Effect of digoxin on sinus nodal reentry in the dog

EXPERIMENTAL STUDIES

Effect of Digoxin on Sinus Nodal Reentry in the Dog

KARLEN L. PAULAY, MD ANTHONY N. DAMATO, MD

Staten Island, New York

From the Cardiopulmonary Laboratory, U. S. Public Health Service Hospital, Staten Island, N. Y. This work was supported in part by the Bureau of Medical Services, U. S. Public Health Service Project Py 75-1, and National Heart and Lung Institute Project HE 12536-04. Manuscript accepted July 24, 1974. Address for reprints: Karlen L. Paulay, MD, Cardiopulmonary Laboratory, U. S. Public Health Service Hospital, Staten Island, N. Y. 10304.

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The effect of digoxin on sinus nodal reentry was examined in 20 open chest mongrel dogs during infusion of digoxin at a rate of 2.5 pug/kg per min. The extrinsic cardiac nerve supply was removed acutely in 10 dogs and was left intact in the remaining 10 dogs. Sinus nodal reentry was relatively unaffected by digoxin in 18 of 20 dogs. In these 18 dogs, digitalis toxicity developed before reentry was abolished and was manifested as increased atrial and ventricular automaticity in 14 and as advanced atrioventricular (A-V) block in four. In the remaining two dogs, sinus nodal reentry was relatively sensitive to digoxin and was abolished before toxicity became manifest as advariced A-V block. The knowledge of the relative insensitivity of sinus nodal reentry to digoxin, at least in this experimental model, contrasts with the previously reported sensitivity of sinus nodal reentry to quinidine, and may be important in the management of sinus nodal reentry in man.

Atria1 arrhythmias consistent with sinus nodal reentry have been observed in the dogl,* and man2m4 and in isolated rabbit heart tissue.5 The requisite conditions for reentry, slow conduction and unidirectional block, are normally present in the sinus node in early atria1 diastole.” Digitalis may depress conduction in the sinus node by a direct effect on sinus nodal tissue” and by an indirect vagotonic effect.7mg Thus, it was speculated that digitalis could conceivably depress sinus nodal conduction sufficiently to prevent sinus nodal reentry from occurring. It was also speculated that the vagal effect of digitalis might resemble the effect of electrical stimulation of the vagus, which has been shown to abolish sinus nodal reentry.‘,* On the other hand, it was recognized that digitalis may actually cause reentry by its effects on conduction and refractoriness.1° The present study was undertaken to examine the effect of the commonly used cardiac glycoside digoxin on sinus nodal reentry in the dog. Methods Twenty mongrel dogs weighing 10 to 27 kg were grouped as follows: Group 1: 10 dogs anesthetized with intravenously administered pentobarbital, 30 mg/kg body weight, and with acute extrinsic cardiac denervation. Denervation involved bilateral stellectomy and thoracic ganglionectomy from T1 to Tq, and section of the cervical vagosympathetic trunks bilaterally. In these dogs the direct effect of digoxin on sinus nodal reentry was studied. Group 2: five dogs anesthetized with intravenously administered alphachloralose, 80 to 100 mg/kg (so as to avoid the vagolytic effect of pentobarbital), in which extrinsic cardiac denervation was not performed. In these dogs we attempted to study the indirect neurally mediated effects of digoxin, especially the well known vagotonic effect of the drug. Group 3: five dogs first premeditated with morphine sulfate, 3 mg/kg subcutaneously, and then anesthetized with intravenously administered alphachloralose, 80 to 100 mg/kg. Morphine was given to increase the number of dogs manifesting digoxin-induced vagotonia. I1 Extrinsic cardiac denervation was not performed in this group.

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FIGURE 1. Dog from Group 1. Sinus nodal reentry during stimulation of the left atrial appendage before (panel A) and during digoxin (DIG) infusion (panels 6 and C). BB = Bachmann’s bundle: ET = sinus nodal escape time; HBE = His bundle electrogram recorded from the low atrial septum; LAA = left atrial appendage: Ll = standard lead I; S = stimulus for the basic (S,) and premature (Ss) beats: SN = sinus nodal region: TL = time lines recorded at 10 and 100 msec intervals. The rapid deflections are retouched in this and subsequent figures for the purpose of reproduction. Details in text.

Recording Techniques In all animals body temperature was monitored by a rectal temperature probe and maintained at 37 f lo C by an electric heating pad. Teflon@-coated bipolar plunge wire electrodes12 were inserted into the regions of the sinus node, Bachmann’s bundle, coronary sinus, right atria1 appendage, left atria1 appendage and the low atria1 septum (His bundle electrogram). Recording and stimulating techniques have recently been described.’ In brief, basic pacing pulses were delivered to selected atria1 sites (left or right atria1 appendage or coronary sinus) at a rate of 150 to 2OO/min. After every 10th basic beat (Al), a premature beat (As) was introduced through the same stimulating electrodes and the atria1 cycle scanned at decreasing coupling intervals (10 to 20 msec decrements of Ai-Az) until the atria1 effective refractory period was reached. Basic pacing pulses were omitted for approximately 1.5 to 2.0 seconds after Az. For each basic cycle length the sinus nodal escape time was determined by omitting Az after the 10th basic beat. All atria1 intervals were measured from the electrogram recorded in the region of the sinus node unless otherwise stated. After control electrophysiologic measurements were made, digoxin was infused intravenously at a rate of 2.5 fig/kg per min after administration of a priming dose of digoxin, 7.5 fig/kg. Definition of Terms A, = the atria1 depolarization of a basic atria1 beat. AZ = the atria1 depolarization of an induced atria1 premature beat. As, Ad, As, etc. = subsequent atria1 beats. AI-AI = the atria1 interval measured during atria1 pacing. Ai-Az = the coupling interval measured from the last paced atria1 beat (Al) to the induced atria1 premature beat (Az).

Az-Aa = the interval measured from the induced atria1 premature beat (Az) to the subsequent atria1 beat (As). Al-As = the sum of the Ai-Az and As-As intervals. As-Ad, Ad-As, etc. = the interval between atria1 depolarizations subsequent to As. Si = the basic beat stimulus. Sz = the premature beat stimulus. Results Group 1 Characteristically, in these dogs, digoxin was ineffective in terminating sinus nodal reentry before toxicity developed (Fig. 1). In Figure 1, a record from a typical experinient, control sinus nodal reentry is shown in panel A. Atria1 activity was first recorded from the left atria1 appendage for both the basic driving (Al) and premature (As) beats, but was first recorded from the sinus nodal region for the sinus nodal reentrant beat (Aa) and for the subsequent spontaneous sinus beats (A4 and As). Atrioventricular (A-V) nodal conduction time, approximated by the A-H interval, measured 55 and 110 msec for the basic and premature beats, respectively. The Al-As interval of 180 msec recorded in the sinus nodal region was 10 msec less than the Si-Sz interval of 190 msec. This phenomenon was due to supernormal atria1 conduction for As between the left atria1 appendage and the sinus nodal region.i3 In panel B, 32 minutes after onset of the digoxin infusion, early digitalis toxicity was manifested as increased ventricular automaticity (open arrows) with ventricular fusion. The smafl increases over control values that occurred in the Ai-Az (5 msec) and AZ-As (25 msec) intervals were presumably due to the direct depressant effect of digoxin on conduction from the left atria1 appendage to the sinus node (increase in Ai-Az) and along the sinus nodal reentrant pathway (increase in Az-As). In panel C, after 40 minutes of digoxin infusion, in-

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FIGURE 2. Dog from Group 2. The presence (panels A and B) and absence (panels C and D) of sinus nodal reentry before (panel A) and during (panels 6, C and D) infusion of digoxin. Stimuli are applied to the right atrial appendage (RAA). Abbreviations as in Figure 1. Details in text.

creased ventricular automaticity with A-V dissociation was more evident and sinus nodal reentry was still present. Atria1 automaticity, also increased at this time, was more easily appreciated when Ss was omitted (panel 0). In panel D, the escape time measured on the sinus nodal electrogram decreased from the control value of 475 to 420 msec. This decrease in the atria1 escape time was due to the

emergence of a new and more rapidly firing atria1pacemaker with an atria1 activation sequence that clearly differed from the control spontaneous sinus beats. For example, in the control period before administration of digoxin (panel A), the sinus nodal electrogram preceded the Bachmann bundle electrogram for the sinus beats, whereas after 40 minutes of digoxin infusion (panel D) the Bachmann bundle electrogram preceded the sinus nodal eleetrogram for the ectopic atria1 beats.

Thus, in these 10 dogs in Group 1 sinus nodal reentry was relatively unaffected by digoxin and could be demonstrated at the onset of toxicity in all dogs. Digitalis toxicity was manifested as increased atria1 automaticity an average of 37 minutes (range 17 to 54 minutes) after the onset of infusion and as increased ventricular automaticity an average of 36 minutes (range 16 to 50 minutes) after the onset of infusion. When digitalis toxicity first appeared, the time for sinus nodal reentry measured by the AZ-As interval had increased in 9 of 10 dogs an average of 31 msec (range 5 to 70 msec). Since these were denervated animals the increase was presumably due to the direct effect of digoxin in delaying conduction along the sinus nodal reentrant pathway. The atria1 effective refractory period measured in eight dogs at the onset of toxicity increased in six dogs an average of 14 msec (range 10 to 30 msec) and remained unchanged in two dogs.

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Group 2

In four of five dogs the response to digoxin was similar to that previously described for dogs in Group 1; that is, digoxin failed to abolish sinus nodal reentry before the development of either increased atria1 or ventricular automaticity. Although in these four dogs the cardiac nerve supply was intact and chloralose anesthesia was used, vagal tone increased only minimally during the digoxin infusion. For example, when digitalis toxicity appeared the sinus nodal escape time and A-H interval had increased an average of only 5 and 9 msec, respectively. Possibly in these four dogs the stress of surgery did not allow for the indirect vagotonic effect of digoxin to become manifest. Figure 2 illustrates the response for the single dog in Group 2 in which vagotonia did develop during digoxin infusion. In panel A, control sinus nodal reentry is shown after premature stimulation of the right atria1 appendage. The sinus nodal escape time is 445, msec. A-V nodal conduction time for the basic and premature beats is 90 and 150 msec, respectively. In panel B, 31 minutes after the start of the digoxin infusion, the escape time increased 50 msec, and A-V nodal conduction time increased 35 msec for the basic drive beat and 70 msec for the premature beat. Sinus nodal reentry was still present, although the time for reentry had increased 70 msec. In panel C, 2 minutes later, the escape time increased another 90 msec, A-V nodal conduction time for the basic drive beat increased an additional 75 msec, the premature beat blocked in the A-V node, and sinus nodal reentry was abolished. The abolition of sinus nodal reentry may have been due to a vagally mediated conduction block along the sinus nodal reentrant pathway. A change in configuration of the sinus nodal electrogram for A:] occurred when sinus

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FIGURE 3. Dog from Group 3. The presence (panels A and B) and absence (panels C and D) of sinus nodal reentry before (panel A) and during (panels B, C and D) digoxin infusion. Stimuli are applied to the left atrial appendage. Abbreviations as in Figure 1. Details in text.

nodal reentry was abolished (Aa in panel C as compared with Aa in panel B). In panel D, 3 minutes later, the escape time increased an additional 355 msec, second degree A-V block developed, and sinus nodal reentry remained absent. Thus, in this dog, digitalis toxicity was manifested as A-V block, and advanced first degree A-V block (panel C) was present when sinus nodal reentry was first abolished.

Group 3 All of the 5 dogs in this group had a significant increase in vagal tone during the digoxin infusion as evidenced by a progressive prolongation of the A-I-I interval and a significant increase in the sinus nodal escape time. The sinus nodal escape time had increased an average of 280 msec when second degree A-V nodal block developed. In three dogs, second degree A-V block developed before sinus nodal reentry was abolished. In the remaining two dogs, sinus nodal reentry was abolished during digoxin infusion before a significant degree of A-V nodal conduction delay occurred, that is before the A-II interval of the basic driving beats exceeded 100 msec (Fig. 3). In the experiment shown in Figure 3, sinus nodal reentry was present during the control period (panel A) and 16 minutes after onset of the digoxin infusion (panel B). Six minutes later (panel C), and after an abrupt increase in the AZ-A3 interval, sinus nodal reentry was abolished at this and at all other coupling intervals. When panel C is compared with the control record (panel A) it can be seen that A-V nodal conduction time increased only 25 msec for

the basic driving beat when sinus nodal reentry was abolished. A-V nodal block for As in panel C occurred because of a short Al-A2 coupling interval and not because of a significant depressant effect of digoxin on A-V nodal conduction in general. In panel D, further increases in A-V nodal conduction and escape times occurred and sinus nodal reentry remained absent. Thus, in two dogs in which digoxin increased vagal tone sinus nodal reentry was abolished before a toxic degree of A-V nodal conduction delay had occurred.

Presumably in these two dogs, increased vagotonia depressed conduction relatively more in the sinus node than in the A-V node and sinus nodal reentry was abolished before a significant degree of A-V block occurred. Digitalis toxicity in the five dogs in Group 3 was manifested as A-V block. Second degree A-V block developed an average of 39 minutes (range 29 to 55 minutes) after onset of digoxin infusion and was associated in four of the five dogs with an average decrease of 16 msec (range 10 to 30 msec) in the atria1 effective refractory period. Discussion This study indicates that sinus nodal reentry atively unaffected by digoxin, especially when gotonic effect of digoxin is minimal or absent. of six dogs in which the vagotonic effect of was present, sinus nodal reentry was abolished digitalis toxicity developed.

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Vagal effects of digoxin and sinus nodal reentry: Previous studies in the dog’s” have shown that electrical stimulation of the right vagus nerve consis-

tently abolished sinus nodal reentry. It was speculated that the vagal effect of digoxin7 might resemble the effect of electrical stimulation of the vagus nerves and thereby terminate sinus nodal reentry. However, when digitalis increases vagal tone it does so in both right and left vagi, and conduction delay can therefore be expected to occur in both the sinus and A-V nodes. If digitalis delays conduction in the sinus node to a greater extent than in the A-V node, then sinus nodal reentry might be abolished before there is a significant degree of A-V nodal conduction delay (Fig. 3). However, if digitalis delays conduction in the A-V node to a greater extent than in the sinus node, then a high degree of A-V block might occur before sinus nodal reentry is abolished (Fig. 2). Only in the first instance could digitalis be considered useful therapeutically in terminating sinus nodal reentry. It was somewhat surprising that digoxin did not increase vagal tone in more than one of the five dogs in Group 2 with intact vagi. A possible explanation may be that the vagotonic effect of digitalis is related in part to increasing the sensitivity of the end organ, such as the sinus node, to the tonic influence of the vagus.14 Probably because little vagal tone existed before digoxin in these open chest dogs the expected vagal effect of digoxin was not seen in four of the five dogs in Group 2. The vagotonic effect of digoxin was seen in the dogs premeditated with morphine (Group 3), which is known to act centrally to increase vagal tone.15 Morphine may have established a resting level of vagal tone upon which digoxin could act. Digitalis toxicity and sinus nodal reentry: In the 14 dogs (10 in Group 1 and 4 in Group 2) in which digoxin had little or no vagal effect, digitalis toxicity manifested as increased automaticity developed before sinus nodal reentry was abolished. Although in most of these dogs the time for reentry was prolonged (increase in AZ-AS interval) because of a conduction delay along the reentrant pathway (presumably the direct effect of digitalis), the magnitude of this delay was inadequate to terminate sinus nodal reentry before digitalis toxicity developed. The method used to expose digitalis toxicity in this study deserves comment. Digitalis toxicity may be either manifest or concealed depending upon several factors. For example, digitalis-induced increased ventricular automaticity that becomes manifest when

the atria1 rate is relatively slow may become concealed when the atria1 rate is relatively fast. Cessation of cardiac pacing has been shown to “unmask” digitalis toxicity.16m1s Early stages of digitalis toxicity may be unmasked after the cessation of rapid cardiac pacing, and relatively later stages of still latent digitalis toxicity may be unmasked after the cessation of relatively slower rates of pacing. In the present study, digitalis toxicity was unmasked after the cessation of atria1 pacing that ranged between 150 to 200 beats/ min. Latent toxicity exposed in this manner usually preceded manifest toxicity during sinus rhythm by 5 to 15 minutes. If faster rates of atria1 pacing had been used then increased atriallg and ventricula9O automaticity would probably have been exposed after a smaller amount of digoxin had been given. Similarly, significant degrees of A-V block would have appeared sooner, after less digoxin, if atria1 pacing had been more rapid.17 A corollary possibility is that digoxin might have been more effective in terminating sinus nodal reentry that was induced during sinus rhythm rather than being induced during atria1 pacing as used in this study. For example, assume that digoxin increases vagal tone and decreases sinus rate. The decrease in sinus rate would tend to oppose the delay in A-V nodal conduction that might occur in response to increased vagal tone. Thus, during sinus rhythm digoxin might increase vagal tone to a point adequate to abolish sinus nodal reentry without an associated significant delay in A-V nodal conduction. Clinical implications: Sinus nodal reentry was relatively unaffected by digoxin in 18 of 20 dogs. In these 18 dogs, 10 with extrinsic cardiac denervation, digitalis toxicity was manifested as increased atria1 and ventricular automaticity in 14 and advanced A-V block in 4. In the remaining two dogs, sinus nodal reentry was relatively sensitive to digoxin and was abolished before digitalis toxicity became manifest as advanced A-V block. The knowledge of the relative insensitivity of sinus nodal reentry to digoxin, at least in this experimental model, contrasts with the previously reported sensitivity of sinus nodal reentry to quinidine,*l and may be important in the management of sinus nodal reentry in man. Acknowledgment We gratefully acknowledge the technical assistance of David Berry, the secretarial help of Anne Mazzella, and the photographic services of Kenneth Donohue.

References 1. Paulay KL, Varghese PJ, Damato AN: Sinus

node reentry: an in in the dog. Circ Res 32:455-463, 1973 2. Chllders RW, Ornsdorf MF, de la Fuente DJ, et al: Sinus nodal echoes: clinical case report and canine studies. Am J Cardiol 31:220-231, 1973 3. Paulay KL, Varghese PJ, Damato AN: Atrial rhythms in response to an early atrial premature depolarization in man. Am Heart J 85:323-33 1, 1973 vivo demonstration

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4. Weisfogel GM, Batsford WP, Paulay KL, et al: Sinus node reentrant tachycardia in man (abstr). Circulation 48:Suppl IV:IV-122, 1973 5. Han J, Malozzi AM, Moe GK: Sino-atrial reciprocation in the isolated rabbit heart. Circ Res 22:355-362, 1968 6. Klein HO, Singer DH, Hoffman BF: Effects of atrial premature systoles on sinus rhythm in the rabbit. Circ Res 32:480-491, 1973

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7. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, second edition, New York, Macmillan, 1958, p 668-710 8. Hoffman BF: Autonomic control of cardiac rhythm. Bull NY Acad Med 43:1087-1096, 1967 9. Hutter OF, Trautwein W: Vagal and sympathetic effects on the pacemaker fibers in the sinus venosusof the heart. J Gen Physioi 39:715-733, 1956 IO. Watanabe Y, Dreifus LS: Effects of digitalis on A-V transmission. In, Mechanisms and Therapy of Cardiac Arrhythmias (Leonard S, Dreifus LS, Likoff W, ed). New York, Grune & Stratton, 1966, p 373-383 II Mendez R, Mendez C: The action of cardiac glycosides on the refractory period of heart tissue. J Pharmacol Exp Ther 107: 24-35, 1953 12. Damato AN, Lau SH, Bobb GA: Studies on ventriculo-atrial conduction and the reentry phenomenon. Circulation 161423-435, 1970 13. Chiiders RW, Merideth J, Moe GK: Supernormality in Bachmann’s bundle: an in vitro and in vivo study in dogs. Circ Res 221363-370, 1968 14. Moe GK, Han J: Digitalis and the autonomic nervous system. in,

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Digitalis (Fisch C, Surawicz 8, ed). New York, Grune & Stratton, 1969. p 110-112 Wikier A: Sites and mechanisms of action of morphine and related drugs in the central nervous system. Pharmacol Rev 2: 435-506.1950 Casteiianos A Jr, Lemburg L, Centurion MJ, et al: Concealed digitalis-induced arrhythmias unmasked by electrical stimulation of the heart. Am Heart J 73:484-490, 1967 Kosowsky BD, Hafl JI, Lau SH, et al: The effects of digitalis on atrioventricular conduction in man. Am Heart J 75:736-742, 1968 Hagemeijer F, Lown B: Effect of heart rate on electrically induced repetitive ventricular responses in the digitalized dog. Circ Res 27~333-344, 1970 Wittenberg SM: Chronotropic effects of ouabain and heart rate on canine atrium in vivo. Circ Res 34:258-267, 1974 Wittenberg SM, Streuii F, Kiocke FJ: Acceleration of ventricular pacemakers by transient increases in heart rate in dogs during ouabain administration. Circ Res 26:705-716, 1970 Pauiay KL, Welsfogel BM, Damato AN: Sinus nodal reentry: the effect of quinidine. Am J Cardiol 33:617-622, 1974

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