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Programmed ventricular stimulation in patients without spontaneous ventricular tachycardia
American Heart Journal Founded in 1925
MAY 1984 Volume 107, Number 5, Part 1
CLINICAL INVESTIGATIONS
Programmed ventricular stimulation in patients without spontaneous ventricular tachycardia Programmed ventricular stimulation was performed in 52 patients who had not had a documented or suspected episode of spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF). Programmed stimulation with up to three extrastimuIi was performed from the right ventricular (RV) apex in all patients and from the left ventricular (LV) apex in 14 patients. A maximum response of one to five intraventricular reentry beats was induced in 52% of patients. Nonsustained VT (six or more repetitive beats terminating spontaneously within 30 seconds) was never induced in the 16 patients without structural heart disease but was induced (usually with triple extrastimuli) in 45% of nine patients with mitral valve prolapse and in 37% of 27 patients with other types of heart disease. Sustained VT was never induced; however, sustained VF was induced in t w o patients. During programmed RV and LV stimulation with up to three extrastimuli (with 2 msec pulses, 5 mA in intensity), (1) a maximum response of one to five repetitive beats is a nonspecific finding of no predictive value; (2) nonsustained VT was not induced in patients without structural heart disease who had not had spontaneous VT; (3) nonsustained VT was frequently induced in patients with structural heart disease who had not previously been known to have had VT; (4) the induction of sustained VT appears to be a response specific to patients who have had spontaneous VT or VF; and (5) sustained VF can be induced infrequently in patients who have never had spontaneous VT or VF. (AM HEART J 107:875, 1984.)
Fred Morady, M.D., William Shapiro, M.D., Edward Shen, M.D., Ruey J. Sung, M.D., and Melvin M. Scheinman, M.D. San Francisco, Calif.
Programmed ventricular stimulation has been demonstrated to be useful both diagnostically and in the evaluation of drug therapy in patients with recurrent ventricular tachycardia (VT), out-of-hospital cardiac arrest, and syncope of unknown cause.I-~A basic premise of this technique is that V T is provocable rarely, if ever, in patients who have never had spontaneous episodes of VT. 7 In support of this premise, previous studies showed induction of V T in only 0.7 % to 2.6 % of patients without documented spontaneous VT. ~,8.9 However, the stimulation protocol employed in these studies consisted of right ventricular (RV) stimulation at twice diastolic threshold, usually with only single or double extrastimuli. Studies in patients who have had spontaneous V T or cardiac arrest indicate that left ventricufar (LV) stimulation or triple extrastimuli m a y at
From the Department of Medicine and the Cardiovascular Research Institute,University of California-San Francisco. Received for publication March 21, 1983; revision received June 24, 1983; accepted July 10, 1983. Reprint requests: Fred Morady, M.D., R o o m 573, Moffltt Hospital, University of California,San Francisco, C A 94143.
times be needed to induce VT. 3,1°,11In addition, some laboratories use pacing stimuli ranging from five times diastolic threshold to 20 mA. 12-14 As pointed out by Horowitz and Morganroth, 15 although the yield of programmed ventricular stimulation can be increased by using triple extrastimuli and/or high-stimulating current strength, their effects on specificity have not yet been adequately evaluated. Recent preliminary reports indicate that 28 % to 55 % of patients with no history of V T who undergo programmed ventricular stimulation with up to four extrastimuli m a y have inducible VT16-~8; in these studies, ventricular stimulation was performed at a current intensity of twice diastolic threshold. 16-18There have as yet been no reports on the specificity of stimulation protocols which use a current intensity greater than twice diastolicthreshold. Accordingly, we studied the effects of programmed R V and L V stimulation with up to three extrastimuli at an intensity level of 5 m A in patients who had never had a spontaneous episode of V T or ventricular fibrillation (VF). W e used a current intensity of 5 m A because of data generated in our laboratory indicating that the absolute ventricular 875
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Table I. Clinical features of 52 patients without spontane-
ous VT Age Male/female Underlying heart disease No structural disease Mitral valve prolapse Ischemic heart disease Valvular heart disease Hypertensive heart disease Hypertrophic cardiomyopathy Congestive cardiomyopathy
55 _+ 18 years* 30/22 16 9 14 5 3 3 2
*Mean _+standard deviation.
r e f r a c t o r y p e r i o d is u s u a l l y r e a c h e d a t or n e a r a c u r r e n t o f 5 m A ( M o r a d y et al., u n p u b l i s h e d observations). METHODS Patients studied. Fifty-two patients were studied who had no documented or suspected episodes of spontaneous VT or cardiac arrest. Before electrophysiologic testing, all patients had at least two 24-hour ambulatory ECG recordings that showed no VT. Thirty-six of the 52 patients underwent programmed ventricular stimulation in the course of an electrophysiologic study performed to evaluate supraventricular tachycardia, sick sinus syndrome, atrioventricular block, or carotid hypersensitivity syndrome. Multiple 24-hour ambulatory ECG recordings demonstrated that symptoms of syncope or presyncope in these patients were due to either a bradyarrhythmia or supraventricular tachycardia. An additional 11 patients had palpitations due to premature ventricular depolarizations; these patients had no history of cardiac arrest, sustained palpitations, syncope, or presyncope, and none had ever undergone direct-current countershock. Programmed ventricular stimulation was performed in these patients specifically to test for VT inducibility. Three patients who underwent electrophysiologic testing for the evaluation of syncope of undetermined cause were demonstrated to have nonarrhythmic syncope after the electrophysiologic study; these three patients experienced their typical symptoms of syncope while undergoing ECG monitoring but had no arrhythmia at the time of syncope. Two patients were referred for electrophysiologic testing because of a family history of sudden death in a sibling; multiple ECGs in these two patients showed a normal QT interval. The QT interval was also normal in all other patients. The clinical characteristics of the patients are summarized in Table I. Sixteen patients had no identifiable structural heart disease by physical examination, exercise treadmill testing, or two-dimensional echocardiography. Nine had isolated mitral valve prolapse. None of the 14 patients with ischemic heart disease had had a myocardial infarction within 6 months of the electrophysiologic study.
The five patients with a history of valvular heart disease had all undergone either mitral or aortic valve replacement 1 to 5 years earlier. Electrophysiologic testing protocol. After obtaining informed consent, electrophysiologic testing was performed in the fasting, nonsedated state. All antiarrhythmic agents were discontinued at least 2 days before the study. A quadripolar electrode catheter inserted percutaneously into a femoral vein was positioned against the RV apex; a second quadripolar catheter was positioned across the tricuspid valve for recording the His bundle electrogram. Systemic blood pressure was monitored with a short polyethylene catheter inserted into a femoral artery. In 14 patients who consented to undergo LV stimulation, a bipolar electrode catheter was inserted percutaneously into a femoral artery and positioned against the apex of the left ventricle. ECG leads V,, I, and III and intracardiac electrograms were recorded with a VR-12 Electronics for Medicine recorder (White Plains, N.Y.). Ventricular stimulation was performed with a programmable stimulator (Bloom, Inc., Narbeth, Pa.); 2 msec pulses were delivered at a constant current of 5 mA. The following stimulation protocol was performed from the RV apex in all 52 patients and from the LV apex in 14 patients. Short bursts (5 to 10 beats) of overdrive pacing were performed at cycle lengths of 600 to 275 msec. Ventricular drive was then instituted for five beats at cycle lengths of 500 and 400 msec and a single extrastimulus ($2) was inserted 450 or 350 msec respectively after the last driven complex (S,) and was moved progressively closer to S, by 10 msec decrements until ventricular refractoriness was reached. $2 was then positioned 30 msec outside the ventricular effective refractory period and a second extrastimulus ($3) was inserted 300 to 400 msec after $2 and was moved progressively closer to Sz until ventricular refractoriness was reached. $2 was then moved closer to S, until $3 again evoked a response. $3 was moved closer to $2 until it again reached ventricular refractoriness. This process was repeated until both $2 and $3 no longer evoked a response. $2 and $3 were then positioned 30 msec outside their respective refractory periods and a third extrastimulus ($4) was inserted 300 to 400 msec after S~ and was moved progressively closer to $3 until it no longer evoked a response. $2 and S,~ were moved simultaneously progressively closer to $1 and diastole was again scanned with $4 until all the extrastimuli failed to evoke a response. Repetitive beats were considered a positive response to ventricular stimulation only if they were of the type presumed to be due to intraventricular reentry, '9 and if they could be reproducibly provoked. Bundle branch reentry beats 2°,2, were not considered a positive response and were excluded from consideration. Nonsustained VT was defined as VT of at least six beats in duration, terminating spontaneously within 30 seconds. Nonsustained VT was considered a positive response only if it could be reproducibly provoked. Sustained VT was defined as VT lasting 30 seconds or requiring direct-
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Specificity of programmed ventricular stimulation
877
Table Ih Results of programmed RV apex stimulation in 52 patients Maximum number of repetitive beats
Stimulation technique
0
Overdrive pacing Single extrastimulus Double extrastimuli Triple extrastimuli
51 37 24 15
2-5 (No. of patients)
1
(98)* (71) (46) (29)
1 12 17 13
(2) (23) (33) (25)
6-20
Sustained VF
0
0
0
3 (6)
0
0
8 (15) 13 (25)
2 (4) 11 (21)
1 (2) 0
Abbreviation: VF = ventricular fibrillation. *Numbers in parentheses refer to the percentage of patients having a particular evoked response. T a b l e III.
Results of programmed LV stimulation in 14 patients Maximum number of repetitive beats
Stimulation technique
Overdrive pacing Single extrastimulus Double extrastimuli Triple extrastimuli
0
13 10 3 1
(93)* (71) (22) (7)
1
1 3 4 3
(7) (22) (28) (22)
2-5 (No. of patients) 0 1 (7) 6 (43) 4 (28)
6-20
21-50
Sustained VF
0 0 0 5 (36)
0 0 1 (7) 0
0 0 0 1 (7)
Abbreviations: VF = ventricular fibrillation. *Numbers in parentheses refer to the percentage of patients having a particular evoked response.
current cardioversion or overdrive pacing for termination. The stimulation protocol was discontinued if sustained VT or VF was provoked. Electropharmacologic testing was performed because of patient or physician concern in the five patients who had either inducible VF or symptomatic nonsustained VT. The drug testing protocol was similar to a protocol previously described2 Two additional patients with inducible nonsustained VT were treated with procainamide or encainide for ventricular premature depolarizations; the remainder were not treated with antiarrhythmic drugs. Follow-up. During the follow-up period, patients were seen periodically by one of the authors or the referring physician. A 24-hour ambulatory ECG recording was obtained at 3- to 4-month intervals. Statistics. Values are expressed as mean _+ 1 standard deviation (SD). Statistical comparisons between patients with and without inducible VT were perfolmed using Student's t test, the Fischer exact test, or the chi square test. RESULTS Response to programmed
ventricular stimulation.
The results of programmed stimulation from the RV apex and LV apex are summarized in Tables Ii and III. Overdrive pacing rarely resulted in repetitive beats. As the number of extrastimuli was increased during programmed ventricular stimulation, the
number of repetitive beats induced also increased. During stimulation from the RV apex, nonsustained VT was induced in 13 of 52 patients (25%) and sustained VF was induced in one patient. LV stimulation induced nonsustained VT in 6 of 14 patients (43%) and sustained VF in one (Fig. 1). Sustained VT was never induced. Pooling the results of RV and LV stimulation, nonsustained VT was induced on 18 occasions. The nonsustained VT was induced by double extrastimuli in 3 of 18 episodes (17 % ) and by triple extrastimuli in 15 of 18 (83%). In one patient sustained VF was induced by double RV extrastimuli and in another by triple LV extrastimuli. In both patients VF was terminated without complications by direct-current countershock. In no patient was there a complication related to the electrophysiologic study. Characteristics of induced VT. I n 11 of 18 episodes
of induced nonsustained VT the pattern of the VT was polymorphic, with a mean duration of 14 _+ 13 beats and a mean cycle length of 215 _+ 32 msec. In five episodes the VT morphology had a right bundle branch block pattern (mean duration 14 _+ 5 beats and mean cycle length of 222 _+ 36 msec), and in two episodes it had a left bundle branch block pattern (mean duration 8 _+ 2 beats and mean cycle length of 290 +_ 57 msec).
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Morady et al.
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1. Induction of VF by LV programmed stimulation with triple extrastimuli in a 39-year-old woman without structural heart disease whose identical twin died suddenly 3 months earlier. From top to bottom are ECG leads V], I, and III, an intracardiac recording from the high lateral right atrium (HRA), two recordings of the His bundle electrogram (HBE), and an arterial blood pressure recording on a scale of 200 mm Hg. Time lines represent 1-second intervals. During basic drive ($1-$1) at a cycle length of 400 msec, introduction of triple extrastimuli ($2, $3, $4) results in induction of sustained VF. The VF was terminated with direct-current countershock (not shown). Abbreviations: A = atrial depolarization; H = His bundle depolarization; V = ventricular depolarization.
Fig.
Table IV. Maximum response to programmed ventricular stimulation correlated with type of heart disease
Maximum number of repetitive beats Underlying heart disease
No. o[ patients
0
1-5
None Mitral valve prolapse Other (see Table l)
16 9 27
6 (38)* 2 (22) 1 (4)
9 (56) 3 (33) 15 (55)
Nonsustained VT~ (No. of patients)
Sustained VF
0 4 (45) 10 (37)
1 (6) 0 1 (4)
Abbreviations: VF = ventricularfibrillation; VT = ventriculartachycardia. *Numbers in parenthesesrefer to the percentageof patients who had a particular evokedresponse. tVentricular tachycardiaof six beats to 30 seconds in duration.
Results of p r o g r a m m e d ventricular stimulation correlated with underlying heart disease (Table IV). I n
p a t i e n t s with no s t r u c t u r a l h e a r t disease, m i t r a l valve prolapse, a n d other t y p e s of h e a r t disease, a m a x i m u m of b e t w e e n one a n d five b e a t s w a s induced in 56 %, 33 %, a n d 55 % of patients, respectively. A m o n g the 16 p a t i e n t s w i t h o u t s t r u c t u r a l h e a r t disease, n o n s u s t a i n e d V T was n e v e r induced. VF was induced in one p a t i e n t (6%), a 39-year-old w o m a n who h a d h a d no cardiovascular s y m p t o m s and h a d no identifiable s t r u c t u r a l h e a r t disease; she h a d an identical twin who h a d died s u d d e n l y 3 m o n t h s earlier. A m o n g the nine p a t i e n t s with m i t r a l
valve prolapse, n o n s u s t a i n e d V T was induced in four of nine p a t i e n t s (45%) a n d sustained V T in none. A m o n g the 27 p a t i e n t s with o t h e r t y p e s of s t r u c t u r a l h e a r t disease, n o n s u s t a i n e d V T was induced in 10 of 27 p a t i e n t s (37 % ). VF was induced in one p a t i e n t (4%) who h a d h y p e r t r o p h i c cardiom y o p a t h y a n d p a l p i t a t i o n s due to f r e q u e n t p r e m a ture ventricular depolarizations. Clinical correlates of VT inducibility.
In
comparing
p a t i e n t s with a n d w i t h o u t inducible V T or VF, t h e r e was no significant d i f f e r e n c e in m e a n age, s e x ratio, or the p r o p o r t i o n of p a t i e n t s with m i t r a l valve prolapse or o t h e r t y p e s of h e a r t disease (Table V). In
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addition, there was no significant difference in the proportion of patients with bundle branch block, congestive heart failure, previous myocardial infarction, ventricular aneurysm, ejection fraction _<0.50, or frequent ventricular premature depolarizations (>700 ventricular premature depolarizations over a 24-hour period of ambulatory monitoring). Follow-up c o u r s e . The 36 patients who did not have inducible VT or VF have had no episodes of symptomatic VT or cardiac arrest during a mean follow-up period of 17.8 + 9 months. In 25 of these patients a maximum of one to five beats had been induced by programmed ventricular stimulation. None were treated with antiarrhythmic drugs. Among the 16 patients who had inducible VT or VF, electropharmacologic drug testing was performed in the two patients in whom VF was induced and in three patients who had inducible symptomatic nonsustained VT, 17 to 50 beats in duration. These five patients have been treated chronically with amiodarone (n = 2), procainamide (n = 2), or nadolol (n = 1), and have had no episodes of symptomatic VT, cardiac arrest, or VT during ambulatory monitoring during a mean follow-up period of 17.1 _+ 6 months. The remaining 11 patients who bad inducible VT did not undergo electropharmacologic drug testing. Two of these patients were treated with procainamide or encainide for suppression of ventricular premature depolarizations; nine patients were not treated with antiarrhythmic drugs. None of the 11 has had an episode of symptomatic VT, cardiac arrest, or VT during ambulatory monitoring during a mean follow-up period of 16.2 _+ 7 months. DISCUSSION
Nonsustained VT. This study examined the cardiac response to an aggressive ventricular stimulation protocol performed in patients without a history of documented or suspected VT or cardiac arrest. Nonsustained VT (VT of 6 beats to 30 seconds in duration) was never induced in patients without structural heart disease. However, this response was induced in 45% and 37% of patients with mitral valve prolapse and other types of structural heart disease, respectively. Therefore in patients with underlying heart disease, the induction of nonsustained VT by programmed ventricular stimulation is not a finding which is specific to patients who have had spontaneous episodes of VT. No conclusions can be drawn regarding the predictive value of inducible nonsustained VT in the five patients without spontaneous VT who had frequent ventricular premature depolarizations,
Specificity
of p r o g r a m m e d ventricular s t i m u l a t i o n
879
Table V. Comparison of patients with and without induc-
ible VT and VF*
No. of patients Age (yr) Males/females Mitral valve prolapse Other heart disease Bundle branch block Congestive heart failure Prior myocardial infarction Ventricular aneurysm Ejection fraction --<0.50 F r e q u e n t VPDs$
No inducible V T or VF
Inducible V T or VF
36 55 _+ 19t 21/15 5 (14)* 16 (44) 5 (14) 4 (11) 5 (14) 1 (3) 6 (17) 8 (22)
16 56 _+ 17t 9/7 4 (25) 11 (69) 5 (31) 6 (37) 6 (37) 3 (19) 7 (44) 5 (31)
Abbreviations: VF = ventricular fibrillation; VPD = ventricular premature depolarization; VT = ventricular tachycardia. *There are no statistically significant differences between patients with or without inducible VT/VF. Numbers in parentheses are percentages. tMean _+ standard deviation. :~>700 VPDs in 24 hours.
because the antiarrhythmic drug with which these patients were treated may have suppressed the occurrence of spontaneous VT during the follow-up period. In the subgroup of patients with inducible nonsustained VT who did not have frequent ventricular premature depolarizations, none were treated with antiarrhythmic drugs and none had spontaneous VT during the follow-up period. This finding suggests that, at least in patients without frequent ventricular premature depolarizations, the induction of nonsustained VT is not predictive of the later occurrence of spontaneous VT. Of note is that triple extrastimuli were usually required to induce nonsustained VT. Vandepol et al. s and Livelli et al. 9 reported induction of nonsustained VT in only 0.7% and 2% of patients without documented VT, but their stimulation protocol included single and double extrastimuli delivered as 1 msec pulses at twice diastolic threshold. The high prevalence of inducible VT in our series may be explained in large part by our use of triple extrastimuli and/or a greater stimuli strength. Thus although programmed stimulation with triple extrastimuli may be more effective than single or double extrastimuli in provoking VT in patients who have had spontaneous VT, the use of triple extrastimuli may also more often result in the induction of a nonclinical arrhythmia. The nonsustained VT that was induced in the patients in our series was most often polymorphic and rapid, usually with a rate of at least 220 bpm. Of note is that Reddy and Sartini 22 reported induction of nonclinical polymorphic VT in 7 of 18 patients
880
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May, 1984 American Heart Journal
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(39 % ) with recurrent sustained VT. They suggested the possibility that patients with VT who have heart disease may have more than one potential site of reentry within the diseased myocardium, and that programmed ventricular stimulation may initiate reentry within circuits not utilized during spontaneous episodes of VT. Our results suggest that a similar phenomenon may occur in patients with heart disease who have not had spontaneous VT. S u s t a i n e d VT. Using single and double RV extrastimuli, Vandepol et al. s and Livelli et a12 reported that sustained VT was never induced in patients without documented VT. Our results confirm and extend these observations to the use of triple extrastimuli and LV stimulation. Although nonsustained VT was induced commonly, sustained VT was never induced in patients who did not have a history of spontaneous VT, despite use of an aggressive ventricular stimulation protocol. This observation suggests that induction of sustained VT is a finding that is limited to patients with spontaneous VT, even when the stimulation protocol includes triple extrastimuli delivered at a current intensity of 5 mA. VF. Although sustained VT was never induced, sustained VF was induced in 2 of 52 patients (4 % ) without documented or suspected VT or VF. In contrast, Spielman et al.23 reported that the induction of VF by programmed stimulation was a finding limited to patients who had had a spontaneous episode of VT or VF; with the use of double ventricular extrastimuli, VF was never induced in a group of 57 patients without documented VT or VF. In our series, VF was induced in one patient by double RV extrastimuli; however, in the second patient induction of VF required triple LV extrastimuli. Thus a more aggressive stimulation protocol may account for our finding of inducible VF in two patients who had not had spontaneous VT or VF. The clinical significance of inducible VF in persons who have never had VT or VF remains open to question. It may be that induction of VF by programmed stimulation is purely a laboratory artifact of no clinical significance. On the other hand, it is possible that induction of VF identifies patients at risk of having a malignant ventricular arrhythmia in the future. One patient in this series who had inducible VF had hypertrophic cardiomyopathy, a condition associated with an estimated incidence of 3% to 5% of sudden deaths per year. 2.27 Although the second patient had no identifiable structural heart disease, she did have a family history of sudden death in a previously healthy identical twin who had no structural heart disease at autopsy. Because of our concern about the risk of sudden
death in these two patients, both patients have been treated chronically with antiarrhythmic drug therapy guided by the results of electropharmacologic testing. However, whether or not induction of VF by programmed stimulation accurately identifies patients at risk of sudden death and whether or not the risk of sudden death can be lowererd with antiarrhythmic drug therapy remains to be determined. Repetitive complexes.
During programmed ven-
tricular stimulation with one to three extrastimuli, a response of one to five complexes was common. This finding occurred irrespective of the pacing site, the number of extrastimuli, or the presence or absence of underlying structural heart disease. This confirms the findings of Livelli et al., 9 who reported the induction of one or two ventricular complexes in 43% of patients without documented VT. In contrast, Farshidi et al. 19 reported induction of repetitive beats of the intraventricular reentry type in only 8.1% of patients who did not have heart disease and in only 9.1% of patients without spontaneous VT or VF. However, their stimulation protocol included single and double RV extrastimuli delivered as 1 msec pulses at twice diastolic threshold (_<3 mA). In the series by Farshidi et al.,19 the lower prevalence of repetitive beats may have been due to a less aggressive stimulation protocol and/or a lower stimulus strength. They concluded that intraventricular reentry beats may be a pathologic phenomenon and may identify patients prone to develop spontaneous VT or VF. However, in our series none of the patients in whom a maximum of one to five intraventricular reentry beats were induced has had a malignant ventricular arrhythmia during the follow-up period. Our results indicate that the induction of one to five repetitive beats may be a nonspecific response, not of predictive value in patients who have never had VT. Limitations. A limitation of this study is that our results may not be applicable to stimulation protocols which use a current intensity other than 5 mA. However, because there is not a standardized, universally accepted stimulation protocol, this limitation is unavoidable. Although many laboratories use a current intensity of twice diastolic threshold, other laboratories have found that the yield of programmed ventricular stimulation is increased by using a current intensity of five times diastolic threshold, 12 10 times diastolic threshold," 10 mA, 28 or 20 mA. ~3 It is therefore clinically relevant to determine the specificity of stimulation protocols performed over a wide range of current intensities. However, to avoid overly lengthy electrophysiologic
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studies, we chose to use a single c u r r e n t intensity of 5 mA, which is near the middle of the range of c u r r e n t intensities used in clinical practice. We routinely use a c u r r e n t intensity of 5 m A during electropharmacologic testing because we have f o u n d t h a t the absolute ventricular refractory period is usually reached at or near a c u r r e n t intensity of 5 m A ( M o r a d y et al., u n p u b l i s h e d observations). Of note is t h a t in recent preliminary reports, up to 62 % of patients with no history of V T h a d inducible V T or VF when undergoing p r o g r a m m e d ventricular stimulation at twice diastolic threshold. 1~-1s T h e r e fore, it is unlikely t h a t the high yield of inducible V T in the present s t u d y is a t t r i b u t a b l e solely to the use of a high stimulating current. C o n c l u s i o n s . On the basis of the results of our study, the following conclusions can be drawn regarding p r o g r a m m e d R V a n d L V stimulation with up to three extrastimuli (using 2 msec pulses at a c u r r e n t of 5 mA). (1) I n d u c t i o n of one to five intraventricular r e e n t r y complexes is a nonspecific finding t h a t is c o m m o n in patients who have never h a d s p o n t a n e o u s V T and is n o t predictive of the later occurrence of s p o n t a n e o u s V T in these patients. (2) In patients w i t h o u t structural h e a r t disease, n o n s u s t a i n e d V T (at least six repetitive beats) is n o t inducible in the absence of a history of s p o n t a n e o u s VT. (3) In patients w h o have mitral valve prolapse or other type of structural h e a r t disease, n o n s u s t a i n e d V T can be induced f r e q u e n t l y (usually with triple extrastimuli) even in the absence of a history of s p o n t a n e o u s VT. T h u s in patients with h e a r t disease who have d o c u m e n t e d V T or syncope of u n k n o w n cause, induction of n o n s u s t a i n e d V T c a n n o t be assumed to be of clinical value, especially if triple extrastimuli are required to induce the VT. (4) Sustained V T c a n n o t be induced in patients who have not had s p o n t a n e o u s VT, regardless of the presence or absence of structural h e a r t disease. I n d u c t i o n of sustained V T appears to be a finding t h a t is limited to patients with spontaneous VT, even when an aggressive stimulation protocol is used. (5) Sustained VF can be induced in a small percentage of patients who have never h a d s p o n t a n e o u s V T or cardiac arrest; the prognostic significance of inducible VF remains to be determined. REFERENCES
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Specificity of programmed ventricular stimulation
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19.
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selection of antiarrhythmic regimens. Circulation 58"986, 1978. Mason JW, Winkle RA: Accuracyof the ventricular tachycardia-induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl J Med 303:1073, 1980. Ruskin JN, DiMarco JP, Garan H: Out-of-hospital cardiac arrest. N Engl J Med 303:607, 1980. DiMarco JP, Garan H, Harthorne JW, Ruskin JN: Intracardiac electrophysiologic techniques in recurrent syncope of unknown cause. Ann Intern Med 95:542, 1981. Hess DS, Morady F, Scheinman MM: Electrophysiologic testing in the evaluation of patients with syncope of undetermined origin. Am J Cardiol 50:1309, 1982. Fisher JD: Ventricular tachycardia--practical and provocative electrophysiology. Circulation 58,1000, 1978. Vandepol CJ, Farshidi A, Spielman SR, Greenspac AM, Horowitz LN, Josephson ME: Incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 45:725, 1980. Livelli FD, Bigger JT, Reiffel JA, Gang ES, Patton JN, Noethling PM, Rolnitzky LM, Gliklich JI: Response to programmed ventricular stimulation: Sensitivity, specificity and relation to heart disease. Am J Cardiol 50:452, 1982. Robertson JF, Cain ME, Horowitz LN, Spielman SR, Greenspan AM, Waxman HL, Josephson ME: Anatomic and electrophysiologic correlates of ventricular tachycardia requiring left ventricular stimulation. Am J Cardiol 48:263, 1981. Morady F, Hess DS, Scheinman MM: Electrophysiologic drug testing in patients with malignant ventricular arrhythmias: Importance of stimulation at more than one ventricular site. Am J Cardiol 50:1055, 1982. DiMarco JP, Garan H, Ruskin JN: Quinidine for ventricular arrhythmias: Value of electrophysiologic testing. AM J Cardiol 51:90, 1983. Richards DA, Cody DV, Denniss AR, Russell PA, Young AA, Uther JB: Ventricular electrical instability: A predictor of death after myocardial infarction. Am J Cardiol 51:75, 1983. Bacaner MB, Benditt DG: Antiarrhythmic, antifibrillatory, and hemodynamic actions of bethanidine sulfate: An orally effective analog of bretylium for suppression of ventricular tachyarrhythmias. Am J Cardiol 50:728, 1982. Horowitz LN, Morganroth J: Can we prevent sudden death? Am J Cardiol 50:535, 1982. Brugada P, Heddle B, Wellens H: Results of a ventricular stimulation protocol using a maximum of four premature stimuli in patients without documented or suspected ventricular arrhythmias (abstr). Circulation 66(suppl II):II-79, 1982. Untereker WJ, Waxman HL, Waspe LE, Marchlinski FE, Buxton AE, Groh WC, Martin JL, Josephson ME: Programmed electrical stimulation in patients without clinical ventricular tachycardia (abstr). Circulation 66(suppl II):II147, 1982. Mann DE, Limacher MC, Luck JC, Magro SA, Griffin JC, Robertson NW, Wyndham CR: Induction of clinical ventricular tachycardia during electrophysiologic study: Value of third and fourth extrastimuli (abstr). Circulation 66(suppl II):IL145, 1982. Farshidi A, Michelson EL, Greenspan AM, Spielman SR, Horowitz LN, Josephson ME: Repetitive responses to ventricular extrastimuli: Incidence, mechanism, and significance. AM HEART J 100:59, 1980.
20. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogunkelu JB, Vargas G: Demonstration of reentry within the HisPurkinje system in man. Circulation 50:1150, 1974. 21. Akhtar M, Gilbert C, Wolf FG, Schmidt DH: Reentry within the His-Purkinje system. Elucidation of reentrant circuit using right bundle branch and His bundle recording. Circulation 58:295, 1978. 22. Reddy DP, Sartini JC: Nonclinical polymorphic ventricular
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Morady et al.
23.
24. 25. 26.
tachycardia induced by programmed cardiac stimulation: Incidence, mechanisms and clinical significance. Circulation 62:988, 1980. Spielman SR, Farshidi A, Horowitz LN, Josephson ME: Ventricular fibrillation during programmed ventricular stimulation: Incidence and clinical implications. Am J Cardiol 42:913, 1978. Hardarson T, de la Calzada CS, Curiel R, Goodwin JF: Prognosis and mortality of hypertrophic obstructive cardiomyopathy. Lancet 2:1462, 1973. Goodwin JF, Krikler DM: Arrhythmia as a cause of sudden death in hypertrophic cardiG~yopathy. Lancet 2:937, 1976. Maron BJ, Roberts WC, Edwards JE, McAllister HA Jr,
American Heart Journal
Foley DD, Epstein SE: Sudden death in patients with hypertrophic cardiomyopathy: Characterization of 26 patients with functional limitation. Am J Cardiol 41:803, 1978. 27. Maron BJ, Savage DD, Wolfson JK, Epstein SE: Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: A prospective study. Am J Cardiol 48:252, 1981. 28. Mercer AB, Simpson R J, Gettes LS, Foster JR: Strengthinterval testing to enhance ventricular tachycardia induction during clinical electrophysiologic study (abstr). Am J Cardiol 49:958, 1982.
Effects of acetyl-strophanthidin on left ventricular function and ventricular arrhythmias Digitalis drugs can suppress ventricular arrhythmias. It is uncertain whether this effect results from improved left ventricular (LV) function. We utilized radionuclide scanning techniques to evaluate changes in LV ejection fraction (EF) after an infusion of acetyl-strophanthidin in 43 patients with frequent ventricular premature beats (VPBs) (44 to 2 4 0 0 / h r ) . Acetyl-strophanthidin suppressed ventricular arrhythmia in 17 patients, but LVEF increased in only six of these patients (57% to 67%), while it was unaltered in 11 patients (28% to 30%). In 26 patients ventricular arrhythmia was not suppressed. Fifteen of these patients had an increase in LVEF (60% vs 71%), while this was unchanged in 11 patients (27% vs 29%). Thus no correlation was observed between the positive inotropic and antiarrhythmic action of acetyl-strophanthidin nor was there any correlation between the type of heart disease and the effect of acetyl-strophanthidin on ventricular arrhythmia and LVEF. We conclude that the suppression of VPBs by acetyl-strophanthidin is independent of the drug's effects on LV function. Evidence is reviewed suggesting that the antiarrhythmic effect of acetyl-strophanthidin on ventricular ectopic activity is due to its vagotonic action. (AM HEART J 107:882, 1984.)
Philip Podrid, M.D., Bernard Lown, M.D., Jason Zielonka, M.D., and B. Leonard Holman, M.D. Boston, Mass.
Techniques such as monitoring 1 and exercise testing 2 are exposing the presence of serious and potentially life-threatening ventricular arrhythmias in substantial numbers of patients with heart disease.
From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health; and the Division of Nuclear Medicine and Department of Medicine of the Brigham and Women's Hospital and Harvard Medical School. Supported by grants No. HL-24456 and HL-07776 from the National Heart, Lung and Blood Institute, National Institutes of Health, United States Public Health Service, Bethesda, Md. Received for publication March i4, 1983; revision received May 12, 1983; accepted May 23, 1983. Reprint requests: Philip J. Podrid, M.D., Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115.
882
Therapy depends on the use of antiarrhythmic drugs. However, agents currently available have frequent and disturbing adverse reactions. In addition, a number have relatively rapid dissipation, necessitating frequent dosing. In order to improve patient acceptance and compliance, an antiarrhythmic drug should have few side effects and have prolonged duration of action requiring only once daily administration. The digitalis drugs in clinical use for two centuries are well tolerated and have dose-related side effects. A long half-life of dissipation allows for once a day dosing. The glycosides are of known benefit in the treatment of atrial arrhythmias, but their role in controlling ventricular ectopic activity is less
MAY 1984 Volume 107, Number 5, Part 1
CLINICAL INVESTIGATIONS
Programmed ventricular stimulation in patients without spontaneous ventricular tachycardia Programmed ventricular stimulation was performed in 52 patients who had not had a documented or suspected episode of spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF). Programmed stimulation with up to three extrastimuIi was performed from the right ventricular (RV) apex in all patients and from the left ventricular (LV) apex in 14 patients. A maximum response of one to five intraventricular reentry beats was induced in 52% of patients. Nonsustained VT (six or more repetitive beats terminating spontaneously within 30 seconds) was never induced in the 16 patients without structural heart disease but was induced (usually with triple extrastimuli) in 45% of nine patients with mitral valve prolapse and in 37% of 27 patients with other types of heart disease. Sustained VT was never induced; however, sustained VF was induced in t w o patients. During programmed RV and LV stimulation with up to three extrastimuli (with 2 msec pulses, 5 mA in intensity), (1) a maximum response of one to five repetitive beats is a nonspecific finding of no predictive value; (2) nonsustained VT was not induced in patients without structural heart disease who had not had spontaneous VT; (3) nonsustained VT was frequently induced in patients with structural heart disease who had not previously been known to have had VT; (4) the induction of sustained VT appears to be a response specific to patients who have had spontaneous VT or VF; and (5) sustained VF can be induced infrequently in patients who have never had spontaneous VT or VF. (AM HEART J 107:875, 1984.)
Fred Morady, M.D., William Shapiro, M.D., Edward Shen, M.D., Ruey J. Sung, M.D., and Melvin M. Scheinman, M.D. San Francisco, Calif.
Programmed ventricular stimulation has been demonstrated to be useful both diagnostically and in the evaluation of drug therapy in patients with recurrent ventricular tachycardia (VT), out-of-hospital cardiac arrest, and syncope of unknown cause.I-~A basic premise of this technique is that V T is provocable rarely, if ever, in patients who have never had spontaneous episodes of VT. 7 In support of this premise, previous studies showed induction of V T in only 0.7 % to 2.6 % of patients without documented spontaneous VT. ~,8.9 However, the stimulation protocol employed in these studies consisted of right ventricular (RV) stimulation at twice diastolic threshold, usually with only single or double extrastimuli. Studies in patients who have had spontaneous V T or cardiac arrest indicate that left ventricufar (LV) stimulation or triple extrastimuli m a y at
From the Department of Medicine and the Cardiovascular Research Institute,University of California-San Francisco. Received for publication March 21, 1983; revision received June 24, 1983; accepted July 10, 1983. Reprint requests: Fred Morady, M.D., R o o m 573, Moffltt Hospital, University of California,San Francisco, C A 94143.
times be needed to induce VT. 3,1°,11In addition, some laboratories use pacing stimuli ranging from five times diastolic threshold to 20 mA. 12-14 As pointed out by Horowitz and Morganroth, 15 although the yield of programmed ventricular stimulation can be increased by using triple extrastimuli and/or high-stimulating current strength, their effects on specificity have not yet been adequately evaluated. Recent preliminary reports indicate that 28 % to 55 % of patients with no history of V T who undergo programmed ventricular stimulation with up to four extrastimuli m a y have inducible VT16-~8; in these studies, ventricular stimulation was performed at a current intensity of twice diastolic threshold. 16-18There have as yet been no reports on the specificity of stimulation protocols which use a current intensity greater than twice diastolicthreshold. Accordingly, we studied the effects of programmed R V and L V stimulation with up to three extrastimuli at an intensity level of 5 m A in patients who had never had a spontaneous episode of V T or ventricular fibrillation (VF). W e used a current intensity of 5 m A because of data generated in our laboratory indicating that the absolute ventricular 875
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Table I. Clinical features of 52 patients without spontane-
ous VT Age Male/female Underlying heart disease No structural disease Mitral valve prolapse Ischemic heart disease Valvular heart disease Hypertensive heart disease Hypertrophic cardiomyopathy Congestive cardiomyopathy
55 _+ 18 years* 30/22 16 9 14 5 3 3 2
*Mean _+standard deviation.
r e f r a c t o r y p e r i o d is u s u a l l y r e a c h e d a t or n e a r a c u r r e n t o f 5 m A ( M o r a d y et al., u n p u b l i s h e d observations). METHODS Patients studied. Fifty-two patients were studied who had no documented or suspected episodes of spontaneous VT or cardiac arrest. Before electrophysiologic testing, all patients had at least two 24-hour ambulatory ECG recordings that showed no VT. Thirty-six of the 52 patients underwent programmed ventricular stimulation in the course of an electrophysiologic study performed to evaluate supraventricular tachycardia, sick sinus syndrome, atrioventricular block, or carotid hypersensitivity syndrome. Multiple 24-hour ambulatory ECG recordings demonstrated that symptoms of syncope or presyncope in these patients were due to either a bradyarrhythmia or supraventricular tachycardia. An additional 11 patients had palpitations due to premature ventricular depolarizations; these patients had no history of cardiac arrest, sustained palpitations, syncope, or presyncope, and none had ever undergone direct-current countershock. Programmed ventricular stimulation was performed in these patients specifically to test for VT inducibility. Three patients who underwent electrophysiologic testing for the evaluation of syncope of undetermined cause were demonstrated to have nonarrhythmic syncope after the electrophysiologic study; these three patients experienced their typical symptoms of syncope while undergoing ECG monitoring but had no arrhythmia at the time of syncope. Two patients were referred for electrophysiologic testing because of a family history of sudden death in a sibling; multiple ECGs in these two patients showed a normal QT interval. The QT interval was also normal in all other patients. The clinical characteristics of the patients are summarized in Table I. Sixteen patients had no identifiable structural heart disease by physical examination, exercise treadmill testing, or two-dimensional echocardiography. Nine had isolated mitral valve prolapse. None of the 14 patients with ischemic heart disease had had a myocardial infarction within 6 months of the electrophysiologic study.
The five patients with a history of valvular heart disease had all undergone either mitral or aortic valve replacement 1 to 5 years earlier. Electrophysiologic testing protocol. After obtaining informed consent, electrophysiologic testing was performed in the fasting, nonsedated state. All antiarrhythmic agents were discontinued at least 2 days before the study. A quadripolar electrode catheter inserted percutaneously into a femoral vein was positioned against the RV apex; a second quadripolar catheter was positioned across the tricuspid valve for recording the His bundle electrogram. Systemic blood pressure was monitored with a short polyethylene catheter inserted into a femoral artery. In 14 patients who consented to undergo LV stimulation, a bipolar electrode catheter was inserted percutaneously into a femoral artery and positioned against the apex of the left ventricle. ECG leads V,, I, and III and intracardiac electrograms were recorded with a VR-12 Electronics for Medicine recorder (White Plains, N.Y.). Ventricular stimulation was performed with a programmable stimulator (Bloom, Inc., Narbeth, Pa.); 2 msec pulses were delivered at a constant current of 5 mA. The following stimulation protocol was performed from the RV apex in all 52 patients and from the LV apex in 14 patients. Short bursts (5 to 10 beats) of overdrive pacing were performed at cycle lengths of 600 to 275 msec. Ventricular drive was then instituted for five beats at cycle lengths of 500 and 400 msec and a single extrastimulus ($2) was inserted 450 or 350 msec respectively after the last driven complex (S,) and was moved progressively closer to S, by 10 msec decrements until ventricular refractoriness was reached. $2 was then positioned 30 msec outside the ventricular effective refractory period and a second extrastimulus ($3) was inserted 300 to 400 msec after $2 and was moved progressively closer to Sz until ventricular refractoriness was reached. $2 was then moved closer to S, until $3 again evoked a response. $3 was moved closer to $2 until it again reached ventricular refractoriness. This process was repeated until both $2 and $3 no longer evoked a response. $2 and $3 were then positioned 30 msec outside their respective refractory periods and a third extrastimulus ($4) was inserted 300 to 400 msec after S~ and was moved progressively closer to $3 until it no longer evoked a response. $2 and S,~ were moved simultaneously progressively closer to $1 and diastole was again scanned with $4 until all the extrastimuli failed to evoke a response. Repetitive beats were considered a positive response to ventricular stimulation only if they were of the type presumed to be due to intraventricular reentry, '9 and if they could be reproducibly provoked. Bundle branch reentry beats 2°,2, were not considered a positive response and were excluded from consideration. Nonsustained VT was defined as VT of at least six beats in duration, terminating spontaneously within 30 seconds. Nonsustained VT was considered a positive response only if it could be reproducibly provoked. Sustained VT was defined as VT lasting 30 seconds or requiring direct-
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Specificity of programmed ventricular stimulation
877
Table Ih Results of programmed RV apex stimulation in 52 patients Maximum number of repetitive beats
Stimulation technique
0
Overdrive pacing Single extrastimulus Double extrastimuli Triple extrastimuli
51 37 24 15
2-5 (No. of patients)
1
(98)* (71) (46) (29)
1 12 17 13
(2) (23) (33) (25)
6-20
Sustained VF
0
0
0
3 (6)
0
0
8 (15) 13 (25)
2 (4) 11 (21)
1 (2) 0
Abbreviation: VF = ventricular fibrillation. *Numbers in parentheses refer to the percentage of patients having a particular evoked response. T a b l e III.
Results of programmed LV stimulation in 14 patients Maximum number of repetitive beats
Stimulation technique
Overdrive pacing Single extrastimulus Double extrastimuli Triple extrastimuli
0
13 10 3 1
(93)* (71) (22) (7)
1
1 3 4 3
(7) (22) (28) (22)
2-5 (No. of patients) 0 1 (7) 6 (43) 4 (28)
6-20
21-50
Sustained VF
0 0 0 5 (36)
0 0 1 (7) 0
0 0 0 1 (7)
Abbreviations: VF = ventricular fibrillation. *Numbers in parentheses refer to the percentage of patients having a particular evoked response.
current cardioversion or overdrive pacing for termination. The stimulation protocol was discontinued if sustained VT or VF was provoked. Electropharmacologic testing was performed because of patient or physician concern in the five patients who had either inducible VF or symptomatic nonsustained VT. The drug testing protocol was similar to a protocol previously described2 Two additional patients with inducible nonsustained VT were treated with procainamide or encainide for ventricular premature depolarizations; the remainder were not treated with antiarrhythmic drugs. Follow-up. During the follow-up period, patients were seen periodically by one of the authors or the referring physician. A 24-hour ambulatory ECG recording was obtained at 3- to 4-month intervals. Statistics. Values are expressed as mean _+ 1 standard deviation (SD). Statistical comparisons between patients with and without inducible VT were perfolmed using Student's t test, the Fischer exact test, or the chi square test. RESULTS Response to programmed
ventricular stimulation.
The results of programmed stimulation from the RV apex and LV apex are summarized in Tables Ii and III. Overdrive pacing rarely resulted in repetitive beats. As the number of extrastimuli was increased during programmed ventricular stimulation, the
number of repetitive beats induced also increased. During stimulation from the RV apex, nonsustained VT was induced in 13 of 52 patients (25%) and sustained VF was induced in one patient. LV stimulation induced nonsustained VT in 6 of 14 patients (43%) and sustained VF in one (Fig. 1). Sustained VT was never induced. Pooling the results of RV and LV stimulation, nonsustained VT was induced on 18 occasions. The nonsustained VT was induced by double extrastimuli in 3 of 18 episodes (17 % ) and by triple extrastimuli in 15 of 18 (83%). In one patient sustained VF was induced by double RV extrastimuli and in another by triple LV extrastimuli. In both patients VF was terminated without complications by direct-current countershock. In no patient was there a complication related to the electrophysiologic study. Characteristics of induced VT. I n 11 of 18 episodes
of induced nonsustained VT the pattern of the VT was polymorphic, with a mean duration of 14 _+ 13 beats and a mean cycle length of 215 _+ 32 msec. In five episodes the VT morphology had a right bundle branch block pattern (mean duration 14 _+ 5 beats and mean cycle length of 222 _+ 36 msec), and in two episodes it had a left bundle branch block pattern (mean duration 8 _+ 2 beats and mean cycle length of 290 +_ 57 msec).
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Morady et al.
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1. Induction of VF by LV programmed stimulation with triple extrastimuli in a 39-year-old woman without structural heart disease whose identical twin died suddenly 3 months earlier. From top to bottom are ECG leads V], I, and III, an intracardiac recording from the high lateral right atrium (HRA), two recordings of the His bundle electrogram (HBE), and an arterial blood pressure recording on a scale of 200 mm Hg. Time lines represent 1-second intervals. During basic drive ($1-$1) at a cycle length of 400 msec, introduction of triple extrastimuli ($2, $3, $4) results in induction of sustained VF. The VF was terminated with direct-current countershock (not shown). Abbreviations: A = atrial depolarization; H = His bundle depolarization; V = ventricular depolarization.
Fig.
Table IV. Maximum response to programmed ventricular stimulation correlated with type of heart disease
Maximum number of repetitive beats Underlying heart disease
No. o[ patients
0
1-5
None Mitral valve prolapse Other (see Table l)
16 9 27
6 (38)* 2 (22) 1 (4)
9 (56) 3 (33) 15 (55)
Nonsustained VT~ (No. of patients)
Sustained VF
0 4 (45) 10 (37)
1 (6) 0 1 (4)
Abbreviations: VF = ventricularfibrillation; VT = ventriculartachycardia. *Numbers in parenthesesrefer to the percentageof patients who had a particular evokedresponse. tVentricular tachycardiaof six beats to 30 seconds in duration.
Results of p r o g r a m m e d ventricular stimulation correlated with underlying heart disease (Table IV). I n
p a t i e n t s with no s t r u c t u r a l h e a r t disease, m i t r a l valve prolapse, a n d other t y p e s of h e a r t disease, a m a x i m u m of b e t w e e n one a n d five b e a t s w a s induced in 56 %, 33 %, a n d 55 % of patients, respectively. A m o n g the 16 p a t i e n t s w i t h o u t s t r u c t u r a l h e a r t disease, n o n s u s t a i n e d V T was n e v e r induced. VF was induced in one p a t i e n t (6%), a 39-year-old w o m a n who h a d h a d no cardiovascular s y m p t o m s and h a d no identifiable s t r u c t u r a l h e a r t disease; she h a d an identical twin who h a d died s u d d e n l y 3 m o n t h s earlier. A m o n g the nine p a t i e n t s with m i t r a l
valve prolapse, n o n s u s t a i n e d V T was induced in four of nine p a t i e n t s (45%) a n d sustained V T in none. A m o n g the 27 p a t i e n t s with o t h e r t y p e s of s t r u c t u r a l h e a r t disease, n o n s u s t a i n e d V T was induced in 10 of 27 p a t i e n t s (37 % ). VF was induced in one p a t i e n t (4%) who h a d h y p e r t r o p h i c cardiom y o p a t h y a n d p a l p i t a t i o n s due to f r e q u e n t p r e m a ture ventricular depolarizations. Clinical correlates of VT inducibility.
In
comparing
p a t i e n t s with a n d w i t h o u t inducible V T or VF, t h e r e was no significant d i f f e r e n c e in m e a n age, s e x ratio, or the p r o p o r t i o n of p a t i e n t s with m i t r a l valve prolapse or o t h e r t y p e s of h e a r t disease (Table V). In
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addition, there was no significant difference in the proportion of patients with bundle branch block, congestive heart failure, previous myocardial infarction, ventricular aneurysm, ejection fraction _<0.50, or frequent ventricular premature depolarizations (>700 ventricular premature depolarizations over a 24-hour period of ambulatory monitoring). Follow-up c o u r s e . The 36 patients who did not have inducible VT or VF have had no episodes of symptomatic VT or cardiac arrest during a mean follow-up period of 17.8 + 9 months. In 25 of these patients a maximum of one to five beats had been induced by programmed ventricular stimulation. None were treated with antiarrhythmic drugs. Among the 16 patients who had inducible VT or VF, electropharmacologic drug testing was performed in the two patients in whom VF was induced and in three patients who had inducible symptomatic nonsustained VT, 17 to 50 beats in duration. These five patients have been treated chronically with amiodarone (n = 2), procainamide (n = 2), or nadolol (n = 1), and have had no episodes of symptomatic VT, cardiac arrest, or VT during ambulatory monitoring during a mean follow-up period of 17.1 _+ 6 months. The remaining 11 patients who bad inducible VT did not undergo electropharmacologic drug testing. Two of these patients were treated with procainamide or encainide for suppression of ventricular premature depolarizations; nine patients were not treated with antiarrhythmic drugs. None of the 11 has had an episode of symptomatic VT, cardiac arrest, or VT during ambulatory monitoring during a mean follow-up period of 16.2 _+ 7 months. DISCUSSION
Nonsustained VT. This study examined the cardiac response to an aggressive ventricular stimulation protocol performed in patients without a history of documented or suspected VT or cardiac arrest. Nonsustained VT (VT of 6 beats to 30 seconds in duration) was never induced in patients without structural heart disease. However, this response was induced in 45% and 37% of patients with mitral valve prolapse and other types of structural heart disease, respectively. Therefore in patients with underlying heart disease, the induction of nonsustained VT by programmed ventricular stimulation is not a finding which is specific to patients who have had spontaneous episodes of VT. No conclusions can be drawn regarding the predictive value of inducible nonsustained VT in the five patients without spontaneous VT who had frequent ventricular premature depolarizations,
Specificity
of p r o g r a m m e d ventricular s t i m u l a t i o n
879
Table V. Comparison of patients with and without induc-
ible VT and VF*
No. of patients Age (yr) Males/females Mitral valve prolapse Other heart disease Bundle branch block Congestive heart failure Prior myocardial infarction Ventricular aneurysm Ejection fraction --<0.50 F r e q u e n t VPDs$
No inducible V T or VF
Inducible V T or VF
36 55 _+ 19t 21/15 5 (14)* 16 (44) 5 (14) 4 (11) 5 (14) 1 (3) 6 (17) 8 (22)
16 56 _+ 17t 9/7 4 (25) 11 (69) 5 (31) 6 (37) 6 (37) 3 (19) 7 (44) 5 (31)
Abbreviations: VF = ventricular fibrillation; VPD = ventricular premature depolarization; VT = ventricular tachycardia. *There are no statistically significant differences between patients with or without inducible VT/VF. Numbers in parentheses are percentages. tMean _+ standard deviation. :~>700 VPDs in 24 hours.
because the antiarrhythmic drug with which these patients were treated may have suppressed the occurrence of spontaneous VT during the follow-up period. In the subgroup of patients with inducible nonsustained VT who did not have frequent ventricular premature depolarizations, none were treated with antiarrhythmic drugs and none had spontaneous VT during the follow-up period. This finding suggests that, at least in patients without frequent ventricular premature depolarizations, the induction of nonsustained VT is not predictive of the later occurrence of spontaneous VT. Of note is that triple extrastimuli were usually required to induce nonsustained VT. Vandepol et al. s and Livelli et al. 9 reported induction of nonsustained VT in only 0.7% and 2% of patients without documented VT, but their stimulation protocol included single and double extrastimuli delivered as 1 msec pulses at twice diastolic threshold. The high prevalence of inducible VT in our series may be explained in large part by our use of triple extrastimuli and/or a greater stimuli strength. Thus although programmed stimulation with triple extrastimuli may be more effective than single or double extrastimuli in provoking VT in patients who have had spontaneous VT, the use of triple extrastimuli may also more often result in the induction of a nonclinical arrhythmia. The nonsustained VT that was induced in the patients in our series was most often polymorphic and rapid, usually with a rate of at least 220 bpm. Of note is that Reddy and Sartini 22 reported induction of nonclinical polymorphic VT in 7 of 18 patients
880
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May, 1984 American Heart Journal
--~oraayet al.
(39 % ) with recurrent sustained VT. They suggested the possibility that patients with VT who have heart disease may have more than one potential site of reentry within the diseased myocardium, and that programmed ventricular stimulation may initiate reentry within circuits not utilized during spontaneous episodes of VT. Our results suggest that a similar phenomenon may occur in patients with heart disease who have not had spontaneous VT. S u s t a i n e d VT. Using single and double RV extrastimuli, Vandepol et al. s and Livelli et a12 reported that sustained VT was never induced in patients without documented VT. Our results confirm and extend these observations to the use of triple extrastimuli and LV stimulation. Although nonsustained VT was induced commonly, sustained VT was never induced in patients who did not have a history of spontaneous VT, despite use of an aggressive ventricular stimulation protocol. This observation suggests that induction of sustained VT is a finding that is limited to patients with spontaneous VT, even when the stimulation protocol includes triple extrastimuli delivered at a current intensity of 5 mA. VF. Although sustained VT was never induced, sustained VF was induced in 2 of 52 patients (4 % ) without documented or suspected VT or VF. In contrast, Spielman et al.23 reported that the induction of VF by programmed stimulation was a finding limited to patients who had had a spontaneous episode of VT or VF; with the use of double ventricular extrastimuli, VF was never induced in a group of 57 patients without documented VT or VF. In our series, VF was induced in one patient by double RV extrastimuli; however, in the second patient induction of VF required triple LV extrastimuli. Thus a more aggressive stimulation protocol may account for our finding of inducible VF in two patients who had not had spontaneous VT or VF. The clinical significance of inducible VF in persons who have never had VT or VF remains open to question. It may be that induction of VF by programmed stimulation is purely a laboratory artifact of no clinical significance. On the other hand, it is possible that induction of VF identifies patients at risk of having a malignant ventricular arrhythmia in the future. One patient in this series who had inducible VF had hypertrophic cardiomyopathy, a condition associated with an estimated incidence of 3% to 5% of sudden deaths per year. 2.27 Although the second patient had no identifiable structural heart disease, she did have a family history of sudden death in a previously healthy identical twin who had no structural heart disease at autopsy. Because of our concern about the risk of sudden
death in these two patients, both patients have been treated chronically with antiarrhythmic drug therapy guided by the results of electropharmacologic testing. However, whether or not induction of VF by programmed stimulation accurately identifies patients at risk of sudden death and whether or not the risk of sudden death can be lowererd with antiarrhythmic drug therapy remains to be determined. Repetitive complexes.
During programmed ven-
tricular stimulation with one to three extrastimuli, a response of one to five complexes was common. This finding occurred irrespective of the pacing site, the number of extrastimuli, or the presence or absence of underlying structural heart disease. This confirms the findings of Livelli et al., 9 who reported the induction of one or two ventricular complexes in 43% of patients without documented VT. In contrast, Farshidi et al. 19 reported induction of repetitive beats of the intraventricular reentry type in only 8.1% of patients who did not have heart disease and in only 9.1% of patients without spontaneous VT or VF. However, their stimulation protocol included single and double RV extrastimuli delivered as 1 msec pulses at twice diastolic threshold (_<3 mA). In the series by Farshidi et al.,19 the lower prevalence of repetitive beats may have been due to a less aggressive stimulation protocol and/or a lower stimulus strength. They concluded that intraventricular reentry beats may be a pathologic phenomenon and may identify patients prone to develop spontaneous VT or VF. However, in our series none of the patients in whom a maximum of one to five intraventricular reentry beats were induced has had a malignant ventricular arrhythmia during the follow-up period. Our results indicate that the induction of one to five repetitive beats may be a nonspecific response, not of predictive value in patients who have never had VT. Limitations. A limitation of this study is that our results may not be applicable to stimulation protocols which use a current intensity other than 5 mA. However, because there is not a standardized, universally accepted stimulation protocol, this limitation is unavoidable. Although many laboratories use a current intensity of twice diastolic threshold, other laboratories have found that the yield of programmed ventricular stimulation is increased by using a current intensity of five times diastolic threshold, 12 10 times diastolic threshold," 10 mA, 28 or 20 mA. ~3 It is therefore clinically relevant to determine the specificity of stimulation protocols performed over a wide range of current intensities. However, to avoid overly lengthy electrophysiologic
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studies, we chose to use a single c u r r e n t intensity of 5 mA, which is near the middle of the range of c u r r e n t intensities used in clinical practice. We routinely use a c u r r e n t intensity of 5 m A during electropharmacologic testing because we have f o u n d t h a t the absolute ventricular refractory period is usually reached at or near a c u r r e n t intensity of 5 m A ( M o r a d y et al., u n p u b l i s h e d observations). Of note is t h a t in recent preliminary reports, up to 62 % of patients with no history of V T h a d inducible V T or VF when undergoing p r o g r a m m e d ventricular stimulation at twice diastolic threshold. 1~-1s T h e r e fore, it is unlikely t h a t the high yield of inducible V T in the present s t u d y is a t t r i b u t a b l e solely to the use of a high stimulating current. C o n c l u s i o n s . On the basis of the results of our study, the following conclusions can be drawn regarding p r o g r a m m e d R V a n d L V stimulation with up to three extrastimuli (using 2 msec pulses at a c u r r e n t of 5 mA). (1) I n d u c t i o n of one to five intraventricular r e e n t r y complexes is a nonspecific finding t h a t is c o m m o n in patients who have never h a d s p o n t a n e o u s V T and is n o t predictive of the later occurrence of s p o n t a n e o u s V T in these patients. (2) In patients w i t h o u t structural h e a r t disease, n o n s u s t a i n e d V T (at least six repetitive beats) is n o t inducible in the absence of a history of s p o n t a n e o u s VT. (3) In patients w h o have mitral valve prolapse or other type of structural h e a r t disease, n o n s u s t a i n e d V T can be induced f r e q u e n t l y (usually with triple extrastimuli) even in the absence of a history of s p o n t a n e o u s VT. T h u s in patients with h e a r t disease who have d o c u m e n t e d V T or syncope of u n k n o w n cause, induction of n o n s u s t a i n e d V T c a n n o t be assumed to be of clinical value, especially if triple extrastimuli are required to induce the VT. (4) Sustained V T c a n n o t be induced in patients who have not had s p o n t a n e o u s VT, regardless of the presence or absence of structural h e a r t disease. I n d u c t i o n of sustained V T appears to be a finding t h a t is limited to patients with spontaneous VT, even when an aggressive stimulation protocol is used. (5) Sustained VF can be induced in a small percentage of patients who have never h a d s p o n t a n e o u s V T or cardiac arrest; the prognostic significance of inducible VF remains to be determined. REFERENCES
1. Fisher JD, Cohen HL, Mehra R, Altschuler H, Escher DJW, Furman S: Cardiac pacing and pacemakers. II. Serial electrophysiologic-pharmacologic testing for control of recurrent tachyarrhythmias. AM HEARTJ 93:658, 1977. 2. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in
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selection of antiarrhythmic regimens. Circulation 58"986, 1978. Mason JW, Winkle RA: Accuracyof the ventricular tachycardia-induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl J Med 303:1073, 1980. Ruskin JN, DiMarco JP, Garan H: Out-of-hospital cardiac arrest. N Engl J Med 303:607, 1980. DiMarco JP, Garan H, Harthorne JW, Ruskin JN: Intracardiac electrophysiologic techniques in recurrent syncope of unknown cause. Ann Intern Med 95:542, 1981. Hess DS, Morady F, Scheinman MM: Electrophysiologic testing in the evaluation of patients with syncope of undetermined origin. Am J Cardiol 50:1309, 1982. Fisher JD: Ventricular tachycardia--practical and provocative electrophysiology. Circulation 58,1000, 1978. Vandepol CJ, Farshidi A, Spielman SR, Greenspac AM, Horowitz LN, Josephson ME: Incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 45:725, 1980. Livelli FD, Bigger JT, Reiffel JA, Gang ES, Patton JN, Noethling PM, Rolnitzky LM, Gliklich JI: Response to programmed ventricular stimulation: Sensitivity, specificity and relation to heart disease. Am J Cardiol 50:452, 1982. Robertson JF, Cain ME, Horowitz LN, Spielman SR, Greenspan AM, Waxman HL, Josephson ME: Anatomic and electrophysiologic correlates of ventricular tachycardia requiring left ventricular stimulation. Am J Cardiol 48:263, 1981. Morady F, Hess DS, Scheinman MM: Electrophysiologic drug testing in patients with malignant ventricular arrhythmias: Importance of stimulation at more than one ventricular site. Am J Cardiol 50:1055, 1982. DiMarco JP, Garan H, Ruskin JN: Quinidine for ventricular arrhythmias: Value of electrophysiologic testing. AM J Cardiol 51:90, 1983. Richards DA, Cody DV, Denniss AR, Russell PA, Young AA, Uther JB: Ventricular electrical instability: A predictor of death after myocardial infarction. Am J Cardiol 51:75, 1983. Bacaner MB, Benditt DG: Antiarrhythmic, antifibrillatory, and hemodynamic actions of bethanidine sulfate: An orally effective analog of bretylium for suppression of ventricular tachyarrhythmias. Am J Cardiol 50:728, 1982. Horowitz LN, Morganroth J: Can we prevent sudden death? Am J Cardiol 50:535, 1982. Brugada P, Heddle B, Wellens H: Results of a ventricular stimulation protocol using a maximum of four premature stimuli in patients without documented or suspected ventricular arrhythmias (abstr). Circulation 66(suppl II):II-79, 1982. Untereker WJ, Waxman HL, Waspe LE, Marchlinski FE, Buxton AE, Groh WC, Martin JL, Josephson ME: Programmed electrical stimulation in patients without clinical ventricular tachycardia (abstr). Circulation 66(suppl II):II147, 1982. Mann DE, Limacher MC, Luck JC, Magro SA, Griffin JC, Robertson NW, Wyndham CR: Induction of clinical ventricular tachycardia during electrophysiologic study: Value of third and fourth extrastimuli (abstr). Circulation 66(suppl II):IL145, 1982. Farshidi A, Michelson EL, Greenspan AM, Spielman SR, Horowitz LN, Josephson ME: Repetitive responses to ventricular extrastimuli: Incidence, mechanism, and significance. AM HEART J 100:59, 1980.
20. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogunkelu JB, Vargas G: Demonstration of reentry within the HisPurkinje system in man. Circulation 50:1150, 1974. 21. Akhtar M, Gilbert C, Wolf FG, Schmidt DH: Reentry within the His-Purkinje system. Elucidation of reentrant circuit using right bundle branch and His bundle recording. Circulation 58:295, 1978. 22. Reddy DP, Sartini JC: Nonclinical polymorphic ventricular
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tachycardia induced by programmed cardiac stimulation: Incidence, mechanisms and clinical significance. Circulation 62:988, 1980. Spielman SR, Farshidi A, Horowitz LN, Josephson ME: Ventricular fibrillation during programmed ventricular stimulation: Incidence and clinical implications. Am J Cardiol 42:913, 1978. Hardarson T, de la Calzada CS, Curiel R, Goodwin JF: Prognosis and mortality of hypertrophic obstructive cardiomyopathy. Lancet 2:1462, 1973. Goodwin JF, Krikler DM: Arrhythmia as a cause of sudden death in hypertrophic cardiG~yopathy. Lancet 2:937, 1976. Maron BJ, Roberts WC, Edwards JE, McAllister HA Jr,
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Effects of acetyl-strophanthidin on left ventricular function and ventricular arrhythmias Digitalis drugs can suppress ventricular arrhythmias. It is uncertain whether this effect results from improved left ventricular (LV) function. We utilized radionuclide scanning techniques to evaluate changes in LV ejection fraction (EF) after an infusion of acetyl-strophanthidin in 43 patients with frequent ventricular premature beats (VPBs) (44 to 2 4 0 0 / h r ) . Acetyl-strophanthidin suppressed ventricular arrhythmia in 17 patients, but LVEF increased in only six of these patients (57% to 67%), while it was unaltered in 11 patients (28% to 30%). In 26 patients ventricular arrhythmia was not suppressed. Fifteen of these patients had an increase in LVEF (60% vs 71%), while this was unchanged in 11 patients (27% vs 29%). Thus no correlation was observed between the positive inotropic and antiarrhythmic action of acetyl-strophanthidin nor was there any correlation between the type of heart disease and the effect of acetyl-strophanthidin on ventricular arrhythmia and LVEF. We conclude that the suppression of VPBs by acetyl-strophanthidin is independent of the drug's effects on LV function. Evidence is reviewed suggesting that the antiarrhythmic effect of acetyl-strophanthidin on ventricular ectopic activity is due to its vagotonic action. (AM HEART J 107:882, 1984.)
Philip Podrid, M.D., Bernard Lown, M.D., Jason Zielonka, M.D., and B. Leonard Holman, M.D. Boston, Mass.
Techniques such as monitoring 1 and exercise testing 2 are exposing the presence of serious and potentially life-threatening ventricular arrhythmias in substantial numbers of patients with heart disease.
From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health; and the Division of Nuclear Medicine and Department of Medicine of the Brigham and Women's Hospital and Harvard Medical School. Supported by grants No. HL-24456 and HL-07776 from the National Heart, Lung and Blood Institute, National Institutes of Health, United States Public Health Service, Bethesda, Md. Received for publication March i4, 1983; revision received May 12, 1983; accepted May 23, 1983. Reprint requests: Philip J. Podrid, M.D., Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115.
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Therapy depends on the use of antiarrhythmic drugs. However, agents currently available have frequent and disturbing adverse reactions. In addition, a number have relatively rapid dissipation, necessitating frequent dosing. In order to improve patient acceptance and compliance, an antiarrhythmic drug should have few side effects and have prolonged duration of action requiring only once daily administration. The digitalis drugs in clinical use for two centuries are well tolerated and have dose-related side effects. A long half-life of dissipation allows for once a day dosing. The glycosides are of known benefit in the treatment of atrial arrhythmias, but their role in controlling ventricular ectopic activity is less