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Limitations of bipolar and unipolar conditioning stimuli for inhibition in the human heart
Limitations of bipolar and unipolar conditioning stimuli for inhibition in the human heart Noncapturing, conditioning electrical stimuli (S,) delivered within the ventricular refractory period can prolong refractorlness and prevent later stimuli from eliciting a propagated response (inhibition). The purpose of this study was (1) to further define the spatial effects of S,, (2) to determine if the effects of SC can be enhanced by the use of unipolar as opposed to bipolar stimulation, and (3) to evaluate the effect of S, on the physiologic spread of excitation during atrioventricular reentry tachycardia. In 23 patients the right ventricular refractory period was determined before and after the introduction of bipolar, unipolar cathodal, and unipolar anodal noncapturing S, with pulse widths of 2 or 9 msec and strengths of twice diastolic threshold and 10 MA. Pacing and conditioning stimuli were delivered at the same site and at sites separated by 3 mm. During ventricular pacing both bipolar and unipolar S, prolonged the ventricular refractory period by 210 msec in 22 of 23 patients when both S, and pacing stimuli were delivered to the same site. However, when SC was delivered 3 mm away from the pacing stimuli, the ventricular refractory period increased by 210 msec in only 1 of 17 patients who received bipolar S, and in none of 13 patients who received unipolar S,. In seven patients bipolar conditioning stimuli were delivered as close as possible to the atrial insertion of an accessory atrfoventricular connection during circus movement tachycardta with a well-localized accessory pathway. S, did not termlnate or slow tachycardia in any patient. We conclude that the limited spatial effect of noncapturing single stimuli precludes their use for termination of reentry tachycardias with current catheter techniques. (AM HEART J 1987; 114:303.)
William G. Stevenson, M.D., Isaac Wiener, M.D., James Weiss, M.D., and Thomas Klitzner, M.D. Los Angeles, Calif.
The ability of noncapturing stimuli to prolong myocardial refractoriness has recently been demonstrated in humans by Prystowsky and Zipes.’ This phenomenon could theoretically be used to terminate reentrant arrhythmias, but its success will be dependent on the degree of prolongation of refractoriness that can be achieved and the area over which this occurs. The increase in refractory period achieved is related to the strength of the noncapturing stirnulL The distance from the stimulus over which the increase in refractoriness occurs has not been defined and may be a major limitation in the usefulness of the technique. Previous investigators have used bipolar stimulation to evaluate the effects of noncapturing stimuli. This may complicate measurements of refractoriness and spatial effects, since excitation may occur at the anode, cathode, or simultaneously at both electrodes.3*4 In addition, bipolar noncapturing From the Divisions of Cardiology, rics, U.C.L.A. School of Medicine Received Reprint U.C.L.A.,
for publication
Sept.
Departments of Medicine and Center for the Health 15, 1986; accepted
requests: William G. Stevenson, M.D., CHS 47-123, Los Angeles, CA 90024.
Feb.
and PediatSciences.
10, 1987.
Division
of Cardiology,
stimuli subject the myocardium to both depolarizing (cathodal) and hyperpolarizing (anodal) current, which may have different effects on excitability and refractoriness5 This study describes the effects of bipolar and unipolar noncapturing stimuli on ventricular refractoriness, further defines the spatial limitations of the technique, and describes the application of noncapturing stimuli for attempted tachycardia termination in seven patients with atrioventricular reentrant tachycardia incorporating a well-localized accessory atrioventricular pathway. METHODS
The effect of noncapturing stimuli on ventricular refractoriness was determined in 23 patients referred for evaluation of sustained ventricular tachycardia or fibrilla-
tion (four patients), syncope (eight patients), supraventricular arrhythmias (one patient), and nonsustained ventricular arrhythmias (10 patients). There were 16 men and seven women ranging in age from 18 to 34 years with a mean age of 51 years. Seven patients had no underlying structural heart disease, six had coronary artery disease, nine had idiopathic dilated cardiomyopathy, and one had mitral valve prolapse. Programmed stimulation was performed in the absence of antiarrhythmic drugs. Diazepam 303
304
Stevenson
Table
I. Pacing configurations evaluated
Distance between SAC h-4 0 0 0 0 0 0 3 3 3 3 3 3 3 B = bipolar pacing; polarity is specified
et al.
S2 polarity
B B u u u u
(-) t-1 (+) (+)
B B u u u u u
t-1 C-1 t-1 (-) t-1
American
S2 PW (msec) 2 2 2 2 2 2 2 2 2 2 2 2 2
s* Ma 2xT 10 2xT 10 2xT 10 2xT 2xT 2xT 2xT 2xT 2xT 2xT
SC PW (msec)
SC polarity
B B u u u u
2 2 2 2 2 2 2 2 2 2 9 2 2
C-J t-1 (+) (+I
B h-, u u u u
Ma = stimulus strength in milliamperes; pts. = patients; as positive (+) or negative (-); T = threshold.
was used to achieve mild sedation. After informed consent and local anesthesia with 2 % mepivicaine HCl, one to four electrode catheters were inserted into femoral or internal jugular veins and positioned at various intracardiac sites. Three to five surface ECG leads and intracardiac electrograms filtered at 30 to 500 Hz were recorded at paper speeds of 75 to 100 mm/set on an Electronics for Medicine VR-12 chart recorder. Cardiac stimulation was performed with a programmable stimulator with two separate outputs that allowed independent current and pulse width settings (Bloom, Ltd.) Stimulation protocol. All ventricular stimulation was performed from the right ventricular apex with a 6 or 5 French hexapolar catheter. The distance between each consecutive ring electrode was 3 mm. Extrastimuli were delivered after an eight-beat ventricular drive at a basic cycle length (S,-S,) of 600 msec. Sinus competition necessitated basic drive cycle lengths of 500 msec in six patients. A single extrastimulus (S,) was used to scan early diastole in 10 msec decrements until a S-S, interval was reached, at which time S, failed to elicit a ventricular response on two consecutive attempts. This S,-S, interval was defined as the ventricular effective refractory period (VERP). The conditioning stimulus (S,) was initially introduced at S, - S, = VERP. S, was then introduced 10 msec beyond S,, and the S,-S, interval increased in 10 msec increments to define the maximal prolongation of refractoriness produced by S,. When S, captured, it was periodically removed to ensure that S, was still not capturing. All stimuli were initially 2 msec in duration and twice the late diastolic threshold in amplitude. When S,, S1, and S, were delivered to the same electrode(s), the amplitude and pulse width of S, were always the same as that of S, and Sz. When S, was delivered to a location different from S, and St, S, and S, always remained twice diastolic threshold and 2 msec in duration, while the amplitude and pulse width of S, was varied. If S, captured
t-1 t-1 (+) (+) PW = stimulus
pulse width
SC Ma
No. pts. tested
2xT 10 2xT 10 2xT 10 2xT 10 2xT 10 10 2xT 10
17 15 13 9 4 3 16 15 12 12 6 3 3
in milliseconds:
U = unipolar
August 1987 Heart Journal
NO.
with inhibition 16 11 13 8 3 1 1 0 0 0 0 0 0 pacing
and the
the ventricle, S,-S, was decreased in 10 msec decrements until capture no longer occurred. The late diastolic threshold at both pacing sites was always less than 2.5 MA. Six different electrode combinations were evaluated as follows (Table I): 1. Bipolar pacing with all stimuli at the same site: The most distal electrode (No. 1) served as the cathode and the next most distal electrode (No. 2) served as the anode for both the basic drive and conditioning stimuli with stimulus strengths of twice diastolic threshold and 10 MA (patients one to 17). 2. Bipolar pacing with S, and pacing stimuli separated by 3 mm: The basic drive and S, were delivered to electrodes 1 and 2 at twice diastolic threshold, and S, was delivered to the adjacent pair of electrodes 3 mm proximal to S, and S, with electrode 3 serving as the cathode and electrode 4 serving as the anode at twice the diastolic threshold for that electrode pair and at 10 MA (patients 1 to 17). 3. Unipolar cathodal pacing with all stimuli at the same site: St, Sz, and S, were delivered to electrode 1, which served as the cathode, and a surface electrode patch, which served as the anode, with all stimuli at twice diastolic threshold and at 10 MA (patients 9 to 20). 4. Unipolar cathodal pacing with S, and pacing stimuli separated by 3 mm: S, and S, were delivered to electrode 1 (cathode) and a surface electrode patch (anode) at twice diastolic threshold, and S, was delivered to electrode 2 (cathode) and a surface electrode patch at twice diastolic threshold and at IO MA (patients 9 to 20), and at 10 MA with a pulse width of 9 msec (patients 14 to 16 and 18 to 20).
5. Unipolar cathodal pacing stimuli and unipolar anodal S, separated by 3 mm: S, and Sz were delivered to electrode 1 (cathode) and a surface electrode patch (anode) at twice diastolic threshold, and S, was delivered to electrode 2 serving as the anode with a surface electrode
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patch serving as the cathode at twice diastolic threshold and 10 MA (patients 17, 18, and 20). 6. Unipolar anodal pacing with all stimuli at the same site: S1, SZ, and S, were delivered to electrode 1 (anode) and a surface electrode patch (cathode) with stimuli at twice diastolic threshold and at 10 MA (patients 20 to 23).
The possible effect of polarization at the pacing electrode on current delivery during closely coupled extrastimuli was evaluated during bipolar pacing at a basic cycle length of 600 msec in a 0.9% saline solution bath and during bipolar ventricular pacing in one patient. The voltage required to achieve a 10 MA, 2 msec S, delivered 2 to 10 msec after a 10 MA, 2 msec S, was measured with an optically isolated oscilloscope connected in parallel to the pacing catheter. The voltage required for delivery of the S, preset current (10 MA) after a conditioning stimulus that was delivered to the same bipolar electrode pair as S1and S, was less than 11 V in both a saline solution bath and during ventricular pacing. This was considerably below the maximum measured voltage output (17 V) of our stimulator. Thus S, did not increase polarization impedance sufficiently to limit current delivery during S,. Conditioning stimuli during circus movement tachy cardia. The effect of noncapturing stimuli on more phys-
iologic excitation was evaluated during circus movement atrioventricular reentrant tachycardia in seven patients with a well-localized accessory pathway. There were four males and three females who were 2,5, 6,9, 10, 15, and 47 years old. Six patients had inducible orthodromic circus movement reentry tachycardia with the atrioventricular node antegradely and an accessory pathway for retrograde conduction. In all six subjects the diagnosis of circus movement tachycardia was confirmed by the ability to preexcite the atria with ventricular stimuli delivered during His bundle refractoriness, the effect of bundlebranch block on tachycardia, or termination of tachycardia by ventricular extrastimuli incapable of conducting to the atrium or atrioventricular node. The atria1 insertion of the accessory pathway was well localized based on extensive atrial mapping during stable circus movement tachycardia in all seven patients and confirmed by epicardial mapping at the time of surgery in one patient. Earliest atria1 activation during tachycardia was recorded at the low-septal tricuspid annulus in one patient, at the distal coronary sinus in two patients, at the high anterior tricuspid valve annulus in one patient, and at the coronary sinus OS in two patients, both of whom had almost incessant atrioventricular reentry tachycardia caused by accessory pathways with long retrograde conduction times (Table I). One patient (patient No. 7) had antidromic circus movement tachycardia with a left lateral accessory pathway in the antegrade direction and the atrioventricular node retrogradely. In this patient the distal electrodes of the coronary sinus catheter were positioned at the earliest site of retrograde atria1 activation during ventricular pacing and were used to deliver conditioning stimuli during antidromic tachycardia. Bipolar conditioning stimuli were delivered to the atrial
Conditioning
stimuli
and refractory
period
305
site closest to the insertion of the accessory pathway during circus movement tachycardia starting 10 msec after the onset of the closest atria1 electrogram. The coupling interval of the conditioning extrastimulus was then increased in 10 msec increments until atrial capture occurred. This was performed with stimulus strengths of twice diastolic threshold with 2 msec pulse width (six patients), 10 MA with 2 msec pulse width (two patients), 10 MA with 5 msec pulse width (four patients), and 10 MA with 9 msec pulse width (three patients). The atria1 effective refractory period, which was defined as the longest stimulus-coupling interval that failed to capture the atria with stimuli of twice the late diastolic threshold, was measured during tachycardia at the same site in all patients. The duration of the excitable gap at the atria1 pacing site was defined as the difference between the tachycardia cycle length and the atria1 effective refractory period measured during tachycardia. Statistical comparisons were made with paired and unpaired Student t tests. Averaged data are presented as mean f standard deviation. RESULTS
Bipolar, twice diastolic threshold conditioning stimuli delivered to the same site as the pacing stimuli prolonged ventricular refractoriness in 16 of 17 patients by 12 f 4 msec (p < 0.001) from 260 f 26 to 272 + 28 msec. Refractoriness increased by 20 msec in four patients and 10 msec in 12 patients. With all stimuli at a strength of 10 MA, S, delivered to the same site as the pacing stimuli prolonged refractoriness in 11 of 15 patients by 8 + 7 msec (p < 0.001) from 230 + 22 to 238 + 24 msec. The greatest increase in refractoriness observed was again 20 msec, which occurred in two patients. Similarly, unipolar cathodal twice diastolic threshold conditioning stimuli delivered to the same site as the unipolar pacing stimuli increased the ventricular refractory period in 13 of 13 patients by 11 + 3 msec (p < 0.001) from 262 k 26 to 273 + 23 msec. Refractoriness increased by 20 msec in one patient and by 10 msec in 12 patients. With all unipolar stimuli at 10 MA ventricular refractoriness was prolonged in eight of nine patients by 11 f 6 msec (p < 0.001) from 262 + 24 to 273 4 23 msec. The greatest increase in refractoriness observed was again 20 msec, which occurred in two patients. Unipolar anodal conditioning stimuli of twice diastolic threshold or 10 MA delivered to the same site as unipolar anodal pacing stimuli prolonged refractoriness in three of four patients. A 20 msec increase was observed in one patient and 10 msec increases occurred in the others. Bipolar twice threshold conditioning stimuli delivered to the electrode pair 3 mm proximal to the pacing electrodes prolonged refractoriness in only 1
August
306
Stevenson et al.
Amerkan
at *
=Psc
electrode
-1 I
1987
Heart Journal
lOma 1,
S,-S2:270 3-5;250
1. Unipolar cathodal stimulation in patient 10. Illustrated from the top of each panel are surface ECG leads I and aVr and the right ventricular bipolar electrogram recorded from the most proximal electrode pair (electrodes 5 and 6) of the pacing catheter positioned in the right ventricular apex. Time lines at the top of panels A and E are at 50 msec intervals. All measurements are expressed in milliseconds. The basic drive cycle length is 600 msec in all panels. In panels A-D (left), all stimuli have a 2 msec pulse with a 10 MA amplitude and are delivered to the most distal electrode (No. l), which serves as the cathode, and a surface electrode patch, which serves as the anode. In A an S, 260 msec after S, captures the ventricle. In B an S, 10 msec earlier than in A fails to capture the ventricle, and the ventricular effective refractory period is therefore 250 msec. In C a conditioning stimulus (SJ with the same amplitude as the pacing stimuli delivered to the same electrode (electrode 1) prevents S, from capturing the ventricle at an S,-S, interval of 270 msec. In D S, at an S,-S, interval of 280 msec captures the ventricle despite the preceding S,. Thus S, prolonged the ventricular-effective refractory period from 250 to 270 msec. In panels E-F (right), all pacing stimuli (S, and S,) are delivered to electrode 1 and have a pulse width of 2 msec and an amplitude of twice the late diastolic threshold (1.8 MA). The conditioning stimulus (S,) is delivered to electrode 2, which is 3 mm proximal to electrode 1. In panel E an S, delivered 270 msec after S, captures the ventricle. In F an Sp10 msec earlier than in E is refractory, and thus the effective refractory period is 260 msec. In G an S, with a 2 msec pulse width and amplitude of 10 MA is delivered to electrode 2 and fails to prevent S, delivered 10 msec later than the refractory period from capturing the ventricle. Panel H demonstrates that S, without S, did not capture the ventricle.
Fig.
of I6 patients, from 240 to 250 msec. Increasing the amplitude of S, to 10 MA failed to prolong refractoriness in any of 15 patients, including the patient in whom refractoriness was prolonged with a twice diastolic threshold S,. Unipolar cathodal twice diastolic threshold and 10 MA conditioning stimuli delivered 3 mm proxi-
ma1 to unipolar cathodal pacing stimuli did not prolong refractoriness in any of 12 patients tested (Fig. 1). An increase of S, to a pulse width of 9 msec and amplitude of 10 MA in six patients also failed to increase ventricular refractoriness 3 mm distal to the conditioning stimuli. Unipolar anodal conditioning stimuli of twice threshold and 10 MA produced
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stimuli
and refractory
period
307
A T I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
370
A
I
I
I
I
AVF
A
B
340
A
340
A
Tliflllllllllflll
340
A
290
A
340
A
I
I
II AVF-
Fig. 2. Circus movement tachycardia in patient 1. From the top are 100 msec time lines, surface ECG leads 1, aVr, and V, and intracardiac electrograms recorded from the distal electrode pair of the catheter positioned at the low septal right atrium (LSRAd), the proximal electrode pair of the same catheter (LSRAp), the His bundle position (HIS), and the right ventricular apex (RVA). In panel A orthodromic circus movement tachycardia with right bundle-branch block and a cycle length of 340 msec is present. Earliest retrograde atrial activation is recorded at the low septal right atrium, slightly below the His catheter (LSRAd). A double electrogram is recorded from this position, the first component of which (arrow) is suggestive of an accessory pathway potential, indicating that the catheter is close to the atria1 insertion of the accessory pathway. A single ventricular extrastimulus (S) delivered immediately after the His bundle depolarization advances atria1 activation, confirming the presence of an accessory pathway. In Panel B from the same patient, the paper speed has been increased from 100 to 150 mm/set, and the distal coronary sinus electrogram (CSd) is now displayed in place of LSRAd. A single extrastimulus (S) with a pulse width of 9 msec and amplitude of 10 MA is delivered to the LSRAd electrodes 150 msec after the local atria1 electrogram recorded from LSRAp. This has no effect on the tachycardia that continues at a cycle length of 350 msec. Stimuli of this intensity delivered later captured the atrium (not shown). no change in the refractory
period measured
twice diastolic threshold unipolar mm distal to the conditioning patients.
with
cathodal stimuli 3 stimuli in three
Thus bipolar and unipolar conditioning stimuli produced a similar increase in the ventricular refractory period when delivered at the site of the pacing stimuli. However, only 1 of 20 patients demon-
308
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et al.
Table
II. Characteristics
American
of circus movement
tachycardia
and S, Maximum noncaptured
Patient
Earliest atria1 site
Threshold Cm A)
Atria1 ERP
Tachycardia cycle length
1 2 3 4 5 6 7
LSRA C&* HARA C& MSRA CSd CSd
2.0 1.1 2.0 2.5 .75 1.2 1.0
190 150 170 110 160 210 190
350 350 310 280 270 460 250
CS, = coronary sinus ostium; CSd = distal coronary sinus; ERP = effective tachycardia: HARA = high-anterior right atrium: LSRA = low-sental - riaht onds. All intervals are in milliseconds.
&rated an increase in refractory period with stimuli delivered 3 mm proximal to the pacing stimuli. Conditioning stimuli in atrioventricular cardia. Noncaptured bipolar stimuli
reentry
August 1987 Heart Journal
tachy-
delivered to the atria1 site closest to the insertion of the accessory pathway did not slow or terminate circus movement tachycardia in any patient (Fig. 2). As shown in Table II, the atrial-effective refractory periods measured with twice diastolic threshold stimuli at these sites during tachycardia were 60 to 250 msec shorter than the tachycardia cycle lengths. This difference represents the excitable gap at that point in the reentry circuit. An increase in refractoriness of a comparable duration would presumably have been required for the circulating wavefront to encounter refractory tissue at these sites after the conditioning stimuli. DISCUSSION
Using bipolar stimuli Prystowsky and Zipes,’ Windle et al.,2 and SkaIe et aI. have shown that noncapturing stimuli delivered during the last 10 to 30 msec of the ventricular or atria1 refractory period are capable of inhibiting or preventing a subsequent stimulus from evoking a propagated response, thus prolonging the myocardial refractory period. This phenomenon is dependent on the strength of the noncapturing conditioning stimulus. The 10 to 20 msec increase in refractory period that we observed after a conditioning stimulus was delivered to the same site as the pacing stimuli is consistent with these previous investigations. We did not observe the large increases in refractoriness of up to 135 msec obtained by WindIe et aL2 when all stimuli were delivered to the same site and stimulus pulse widths of up to 100 msec were used.2 However, we did not independently vary the strength of the S,
Duration excitable
refractory period measured atrium; MSRA = midseptal
of
gap
160 200 140 170 110 250 60
strength of S, tested
Amplitude (mA) 10 10 10 10 10 2.4 10
by twice threshold stimuli during right atrium; MA = millamperes;
Duration (msec) 9 2 5 9 9 2 5 circus movement msec = millisec-
and pacing stimuli when both were delivered to the of both S, and S, was increased during their delivery to the same site, the increased strength of S, shortened the measured ventricular refractory period and also appeared to diminish the effect of S,. We also did not use the markedly increased pulse widths that are not commonly available. The distance from the stimulating electrode over which this phenomenon occurs is critical for its potential clinical application for tachycardia termination. Although inhibition was demonstrated in three of nine patients with stimuli 1 cm apart, in an initial study’ a subsequent canine study from the same group was unable to demonstrate inhibition when conditioning stimuli were delivered 5 and 10 mm from the pacing stimuli.6 In our study inhibition was observed in only 1 of 17 patients with bipolar stimuli delivered 3 mm away from the pacing stimuli. However, we did not attempt to detect increases in refractoriness of Cl0 msec and cannot exclude that smaller changes may occur more frequently. Previous studies have used bipolar stimulation for both pacing and conditioning stimuli. Several aspects inherent to bipolar stimulation could potentially influence the occurrence of inhibition. First, bipolar stimulation subjects the myocardium adjacent to the cathode to depolarizing current and that adjacent to the anode to hyperpolarixing current,’ which may have a different effect on refractoriness. When delivered during phase 3 of the action potential, cathodal current would tend to prolong the action potential duration whereas anodal current would be expected to shorten it. Antxelevitch and Moe” have shown that subthreshold anodal and cathodal current delivered after repolarization have different effects on the amount of current required same site. Thus when the current
Volume 114 Number 2
to elicit a subsequent depolarization. Hyperpolarizing current lowered while depolarizing current increased the subsequent excitation threshold.5 Second, during bipolar stimulation a propagated response may arise at the anode, the cathode, or simultaneously at both sites depending on the stimulus strength, prematurity, and excitation threshold.3 We have previously shown that variations in the contribution of the anode and cathode to myocardial excitation commonly occur during programmed electrical stimulation in humans.4 Third, when the conditioning and pacing stimuli are delivered to adjacent bipolar pairs of electrodes on a single pacing catheter, as used in this and a previous study,’ the distance between the respective cathodes of the conditioning and pacing stimuli, as well as between the anodes, is greater than the minimum interelectrode distance of the catheter. Thus although the bipolar pairs in our study were separated end to end by 3 mm, the distance between cathodes of the pacing and conditioning stimuli was greater than 6 mm. To define more clearly the earliest site of myocardial excitation and avoid potentially complicating factors associated with bipolar pacing, we also performed unipolar cathodal and unipolar anodal pacing. Although inhibition was again seen when conditioning and pacing stimuli were delivered to the same site, conditioning stimuli 3 mm away from the pacing stimuli had no effect. Polarization. During electrical stimulation of the heart, oppositely charged particles accumulate at the electrode-myocardium interface, adding a nonlinear polarization impedance to the system.8 The very local effect of noncapturing stimuli led us to consider the possibility that an increase in impedance caused by further polarization at the pacing site immediately after the noncapturing stimulus resulted in lower current delivery with the following Sz. A sufficient increase in impedance after the noncapturing stimulus could prevent the delivery of the preset current of S, if the voltage required exceeded the maximal voltage output of our stimulator. Therefore the voltage attained with closely coupled extrastimuli was measured during bipolar pacing in physiologic saline solution and during ventricular stimulation. Extrastimuli coupled as closely as 2 msec required less than 11 V to provide a current of 10 MA. Thus the apparent effect of noncapturing stimuli did not appear to be due to decreased current delivery during the subsequent closely coupled stimulus. Mechanism. Two mechanisms of prolongation of refractoriness by noncapturing conditioning stimuli
Conditioning
stimuli
and refractory
period
309
have been proposed. The S, delivered during phase 3 of the action potential may prolong action potential duration by an electrotonic effect, or S, may elicit a very local threshold response that is extinguished on entering adjacent tissue.2 Preliminary reports of in vitro cellular recordings have been presented supporting both mechanisms.s~lo We found that both unipolar cathodal and unipolar anodal stimuli are capable of prolonging refractoriness when the pacing and conditioning stimuli are delivered to the same site. Since the electrotonic effect of anodal stimulation should be to shorten action potential duration, our data suggest that the production of a very local threshold response is the more likely mechanism of this phenomenon. Noncaptured stimuli for termination of reentry. Cur study demonstrates that the effect of noncapturing stimuli occurs only within a few millimeters of the stimulating electrode. However, pacing stimuli of twice diastolic threshold may be a much stronger stimulus for excitation than a physiologic wavefront of excitation. Thus a greater spatial effect of noncapturing stimuli on the more physiologic spread of excitation may have gone undetected by our methods. Atrioventricular reentry is an ideal substrate for testing this hypothesis, since the atria1 insertion of the accessory pathway can be reasonably well localized by catheter techniques. Noncapturing stimuli did not slow or terminate circus movement tachycardia in any of our patients. However, for a noncapturing stimulus to terminate a reentry arrhythmia, it must prolong refractoriness in a critical area of the reentry circuit such that the subsequent wavefront of excitation arrives while the tissue is still refractory. Thus the increase in refractory period must exceed the duration of “the excitable gap” at that point in the reentry circuit. Windle et a1.2 demonstrated that stimuli of 10 msec pulse width and 10 MA prolonged refractoriness by a mean of 33 + 11 msec, and an increase of 81 & 31 msec could be achieved by further increasing the pulse width of the conditioning stimuli to 100 msec. In our patients the shortest excitable gap was 60 msec. Thus even if the pacing catheter was ideally located, the increase in refractoriness achieved may have been insufficient to terminate the tachycardia. Conditioning stimuli would be most effective at the sites in the reentry circuit having the shortest excitable gap, frequently the atrioventricular node in atrioventricular reentry. However, if the increase in refractoriness occurs in only a small island of tissue in the reentry pathway, the circulating wavefront of excitation will merely continue around it. In
310
Stevenson et al.
American
addition, the limitations of catheter mapping and the possible intramural location of portions of reentry circuits may prevent placement of a pacing electrode close enough to the reentry circuit for the conditioning stimulus to have any effect. However, one case of termination of ventricular tachycardia by an apparently noncaptured stimulus has been reported.” CONCLUSIONS
The effects of noncapturing single stimuli with pulse widths of up to 9 msec and current strengths of up to 10 MA are limited to a distance of less than 3 mm from the stimulating electrode and are not enhanced by unipolar stimulation. These limitations preclude the use of single noncapturing stimuli for tachycardia termination with current catheter techniques.
August 1987 Heart Journal
3. Van Dam RT, Durrer D, Strackee J, Tweel HVD. The excitability cycle of the dogs left ventricle determined by anodal, cathodal, and bipolar stimulation. Circ Res 1956; 4:196. 4. Stevenson WG, Wiener I, Weiss JN. Contribution of the anode to ventricular excitation during programmed electrical stimulation in humans. Am J Cardiol 1986;57:582. 5. Antzelevitch C, Moe GK. Electrotonic inhibition and summation of impulse conduction in mammalian purkinje fibers. Am J Physiol 1983;245:H42. 6. Skale BT, Kallok MJ, Prystowsky EN, Gill RM, ‘Zipes DP. Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli. J Am Co11 Cardiol 1985; 6:133. 7. Weidmann S. Effect of current flow on the membrane notential of cardiac muscle. J Phvsiol 1951;115:227. 8. Rarold SS, Ong LS, Heinle RA: Stimulation and sensing thresholds for cardiac pacing: electrophysiologic and technical aspects. Prog Cardiovasc Dis 1981;44:1. 9. Windle JR, Prystowsky EN, Zipes DP, Gilmour RF. Inhibition of propagated myocardial excitation by subthreshold stimulation: clinical and cellular correlation. PACE 1985; 8~765.
10. Windle JR, Zipes DP, Prystowsky EN, Gilmour RF. Inhibition in isolated human myocardium. J Am Co11 Cardiol 1986;7:100.
REFERENCES
1. Prystowsky EN, Zipes DP. Inhibition in the human heart. Circulation 1988;68:707. 2. Windle JR, Miles WM, Zipes DP, Prystowsky EN. Subthreshold conditioning stimuli prolong human ventricular refractoriness. Am J Cardiol 1986;57:381.
BOUND VOLUMES
AVAILABLE
11. Ruffy R, Friday KJ, Southworth WF. Termination of ventricular tachycardia by single extrastimulation during the ventricular effective refractory period. Circulation 1983;67:457.
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William G. Stevenson, M.D., Isaac Wiener, M.D., James Weiss, M.D., and Thomas Klitzner, M.D. Los Angeles, Calif.
The ability of noncapturing stimuli to prolong myocardial refractoriness has recently been demonstrated in humans by Prystowsky and Zipes.’ This phenomenon could theoretically be used to terminate reentrant arrhythmias, but its success will be dependent on the degree of prolongation of refractoriness that can be achieved and the area over which this occurs. The increase in refractory period achieved is related to the strength of the noncapturing stirnulL The distance from the stimulus over which the increase in refractoriness occurs has not been defined and may be a major limitation in the usefulness of the technique. Previous investigators have used bipolar stimulation to evaluate the effects of noncapturing stimuli. This may complicate measurements of refractoriness and spatial effects, since excitation may occur at the anode, cathode, or simultaneously at both electrodes.3*4 In addition, bipolar noncapturing From the Divisions of Cardiology, rics, U.C.L.A. School of Medicine Received Reprint U.C.L.A.,
for publication
Sept.
Departments of Medicine and Center for the Health 15, 1986; accepted
requests: William G. Stevenson, M.D., CHS 47-123, Los Angeles, CA 90024.
Feb.
and PediatSciences.
10, 1987.
Division
of Cardiology,
stimuli subject the myocardium to both depolarizing (cathodal) and hyperpolarizing (anodal) current, which may have different effects on excitability and refractoriness5 This study describes the effects of bipolar and unipolar noncapturing stimuli on ventricular refractoriness, further defines the spatial limitations of the technique, and describes the application of noncapturing stimuli for attempted tachycardia termination in seven patients with atrioventricular reentrant tachycardia incorporating a well-localized accessory atrioventricular pathway. METHODS
The effect of noncapturing stimuli on ventricular refractoriness was determined in 23 patients referred for evaluation of sustained ventricular tachycardia or fibrilla-
tion (four patients), syncope (eight patients), supraventricular arrhythmias (one patient), and nonsustained ventricular arrhythmias (10 patients). There were 16 men and seven women ranging in age from 18 to 34 years with a mean age of 51 years. Seven patients had no underlying structural heart disease, six had coronary artery disease, nine had idiopathic dilated cardiomyopathy, and one had mitral valve prolapse. Programmed stimulation was performed in the absence of antiarrhythmic drugs. Diazepam 303
304
Stevenson
Table
I. Pacing configurations evaluated
Distance between SAC h-4 0 0 0 0 0 0 3 3 3 3 3 3 3 B = bipolar pacing; polarity is specified
et al.
S2 polarity
B B u u u u
(-) t-1 (+) (+)
B B u u u u u
t-1 C-1 t-1 (-) t-1
American
S2 PW (msec) 2 2 2 2 2 2 2 2 2 2 2 2 2
s* Ma 2xT 10 2xT 10 2xT 10 2xT 2xT 2xT 2xT 2xT 2xT 2xT
SC PW (msec)
SC polarity
B B u u u u
2 2 2 2 2 2 2 2 2 2 9 2 2
C-J t-1 (+) (+I
B h-, u u u u
Ma = stimulus strength in milliamperes; pts. = patients; as positive (+) or negative (-); T = threshold.
was used to achieve mild sedation. After informed consent and local anesthesia with 2 % mepivicaine HCl, one to four electrode catheters were inserted into femoral or internal jugular veins and positioned at various intracardiac sites. Three to five surface ECG leads and intracardiac electrograms filtered at 30 to 500 Hz were recorded at paper speeds of 75 to 100 mm/set on an Electronics for Medicine VR-12 chart recorder. Cardiac stimulation was performed with a programmable stimulator with two separate outputs that allowed independent current and pulse width settings (Bloom, Ltd.) Stimulation protocol. All ventricular stimulation was performed from the right ventricular apex with a 6 or 5 French hexapolar catheter. The distance between each consecutive ring electrode was 3 mm. Extrastimuli were delivered after an eight-beat ventricular drive at a basic cycle length (S,-S,) of 600 msec. Sinus competition necessitated basic drive cycle lengths of 500 msec in six patients. A single extrastimulus (S,) was used to scan early diastole in 10 msec decrements until a S-S, interval was reached, at which time S, failed to elicit a ventricular response on two consecutive attempts. This S,-S, interval was defined as the ventricular effective refractory period (VERP). The conditioning stimulus (S,) was initially introduced at S, - S, = VERP. S, was then introduced 10 msec beyond S,, and the S,-S, interval increased in 10 msec increments to define the maximal prolongation of refractoriness produced by S,. When S, captured, it was periodically removed to ensure that S, was still not capturing. All stimuli were initially 2 msec in duration and twice the late diastolic threshold in amplitude. When S,, S1, and S, were delivered to the same electrode(s), the amplitude and pulse width of S, were always the same as that of S, and Sz. When S, was delivered to a location different from S, and St, S, and S, always remained twice diastolic threshold and 2 msec in duration, while the amplitude and pulse width of S, was varied. If S, captured
t-1 t-1 (+) (+) PW = stimulus
pulse width
SC Ma
No. pts. tested
2xT 10 2xT 10 2xT 10 2xT 10 2xT 10 10 2xT 10
17 15 13 9 4 3 16 15 12 12 6 3 3
in milliseconds:
U = unipolar
August 1987 Heart Journal
NO.
with inhibition 16 11 13 8 3 1 1 0 0 0 0 0 0 pacing
and the
the ventricle, S,-S, was decreased in 10 msec decrements until capture no longer occurred. The late diastolic threshold at both pacing sites was always less than 2.5 MA. Six different electrode combinations were evaluated as follows (Table I): 1. Bipolar pacing with all stimuli at the same site: The most distal electrode (No. 1) served as the cathode and the next most distal electrode (No. 2) served as the anode for both the basic drive and conditioning stimuli with stimulus strengths of twice diastolic threshold and 10 MA (patients one to 17). 2. Bipolar pacing with S, and pacing stimuli separated by 3 mm: The basic drive and S, were delivered to electrodes 1 and 2 at twice diastolic threshold, and S, was delivered to the adjacent pair of electrodes 3 mm proximal to S, and S, with electrode 3 serving as the cathode and electrode 4 serving as the anode at twice the diastolic threshold for that electrode pair and at 10 MA (patients 1 to 17). 3. Unipolar cathodal pacing with all stimuli at the same site: St, Sz, and S, were delivered to electrode 1, which served as the cathode, and a surface electrode patch, which served as the anode, with all stimuli at twice diastolic threshold and at 10 MA (patients 9 to 20). 4. Unipolar cathodal pacing with S, and pacing stimuli separated by 3 mm: S, and S, were delivered to electrode 1 (cathode) and a surface electrode patch (anode) at twice diastolic threshold, and S, was delivered to electrode 2 (cathode) and a surface electrode patch at twice diastolic threshold and at IO MA (patients 9 to 20), and at 10 MA with a pulse width of 9 msec (patients 14 to 16 and 18 to 20).
5. Unipolar cathodal pacing stimuli and unipolar anodal S, separated by 3 mm: S, and Sz were delivered to electrode 1 (cathode) and a surface electrode patch (anode) at twice diastolic threshold, and S, was delivered to electrode 2 serving as the anode with a surface electrode
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patch serving as the cathode at twice diastolic threshold and 10 MA (patients 17, 18, and 20). 6. Unipolar anodal pacing with all stimuli at the same site: S1, SZ, and S, were delivered to electrode 1 (anode) and a surface electrode patch (cathode) with stimuli at twice diastolic threshold and at 10 MA (patients 20 to 23).
The possible effect of polarization at the pacing electrode on current delivery during closely coupled extrastimuli was evaluated during bipolar pacing at a basic cycle length of 600 msec in a 0.9% saline solution bath and during bipolar ventricular pacing in one patient. The voltage required to achieve a 10 MA, 2 msec S, delivered 2 to 10 msec after a 10 MA, 2 msec S, was measured with an optically isolated oscilloscope connected in parallel to the pacing catheter. The voltage required for delivery of the S, preset current (10 MA) after a conditioning stimulus that was delivered to the same bipolar electrode pair as S1and S, was less than 11 V in both a saline solution bath and during ventricular pacing. This was considerably below the maximum measured voltage output (17 V) of our stimulator. Thus S, did not increase polarization impedance sufficiently to limit current delivery during S,. Conditioning stimuli during circus movement tachy cardia. The effect of noncapturing stimuli on more phys-
iologic excitation was evaluated during circus movement atrioventricular reentrant tachycardia in seven patients with a well-localized accessory pathway. There were four males and three females who were 2,5, 6,9, 10, 15, and 47 years old. Six patients had inducible orthodromic circus movement reentry tachycardia with the atrioventricular node antegradely and an accessory pathway for retrograde conduction. In all six subjects the diagnosis of circus movement tachycardia was confirmed by the ability to preexcite the atria with ventricular stimuli delivered during His bundle refractoriness, the effect of bundlebranch block on tachycardia, or termination of tachycardia by ventricular extrastimuli incapable of conducting to the atrium or atrioventricular node. The atria1 insertion of the accessory pathway was well localized based on extensive atrial mapping during stable circus movement tachycardia in all seven patients and confirmed by epicardial mapping at the time of surgery in one patient. Earliest atria1 activation during tachycardia was recorded at the low-septal tricuspid annulus in one patient, at the distal coronary sinus in two patients, at the high anterior tricuspid valve annulus in one patient, and at the coronary sinus OS in two patients, both of whom had almost incessant atrioventricular reentry tachycardia caused by accessory pathways with long retrograde conduction times (Table I). One patient (patient No. 7) had antidromic circus movement tachycardia with a left lateral accessory pathway in the antegrade direction and the atrioventricular node retrogradely. In this patient the distal electrodes of the coronary sinus catheter were positioned at the earliest site of retrograde atria1 activation during ventricular pacing and were used to deliver conditioning stimuli during antidromic tachycardia. Bipolar conditioning stimuli were delivered to the atrial
Conditioning
stimuli
and refractory
period
305
site closest to the insertion of the accessory pathway during circus movement tachycardia starting 10 msec after the onset of the closest atria1 electrogram. The coupling interval of the conditioning extrastimulus was then increased in 10 msec increments until atrial capture occurred. This was performed with stimulus strengths of twice diastolic threshold with 2 msec pulse width (six patients), 10 MA with 2 msec pulse width (two patients), 10 MA with 5 msec pulse width (four patients), and 10 MA with 9 msec pulse width (three patients). The atria1 effective refractory period, which was defined as the longest stimulus-coupling interval that failed to capture the atria with stimuli of twice the late diastolic threshold, was measured during tachycardia at the same site in all patients. The duration of the excitable gap at the atria1 pacing site was defined as the difference between the tachycardia cycle length and the atria1 effective refractory period measured during tachycardia. Statistical comparisons were made with paired and unpaired Student t tests. Averaged data are presented as mean f standard deviation. RESULTS
Bipolar, twice diastolic threshold conditioning stimuli delivered to the same site as the pacing stimuli prolonged ventricular refractoriness in 16 of 17 patients by 12 f 4 msec (p < 0.001) from 260 f 26 to 272 + 28 msec. Refractoriness increased by 20 msec in four patients and 10 msec in 12 patients. With all stimuli at a strength of 10 MA, S, delivered to the same site as the pacing stimuli prolonged refractoriness in 11 of 15 patients by 8 + 7 msec (p < 0.001) from 230 + 22 to 238 + 24 msec. The greatest increase in refractoriness observed was again 20 msec, which occurred in two patients. Similarly, unipolar cathodal twice diastolic threshold conditioning stimuli delivered to the same site as the unipolar pacing stimuli increased the ventricular refractory period in 13 of 13 patients by 11 + 3 msec (p < 0.001) from 262 k 26 to 273 + 23 msec. Refractoriness increased by 20 msec in one patient and by 10 msec in 12 patients. With all unipolar stimuli at 10 MA ventricular refractoriness was prolonged in eight of nine patients by 11 f 6 msec (p < 0.001) from 262 + 24 to 273 4 23 msec. The greatest increase in refractoriness observed was again 20 msec, which occurred in two patients. Unipolar anodal conditioning stimuli of twice diastolic threshold or 10 MA delivered to the same site as unipolar anodal pacing stimuli prolonged refractoriness in three of four patients. A 20 msec increase was observed in one patient and 10 msec increases occurred in the others. Bipolar twice threshold conditioning stimuli delivered to the electrode pair 3 mm proximal to the pacing electrodes prolonged refractoriness in only 1
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306
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Amerkan
at *
=Psc
electrode
-1 I
1987
Heart Journal
lOma 1,
S,-S2:270 3-5;250
1. Unipolar cathodal stimulation in patient 10. Illustrated from the top of each panel are surface ECG leads I and aVr and the right ventricular bipolar electrogram recorded from the most proximal electrode pair (electrodes 5 and 6) of the pacing catheter positioned in the right ventricular apex. Time lines at the top of panels A and E are at 50 msec intervals. All measurements are expressed in milliseconds. The basic drive cycle length is 600 msec in all panels. In panels A-D (left), all stimuli have a 2 msec pulse with a 10 MA amplitude and are delivered to the most distal electrode (No. l), which serves as the cathode, and a surface electrode patch, which serves as the anode. In A an S, 260 msec after S, captures the ventricle. In B an S, 10 msec earlier than in A fails to capture the ventricle, and the ventricular effective refractory period is therefore 250 msec. In C a conditioning stimulus (SJ with the same amplitude as the pacing stimuli delivered to the same electrode (electrode 1) prevents S, from capturing the ventricle at an S,-S, interval of 270 msec. In D S, at an S,-S, interval of 280 msec captures the ventricle despite the preceding S,. Thus S, prolonged the ventricular-effective refractory period from 250 to 270 msec. In panels E-F (right), all pacing stimuli (S, and S,) are delivered to electrode 1 and have a pulse width of 2 msec and an amplitude of twice the late diastolic threshold (1.8 MA). The conditioning stimulus (S,) is delivered to electrode 2, which is 3 mm proximal to electrode 1. In panel E an S, delivered 270 msec after S, captures the ventricle. In F an Sp10 msec earlier than in E is refractory, and thus the effective refractory period is 260 msec. In G an S, with a 2 msec pulse width and amplitude of 10 MA is delivered to electrode 2 and fails to prevent S, delivered 10 msec later than the refractory period from capturing the ventricle. Panel H demonstrates that S, without S, did not capture the ventricle.
Fig.
of I6 patients, from 240 to 250 msec. Increasing the amplitude of S, to 10 MA failed to prolong refractoriness in any of 15 patients, including the patient in whom refractoriness was prolonged with a twice diastolic threshold S,. Unipolar cathodal twice diastolic threshold and 10 MA conditioning stimuli delivered 3 mm proxi-
ma1 to unipolar cathodal pacing stimuli did not prolong refractoriness in any of 12 patients tested (Fig. 1). An increase of S, to a pulse width of 9 msec and amplitude of 10 MA in six patients also failed to increase ventricular refractoriness 3 mm distal to the conditioning stimuli. Unipolar anodal conditioning stimuli of twice threshold and 10 MA produced
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stimuli
and refractory
period
307
A T I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
370
A
I
I
I
I
AVF
A
B
340
A
340
A
Tliflllllllllflll
340
A
290
A
340
A
I
I
II AVF-
Fig. 2. Circus movement tachycardia in patient 1. From the top are 100 msec time lines, surface ECG leads 1, aVr, and V, and intracardiac electrograms recorded from the distal electrode pair of the catheter positioned at the low septal right atrium (LSRAd), the proximal electrode pair of the same catheter (LSRAp), the His bundle position (HIS), and the right ventricular apex (RVA). In panel A orthodromic circus movement tachycardia with right bundle-branch block and a cycle length of 340 msec is present. Earliest retrograde atrial activation is recorded at the low septal right atrium, slightly below the His catheter (LSRAd). A double electrogram is recorded from this position, the first component of which (arrow) is suggestive of an accessory pathway potential, indicating that the catheter is close to the atria1 insertion of the accessory pathway. A single ventricular extrastimulus (S) delivered immediately after the His bundle depolarization advances atria1 activation, confirming the presence of an accessory pathway. In Panel B from the same patient, the paper speed has been increased from 100 to 150 mm/set, and the distal coronary sinus electrogram (CSd) is now displayed in place of LSRAd. A single extrastimulus (S) with a pulse width of 9 msec and amplitude of 10 MA is delivered to the LSRAd electrodes 150 msec after the local atria1 electrogram recorded from LSRAp. This has no effect on the tachycardia that continues at a cycle length of 350 msec. Stimuli of this intensity delivered later captured the atrium (not shown). no change in the refractory
period measured
twice diastolic threshold unipolar mm distal to the conditioning patients.
with
cathodal stimuli 3 stimuli in three
Thus bipolar and unipolar conditioning stimuli produced a similar increase in the ventricular refractory period when delivered at the site of the pacing stimuli. However, only 1 of 20 patients demon-
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et al.
Table
II. Characteristics
American
of circus movement
tachycardia
and S, Maximum noncaptured
Patient
Earliest atria1 site
Threshold Cm A)
Atria1 ERP
Tachycardia cycle length
1 2 3 4 5 6 7
LSRA C&* HARA C& MSRA CSd CSd
2.0 1.1 2.0 2.5 .75 1.2 1.0
190 150 170 110 160 210 190
350 350 310 280 270 460 250
CS, = coronary sinus ostium; CSd = distal coronary sinus; ERP = effective tachycardia: HARA = high-anterior right atrium: LSRA = low-sental - riaht onds. All intervals are in milliseconds.
&rated an increase in refractory period with stimuli delivered 3 mm proximal to the pacing stimuli. Conditioning stimuli in atrioventricular cardia. Noncaptured bipolar stimuli
reentry
August 1987 Heart Journal
tachy-
delivered to the atria1 site closest to the insertion of the accessory pathway did not slow or terminate circus movement tachycardia in any patient (Fig. 2). As shown in Table II, the atrial-effective refractory periods measured with twice diastolic threshold stimuli at these sites during tachycardia were 60 to 250 msec shorter than the tachycardia cycle lengths. This difference represents the excitable gap at that point in the reentry circuit. An increase in refractoriness of a comparable duration would presumably have been required for the circulating wavefront to encounter refractory tissue at these sites after the conditioning stimuli. DISCUSSION
Using bipolar stimuli Prystowsky and Zipes,’ Windle et al.,2 and SkaIe et aI. have shown that noncapturing stimuli delivered during the last 10 to 30 msec of the ventricular or atria1 refractory period are capable of inhibiting or preventing a subsequent stimulus from evoking a propagated response, thus prolonging the myocardial refractory period. This phenomenon is dependent on the strength of the noncapturing conditioning stimulus. The 10 to 20 msec increase in refractory period that we observed after a conditioning stimulus was delivered to the same site as the pacing stimuli is consistent with these previous investigations. We did not observe the large increases in refractoriness of up to 135 msec obtained by WindIe et aL2 when all stimuli were delivered to the same site and stimulus pulse widths of up to 100 msec were used.2 However, we did not independently vary the strength of the S,
Duration excitable
refractory period measured atrium; MSRA = midseptal
of
gap
160 200 140 170 110 250 60
strength of S, tested
Amplitude (mA) 10 10 10 10 10 2.4 10
by twice threshold stimuli during right atrium; MA = millamperes;
Duration (msec) 9 2 5 9 9 2 5 circus movement msec = millisec-
and pacing stimuli when both were delivered to the of both S, and S, was increased during their delivery to the same site, the increased strength of S, shortened the measured ventricular refractory period and also appeared to diminish the effect of S,. We also did not use the markedly increased pulse widths that are not commonly available. The distance from the stimulating electrode over which this phenomenon occurs is critical for its potential clinical application for tachycardia termination. Although inhibition was demonstrated in three of nine patients with stimuli 1 cm apart, in an initial study’ a subsequent canine study from the same group was unable to demonstrate inhibition when conditioning stimuli were delivered 5 and 10 mm from the pacing stimuli.6 In our study inhibition was observed in only 1 of 17 patients with bipolar stimuli delivered 3 mm away from the pacing stimuli. However, we did not attempt to detect increases in refractoriness of Cl0 msec and cannot exclude that smaller changes may occur more frequently. Previous studies have used bipolar stimulation for both pacing and conditioning stimuli. Several aspects inherent to bipolar stimulation could potentially influence the occurrence of inhibition. First, bipolar stimulation subjects the myocardium adjacent to the cathode to depolarizing current and that adjacent to the anode to hyperpolarixing current,’ which may have a different effect on refractoriness. When delivered during phase 3 of the action potential, cathodal current would tend to prolong the action potential duration whereas anodal current would be expected to shorten it. Antxelevitch and Moe” have shown that subthreshold anodal and cathodal current delivered after repolarization have different effects on the amount of current required same site. Thus when the current
Volume 114 Number 2
to elicit a subsequent depolarization. Hyperpolarizing current lowered while depolarizing current increased the subsequent excitation threshold.5 Second, during bipolar stimulation a propagated response may arise at the anode, the cathode, or simultaneously at both sites depending on the stimulus strength, prematurity, and excitation threshold.3 We have previously shown that variations in the contribution of the anode and cathode to myocardial excitation commonly occur during programmed electrical stimulation in humans.4 Third, when the conditioning and pacing stimuli are delivered to adjacent bipolar pairs of electrodes on a single pacing catheter, as used in this and a previous study,’ the distance between the respective cathodes of the conditioning and pacing stimuli, as well as between the anodes, is greater than the minimum interelectrode distance of the catheter. Thus although the bipolar pairs in our study were separated end to end by 3 mm, the distance between cathodes of the pacing and conditioning stimuli was greater than 6 mm. To define more clearly the earliest site of myocardial excitation and avoid potentially complicating factors associated with bipolar pacing, we also performed unipolar cathodal and unipolar anodal pacing. Although inhibition was again seen when conditioning and pacing stimuli were delivered to the same site, conditioning stimuli 3 mm away from the pacing stimuli had no effect. Polarization. During electrical stimulation of the heart, oppositely charged particles accumulate at the electrode-myocardium interface, adding a nonlinear polarization impedance to the system.8 The very local effect of noncapturing stimuli led us to consider the possibility that an increase in impedance caused by further polarization at the pacing site immediately after the noncapturing stimulus resulted in lower current delivery with the following Sz. A sufficient increase in impedance after the noncapturing stimulus could prevent the delivery of the preset current of S, if the voltage required exceeded the maximal voltage output of our stimulator. Therefore the voltage attained with closely coupled extrastimuli was measured during bipolar pacing in physiologic saline solution and during ventricular stimulation. Extrastimuli coupled as closely as 2 msec required less than 11 V to provide a current of 10 MA. Thus the apparent effect of noncapturing stimuli did not appear to be due to decreased current delivery during the subsequent closely coupled stimulus. Mechanism. Two mechanisms of prolongation of refractoriness by noncapturing conditioning stimuli
Conditioning
stimuli
and refractory
period
309
have been proposed. The S, delivered during phase 3 of the action potential may prolong action potential duration by an electrotonic effect, or S, may elicit a very local threshold response that is extinguished on entering adjacent tissue.2 Preliminary reports of in vitro cellular recordings have been presented supporting both mechanisms.s~lo We found that both unipolar cathodal and unipolar anodal stimuli are capable of prolonging refractoriness when the pacing and conditioning stimuli are delivered to the same site. Since the electrotonic effect of anodal stimulation should be to shorten action potential duration, our data suggest that the production of a very local threshold response is the more likely mechanism of this phenomenon. Noncaptured stimuli for termination of reentry. Cur study demonstrates that the effect of noncapturing stimuli occurs only within a few millimeters of the stimulating electrode. However, pacing stimuli of twice diastolic threshold may be a much stronger stimulus for excitation than a physiologic wavefront of excitation. Thus a greater spatial effect of noncapturing stimuli on the more physiologic spread of excitation may have gone undetected by our methods. Atrioventricular reentry is an ideal substrate for testing this hypothesis, since the atria1 insertion of the accessory pathway can be reasonably well localized by catheter techniques. Noncapturing stimuli did not slow or terminate circus movement tachycardia in any of our patients. However, for a noncapturing stimulus to terminate a reentry arrhythmia, it must prolong refractoriness in a critical area of the reentry circuit such that the subsequent wavefront of excitation arrives while the tissue is still refractory. Thus the increase in refractory period must exceed the duration of “the excitable gap” at that point in the reentry circuit. Windle et a1.2 demonstrated that stimuli of 10 msec pulse width and 10 MA prolonged refractoriness by a mean of 33 + 11 msec, and an increase of 81 & 31 msec could be achieved by further increasing the pulse width of the conditioning stimuli to 100 msec. In our patients the shortest excitable gap was 60 msec. Thus even if the pacing catheter was ideally located, the increase in refractoriness achieved may have been insufficient to terminate the tachycardia. Conditioning stimuli would be most effective at the sites in the reentry circuit having the shortest excitable gap, frequently the atrioventricular node in atrioventricular reentry. However, if the increase in refractoriness occurs in only a small island of tissue in the reentry pathway, the circulating wavefront of excitation will merely continue around it. In
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addition, the limitations of catheter mapping and the possible intramural location of portions of reentry circuits may prevent placement of a pacing electrode close enough to the reentry circuit for the conditioning stimulus to have any effect. However, one case of termination of ventricular tachycardia by an apparently noncaptured stimulus has been reported.” CONCLUSIONS
The effects of noncapturing single stimuli with pulse widths of up to 9 msec and current strengths of up to 10 MA are limited to a distance of less than 3 mm from the stimulating electrode and are not enhanced by unipolar stimulation. These limitations preclude the use of single noncapturing stimuli for tachycardia termination with current catheter techniques.
August 1987 Heart Journal
3. Van Dam RT, Durrer D, Strackee J, Tweel HVD. The excitability cycle of the dogs left ventricle determined by anodal, cathodal, and bipolar stimulation. Circ Res 1956; 4:196. 4. Stevenson WG, Wiener I, Weiss JN. Contribution of the anode to ventricular excitation during programmed electrical stimulation in humans. Am J Cardiol 1986;57:582. 5. Antzelevitch C, Moe GK. Electrotonic inhibition and summation of impulse conduction in mammalian purkinje fibers. Am J Physiol 1983;245:H42. 6. Skale BT, Kallok MJ, Prystowsky EN, Gill RM, ‘Zipes DP. Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli. J Am Co11 Cardiol 1985; 6:133. 7. Weidmann S. Effect of current flow on the membrane notential of cardiac muscle. J Phvsiol 1951;115:227. 8. Rarold SS, Ong LS, Heinle RA: Stimulation and sensing thresholds for cardiac pacing: electrophysiologic and technical aspects. Prog Cardiovasc Dis 1981;44:1. 9. Windle JR, Prystowsky EN, Zipes DP, Gilmour RF. Inhibition of propagated myocardial excitation by subthreshold stimulation: clinical and cellular correlation. PACE 1985; 8~765.
10. Windle JR, Zipes DP, Prystowsky EN, Gilmour RF. Inhibition in isolated human myocardium. J Am Co11 Cardiol 1986;7:100.
REFERENCES
1. Prystowsky EN, Zipes DP. Inhibition in the human heart. Circulation 1988;68:707. 2. Windle JR, Miles WM, Zipes DP, Prystowsky EN. Subthreshold conditioning stimuli prolong human ventricular refractoriness. Am J Cardiol 1986;57:381.
BOUND VOLUMES
AVAILABLE
11. Ruffy R, Friday KJ, Southworth WF. Termination of ventricular tachycardia by single extrastimulation during the ventricular effective refractory period. Circulation 1983;67:457.
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