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Local effects of electrical and mechanical stimulation on the recovery properties of the canine ventricle
EXPERIMENTAL STUDIES
Local Effects of Electrical and Mechanical Stimulation on the Recovery Properties of the Canine Ventricle
BOAZ AVITALL, MD, PhD HERBERT J. LEVINE, MD, FACC SHAPUR NAIMI, MD, FACC RICHARD P. DONAHUE, MPH STEPHEN G. PAUKER, MD, FACC DAN ADAM. PhD Boston, Massachusetts
From the Tufts-New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts. This research was supported in part by Grant HL07 139 from the National Institutes of Health, Bethesda, Maryland, by Grant 76665 from the American Heart Association, Dallas, Texas, and by Grant 13-524-767 from the American Heart Association, Massachusetts Affiliate, Boston, Massachusetts. Dr. Pauker is a recipient of Research Career Development Award lK04GM00349 from the National Institutes of Health, Bethesda, Maryland. Manuscript received November 16, 1961; revised manuscript received January 25, 1962, accepted February 11, 1982. Address for reprints: Herbert J. Levine, MD, 171 Harrison Avenue, Boston, Massachusetts 02111.
The effects of electrical stimulation on local recovery properties of the canine ventricle were studied. Ventricular excitability was examined by an analysis of unipolar or bipolar strength-interval curves, and the effective refractory period was derived from the steep portion of the curve. Conduction times of all propagated responses to testing stimuli were recorded. When ventricular driving and testing sites were the same, effective refractory periods were significantly shorter (probability [p]
It has long been recognized that electrical stimulation of the myocardium that results in propagated depolarizations also produces localized electrophysiologic disturbances confined to a specific distance from the stimulation sites1 Subsequently, these changes were linked to the mechanism by which intense repetitive stimulation reduces the threshold for ventricular fibrillation.2 More recently, the response to electrically induced ventricular extrasystoles has been used to evaluate vulnerability to ventricular fibrillation in patients with heart disease.3-fi Although this technique has proved a useful clinical tool, the role of local changes in excitability and conduction that occur as a consequence of the testing stimulus itself remains unclear. The present study was undertaken to examine the electrophysiologic effects of cardiac pacing on the local recovery properties of the ventricle, using both electrical and mechanical stimuli to initiate depolarizations. The effects of coupling interval, the nature and intensity of the driving stimulus and the location of testing stimuli on ventricular refractoriness and the conduction time of propagated extrasystoles were examined in
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the intact dog heart. Localized alterations in refractoriness and conduction were observed after electrical stimulation of the ventricle that would be expected to facilitate reentrant arrhythmias. These local alterations were a function of current intensity and time and were not observed after depolarizations initiated by mechanical stimulation of the ventricle.
mvocardium
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Methods Experimental preparation: Experiments were performed in 52 mongrel dogs weighing 15 to 22 kg and anesthetized with an initial dose of 30 to 35 mg/kg body weight of sodium pentobarbital and additional bolus injections of 2 mg/kg as needed to maintain deep anesthesia. Ventilation was controlled by a Harvard respirator by way of a cuffed endotracheal tube. The chest was opened through a median sternotomy and the heart suspended in a pericardial cradle. The sinus node was crushed and the right atrium paced by way of a bipolar electrode. A 3 mm2 silver-silver chloride disk electrode was sewn to the anterior surface of the left ventricle for ventricular drive and for delivering premature ventricular stimuli. Atrial stimuli were bipolar and ventricular driving stimuli were cathodal or bipolar; both were 2 ms in duration with current strengths of twice threshold. A 6 cm2 plate electrode placed subcutaneously in the right hind limb served as the indifferent electrode for unipolar ventricular stimulation. A bipolar electrode consisting of a central ring (diameter 3 mm) and an outer ring (diameter 15 mm) was sutured to the right ventricular outflow tract for detection of premature ventricular complexes (Fig. I).
FIGURE 1. Schematic diagram of driving and testing electrode array used in the analysis of electrical and mechanical stimulation on ventricular recovery properties. See text.
Driving stimuli (Sl) were delivered to either the atria1 or the left ventricular electrode to produce an effective rate of 150 beatslmin. During atria1 drive, ventricular responses to
these stimuli (RI) were detected at the left ventricular electrode, and testing stimuli (S&--cathodal, anodal or bipolar and 2 ms in duration-were delivered to the same ventricular electrode at varying intervals after Ri for the determination of ventricular strength-interval curve (see later). The Ri was monitored continuously on a high persistence oscilloscope (Tektronix model 5103N), and a digital marker signaling to the computer the onset of depolarization was aligned visually with the steep phase of the Ri electrogram. This alignment was adjusted if necessary after each strength-interval curve; during the course of our experiment, this correction rarely amounted to more than f5 ms. Ventricular refractoriness and conduction: Excitability characteristics of the ventricle after basic driven beats or after premature beats were derived from an analysis of unipolar or bipolar strength-interval curves. These curves were generated at the ventricular disk electrode under complete computer control as described previously.7v8 After the response to Si (Ri), a testing stimulus (Ss) was delivered by way of Hewlett-Packard 6140A constant current unit under control of a PDP lab 8/e computer. The Ss pulse, delivered in late d&stole, was increased in intensity until a premature ventricular complex was evoked. The Ri-Ss interval was then decreased as the strength-interval curve was tracked leftward into the refractory period. The early portion of the strength-interval curve was inscribed using 2 ms decrements of the Ri-Ss interval; 5 ms decrements were used during the late diastolic curve. After each premature ventricular complex one Si pulse was inhibited and four recovery beats were allowed before testing stimulation was resumed. At an average heart rate of 150 beats/min a strength-interval curve composed of 30 to 50 points could be generated in this fashion every 2 to 3 minutes.
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In a previous study, no significant differences in effective refractory period were observed when 12 rather than 4 recovery beats were allowed after each premature ventricular complex.7 Similarly, no differences in effective refractory period were found when testing stimuli were delivered after every 12th driven beat. The conduction time was defined as the time elapsed from the delivery of Ss to the moment a propagated premature ventricular complex was recognized by the right ventricular recording electrode. The algorithm utilized for detection of premature ventricular complexes has been described elsewhere.7a8 In the analysis of strength-interval curves, three specific measurements were examined: (1) Effective refractory period
was defined as the shortest Ri-Ss interval at which a premature ventricular complex was evoked using currents of less than 1,800 PA. Thus, this interval identified the steep portion of the falling limb of the strength-interval curve. (2) Late diastolic threshold was the threshold current strength required during the late, flat portion of the strength-interval curve. (3) In the case of anodal strength-interval curves, the phase 3 dip threshold was determined. In each instance, average date were obtained from three consecutive strength-interval curves recorded during a steady state. Driving and testing stimuli: Figure 1 illustrates the arrangement of driving and testing electrodes. During atria1 drive, Ri-Ss intervals were recorded at the left ventricular electrode to ensure recovery times comparable with those found during ventricular drive. The effect of varying the distance between the ventricular driving and testing stimuli on the recovery properties of the ventricle was tested in the following fashion. A gang of six electrodes was constructed so that the first electrode in this linear arrangement was identical
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to the ventricular disk electrode described earlier. The remaining electrodes were 2 mm2 silver-silver chloride electrodes positioned 5,10,15,20 and 25 mm, respectively, from the first electrode and embedded in flexible rubber. The electrodes were sutured to the left ventricle with the long axis of the gang parallel to the left anterior descending coronary artery. Ventricular driving stimuli (Si) were delivered to each of the six electrodes in turn, while the testing stimuli (Ss) were always applied to the 3 mm2 disk electrode. In most experiments, and unless specified otherwise, ventricular driving and testing stimuli were cathodal. Phase 3 dip phenomena in six dogs were examined using cathodal ventricular drive and anodal testing stimuli. In five additional dogs, the effects of bipolar stimulation and electrode size were examined. In these experiments bipolar driving and testing stimuli were delivered to the ventricle via a pair of either 3 mm2 or 0.8 mm2 electrodes, each pair separated by 4 mm. Ventricular depolarization was initiated by mechanical stimulation of the heart as follows. A 15 gauge intracardiac
guide wire with a 4 mm ball tip attached to one end was inserted into a Teflon@ tube with the ball tip just protruding and barely touching the myocardium. Using the Teflon tube as a conduit for the guide wire, the opposite end of the wire was attached to a magnetic stylus, which in turn was activated by the computer system by way of an S-88 stimulator (Fig. 1). At specified cycle lengths, primary stimulation of the ventricle was accomplished by activating the stylus which delivered a brisk flick of the ball tip against the epicardium causing a depolarization. When mechanical impulses were used in this fashion for ventricular drive, variable distances between driving and testing stimuli were achieved by moving the testing electrode rather than the driving electrode because it was impractical to move the latter. In four dogs, the refractory period of the ventricle was determined using mechanical stimulation to initiate testing stimuli (Ss). In this instance, the effective refractory period was derived as the shortest interval following Ri when a mechanical Ss could initiate a propagated premature ventricular complex. The effect of varying the intensity of ventricular driving stimuli on the effective refractory period was examined in four dogs. In these experiments, Si pulses of threshold, twice
threshold and 10 times threshold intensity were delivered either to the same electrode used for the testing stimuli or to an electrode 15 mm from the S2 electrode. Propranolol was administered to three dogs in an intravenous bolus dose of 0.8 mg/kg 10 minutes before strength-interval curves were recorded. Four dogs were given reserpine, 0.3 mg/kg intramuscularly daily for 3 days, and on the day of the study, bilateral adrenalectomy and bilateral stellectomy were performed immediately before the electrophysiologic studies. Changes in cycle length: In eight dogs three driving modes were used to examine the effect of changes in cycle length on ventricular effective refractory period. In the first instance, regular atrial drive with a cycle length of 400 ms was compared with that when the steady state cycle length was reduced to 250 ms. In the second circumstance, ventricular effective refractory periods were measured after short coupling intervals (250 ms) introduced every 8th beat during regular atria1 drive (cycle length 400 ms). Lastly, ventricular effective refractory periods were measured after short coupling intervals (250 ms) during stable atria1 bigeminy. when the pause after the premature beat was fully compensatory and mean cycle length remained cons&t at 400 ms. In order to examine the effect of local electrical stimulation on the effective refractory period of closely coupled beats, the effect of a reduction in cycle length on ventricular effective refractory period was compared
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during stable atria1 and ventricular bigeminy. Maintaining a constant mean cycle length of 400 ms, the short cycle length of the bigeminal rhythm was reduced progressively from 400 to 350, 300 and 250 ms, each with a full compensatory pause. Experimental design: After the implantation of all electrodes, atria1 pacing at a rate of 150 beats/min was begun and sequential strength-interval curves were recorded to assure a stable state. During the course of a given experiment, strength-interval curves during atria1 pacing (150 beats/min) were repeated after every 20 to 25 curves to be certain the control state remained unchanged. Stability of the preparation was monitored by examination of the femoral arterial pressure and lead II of the scalar electrocardiogram using an Electronics for Medicine DR-8 recorder. The right ventricular electrogram and the Sz artifact were monitored on the high persistence oscilloscope. Arterial blood gases were measured two to three times during an experiment and arterial partial pressure of oxygen (PO,) was maintained above 100 mm Hg with supplemental inspired oxygen. Statistical analyses: Statistical analyses were performed using standard analysis of variance technics.” Data from any given animal were treated as “paired” in a nested analysis of variance schedule. The significance level of multiple comparisons was examined using Bonferronne bounds for prespecified hypothesis and by the Scheffe test for large unexpected differences.*0
Results Effect of separation of ventricular driving and testing site on effective refractory period and conduction (Fig. 2): Ventricular effective refractory periods and conduction times were measured during ventricular pacing when the driving (S1) and testing (SZ) electrodes were separated by 0,5,10,15,20 and 25 mm. When Si and SZ were delivered to the same ventricular electrode (interelectrode distance O), effective refractory periods were significantly shorter than during atria1 drive. However, as the distance between the ventricular driving and testing electrode was increased, effective refractory periods increased, until at interelectrode distances greater than 15 mm, they returned to levels similar to those observed during atrial drive. Also, when the ventricular driving and testing stimuli were applied to the same electrode, conduction times of propagated premature ventricular complexes were significantly longer than during atria1 drive. Conduction times shortened as the interelectrode distance was increased, and at 10 mm conduction time was similar to that observed during atria1 drive. Because the conduction times shown were recorded at the RI-S:! interval that defined the effective refractory period, prolonged conduction times were generally associated with shortened effective refractory periods. However, at an interelectrode distance of 10 mm, conduction times were the same during atria1 and ventricular drive, while effective refractory periods were still significantly shorter during ventricular drive than during atrial drive. No significant differences in late diastolic thresholds were observed during atria1 drive or ventricular drive when the drive and test site were the same. In three dogs given propranolol and in four additional dogs receiving reserpine that underwent bilateral
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effective refractory periods were measured first with the Si and Ss stimuli applied to the same electrode and then applied to electrodes separated by 15 mm. With Si and S:! stimuli delivered to the same electrode, the effective refractory period shortened by 8.2 percent (p
I
1
I
I
I
I
0
5
10
15
20
Distance
’ Tkl
25
Drive
of Ventricular Drive Electrode from Test Electrode, mm
FIGURE 2. Ventricular effective refractory periods and conduction times during atrial drive and during ventricular drive at varying distances between the driving and testing electrodes. Driving intervals were 400 ms. Ventricular driving and testing stimuli were cathodal. At long distances (15 to 25 mm), effective refractory periods and conduction times were similar to those during atrial drive. During ventricular drive, as the driving electrode was moved progressively closer to the testing electrode, effective refractory periods shortened and conduction times prolonged. Values represent mean values f standard error of the mean in six dogs. Asterisks indicate a significant difference (p <0.005) compared with atrial drive values. See text.
electrodes separated by 4 mm), shortening of the effective refractory period was similar to that observed when cathodal stimuli were used. Thus, when bipolar stimulation was used in five dogs, ventricular effective refractory period was 162.2 f 1.8 ms (mean f standard error of the mean) during atria1 drive, 161.8 f 1.8 ms during ventricular drive when the driving and testing electrodes were separated by 15 mm, and 132.8 f 1.2 ms when the bipolar ventricular drive and test site were the same (-18 percent; p
adrenalectomy and bilateral stellectomy just before electrophysiologic study, shortening of ventricular effective refractory periods was demonstrated at close Si-S2 electrode distances and was indistinguishable from that shown in Figure 2. Influence of S1 intensity and mode of stimulation on local effective refractory period (Table I): Effective refractory periods were measured in four dogs using Sr stimuli that were just threshold, twice threshold and 10 times threshold intensity. In each instance
B
I
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Influence of S, Intensity on Effective Refractory Period Threshold
srs2
Distance (mm)
x10
Xl
x2
0
147.0 f 4.6
15
168.3 f 5.3
134.9 f 4.3 p
124.5 f 3.5 p
Probability (p) values compared with threshold X 1. Values (ms) respresent mean values f standard error of the mean in four dogs. NS = not significant. l
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I
I
I
I
5
IO
I5
20
25
Test
Electrode
Distance from
Mechmcal Ventrrculor
I
Ventricular
of
Drive
Electrode,
Drive
mm
FIGURE 3. Effect of distance between ventricular driving and testing sites on effective refractory period of depolarizations initiated by electrical and mechanical stimulation of the ventricle. Driving intervals were 400 ms. Ventricular driving and testing stimuli were cathodal. Testing stimuli were delivered to each of five electrodes positioned 5 to 25 mm from the ventricular drive electrode. At each testing electrode, effective refractory period was measured during atrial drive. With reduction in the distance between ventricular driving and testing electrodes, the effective refractory period shortened progressively during electrical ventricular drive, but remained unchanged during mechanical ventricular drive and during atrial drive. Values represent mean value f standard error of the mean in six dogs. * indicates significant differences (p
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TABLE II Effect of Stimulation Mode on Effective Refractory Period and Conduction Time (mean value f standard error of the mean) Mode 1
Mode 2
Mode 3
Mode 4
Mode 5
Atrial (E) Vent. (E)
Atrial (E) Vent. (M)
Vent. (M) Vent. (E)+
Vent. (E) Vent. (E)+
Vent. (E) Vent. (M)+
177.3 f 2.1 78.4 f 2.9
183.0 f 3.8 112.1 k 4.2
St 52
ERP (ms) Conduction time (ms) E = electrical of 5 mm.
stimulation; ERP = effective refractory
171.0 f 4.6 73.5 f 3.1
149.1 f 4.2 100.2 f 2.5
period; M = mechanical stimulation; Vent. = ventricular:
examined after depolarizations initiated by mechanical stimulation of the ventricle. Because it was not possible to stimulate the ventricle mechanically and deliver testing stimuli at the same location, effective refractory periods were measured at distances of 5,10,15,20 and 25 mm from the Sr electrode. As in the experiments presented in Figure 2, effective refractory periods were similar during atria1 and ventricular drive at Sq-Sz electrode distances greater than 15 mm but as the SI-SZ distance decreased during electrical ventricular drive, effective refractory periods shortened progressively. However, when Sr was initiated by mechanical stimulation of the ventricle, effective refractory periods during ventricular and atria1 drive were indistinguishable at all SI-& electrode distances. Although the effective refractory period appeared to increase somewhat during mechanical drive at shorter S1-Sz electrode distances, this increase was not statistically significant and likely was due to different test electrode locations. This conclusion is supported by our observation of a parallel increase in effective refractory period during atria1 drive, when the same testing electrodes were used. The effects of varying pacing and testing modes on ventricular effective refractory periods and conduction times are summarized in Table II. When mechanical
impulses for initiating testing stimuli were used, ventricular effective refractory periods were similar to those derived from electrical testing stimuli regardless of whether atria1 drive (column 1 versus column 2) or ventricular drive (column 4 versus column 5) was employed. Thus, the manner in which testing stimuli are generated does not appear to influence the measure-
146.3 f 129.6 f
2.3 1.5
-I- = S,-Sz electrode distance
ment of the effective refractory period. However, when ventricular drive was accomplished using a mechanical impulse (column 3), effective refractory periods were significantly longer (p
TABLE Ill Effect of Reduction in Cycle Length on Effective Refractory Period* Regular Atrial Drive RI-RI 400 ms 181.2 f 183.3 f 185.1 f
1.1 1.4 1.6
RI-RI
250 ms 154.3 f
Pacing Every 8th Beat: RI-RI 400 ms; RI-R2 250 ms
Atrial Bigeminy: RI-R* 250 ms; R2-RI 550 ms
1.9 i75.i.k
2.1
.
181.3’j
1.5
P Value
* Values, expressed in milliseconds, indicate the mean effective refractory period (rt standard error of the mean) in six dogs. NS = not significant; p = probability; R,-RI = cycle length of driving stimuli; R,-R2 = coupling interval of premature beat; RTRl = coupling interval of postpremature beat pause.
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A
Atrial Drove
0
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A atrial drive CI ventricular drive
800
Bwe
170
p
700
\ S c”
600
P iT
250
300
Coupling
L
I
I
I
I
250
300
350
400
Coupling
Interval,
msec.
FIGURE 4. Effect of reduction in cycle length on ventricular effective refractory periods and conduction times measured during atrial and ventricular drive. The basic driving interval was 400 ms. Coupling intervals of 350, 300 and 250 ms represent the short cycle of stable bigeminy with a full compensatory pause (mean cycle length 400 ms). The ventricular driving and testing sites were the same. Values represent mean value f standard error of the mean in 25 dogs. During ventricular drive, effective refractory periods were shorter (p
350
Interval,
400
msec.
FIGURE 5. Anodal dip threshold during atrial and ventricular drive. The basic driving interval was 400 ms. Coupling intervals of 350, 300 and 250 ms represent the short cycle of stable bigeminy with a full compensatory pause (mean cycle length 400 ms). Ventricular driving stimuli were cathodal; testing stimuli were anodal. Ventricular test and drive sites were the same. Values represent mean value f standard error of the mean in six dogs. Although dip thresholds were lower (p
examine phase 3 dip phenomena (Fig. 5). At each coupling interval, dip thresholds were significantly lower when the ventricular drive and test sites were the same as the dip thresholds during atria1 drive. Discussion
350,300 and 250 ms (Fig. 4). In each instance, a full compensatory pause was maintained so that mean cycle length remained constant at 400 ms. Consistent with the data presented in Table III, during atria1 bigeminy no change in ventricular effective refractory period was observed as the coupling interval was reduced from 400 to 250 ms. However, during ventricular bigeminy, the effective refractory period measured at the driving electrode shortened from 142 f 3.0 to 130 f 2.3 ms (p
to
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Effect of stimulation site on local effective refractory period: In 1966, Han et a1.l found that the average ventricular refractory period was shorter at points close to the stimulation site than at points farther away. In addition, they reported that the ventricular fibrillation threshold was lower after early premature beats than after depolarizations initiated in fully excitable tissue. This effect was exaggerated “at points near the origin of the premature response,” and was attributed to greater dispersion of refractoriness measured within a 10 to 15 mm radius of the stimulating electrode. In the present study, the observation that refractory periods are shortened near the stimulating electrode was confirmed, and the effect was found to decay over the same distance from the stimulating electrode (about 15 mm) as that observed by Han et al. Moreover, in a previous study, well found fibrillation threshold to decrease progressively as the S1-S2 interelectrode distance was decreased from 25 to 0 mm. The observation that conduction times were longer at sites close to the stimulating electrode provides a factor in addition to dispersion of refractoriness that might favor reentrant arrthythmias and lower fibrillation threshold. A possible relation between these altered recovery properties and a lower fibrillation threshold is also suggested by the demonstration that shortening of the
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effective refractory period at the ventricular driving site was observed with bipolar as well as with cathodal drive. The finding that dip thresholds of anodai strengthinterval curves were lower when the ventricular drive and test sites were the same provides additional support for this view. In studies of human ventricular refractoriness,
Cuss
et a1.12observed that the ventricular effective refractory period after premature atrial beats was longer, at a given cycle length, than that occurring after electrically induced premature ventricular beats. In this study, we found this to be true only if the ventricular driving and testing sites were close to one another. However, ventricular effective refractory periods measured at a distance from the ventricular stimulating electrode were essentially the same as those occurring after atria1 premature beats, suggesting that local effects of the current applied at the stimulation site-rather than the origin of the impulse in the atrium or ventricle-were largely responsible for this difference. Effect of current intensity and electrode size: Spear et al.” demonstrated that increasing the current intensity of a pulse or train of pulses increased the temporal dispersion of refractoriness within an 8 mm radial distance of the stimulating electrode and lowered the ventricular fibrillation threshold. Furthermore, the effective refractory period measured at a given electrode site tended to shorten as pulse intensity was increased. In the present study, increases in current intensity shortened the effective refractory period measured at the site of the stimulating electrode (Sr), and the magnitude of this effect, both at the Sr electrode and at a site 15 mm from it, was dependent on the intensity of the driving stimulus itself. In contrast to our findings, Toyoshima and Burges&l recently found that canine effective refractory periods were 4.7 percent longer when the driving and testing electrodes were the same than when the two electrodes were separated by 40 to 60 mm. The difference between their data and ours may be due in part to differences in stimulation technique. The thin wire assembly used by Toyoshima and Burgess required much smaller current intensities for excitation and thus the local effects of electrical stimulation would be less and should have been dissipated within a very short distance of the drivirg site. Although substantial local alterations of recovery properties were found in our study with electrode surface areas of only 0.8 mm2, these electrotonic effects still may be due in part to relatively large electrodes and thus were avoided with the much smaller electrodes employed by Toyoshima and Burgess. In addition, the testing stimuli they used to measure effective refractory periods were 1.5 to 2.0 times threshold and may have identified the slowly rising portion of the strength-interval curve. -4s Greenspan et a1.14 noted, values for effective refractory period determined in this fashion might be influenced by threshold changes rather than by refractoriness as such. Effect of mechanical stimulation: The observation that mechanical stimulation of the ventricle, capable of initiating a propagated premature beat, fails to pro-
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duce effective refractory period shortening near the stimulating electrode strongly supports the view that effective refractory period shortening in the vicinity of the stimulating electrode is a consequence of the electrical stimulus itself. In this regard, it is noteworthy that when testing and driving sites were separated by 20 mm or more, ventricular effective refractory periods were similar after all modes of stimulation-atria1 drive, ventricular mechanical drive or ventricular electrical drive. However, when mechanical impulses were used as testing stimuli (Ss), conduction times of premature beats were consistently about 30 ms longer than when electrical Ss pulses were used (Table II). This interval, which likely reflects the time between mechanical deformation and local depolarization of the myocardium, agrees closely with the data obtained by Zoll et a1.15 using an external device to effect cardiac stimulation. In their studies a consistent 40 ms interval was observed between mechanical displacement of the heart and the electrical ventricular response. In our study, mechanical stimuli were never observed to evoke a repetitive ventricular response, although this response occasionally occurred when electrical stimulation was used. Zoll et a1.r5 also failed to observe repetitive ventricular responses after external mechanical stimulation even “in the relative refractory period at energies IO times threshold levels.” Influence of heart rate and coupling interval: Moore et al.‘” showed that a depolarization induced by a premature stimulus results in a shortened action potential duration and effective refractory period. In another study of refractory periods after sudden increases in frequency,17 a time-dependent shortening of the refractory period was demonstrated with approximately 30 percent of the total shortening occurring within the first beat, and a new steady state was established only after a few hundred beats. In our study, too, the shortening of the effective refractory period observed after single premature atria1 beats (coupling interval 250 ms) was 30 percent of that found during regular atria1 drive at the same cycle length. However, if during atria1 bigeminy, the diastolic pause preceding the closely coupled beat was fully compensatory and mean cycle length remained constant, no shortening of the effective refractory period was observed (Table III; Fig. 4). Thus, it appears that prolonged effective refractory periods induced by the long cycle of a bigeminal rhythm are “remembered” during the subsequent short cycle and nullify the effect of the short cycle in reducing effective refractory period. The constancy of ventricular effective refractory periods during atria1 bigeminy, despite a variable coupling interval, provided a convenient reference point for examining the effect of time dependency of ventricular stimulation on local refractoriness. Thus, although no change in effective refractory period was observed during atrial bigeminal drive when the coupling interval was reduced from 400 to 250 ms, during ventricular drive significant shortening of the effective refractory period was found when refractoriness was measured at or near the stimulating electrode site. These observa-
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tions suggest that the effect of coupling interval on ventricular effective refractory period are somewhat exaggerated by closely positioned testing and driving sites, and that local effects of stimulation constitute a major factor in observed effective refractory period responses to changes in coupling intervals when the mean coupling interval or the immediately preceding coupling interval has already been shortened. Because closely positioned driving and testing electrodes generally have been used in studies of the effect of cycle length on the effective refractory period,16J7 one wonders to what extent the reported alterations in the effective refractory period represent time-dependent characteristics of the local effects of electrical stimulation. Whatever may be the mechanism for effective refractory period shortening near the driving site, it would appear that local adrenergic stimulation was not responsible, because stellate ablation and adrenalectomy in dogs receiving reserpine did not influence this phenomenon In other studies,‘s too, parasympathetic blockade with atropine had no effect on ventricular effective refractory period measured at or near the driving electrode. Clinical implications: Because published studies of ventricular refractoriness generally have examined responses at or near the driving electrode with stimuli 1.5 to 3 times threshold, there is reason to believe that
a systematic error may have been introduced into many studies of refractory period. Because the local effects of electrical stimulation of muscle are a function of current intensity and time, the relation between effective refractory period and both coupling interval and mean cycle length might well be reexamined using methods that minimize these local effects. Similarly, caution is urged in the interpretation of clinical and experimental studies that use provocative stimuli to detect vulnerability to ventricular arrhythmias, especially those that use large electrodes and stimuli well above threshold. Not only do the stimulation techniques used in our study produce localized shortening of the effective refractory period, but also conduction times of premature beats propagated during early recovery of driven beats are greatly prolonged and dip thresholds are lower, thus establishing conditions favorable to repetitive reentrant arrhythmias. Because the methods used in clinical studies of programmed stimulation utilize bipolar electrodes with surface areas that often exceed those used in our study and use stimuli of 2 to 5 times threshold, there is reason to believe that local electrotonic effects of applied current may play a role in initiating provoked ventricular tachyarrhythmias. Whether the clinical utility of programmed stimulation would be enhanced by the use of stimulation techniques that minimize these local electrotonic effects remains to be shown.
References 1. Han J, Garcia de Jalon PD, Moe GK. Fibrillation threshold of premature ventricular responses. Circ Res 1966; 18: 18-25. 2. Spear JF, Moore EN, Horowitz LN. Effect of current pulses delivered during the ventricular vulnerable period upon the ventricular fibrillation threshold. Am J Cardiol 1973;32:814-22. 3. Spielman SR, FarshMl A, Horowllz LN, Josephson ME. Ventricular fibrillation during programmed ventricular stimulation: incidence and clinical implications. Am J Cardiol 1978;42:913-8. 4. Greene LH, Reld PR, Schaeffer AH. The repetitive ventricular response in man. A predictor of sudden death. N Engl J Med 1978;299:729-34. 5. Ruskln JN, DlMarco JP, Garan H. Repetitive responses to single ventricular extrastimuli in patients with serious ventricular arrhythmias: incidence and clinical significance. Circulation 1980; 63:767-72. 6. Mason JW. Repetitive beating afler single ventricular extrastimuli: incidence and prognostic significance in patients with recurrent ventricular tachycardia. Am J Cardiol 1980;45: 1126-31. 7. Levine HJ, Avltall 6, Pauker SG, Nalml S. Sequential unipolar strength-interval curves and conduction times during myocardial ischemia and reperfusion in the dog. Circ Res 1978;43:63-72. 8. Pauker SG, Avltall 6, Levlne HJ, Nalmi S. The rapid generation of strength-interval curves under computer control. Comput Progams Biomed 1979:10:209-17.
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9. Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames, Iowa: Iowa State University Press, 1967: 258-98. 10. Morrlson DR. Multivariate Statistical Methods. New York: McGraw-Hill, 1976:128-69. 11. Avltall 8. The electrophysiological effects of alternate vs. single electrode pacing. J Electrocardiol 1981;14:61-6. 12. GUSSSB, Kaslor JA, Josephson ME, Sharf DL. Human ventricular refractoriness: effects of cycle length, pacing site and atropine. Circulation 1976;53:450-5. 13. Toyoshlma H, Burgess MJ. Electronic interaction during canine ventricular repolarization. Circ Res 1978;43:348-56. 14. Greenspan AM, Camardo JS, Horowitz LN, Splelman SR, Josephson ME. Human ventricular refractoriness: effects of increasing current. Am J Cardiol 1981;47:244-50. 15. 2011 PM, Belgard AH, Welntraub MJ, Frank AH. External mechanical cardiac stimulation. N Engl J Med 1976;23:1274-5. 16. Moore EN, Preston JB, Moe GK. Durations of transmembrane action potentials and functional refractory periods of canine false tendon and ventricular myocardium: comparisons in single fibers. Circ Res 1965; 17:259-73. 17. Janse MJ, van der Steen AMD, van Dam RTH, Durrer D. Refractory period of the dog’s ventricular myocardium following sudden changes in frequency. Circ Res 1969;24:251-62.
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Local Effects of Electrical and Mechanical Stimulation on the Recovery Properties of the Canine Ventricle
BOAZ AVITALL, MD, PhD HERBERT J. LEVINE, MD, FACC SHAPUR NAIMI, MD, FACC RICHARD P. DONAHUE, MPH STEPHEN G. PAUKER, MD, FACC DAN ADAM. PhD Boston, Massachusetts
From the Tufts-New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts. This research was supported in part by Grant HL07 139 from the National Institutes of Health, Bethesda, Maryland, by Grant 76665 from the American Heart Association, Dallas, Texas, and by Grant 13-524-767 from the American Heart Association, Massachusetts Affiliate, Boston, Massachusetts. Dr. Pauker is a recipient of Research Career Development Award lK04GM00349 from the National Institutes of Health, Bethesda, Maryland. Manuscript received November 16, 1961; revised manuscript received January 25, 1962, accepted February 11, 1982. Address for reprints: Herbert J. Levine, MD, 171 Harrison Avenue, Boston, Massachusetts 02111.
The effects of electrical stimulation on local recovery properties of the canine ventricle were studied. Ventricular excitability was examined by an analysis of unipolar or bipolar strength-interval curves, and the effective refractory period was derived from the steep portion of the curve. Conduction times of all propagated responses to testing stimuli were recorded. When ventricular driving and testing sites were the same, effective refractory periods were significantly shorter (probability [p]
It has long been recognized that electrical stimulation of the myocardium that results in propagated depolarizations also produces localized electrophysiologic disturbances confined to a specific distance from the stimulation sites1 Subsequently, these changes were linked to the mechanism by which intense repetitive stimulation reduces the threshold for ventricular fibrillation.2 More recently, the response to electrically induced ventricular extrasystoles has been used to evaluate vulnerability to ventricular fibrillation in patients with heart disease.3-fi Although this technique has proved a useful clinical tool, the role of local changes in excitability and conduction that occur as a consequence of the testing stimulus itself remains unclear. The present study was undertaken to examine the electrophysiologic effects of cardiac pacing on the local recovery properties of the ventricle, using both electrical and mechanical stimuli to initiate depolarizations. The effects of coupling interval, the nature and intensity of the driving stimulus and the location of testing stimuli on ventricular refractoriness and the conduction time of propagated extrasystoles were examined in
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the intact dog heart. Localized alterations in refractoriness and conduction were observed after electrical stimulation of the ventricle that would be expected to facilitate reentrant arrhythmias. These local alterations were a function of current intensity and time and were not observed after depolarizations initiated by mechanical stimulation of the ventricle.
mvocardium
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Methods Experimental preparation: Experiments were performed in 52 mongrel dogs weighing 15 to 22 kg and anesthetized with an initial dose of 30 to 35 mg/kg body weight of sodium pentobarbital and additional bolus injections of 2 mg/kg as needed to maintain deep anesthesia. Ventilation was controlled by a Harvard respirator by way of a cuffed endotracheal tube. The chest was opened through a median sternotomy and the heart suspended in a pericardial cradle. The sinus node was crushed and the right atrium paced by way of a bipolar electrode. A 3 mm2 silver-silver chloride disk electrode was sewn to the anterior surface of the left ventricle for ventricular drive and for delivering premature ventricular stimuli. Atrial stimuli were bipolar and ventricular driving stimuli were cathodal or bipolar; both were 2 ms in duration with current strengths of twice threshold. A 6 cm2 plate electrode placed subcutaneously in the right hind limb served as the indifferent electrode for unipolar ventricular stimulation. A bipolar electrode consisting of a central ring (diameter 3 mm) and an outer ring (diameter 15 mm) was sutured to the right ventricular outflow tract for detection of premature ventricular complexes (Fig. I).
FIGURE 1. Schematic diagram of driving and testing electrode array used in the analysis of electrical and mechanical stimulation on ventricular recovery properties. See text.
Driving stimuli (Sl) were delivered to either the atria1 or the left ventricular electrode to produce an effective rate of 150 beatslmin. During atria1 drive, ventricular responses to
these stimuli (RI) were detected at the left ventricular electrode, and testing stimuli (S&--cathodal, anodal or bipolar and 2 ms in duration-were delivered to the same ventricular electrode at varying intervals after Ri for the determination of ventricular strength-interval curve (see later). The Ri was monitored continuously on a high persistence oscilloscope (Tektronix model 5103N), and a digital marker signaling to the computer the onset of depolarization was aligned visually with the steep phase of the Ri electrogram. This alignment was adjusted if necessary after each strength-interval curve; during the course of our experiment, this correction rarely amounted to more than f5 ms. Ventricular refractoriness and conduction: Excitability characteristics of the ventricle after basic driven beats or after premature beats were derived from an analysis of unipolar or bipolar strength-interval curves. These curves were generated at the ventricular disk electrode under complete computer control as described previously.7v8 After the response to Si (Ri), a testing stimulus (Ss) was delivered by way of Hewlett-Packard 6140A constant current unit under control of a PDP lab 8/e computer. The Ss pulse, delivered in late d&stole, was increased in intensity until a premature ventricular complex was evoked. The Ri-Ss interval was then decreased as the strength-interval curve was tracked leftward into the refractory period. The early portion of the strength-interval curve was inscribed using 2 ms decrements of the Ri-Ss interval; 5 ms decrements were used during the late diastolic curve. After each premature ventricular complex one Si pulse was inhibited and four recovery beats were allowed before testing stimulation was resumed. At an average heart rate of 150 beats/min a strength-interval curve composed of 30 to 50 points could be generated in this fashion every 2 to 3 minutes.
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In a previous study, no significant differences in effective refractory period were observed when 12 rather than 4 recovery beats were allowed after each premature ventricular complex.7 Similarly, no differences in effective refractory period were found when testing stimuli were delivered after every 12th driven beat. The conduction time was defined as the time elapsed from the delivery of Ss to the moment a propagated premature ventricular complex was recognized by the right ventricular recording electrode. The algorithm utilized for detection of premature ventricular complexes has been described elsewhere.7a8 In the analysis of strength-interval curves, three specific measurements were examined: (1) Effective refractory period
was defined as the shortest Ri-Ss interval at which a premature ventricular complex was evoked using currents of less than 1,800 PA. Thus, this interval identified the steep portion of the falling limb of the strength-interval curve. (2) Late diastolic threshold was the threshold current strength required during the late, flat portion of the strength-interval curve. (3) In the case of anodal strength-interval curves, the phase 3 dip threshold was determined. In each instance, average date were obtained from three consecutive strength-interval curves recorded during a steady state. Driving and testing stimuli: Figure 1 illustrates the arrangement of driving and testing electrodes. During atria1 drive, Ri-Ss intervals were recorded at the left ventricular electrode to ensure recovery times comparable with those found during ventricular drive. The effect of varying the distance between the ventricular driving and testing stimuli on the recovery properties of the ventricle was tested in the following fashion. A gang of six electrodes was constructed so that the first electrode in this linear arrangement was identical
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to the ventricular disk electrode described earlier. The remaining electrodes were 2 mm2 silver-silver chloride electrodes positioned 5,10,15,20 and 25 mm, respectively, from the first electrode and embedded in flexible rubber. The electrodes were sutured to the left ventricle with the long axis of the gang parallel to the left anterior descending coronary artery. Ventricular driving stimuli (Si) were delivered to each of the six electrodes in turn, while the testing stimuli (Ss) were always applied to the 3 mm2 disk electrode. In most experiments, and unless specified otherwise, ventricular driving and testing stimuli were cathodal. Phase 3 dip phenomena in six dogs were examined using cathodal ventricular drive and anodal testing stimuli. In five additional dogs, the effects of bipolar stimulation and electrode size were examined. In these experiments bipolar driving and testing stimuli were delivered to the ventricle via a pair of either 3 mm2 or 0.8 mm2 electrodes, each pair separated by 4 mm. Ventricular depolarization was initiated by mechanical stimulation of the heart as follows. A 15 gauge intracardiac
guide wire with a 4 mm ball tip attached to one end was inserted into a Teflon@ tube with the ball tip just protruding and barely touching the myocardium. Using the Teflon tube as a conduit for the guide wire, the opposite end of the wire was attached to a magnetic stylus, which in turn was activated by the computer system by way of an S-88 stimulator (Fig. 1). At specified cycle lengths, primary stimulation of the ventricle was accomplished by activating the stylus which delivered a brisk flick of the ball tip against the epicardium causing a depolarization. When mechanical impulses were used in this fashion for ventricular drive, variable distances between driving and testing stimuli were achieved by moving the testing electrode rather than the driving electrode because it was impractical to move the latter. In four dogs, the refractory period of the ventricle was determined using mechanical stimulation to initiate testing stimuli (Ss). In this instance, the effective refractory period was derived as the shortest interval following Ri when a mechanical Ss could initiate a propagated premature ventricular complex. The effect of varying the intensity of ventricular driving stimuli on the effective refractory period was examined in four dogs. In these experiments, Si pulses of threshold, twice
threshold and 10 times threshold intensity were delivered either to the same electrode used for the testing stimuli or to an electrode 15 mm from the S2 electrode. Propranolol was administered to three dogs in an intravenous bolus dose of 0.8 mg/kg 10 minutes before strength-interval curves were recorded. Four dogs were given reserpine, 0.3 mg/kg intramuscularly daily for 3 days, and on the day of the study, bilateral adrenalectomy and bilateral stellectomy were performed immediately before the electrophysiologic studies. Changes in cycle length: In eight dogs three driving modes were used to examine the effect of changes in cycle length on ventricular effective refractory period. In the first instance, regular atrial drive with a cycle length of 400 ms was compared with that when the steady state cycle length was reduced to 250 ms. In the second circumstance, ventricular effective refractory periods were measured after short coupling intervals (250 ms) introduced every 8th beat during regular atria1 drive (cycle length 400 ms). Lastly, ventricular effective refractory periods were measured after short coupling intervals (250 ms) during stable atria1 bigeminy. when the pause after the premature beat was fully compensatory and mean cycle length remained cons&t at 400 ms. In order to examine the effect of local electrical stimulation on the effective refractory period of closely coupled beats, the effect of a reduction in cycle length on ventricular effective refractory period was compared
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during stable atria1 and ventricular bigeminy. Maintaining a constant mean cycle length of 400 ms, the short cycle length of the bigeminal rhythm was reduced progressively from 400 to 350, 300 and 250 ms, each with a full compensatory pause. Experimental design: After the implantation of all electrodes, atria1 pacing at a rate of 150 beats/min was begun and sequential strength-interval curves were recorded to assure a stable state. During the course of a given experiment, strength-interval curves during atria1 pacing (150 beats/min) were repeated after every 20 to 25 curves to be certain the control state remained unchanged. Stability of the preparation was monitored by examination of the femoral arterial pressure and lead II of the scalar electrocardiogram using an Electronics for Medicine DR-8 recorder. The right ventricular electrogram and the Sz artifact were monitored on the high persistence oscilloscope. Arterial blood gases were measured two to three times during an experiment and arterial partial pressure of oxygen (PO,) was maintained above 100 mm Hg with supplemental inspired oxygen. Statistical analyses: Statistical analyses were performed using standard analysis of variance technics.” Data from any given animal were treated as “paired” in a nested analysis of variance schedule. The significance level of multiple comparisons was examined using Bonferronne bounds for prespecified hypothesis and by the Scheffe test for large unexpected differences.*0
Results Effect of separation of ventricular driving and testing site on effective refractory period and conduction (Fig. 2): Ventricular effective refractory periods and conduction times were measured during ventricular pacing when the driving (S1) and testing (SZ) electrodes were separated by 0,5,10,15,20 and 25 mm. When Si and SZ were delivered to the same ventricular electrode (interelectrode distance O), effective refractory periods were significantly shorter than during atria1 drive. However, as the distance between the ventricular driving and testing electrode was increased, effective refractory periods increased, until at interelectrode distances greater than 15 mm, they returned to levels similar to those observed during atrial drive. Also, when the ventricular driving and testing stimuli were applied to the same electrode, conduction times of propagated premature ventricular complexes were significantly longer than during atria1 drive. Conduction times shortened as the interelectrode distance was increased, and at 10 mm conduction time was similar to that observed during atria1 drive. Because the conduction times shown were recorded at the RI-S:! interval that defined the effective refractory period, prolonged conduction times were generally associated with shortened effective refractory periods. However, at an interelectrode distance of 10 mm, conduction times were the same during atria1 and ventricular drive, while effective refractory periods were still significantly shorter during ventricular drive than during atrial drive. No significant differences in late diastolic thresholds were observed during atria1 drive or ventricular drive when the drive and test site were the same. In three dogs given propranolol and in four additional dogs receiving reserpine that underwent bilateral
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effective refractory periods were measured first with the Si and Ss stimuli applied to the same electrode and then applied to electrodes separated by 15 mm. With Si and S:! stimuli delivered to the same electrode, the effective refractory period shortened by 8.2 percent (p
I
1
I
I
I
I
0
5
10
15
20
Distance
’ Tkl
25
Drive
of Ventricular Drive Electrode from Test Electrode, mm
FIGURE 2. Ventricular effective refractory periods and conduction times during atrial drive and during ventricular drive at varying distances between the driving and testing electrodes. Driving intervals were 400 ms. Ventricular driving and testing stimuli were cathodal. At long distances (15 to 25 mm), effective refractory periods and conduction times were similar to those during atrial drive. During ventricular drive, as the driving electrode was moved progressively closer to the testing electrode, effective refractory periods shortened and conduction times prolonged. Values represent mean values f standard error of the mean in six dogs. Asterisks indicate a significant difference (p <0.005) compared with atrial drive values. See text.
electrodes separated by 4 mm), shortening of the effective refractory period was similar to that observed when cathodal stimuli were used. Thus, when bipolar stimulation was used in five dogs, ventricular effective refractory period was 162.2 f 1.8 ms (mean f standard error of the mean) during atria1 drive, 161.8 f 1.8 ms during ventricular drive when the driving and testing electrodes were separated by 15 mm, and 132.8 f 1.2 ms when the bipolar ventricular drive and test site were the same (-18 percent; p
adrenalectomy and bilateral stellectomy just before electrophysiologic study, shortening of ventricular effective refractory periods was demonstrated at close Si-S2 electrode distances and was indistinguishable from that shown in Figure 2. Influence of S1 intensity and mode of stimulation on local effective refractory period (Table I): Effective refractory periods were measured in four dogs using Sr stimuli that were just threshold, twice threshold and 10 times threshold intensity. In each instance
B
I
TABLE
Influence of S, Intensity on Effective Refractory Period Threshold
srs2
Distance (mm)
x10
Xl
x2
0
147.0 f 4.6
15
168.3 f 5.3
134.9 f 4.3 p
124.5 f 3.5 p
Probability (p) values compared with threshold X 1. Values (ms) respresent mean values f standard error of the mean in four dogs. NS = not significant. l
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I
I
I
I
5
IO
I5
20
25
Test
Electrode
Distance from
Mechmcal Ventrrculor
I
Ventricular
of
Drive
Electrode,
Drive
mm
FIGURE 3. Effect of distance between ventricular driving and testing sites on effective refractory period of depolarizations initiated by electrical and mechanical stimulation of the ventricle. Driving intervals were 400 ms. Ventricular driving and testing stimuli were cathodal. Testing stimuli were delivered to each of five electrodes positioned 5 to 25 mm from the ventricular drive electrode. At each testing electrode, effective refractory period was measured during atrial drive. With reduction in the distance between ventricular driving and testing electrodes, the effective refractory period shortened progressively during electrical ventricular drive, but remained unchanged during mechanical ventricular drive and during atrial drive. Values represent mean value f standard error of the mean in six dogs. * indicates significant differences (p
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TABLE II Effect of Stimulation Mode on Effective Refractory Period and Conduction Time (mean value f standard error of the mean) Mode 1
Mode 2
Mode 3
Mode 4
Mode 5
Atrial (E) Vent. (E)
Atrial (E) Vent. (M)
Vent. (M) Vent. (E)+
Vent. (E) Vent. (E)+
Vent. (E) Vent. (M)+
177.3 f 2.1 78.4 f 2.9
183.0 f 3.8 112.1 k 4.2
St 52
ERP (ms) Conduction time (ms) E = electrical of 5 mm.
stimulation; ERP = effective refractory
171.0 f 4.6 73.5 f 3.1
149.1 f 4.2 100.2 f 2.5
period; M = mechanical stimulation; Vent. = ventricular:
examined after depolarizations initiated by mechanical stimulation of the ventricle. Because it was not possible to stimulate the ventricle mechanically and deliver testing stimuli at the same location, effective refractory periods were measured at distances of 5,10,15,20 and 25 mm from the Sr electrode. As in the experiments presented in Figure 2, effective refractory periods were similar during atria1 and ventricular drive at Sq-Sz electrode distances greater than 15 mm but as the SI-SZ distance decreased during electrical ventricular drive, effective refractory periods shortened progressively. However, when Sr was initiated by mechanical stimulation of the ventricle, effective refractory periods during ventricular and atria1 drive were indistinguishable at all SI-& electrode distances. Although the effective refractory period appeared to increase somewhat during mechanical drive at shorter S1-Sz electrode distances, this increase was not statistically significant and likely was due to different test electrode locations. This conclusion is supported by our observation of a parallel increase in effective refractory period during atria1 drive, when the same testing electrodes were used. The effects of varying pacing and testing modes on ventricular effective refractory periods and conduction times are summarized in Table II. When mechanical
impulses for initiating testing stimuli were used, ventricular effective refractory periods were similar to those derived from electrical testing stimuli regardless of whether atria1 drive (column 1 versus column 2) or ventricular drive (column 4 versus column 5) was employed. Thus, the manner in which testing stimuli are generated does not appear to influence the measure-
146.3 f 129.6 f
2.3 1.5
-I- = S,-Sz electrode distance
ment of the effective refractory period. However, when ventricular drive was accomplished using a mechanical impulse (column 3), effective refractory periods were significantly longer (p
TABLE Ill Effect of Reduction in Cycle Length on Effective Refractory Period* Regular Atrial Drive RI-RI 400 ms 181.2 f 183.3 f 185.1 f
1.1 1.4 1.6
RI-RI
250 ms 154.3 f
Pacing Every 8th Beat: RI-RI 400 ms; RI-R2 250 ms
Atrial Bigeminy: RI-R* 250 ms; R2-RI 550 ms
1.9 i75.i.k
2.1
.
181.3’j
1.5
P Value
* Values, expressed in milliseconds, indicate the mean effective refractory period (rt standard error of the mean) in six dogs. NS = not significant; p = probability; R,-RI = cycle length of driving stimuli; R,-R2 = coupling interval of premature beat; RTRl = coupling interval of postpremature beat pause.
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Atrial Drove
0
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A atrial drive CI ventricular drive
800
Bwe
170
p
700
\ S c”
600
P iT
250
300
Coupling
L
I
I
I
I
250
300
350
400
Coupling
Interval,
msec.
FIGURE 4. Effect of reduction in cycle length on ventricular effective refractory periods and conduction times measured during atrial and ventricular drive. The basic driving interval was 400 ms. Coupling intervals of 350, 300 and 250 ms represent the short cycle of stable bigeminy with a full compensatory pause (mean cycle length 400 ms). The ventricular driving and testing sites were the same. Values represent mean value f standard error of the mean in 25 dogs. During ventricular drive, effective refractory periods were shorter (p
350
Interval,
400
msec.
FIGURE 5. Anodal dip threshold during atrial and ventricular drive. The basic driving interval was 400 ms. Coupling intervals of 350, 300 and 250 ms represent the short cycle of stable bigeminy with a full compensatory pause (mean cycle length 400 ms). Ventricular driving stimuli were cathodal; testing stimuli were anodal. Ventricular test and drive sites were the same. Values represent mean value f standard error of the mean in six dogs. Although dip thresholds were lower (p
examine phase 3 dip phenomena (Fig. 5). At each coupling interval, dip thresholds were significantly lower when the ventricular drive and test sites were the same as the dip thresholds during atria1 drive. Discussion
350,300 and 250 ms (Fig. 4). In each instance, a full compensatory pause was maintained so that mean cycle length remained constant at 400 ms. Consistent with the data presented in Table III, during atria1 bigeminy no change in ventricular effective refractory period was observed as the coupling interval was reduced from 400 to 250 ms. However, during ventricular bigeminy, the effective refractory period measured at the driving electrode shortened from 142 f 3.0 to 130 f 2.3 ms (p
to
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Effect of stimulation site on local effective refractory period: In 1966, Han et a1.l found that the average ventricular refractory period was shorter at points close to the stimulation site than at points farther away. In addition, they reported that the ventricular fibrillation threshold was lower after early premature beats than after depolarizations initiated in fully excitable tissue. This effect was exaggerated “at points near the origin of the premature response,” and was attributed to greater dispersion of refractoriness measured within a 10 to 15 mm radius of the stimulating electrode. In the present study, the observation that refractory periods are shortened near the stimulating electrode was confirmed, and the effect was found to decay over the same distance from the stimulating electrode (about 15 mm) as that observed by Han et al. Moreover, in a previous study, well found fibrillation threshold to decrease progressively as the S1-S2 interelectrode distance was decreased from 25 to 0 mm. The observation that conduction times were longer at sites close to the stimulating electrode provides a factor in addition to dispersion of refractoriness that might favor reentrant arrthythmias and lower fibrillation threshold. A possible relation between these altered recovery properties and a lower fibrillation threshold is also suggested by the demonstration that shortening of the
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effective refractory period at the ventricular driving site was observed with bipolar as well as with cathodal drive. The finding that dip thresholds of anodai strengthinterval curves were lower when the ventricular drive and test sites were the same provides additional support for this view. In studies of human ventricular refractoriness,
Cuss
et a1.12observed that the ventricular effective refractory period after premature atrial beats was longer, at a given cycle length, than that occurring after electrically induced premature ventricular beats. In this study, we found this to be true only if the ventricular driving and testing sites were close to one another. However, ventricular effective refractory periods measured at a distance from the ventricular stimulating electrode were essentially the same as those occurring after atria1 premature beats, suggesting that local effects of the current applied at the stimulation site-rather than the origin of the impulse in the atrium or ventricle-were largely responsible for this difference. Effect of current intensity and electrode size: Spear et al.” demonstrated that increasing the current intensity of a pulse or train of pulses increased the temporal dispersion of refractoriness within an 8 mm radial distance of the stimulating electrode and lowered the ventricular fibrillation threshold. Furthermore, the effective refractory period measured at a given electrode site tended to shorten as pulse intensity was increased. In the present study, increases in current intensity shortened the effective refractory period measured at the site of the stimulating electrode (Sr), and the magnitude of this effect, both at the Sr electrode and at a site 15 mm from it, was dependent on the intensity of the driving stimulus itself. In contrast to our findings, Toyoshima and Burges&l recently found that canine effective refractory periods were 4.7 percent longer when the driving and testing electrodes were the same than when the two electrodes were separated by 40 to 60 mm. The difference between their data and ours may be due in part to differences in stimulation technique. The thin wire assembly used by Toyoshima and Burgess required much smaller current intensities for excitation and thus the local effects of electrical stimulation would be less and should have been dissipated within a very short distance of the drivirg site. Although substantial local alterations of recovery properties were found in our study with electrode surface areas of only 0.8 mm2, these electrotonic effects still may be due in part to relatively large electrodes and thus were avoided with the much smaller electrodes employed by Toyoshima and Burgess. In addition, the testing stimuli they used to measure effective refractory periods were 1.5 to 2.0 times threshold and may have identified the slowly rising portion of the strength-interval curve. -4s Greenspan et a1.14 noted, values for effective refractory period determined in this fashion might be influenced by threshold changes rather than by refractoriness as such. Effect of mechanical stimulation: The observation that mechanical stimulation of the ventricle, capable of initiating a propagated premature beat, fails to pro-
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duce effective refractory period shortening near the stimulating electrode strongly supports the view that effective refractory period shortening in the vicinity of the stimulating electrode is a consequence of the electrical stimulus itself. In this regard, it is noteworthy that when testing and driving sites were separated by 20 mm or more, ventricular effective refractory periods were similar after all modes of stimulation-atria1 drive, ventricular mechanical drive or ventricular electrical drive. However, when mechanical impulses were used as testing stimuli (Ss), conduction times of premature beats were consistently about 30 ms longer than when electrical Ss pulses were used (Table II). This interval, which likely reflects the time between mechanical deformation and local depolarization of the myocardium, agrees closely with the data obtained by Zoll et a1.15 using an external device to effect cardiac stimulation. In their studies a consistent 40 ms interval was observed between mechanical displacement of the heart and the electrical ventricular response. In our study, mechanical stimuli were never observed to evoke a repetitive ventricular response, although this response occasionally occurred when electrical stimulation was used. Zoll et a1.r5 also failed to observe repetitive ventricular responses after external mechanical stimulation even “in the relative refractory period at energies IO times threshold levels.” Influence of heart rate and coupling interval: Moore et al.‘” showed that a depolarization induced by a premature stimulus results in a shortened action potential duration and effective refractory period. In another study of refractory periods after sudden increases in frequency,17 a time-dependent shortening of the refractory period was demonstrated with approximately 30 percent of the total shortening occurring within the first beat, and a new steady state was established only after a few hundred beats. In our study, too, the shortening of the effective refractory period observed after single premature atria1 beats (coupling interval 250 ms) was 30 percent of that found during regular atria1 drive at the same cycle length. However, if during atria1 bigeminy, the diastolic pause preceding the closely coupled beat was fully compensatory and mean cycle length remained constant, no shortening of the effective refractory period was observed (Table III; Fig. 4). Thus, it appears that prolonged effective refractory periods induced by the long cycle of a bigeminal rhythm are “remembered” during the subsequent short cycle and nullify the effect of the short cycle in reducing effective refractory period. The constancy of ventricular effective refractory periods during atria1 bigeminy, despite a variable coupling interval, provided a convenient reference point for examining the effect of time dependency of ventricular stimulation on local refractoriness. Thus, although no change in effective refractory period was observed during atrial bigeminal drive when the coupling interval was reduced from 400 to 250 ms, during ventricular drive significant shortening of the effective refractory period was found when refractoriness was measured at or near the stimulating electrode site. These observa-
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tions suggest that the effect of coupling interval on ventricular effective refractory period are somewhat exaggerated by closely positioned testing and driving sites, and that local effects of stimulation constitute a major factor in observed effective refractory period responses to changes in coupling intervals when the mean coupling interval or the immediately preceding coupling interval has already been shortened. Because closely positioned driving and testing electrodes generally have been used in studies of the effect of cycle length on the effective refractory period,16J7 one wonders to what extent the reported alterations in the effective refractory period represent time-dependent characteristics of the local effects of electrical stimulation. Whatever may be the mechanism for effective refractory period shortening near the driving site, it would appear that local adrenergic stimulation was not responsible, because stellate ablation and adrenalectomy in dogs receiving reserpine did not influence this phenomenon In other studies,‘s too, parasympathetic blockade with atropine had no effect on ventricular effective refractory period measured at or near the driving electrode. Clinical implications: Because published studies of ventricular refractoriness generally have examined responses at or near the driving electrode with stimuli 1.5 to 3 times threshold, there is reason to believe that
a systematic error may have been introduced into many studies of refractory period. Because the local effects of electrical stimulation of muscle are a function of current intensity and time, the relation between effective refractory period and both coupling interval and mean cycle length might well be reexamined using methods that minimize these local effects. Similarly, caution is urged in the interpretation of clinical and experimental studies that use provocative stimuli to detect vulnerability to ventricular arrhythmias, especially those that use large electrodes and stimuli well above threshold. Not only do the stimulation techniques used in our study produce localized shortening of the effective refractory period, but also conduction times of premature beats propagated during early recovery of driven beats are greatly prolonged and dip thresholds are lower, thus establishing conditions favorable to repetitive reentrant arrhythmias. Because the methods used in clinical studies of programmed stimulation utilize bipolar electrodes with surface areas that often exceed those used in our study and use stimuli of 2 to 5 times threshold, there is reason to believe that local electrotonic effects of applied current may play a role in initiating provoked ventricular tachyarrhythmias. Whether the clinical utility of programmed stimulation would be enhanced by the use of stimulation techniques that minimize these local electrotonic effects remains to be shown.
References 1. Han J, Garcia de Jalon PD, Moe GK. Fibrillation threshold of premature ventricular responses. Circ Res 1966; 18: 18-25. 2. Spear JF, Moore EN, Horowitz LN. Effect of current pulses delivered during the ventricular vulnerable period upon the ventricular fibrillation threshold. Am J Cardiol 1973;32:814-22. 3. Spielman SR, FarshMl A, Horowllz LN, Josephson ME. Ventricular fibrillation during programmed ventricular stimulation: incidence and clinical implications. Am J Cardiol 1978;42:913-8. 4. Greene LH, Reld PR, Schaeffer AH. The repetitive ventricular response in man. A predictor of sudden death. N Engl J Med 1978;299:729-34. 5. Ruskln JN, DlMarco JP, Garan H. Repetitive responses to single ventricular extrastimuli in patients with serious ventricular arrhythmias: incidence and clinical significance. Circulation 1980; 63:767-72. 6. Mason JW. Repetitive beating afler single ventricular extrastimuli: incidence and prognostic significance in patients with recurrent ventricular tachycardia. Am J Cardiol 1980;45: 1126-31. 7. Levine HJ, Avltall 6, Pauker SG, Nalml S. Sequential unipolar strength-interval curves and conduction times during myocardial ischemia and reperfusion in the dog. Circ Res 1978;43:63-72. 8. Pauker SG, Avltall 6, Levlne HJ, Nalmi S. The rapid generation of strength-interval curves under computer control. Comput Progams Biomed 1979:10:209-17.
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9. Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames, Iowa: Iowa State University Press, 1967: 258-98. 10. Morrlson DR. Multivariate Statistical Methods. New York: McGraw-Hill, 1976:128-69. 11. Avltall 8. The electrophysiological effects of alternate vs. single electrode pacing. J Electrocardiol 1981;14:61-6. 12. GUSSSB, Kaslor JA, Josephson ME, Sharf DL. Human ventricular refractoriness: effects of cycle length, pacing site and atropine. Circulation 1976;53:450-5. 13. Toyoshlma H, Burgess MJ. Electronic interaction during canine ventricular repolarization. Circ Res 1978;43:348-56. 14. Greenspan AM, Camardo JS, Horowitz LN, Splelman SR, Josephson ME. Human ventricular refractoriness: effects of increasing current. Am J Cardiol 1981;47:244-50. 15. 2011 PM, Belgard AH, Welntraub MJ, Frank AH. External mechanical cardiac stimulation. N Engl J Med 1976;23:1274-5. 16. Moore EN, Preston JB, Moe GK. Durations of transmembrane action potentials and functional refractory periods of canine false tendon and ventricular myocardium: comparisons in single fibers. Circ Res 1965; 17:259-73. 17. Janse MJ, van der Steen AMD, van Dam RTH, Durrer D. Refractory period of the dog’s ventricular myocardium following sudden changes in frequency. Circ Res 1969;24:251-62.
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