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Sustained, paired electrical stimuli
Sustained, Paired Electrical Slowing of the Ventricular
Rate and Augmentation
of Contractile NINA S. BRAUNWALD,
M.D., WILLIAM
Stimuli
A. GAY,
Force*
JR., M.D., ANDREW G. MORROW,
M.D. and
EUGENE BRAUNWALD, M.D. Bethesda,
T
he recovery
of the heart
depolarization
and
following
activation
con-
elements
is a complex
process,
and
the
precise
temporal
relationship
between
the
res-
of electrical
excitability
and
METHODS
electrical
of the
tractile toration
Maryland
Paired electrical stimuli were delivered by a transistorized, battery-driven, coupled pulse generatort (Medtronic). This unit permits variation of the time interval between each pair of stimuli, as well as of the time interval between the two stimuli of each pair. It delivers constant current pulses of rectangular wave form. In most experiments 3 milliampere stimuli with a duration of 3 msec. were employed. Stimulation was applied through a pair of wire electrodes sutured to the left ventricular epicardium. Experiments were done in 19 open-chest dogs
the ability
has been defined only recently. In 1959, Siebens and his collaborators’ demonstrated that recovery of electrical excitability clearly precedes recovery of contractile activity. In experiments in dogs, these investigators demonstrated that some degree of electrical excitability had returned by the time of the peak ventricular systolic pressure, but that the muscle could not contract again until approximately 100 msec. later. From these studies it became apparent that it is possible to introduce an electrical impulse immediately after the termination of the absolute refractory period which would result in a propagated depolarization wave but which would not be followed by a clearly defined mechanical event. Lopez and his associates* have recently suggested and Chardack et a1.3,4 have shown that when the ventricle is electrically stimulated by appropriately timed, paired stimuli, a propagated depolarization follows each stimulus, but that only the first depolarization is followed by a ventricular contraction. The purpose of the present experiments was to study two fundamental consequences of such paired electrical stimuli in the dog: to contract
(1) the prolongation the ventricle
of the time during
is unresponsive
t Supplied through Chardack.
TABLE
Dog No. 1 2 3 4 5 6 7 8 9 IO 11 12 13 15 16 19
which
to other stimuli, and
stimuli.
* From the Surgery Branch and the Cardiology VOLUME
14,
SEPTEMBER
1964
of Dr. William M.
I
Suppression of Sinus Tachycardia with Sustained, Paired Electrical Stimuli
(2) the effects on the ventricle’s contractile response. In addition, a preliminary investigation was made of the responses of the human heart to paired electrical
the courtesy
Spontaneous Ventricular Rate (contractions/min.) 162 155 140 120 150 160 170 140 140 200 200 162 140 140 140 115
Ventricular Rate During Paired Stimulation (contractions/min.) 80 118 100 110 115 110 110 110 104 110 140 115 130 105 95 88
Branch of the National Heart Institute, Bethesda, Md. 385
Braunwald,
386
FA PRESSURE mm&
Gay,
Jr.,
Morrow
and Braunwald
150 ,oo 50
0
PACEMAUER
M.C.F mm
EKG
LV PRESSURE
mmHg -PI*__
I--RATE
I sec. -----I
I 15 / MIN
INTERVAL
200
RATE
I55
/MIN.
MSEC
FIG. 1. Suppwssion of spontaneoussinus tachycardinwith paired electrical stimuli. Panels A, B and C are recordings during delivery of paired stimuli, while panels D and E are recordings made during sinus tachycardia, immediately after cessation of stimulation. FA = femoral artery. M.C.F. = myocardial contractile force. LV = left ventricle. Znterual refers to the time interval between the first and second stimuli of each pair. Rate refers to the number of contractions per minute rather than the number of depolarizations. Panels A and E were recorded at 25 mm./sec., panel B at 50 mm./sec. and panels C and D at 0.25 mm./sec.
which had been anesthetized with sodium thiopental; ventilation with room air was supplied from a mechanical respirator. The pacemaker impulses, the electrocardiogram, the left ventricular and femoral artery pressure pulses, and right ventricular contractile force were recorded simultaneously on a multichannel recorder. Pressures were measured with Statham transducers; a Walton-Brodie strain gauge arch5 on the right ventricle was utilized to determine myocardial contractile force. RESULTS Suppression of Sinus Tachycardia: Paired electrical stimuli were applied to the ventricles of 16 dogs with spontaneous sinus tachycardia. In each instance the ventricle could be captured by the pacemaker, and the number of contractions per minute was diminished from an average of 152 to 109 (Table I). Figures 1 and 2 show
the effects of paired electrical stimuli; in both of these experiments, as well as the other 14, the underlying sinus tachycardia recurred when pacing was discontinued. Suppression of Ventricular Tachycardia: In 6 animals, ventricular tachycardia was produced by means of a separate Grass stimulator (Model S4G) which delivered single impulses through an electrode on the surface of the right ventricle. While stimulation with the Grass stimulator was maintained at a rate between 180 and 290 per min., the delivery of paired stimuli with the Medtronic unit was begun (Fig. 3). It was possible in each instance to capture the ventricle with the paired electrical stimuli and to slow the rate of ventricular contraction by an average of 72/min (Table II). In 8 animals, ventricular tachycardia was produced by the infusion THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Paired Electrical
,,
/,
._A_
-
_,,I‘
.
”
..1(
,...
VOLUME
14,
387
Stimuli
SEPTEMBER
1964
-
Braunwald,
388
(Gay, Jr.,
Xlorro~~
and Braunwald
PACEMAKER
PRESSURE
50
--_-----PC___
t-l
RATE
SIC.1
190/MIN.
RATE
102/MIN.
INTERVAL
210 MSEC.
‘The Crass pacemaker (I/ clect~irrrlly-induced ventriculnr lu&cardiu by ~P(INI of fioirpd rlcctricul stimuli. the ventricles at a rate of 190/n% throughout panels A and B; while panel B was recorded? paired stimualso given. The ventricular tachycardia produced in panel A resulted in severe pufsus alternans and hypoPaired electrical stimulation not only slowed the venwicular rate from 190/min. to 102/min. but also elimiThe recordings in pulsus alternans, increased mvocardial contractile force, and raised arterial pressure. panels A and R were not continuous. FIG.
3.
.?uppression
stimulated lation was tension. nated the
TABLE
Suppression
Dog No.
1 2 3 4 5 8 10 11 12 13 14 17 17 18
Method
Elec.t Ouabain Elec. Ouabain Ouabain Ouabain Ouabain Ouabain Ouahain Elcc. Elec. Ouabain
Elec Elec.
II
of Ventricular Paired Electrical
*
Rate During ‘Tachycardia
Tachycardia Stimuli
with
Rate During Paired Stimulation
250 220 180 220 170 180 200 198 150 250 187 170 180 180
* .W&hod refers to the technic employed tion of ventricular tachycardia. t HPC. refers to electrical stimulation sqarate electrical stimulator.
120 130 140 140 110 140 125 145 115 145 130 140 160 102 for the producwith
a swond.
of a toxic dose of ouabain. With paired electrical stimuli it was always possible to suppress the ectopic focus, and the number of ventricular contractions was reduced by an average of 68/min. (Fig. 4). Augmentation oj Contractile Force: In the aforementioned experiments, in which the rate of ventricular contraction was slowed, an increase in myocardial contractile force was uniformly noted during paired electrical stimulation (Fig. force diminished when l-41, and contractile paired electrical stimulation was discontinued (Fig. 1 and 2). The interpretation of these findings is complicated by the simultaneous change in the rate of ventricular contraction, since changes in rate per se alter the contractile state of the myocardium.6 Accordingly, the effects of paired stimuli on myocardial contractile force were determined at a constant ventricular contraction rate. Figure 5 is a tracing representative of the eight experiments in which paired electrical stimulation increased ventricular contractile force to an average of 275 per 1‘IfE AMERICAN
JOURNAL
OF
CARDIOLOGY
Paired
Electrical
Stimuli
FA FRESSLJRE mm Hg
PACEMAKER
M.C F mm I
I
EKG
LV PRESSURE
,O
mm.Hp
---_c____
.--“-
-_
b---l
see.----+ RATE
170/
MIN.
RATE
150/t&N
INTERVAL
160 MSEC
FIG. 4. E@ects ofpaired stimuli on ventricular tachycardininduced by a toxic dose of ouabain. The recordings during paired stimulation are shown in panels C and D. Panels A and C were recorded at 25 mm./sec., panels B and D at SO mm./
cent of the levels observed with a sinus tachycardia at an identical ventricular rate. Augmentation of contractile force was sustained for the time during which paired stimulation was applied, periods up to three hours in duration. When paired electrical stimulation was begun, the increase in contractile force did not occur after the first pair of impulses but always commenced after the second pair and then rose progressively to reach a new plateau several contractions later (Fig. 6). Similarly, when paired electrical stimulation was suddenly discontinued, myocardial contractile force began to decrease after the second single stimulus, and declined to a new plateau several contractions later (Fig. 7). Experiments on Man: The effects of paired stimuli in man are demonstrated by the records reproduced in Figure 8, which are representative of those recorded in 4 patients. The paVOLUME
14,
SEPTEMBER
1964
tient, a 34 year old man with mitral stenosis and atria1 fibrillation, was studied at the time of operation, the stimuli being delivered through a bipolar electrode on the left ventricle. During stimulation the rate became regular, and left ventricular contractile force increased 100 per cent. DISCUSSION
The present investigation, together with the recent reports by Lopez et al.,* Chardack et al.3e4 and Ross et al.,7 shows that appropriately timed, paired, electrical stimuli to the ventricles cause profound alterations in both the electrical and contractile properties of the mammalian heart. First of all, it is clear that the ventricle will respond to electrical stimulation during mechanical systole and that such stimulation will result in a propagated depolarization. In addition, when the second depolarization occurs early in
Hraunwald,
390
Gay,
Jr.,
Morrow
and
Braunwalcl
FA PRESSURE mm lip
PACEMAKER
M.C.F. mm
-4
I----
RATE
I
set -4
I50/?vlIN
RATE
150/MIN.
INTERVAL
160 MSEC.
FIG. 5. Effects ofpaired stimuli on myocardiul contrztile forceat a constant rate of contraction. In panels A, B and C there is sinus rhythm, and paired electrical stimulation was given during panels D, E and F. There is a profound increase in contractile force, even though the ventricular contraction rat? x-mains constant throughout at 150/min. Panels A and E were recorded at 50 mm./sec., B and D at 25 mm./sec. and C and F at 10 mm./sec.
the recovery period, a discrete second contraction does not necessarily occur; and only a slight slurring or prolongation of the downstroke of the ventricular pressure pulse or of the contractile force tracing may be evident. When the second stimulus arrives later, however, after the ventricle has regained its ability to contract, a simple premature contraction results. These findings are entirely in accord with those of Siebens et al.,’ who demonstrated the period during which the ventricle can be depolarized but during which a clearly defined second contraction does not occur. In addition, it was observed that this apparent dissociation between electrical and mechanical activity could be induced repetitively, i.e., after every ventricular contraction. Mechanism of Slowing of Ventricular Rate: During paired electrical stimulation, each of the two ventricular depolarizations is followed by a Since the second stimulus refractory period. is delivered immediately after the completion of
the first refractory period, the period during which the ventricle is unresponsive to other stimuli, intrinsic or extrinsic, is essentially doubled. Thus, prolongation of refractiveness is the mechanism by which the paired stimuli slow the rate of ventricular contraction. Slowing can be achieved when the total number of impulses delivered by the artificial pacemaker exceeds that of the intrinsic pacemaker, and it is in this manner that the artificial pacemaker assumes control of the ventricle from the intrinsic pacemaker. However, when the stimuli are appropriately spaced, a clearly defined mechanical event does not follow the second depolarization, and the ventricular contraction rate is thus reduced. Mechanism of Augmentation of Myocardial Contraction (Postextrasystolic Potentiation): A second major consequence of paired electrical stimulation was found to be a striking augmentation of myocardial contractile force, and of special importance is the fact that augmentation ocTHE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Paired
Electrical
Stimuli
391
EKG PACEMAKER SIGNAL
RV STRAIN GAUGE mm.
FAm. PRESSURE mm.Hg FA p. PRESSURE mm Hg LV PRESSURE mm.Hg Continuous recording aspairedelectrical stimulation was suddenly begun, in the center of the tracing. Augmentation of myocardial contractile force commences with the second pair of impulses, increases progressively duriq the ensuing five cycles and is maintained at a greatly increased level thereafter. FAm. = mean femoral artery pressure. FAp. = phasic femoral artery pressure. -
FIG. 6.
curred even when the ventricular contraction rate remained unchanged (Fig. 5). It seems likely that this augmentation of myocardial contractile force represents a sustained form of postextrasystolic potentiation. Since the studies of Langendorfs in 1885, it has been known that the strength of contraction of the postextrasystolic beat exceeds that of the normal beat in the vertebrate heart. Numerous studies have been designed to elucidate the mechanism of postextrasystolic potentiation,9’1° and these have recently been reviewed by Koch-Weser and In the intact heart, the increased fillBlinks.‘j ing of the ventricles during the compensatory pause undoubtedly contributes to the strength of the postextrasystolic beat. However, this process can also be demonstrated in the absence of a compensatory pause, i.e., when the extrasystole is interpolated and when ventricular filling is certainly not augmented.9s10 Furthermore, postextrasystolic potentiation may also be demonstrated in isolated strips of atrium or ventricle mounted in such a manner that only isoThus, one commetric contraction can occur. ponent of postextrasystolic potentiation in the VOLUME
14,
SEPTEMBER
1964
intact heart is a fundamental improvement of the contractile state of the myocardium. It is also recognized that the magnitude of postextrasystolic potentiation is inversely related to the time interval by which the extrasystole follows the preceding depolarization : The earlier the extrasystole, the greater the postextrasystolic potentiation.1~9~11 In addition, when the extrasystole is only electrical, i.e., when depolarization occurs so early that it fails to evoke a mechanical response, postextrasystolic potentiation occurs nonetheless.‘j,rl Clearly then, it is the second excitation and the propagated depolarization which follows it, not the mechanical event, which sets into motion those fundamental processes responsib!e for postextrasystolic potentiation. In view of the considerations just presented, it appears that the striking augmentation of contractile force induced by paired electrical stimuli is a form of postextrasystolic potentiation. This concept is supported by the finding that the improvement of the contractile state of the heart does not occur following the first pair of stimuli, .but is associated with the second
392
Kraurl\~alci.
(;a).
Jr..
Yforro\z- and Braunwald
PACEMAKER SIGNAL
EKG STRAIN GAUGE mm. FA m. mm. Hg
FA p. mm. Hg
h
c
5
FIG. 8. Effect o/,buired &cl,-iul stbnulntion m u .&I ~PUPold fmtirnt zctth mttra! stenosis who zoa~ studied ut thr tinv of n@zlion. Panel A shows the spontaneous rhythm, atria1 fibrillation (RF). Panels B and C show the regularization of the rhythm during paired electrical stimulation. Contractile force incrrases 100 per cent. When the.interval between the two stimuli was increased by only 2 msec., between panels R and C, the contraction became distinctly less fused.
pair of stimuli (Fig. 6) and begins to decline with the second contraction after discontinuation of paired electrical stimulation (Fig. 7). However, the improvement in contractile force noted in these experiments differs from the classical forms of postextrasystolic potentiation in two respects. First of all, when the time interl.al between the stimuli is carefully adjusted, the augmentation may occur without a discrete second mechanical event. Secondly, in the investigation presented herein, not only did the
potentiation occur after a single extrasystole, as in most previous experiments, but it was found to be sustained for as long as the appropriately timed, paired stimuli were applied to the ventricle. Clinical L4pplication: The observation that the human heart reacts to paired stimuli in a manner similar to the dog heart (Fig. 8) suggests that double stimulation may have clinical application. It is possible that both the slowing of the ventricular contraction rate and the augmentaTHE
AMERICAN
JOURNAL
OF
C.ARDIOLOGY
Paired
Electrical
tion of contractile force which result from paired clcctrical stimulation would be advantageous in the treatment of patients with various forms of cardiac disease. It must be appreciated, howe\er: that this method of stimulation may not be In order to be effecentirely without hazard. ti\.e, the second impulse of the pair must be delivered very shortly after the termination of the ventricle’s absolute refractory period, in or near the so-called vulnerable period, and ventricular fibrillation could result. Hopefully, however, this disastrous complication can be avoided by careful attention to the magnitude of the stimuli delivered to the heart. SUMMARY
When the ventricle is electrically stimulated immediately after the termination of the absolute refractory period, a propagated depolarization occurs which does not result in a clearly defined In secondary rise in intraventricular pressure. 19 dogs, two fundamental consequences of such paired electrical stimuli were studied. Since the second depolarization is followed by a second refractory period, the time during which the ventricle is unresponsive to other electrical stimuli is effectively doubled. Rapid ventricular rates could thus be slowed by paired stimuli, In regardless of the mechanism of tachycardia. each of 16 dogs, spontaneously occurring sinus tachycardia was suppressed by paired electrical stimulation. In 8 animals, ventricular tachycardia was induced by digitalis intoxication and in 6 by means of exogenous stimulation with a separate electrical pacemaker; paired stimuli slowed the ventricular rate in every aniStriking mal by an average of 57 beats per min. augmentation of the ventricle’s contractile response was found to be a second consequence of paired stimulation. This phenomenon was demonstrated in 8 dogs in which right ventricular contractile force was measured with a strain Paired electrical stimuli increased gauge arch. ventricular contractile force to an average of 275 per cent of the levels observed with single Prelimiimpulses delivered at the same rate.
VOLUME
14, SEPTEMBER 1964
393
Stimuli
nary studies in man indicate that slowing and augmentation of contractile force also occur when the human heart is stimulated in a similar manner. ,4ppropriately timed, paired electrical stimuli to the ventricles result in profound alterations in both the electrical and contractile properties It is possible that this of the mammalian heart. technic will be applicable and beneficial in certain patients, when a slower heart rate and/or augmented myocardial contractile force is desirable. REFERENCES 1. SIEBENS, A. A., HOFFMAN, B. F., CRANEFIELD, P. F. and McC. BROOKS, C. Regulation of contractile force during ventricular arrhythmias. Am. J. Physiol., 197: 968, 1959. 2. LOPEZ, J. F., EDELIST, A. and KATZ, L. N. Slowing of the heart rate by artificial electrical stimulation with pulses of long duration in the dog (Abstr.). Circulation, 28: 759, 1963. 3. DEAN, D., CHARDACK,W. and GAGE, A. Slowing of the heart rate by paired electrical stimuli (Abstr.). Clin. Res., 12: 180, 1964. 4. CHARDACK,W. M., GAGE, A. A. and DEAN, D. C. Slowing of the heart by paired pulse pacemaking. Am. J. Cardiot., 14:374. 1964. 5. BONIFACE, K. J.,‘BRoDIE; 0. J. and WALTON, R. P. Resistance strain gauge arches for direct measurement of heart contractile force in animals. Proc. Sot. Exp. Biol. B Med., 84: 263, 1953. The influence 6. KOCH-WESER, J. and BLINKS, J. R. of the interval between beats on myocardial contractility. Pharmacol. Rev., 15: 601, 1963. 7. Ross, J., JR., SONNENBLICK,E. H., KAISER, G. A., FROMMER,P. L. and BRAUNWALI),E. Augmentation of ventricular performance and oxygen consumption by repetitive application of paired elecPhysiologist, in press. trical stimuli (Abstr.). 8. LANGENDORF, 0. Ueber elektrische Reizung des Herzens. Arch. Physiol., pp. 284-287, 1885. 9. HOFFMAN, B. F., BINDLER, E. and SUCKLING, E. F. Postextrasystolic potentiation of contraction in cardiac muscle. Am. J. Physiol., 185: 95, 1956. 10. GARB, S. and PENNA, M. Some quantitative aspects of the relation of rhythm to the contractile Am. J. force of mammalian ventricular muscle. Physiol., 182: 601, 1955. 11. KRUTA, V. and BRAVENY, P. Restitution de la contractiliti du myocarde entre les contractions et Arch. internat. de les phenomenes de potentiation. Physiol. et Biochem., 69: 645, 1961.
Rate and Augmentation
of Contractile NINA S. BRAUNWALD,
M.D., WILLIAM
Stimuli
A. GAY,
Force*
JR., M.D., ANDREW G. MORROW,
M.D. and
EUGENE BRAUNWALD, M.D. Bethesda,
T
he recovery
of the heart
depolarization
and
following
activation
con-
elements
is a complex
process,
and
the
precise
temporal
relationship
between
the
res-
of electrical
excitability
and
METHODS
electrical
of the
tractile toration
Maryland
Paired electrical stimuli were delivered by a transistorized, battery-driven, coupled pulse generatort (Medtronic). This unit permits variation of the time interval between each pair of stimuli, as well as of the time interval between the two stimuli of each pair. It delivers constant current pulses of rectangular wave form. In most experiments 3 milliampere stimuli with a duration of 3 msec. were employed. Stimulation was applied through a pair of wire electrodes sutured to the left ventricular epicardium. Experiments were done in 19 open-chest dogs
the ability
has been defined only recently. In 1959, Siebens and his collaborators’ demonstrated that recovery of electrical excitability clearly precedes recovery of contractile activity. In experiments in dogs, these investigators demonstrated that some degree of electrical excitability had returned by the time of the peak ventricular systolic pressure, but that the muscle could not contract again until approximately 100 msec. later. From these studies it became apparent that it is possible to introduce an electrical impulse immediately after the termination of the absolute refractory period which would result in a propagated depolarization wave but which would not be followed by a clearly defined mechanical event. Lopez and his associates* have recently suggested and Chardack et a1.3,4 have shown that when the ventricle is electrically stimulated by appropriately timed, paired stimuli, a propagated depolarization follows each stimulus, but that only the first depolarization is followed by a ventricular contraction. The purpose of the present experiments was to study two fundamental consequences of such paired electrical stimuli in the dog: to contract
(1) the prolongation the ventricle
of the time during
is unresponsive
t Supplied through Chardack.
TABLE
Dog No. 1 2 3 4 5 6 7 8 9 IO 11 12 13 15 16 19
which
to other stimuli, and
stimuli.
* From the Surgery Branch and the Cardiology VOLUME
14,
SEPTEMBER
1964
of Dr. William M.
I
Suppression of Sinus Tachycardia with Sustained, Paired Electrical Stimuli
(2) the effects on the ventricle’s contractile response. In addition, a preliminary investigation was made of the responses of the human heart to paired electrical
the courtesy
Spontaneous Ventricular Rate (contractions/min.) 162 155 140 120 150 160 170 140 140 200 200 162 140 140 140 115
Ventricular Rate During Paired Stimulation (contractions/min.) 80 118 100 110 115 110 110 110 104 110 140 115 130 105 95 88
Branch of the National Heart Institute, Bethesda, Md. 385
Braunwald,
386
FA PRESSURE mm&
Gay,
Jr.,
Morrow
and Braunwald
150 ,oo 50
0
PACEMAUER
M.C.F mm
EKG
LV PRESSURE
mmHg -PI*__
I--RATE
I sec. -----I
I 15 / MIN
INTERVAL
200
RATE
I55
/MIN.
MSEC
FIG. 1. Suppwssion of spontaneoussinus tachycardinwith paired electrical stimuli. Panels A, B and C are recordings during delivery of paired stimuli, while panels D and E are recordings made during sinus tachycardia, immediately after cessation of stimulation. FA = femoral artery. M.C.F. = myocardial contractile force. LV = left ventricle. Znterual refers to the time interval between the first and second stimuli of each pair. Rate refers to the number of contractions per minute rather than the number of depolarizations. Panels A and E were recorded at 25 mm./sec., panel B at 50 mm./sec. and panels C and D at 0.25 mm./sec.
which had been anesthetized with sodium thiopental; ventilation with room air was supplied from a mechanical respirator. The pacemaker impulses, the electrocardiogram, the left ventricular and femoral artery pressure pulses, and right ventricular contractile force were recorded simultaneously on a multichannel recorder. Pressures were measured with Statham transducers; a Walton-Brodie strain gauge arch5 on the right ventricle was utilized to determine myocardial contractile force. RESULTS Suppression of Sinus Tachycardia: Paired electrical stimuli were applied to the ventricles of 16 dogs with spontaneous sinus tachycardia. In each instance the ventricle could be captured by the pacemaker, and the number of contractions per minute was diminished from an average of 152 to 109 (Table I). Figures 1 and 2 show
the effects of paired electrical stimuli; in both of these experiments, as well as the other 14, the underlying sinus tachycardia recurred when pacing was discontinued. Suppression of Ventricular Tachycardia: In 6 animals, ventricular tachycardia was produced by means of a separate Grass stimulator (Model S4G) which delivered single impulses through an electrode on the surface of the right ventricle. While stimulation with the Grass stimulator was maintained at a rate between 180 and 290 per min., the delivery of paired stimuli with the Medtronic unit was begun (Fig. 3). It was possible in each instance to capture the ventricle with the paired electrical stimuli and to slow the rate of ventricular contraction by an average of 72/min (Table II). In 8 animals, ventricular tachycardia was produced by the infusion THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Paired Electrical
,,
/,
._A_
-
_,,I‘
.
”
..1(
,...
VOLUME
14,
387
Stimuli
SEPTEMBER
1964
-
Braunwald,
388
(Gay, Jr.,
Xlorro~~
and Braunwald
PACEMAKER
PRESSURE
50
--_-----PC___
t-l
RATE
SIC.1
190/MIN.
RATE
102/MIN.
INTERVAL
210 MSEC.
‘The Crass pacemaker (I/ clect~irrrlly-induced ventriculnr lu&cardiu by ~P(INI of fioirpd rlcctricul stimuli. the ventricles at a rate of 190/n% throughout panels A and B; while panel B was recorded? paired stimualso given. The ventricular tachycardia produced in panel A resulted in severe pufsus alternans and hypoPaired electrical stimulation not only slowed the venwicular rate from 190/min. to 102/min. but also elimiThe recordings in pulsus alternans, increased mvocardial contractile force, and raised arterial pressure. panels A and R were not continuous. FIG.
3.
.?uppression
stimulated lation was tension. nated the
TABLE
Suppression
Dog No.
1 2 3 4 5 8 10 11 12 13 14 17 17 18
Method
Elec.t Ouabain Elec. Ouabain Ouabain Ouabain Ouabain Ouabain Ouahain Elcc. Elec. Ouabain
Elec Elec.
II
of Ventricular Paired Electrical
*
Rate During ‘Tachycardia
Tachycardia Stimuli
with
Rate During Paired Stimulation
250 220 180 220 170 180 200 198 150 250 187 170 180 180
* .W&hod refers to the technic employed tion of ventricular tachycardia. t HPC. refers to electrical stimulation sqarate electrical stimulator.
120 130 140 140 110 140 125 145 115 145 130 140 160 102 for the producwith
a swond.
of a toxic dose of ouabain. With paired electrical stimuli it was always possible to suppress the ectopic focus, and the number of ventricular contractions was reduced by an average of 68/min. (Fig. 4). Augmentation oj Contractile Force: In the aforementioned experiments, in which the rate of ventricular contraction was slowed, an increase in myocardial contractile force was uniformly noted during paired electrical stimulation (Fig. force diminished when l-41, and contractile paired electrical stimulation was discontinued (Fig. 1 and 2). The interpretation of these findings is complicated by the simultaneous change in the rate of ventricular contraction, since changes in rate per se alter the contractile state of the myocardium.6 Accordingly, the effects of paired stimuli on myocardial contractile force were determined at a constant ventricular contraction rate. Figure 5 is a tracing representative of the eight experiments in which paired electrical stimulation increased ventricular contractile force to an average of 275 per 1‘IfE AMERICAN
JOURNAL
OF
CARDIOLOGY
Paired
Electrical
Stimuli
FA FRESSLJRE mm Hg
PACEMAKER
M.C F mm I
I
EKG
LV PRESSURE
,O
mm.Hp
---_c____
.--“-
-_
b---l
see.----+ RATE
170/
MIN.
RATE
150/t&N
INTERVAL
160 MSEC
FIG. 4. E@ects ofpaired stimuli on ventricular tachycardininduced by a toxic dose of ouabain. The recordings during paired stimulation are shown in panels C and D. Panels A and C were recorded at 25 mm./sec., panels B and D at SO mm./
cent of the levels observed with a sinus tachycardia at an identical ventricular rate. Augmentation of contractile force was sustained for the time during which paired stimulation was applied, periods up to three hours in duration. When paired electrical stimulation was begun, the increase in contractile force did not occur after the first pair of impulses but always commenced after the second pair and then rose progressively to reach a new plateau several contractions later (Fig. 6). Similarly, when paired electrical stimulation was suddenly discontinued, myocardial contractile force began to decrease after the second single stimulus, and declined to a new plateau several contractions later (Fig. 7). Experiments on Man: The effects of paired stimuli in man are demonstrated by the records reproduced in Figure 8, which are representative of those recorded in 4 patients. The paVOLUME
14,
SEPTEMBER
1964
tient, a 34 year old man with mitral stenosis and atria1 fibrillation, was studied at the time of operation, the stimuli being delivered through a bipolar electrode on the left ventricle. During stimulation the rate became regular, and left ventricular contractile force increased 100 per cent. DISCUSSION
The present investigation, together with the recent reports by Lopez et al.,* Chardack et al.3e4 and Ross et al.,7 shows that appropriately timed, paired, electrical stimuli to the ventricles cause profound alterations in both the electrical and contractile properties of the mammalian heart. First of all, it is clear that the ventricle will respond to electrical stimulation during mechanical systole and that such stimulation will result in a propagated depolarization. In addition, when the second depolarization occurs early in
Hraunwald,
390
Gay,
Jr.,
Morrow
and
Braunwalcl
FA PRESSURE mm lip
PACEMAKER
M.C.F. mm
-4
I----
RATE
I
set -4
I50/?vlIN
RATE
150/MIN.
INTERVAL
160 MSEC.
FIG. 5. Effects ofpaired stimuli on myocardiul contrztile forceat a constant rate of contraction. In panels A, B and C there is sinus rhythm, and paired electrical stimulation was given during panels D, E and F. There is a profound increase in contractile force, even though the ventricular contraction rat? x-mains constant throughout at 150/min. Panels A and E were recorded at 50 mm./sec., B and D at 25 mm./sec. and C and F at 10 mm./sec.
the recovery period, a discrete second contraction does not necessarily occur; and only a slight slurring or prolongation of the downstroke of the ventricular pressure pulse or of the contractile force tracing may be evident. When the second stimulus arrives later, however, after the ventricle has regained its ability to contract, a simple premature contraction results. These findings are entirely in accord with those of Siebens et al.,’ who demonstrated the period during which the ventricle can be depolarized but during which a clearly defined second contraction does not occur. In addition, it was observed that this apparent dissociation between electrical and mechanical activity could be induced repetitively, i.e., after every ventricular contraction. Mechanism of Slowing of Ventricular Rate: During paired electrical stimulation, each of the two ventricular depolarizations is followed by a Since the second stimulus refractory period. is delivered immediately after the completion of
the first refractory period, the period during which the ventricle is unresponsive to other stimuli, intrinsic or extrinsic, is essentially doubled. Thus, prolongation of refractiveness is the mechanism by which the paired stimuli slow the rate of ventricular contraction. Slowing can be achieved when the total number of impulses delivered by the artificial pacemaker exceeds that of the intrinsic pacemaker, and it is in this manner that the artificial pacemaker assumes control of the ventricle from the intrinsic pacemaker. However, when the stimuli are appropriately spaced, a clearly defined mechanical event does not follow the second depolarization, and the ventricular contraction rate is thus reduced. Mechanism of Augmentation of Myocardial Contraction (Postextrasystolic Potentiation): A second major consequence of paired electrical stimulation was found to be a striking augmentation of myocardial contractile force, and of special importance is the fact that augmentation ocTHE
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RV STRAIN GAUGE mm.
FAm. PRESSURE mm.Hg FA p. PRESSURE mm Hg LV PRESSURE mm.Hg Continuous recording aspairedelectrical stimulation was suddenly begun, in the center of the tracing. Augmentation of myocardial contractile force commences with the second pair of impulses, increases progressively duriq the ensuing five cycles and is maintained at a greatly increased level thereafter. FAm. = mean femoral artery pressure. FAp. = phasic femoral artery pressure. -
FIG. 6.
curred even when the ventricular contraction rate remained unchanged (Fig. 5). It seems likely that this augmentation of myocardial contractile force represents a sustained form of postextrasystolic potentiation. Since the studies of Langendorfs in 1885, it has been known that the strength of contraction of the postextrasystolic beat exceeds that of the normal beat in the vertebrate heart. Numerous studies have been designed to elucidate the mechanism of postextrasystolic potentiation,9’1° and these have recently been reviewed by Koch-Weser and In the intact heart, the increased fillBlinks.‘j ing of the ventricles during the compensatory pause undoubtedly contributes to the strength of the postextrasystolic beat. However, this process can also be demonstrated in the absence of a compensatory pause, i.e., when the extrasystole is interpolated and when ventricular filling is certainly not augmented.9s10 Furthermore, postextrasystolic potentiation may also be demonstrated in isolated strips of atrium or ventricle mounted in such a manner that only isoThus, one commetric contraction can occur. ponent of postextrasystolic potentiation in the VOLUME
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intact heart is a fundamental improvement of the contractile state of the myocardium. It is also recognized that the magnitude of postextrasystolic potentiation is inversely related to the time interval by which the extrasystole follows the preceding depolarization : The earlier the extrasystole, the greater the postextrasystolic potentiation.1~9~11 In addition, when the extrasystole is only electrical, i.e., when depolarization occurs so early that it fails to evoke a mechanical response, postextrasystolic potentiation occurs nonetheless.‘j,rl Clearly then, it is the second excitation and the propagated depolarization which follows it, not the mechanical event, which sets into motion those fundamental processes responsib!e for postextrasystolic potentiation. In view of the considerations just presented, it appears that the striking augmentation of contractile force induced by paired electrical stimuli is a form of postextrasystolic potentiation. This concept is supported by the finding that the improvement of the contractile state of the heart does not occur following the first pair of stimuli, .but is associated with the second
392
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Yforro\z- and Braunwald
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h
c
5
FIG. 8. Effect o/,buired &cl,-iul stbnulntion m u .&I ~PUPold fmtirnt zctth mttra! stenosis who zoa~ studied ut thr tinv of n@zlion. Panel A shows the spontaneous rhythm, atria1 fibrillation (RF). Panels B and C show the regularization of the rhythm during paired electrical stimulation. Contractile force incrrases 100 per cent. When the.interval between the two stimuli was increased by only 2 msec., between panels R and C, the contraction became distinctly less fused.
pair of stimuli (Fig. 6) and begins to decline with the second contraction after discontinuation of paired electrical stimulation (Fig. 7). However, the improvement in contractile force noted in these experiments differs from the classical forms of postextrasystolic potentiation in two respects. First of all, when the time interl.al between the stimuli is carefully adjusted, the augmentation may occur without a discrete second mechanical event. Secondly, in the investigation presented herein, not only did the
potentiation occur after a single extrasystole, as in most previous experiments, but it was found to be sustained for as long as the appropriately timed, paired stimuli were applied to the ventricle. Clinical L4pplication: The observation that the human heart reacts to paired stimuli in a manner similar to the dog heart (Fig. 8) suggests that double stimulation may have clinical application. It is possible that both the slowing of the ventricular contraction rate and the augmentaTHE
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tion of contractile force which result from paired clcctrical stimulation would be advantageous in the treatment of patients with various forms of cardiac disease. It must be appreciated, howe\er: that this method of stimulation may not be In order to be effecentirely without hazard. ti\.e, the second impulse of the pair must be delivered very shortly after the termination of the ventricle’s absolute refractory period, in or near the so-called vulnerable period, and ventricular fibrillation could result. Hopefully, however, this disastrous complication can be avoided by careful attention to the magnitude of the stimuli delivered to the heart. SUMMARY
When the ventricle is electrically stimulated immediately after the termination of the absolute refractory period, a propagated depolarization occurs which does not result in a clearly defined In secondary rise in intraventricular pressure. 19 dogs, two fundamental consequences of such paired electrical stimuli were studied. Since the second depolarization is followed by a second refractory period, the time during which the ventricle is unresponsive to other electrical stimuli is effectively doubled. Rapid ventricular rates could thus be slowed by paired stimuli, In regardless of the mechanism of tachycardia. each of 16 dogs, spontaneously occurring sinus tachycardia was suppressed by paired electrical stimulation. In 8 animals, ventricular tachycardia was induced by digitalis intoxication and in 6 by means of exogenous stimulation with a separate electrical pacemaker; paired stimuli slowed the ventricular rate in every aniStriking mal by an average of 57 beats per min. augmentation of the ventricle’s contractile response was found to be a second consequence of paired stimulation. This phenomenon was demonstrated in 8 dogs in which right ventricular contractile force was measured with a strain Paired electrical stimuli increased gauge arch. ventricular contractile force to an average of 275 per cent of the levels observed with single Prelimiimpulses delivered at the same rate.
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nary studies in man indicate that slowing and augmentation of contractile force also occur when the human heart is stimulated in a similar manner. ,4ppropriately timed, paired electrical stimuli to the ventricles result in profound alterations in both the electrical and contractile properties It is possible that this of the mammalian heart. technic will be applicable and beneficial in certain patients, when a slower heart rate and/or augmented myocardial contractile force is desirable. REFERENCES 1. SIEBENS, A. A., HOFFMAN, B. F., CRANEFIELD, P. F. and McC. BROOKS, C. Regulation of contractile force during ventricular arrhythmias. Am. J. Physiol., 197: 968, 1959. 2. LOPEZ, J. F., EDELIST, A. and KATZ, L. N. Slowing of the heart rate by artificial electrical stimulation with pulses of long duration in the dog (Abstr.). Circulation, 28: 759, 1963. 3. DEAN, D., CHARDACK,W. and GAGE, A. Slowing of the heart rate by paired electrical stimuli (Abstr.). Clin. Res., 12: 180, 1964. 4. CHARDACK,W. M., GAGE, A. A. and DEAN, D. C. Slowing of the heart by paired pulse pacemaking. Am. J. Cardiot., 14:374. 1964. 5. BONIFACE, K. J.,‘BRoDIE; 0. J. and WALTON, R. P. Resistance strain gauge arches for direct measurement of heart contractile force in animals. Proc. Sot. Exp. Biol. B Med., 84: 263, 1953. The influence 6. KOCH-WESER, J. and BLINKS, J. R. of the interval between beats on myocardial contractility. Pharmacol. Rev., 15: 601, 1963. 7. Ross, J., JR., SONNENBLICK,E. H., KAISER, G. A., FROMMER,P. L. and BRAUNWALI),E. Augmentation of ventricular performance and oxygen consumption by repetitive application of paired elecPhysiologist, in press. trical stimuli (Abstr.). 8. LANGENDORF, 0. Ueber elektrische Reizung des Herzens. Arch. Physiol., pp. 284-287, 1885. 9. HOFFMAN, B. F., BINDLER, E. and SUCKLING, E. F. Postextrasystolic potentiation of contraction in cardiac muscle. Am. J. Physiol., 185: 95, 1956. 10. GARB, S. and PENNA, M. Some quantitative aspects of the relation of rhythm to the contractile Am. J. force of mammalian ventricular muscle. Physiol., 182: 601, 1955. 11. KRUTA, V. and BRAVENY, P. Restitution de la contractiliti du myocarde entre les contractions et Arch. internat. de les phenomenes de potentiation. Physiol. et Biochem., 69: 645, 1961.