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Significant variability in the mode of ventricular tachycardia induction and its implications for interpretation of acute drug testing
Significant variability in the mode of ventricular tachycardia induction and its implications for interpretation of acute drug testing Fifty-four patients with previous myocardiai infarction and sustained ventricular tachycardia on fibrillation underwent two eiectrophysioiogic studies in the drug-free state within 72 hours. Akhough the concordance of overall ventricular tachycardia induction over the 2 days was good (87% of patients), there was variability in the number of extrastimuli needed to induce sustained ventricular tachycardia on each day in 80% of patients. Of those in whom ventricular tachycardia was inducible on both days, 40% required additional extrastimuit and 20% required fewer extrastimuli. A change by two or more extrastlmuti was found in 12% of patients. There was no correlation between the variability observed and multiple clinical and laboratory parameters (including the aggressiveness of the stimulation protocol); however, the direction of the variability (easier or harder to induce) correlated with changes in ventricular refractoriness. inherent day-to-day variability may affect the reproducibility of eiectrophysioiogic studies and influence the results of serial drug testing. (AM HEART J 1988;116:718.)
Karen J. Beckman, MD, Carlos E. Velasco, MD, Jack Krafchek, MD, Huang-Ta Lin, MD, Sharon A. Magro, PA-C, and Christopher R. C. Wyndham,
MD.
Houston, Texas
In the past 10 years serial electrophysiologic studies have become an accepted means of selecting antiarrhythmic drugs for patients with sustained ventricular tachycardia.1-3 Usually patients undergo a single control study that then serves as the reference point for ensuing drug trials. This approach assumes that the inducibility of ventricular tachycardia is stable and reproducible from one day to the next; however, recent studies4e7 have called that assumption into serious question. The purpose of this article is to report the variability of ventricular tachycardia induction over two control studies in our laboratory, review the experiences of previous investigators, examine the possible causes of variability, and comment on the clinical relevance of this variability in From the Department of Medicine, Section of Medicine, The Methodist Hospital. Computational assistance grant RR-00350, Division Health, Bethesda, Md.
was provided of Research
of Cardiology,
Baylor
College
by the CLINFO project funded Resources, National Institutes
by of
Supported by an Albert S. Hyman Fellowship Award in Cardiac Pacing, presented by the North American Society of Pacing and Electrophysiology for the academic year 1985-1986 (Dr. Beckman). Received
for publication
Dec.
14, 1987;
revision
accepted
May
4, 1988.
Reprint requests: Christopher R. C. Wyndham, MD, Section of Cardiology, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231.
718
evaluations ing.
of serial electrophysiologic
drug test-
METHODS
Between June, 1982, and December, 1985,a total of 109 consecutive patients with coronary artery diseaseand documented sustained ventricular tachycardia or fibrillation underwent ventricular programmed electrical stimulation in the drug-free state. The charts were reviewed to find those who had had a previous myocardial infarction and had undergone two control electrophysiologic studies within 72 hours of each other. Fifty-four of 109 patients met both of these criteria and form the basis of this retrospective analysis. Patient characteristics are listed in Table I. Forty-seven patients had sustained monomorphic ventricular tachycardia, defined aslasting 2 30 secondsor requiring cardioversion, and seven had ventricular fibrillation alone. The cycle length of the spontaneousventricular tachycardia was known in 39 patients (range 200 to 440, mean 336 +- 59 msec). All patients had had a prior myocardial infarction. In one patient ventricular tachycardia first appeared 3 weeks after infarction; infarction was remote (greater than 3 months) in the rest. Coronary anatomy, left ventricular ejection fraction. and nnellry:E ffivmn+;.-r --....-Y.“II. were determined by cardiac catheterization in 42 patients and by echocardiography and gated radionuclide ventriculography in the remainder. All patients had regional wall motion abnormalities; 58% had aneurysms(defined as a
Volume Number
116 3
dyskinetic area). All but two patients had a decreased ejection fraction (range of 0.10 to 0.60; mean of 0.30 * 0.12). After antiarrhythmic drugs were discontinued for at least five half-lives, patients were brought to the electrophysiology laboratory in the fasting, unsedated state. Three quadripolar catheters were inserted percutaneously through the right femoral and left subclavian veins and positioned in the high right atrium, across the triscuspid valve to record the His bundle electrogram, and in the right ventricular apex. Programmed electrical stimulation was performed with a programmable stimulator (Bloom DTU-lOlC, Bloom Associates, Philadelphia, Pa.) with a 2 msec pulse width at twice diastolic threshold. After basic conduction intervals and anterograde refractory periods had been assessed, the following ventricular stimulation protocol was followed at the right ventricular apex and the right ventricular septum: one extrastimulus was introduced during sinus rhythm and drive cycle lengths of 600 and 500 msec; two, three, and four extrastimuli were introduced during a drive cycle length of 500 msec. Each extrastimulus was introduced once at each coupling interval. Coupling intervals were decreased by 10 msec until ventricular refractoriness was reached. The extrastimulus was then positioned 20 msec beyond the refractory period before the next extrastimulus was introduced. Stimulation was continued until sustained monomorphic ventricular tachycardia had been induced twice or until the end of the protocol was reached. The pacing protocol was also terminated after two cardioversions. The subclavian catheter was left in the right ventricular apex for a second control study that was always done within 72 hours of the first. The pacing protocol followed at the apex during the second study was identical to that at the first. Although two right ventricular sites were tested during the first study, for the purposes of this analysis, only data from the right ventricular apex for each day were compared. There was no change in nonantiarrhythmic medications (such as digoxin and diuretics) between the two studies. There were no electrolyte abnormalities or clinically overt episodes of acute ischemia on either study day. Definitions. Ventricular tachycardia was considered inducible when sustained monomorphic ventricular tachycardia lasting 2 30 seconds or requiring cardioversion was provoked twice. The monomorphic ventricular tachycardia induced on day 1 did not have to have the same QRS morphology as that which had occurred spontaneously. Polymorphic ventricular tachycardia and ventricular fibrillation were considered to be induced rhythms only if ventricular fibrillation had been the spontaneous arrhythmia. Ventricular tachycardia was considered noninducible if sustained ventricular tachycardia was not provoked. Nonsustained ventricular tachycardia lasting <30 seconds was considered to be noninducible. Induction of ventricular tachycardia was considered nonvariable in patients whose tachycardia was either inducible on both days with the same number of extrastimuli or noninducible on both days. The monomorphic
EPS reproducibility Table
I. Patient
? 19
characteristics
Characteristics
No. of patients Sex Male Female Age (yr)
No. of vessels obstructed ~75% Left ventricular ejection fraction (normal
54 51 3 41-74 (60.5 f 7.7) l-3 (2.4 +I 0.8) 0.10-0.60
(0.30
rt 0.12)
r0.55)
Aneurysm Spontaneous arrhythmia VT VF Cycle length of spontaneous VT (msec)
28 (58%) 47 (87%) 7 (13%) 200-440 (336
t 59)
VT = ventricular tachycardia; VF = ventricular fibrillation. Data expressed as range (mean + 1 standard deviation).
ventricular tachycardia induced on day 2 did not necessarily have to have the same QRS morphology as on day 1. Induction was considered variable in patients whose tachycardia was either inducible only on one of the two days or inducible on both days but required a different number of extrastimuli for induction. Statistical analysis. Numeric data were tested for significance by paired and unpaired t tests and by chisquare analysis. Where normality or equal variance could not be assumed, nonparametric methods were used. RESULTS
Sustained monomorphic ventricular tachycardia was induced in 45 of 54 (83 % ) patients at the first electrophysiologic study and in 46 of 54 (85 % ) at the second. Ventricular tachycardia was induced at both studies in 42 of 54 (78% 1 patients and at neither study in five patients (9 % ) for a concordant result of 87 % . Ventricular tachycardia was induced at only one study in seven patients: three at the first study and four at the second (discordant result 13%). In only one patient was an episode of ventricular fibrillation induced. In no patient was clinically relevant ventricular fibrillation induced as defined previously. The longest episode of nonsustained ventricular tachycardia in a patient in whom sustained ventricular tachycardia was not induced was 12 seconds.
Pacing thresholds (0.98 t- 0.6 vs 1.0 t 0 mA), ventricular effective refractory periods (234 f 26 vs 238 k 20 msec), and resting heart rates (78 + 16 vs 78 k 13 beats/min) were not significantly changed over the 2 days. Changes in the inducing sequence from day to day
720
Beckman
Table
II. Number
et al.
Amerlcen
of extrastimuli
required
EPS
Table
1 = electrophysiologic
III. Comparison
study
ES
1; EPS
of clinical
7
17
13
5
42
1 6 6/7
8 3 6 9/17 l/l7
4 4 5 9/13 l/l3
4 1 l/5 l/5
17 8 17 25 5
2 = electrophysiologic
study
characteristics
Variable
No. of patients Spontaneous arrhythmia VT VF Left ventricular ejection fraction Aneurysm Cycle length of spontaneous VT (msec)
32
22
29 3 0.31 f 0.12
18 4 0.29 A 0.11
NS NS
16 330 k 65
12 346 + 51
NS NS
expressed
as mean
+ SD. Abbreviations
on 2 days in 42 patients 4ES
Characteristics
Data
tachycardia 3ES
217 day
ventricular 2ES
1
EPS 1 EPS 2 Same number ES Lesser number ES Greater number ES Variability 21 ES Variability 52 ES
to induce
Nonvariable
as in Table
p
I.
were examined in the 42 patients in whom ventricular tachycardia was inducible on both days (Table II). At the first study one extrastimulus was needed in seven patients, two extrastimuli in 17 patients, three extrastimuli in 13 patients and four extrastimuli in five patients. At the second study one extrastimulus was needed in five patients, two extrastimuli in 16 patients, three extrastimuli in 11 patients and four extrastimuli in 10 patients. Of the seven patients requiring one estrastimulus on day 1, only one could still have ventricular tachycardia induced with a single extrastimulus. The other six patients required more extrastimuli for induction of ventricular tachycardia. Of the 17 patients in whom ventricular tachycardia was induced on day 1 with two extrastimuli, eight required the same number, three required fewer and six required a greater number of extrastimuli on day 2. Of the 13 patients in whom ventricular tachycardia was induced with three extrastimuli, four patients required the same number, five required more and four required fewer extrastimuli. Of the five patients in whom ventricular tachycardia was induced with four extrastimuli on day 1, four natients still required fnnr extmnt.imuli and one required fewer extrastimuli. Thus in 17 of the 42 (40.5%) patients ventricular tachycardia was induced with the same number of extrastimuli
day
Safitember 1988 Heart Journal
Total patients
(40.5%) (19%) (40.5%) (59.5%) (12%)
2; ES = extrastimuli.
as in the initial study; however, 25 of the 42 (59.5%) patients required either fewer (8 patients, 19%) or more (17 patients, 40.5 % ) extrastimuli. Five of the patients requiring a different sequence differed by two or more extrastimuli (12 % ). Overall variability (patients requiring a different number of extrastimuli and patients with inducible ventricular tachycardia on only one day) was 32 of 54 (59%). Fig. 1 summarizes data from all 54 patients. Possible relationships between the presence or absence of variability in induction of ventricular tachycardia and various clinical parameters were examined (Table III). There was no correlation between the variability seen and the presence of an aneurysm, the degree of left ventricular dysfunction, the spontaneous arrhythmia (ventricular tachycardia vs fibrillation) or the cycle length of spontaneous ventricular tachycardia. In an attempt to ascertain whether reproducibility of ventricular tachycardia induction could be predicted from results of the initial electrophysiologic study, various electrophysiologic parameters from day 1 were analyzed (Table IV). There was no correlation between variability and the pacing thresholds, effective refractory periods, and cycle lengths of ventricular tachycardia induced on day 1. In particular the lack of reproducibility bore no relation to the aggressiveness of the stimulation protocol used. As shown in Table IV, patients in whom ventricular tachycardia was induced with one or two extrastimuli at the first study were as likely to be variable at a second study (17 of 26) as those in whom ventricular tachycardia had been induced with three or four extrastimuli (11 of 19). If the variable group of patients was then divided into subsets of those easier and harder to induce, there was still no significant difference in heart rate or ,“ewipag thmo ~1~. hnrv.~---*I” vv 0 ” cil , there was a significant “I-L ““**“*u, increase in the ventricular effective refractory period on day 2 compared to that on day 1 in the patients with ventricular tachycardia that was hard-
Vohmr Numbbr
116 3
EPS
PTS Requiring More #ES
PTS Fiequiring Same #ES
PTS Roquirlng Less #ES
Day 1 Day 2 20 PTS
Day 1 Day 2 22 PTS
Day 1 Day 2 12 PTS
721
reproducibility
K@Y 0: No VT inductlon 1: Induction wlth 1 ES 2: Induction with 2 ES
3: lnductlon 4: Induction
with with
3 ES 4 ES
Fig. 1. Comparison of “ease” of induction of VT in all 54 patients. Each panel comparesinducibility of VT on day 1 with that on day 2 in patients requiring more, the same,or fewer extrastimuli at secondstudy, respectively. 0 = Noninducibility of VT despite use of four extrastimuli. The 20 patients requiring more extrastimuli include three in whom VT wasnoninducible at secondstudy. The 12 patients requiring fewer extrastimuli include four in whom VT was inducible only at secondstudy. #ES, Number of extrastimuli; Pts, patients; VT, ventricular tachycardia.
Table
IV. Comparison of baselineelectrophysiologic characteristics Characteristics
Variable
32
No. of patients Pacingthreshold(mA) Ventricular effective refractory period (msec) No. of patientswith VT inducedby 1 or 2 ES 3 or 4 ES Cyclelengthof VT inducedat EPS 1 (msec) Data expressed
Table
as mean 5 1 SD. Abbreviations
Nonvariable
Significance
236 + 29
22 0.76 k 0.4 239 -+ 19
NS NS
17 11
9 8
NS
286 f 57
294 f 57
NS
1.1 k 0.06
aa in Tables I and II.
V. Variability as a function of change in electrophysiologic parameters
---
VT induction (n =
easier
____-
Heart rate (beats/min Pacingthreshold(mA) Ventricular effectiverefractory period (msec) -__
VT = Ventricular
__--
Da,s 1
Parameters
-__----_____
Day
2
. ...-~__
P .---..NS
69 k 13
74 5 9
1.09 t 0.63 248 + 39
1.15 + 0.5
NS
220 t 21
0.059
..~
VT induction harder (n = 20)
12) Day
1
Day 2 P .l__l_ -_.-..-..-.-.___. 78 2 17 NS NS 1.07 + 0.5 0.79 L 0.32 <0.05 227 + 18 242 + 17 -.--___-~ - --___
-.---.79 t 18
tachycardia.
er to induce, and although not statistically significant there was a downward trend in the ventricular effective refractory period of patients in whom ventricular tachycardia was more easily induced (Table V).
DISCUSSION
It has long been recognized that the frequency of ventricular ectopy in patients with malignant ventricular arrhythmias can vary widely over time.*-12 One of the major limitations in using 24-hour an&u-
722
Beckman
Table
VI.
September tS88 Amerlcsn Heart Journal
et al.
Variability
of ventricular
tachycardia
induction
in the electrophysiology
laboratory:
Summary
of previous
studies
Reference Horowitz et a1.14 Schoenfeld et al.’ McPherson et aLs Livelli et al.l” Duff et a1.16t Lombardi et al.6 Kudenchuk et al.’ Present study
No. of patients
% of VT population studied
Heart disease
20 17
NA NA
77 22 24
NA NA
H H H NA NA
114
NA 100
H H
54
50
CAD
42
53
Clinical arrhythmia VT/W VT/VF/NVT VT/VFlNVT/PVC VT S/NVT/VT VT/VF VT/VF VTIVF
Aneurysm 65% 47% NA NA NA NA NA 52%
CAD = coronary artery disease; EPS 2 = electrophysiologic study day 2; ES = extrastimuli; H = heterogeneous causes; N = not performed or used; NA = not available; NVT = nonsustained ventricular tachycardia; PVC = premature ventricular complex; S = syncope; VF = ventricular fibrillation; VT = sustained ventricular tachycardia; Y = performed or used. *Variable criteria as defined by authors. tData shown summarize only first two of five electrophysiologie studies. SThirteen patients had indwelling catheters for serial studies; 11 patients had new catheters inserted at each study.
latory monitoring to assess drug efficacy is that wide swings in baseline ectopy (because of inherent variability) can be mistaken for a drug effect.8-10 It had been hoped that electrophysiologic testing (where tachycardias are actively provoked rather than spontaneous rhythms passively observed) would obviate this difficulty; however, there is no a priori reason to assume that the factors causing the variability seen clinically on ECG monitoring would not operate in the electrophysiology laboratory as well. In our patients, although the overall concordance of ventricular tachycardia induction over 2 days was good (87%), in only 40% of patients could ventricular tachycardia be induced by the same number of extrastimuli on day 2 as on day 1. The other 60% of patients either required a different (usually greater) number of extrastimuli or no longer had inducible tachycardia. This lack of reproducibility in induction mode was seen despite a uniform patient population and strict definitions of inducibility. Our study population consisted of a homogeneous group of patients with coronary artery disease, previous myocardial infarction, and sustained ventricular tachycardia or ventricular fibrillation. Such patients have been purported to have ventricular tachycardia inducible by programmed electrical stimulation at a single control study 85% to 90% of the time.13 Our results (ventricular tachycardia in 83 % ) are in accordance with previous reports, but in addition we fmmd vnriahility in.- the .___ Frrd __I_ e of induction in 60% of patients. If any group of patients might reasonably be expected to have reproducibility in the mode of induction, it would be this one. Our finding of 60% variability in mode of induc-
tion is in contradistinction to that reported by Horowitz et al.‘* They reported that 20 patients with mainly coronary artery disease and sustained ventricular tachycardia had 100% concordance in overall induction and no variability in the mode of induction between two control studies. This early study represents a smaller, highly select group of patients with multiple episodes of aborted sudden death and is probably not typical of patients currently being investigated. Subsequent work by Schoenfeld et al.,4 McPherson et al.,s Lombardi et a1.,6 Livelli et al.,15 Duff et a&l6 and Kudenchuk et aL7 showed that significant variability exists both in terms of overall induction of ventricular tachycardia (11% to 75% ) and the mode of induction (27 % to 73 % ). Results of these studies are summarized in Table VI. It should be noted that these studies are extremely heterogeneous in terms of patient populations and diverse in methods and definitions. The patients studied by Schoenfeld et al.,4 McPherson et al.,5 and Kudenchuk et al.’ exhibited a wide range of underlying heart disease and left ventricular function (Livelli et a1.15 and Duff et a1.16 did not define their study populations). The presenting arrhythmia in most instances was sustained ventricular tachycardia and fibrillation; however, Schoenfeld et al.* included patients with nonsustained ventricular tachycardia, McPherson et a1.5 included patients with both nonsustained ventricular tachycardia and premature ventricular contractions, and Duff et al.16 included patients with syncope. A variety of pacing protocols was used, with two to four extrastimuli, burst pacing, and one to two pacing sites. Most investigators
Volume Number
116 3
EPS reproducibility
Protocol
No. of
Maximum
no. of ES
Maximum no. of days between studies
Burst
sites
2 3 3 3 3
Y Y Y N Y
1 1 1 1 1
1 18 mo 3 3 2
2 4 4
N Y N
1 2 1
32 1 3
used indwelling catheters for the second study. The definitions of induction and reproducibility were equally diverse and ranged from extremely open (in the study of McPherson et a1.,5 tachycardia of >3 beats was considered inducible and induction of any ventricular tachycardia on both days reproducible) to extremely strict (in the study of Lombardi et al., for the tachycardia to be inducible the patient had to have ventricular tachycardia induced in two of three attempts at the same coupling interval). Despite these limitations it appears clear that the mode of induction of ventricular tachycardia in a given patient is not nearly as reproducible as first thought. The most important implications of variability in induction of ventricular tachycardia relate to interpretation of the results of acute drug testing done in the electrophysiology laboratory. Much has been written about the optimal stimulation protocol for induction of ventricular tachycardia in the control state (including number of drive cycle lengths, sites, number of extrastimuli)17-27; comparatively little discussion has been directed at how aggressive the stimulation protocol should be during serial drug testing.5’“4 If the inherent variability is not taken into consideration, changes in inducibility may be mistaken for a beneficial or detrimental drug effect. This may be especially true in protocols that assess drug efficacy by testing only through the number of extrastimuli at which ventricular tachycardia was originally induced or by delivering a standard number of extrastimuli regardless of how ventricular tachycardia was originally induced in the control state.24 Protocols that require suppression of arrhythmia through the entire stimulation protocol would minimize the chances of false predictions of drug success but may be overly stringent.14* 25 There are several ways to address this problem.
Variability Indwelling catheter EPS 2 Y N Y NA yt N Y Y Y
Induction of VT 0% 30% 18% 18% 0% 0% 43% 11% 13%
723
in*
VT
Mode of induction 0% 70% 53% 41% 23% 18% 73% 27% 60%
First it may be possible to identify subsets of variable and nonvariable patients. This would require at least two control studies, since it would be impossible to predict who would be variable on the basis of the results of the initial study. Patients with reproducible modes of induction could undergo serial drug studies with increased confidence that the test results would accurately reflect the effects of the antiarrhythmic drugs. In patients with marked variability the baseline would need to be reassessed before each drug trial; however, this would require that all drug testing be done intravenously. Alternatively it may be possible to compensate for possible variance by modifications of the pacing protocol based on the number of extrastimuli required at the initial electrophysiologic study. For example, among the 45 patients in whom ventricular tachycardia was induced at the first study, induction at the second study was more difficult by at least one extrastimulus in 20 of 45 (44 % ); however, only six of these patients (13 % ) required two or more additional extrastimuli on the second day. Thus if one were to define successful drug testing as “suppression of arrhythmia despite delivery of one additional extrastimulus over the number required to induce ventricular tachycardia in the control study,” one could conceivably encompass all but 13% of the variability in patients induced at the first study. On the other hand, since ventricular tachycardia became “easier” to induce in 8 of 45 patients (18 % ), such a system might increase the number of drugs falsely declared ineffective. Requiring suppression of arrhythmia one extrastimulus beyond that required at the initial study in these patients may be overly stringent and may lead to drugs being discarded prematurely (although not as frequently as would be the case if the entire stimulation protocol was used). The problem of variability might also be
724
Beckman
et al.
American
surmounted by testing at multiple ventricular sites2” or by using different end points, such as nonsustained ventricular tachycardia.28 Another alternative would be to define drug efficacy as noninduction of tachycardia through the entire stimulation protocol, regardless of how tachycardia was initially induced. Prospective studies are needed to determine whether any of these suggestions are valid. The lack of reproducibility in the mode of induction of ventricular tachycardia and its relation to acute drug testing is clinically relevant only in so far as it affects the results of long-term therapy. The incidence of recurrent ventricular tachycardia and sudden death in patients receiving antiarrhythmic drugs at the time of discharge, who are predicted to be successful based on results of electrophysiologic testing, is estimated to be between 5 % and 20 % and has been reported to be as high as 32 % .2,2g,3oClinical experience suggests that the reasons for drug failure (such as progression of underlying heart disease, inability to maintain drug levels tested in the electrophysiology laboratory, and metabolic imbalance) are multifactorial but may include failure to take intrinsic variability into consideration at the time of acute drug testing. The cause of variability in induction of ventricular tachycardia is uncertain and may also be multifactorial. Previous authors have asserted that it is the result of an unstable myocardial substrate (i.e., not seen in patients with aneurysms),4 the use of chronic indwelling pacing catheters,16 or the aggressiveness of the stimulation protocol.5 In our study variability did not correlate with the preceding factors and other clinical and electrophysiologic parameters. There was a suggestion that in the group of variable patients, changes in ventricular refractoriness corresponded to changes in the mode of ventricular tachycardia induction (i.e., in patients in whom tachycardia became easier to induce, the ventricular effective refractory periods shortened compared to day 1, whereas in patients in whom tachycardia became harder to induce, the effective refractory periods lengthened in comparison to day 1). The relationship between ventricular effective refractory periods measured during programmed stimulation and during ventricular induction is not well understood. It may be that the ability to achieve shorter effective refractory periods facilitates induction of ventricular tachycardia by “peeling back” refractoriness in some areas of the ventricle and nmot;nn
. .r,
,In;,-l;rn~+;c.,,l . .I.&‘A. “C LIVAIUI
LlfinL UI”bA.
:-111 Act.,... “UIIL,,I
areas.
on
t E 1c
other hand, changes in refractoriness may be only a marker for other influences that modulate induction of tachycardia.
September 1988 Heart Journal
In any case we can only speculate on the possible causes of variability in this study. All of our patients had coronary artery disease, and although no patients had ischemic symptoms or repolarization changes at the time of either study, the possibility that subclinical ischemia intermittently causes decreased tachycardia threshold and ventricular refractoriness cannot be excluded. There is mounting epidemiologic data to indicate that stress may be an independent risk factor in sudden cardiac death.3* Experimental work in animals suggests that vulnerability to malignant cardiac arrhythmias is heightened by psychological stress.32,33 Although one must be cautious in extrapolating animal work to humans, it is interesting that ventricular tachycardia in our patients tended to be “easier” to induce on the first day (when catheters were inserted and the laboratory was unfamiliar) and became “harder” to induce on a subsequent day (? when patients were more adapted to the procedure). More work is needed to define better the relationship between the central nervous system and cardiac arrhythmias. Limitations. As always in retrospective studies, there may have been unappreciated bias and selection that affected results. Because only two control studies were performed, it is not known whether the variable patients would have remained variable and the nonvariable patients nonvariable at a third and fourth study. Also our results may not reflect the variability over shorter (hour to hour) or longer (month to month) periods. Only data from one ventricular site at one pacing cycle were analyzed; the use of multiple pacing sites and cycle lengths could have conceivably minimized the variability seen. Based on previous work16 the use of an indwelling catheter for the second study may be a serious limitation. Because the results of the second control study were known (and acted upon) it is not possible to know how acute drug testing and long-term drug efficacy would have been affected by variability. The results of this study may not be applicable to other subsets of patients (nonsustained ventricular tachycardia or ventricular tachycardia in patients without coronary artery disease). Clinical Implications. Although the reproducibility of ventricular tachycardia induction from one day to the next is good, there is significant variability in the mode of ventricular tachycardia induction (number of extrastimuli needed). This variability is not related to the aggressiveness of the stimulation protocol. Its significance is unclear but may account for some of the apparent failures of drugs selected by electrophysiologic testing and for premature discon-
Voiumo Number
116 3
EPS reproducibility
tinuation of other drugs. Our results suggest that multiple control electrophysiologic studies performed whenever possible may be helpful in assessing the reproducibility of the mode of ventricular tachycardia induction in individual patients. Stimulation protocols during serial drug testing may need to be modified to allow for intrinsic variability (such as defining the success of a drug as absence of induction of ventricular tachycardia by a protocol that uses one extrastimulus beyond the number required for original induction). Prospective studies are needed to elucidate better the incidence, mechanism, and clinical significance of variability in the electrophysiologic laboratory. We thank Kalene of this manuscript.
Farley
for her assistance
in the preparation
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1977;93:658. 4. Schoenfeld M, McGovern B, Garan H, Ruskin J. Long-term reproducibility of response to programmed cardiac stimulation in spontaneous ventricular tachyarrhythmias. Am J Cardiol 1985$X564. 5. McPherson C, Rosenfeld L, Batsford W. Day-to-day reproducibility of response to right ventricular programmed electrical stimulation: implications for serial drug testing. Am J Cardiol 1985;55:689. 6. Lombardi F, Stein J, Podrid P, Graboys T, Lown B. Daily reproducibility of electrophysiologic test results in malignant ventricular arrhythmia. Am J Cardiol 1986;57:96. 7. Kudenchuk P, Kron J, Wallance C, Murphy E, Morris C, Griffith K, McAnulty J. Reproducibility of arrhythmia induction with intracardiac electrophysiologic testing: patients with clinical sustained ventricular tachyarrhythmias. J Am Co11 Cardiol 1986;7:819. 8. Winkle RA. Ant&rhythmic drug effect mimicked by spontaneous variability of ventricular ectopy. Circulation 1978; 57:1116. 9. Morganroth J, Michelson E, Horowitz L, Josephson Mi Pearlman A, Durkman W. Limitations of routine long-term electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 197858408. 10. Pratt C, Slymen D, Wierman A, Young JB, Francis MJ, Seals AA, Quinones MA, Roberts R. Analysis of the spontaneous variability of ventricular arrhythmias: consecutive ambulatory electrocardiographic recordings of ventricular tachycardia. Am J Cardiol 1985;56:67. 11. Ezri M, Huang S, Denes P. The role of Holter monitoring in patients with recurrent sustained ventricular tachycardia: an electrophysiologic correlation. AM HEART J 1984$08:1229. 12. Swerdlow C, Peterson J. Prospective comparison of Holter monitoring and electrophysiologic study in patients with coronary artery disease and sustained ventricular tachyarrhythm& Am J Cardiol 1985;56:577. 13. Vanderpol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME. Incidence and clinical signifi-
725
came of induced ventricular tachycardia. Am J Cardiol 1980;45:725. 14. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in selection of antiarrhvthmic regimens. Circulation 1978;
58:986. 15. Livelli F, Gang E, Reiffel J, Ferrick K, Gliklich J, Bigger J. Renroducibilitv of inducible ventricular tachycardia [Abstract]. Circulation 1982;66(suppl 11):146. 16. Duff HJ, Mitchell LB, Wyse DG. Programmed electrical stimulation studies for ventricular tachycardia induction in Humans. II. Comparison of indwelling electrode catheter and daily catheter replacement. J Am Co11 Cardiol 1986;8:576. 17. Herre J. Mann D. Luck J. Maero SA. Fiahali S. Breen T. Wyndham CRC. Effect of incre&ed curreni, multiple pacing sites and numbers of extrastimuli on induction of ventricular tachycardia. Am J Cardiol 1986;57:102. 18. Morady F, DiCarlo L, Winston S, Davis J, Scheinman M. A prospective comparison of triple extrastimuli and LV stimulation in studies of ventricular tachycardia induction. Circulation 1984;70:52. 19. Mann DE, Luck JC, Griffin JC, Herre JM, Limacher MC, Magro SA, Robertson NW, Wyndham CRC. Induction of clinical ventricular tachycardia using programmed stimulation: value of third and fourth extrastimuli. Am J Cardiol 1983;52:501. 20. Platia E, Greene HL, Vlay SC, Werner JA, Gross B, Reid PR. Sensitivity of various extrastimulus techniques in patients with serious ventricular arrhythmias. AM HEART J 1983;
106:698. 21. Buxton AE, Waxman HL, Marchlinski FE, Untereker WJ, Waspe LE, Josephson ME. Role of triple extrastimuli during electrophysiologic study of patients with documented sustained ventricular tachycardia. Circulation 1984;69:532. 22. Brugada P, Green M, Abdollah H, Wellens HJJ. Significance of ventricular arrhythmias initiated by programmed stimulation: the importance of the type of arrhythmia induced and the number of extrastimuli required. Circulation 1984; 6987. 23. Waldo AL, Akhtar M, Brugada P, Henthorn R, Scheinman M, Ward D, Wellens HJJ. The minimally appropriate electrophysiologic study for the initial assessment of patients with documented sustained monomorphic ventricular tachycardia. J Am Co11 Cardiol 1985;6:1174. 24. Swerdlow C, Blum J, Winkle R, Griffin J, Ross D, Mason J. Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with use of a third extrastimulus. AM HEART J 1982;104:1004. 25. Morady F, Hess D, Scheinman M. Electrophysiologic drug testing in patients with malignant ventricular arrhythmia: importance of stimulation at more than one ventricular site. Am J Cardiol 1982;50:1055. 26. Lin HT, Mann DE, Luck JC, Krafchek J, Magro SA, Sakun V, Wyndham CRC. Prospective comparison of right and left ventricular stimulation in the induction of sustained ventricular tachycardia. Am J Cardiol 1987;59:559. 27. Brugada P. Its never too late (Editorial). Am J Cardiol 1987;59:689. 28. Swerdlow C, Winkle R, Mason J. Prognostic significance of the number of induced ventricular complexes during assessment of therapy for ventricular tachycardias. Circulation 1983;6&400. 29. Benditt DG, Benson DW, Klein GJ. Prevention of recurrent sudden cardiac arrest: role of provocative electrophysiologic testing. J Am Co11 Cardiol 1983;2:428. 30. Morady F, Scheinman MM, Hess DS. Electrophysiologic testing in the management of survivors of out-of-hospital cardiac arrest. Am J Cardiol 1983;51:85. 31. Lown B, Verrier L, Corbalan R. Psychologic stress and threshold for repetitive ventricular response. Science 1973; 182~834.
Beckman
et al.
American
32. Skinner JE, Lee JT, Entman ML. Modification fibrillation latency following coronary artery conscious pig-the effects of psychological adrenergic blockade. Circulation 1975;51:656.
of ventricular occlusion in the stress and beta-
Magnet unresponsive tachycardia
pacemaker
33. Skinner JE, Reed pathway prevents heart in pigs. Am
endless
JC. Blockade of frontal ventricular fibrillation J Physiol 1981;240:H156.
September 1988 Heart Journal
cortical brainstem of the ischemic
loop
Endless loop tachycardia is a well-known complication of DDD pacing and is almost invariably terminated by conversion to the asynchronous DO0 mode upon application of a magnet over the pulse generator. Occasionally magnet application is ineffectual because the ventriculoatrial (VA) synchrony of endless loop tachycardia Is converted directly or indirectly to an atrioventricular (AV) desynchronlzation arrhythmia, another form of VA synchrony. This occurs when a paced ventricular beat engenders an unsensed retrograde P wave and the continual delivery of an Ineffectual atrial stimulus during the atrial myocardial refractory period creates self-perpetuating VA synchrony. Upon magnet removal, AV desynchronization arrhythmia reverts immediately to endless loop tachycardia. In the absence of access to programmers, magnet unresponsive endless loop tachycardia can be easily and reliably terminated by chest wall stimulation through inhibition of the ventricular channel of the DDD pulse generator. (AM HEART J 1988;116:726.)
S. Serge Barold, MB, BS, FRACP, Michael Robert A. Heinle, MD. Rochester, N.Y.
D. Falkoff,
Endless loop (reentrant) tachycardia is a wellknown complication of dual chamber pacing with DDD (or VDD) pulse generators.‘e8 Despite the very sophisticated programmability of contemporary DDD pulse generators, endless loop tachycardia (ELT) will probably continue to be a potential problem because of inappropriate pacemaker programming or unpredictable variation of retrograde ventriculoatrial (VA) conduction occurring spontaneously or secondary to the administration of cardiac drugs. ‘pg-14The easiest way of terminating ELT is by application of the test magnet over the DDD pulse generator. Conversion to the DO0 mode disrupts VA synchrony and almost invariably termi-
nates ELT.1-7 Occasionally ELT cannot be terminated by application and removal of the test magnet. Magnet unresponsive endless loop tachycardia is From the Division of Cardiology, Hospital, and the Universitv of
Department Rochester
School
of Medicine, nf Mdicine
The Genesee and
non&t-
ry.
Received for publication March 1, 1988; accepted Apr. 11, 1988. Reprint requests: Dr. S. Serge Barold, The Genesee Hospital, 224 Alexander St., Rochester, NY 14607.
726
MD, Ling S. Ong, MD, and
often linked to the development of another form of VA synchrony or atrioventricular (AV) desynchronization arrhythmia. During AV desynchronization arrhythmia, a paced ventricular beat engenders an unsensed retrograde P wave and the continual delivery of an ineffectual atrial stimulus during the atria1 myocardial refractory period creates a self-perpetuating form of VA synchrony.15-17 In this report, we describe the characteristics of magnet unresponsive
ELT, its relationship to AV desynchronization arrhythmia, and describe its termination by chest wall stimulation, a simple technique that does not require access to a programmer. ILLUSTRATIVE
EXAMPLES
Case No. 1. Inability to terminate endless loop tachycardia by magnet application. Conversion to AV desynchronlzation arrhythmia and return of endless loop tachycardia upon withdrawal of the magnet. The
electrocardiogram (ECG) in Fig. 1 showsan ELT caused by a Medtronic (Medtronic, Inc., Minneapolis, Minn.) 7000 DDD pulse generator programmed to the following settings: lower rate interval = 750 msec (rate = 80 pulses per minute [ppm]), upper rate interval = 480 msec (rate = 125 ppm), AV interval = 250 msec,post-ventricu-
Karen J. Beckman, MD, Carlos E. Velasco, MD, Jack Krafchek, MD, Huang-Ta Lin, MD, Sharon A. Magro, PA-C, and Christopher R. C. Wyndham,
MD.
Houston, Texas
In the past 10 years serial electrophysiologic studies have become an accepted means of selecting antiarrhythmic drugs for patients with sustained ventricular tachycardia.1-3 Usually patients undergo a single control study that then serves as the reference point for ensuing drug trials. This approach assumes that the inducibility of ventricular tachycardia is stable and reproducible from one day to the next; however, recent studies4e7 have called that assumption into serious question. The purpose of this article is to report the variability of ventricular tachycardia induction over two control studies in our laboratory, review the experiences of previous investigators, examine the possible causes of variability, and comment on the clinical relevance of this variability in From the Department of Medicine, Section of Medicine, The Methodist Hospital. Computational assistance grant RR-00350, Division Health, Bethesda, Md.
was provided of Research
of Cardiology,
Baylor
College
by the CLINFO project funded Resources, National Institutes
by of
Supported by an Albert S. Hyman Fellowship Award in Cardiac Pacing, presented by the North American Society of Pacing and Electrophysiology for the academic year 1985-1986 (Dr. Beckman). Received
for publication
Dec.
14, 1987;
revision
accepted
May
4, 1988.
Reprint requests: Christopher R. C. Wyndham, MD, Section of Cardiology, Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231.
718
evaluations ing.
of serial electrophysiologic
drug test-
METHODS
Between June, 1982, and December, 1985,a total of 109 consecutive patients with coronary artery diseaseand documented sustained ventricular tachycardia or fibrillation underwent ventricular programmed electrical stimulation in the drug-free state. The charts were reviewed to find those who had had a previous myocardial infarction and had undergone two control electrophysiologic studies within 72 hours of each other. Fifty-four of 109 patients met both of these criteria and form the basis of this retrospective analysis. Patient characteristics are listed in Table I. Forty-seven patients had sustained monomorphic ventricular tachycardia, defined aslasting 2 30 secondsor requiring cardioversion, and seven had ventricular fibrillation alone. The cycle length of the spontaneousventricular tachycardia was known in 39 patients (range 200 to 440, mean 336 +- 59 msec). All patients had had a prior myocardial infarction. In one patient ventricular tachycardia first appeared 3 weeks after infarction; infarction was remote (greater than 3 months) in the rest. Coronary anatomy, left ventricular ejection fraction. and nnellry:E ffivmn+;.-r --....-Y.“II. were determined by cardiac catheterization in 42 patients and by echocardiography and gated radionuclide ventriculography in the remainder. All patients had regional wall motion abnormalities; 58% had aneurysms(defined as a
Volume Number
116 3
dyskinetic area). All but two patients had a decreased ejection fraction (range of 0.10 to 0.60; mean of 0.30 * 0.12). After antiarrhythmic drugs were discontinued for at least five half-lives, patients were brought to the electrophysiology laboratory in the fasting, unsedated state. Three quadripolar catheters were inserted percutaneously through the right femoral and left subclavian veins and positioned in the high right atrium, across the triscuspid valve to record the His bundle electrogram, and in the right ventricular apex. Programmed electrical stimulation was performed with a programmable stimulator (Bloom DTU-lOlC, Bloom Associates, Philadelphia, Pa.) with a 2 msec pulse width at twice diastolic threshold. After basic conduction intervals and anterograde refractory periods had been assessed, the following ventricular stimulation protocol was followed at the right ventricular apex and the right ventricular septum: one extrastimulus was introduced during sinus rhythm and drive cycle lengths of 600 and 500 msec; two, three, and four extrastimuli were introduced during a drive cycle length of 500 msec. Each extrastimulus was introduced once at each coupling interval. Coupling intervals were decreased by 10 msec until ventricular refractoriness was reached. The extrastimulus was then positioned 20 msec beyond the refractory period before the next extrastimulus was introduced. Stimulation was continued until sustained monomorphic ventricular tachycardia had been induced twice or until the end of the protocol was reached. The pacing protocol was also terminated after two cardioversions. The subclavian catheter was left in the right ventricular apex for a second control study that was always done within 72 hours of the first. The pacing protocol followed at the apex during the second study was identical to that at the first. Although two right ventricular sites were tested during the first study, for the purposes of this analysis, only data from the right ventricular apex for each day were compared. There was no change in nonantiarrhythmic medications (such as digoxin and diuretics) between the two studies. There were no electrolyte abnormalities or clinically overt episodes of acute ischemia on either study day. Definitions. Ventricular tachycardia was considered inducible when sustained monomorphic ventricular tachycardia lasting 2 30 seconds or requiring cardioversion was provoked twice. The monomorphic ventricular tachycardia induced on day 1 did not have to have the same QRS morphology as that which had occurred spontaneously. Polymorphic ventricular tachycardia and ventricular fibrillation were considered to be induced rhythms only if ventricular fibrillation had been the spontaneous arrhythmia. Ventricular tachycardia was considered noninducible if sustained ventricular tachycardia was not provoked. Nonsustained ventricular tachycardia lasting <30 seconds was considered to be noninducible. Induction of ventricular tachycardia was considered nonvariable in patients whose tachycardia was either inducible on both days with the same number of extrastimuli or noninducible on both days. The monomorphic
EPS reproducibility Table
I. Patient
? 19
characteristics
Characteristics
No. of patients Sex Male Female Age (yr)
No. of vessels obstructed ~75% Left ventricular ejection fraction (normal
54 51 3 41-74 (60.5 f 7.7) l-3 (2.4 +I 0.8) 0.10-0.60
(0.30
rt 0.12)
r0.55)
Aneurysm Spontaneous arrhythmia VT VF Cycle length of spontaneous VT (msec)
28 (58%) 47 (87%) 7 (13%) 200-440 (336
t 59)
VT = ventricular tachycardia; VF = ventricular fibrillation. Data expressed as range (mean + 1 standard deviation).
ventricular tachycardia induced on day 2 did not necessarily have to have the same QRS morphology as on day 1. Induction was considered variable in patients whose tachycardia was either inducible only on one of the two days or inducible on both days but required a different number of extrastimuli for induction. Statistical analysis. Numeric data were tested for significance by paired and unpaired t tests and by chisquare analysis. Where normality or equal variance could not be assumed, nonparametric methods were used. RESULTS
Sustained monomorphic ventricular tachycardia was induced in 45 of 54 (83 % ) patients at the first electrophysiologic study and in 46 of 54 (85 % ) at the second. Ventricular tachycardia was induced at both studies in 42 of 54 (78% 1 patients and at neither study in five patients (9 % ) for a concordant result of 87 % . Ventricular tachycardia was induced at only one study in seven patients: three at the first study and four at the second (discordant result 13%). In only one patient was an episode of ventricular fibrillation induced. In no patient was clinically relevant ventricular fibrillation induced as defined previously. The longest episode of nonsustained ventricular tachycardia in a patient in whom sustained ventricular tachycardia was not induced was 12 seconds.
Pacing thresholds (0.98 t- 0.6 vs 1.0 t 0 mA), ventricular effective refractory periods (234 f 26 vs 238 k 20 msec), and resting heart rates (78 + 16 vs 78 k 13 beats/min) were not significantly changed over the 2 days. Changes in the inducing sequence from day to day
720
Beckman
Table
II. Number
et al.
Amerlcen
of extrastimuli
required
EPS
Table
1 = electrophysiologic
III. Comparison
study
ES
1; EPS
of clinical
7
17
13
5
42
1 6 6/7
8 3 6 9/17 l/l7
4 4 5 9/13 l/l3
4 1 l/5 l/5
17 8 17 25 5
2 = electrophysiologic
study
characteristics
Variable
No. of patients Spontaneous arrhythmia VT VF Left ventricular ejection fraction Aneurysm Cycle length of spontaneous VT (msec)
32
22
29 3 0.31 f 0.12
18 4 0.29 A 0.11
NS NS
16 330 k 65
12 346 + 51
NS NS
expressed
as mean
+ SD. Abbreviations
on 2 days in 42 patients 4ES
Characteristics
Data
tachycardia 3ES
217 day
ventricular 2ES
1
EPS 1 EPS 2 Same number ES Lesser number ES Greater number ES Variability 21 ES Variability 52 ES
to induce
Nonvariable
as in Table
p
I.
were examined in the 42 patients in whom ventricular tachycardia was inducible on both days (Table II). At the first study one extrastimulus was needed in seven patients, two extrastimuli in 17 patients, three extrastimuli in 13 patients and four extrastimuli in five patients. At the second study one extrastimulus was needed in five patients, two extrastimuli in 16 patients, three extrastimuli in 11 patients and four extrastimuli in 10 patients. Of the seven patients requiring one estrastimulus on day 1, only one could still have ventricular tachycardia induced with a single extrastimulus. The other six patients required more extrastimuli for induction of ventricular tachycardia. Of the 17 patients in whom ventricular tachycardia was induced on day 1 with two extrastimuli, eight required the same number, three required fewer and six required a greater number of extrastimuli on day 2. Of the 13 patients in whom ventricular tachycardia was induced with three extrastimuli, four patients required the same number, five required more and four required fewer extrastimuli. Of the five patients in whom ventricular tachycardia was induced with four extrastimuli on day 1, four natients still required fnnr extmnt.imuli and one required fewer extrastimuli. Thus in 17 of the 42 (40.5%) patients ventricular tachycardia was induced with the same number of extrastimuli
day
Safitember 1988 Heart Journal
Total patients
(40.5%) (19%) (40.5%) (59.5%) (12%)
2; ES = extrastimuli.
as in the initial study; however, 25 of the 42 (59.5%) patients required either fewer (8 patients, 19%) or more (17 patients, 40.5 % ) extrastimuli. Five of the patients requiring a different sequence differed by two or more extrastimuli (12 % ). Overall variability (patients requiring a different number of extrastimuli and patients with inducible ventricular tachycardia on only one day) was 32 of 54 (59%). Fig. 1 summarizes data from all 54 patients. Possible relationships between the presence or absence of variability in induction of ventricular tachycardia and various clinical parameters were examined (Table III). There was no correlation between the variability seen and the presence of an aneurysm, the degree of left ventricular dysfunction, the spontaneous arrhythmia (ventricular tachycardia vs fibrillation) or the cycle length of spontaneous ventricular tachycardia. In an attempt to ascertain whether reproducibility of ventricular tachycardia induction could be predicted from results of the initial electrophysiologic study, various electrophysiologic parameters from day 1 were analyzed (Table IV). There was no correlation between variability and the pacing thresholds, effective refractory periods, and cycle lengths of ventricular tachycardia induced on day 1. In particular the lack of reproducibility bore no relation to the aggressiveness of the stimulation protocol used. As shown in Table IV, patients in whom ventricular tachycardia was induced with one or two extrastimuli at the first study were as likely to be variable at a second study (17 of 26) as those in whom ventricular tachycardia had been induced with three or four extrastimuli (11 of 19). If the variable group of patients was then divided into subsets of those easier and harder to induce, there was still no significant difference in heart rate or ,“ewipag thmo ~1~. hnrv.~---*I” vv 0 ” cil , there was a significant “I-L ““**“*u, increase in the ventricular effective refractory period on day 2 compared to that on day 1 in the patients with ventricular tachycardia that was hard-
Vohmr Numbbr
116 3
EPS
PTS Requiring More #ES
PTS Fiequiring Same #ES
PTS Roquirlng Less #ES
Day 1 Day 2 20 PTS
Day 1 Day 2 22 PTS
Day 1 Day 2 12 PTS
721
reproducibility
K@Y 0: No VT inductlon 1: Induction wlth 1 ES 2: Induction with 2 ES
3: lnductlon 4: Induction
with with
3 ES 4 ES
Fig. 1. Comparison of “ease” of induction of VT in all 54 patients. Each panel comparesinducibility of VT on day 1 with that on day 2 in patients requiring more, the same,or fewer extrastimuli at secondstudy, respectively. 0 = Noninducibility of VT despite use of four extrastimuli. The 20 patients requiring more extrastimuli include three in whom VT wasnoninducible at secondstudy. The 12 patients requiring fewer extrastimuli include four in whom VT was inducible only at secondstudy. #ES, Number of extrastimuli; Pts, patients; VT, ventricular tachycardia.
Table
IV. Comparison of baselineelectrophysiologic characteristics Characteristics
Variable
32
No. of patients Pacingthreshold(mA) Ventricular effective refractory period (msec) No. of patientswith VT inducedby 1 or 2 ES 3 or 4 ES Cyclelengthof VT inducedat EPS 1 (msec) Data expressed
Table
as mean 5 1 SD. Abbreviations
Nonvariable
Significance
236 + 29
22 0.76 k 0.4 239 -+ 19
NS NS
17 11
9 8
NS
286 f 57
294 f 57
NS
1.1 k 0.06
aa in Tables I and II.
V. Variability as a function of change in electrophysiologic parameters
---
VT induction (n =
easier
____-
Heart rate (beats/min Pacingthreshold(mA) Ventricular effectiverefractory period (msec) -__
VT = Ventricular
__--
Da,s 1
Parameters
-__----_____
Day
2
. ...-~__
P .---..NS
69 k 13
74 5 9
1.09 t 0.63 248 + 39
1.15 + 0.5
NS
220 t 21
0.059
..~
VT induction harder (n = 20)
12) Day
1
Day 2 P .l__l_ -_.-..-..-.-.___. 78 2 17 NS NS 1.07 + 0.5 0.79 L 0.32 <0.05 227 + 18 242 + 17 -.--___-~ - --___
-.---.79 t 18
tachycardia.
er to induce, and although not statistically significant there was a downward trend in the ventricular effective refractory period of patients in whom ventricular tachycardia was more easily induced (Table V).
DISCUSSION
It has long been recognized that the frequency of ventricular ectopy in patients with malignant ventricular arrhythmias can vary widely over time.*-12 One of the major limitations in using 24-hour an&u-
722
Beckman
Table
VI.
September tS88 Amerlcsn Heart Journal
et al.
Variability
of ventricular
tachycardia
induction
in the electrophysiology
laboratory:
Summary
of previous
studies
Reference Horowitz et a1.14 Schoenfeld et al.’ McPherson et aLs Livelli et al.l” Duff et a1.16t Lombardi et al.6 Kudenchuk et al.’ Present study
No. of patients
% of VT population studied
Heart disease
20 17
NA NA
77 22 24
NA NA
H H H NA NA
114
NA 100
H H
54
50
CAD
42
53
Clinical arrhythmia VT/W VT/VF/NVT VT/VFlNVT/PVC VT S/NVT/VT VT/VF VT/VF VTIVF
Aneurysm 65% 47% NA NA NA NA NA 52%
CAD = coronary artery disease; EPS 2 = electrophysiologic study day 2; ES = extrastimuli; H = heterogeneous causes; N = not performed or used; NA = not available; NVT = nonsustained ventricular tachycardia; PVC = premature ventricular complex; S = syncope; VF = ventricular fibrillation; VT = sustained ventricular tachycardia; Y = performed or used. *Variable criteria as defined by authors. tData shown summarize only first two of five electrophysiologie studies. SThirteen patients had indwelling catheters for serial studies; 11 patients had new catheters inserted at each study.
latory monitoring to assess drug efficacy is that wide swings in baseline ectopy (because of inherent variability) can be mistaken for a drug effect.8-10 It had been hoped that electrophysiologic testing (where tachycardias are actively provoked rather than spontaneous rhythms passively observed) would obviate this difficulty; however, there is no a priori reason to assume that the factors causing the variability seen clinically on ECG monitoring would not operate in the electrophysiology laboratory as well. In our patients, although the overall concordance of ventricular tachycardia induction over 2 days was good (87%), in only 40% of patients could ventricular tachycardia be induced by the same number of extrastimuli on day 2 as on day 1. The other 60% of patients either required a different (usually greater) number of extrastimuli or no longer had inducible tachycardia. This lack of reproducibility in induction mode was seen despite a uniform patient population and strict definitions of inducibility. Our study population consisted of a homogeneous group of patients with coronary artery disease, previous myocardial infarction, and sustained ventricular tachycardia or ventricular fibrillation. Such patients have been purported to have ventricular tachycardia inducible by programmed electrical stimulation at a single control study 85% to 90% of the time.13 Our results (ventricular tachycardia in 83 % ) are in accordance with previous reports, but in addition we fmmd vnriahility in.- the .___ Frrd __I_ e of induction in 60% of patients. If any group of patients might reasonably be expected to have reproducibility in the mode of induction, it would be this one. Our finding of 60% variability in mode of induc-
tion is in contradistinction to that reported by Horowitz et al.‘* They reported that 20 patients with mainly coronary artery disease and sustained ventricular tachycardia had 100% concordance in overall induction and no variability in the mode of induction between two control studies. This early study represents a smaller, highly select group of patients with multiple episodes of aborted sudden death and is probably not typical of patients currently being investigated. Subsequent work by Schoenfeld et al.,4 McPherson et al.,s Lombardi et a1.,6 Livelli et al.,15 Duff et a&l6 and Kudenchuk et aL7 showed that significant variability exists both in terms of overall induction of ventricular tachycardia (11% to 75% ) and the mode of induction (27 % to 73 % ). Results of these studies are summarized in Table VI. It should be noted that these studies are extremely heterogeneous in terms of patient populations and diverse in methods and definitions. The patients studied by Schoenfeld et al.,4 McPherson et al.,5 and Kudenchuk et al.’ exhibited a wide range of underlying heart disease and left ventricular function (Livelli et a1.15 and Duff et a1.16 did not define their study populations). The presenting arrhythmia in most instances was sustained ventricular tachycardia and fibrillation; however, Schoenfeld et al.* included patients with nonsustained ventricular tachycardia, McPherson et a1.5 included patients with both nonsustained ventricular tachycardia and premature ventricular contractions, and Duff et al.16 included patients with syncope. A variety of pacing protocols was used, with two to four extrastimuli, burst pacing, and one to two pacing sites. Most investigators
Volume Number
116 3
EPS reproducibility
Protocol
No. of
Maximum
no. of ES
Maximum no. of days between studies
Burst
sites
2 3 3 3 3
Y Y Y N Y
1 1 1 1 1
1 18 mo 3 3 2
2 4 4
N Y N
1 2 1
32 1 3
used indwelling catheters for the second study. The definitions of induction and reproducibility were equally diverse and ranged from extremely open (in the study of McPherson et a1.,5 tachycardia of >3 beats was considered inducible and induction of any ventricular tachycardia on both days reproducible) to extremely strict (in the study of Lombardi et al., for the tachycardia to be inducible the patient had to have ventricular tachycardia induced in two of three attempts at the same coupling interval). Despite these limitations it appears clear that the mode of induction of ventricular tachycardia in a given patient is not nearly as reproducible as first thought. The most important implications of variability in induction of ventricular tachycardia relate to interpretation of the results of acute drug testing done in the electrophysiology laboratory. Much has been written about the optimal stimulation protocol for induction of ventricular tachycardia in the control state (including number of drive cycle lengths, sites, number of extrastimuli)17-27; comparatively little discussion has been directed at how aggressive the stimulation protocol should be during serial drug testing.5’“4 If the inherent variability is not taken into consideration, changes in inducibility may be mistaken for a beneficial or detrimental drug effect. This may be especially true in protocols that assess drug efficacy by testing only through the number of extrastimuli at which ventricular tachycardia was originally induced or by delivering a standard number of extrastimuli regardless of how ventricular tachycardia was originally induced in the control state.24 Protocols that require suppression of arrhythmia through the entire stimulation protocol would minimize the chances of false predictions of drug success but may be overly stringent.14* 25 There are several ways to address this problem.
Variability Indwelling catheter EPS 2 Y N Y NA yt N Y Y Y
Induction of VT 0% 30% 18% 18% 0% 0% 43% 11% 13%
723
in*
VT
Mode of induction 0% 70% 53% 41% 23% 18% 73% 27% 60%
First it may be possible to identify subsets of variable and nonvariable patients. This would require at least two control studies, since it would be impossible to predict who would be variable on the basis of the results of the initial study. Patients with reproducible modes of induction could undergo serial drug studies with increased confidence that the test results would accurately reflect the effects of the antiarrhythmic drugs. In patients with marked variability the baseline would need to be reassessed before each drug trial; however, this would require that all drug testing be done intravenously. Alternatively it may be possible to compensate for possible variance by modifications of the pacing protocol based on the number of extrastimuli required at the initial electrophysiologic study. For example, among the 45 patients in whom ventricular tachycardia was induced at the first study, induction at the second study was more difficult by at least one extrastimulus in 20 of 45 (44 % ); however, only six of these patients (13 % ) required two or more additional extrastimuli on the second day. Thus if one were to define successful drug testing as “suppression of arrhythmia despite delivery of one additional extrastimulus over the number required to induce ventricular tachycardia in the control study,” one could conceivably encompass all but 13% of the variability in patients induced at the first study. On the other hand, since ventricular tachycardia became “easier” to induce in 8 of 45 patients (18 % ), such a system might increase the number of drugs falsely declared ineffective. Requiring suppression of arrhythmia one extrastimulus beyond that required at the initial study in these patients may be overly stringent and may lead to drugs being discarded prematurely (although not as frequently as would be the case if the entire stimulation protocol was used). The problem of variability might also be
724
Beckman
et al.
American
surmounted by testing at multiple ventricular sites2” or by using different end points, such as nonsustained ventricular tachycardia.28 Another alternative would be to define drug efficacy as noninduction of tachycardia through the entire stimulation protocol, regardless of how tachycardia was initially induced. Prospective studies are needed to determine whether any of these suggestions are valid. The lack of reproducibility in the mode of induction of ventricular tachycardia and its relation to acute drug testing is clinically relevant only in so far as it affects the results of long-term therapy. The incidence of recurrent ventricular tachycardia and sudden death in patients receiving antiarrhythmic drugs at the time of discharge, who are predicted to be successful based on results of electrophysiologic testing, is estimated to be between 5 % and 20 % and has been reported to be as high as 32 % .2,2g,3oClinical experience suggests that the reasons for drug failure (such as progression of underlying heart disease, inability to maintain drug levels tested in the electrophysiology laboratory, and metabolic imbalance) are multifactorial but may include failure to take intrinsic variability into consideration at the time of acute drug testing. The cause of variability in induction of ventricular tachycardia is uncertain and may also be multifactorial. Previous authors have asserted that it is the result of an unstable myocardial substrate (i.e., not seen in patients with aneurysms),4 the use of chronic indwelling pacing catheters,16 or the aggressiveness of the stimulation protocol.5 In our study variability did not correlate with the preceding factors and other clinical and electrophysiologic parameters. There was a suggestion that in the group of variable patients, changes in ventricular refractoriness corresponded to changes in the mode of ventricular tachycardia induction (i.e., in patients in whom tachycardia became easier to induce, the ventricular effective refractory periods shortened compared to day 1, whereas in patients in whom tachycardia became harder to induce, the effective refractory periods lengthened in comparison to day 1). The relationship between ventricular effective refractory periods measured during programmed stimulation and during ventricular induction is not well understood. It may be that the ability to achieve shorter effective refractory periods facilitates induction of ventricular tachycardia by “peeling back” refractoriness in some areas of the ventricle and nmot;nn
. .r,
,In;,-l;rn~+;c.,,l . .I.&‘A. “C LIVAIUI
LlfinL UI”bA.
:-111 Act.,... “UIIL,,I
areas.
on
t E 1c
other hand, changes in refractoriness may be only a marker for other influences that modulate induction of tachycardia.
September 1988 Heart Journal
In any case we can only speculate on the possible causes of variability in this study. All of our patients had coronary artery disease, and although no patients had ischemic symptoms or repolarization changes at the time of either study, the possibility that subclinical ischemia intermittently causes decreased tachycardia threshold and ventricular refractoriness cannot be excluded. There is mounting epidemiologic data to indicate that stress may be an independent risk factor in sudden cardiac death.3* Experimental work in animals suggests that vulnerability to malignant cardiac arrhythmias is heightened by psychological stress.32,33 Although one must be cautious in extrapolating animal work to humans, it is interesting that ventricular tachycardia in our patients tended to be “easier” to induce on the first day (when catheters were inserted and the laboratory was unfamiliar) and became “harder” to induce on a subsequent day (? when patients were more adapted to the procedure). More work is needed to define better the relationship between the central nervous system and cardiac arrhythmias. Limitations. As always in retrospective studies, there may have been unappreciated bias and selection that affected results. Because only two control studies were performed, it is not known whether the variable patients would have remained variable and the nonvariable patients nonvariable at a third and fourth study. Also our results may not reflect the variability over shorter (hour to hour) or longer (month to month) periods. Only data from one ventricular site at one pacing cycle were analyzed; the use of multiple pacing sites and cycle lengths could have conceivably minimized the variability seen. Based on previous work16 the use of an indwelling catheter for the second study may be a serious limitation. Because the results of the second control study were known (and acted upon) it is not possible to know how acute drug testing and long-term drug efficacy would have been affected by variability. The results of this study may not be applicable to other subsets of patients (nonsustained ventricular tachycardia or ventricular tachycardia in patients without coronary artery disease). Clinical Implications. Although the reproducibility of ventricular tachycardia induction from one day to the next is good, there is significant variability in the mode of ventricular tachycardia induction (number of extrastimuli needed). This variability is not related to the aggressiveness of the stimulation protocol. Its significance is unclear but may account for some of the apparent failures of drugs selected by electrophysiologic testing and for premature discon-
Voiumo Number
116 3
EPS reproducibility
tinuation of other drugs. Our results suggest that multiple control electrophysiologic studies performed whenever possible may be helpful in assessing the reproducibility of the mode of ventricular tachycardia induction in individual patients. Stimulation protocols during serial drug testing may need to be modified to allow for intrinsic variability (such as defining the success of a drug as absence of induction of ventricular tachycardia by a protocol that uses one extrastimulus beyond the number required for original induction). Prospective studies are needed to elucidate better the incidence, mechanism, and clinical significance of variability in the electrophysiologic laboratory. We thank Kalene of this manuscript.
Farley
for her assistance
in the preparation
REFERENCES
1. Ruskin J, Di Marco J, Garan H. Out-of-hospital cardiac arrest, electrophysiologic observations and selection of longterm antiarrhythmic therapy. N Engl J Med 1980;303:607. 2. Mason J, Winkle R. Accuracy of the ventricular tachycardia induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl J Med 1980;303:1073. 3. Fisher JD, Cohen HL, Mehra R, Altschuler H, Escher DJW, Furman S. Serial electrophysiologic-pharmacologic testing for control of recurrent tachyarrhythmia. AM HEART J
1977;93:658. 4. Schoenfeld M, McGovern B, Garan H, Ruskin J. Long-term reproducibility of response to programmed cardiac stimulation in spontaneous ventricular tachyarrhythmias. Am J Cardiol 1985$X564. 5. McPherson C, Rosenfeld L, Batsford W. Day-to-day reproducibility of response to right ventricular programmed electrical stimulation: implications for serial drug testing. Am J Cardiol 1985;55:689. 6. Lombardi F, Stein J, Podrid P, Graboys T, Lown B. Daily reproducibility of electrophysiologic test results in malignant ventricular arrhythmia. Am J Cardiol 1986;57:96. 7. Kudenchuk P, Kron J, Wallance C, Murphy E, Morris C, Griffith K, McAnulty J. Reproducibility of arrhythmia induction with intracardiac electrophysiologic testing: patients with clinical sustained ventricular tachyarrhythmias. J Am Co11 Cardiol 1986;7:819. 8. Winkle RA. Ant&rhythmic drug effect mimicked by spontaneous variability of ventricular ectopy. Circulation 1978; 57:1116. 9. Morganroth J, Michelson E, Horowitz L, Josephson Mi Pearlman A, Durkman W. Limitations of routine long-term electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 197858408. 10. Pratt C, Slymen D, Wierman A, Young JB, Francis MJ, Seals AA, Quinones MA, Roberts R. Analysis of the spontaneous variability of ventricular arrhythmias: consecutive ambulatory electrocardiographic recordings of ventricular tachycardia. Am J Cardiol 1985;56:67. 11. Ezri M, Huang S, Denes P. The role of Holter monitoring in patients with recurrent sustained ventricular tachycardia: an electrophysiologic correlation. AM HEART J 1984$08:1229. 12. Swerdlow C, Peterson J. Prospective comparison of Holter monitoring and electrophysiologic study in patients with coronary artery disease and sustained ventricular tachyarrhythm& Am J Cardiol 1985;56:577. 13. Vanderpol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME. Incidence and clinical signifi-
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58:986. 15. Livelli F, Gang E, Reiffel J, Ferrick K, Gliklich J, Bigger J. Renroducibilitv of inducible ventricular tachycardia [Abstract]. Circulation 1982;66(suppl 11):146. 16. Duff HJ, Mitchell LB, Wyse DG. Programmed electrical stimulation studies for ventricular tachycardia induction in Humans. II. Comparison of indwelling electrode catheter and daily catheter replacement. J Am Co11 Cardiol 1986;8:576. 17. Herre J. Mann D. Luck J. Maero SA. Fiahali S. Breen T. Wyndham CRC. Effect of incre&ed curreni, multiple pacing sites and numbers of extrastimuli on induction of ventricular tachycardia. Am J Cardiol 1986;57:102. 18. Morady F, DiCarlo L, Winston S, Davis J, Scheinman M. A prospective comparison of triple extrastimuli and LV stimulation in studies of ventricular tachycardia induction. Circulation 1984;70:52. 19. Mann DE, Luck JC, Griffin JC, Herre JM, Limacher MC, Magro SA, Robertson NW, Wyndham CRC. Induction of clinical ventricular tachycardia using programmed stimulation: value of third and fourth extrastimuli. Am J Cardiol 1983;52:501. 20. Platia E, Greene HL, Vlay SC, Werner JA, Gross B, Reid PR. Sensitivity of various extrastimulus techniques in patients with serious ventricular arrhythmias. AM HEART J 1983;
106:698. 21. Buxton AE, Waxman HL, Marchlinski FE, Untereker WJ, Waspe LE, Josephson ME. Role of triple extrastimuli during electrophysiologic study of patients with documented sustained ventricular tachycardia. Circulation 1984;69:532. 22. Brugada P, Green M, Abdollah H, Wellens HJJ. Significance of ventricular arrhythmias initiated by programmed stimulation: the importance of the type of arrhythmia induced and the number of extrastimuli required. Circulation 1984; 6987. 23. Waldo AL, Akhtar M, Brugada P, Henthorn R, Scheinman M, Ward D, Wellens HJJ. The minimally appropriate electrophysiologic study for the initial assessment of patients with documented sustained monomorphic ventricular tachycardia. J Am Co11 Cardiol 1985;6:1174. 24. Swerdlow C, Blum J, Winkle R, Griffin J, Ross D, Mason J. Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with use of a third extrastimulus. AM HEART J 1982;104:1004. 25. Morady F, Hess D, Scheinman M. Electrophysiologic drug testing in patients with malignant ventricular arrhythmia: importance of stimulation at more than one ventricular site. Am J Cardiol 1982;50:1055. 26. Lin HT, Mann DE, Luck JC, Krafchek J, Magro SA, Sakun V, Wyndham CRC. Prospective comparison of right and left ventricular stimulation in the induction of sustained ventricular tachycardia. Am J Cardiol 1987;59:559. 27. Brugada P. Its never too late (Editorial). Am J Cardiol 1987;59:689. 28. Swerdlow C, Winkle R, Mason J. Prognostic significance of the number of induced ventricular complexes during assessment of therapy for ventricular tachycardias. Circulation 1983;6&400. 29. Benditt DG, Benson DW, Klein GJ. Prevention of recurrent sudden cardiac arrest: role of provocative electrophysiologic testing. J Am Co11 Cardiol 1983;2:428. 30. Morady F, Scheinman MM, Hess DS. Electrophysiologic testing in the management of survivors of out-of-hospital cardiac arrest. Am J Cardiol 1983;51:85. 31. Lown B, Verrier L, Corbalan R. Psychologic stress and threshold for repetitive ventricular response. Science 1973; 182~834.
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of ventricular occlusion in the stress and beta-
Magnet unresponsive tachycardia
pacemaker
33. Skinner JE, Reed pathway prevents heart in pigs. Am
endless
JC. Blockade of frontal ventricular fibrillation J Physiol 1981;240:H156.
September 1988 Heart Journal
cortical brainstem of the ischemic
loop
Endless loop tachycardia is a well-known complication of DDD pacing and is almost invariably terminated by conversion to the asynchronous DO0 mode upon application of a magnet over the pulse generator. Occasionally magnet application is ineffectual because the ventriculoatrial (VA) synchrony of endless loop tachycardia Is converted directly or indirectly to an atrioventricular (AV) desynchronlzation arrhythmia, another form of VA synchrony. This occurs when a paced ventricular beat engenders an unsensed retrograde P wave and the continual delivery of an Ineffectual atrial stimulus during the atrial myocardial refractory period creates self-perpetuating VA synchrony. Upon magnet removal, AV desynchronization arrhythmia reverts immediately to endless loop tachycardia. In the absence of access to programmers, magnet unresponsive endless loop tachycardia can be easily and reliably terminated by chest wall stimulation through inhibition of the ventricular channel of the DDD pulse generator. (AM HEART J 1988;116:726.)
S. Serge Barold, MB, BS, FRACP, Michael Robert A. Heinle, MD. Rochester, N.Y.
D. Falkoff,
Endless loop (reentrant) tachycardia is a wellknown complication of dual chamber pacing with DDD (or VDD) pulse generators.‘e8 Despite the very sophisticated programmability of contemporary DDD pulse generators, endless loop tachycardia (ELT) will probably continue to be a potential problem because of inappropriate pacemaker programming or unpredictable variation of retrograde ventriculoatrial (VA) conduction occurring spontaneously or secondary to the administration of cardiac drugs. ‘pg-14The easiest way of terminating ELT is by application of the test magnet over the DDD pulse generator. Conversion to the DO0 mode disrupts VA synchrony and almost invariably termi-
nates ELT.1-7 Occasionally ELT cannot be terminated by application and removal of the test magnet. Magnet unresponsive endless loop tachycardia is From the Division of Cardiology, Hospital, and the Universitv of
Department Rochester
School
of Medicine, nf Mdicine
The Genesee and
non&t-
ry.
Received for publication March 1, 1988; accepted Apr. 11, 1988. Reprint requests: Dr. S. Serge Barold, The Genesee Hospital, 224 Alexander St., Rochester, NY 14607.
726
MD, Ling S. Ong, MD, and
often linked to the development of another form of VA synchrony or atrioventricular (AV) desynchronization arrhythmia. During AV desynchronization arrhythmia, a paced ventricular beat engenders an unsensed retrograde P wave and the continual delivery of an ineffectual atrial stimulus during the atria1 myocardial refractory period creates a self-perpetuating form of VA synchrony.15-17 In this report, we describe the characteristics of magnet unresponsive
ELT, its relationship to AV desynchronization arrhythmia, and describe its termination by chest wall stimulation, a simple technique that does not require access to a programmer. ILLUSTRATIVE
EXAMPLES
Case No. 1. Inability to terminate endless loop tachycardia by magnet application. Conversion to AV desynchronlzation arrhythmia and return of endless loop tachycardia upon withdrawal of the magnet. The
electrocardiogram (ECG) in Fig. 1 showsan ELT caused by a Medtronic (Medtronic, Inc., Minneapolis, Minn.) 7000 DDD pulse generator programmed to the following settings: lower rate interval = 750 msec (rate = 80 pulses per minute [ppm]), upper rate interval = 480 msec (rate = 125 ppm), AV interval = 250 msec,post-ventricu-