of 200 msec, an early 3 appeared. Because the P-wave morphology and the atrial activation sequence of 3 resembled those of the preceding and the subsequent sinus beats, the term 3 (SN) will designate this type of early response. s the i-s interval was shortened beyond that shown in Figure 1C, the i- 2 interval decreased from 200 msec to 170 msec and the 2-3 interval decreased from 230 msec to 165 msec. With still shorter i-s intervals the stimulus fell within the atrial relative refractory period, and an i- 2 interval shorter than 170 msec could not be achieved. In Figure ID, at an t-s interval of 120 msec, the stimulus fell within the atrial effective refractory period, and atrial capture did not occur. During sinus rhythm there was a range of requisite i- 2 intervals measured in the sinus node region for the appearance of 3 (SN); this range is termed the reentry zone. The zone was reached in seven dogs when the stimulus was applied to the base of the right atrial appendage but it was reached in only two of these dogs when the stimulus was applied to the tip of the right atrial Circulation Research, Vol. XXXII, pril 1973 TL SL- I I..SL I SLSLSIIM I I, I i 220 I I I 1 I I 1 1 I I I I I 1 1 I I I C. y i- [ 400 [, Jl..?.1, I I I U.iml.U..I..L I.,., I,,1.1 l.,.,...l I lm...,l., FIGURE 2 Effect of early atrial premature stimulation during atrial pacing in a dog. HBE = His bundle electrogram recorded from the low atrial septum, CS = coronary sinus, and BP = atrial refractory period. Other abbreviations are the same as in Figure 1. See text for details. ' - «-

4 458 PULY, VRGHESE, DMTO Figure 2, atrial depolarization occurred first (open arrows) in the region of the low atrial septum; depolarization in Bachmann's bundle preceded that in the sinus node, and the P waves on the surface electrocardiogram were inverted for both i and 2. t a coupling interval of 230 msec (or greater), typical sinus suppression was seen. However, when the coupling interval was decreased by 10 msec to 220 msec (Fig. 2B), an early 3 (SN) appeared. 3 (SN) resembled the subsequent sinus beats, especially the last sinus beat in Figure 2C, i.e., the sinus node region was the first to be activated (solid arrow) and the P wave became upright. The basis for minor differences in atrial electrogram sequence and configuration for 3 (SN) compared with subsequent sinus beats is detailed in the Discussion. The escape time of the sinus node for the basic driving rate (Si-Sx 400 msec) was determined when S 2 fell within the atrial refractory period (Fig. 2C), and atrial capture did not occur. In Figure 2B, the early appearance of 3 (SN) suggests that 2 failed to enter the sinus node, i.e., sinus node entrance block, and to discharge the pacemaker cells thus allowing 3 to appear on time, i.e., 2 was an interpolated beat. Under these conditions, the presence or the absence of 2 should not affect the appearance time of 3, and the sum of the i- 2 and 2-3 intervals should equal the escape time. However, the sum of i- 2 and 2-3 equaled 420 msec (Fig. 2B) and not 520 msec (Fig. 2C) as would be expected from entrance block alone. When the sum of t - 2 and 2-3 exactly equals the escape time, sinus node entrance block is more strongly suggested. In another experiment (Fig. 3), the sum of t - 2 (240 msec) and 2-3 (270 msec) exactly equaled the escape time of 510 msec (Fig. 3B). If sinus node entrance block for 2 did in fact occur, then the 3-4 interval should measure 465 msec as it did in Figure 3B and not 500 msec as is indicated in Figure 3. This numerical disparity is not a chance phenomenon related to spontaneous variation in cycle length. ECG v T^70 «500 **!. FIGURE 3 Effect of early atrial premature stimulation during atrial pacing that simulates sinus node entrance block. bbreviations are the same as in Figure 1. See text for details. The early appearance of 3 (SN) was independent of the site at which 2 was introduced but was dependent on the arrival time of excitation in the region of the sinus node, i.e., on the coupling interval in the sinus node region. Thus, an early a(sn) appeared following S 2 introduced at any one of several atrial sites (see Methods) when the i- 2 coupling interval fell within the reentry zone. This zone ranged from 180 msec to 240 msec and had an average duration of 26 msec. Within this zone no consistent relationship was observed between the i- 2 and the 2-3 (SN) intervals for the different dogs. In one dog, 2 was followed by multiple atrial responses (maximum of three) that appeared to originate from the sinus node region. This type of response is illustrated in Figure 4 during stimulation of the tip of the right atrial appendage. t very close S!-S 2 intervals in 12 dogs, 3 appeared to originate from the stimulation site and not from the sinus node region. For this type of response the atrial activation sequence of 2 and 3 was similar. Characteristically this response occurred when S 2 fell within the atrial relative refractory period of i as evidenced by latency (the interval between the stimulus and the atrial response seen during stimulation within the atrial relative refractory period) or intra-atrial conduction delay. Si and S 2 applied to the region of the coronary sinus at an S x -S 2 interval of 180 msec were followed by an 3 which originated from the sinus node region (Fig. 5). However, at an Si-S 2 interval of 170 msec (Fig. 5B), 3 originated from the stimulation site, because the activation sequence of 2 and 3 was similar. t an even shorter Si-S 2 interval of 130 msec, atrial fibrillation was elicited (Fig. 5C). s the Si-S 2 interval was decreased, the appearance of an early 3 from the sinus node EC6 SN BB R LS S TL i, i S t 13b, 140 1,2 3 M 400,160, S1 S2 R TIP 1!_ FIGURE Multiple atrial responses that originate from the region of the sinus node following early atrial premature stimulation during atrial pacing. bbreviations are the same as in Figure 1. 'e Circulation Research, Vol. XXXII, pril 197i

5 SINUS NODE REENTRY IN THE DOG 459 region (Fig. 5) always progressed first to the type of response shown in Figure 5B before atrial fibrillation developed (6 dogs). Thus, atrial fibrillation could be avoided if attention was directed to the atrial activation sequence and if the Sj-S 2 interval was not further decreased when 3 appeared to originate from the stimulation site. trioventricular (V) node reentry, which is characterized by an inverted P wave in lead II, a reversed sinus node-bachmann's bundle sequence, and a critical x - 2 interval, was not observed in this study. The response shown in Figure 5B resembled V node reentry simply because the stimulation site was in the region of the coronary sinus. In this dog, when closely coupled stimuli were applied to other sites (left atrial appendage, Bachmann's bundle, right atrial appendage) 3 appeared to originate either from the sinus node region or the stimulation site but not from the V node. Vagal Stimulation Effects. Because the vagus nerve was stimulated by using insulated close bipolar plunge wire electrodes exposed only at the tip, relatively high voltages (20-40 v) were necessary to achieve a vagal effect. Vagal stimulation abolished the early appearance of 3 (SN) in all seven dogs studied by this technique. Figure 6 shows the early appearance of 3 from the sinus node region during coronary sinus stimulation. Vagal stimulation effectively abolished the early appearance of 3 (SN) (Fig. 6B). When 3 occurred at a shorter Si-S 2 interval and appeared to originate at the site of stimulation (Fig. 6C), vagal stimulation then resulted in either rapid repetitive firing (Fig. 6D) or atrial fibrillation (not shown). The abolition of an early 3 during vagal stimulation was only observed when the activation sequence indicated that 3 originated from the sinus node region. 3 -ts. 2OO. SI S2 CS BCL 400 (SI-SI) HM- -H i VI I»l M * FIGURE 6 Effect of vagal stimulation (B and D) on an early s that originates either from the sinus node region () or locally in the region of stimulation (C). bbreviations are the same as in Figure 1, except that BCL = basic cycle length. See text for details. The effect of graded vagal stimulation on the a - 3 interval at a specific coupling interval was assessed in three dogs during atrial pacing and premature atrial stimulation. Vagal stimulus strength was increased in 1-2-v increments. The escape time from the basic drive (ten beats) was also determined at every level (voltage) of vagal stimulation. Figure 7-G shows the progressive increase in the 2-3 interval during graded vagal stimulation (0-10 v). Because of the increase in the 2-3 interval, the sum of i- 2 and 2-3 CONTROL 7v BCL 400(S -SI) FIGURE 5 Distinction between an early, that originates in the sinus node region () and at the stimulation site (B) and the subsequent development of atrial fibrillation (C). bbreviations are the same as in Figure 1, except that BCL = basic cycle length. See text for details. Circulation Research, Vol. XXXll, pril 1975 FIGURE 7 Effect of graded vagal stimulation on the 2-3 interval during coronary sinus stimulation in a dog. ET = escape time. Other abbreviations are the same as in Figures 1 and 2. See text for details.

6 460 PULY, VRGHESE, DMTO MSEC ) arose from an escape ectopic atrial focus. Local rapid repetitive firing was still observed after the sinus node was crushed. In one dog (not included above), an early 3 (SN) was not observed either before or after the entire sinus node was crushed, i.e., injury to the region of the sinus node did not allow for the appearance of an early 3 (SN) previously absent in this dog OO(S1S1) S1S2 CS FIGURE 8 VOLTS graphic depiction of data in Figure 7. See text for details. approached the escape time in Figure 7-F and then slightly (20 msec) exceeded it (Fig. 7G). This changing relationship is graphically depicted in Figure 8. When the curve representing the sum of i-a and 2-3 was below the escape-time curve, the phenomenon of sinus node entrance block for o could be excluded. The progressive increase in the 2-3 interval during graded vagal stimulation was observed in all three dogs studied by this method. Crushing of the Sinus Node. Crushing the sinus node prevented the early appearance of 3 (SN) at all coupling intervals in nine dogs studied with this technique. This situation occurred after the clamp was applied to the upper third of the sinus node in two dogs, the upper and middle thirds in two dogs, and the entire node in five dogs. Figure 9 shows a typical record before (left) and after (right) a clamp was applied to the entire sinus node in a dog. The absence of an early 3 after the sinus node was crushed is apparent. The late 3 (755 msec after BEFORE FTER f 400 f gio * SI SI ST FIGURE 9 Presence (left) and absence (right) of an early s before (left) and after (right) the sinus node was crushed. bbreviations are the same as in Figures 1 and 2. See text for details. Discussion This study clearly showed that a closely coupled atrial premature depolarization, 2> introduced at any one of several atrial sites in the dog could be followed by an early subsequent beat, 3 (SN), that appeared to originate from the region of the sinus node. We propose that the data are most consistent with the hypothesis that :i (SN) represents a reentrant beat that has emerged from a reentrant pathway involving either the sinus node proper or the adjacent perinodal area. ccording to this hypothesis, 2 arrives at the sinus node region during its relative refractory period, is blocked along one front, enters at another site, and then slowly conducts along the relatively refractory nodal tissue (1). The slight difference in the electrogram morphology, the P wave, and the atrial activation sequence seen in some experiments most likely results from a different sinus node exit site of the reentrant beat compared with that of the spontaneous sinus beat and from aberrant atrial conduction occurring because of the relatively short 2-3 interval. lso, during the 2-3 interval when slow conduction and reentry are occurring the sinus node pacemaker could be prematurely discharged, and the site of spontaneous impulse formation could shift. Because of this shift the impulse could exit from a slightly different sinus node site, and beat 4 could also appear to be slightly different despite a relatively long 3-4 interval (Figs. 1C and 2B). Crushing the sinus node effectively interrupts the reentrant pathway and prevents the appearance of 3 (SN). Weak vagal stimulation slows conduction along the reentrant pathway, presumably by acetylcholine release, and delays the emergence of 3 (SN); strong vagal stimulation effectively blocks conduction along the reentrant pathway so that the reentrant beat, 3 (SN), fails to appear. We recognize that the methods used in this study do not allow us to formulate more than a generalized, simplified hypothesis for sinus node reentry nor do they allow us to know the exact site of turnaround or reentry within the sinus node region. The fibers (6) in the perinodal zone that Circulation Research, Vol. XXXII, pril 1973

7 SINUS NODE REENTRY IN THE DOG 461 surrounds the sinus node exhibit electrophysiological properties intermediate between those of the sinus node and the crista terminalis and could well be the actual site of reentry. Similarly, a site of reentry within the specialized atrial tracts adjacent to the sinus node is another possibility. Reentry in these same tracts at a point distant from the sinus node is much less likely, since the sinus node Bachmann's bundle activation sequence for ^ would probably be different from that observed and resemble instead the sequence following stimulation of the region of the anterior internodal tract in the low atrial septum or of Bachmann's bundle (7). More information obtained by various techniques is necessary before the findings which we described can be more completely understood. s an alternative explanation for our findings we considered the recent study by Bonke and coworkers (8) which used microelectrode techniques to investigate rabbit tissue. In this study the authors concluded that an early atrial premature beat "discharges the S node only fractionally" and that the nondischarged fibers in the neighborhood of the activated area are influenced electronically by the approaching wave front of the premature beat. One effect of this electrotonic influence was the premature discharge of protected sinus node fibers. If such a phenomenon were operative in response to 2 in our study, 3 might indeed appear earlier than expected. However, the authors observed that "the sum of the pre- and postextrasystolic pause" measured from the atrial electrogram recordings (i.e., the i- 3 interval in the present study) was about the same as the duration of a normal spontaneous interval. This finding is in contrast to the results in the present study in which this sum was significantly less than the normal spontaneous interval. Furthermore, in the study by Bonke et al. (8) premature discharge of sinus node fibers was relatively brief, i.e., only one sinus cycle, and therefore could not explain the accelerated sinus beats that recurred for three to five consecutive atrial cycles in three dogs that we studied. Finally, it is difficult to reconcile the effects of graded vagal stimulation that we observed with the concept of increased automaticity in the sinus node occurring in response to o. For example, in Figure 8, if we assume that before vagal stimulation the 2-3 interval (lower curve) is short because of a postulated increase in sinus node automaticity, then the progressive increase in this interval during graded vagal stimulation could be considered secondary to the decrease in automaticity of the Circulation Research, Vol. XXXII, pril 1973 sinus node caused by acetylcholine (9). However, the unchanging sinus node escape time (top curve) indicates no change in sinus node automaticity during the initial increase in 2-3 and, thus, seriously questions the validity of the original premise. We suggest that the results can be explained by assuming an initially selective depressant effect of the vagus nerve on the reentrant pathway. lternatively, it is conceivable that, because of our method of vagal stimulation, only vagal fibers destined for one site within the sinus node were stimulated. Functional Requirements for Sinus Node Reentry. The arrival of excitation from 2 within the relative refractory period of the sinus node region is a function of the total duration of the refractory period of the sinus node relative to the surrounding atrial tissue, the atrial conduction time, and the site of atrial stimulation. Consideration of these three variables is detailed schematically in Figure 10, which explains why So applied to the tip of the right atrial appendage during sinus rhythm only occasionally (2 dogs) resulted in sinus node reentry whereas S 2 applied to the base of the right atrial appendage more commonly (7 dogs) resulted in sinus node reentry and why sinus node reentry was regularly seen when the atrium was paced (18 dogs) but not so regularly seen when it was beating spontaneously (7 dogs). In Figure 10 the stimulus is applied to the tip of the right atrial appendage at. NSR 250 SN p mm p 40\1 \1 /2 \3 W 200 i210; <; : is R TIP C. NSR SN 10 1 }1 f2(3 R m! S R BSE FIGURE 10 B. NSR 300 SN m>m 40\1 \1 <2\3 '^1 ^ 200 J21O: S R TIP D. TRIL PCE SN mm 4O/1 /1 /2 \3 RJH mm, m TIP me mm?, ^ 200 pio^ S1 S1 S2 R TIP Schematic representation of postextrasystolic sinus suppression () and sinus node reentry (B, C, and D) when the stimulus is applied to the tip of the right atrial appendage during sinus rhythm (, B, and C) and during atrial pacing (D). The solid and the hatched areas depict the absolute and the relative refractory periods, respectively, of the sinus node. NSR = normal sinus rhythm, SN = sinus node, R = right atrial appendage, S = stimulus. See text for details.

8 462 PULY, VRGHESE, DMTO the shortest coupling interval, i.e., just outside the relative refractory period for that site. Because of the postulated conduction time of 40 msec from sinus node to right atrial appendage tip and from right atrial appendage tip to sinus node, 2 arrives at the sinus node outside its relative refractory period and sinus node reentry does not occur. (The refractory period of 250 msec for the sinus node and 200 msec for the surrounding atrial tissue is not inconsistent with previous findings [2, 3].) longer duration of refractoriness in the sinus node (300 msec) relative to the surrounding atrium (Fig. 10B) is one explanation for the occasional occurrence of sinus node reentry (2 dogs) when the stimulus is applied to the right atrial appendage tip: 2 falls within the relative refractory period of j. In contrast to Figure 10, the application of stimuli to the right atrial appendage base (Fig. 10C) results in sinus node reentry, because the short conduction time (10 msec) between right atrial appendage base and adjacent sinus node allows 2 to arrive in the sinus node region during its relative refractory period. trial pacing (Fig. 10D) effectively shifts the sinus node refractory period to the right and greatly facilitates sinus node reentry. Theoretically, if 2 arrives at the sinus node during its absolute refractory period, then entrance block (2) for 2 would occur. However, sinus node entrance block was not observed in this study, except possibly during strong vagal stimulation, because atrial latency at the site of stimulation or intra-atrial conduction delay probably prevented 2 from arriving at the sinus node during its absolute refractory period. Drury and Brow (2) failed to recognize that their experimental results in dogs were consistent with sinus node reentry, although the authors did recognize local atrial reentry and distinguished this phenomenon from what they considered to be sinus node entrance block. The authors failed to appreciate the significance of their observation that the sum of the "forced cycle" ( x - 2 ) and "returning cycle" ( 2 - s ) was frequently slightly less than the "natural cycle" (i- t ) during sinus rhythm or the "rhythmic to natural interval" (escape time) during atrial pacing. In 1934, Eccles and Hoff (10) focused on this numerical disparity and further stated that "it is not unlikely that the occasional occurrence of a subsequent beat ( 8 in the present study) at the moment when it would have arisen in the undisturbed pacemaker is merely a chance happening." Sinus node reentry was not considered by these authors. In this study the sum of the i- 2 and 2-3 intervals sometimes included values in the same dog that were less than, equal to, or slightly greater than the escape time of the sinus node. The specific value of this sum is determined by the coupling interval. When this sum exactly equals the escape time, sinus node entrance block is suggested. lternatively, this numerical equality may represent one point on a continuum during sinus node reentry that simulates sinus node entrance block. Wallace and Daggett (11) suggested that sinus node reentry could occur spontaneously during vagal stimulation. Because of the absence of multiple electrogram recordings in their study, we are unsure of the exact site of origin of the reentrant beat. lso the present study indicates that vagal stimulation abolishes sinus node reentry but perpetuates atrial reentry outside the sinus node (Fig. 6). The possibility that some atrial premature depolarizations and certain atrial tachyarrhythmias in man might represent sinus node reentry is suggested by this study. However, the relatively brief duration of the reentry zone may be a factor that limits the frequency with which sinus node reentry occurs. cknowledgment The authors gratefully acknowledge the technical assistance of David Berry, the secretarial help of nne Mazzella, and the photographic services of Kenneth Donohue. References 1. HN, J., MLOZZI,.M., ND MOE, G.K.: Sino-atrial reciprocation in the isolated rabbit heart. Circ Res 22: , DRURY,.N., ND BROW, G.R.: Observations relating to the unipolar electrical curves of the heart muscle with especial reference to the mammalian auricle. Heart 12: , CERVONI, P., WEST, T.C., ND FLK, G.: Multiple intracellular recording from atrial and sino-atrial cells: Correlation with contractile tension. Proc Soc Exp Biol Med 93:36-39, PULY, K.L., VRGHESE, P.J., ND DMTO,.N.: trial rhythms in response to an early atrial premature depolarization in man. m Heart J, in press. 5. DMTO,.N., LU, S.H., ND BOBB, G..: Studies on ventriculoatrial conduction and the reentry phenomenon. Circulation 16: , STRUSS, H.C., ND BIGGER, J.T., JR.: Electrophysiological properties of the rabbit sinoatrial perinodal fibers. Circ Res 31: , Circulation Research, Vol. XXX11, pril 1973

9 SINUS NODE REENTRY IN THE DOG WLDO,.L., BUSH, H.L., JR., GELBND, H., ZORNE, ology of the Heart. New York, McGraw-Hill, 1960, G.L., JR., VITIKINEN, K.J., ND HOFFMN, B.F.: pp Effects on the canine P wave of discrete lesions in the IQ. ECCLES, J.C., ND HOFF, H.E.: Rhythm of the heart specialized atrial tract. Circ Res 29: , beat. m Disturbances of rhythm produced by early 8. BONKE, F.I.M., BOUMN, L.N., ND SCHOPMN, J.G.: premature beats. Proc R Soc Lond [Biol] 115:352- Effect of an early atrial premature beat on activity of 369, the sinoatrial node and atrial rhythm in the rabbit. 1L WLLCE,.G., ND DGGETT, W.M.: Re-excitation of Circ Res 29: , the atrium. Th e echo phenomenon. m Heart J 9. HOFFMN, B.F., ND CRNEFIELD, P.F.: Electrophysi- 68: , Circulation Research, Vol. XXXII, pril 1973