Action of Driving Stimuli from Intrinsic and Extrinsic Sources on in Situ Cardiac Pacemaker Tissues

Action of Driving Stimuli from Intrinsic and Extrinsic Sources on in Situ Cardiac Pacemaker Tissues By Gertrude Lange, Ph.D. It is common knowledge that the heart possesses subsidiary pacemaker tissues capable of initiating effective heart action in the absence of normal sinoatrial node function. 1 ' 2 When sinoatrial node pacemaker action is stopped by crushing or by quick inactivation, a heart beat originates in the atrioventricular conducting system or from another region of the myocardium but only after some delay, as though "latent" or subsidiary pacemakers are normally somewhat depressed. Furthermore, these subsidiary pacemakers do not immediately attain their maximum rate of action after inactivation of the sinoatrial node. Termination of imposed drive may likewise result in a period of asystole followed by slow acceleration of pacemaker action. As early as 1884, Gaskell 3 found that intrinsic pacemaker activity tended to be inhibited by a series of rapidly applied stimuli. Among the problems which have been encountered by those who deal with failure of intrinsic pacemakers and with the use of artificial cardiac pacemakers 4-5 are subnormality of function related to pacemaker placement, the consequences of various rates of drive, and the abnormality of cardiac activity subsequent to drive termination. In studies of isolated tissues it has been found that after imposed drive there is a period of depressed activity followed by a late acceleration of pacemaker action. 0 " 8 In the work to be re- From the Department of Physiology, Downstate Medical Center, State University of New York, Brooklyn, New York. Supported by a grant from the Life Insurance Medical Research Fund to Dr. C. McC. Brooks. In partial fulfillment of the requirement for the degree of Doctor of Philosophy in Biology, New York University. Accepted for publication May 27, 1965. ported here an attempt was made to analyze the bases for the post-drive phenomena observed in the intact heart. Results obtained have bearing on the question of how pacemakers maintain their dominance and on the problem of ectopic beat origin. It provides further information concerning factors which influence pacemaker action in the intact heart. Methods In all 32 experiments from which data are reported, male dogs anesthetized with pentobarbital sodium (30 mg/kg) were used. The heart was exposed by a midsternal incision and supported in a pericardial cradle. Artificial respiration was established and body temperatures maintained at approximately normal levels (35 to 38 C). Small plastic-encased silver wire electrodes were stitched to the superficial tissues of the myocardium. 9 These were used either for driving or for recording electrical activity. Customarily three pairs were attached to the right atrium, one over the sinoatrial node, another at the extreme tip of the right auricle, and a third toward the base midway between. Three ventricular electrodes were placed, one at the base of the right ventricle and the others at the apex of each chamber. Electrograms as desired were recorded on a four-channel Sanborn electrocardiograph, model 964. Limb lead electrocardiograms were taken simultaneously and femoral artery pressures were monitored continuously. For driving the heart a stimulation circuit incorporating and depending upon a digital timer (Devices Sales Ltd., model no. DD4-41) was used. This permitted drive cycle length gradients from 50 to 2000 msec with variations in constancy of less than 5 msec. Strengths of the 1 msec duration rectangular pulse driving stimuli were monitored by means of an ammeter incorporated in the circuit, and were normally held at twice threshold strengths (1 to 2 milliamperes). In some experiments the heart was driven from the electrodes attached to atrium or ventricle merely by imposing rates of stimulation faster than those of the intrinsic pacemaker in the sinoatrial node. Other details of this procedure will be described with the reporting of results. Circulation Research, Vol. XVII, November 1965 449

450 LANGE When action of pacemaker tissues other than those of the sinoatrial node were to be studied, this node was inactivated by crushing. 9 Clamps remained on and the sinoatrial node was never permitted to recover its action. Atrioventricular block was similarly produced by a clamp introduced through the right atrium. Dextran or saline was occasionally administered by intravenous drip and drugs were given by means of a multispeed infusion-withdrawal pump. Cardiac denervations were performed by cutting the vagi and removing the thoracic sympathetic chains, as well as the stellate and cervical ganglia. Other procedures employed will be described in the course of presentation of results. Results Following crushing of the sinoatrial node a few rapid atrial and ventricular beats were recorded frequently but with few exceptions a period of asystole soon occurred, followed by development of a slower rate of beating paced usually from the atrioventricular nodal region. When the heart was then driven through an artificial pacemaker at the control rate, and drive abruptly terminated, a similar depression of rate occurred but usually one of slightly different duration. Figure 1 is from one of the six experiments in which this exact procedure was followed. As shown, a temporary overshoot or late acceleration occasionally occurred following crushing of the SA node before a new basal rate was established. The consequences of atrial drive imposed on the normal heart with sinoatrial node intact depended to a major degree upon rate and duration of the drive. A drive of somewhat less than ten to fifteen per cent above the intrinsic rate generally provoked a compensatory acceleration within the sinoatrial pacemaker which resulted in resetting of pacemaker discharge at a temporarily higher level. Figure 2 is from one of the six experiments in which such slow driving was attempted and it typifies the reactions observed. Similarly, brief periods of atrial flutter were occasionally followed by a temporary acceleration of the sinoatrial node's pacemaker action. When stimuli were applied at rates identical with or slightly lower than the (fig I) r Drive oo-oo-o 6 & / // ' 1H 10 15 30 60 FIGURE 1 Development of AV nodal pacemaker action following cut-off of drive from SA node by crushing: connected filled circles show heart rate before (to left of bar) and after crushing (to right of bar). Note oscillation, temporary overshoot, before assumption of post-crushing control rate. Connected open circles show AV nodal rate before, during, and after a five minute drive of this heart at its initial (SA node) rate. Circulation Research, Vol. XVII, November 1965

EFFECTS OF IMPOSED DRIVE ON PACEMAKERS 451 intrinsic rate, a temporary atrial flutter or, fibrillation frequently developed or, in other instances, a less disorganized rhythm of response occurred. Similarly, when driving the ventricle directly after the sinoatrial node had been crushed, atrioventricular nodal rhythm tended to accelerate and break through and drive, if pacing at cycle lengths only slightly above nodal rhythms was attempted. The ability of an intrinsic pacemaker to continue competitive action and even to accelerate when slow extrinsic drive was attempted was so clearly demonstrated initially that this was tested directly in only eight experiments. Driving of the normal intact heart from an atrial pacemaker at rates greater than twenty per cent above the intrinsic rate invariably resulted in an initial post-drive depression of o UJ CO 200 - - IUJ l Ul o 5 500-600 2 4 6 8 10 12 14 16 " 20 30 '60 i«««figure 2 Temporary acceleration and resetting of SA node pacemaker action (filled circles) due to a drive only slightly in excess of intrinsic rate. Depression (crosses) following a faster rate of drive. 1SEC 2 2 ENGTH _i UJ o 200 200 500 Drive 5 min 15 min. j is" f : i i! i Y A y~r> 8 5 min B 12 FIGURE 3 A: post-drive depression resulting from different durations and B: different rates of drive. Rates expressed in terms of cycle length. Initial control intrinsic rates are shown preceding drive. Circulation Research, Vol. XVII, November 1963

452 LANGE S-A NOOE INTACT S-A NODE INTACT < z o 20 40 60 HO 100 120 i </> I 0 O (fig.4) 100 200 RATE OF DRIVE (Bears / min) 20 40 60 80 100 DURATION OF DRIVE sec I FIGURE 4 A and B: post-drive depressions related to rate of drive, expressed in terms of excess time required for the first 20 beats. Rate of atrial drive shown on abscissa in beats per minute. Durations of drive expressed in seconds (3, 9, 18, 62, 47). It can be seen that suppression is somewhat less following longest drive. C and D: show durations of depression following termination of fast drives and fibrillations of varying durations. Longer drive is shown to have somewhat less depressant effect than did intermediate durations of driving (particularly after the sinoatrial node was eliminated as in D). sinoatrial node activity. The intensity and duration of the depression became greater as rates and durations of drive were increased (fig. 3). This trend was reversed at very high rates or when the fast driving continued for long periods of time (fig. 4). There was considerable variation in the duration of drive which produced maximal post-drive depression, but in general it can be said that, after a few minutes, some adaptive adjustments occurred. However, following imposed drives of thirty minutes or an hour very significant postdrive depression of the SA node was still observed. It is interesting that equal periods of atrial fibrillation, which can be considered as comparable to an abnormally fast drive, had similar depressant effects (fig. 4C and D). When the heart was driven from a right ventricular pacemaker some post-drive depression of sinoatrial node pacemaker action was seen but it was not as intense or long lasting as that produced by similar rates and durations of drive from a pacemaker located on the left atrial appendage. On the other hand, drive from a pacemaker attached to the surface of the atrium just above the sinoatrial node gave much greater degrees of depression (fig. 5). When after crushing the sinoatrial node the atrioventricular node was serving as the in- Circulation Research, Vol. XVII, November 1965

EFFECTS OF IMPOSED DRIVE ON PACEMAKERS 453 trinsic pacemaker it was found to be much more readily depressed by imposed fast drive than was the sinoatrial node pacemaker under similar circumstances (fig. 6). It was also found that imposed drive from an atrial pacemaker depressed AV nodal action much more than did drive from a ventricular pacemaker. As in the case of the SA node, faster rates and longer durations of drive produced greater depressions as already shown in figure 4B and D. In those preparations in which crushing of the sinoatrial node was followed by establishment of intrinsic drive from a lower atrial (inverted P wave and short PR interval), rather than an AV nodal pacemaker, drive from atrium or ventricle depressed this atrial pacemaker's action more severely than such drives had previously depressed the sinoatrial node. Idioventricular pacemakers, however, showed much less depression following imposed ventricular drive than did other pacemakers studied. They, like the AV node, however, required some time to come into action and establish their maximum rate after surgically produced atrioventricular dissociation. Figure 7 gives, in more quantitative terms, the evidence supporting these conclusions. Another consequence of the turning off of an imposed drive was escape and periodic action of ectopic pacemakers. The resistance to depression and the speed of recovery of the sinoatrial node was such that beats of ectopic origin seldom occurred before its full recovery. When intrinsic drive was from a low atrial or an AV nodal pacemaker, the first beats which followed termination of imposed drive were more often than not from other regions. A protracted period of competition elapsed before dominance by the "normal" intrinsic pacemaker was reestablished (fig. 8). Post-drive depression of the sinoatrial node, lower atrial, and AV nodal pacemaker action terminated in an overshoot or acceleration above control rates or above the rates eventually established (figs. 1, 6, 7). The magnitude of this late acceleration, like the postdrive depression of intrinsic pacemaker action, was greater following longer and faster driving up to a limit beyond which greater effects were not produced. The periods of acceleration lasted approximately as long as did the Drive *-~ Sinus o-o-o Atrium Ventricle 900 0 2 4 6 8 10 12 14 16 " 20 " 30 " 60 " SECONDS AFTER DRIVE FIGURE 5 Comparison of depressions following comparable rates of driving from electrodes attached to atrial appendage (open circles), to sinoatrial node region (filled circles), or to base of ventricle (crosses). Note late overacceleration after drive from sinus area. Circulation Research, Vol. XVII, November 196}

454 LANGE - [ jnve 3min *«S-A NODE - 500- - \f S 500- a> VI E x 600- y 700-5^ 800- o 900- > 1000-2000- 0-0 (fig. 6) / / / I A-V NODE P * : 10 15 3045 60 180 FIGURE 6 A comparison of post-drive depression of sinoatrial node (upper tracing) and atrioventricular node (lower tracing) pacemakers by drives from electrodes on the right atrial appendage. Sinus node crushed to bring AV node into action. Rate expressed in terms of cycle length. Note late overacceleration before steady rate was reestablished. depressions. The relative strengths of depressing and accelerating influences varied considerably in different preparations and this affected durations of depression and times of commencement of acceleration. It was found that section of the vagi had only a minor effect on post-drive depression and acceleration of the SA node, but section of the sympathetic cardiac accelerator nerves by removal of thoracic ganglia did augment depression. More significant were the observations that stimulation of the vagi, though continued for only the terminal 15 seconds of driving, greatly prolonged and augmented post-drive depression. Stimulation of the accelerator nerves, also only during driving, minimized post-drive depression of the SA node and augmented the overshoot or late acceleration. Injection of norepinephrine (perfusion rate sufficient to maintain blood pressure 50% above normal) had a general excitatory action reducing post-drive depression to some degree but did not abolish it. Administration of cocaine (5 mg/kg) augmented post-drive acceleration (fig. 9) and reduced post-drive depression, while pretreatment Circulation Research, Vol. XVU, November 1965

EFFECTS OF IMPOSED DRIVE ON PACEMAKERS 455 with reserpine (1 mg/kg 24 hours previously) or guanethidine (10 mg/kg) practically abolished the late acceleration; the post-drive depression was also somewhat augmented (fig. 10). Neostigmine (Prostigmin) (1 mg rv supported by infusion of 1 ml per min of a 1:50,000 solution), on the other hand, greatly increased post-drive depression while atropine (iv infusion of 0.8 ml/min of a 1:250,000 solution) reduced it significantly without greatly affecting late peak acceleration (fig. 11). Infusions of potassium chloride (1 ml/ min rv of a 0.15 M solution) did increase postdrive depressions but at a time when conduction and contractility were beginning to fail. The above was also found true for the AV node and nonnodal atrial pacemaker tissues. LU O CHA H -- LJ O (t -- UJ a. -200-100- -50 + 25-0-5 5.1-10 IO.I-2O 20.1-30 30.1-40 40.1-50 50.1-60 60J-70 I! -j T. 1i! 1 1 1 i 1 h...,» 0-5 5.H0 10.1-20 20.1-30 3ai-40 40.1-50 50,1-60 60.1-70 TQI-80 (Tig.7) RATE OF DRIVE IN % SHORTENING OF CYCLE LENGTH FIGURE 7 Depressant effects of driving at rates above that of intrinsic pacemaker. Durations of fast driving 5 to 10 minutes. Drive rates expressed in per cent shortening of cycle length (abscissa). Effects of imposed drive are shown by per cent change in duration of the first post-drive cycle. Extremes of results are shown by vertical lines at top of each bar. A: sinoatrial node pacemaker. Drive of ventricle (solid bars), drive from atrial appendage (open bars), drive from sinoatrial node region (hatched bars). B: sinoatrial node crushed; atrioventricular node pacemaker. Drive of ventricle (solid bars) and of atrium (open bars). A minimum of 5 and maximum of 10 experiments. Circulation Research, Vol. XVII, November 196)

456 LANGE Studies of possible effects of ion shifts due to driving were continued on isolated preparations. Discussion The results obtained in this study support the idea that both intrinsic and artificial pacemakers suppress pacemaker action in latent or subsidiary pacemaker tissues. Sustained flutter and fibrillation do the same. The sinoatrial node in addition to having the fastest intrinsic rate is less readily depressed by imposed drive and recovers more quickly than do other pacemakers when drive is terminated. This normal pacemaker appears to assert its dominance with a considerable factor of safety. Although subnormal rates of beating can be imposed on the heart by applied drive 10 this is difficult to achieve and attempts to use minimal strengths of stimulation frequently result in arrhythmias. The atrioventricular node and lower atrial pacemakers, after brief periods of quiescence 200 LJ 500 5 600 z 700 I fe 800 : z LJ 1600 4U 1700 1800 1900 2000 [tig 8) 2100 0 2 4 6 8 1 0 12 14 16 18 20 22 24 26 26 30 32 34 36 58 40" 60 " SECONDS AFTER FIGURE 8 Escape of idioventricular pacemaker from AV nodal dominance during AV node depression following fast drive of the heart by an artificial atrial pacemaker. 200 500 -*- x-x-x DRIVE X-X..X-X- Before Cocoine After Cocoine -K-X-X- -K-X-X 600 -I I I I I / i if II II ' 0 2 4 6 8 10^ 12 14 16 " 20 " 30 "60 " FIGURE 9 Potentiating effect of cocaine on the post-drive phase of acceleration. Note slower return to control rate. Circulation Research, Vol. XVII, November

EFFECTS OF IMPOSED DRIVE ON PACEMAKERS 457 I I o z u 200 600 following inactivation of the sinoatrial node, begin to accelerate and build up a rate of drive which is quite adequate to sustain cardiac function. Their rhythm is less regular and they are more readily depressed by imposed drive. Ectopic pacemakers also escape more frequently. This indicates a lesser dominating power. In a few experiments there was little depression of the idioventricular pacemaker by pacemaker drive of the ventricle. This was ascribed to the absence or sparseness of vagus fibers in the ventricle and a lesser acetylcholine release. These results on the in situ heart confirm suggestions by West and his associates 7 - s that electrical stimulation of the heart tissue releases acetylcholine and catecholamines from storage in the tissue or nerve terminals. Positioning of driving electrodes over the sinoatrial node, where nerve fibers are supposed- 500- - - 500-600- (l.g.io) -C 10 20 30 60 90 120 AFTER GUANETHEDINE 10 20 30 60 90 120 FIGURE 10 Abolition of late acceleration following drive from atrial appendage (crosses) and sinoatrial regions (filled circles) bij guanethidine. Upper tracing obtained before and lower tracing after guanethidine action. Rates of intrinsic pacemaker shown by broken line, C. Circulation Research, Vol. XVII, November 1965 ly converging, did have both a greater depressing and accelerating effect than did pacemakers otherwise placed. Anticholinesterase potentiated post-drive depression in the in situ heart and atropine reduced it as would be expected. Cocaine potentiated the postdrive acceleration and the depletion of stored catecholamines by reserpine or guanethidine reduced it. It seems to be demonstrated beyond question that mediators are liberated during cardiac drive by artificial pacemakers. The fact that the sinoatrial node can be depressed by drive from the atrial appendage or ventricle and that this is potentiated by Prostigmin suggests that a propagated action potential as well as applied current can release stored acetylcholine, and catecholamines also for that matter. These materials are thought to be released from storage primarily in nerve terminals. 11 Once released by local or propagated excitation they act locally. 12 Reflex reaction could have made only minimal contribution to effects seen in these experiments because the vagi were cut in all cases, because blood pressure remained relatively normal during driving, and because the phase of late acceleration remained after removal of stellates and thoracic chains. Atropine does not abolish the post-drive depression, therefore it is reasonable to assume that a reaction other than acetylcholine release contributes to the after effect of drive. Scher et al. 13 have suggested that potassium release or a potassium flux built up by the driving stimuli might cause the post-drive depression. Although administration of potassium chloride did augment post-drive depression in the in situ heart, side effects occurred and the matter was pursued in studies of isolated pacemaker tissues. 12 Other conclusions which are suggested by this work are that pacemakers can accelerate somewhat to compete with low rates of drive and a disorganization of heart action is likely to result. Post-drive effects seem to be of lesser magnitude after long continued drive as though excess stores of mediator become depleted, or adaptive reactions occur. It would seem, however, that turning off a pace-

458 LANGE CONTROL «-^-» AFTER ATROPINE X-*-X AFTER PROSTIGMINE (fig 11) 700 0 5 10 15 30 45 60 180 FIGURE 11 Effects of Prostigmin and atropine on depression of sinoatrial node pacemaker action following fast driving by a pacemaker applied to the sinoatrial node. Control (open circles), after Prostigmin (crosses), and after atropine (filled circles). maker is fraught with danger of prolonged asystole or disorganized rhythms particularly if drive has been fast and if the sinoatrial node has been inactivated and cannot assume control. Driving of the ventricle normally paced by an idioventricular pacemaker has not been studied sufficiently well to warrant any general conclusions about optimum rate of drive on events subsequent to sudden termination of drive. It was not found that the locus of placement of an artificial pacemaker on the ventricle influenced the degree of pacemaker depression produced thereby, but, as is well recognized, 14 placement of the pacemaker does influence the effectiveness of ventricular pumping action. Summary The interactions between pacemakers, and the effects on pacemakers, of terminating imposed driving were studied in the in situ heart of anesthetized dogs. Following atrial fibrillation or termination of a fast drive imposed through an artificial pacemaker, pacemaker action in intrinsic pacemakers is suppressed. Pacemakers tend to accelerate and compete with imposed drives which exceed control rates by only a small percentage (10 to 15%). Arrhythmias may result if imposed drive is slower than or identical with intrinsic pacemaker rate. Post-drive depression of pacemakers and the resulting deceleration of the heart is followed normally by an overshoot or supranormal acceleration. The magnitudes and durations of depression and late acceleration are proportional, within limits, to the rate and duration of drive. Atrioventricular and ectopic atrial pacemakers are much more readily depressed than is the sinoatrial pacemaker. Furthermore, beats of ectopic origin are much more likely to occur while subsidiary pacemakers are recovering from post-drive depression. Circulation Research, Vol. XVII, November 1965

EFFECTS OF IMPOSED DRIVE ON PACEMAKERS 459 Augmentation of depression by Prostigmin. its diminution by atropine, and the potentiation of late acceleration by cocaine and its absence after reserpine or guanethidine pretreatment, indicate that acetylcholine and catecholamines are liberated by driving stimuli. Placement of the pacemaker over the sinoatrial node, or near to regions where nerve terminals are concentrated, results in the greatest post-drive effects. The fact that propagated action potentials cause depressions and accelerations subject to drug block or potentiation indicates that mediators are also released in the course of propagated activity. Since atropine does not completely block post-drive depression, it is thought that a potassium ion shift may be involved. References 1. ERLANCER, J.: Observations on auricular strips of the cat's heart. Am. J. Physiol. 27: 87, 1910. 2. EYSTER, J. A. E., AND MEEK, W. J.: The origin and conduction of the heart beat. Physiol. Rev. 1: 1, 1921. 3. GASKELL, W. H.: On the innervation of the heart with especial reference to the heart of tortoise. J. Physiol. 4: 43, 1884. 4. WHIPPLE, H. E., ed.: Cardiac pacemakers. Ann. N. Y. Acad. Sci. 3: 813-1122, 1964. 5. DA VIES, J. G., AND SOWTON, G. E.: Cardiac pacemakers. Phys. Med. Biol. 9: 257, 1964. 6. WEST, T. C: Effects of chronotropic influences on sub-threshold oscillations in the sinoatrial node. In Specialized Tissues of the Heart, ed. by A. Paes de Carvalho, W. C. de Mello, and B. F. Hoffman, New York, Elsevier Publishing Company, 1961, p. 81. 7. AMORY, D. W., AND WEST, T. C: Chronotropic response following direct electrical stimulation of the isolated sinoatrial node: A pharmacological evaluation. J. Pharmacol. Exptl. Therap. 137: 14, 1962. 8. VINCENZI, F. F., AND WEST, T. C: Release of autonomic mediators in cardiac tissue by direct subthreshold electrical stimulation. J. Pharmacol. Exptl. Therap. 141: 185, 1963. 9. BROOKS, C. MCC, HOFFMAN, B. F., SUCKLING, E. E., AND ORIAS, O.: Excitability of the Heart. New York, Grune and Stratton Inc., 1955. 10. LOPEZ, J. F., EDELIST, A., AND KATZ, L. N.: Reducing heart rate of the dog by electrical stimulation. Circulation Res. 15: 414, 1964. 11. HUTTER, O. F., AND TRAUTWEIN, W.: Vagal and sympathetic effects on the pacemaker fibers in the sinus venosus of the heart. J. Gen. Physiol. 39: 715, 1956. 12. Lu, H. H., LANCE, G., AND BROOKS, C. MCC.: Factors controlling pacemaker action in cells of the sinoatrial node. Circulation Res. 17: 460, 1965. 13. SCHER, A. M., RODRIGUES, M. I., LUKANE, J., AND YOUNG, A. C.: The mechanism of atrioventricular conduction. Circulation Res. 7: 54, 1959. 14. LISTER, J. W., KLOTZ, D. H., JOMAIN, S. L., STUCKEY, J. H., AND HOFFMAN, B. F.: Effect of pacemaker site on cardiac output and ventricular activation in dogs with complete heart block. Am. J. Cardiol. 14: 494, 1964. Circulation Research, Vol. XVII, November 1963