Conduction defects in experimental atrial arrhythmia

Conduction defects in experimental atrial arrhythmia

btpetimentai Conduction arrhythmia and laboratory defects Patrick R. Montgomery, Peter E. Dresel, Ph.D. reports in experimental atrial M.D. Win...

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btpetimentai Conduction arrhythmia

and laboratory defects

Patrick R. Montgomery, Peter E. Dresel, Ph.D.

reports

in experimental

atrial

M.D.

Winnipeg, Manitoba, Canada

It has long been known that early ectopic beats may initiate atria1 arrhythmias. Clinical studies by continuous cardiac monitoring have shown that atria1 fibrillation and other atria1 arrhythmias are often preceded by premature atria1 activations, and that premature beats followed by arrhythmias have a shorter coupling interval than those which are not.1-4 In experimental animals, electrical stimuli placed early in diastole are well known to produce atria1 arrhythmias,3y5-g and acetylcholine is known to potentiate the effects of these shocks.“J”How shocks of near-threshold strength produce arrhythmias is controversial. We have studied the response of the atria to early diastolic stimuli in order to determine whether extrasystoles which result in arrhythmias are conducted in a different fashion from extrasystoles which do not. Attention was given to the specialized conducting system whose long refractory period, and relative insensitivity to acetylcholine11J2 might be of significance. Methods

Isolated dog hearts were perfused with blood from a donor dog by the technique of Alanis Gonzales, and Lopez,13 as modified by Kirk and Dresel.14The recipient hearts were obtained from mongrel 10 to 15 kilogram dogs of either sex, anesthetized intravenously with Na-pentobarbital (30 mg. per kilogram). They were rapidly removed to cold, oxygenated Krebs-Henseleit From the Department Medicine, University This

work

Received

was

supported

for publication

Reprint requests and Theraputics, nipeg, R3E OW3,

August,

of Pharmacology and Therapeutics, of Manitoba, Winnipeg. by the Medical July

Research

Council

Faculty of Canada.

19, 1973.

to: Dr. P. E. Dresel, Faculty of Medicine, Manitoba, Canada.

Department University

1974, Vol. 88, No. 2, pp. 191-197

of Pharmacology of Manitoba, Win-

of

solution, the pericardium and adjacent tissues were removed, and the heart was perfused through the aorta. In most cases, the ventricles fibrillated when perfusion was begun and they were allowed to do so throughout the experiment. In all cases, the atria beat spontaneously at a regular rate. The donor dog was anesthetized with Na-pentobarbital (30 mg. per kilogram), heparinized (400 units per kilogram), and respired with 100 per cent oxygen with a Palmer Ideal pump. A double-headed DeBakey roller pump was used to perfuse the recipient heart with blood from the carotid artery. Perfusion pressure was 100 mm. Hg. The temperature of the perfusate was kept at 37 +- 0.5” C. by a water-jacketed coil condenser at the inflow. Coronary venous outflow was collected in a funnel and returned to the donor jugular vein via the second head of the roller pump. The surface of the heart was kept moist by frequent application of 0.9 per cent NaCl solution warmed to 37” C. Four sets of bipolar silver recording electrodes were sewn to the atria1 epicardial surface. One set was placed on the anterior left atrium over Bachman’s bundle, approximately 35 mm. from the stimulating electrodes (see below). One set was placed either on the left atria1 appendage or on the posterior surface of the left atrium beneath the pulmonary veins, about 65 mm. from the stimulating electrodes in either case. Electrodes were sewn over the s&us terminalis (20 mm.) and either on the tip of the right atria1 appendage (30 mm.) or on the anterior right atrium, less than 10 mm. from the stimulating electrodes. Potentials from these four electrodes were monitored and recorded with an Electronics for Medicine recorder at 20 cm. per second paper speed with filter settings 4/500. Records were analyzed with the aid of a cali-

American

Heart Journal

19 1

Montgomery and Dresel

Fig.

1.

normal one to sulcus trodes. tween RA; 0

Left side: atria1 electrograms showing arrhythmia after a single extra stimulus. The last beat of the drive CN) and the extra stimulus Cx) 126 msec. later are followed by five unstimulated beats labeled five. Time lines are 40 msec. apart, electrode positions are RA -right atrium near stimulus origin, ST terminalis, LA -left atrium, and BB -Bachman’s bundle. Right side: order of activation of the elecThe intervals between successive potentials is plotted for eachof the electrode positions. Intervals bethe last normal beat, the single extra stimulus, and each unstimulated beat are shown. Symbols: 0 -LA; A -ST; 0 -BB.

brated loupe, with conduction times measured with a precision of f 0.5 msec. from the stimulus artifacts to where the intrinsic biphasic deflection of the atria1 electrograms crossed the baseline. The hearts were driven at rates suflicient to suppress natural pacemakers with steel-clip electrodes placed on or near the sinoatrial @A) node. A Tektronix stimulator (Type 161,162) yielded 5 msec. square wave pulses of 1.5 threshold strength. The basal drive was electronically counted and one to four extra stimuli were added after every twentieth beat. These were timed by a quartz crystal controlled pulse generator (Digitimer, Devices). The regular drive could be interrupted for variable periods during and after the extra stimuli. Acetylcholine chloride (Sigma Chemicals) was infused into the perfusate by means of a continuously variable Harvard pump, and its concentration calculated by measuring the venous outflow. Results The effects of single extra stimuli. Extra stimuli placed early in diastole resulted in speeding of conduction of up to 15 per cent to all electrode positions. This phase of supernormal conduction was present in 9 out of 14 hearts and occurred

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most commonly at coupling intervals of 140 to 200 msec.“J2 By placing an extra stimulus progressively earlier, i.e., beyond the supernormal period, it was possible to produce a transient arrhythmia consisting of 1 to 10 unstimulated beats starting less than 150 msec. after the last stimulus. Fig. 1 shows a typical occurrence. The top tracing, taken from an electrode 6 mm. from the stimulus electrode, shows large stimulus artifacts which precede the atria1 electrograms of the last beat of the regular drive (NJ and of the single extra-stimulated beat (X1. Starting 90 msec. after the last stimulus, there is a series of five unstimulated beats at an irregular rate of approximately 600 per minute. The shape of the potentials differs between the stitiulated and unstimulated beats; this is especially noticeable in the top tracing. The right half of Fig. 1 compares the order of activation of the electrodes by plotting the intervals between successive potentials. If the origin of the unstimulated beats were tissue under the stimulating electrode, the intervals between successive potentials would most probably be similar for all of the electrodes. This was not the case, especially for the last three unstimulated beats, all of which appear to have originated from different loci. Effects of multiple extra stimuli. Arrhythmia could only infrequently be produced with a single

August, 1974, Vol. 88, No. 2

Conduction defects in experimental atria1 arrhythmia

A. RAA ;; 80 01 E

ST IAA

4M Coupling

interval

( msec)

Fig. 2. Conduction times to the four electrodes of a second extra stimulus as the coupling interval is decreased. Times are plotted from the last normal beat. The first, ineffective extra stimulus was given at 90 msec. Arrhythmia occurred at the times shown between the dotted lines. Symbols as in Fig. 1.

RAA

ST LAA

extra stimulus. We therefore introduced series of up to four extra stimuli in most experiments. The first of the series was timed 5 to 10 msec. after the effective refractory period (ERP),16 and a second stimulus was added at progressively shorter intervals until arrhythmia was produced or the ERP was reached. Third and fourth extra stimuli were also added, with the preceding stimuli placed 5 to 10 msec. outside the ERP or at intervals 5 to 10 msec. longer than the maximum interval at which they had caused arrhythmia. Two stimuli were sufkient to cause arrhythmia in most hearts. Series of three or four stimuli were always effective. Nevertheless, our data do not indicate a statistically significant difference between two, three, and four stimuli in their efficacy to produce arrhythmias. However, repeated production of transient arrhythmias by multiple extra stimuli facilitated the production of arrhythmias by stimuli found inadequate previously. Thus a single, previously ineffective stimulus was often able to produce arrhythmias for a short time following repeated arrhythmias produced by multiple extra stimuli. Fig. 2 shows the conduction times of a second extra stimulus as the coupling interval was shortened in steps of 4 msec. Arrhythmia occurred when this stimulus was timed 182 and 186 msec. after the last normal driven beat (92 and 96

American Heart Journal

BB Fig. 3. Sequencesof extra stimuli that are ineffective and effective in producing arrhythmia. Explanation in test. Electrode positions RAA -right atria1 appendage, ST -sulcus terminal& LAA -left atria1 appendage, and BB -Bachman’s bundle.

msec. after the first extra stimulus of the series), but the very earliest conducted heats did not produce arrhythmia. Thus, there is a limited range of coupling intervals over which arrhythmia could be produced. A similar range could be demonstrated one or more times in six out of seven hearts by some combination of one or more stimuli, but in many other cases the range of effective coupling intervals reached the effective refractory period. The width of the range within which arrhythmia could be induced varied from 4 to 24 msec. We found no indication of altered conduction to the various recording sites of stimuli which caused arrhythmia. The curves of conduction times in Fig. 2 are parallel within the arrhythmic range. This was the general finding. The single exception was an experiment in which there was rapid change in conduction times to

193

Montgomery

and Dresel

BB

Fig. 4. Onset of fibrilatory arrhythmia. Electrode positions as in Fig. 1.

Explanation

in text.

the sulcus terminalis electrode, producing a sigmoid-shaped curve within the arrhythmic range. Fig. 2 shows that extra stimuli which cause arrhythmia appear to have the same conduction times as extra stimuli which do not, except for the small changes due to increasing refractoriness. This is illustrated in Fig. 3. Fig. 3, A shows atria1 electrograms from a heart in which the last beat of the regular drive, as well as four extra-stimulated beats are seen. In Fig. 3, B, the last stimulated beat is timed only 2 msec. earlier than in Fig. 3, A. Multiple unstimulated beats now follow. There is no difference in the shape of the stimulated potentials between A and B, and the conduction times of the last stimulated beat in B are only 1 to 3 msec. longer than in A. This was true in all the hearts studied. Thus, the production of arrhythmia could never be associated with specific changes in conduction to any of the electrodes. Effects of acetylcholine. Acetylcholine chloride was infused at varying rates to obtain concentrations of 0.5 to 8.0 pg per milliliter. As expected, there was speeding of conduction of normal driven beats and of extra stimuli. The effective refractory period was diminished and the supernormal phase of conduction abolished.11J2 Acetylcholine facilitated the production of atria1 arrhythmias. Concentrations below 2.5 pug per milliliter usually had no effect. High concentration (4 to 8 I.cg per milliliter) caused a sustained atria1 arrhythmia with onset during the regular drive. We define sustained arrhythmia as one which persisted until shortly after cessation of the infusion. With intermediate concentrations of acetylcholine, transient or sustained and often disorganized atria1 arrhythmias could be produced by extra stimuli. Multiple extra stimuli

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and shorter coupling intervals favored the production of a sustained arrhythmia, but the acetylcholine concentration was also critical in determining the type of arrhythmia. A single extra stimulus could produce transient arrhythmia in all hearts in the presence of intermediate concentrations of acetylcholine. Arrhythmias produced by extra stimuli were studied in the same manner as described above for the control conditions. Changes in conduction times to any of the electrodes again could not be related causally to the production of arrhythmias. Onset of disorganized arrhythmias. This arrhythmia was characterized by continuous, rapid, low-voltage activity recorded from at least one electrode. There were two modes of onset. Fig. 4 shows an experiment in which the onset of disorganized activity was abrupt. The last beat of the regular drive and one extra stimulus timed 116 msec. later are followed by a sustained arrhythmia. The top two tracings taken from the right atrium show the arrhythmia beginning with three well-formed potentials more than 80 msec. apart. The top tracing was taken from a site less than 10 mm. from the stimulating electrode. The second tracing, taken from the sulcus terminalis shows the abrupt onset of disorganized activity at the arrow. Before the onset of disorganized activity, the electrode on the sulcus terminalis was activated later than the anterior right atrium except for the beat immediately preceding the arrow in which the activations occur simultaneously. The left atria1 electrode stopped following the other recording sites at the same time, but disorganized activity did not result from this change in order of activation. The electrode near Bachman’s bundle first shows an irregular series of unstimulated beats timed 80 to 100 msec. apart. Four hundred milliseconds after disorganized activity appeared in the sulcus terminalis electrode, similar activity appears in this record at the arrow. Note that the rate of the unstimulated beats did not accelerate prior to the abrupt onset of disorganized activity. This illustration is typical in that disorganized activity was often recorded by one or two electrodes without involvement of the other sites. The site from which disorganized activity was first recorded varied. The other mode of onset is shown in Fig. 5. Here, disorganized activity begins after an accelerating tachycardia.

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Conduction

The last normal beat and three stimulated extra beats are followed by unstimulated beats at a rapidly increasing frequency leading shortly to disorganized activity under the Bachman’s bundle electrode. This process is also seen in the other left atria1 electrode, but is not reflected in electrograms taken from the right atrium. The two modes of onset of disorganized activity were seen with equal frequency, each heart usually showing only one kind. The dissociation of frequency of activation between atria and between electrodes on the same atrium, demonstrated in Figs. 4 and 5, was seen commonly. Variability in the conduction times produced by caused dose-related acstylcholine. Acetylcholine

variations in the conduction times of extra stimuli. This was studied by recording consecutive sequences of a single extra stimulus introduced at a constant coupling interval after every twentieth beat of the regular drive. Fig. 6, A shows the results in the absence of acetylcholine; there is little variability in the conduction times of the extra stimulus. In Fig. 6, B, acetylcholine was present at a concentration of 2.6 pg per milliliter, an amount insufficient to allow the production of arrhythmia in that heart. Considerable variability is demonstrated in the conduction times to the electrodes, although none of these beats were followed by an arrhythmia of any kind. In Fig. 6, C, acetylcholine was present at 3.1 pg per milliliter, an amount sufficient to allow the induction of sustained disorganized arrhythmias when multiple extra stimuli were introduced. At this concentration, there is gross variability, and transient arrhythmias occurred after several of the (single) extra stimuli. The shape of the potentials also varied. The other two electrodes showed the same variations in conduction times illustrated in Fig. 6, C. However, many examples were seen in which variations of conduction times between the same beats were widely different between electrode positions. Whenever great variability was seen, a sustained disorganized arrhythmia could be induced quite easily by additional extrasystoles, by changes in the timing of the single extrasystole, or without known change in experimental conditions (Fig. 7). Despite the gross variability, specific changes in conduction to any one electrode or in the pattern of conduction to the four electrodes could not be linked to the subsequent occurrence of arrhythmia, either transient or sustained. An extra

American

Heart

Journal

defects in experimental

atria1 arrhythmia

LA

Fig. 5. Onset of fibrilatory arrhythmia. Electrode positions as in Fig. 1.

Explanation

in text.

C.

Ach 3.1 Fig. 6. Variability of conduction times caused by acetylcholine. Consecutive sequences of conduction times of normal extra stimuli interpolated after every twentieth driven beat without acetykholine present (control), at 2.6 /*g per milfiliter, and at 3.1 pg per milliliter. Symbols as in Fig. 1.

beat resulting in arrhythmia could be conducted slower, faster, or the same as the immediately preceding extra beat which did not cause arrhythmia. Fig. 7 illustrates this point with consecutive sequences showing the last normal beat followed by an extra stimulus 90 msec. later. In Fig. 7, A, the extra stimulus is not followed by any arrhythmia, while in Fig. 7, B, a sustained but not disorganized arrhythmia ensues. The conduction times of the stimuli are the same in A and B, as are the shapes of the stimulated potentials. In two hearts, a disorganized arrhythmia

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Montgomery and Dresel

WAA

7. Variability in efficacy of a single extra stimulus. A, couplinginterval 90 maec.,no arrhythmia. B, after 19 beats at the usualrate; couplinginterval the same;arrhythmia. Fig.

which reverted spontaneously within 30 to 180 seconds could be induced in the absence of acetylcholine. Gross variability of conduction times was. also found under these conditions. Variability was not seen in other hearts under similar conditions when a prolonged arrhythmia could not be induced.

Extra stimuli placed early in the diastolic period produced transient arrhythmias. Our hypothesis was that the effectiveness of such extra stimuli should be associated with a change in the pattern of their conduction to the recording electrodes. However, we failed to demonstrate any changes in conduction that could be related causally to the production of arrhythmia, either in the presence or the absence of acetylcholine. Explanations for the mechanism allowing production of arrhythmia must consider the major theories concerning atria1 arrhythmia; i.e., a circus movement., activation of latent automatic foci, and re-entry. The possibility of a classic circus movement of Rosenblueth and Garcia RamoP is unlikely because there was no regularity in the sequence in which the electrodes were activated during arrhythmia (Fig. 11, because we show that the activity could be local (Fig. 41, and because the unstimulated beats came at an irregular frequency. Our results are, therefore, clearly different from those of Allessie,

Bonke, and Schopmanl’ who demonstrated recently that tachycardias induced by single extrasystoles in isolated rabbit left atria are due to circus movements. Differences in the size of the atria, the species, or the oxygen supply, as well as the possible exclusion of the atria1 conducting system from their preparations, may all have contributed to the opposite results in the two laboratories. Activation of a single rapidly firing focus as proposed by ScheflBis unlikely. The arrhythmias appeared to originate from multiple regions of the atria, their rate was irregular and was different at different recording sites. The sinus node has been shown to be of importance in the production of atria1 fibrillation.lv Multiple re-entry at, this location cannot be excluded in some of our experiments (Figs. 5 and 7), but other experiments show that this cannot be the only site of origin of the unstimulated beats. Supra-threshold induction shocks in the ventricle20 as well as 1.5 X threshold shocks in the atria6 have been shown to cause high-frequency discharges from under the stimulating electrode. Electrograms in those studies showed an accelerating series of potentials best. seen near the stimulating electrode. We cannot exclude this mechanism in some of our experiments in which an accelerating tachycardia was observed in some electrodes. However, other experiments represented by Fig. 4 are incompatible with this mechanism because even electrodes very close to the stimulus origin do not. show an accelerating tachycardia. A re-entry mechanism in the body of the atria best fits our observations. The multiple sites of origin of the unstimulated beats might be expected with re-entry occurring at different sites within the tissue. The existence of a range of coupling intervals within which arrhythmia could be induced is also suggestive, since the timing of extrasystoles is critical for the occurrence of re-entry. Stimuli timed too early or too late would fail to complete the re-entry pathway. Acetylcholine, which facilitated the production of and changed the character of the arrhythmias, is well known to shorten the refractory period and to speed conduction. We have shown that acetylcholine produces variability in conduction times to the sites of the recording electhat is not always in the same trodes, variability

direction for different electrode positions. We also observed that the shape of the potentials August, 1974, Vol. 88, No. 2

Conduction defects in experimental atrial arrhythmia

produced by early extra stimuli were variable that multiple after acetylcholine, suggesting pathways for activation of the recording sites were present after the drug. All these properties would enhance the possibility for re-entry. We observed that one electrode, or one atrium frequently showed disorganized activity while the other electrodes showed activity at a much slower frequency (Fig. 51. This indicates conduction block, a necessary condition for re-entry. Unidirectional block and greatly abbreviated action potentials have recently been demonstrated to occur in atria1 tissues under special conditions.21 These phenomena have been shown by Sasyniuk and Mendezz2 to be important precursors for re-entry occurring in the ventricle. Sharma23 showed evidence for re-entry in aconitineinduced arrhythmias but did not observe dissociation of the atria. However, Byrne and Drese124 have observed inter-atria1 block during the recurrence of aconitine-induced atria1 fibrillation after direct current counter shock. Re-entry in the ventricle has been demonstrated at junctions with a low safety factor of conduction as well as at sites where conduction velocities differed in adjacent groups of cells.22925 The atria1 musculature has generally been considered to be syncytial, but considerable attention has been given recently to specialized conducting fibers which differ from muscle in having a faster conduction velocity and a longer refractory period. Acetylcholine shortens refractoriness more in muscle than in conducting fibers, thus increasing the differential between them.11 It would appear possible, therefore, that junctions of atria1 muscle and conducting system fibers may be involved in atria1 reentry. REFERENCES

1. Killip, T., and GauIt, J. H. : Mode of onset of atria1 fibrillation in man, AM.HEART J. 70:172,1966.. 2. Bennett, M. A., and Pentecost, B. L.: The pattern of onset and spontaneous cessation of atria1 fibrillation in man, Circulation 41:981, 1970. 3. Csapo, G.: Role of ventricular premature beats in initiation and termination of atria1 arrhythmias, Br. Heart J. 33:105,1971. 4. Rytand, D. A.: Electrocardiographic patterns of the termination of atria1 flutter, AM. HEART J. 74:741,1967. 5. Sano, T., and Scher, A. M.: Multiple recording during electrically induced atria1 fibrillation, Circ. Res. 14117, 1964.

American Heart Journal

6. Grias, O., Gilbert, J. L., Siebens, A. A., Suckling, E. E., and McC. Brooks, C.: Effectiveness of single rectangtdar electrical pulses of known duration and strength in evoking auricular fibrillation, Am. J. Physiol. 162219, 1950. 7. Alessi, R., Nusynowits, M., Abildskov, J. A., and Moe, G. K.: Nonuniform distribution of vagal effects on the atria1 refractory period, Am. J. Physiol. 194~406, 1968. factor in 8. Hoff, H. E., and Geddes, L. A.: Choline&c auricular fibrillation, J. Appl. Physiol. 9177, 1965. 9. Dawes, G. S., and Vane, J. R.: Repetitive discharges from the isolated atria, J. Physiol. 112:28P, 1951. 10. Andrus, E. C., and Carter, E. P.: The refractory period of the normally beating dog’s auricle; with a note on the occurrence of auricular fibrillation following a single stimulus, J. Exp. Med. 51:357, 1930. 11. Wagner, M. L., Lasxara, R., Weiss, R. M., and Hoffman, B. F.: Specialized conducting fibers in the interatrial band, Circ. Res. 19502, 1966. 12. Childers, R. W., Meredith, J., and Moe, G. K.: Supernormality in Bachman’s bundle, Circ. Res. 22363, 1968. 13. Alanis, J., Gonzales, H., and Lopez, E.: The electrical activity of the bundle of His, J. Physiol. 142:127, 1958. 14. Kirk, B. W., and Diesel, P. E.: Effects of amodiaquin and quinidine on cardiac conduction, Can. J. Physiol. Pharmacol. -29, 1965. 15. Hoffman, B. F., Kao, C. Y., and Suckling, E. E.: Refractoriness in cardiac muscle, Am. J. Physiol. 190~473, 1957. 16. Rosenblueth, A., and Garcia Ramos, J.: Studies on flutter and fibrillation. II. The influence of artificial obstacles on experimental auricular flutter, AM. HEART J. 33:677, 1947. 17. Allessie, M. A., Bonke, F. I. M., and Schopman, F. J. G.: Circus movement in rabbit atria1 muscle as a mecha nism of tachycardia, Cire. Res. 33:54, 1973. 18. Scherf, D.: The mechanism of flutter and fibrillation, AMHEART J. 71:273,1966. 19. Nadeau, R. A., Roberge, F. A., and Billette, J.: Role of the sinus node in the mechanism of cholinergic atrial fibrillation, Circ. Res. 27:129, 1970. 20. Moe, G. K., Harris, A. S., and Wiggers, C. J.: Analysis of the initiation of fibrillation by electrographic studies, Am. J. Physiol. 134:473, 1941. 21. de la Fuente, D., Sasyniuk, B. I., and Moe, G. K.: Conduction through a narrow isthmus in isolated canine atria1 tissue, Circulation 44:803, 1971, 22. Sasyniuk, B. I., and Mendez, C.: A mechanism for re-entry in canine ventricular tissue, Circ. Res. 28:3, 1971. 23. Sharma, P. L.: Mechanism of atria1 flutter and fibrillation induced by aconitine in the dog, with observation on the role of cholinergic factors, Br. J. Pharmacol. 21:368, 1963. 24. Byrne, J. E., and Dresel, P. E.: The efficacy of antiarrhythmic drugs in the prevention of recurrence of aconitine-induced atria1 fibrillation after electrical conversion, Can. J. Physiol. Pharmacol. 4890, 1970. 25. Myerburg, R. J., Steward, J. W., and Hoffman, B. F.: Electrophysiological effects in canine peripheral A-V conduction system, Circ. Res. 26361, 1970.

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