- Email: [email protected]
Role of programmed stimulation in assessing vulnerability to ventricular arrhythmias
Programmed electrical stimulation can now be safely performed in humans for the evaluation of therapy for recurrent ventricular tachyarrhythmia. Such studies may also eventually be found useful in predtcting the risk of developing life-threatening ventricular tachyarrhythmtas. The repetitive ventricular response phenomenon has been evaluated. Although an association between the lntraventricular reentrant phenomenon and sustelned ventricular tacbyafrhytbmlas has been found, its predictive value in a popUl8tlOn at risk is not suffkient for use in cllnlcal declslon making. On the other hand, the inltlatfon of sustained ventricular tachycardia or fibrillation appears closely related to Its actual spontaneous clinical occurrence. Serial electrophyslologk studies can be performed and are effective In prospectively evafuabng the response to antlarrhythmlc drugs. The efficacy of therapy based on the rerutts of programmed stimulation appears to be good. (AM HEART J 103:604, 1982.)
Leonard N. Horowitz, M.D., Scott R. Spielman, Mark E. Josephson, M.D. Philadelphia, Pa.
M.D., Allan M. Greenspan,
Sudden cardiac death accounts for approximately 500,000 deaths yearly in the United States, the majority of which are nearly instantaneous and without warning. Since 1940, many attempts have been made to assess vulnerability to ventricular arrhythmias by using electrical stimulation of the heart. Recently, however, because of increased survival from sudden cardiac arrest, a group of patients now exists that can be studied to develop techniques for predicting vulnerability to ventricular arrhythmias and to test newer methods of therapy. The use of programmed electrical stimulation in the human heart to assess vulnerability to arrhythmias and the effect of antiarrhythmic therapy are discussed here. The protocols discussed have been approved by The Committee for Human Studies of The University of and all patients gave written Pennsylvania, informed consent. From the Clinical Electrophysiology Laboratory, Cardiovascular Department of Medicine, University of Pennsylvania School and Hospital of the University of Pennsylvania.
Section, of Medicine,
Supported in part by grants from the American Heart Association, Southeastern Pennsylvania Chapter, Philadelphia, and from the National Heart, Lung and Blood Institute. Dr. Horowitz is supported by the Young Investigator Award from the National Heart, Lung and Blood Institute (R23 HL21292). Dr. Greenspan is supported by the Special Investigatorship Award from the American Heart Association, Southeastern Pennsylvania Affiliate. Dr. Josephson is supported by the Research Career Development Award from the National Heart, Lung and Blood Institute (K04 HLOO361). Reprint requests: Leonard N. Horowitz, M.D., Director, Clinical Electrophysiology Laboratory, Likoff Cardiovascular Institute, mann Medical College & Hospital, 230 N. Broad St., Philadelphia, 19102.
604
Cardiac HabnePA
M.D., and
TECHNtQUE
Programmed electrical stimulation is performed with electrode catheters that have been inserted percutaneously and advanced into the heart under fluoroecopic guidance. Our stimulation protocoP2 includes rapid ventricular pacing at cycle lengths of 600 to 250 msec for 15 to 60 seconds and premature ventricular stimulation, includii single and double extrastimuli, at two or more paced cycle lengths. In selected patients, triple extrastimuli are also used. Stimulation is performed at the right ventricular apex in all patients and at other right and left ventricular sites in selected patients. Stimuli are 1 msec in duration and twice diastolic threshold in intensity. We wish to emphasize that the data discussed here are derived from studies in which the stimulation protocol was rigorously applied. All observations are reproducible and not chance occurrences. Reproducibility is particularly important when electrophysiologic studies are used for choosing antiarrhythmic therapye2 A standardized protocol is important because experience with it in a large group of patients allows signi&ance to be assigned to an individual observation in a specific patient. RESPONSES
TO PFt00iRAMf6ED
STWLATION
Programmed ventricular stimulation can produce repetitive ventricular responses, ventricular tachycardia (VT), and ventricular fibrillation. Repetitive ventricular response(s), are defined as single or multiple extra ventricular complexes that are reproducibly induced by one or more ventricular 0002-8703/82/040604
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1. Repetitive ventricular responses.In both panels,ECG leads2 and V, are shownwith a His bundle electrogram (HBE) and time lines (TL) (10 msec). Upper panel: During ventricular pacing (5’3, a premature stimulus (SJ was introduced, followed by the V, responseand an extra response(VA due to BBR. Note the similarity of the BBR responseto the paced complexesand the preceding His bundle potential (23). Bottom panel: A premature stimulus (S,, was introduced and followed by the V, response and an extra response(VJ, which, in this example, was due to IVR. Note that the IVR responseis dissimilar in QRS morphology from the paced complexesand is not preceded by a His potential (No HI. Fig.
extrastimuli.3s4 There are two types of repetitive ventricular responses: bundle branch reentry (BBR) and intraventricular reentry (IVR) (Fig. 1). BBR is
recognized by the appearance of an extra ventricular depolarization, which is dependent on the creation of a critical degree of retrograde His-Purkinje conduction delay in response to a premature stimulus. The QRS morphology of this type of repetitive response typically has a configuration similar to that of the paced complex and is preceded by a His bundle potential with an HV interval equal to or greater than that of a normally conducted antegrade complex. IVR responses are extra complexes that are independent of retrograde His-Purkinje delay and that take place either in the absence of His potentials or with a His potential occurring before the repetitive response with an HV interval less than that observed during sinus rhythm in that particular patient. Other ventricular responses due to AV nodal reentrant echoes are not considered repetitive ventricular responses. The second class of responses to programmed ventricular stimulation includes ventricular tachycardia (VT) and ventricular fibrillation (VF). Several groups have studied the predictive value of the repetitive ventricular response in selecting
patients at risk for ventricular arrhythmias.‘-7 The BBR response is considered by most investigators to be a normal physiologic occurrence. It is observed in 50% or more of patients, with or without heart disease. IVR, on the other hand, is seen in less than 10% of normal patients and is considered a pathologic response. We have, therefore, analyzed the repetitive response by grouping patients by the presence or absence of IVR during programmed stimulation. The group with no IVR may have either no repetitive ventricular response or BBR only. We have correlated the clinical occurrence of ventricular tachyarrhythmias with the results of programmed ventricular stimulation in 424 consecutive patients undergoing elsctrophysiologic study for a variety of clinical indications.4 It should be emphasized in this study that we used both single and double premature stimuli delivered during ventricular pacing. The results are shown in Table I. Seventy-eight patients with IVR during programmed electrical stimulation had clinically documented VT or VF, and 253 patients who had no IVR were clinically free of ventricular tachyarrhythmias. This relationship was statistically significant. When the clinical usefulness of the test is assessed by analyzing the sensitivity, however, the IVR response was only 65 %
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1. Relationship of the results of programmed ventricular stimulation and the clinical occurrence of VT/ VF Table
Ii. Relationship of laboratory inducibility of sustained VT to clinical occurrence of arrhythmia Table
Electrophysiologj laboratory stud.v
Programmed ventricular stimulation IVR Clinical VT/VF No clinical VT/VF Sensitivity Specificity
78 52 = 78 = 6576 ii9 = 253 = 83% 305
1982
Heart Journal
VT
No VT
48 3
9 109
No IVR 41 253
Study population included patients in whom ventricular stimulation was performed at the right ventricular apex using single and double extrastimuli. IVR, intraventricular reentry.
sensitive in this population in identifying those patients who have ventricular tachyarrhythmias clinically. Its specificity is somewhat higher. Thus, although it appears that IVR is a pathologic phenomenon related to ventricular arrhythmias, it would not be a useful predictive marker in large population studies. The other type of response to programmed stimulation is the initiation of a ventricular tachyarrhythmia, i.e., VT or VF. The use of programmed stimulation to determine vulnerability to arrhythmias and the efficacy of antiarrhythmic drugs is baaed on the assumptions that an arrhythmia can be initiated only in susceptible patients and that the arrhythmia produced by programmed stimulation is identical to the clinical arrhythmia. The first assumption is supported by the results of programmed ventricular stimulation in 527 patients undergoing electrophysiologic study.8 Fifty-seven patients had spontaneously occurring sustained VT, 29 had nonsustained VT clinically, and 441 had no VT. Among the patients with sustained VT, the arrhythmia was inducible in the laboratory in 95 % . Left ventricular stimulation was necessary to induce VT in six patients. Even if left ventricular stimulation were not included, inducibility of VT in patients with sustained VT clinically would be 84 % (Table II). VT was induced in only three patients in whom it had not occurred clinically, and in those three, the induced VT was nonsustained. In patients with nonsustained VT clinically, the rate of inducibility was 62%. Thus ventricular arrhythmias are rarely induced by programmed ventricular stimulation in patients without clinical ventricular tachyarrhythmiss, and conversely, in tbose patienta witi sustained VT clinically, the arrhythmias are very frequently inducible in the electrophysiology laboratory.
Clinical VT No clinical VT Sensitivity
Specificity Predictive value of a positive test
= 84% = 97% = 94 “;,
Predictivevalue
= 926 of a negative test Overall accuracy = 93%
Study included a group of patients who underwent electrophysiologic study for a variety of clinical indications. In all patients, single and double premature stimuli were delivered to the right ventricular apex. Right ventricular outflow tract and left ventricular pacing were discounted for this analysis because not all patients underwent stimulation at these latter sites.
The second assumption-that the arrhythmia initiated by programmed electrical stimulation is identical to the clinical arrhythmia and repruduces its effects-is also supported by our data. We were able to compare the QRS morphologies and cycle len@hs of clinical and induced VT in 43 patienthi. Eightyseven percent of the induced tachycardia morphologies were documented to occur spontaneously. The difference in cycle lengths between clinical and induced VT was less than 10 msec in 50% of- the episodes and ranged from 10 to 80 msec in the remaining episodes of tachycardia. SERIAL ELECTROPHYSNXQOIC EVALUATE MUG EFFICACY
STUWS
TO
Programmed ventricular stimulation can reproduce clinical sustained VT in most patients susceptible to it, and this observation can be u&d to devise antiarrhytbmic therapy. Our protocol for selecting antiarrhythmic therapy by electrophysiologic testing is as follows. Control programmed ventricular stimulation is performed to demonstrate reproducible initiation of ventricular tachyarrhythmia. Drugs are administered intravenously when possible, although certain agents must be given orally. Programmed stimulation is then repeated. Plasma concentrations are measured at the time of the study. After acute testing has been completed, the best regimen is selected for long-term therapy. After 48 to 72 hours of this regimen, programmed sti-mnulation is done again to confirm the effect of the regimen. An exam&e of such a serial eleetrophysi&gic study performed for selecting an antiarrhythmic drug for VT is shown in Fig. 2. In evaluating serial electrophysiologic studies to
Volume Number
103 4, part 2
Assessment
III. Relationship of laboratory electrophysiologic testing results with clinical outcome in selecting antiarrhythmic regimensfor recurrent sustainedVT
Table
Laboratory
electrophysiologic
Success (no VT with drug)
of
ventricular
uukzerability
607
CONThtX
testing
Failure (VT induced with drug)
4 Clinical success 61 Clinical failure 4 42 Predictive value of successful test = 93% Predictive value of unsuccessful test = 90% Overall accuracy = 92% In this study, antiarrhythmic regimens used for chronic outpatient therapy were classified as successful if the oral regimen prevented initiation of VT by programmed stimulation and as unsuccessful (failure) if it did not prevent initiation of sustained VT. Clinical success was defined as prevention of palpitations, syncopa, documented sustained VT, and sudden death; failure was the occurrence of any of these. This analysis included patients receiving only standard, commonly available antiarrhythmic agents; experimental agents were specifically excluded. Clinical failure of these regimens was evaluated by retrospective as well as prospective follow-up.
select antiarrhythmic therapy, several potential measures of drua efficacy are available. We have found that the only reliable end point is prevention of initiation of VT. Changes in the width of the tachycardia zone, ease of inducibility of the tachycardia, and rate of the induced tachycardia are unreliable in predicting long-term efficacy. In addition to identifying effective antiarrhythmic drugs, the necessary concentration of the specific drug can testbe determined by the acute electrophysiologic ing. Antiarrhythmic drug concentrations can be increased in a stepwise fashion with electrophysiologic testing at each drug level until the concentration that prevents induction of the tachycardia is found. The plasma concentrations produced by
acute administration of antiarrhythmic drugs can be used to devise oral regimens2ss The results of our previous studies have shown that the levels achieved during acute testing accurately predict successful
chronic levels. The average plasma concentrations of antiarrhythmic drugs, particularly procainamide, that are required to prevent initiation of VT are higher than have been previously considered acceptable.2vgs lo
We have analyzed the clinical
results of antiar-
D/sOPYUAME
8.4 mg/L.
L&t/N/D/NE
48 mg/L.
QUSWXNE
q7 mg/L
600mg
q6h
Fig. 2. Serial drug study for recurrent sustainedVT. In
eachpanel, ECG lead V, is shownwith a right ventricular apical electrogram. Ten-millisecond time lines (T) are shown at the bottom. The numbers at the right are the cycle lengths of the induced VT. During the control study, programmed stimulation reproducibly induced sustained VT with a cycle length of 260 msec. Lidocaine at a concentration of 5.1 mg/L did not prevent induction of VT. Phenytoin at a concentration of 17.8 mg/L alsofailed to prevent initiation of VT. Neither lidocaine nor phenytoin significantly changedthe cycle length of the induced VT. Procainamide at a concentration of 14.8 mg/L prevented the initiation of sustained VT. However, note a single extra response,which was identical in morphology to the VT that occurred. Disopyramide at a level of 8.4 mg/L did not prevent initiation of sustainedVT, although the drug prolonged the cycle length to 310 msec.Intravenous quinidine that produced a blood level of 4.8 mg/L prevented initiation of VT. Oral quinidine (600mg every 6 hours) administered for 72 hours reproduced this same effect.
rhythmic regimens for recurrent sustained VT that
were devised evaluated in 111 patients.
by electrophysiologic
testing
This analysis was restricted
to
patients treated with currently available nonexperimental drugs. Average follow-up in this group of patients was 18 months (9 to 54 months) (Table III). Sixty-one patients in whom a regimen was evaluated during electrophysiologic studies that was judged to be successful (prevention of the initiation of VT)
had a clinical success. Clinical success was defined as no sustained or symptomatic tachyarrhythmias during chronic treatment with the testing drug. In four patients, these regimens, which were predicted to prevent VT, failed to do so. Forty-two patients in whom the laboratory studies predicted failure indeed had clinical failure (recurrence of VT) while taking the tested regimen, either prior to study or
April,
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et al.
following discharge on the evaluated regimen which was predicted to fail. Only four patients who were predicted to have recurrences of VT actually had a successful outcome. The predictive value of the electrophysiologic study for selecting antiarrhythmic regimens for sustained VT is quite good. The predictive value of a laboratory success is 93%) that of a laboratory failure is 90%, and the overall accuracy of the test is 92 % . If we select for evaluation only those patients in this group who had suffered a cardiac arrest, the results are similar. Thirty patients in this group suffered out-of-hospital cardiac arrest, and among them, the predictive value of either a successful or an unsuccessful test was 87 % , with an overall accuracy for the test of 87%. These values are not significantly different from those recently reported by others.sr”-13 Experience with electrophysiologic drug testing for recurrent sustained VT is extensive, and many groups are in substantial agreement regarding its utility. On the other hand, data on the use of programmed stimulation for selecting treatment of other recurrent ventricular tachyarrhythmias or in patients who are at high risk of suffering sudden cardiac death are rudimentary. Serial electrophysiologic studies can be performed in patients with recurrent VF, although these studies are significantly more difficult because the arrhythmia cannot be terminated by programmed electrical stimulation and cardioversion is frequently necessary. Spontaneous conversion to normal sinus rhythm occasionally occurs.14,15 The results of provocative electrophysiologic study in this group of patients appears promising, but only a small number of such patients have been studied.gr 14+15Furthermore, provocative electrophysiologic testing in patients potentially at risk of sudden death (e.g., those with frequent multiform premature ventricular depolarizations or survivors of recent myocardial infarction) has been largely unstudied. Initiation of sustained tachyarrhythmia in this group of patients, who have never had a clinically observed sustained episode of VT or VF, may be predictive of subsequent clinical events, but this possibility requires prospective evaluation. CONCLUSIONS
An association exists between the pathologic phenomenon of IVR and sustained ventricular tachyarrhythmias. However, its value in predicting the occurrence of VT or VF in a homogeneous population at risk is controversial. On the other hand, the induction of sustained VT with programmed ven-
American
Heart
t982
Journal
tricular stimulation in patients suspected clinically of having ventricular tachyarrhythmias correlates closely with the spontaneous occurrence of the arrhythmia, and the prediction of therapy based on the results of programmed stimulation appears to be highly accurate for that group. We wish to thank Ms. Helaine Corr for secretarial assistance in preparation of the manuscript, Dr. David McCarthy for assistance in statistical evaluation and editorial review, and Dr. John A. Kastor, Chief of the Cardiovascular Section, for continued enthuasiastic support. REFERENCES
1. Josephson ME, Horowitz LN, Farshidi A, Kastor JA: Recurrent sustained ventricular tachycardia. I. Mechanisms. Circulation 57:431, 1978. 2. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM Recurrent sustained ventricular tachycardia. III. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 58:986, 1978. 3. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogrenkelu JB, Vargas G: Demonstration of reentry within the HisPurkinje system in man. Circulation 49:1150, 1974. 4. Farshidi A, Michelson EL, Greenspan AM, Spielman SR, Horowitz LN, Josephson ME: Repetitive responses to ventricular extrastimuli: Incidence, mechanism and significance. AM HEART J 199:59, 1980. 5. Greene HL, Reid PR, Schaeffer AH: The repetitive ventricular response in man: A predictor of sudden death. N Engl J Med 299:729, 1978. 6. Troup PJ, Pederson DN, Zipes DP: Effects of premature ventricular stimulation in patients with ventricular tachycardia. Circulation 58(suppl II):154, 1978. (Abst.1 7. Mason JW: Repetitive beating after single ventricular extrastimuli: Incidence and prognostic significance in patients with recurrent ventricular tachycardia. Am J Cardiol45407, 1980. (abst.1 8. VandePol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME: The incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 45:725, 1980. 9. Horowitz LN, Josephson ME, and Kastor JA: Intracardiac electrophysiologic studies aa a method for the optimization of drug therapy in chronic ventricular arrhythmia. Progr Cardiovasc Dis 23:81, 1930. 10. Greenspan AM, Horowitz LN, Spielman SR, Josephson ME: Large dose procainamide therapy for ventricular tachyarrhythmia. Am J Cardiol 46:453, 1980. 11. Mason JW, Winkle RA: Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circuiation 583971, 1978. 12. Mason JW, Winkle R: Arrhythmic induction in patients with recurrent ventricular tachycardia: New findings. Circulation 69(suppl 11):24, 1979. 13. Ruskin JN, DiMarco JP, Garan H: Out-of-hospital cardiac arrest: Electrophysiologic observations and selection of longterm antiarrhythmic therapy. N Engl J Med 303:607, 1980. 14. Spielman SR, Farshidi A, Horowitz LN, Josephson ME: Ventricular fibrillation during programmed ventricular stimulation: Incidence and clinical implications. Am J Cardiol 42:918, 1978. 15. Josephson ME, Horowitz LN, Spielman SR, Greenspan AM: Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardiol 46:948, 1980.
Volume Number
103 4, pari
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DISCUSSION Dr. Wellens: I think I would agreewith you about the predictive value of serial drug testing, except that with certain drugs, asyou know, there is no correlation between the effects during programmed stimulation and the clinical course of a particular patient. When you talk about predictive value, you have to take into account the type of drug you are studying. A typical example is amiodarone.If you give amiodarone to patients with sustained VT in whom you can induce an arrhythmia during the stimulation study and then you study them again after 4 weeks,it becomeseasier to initiate VT in nearly all of them. In some patients, it even becomespossible to initiate a tachycardia with one rather than two premature beats. Dr. Horowitz: I completely agree. The data I showed were generated from drugs that are available for routine use in this country. No patients taking amiodaronewere included in this study. We do, however, have about 40 patients taking amiodarone and can induce VT in more than half of them, yet many, if not most, of them have a successful outcome. We have seen some failures with amiodarone, as you know, but there appears to be no correlation between the laboratory results and the clinical results with that drug. We have not seenthat samelack of correlation with other experimental antiarrhythmic drugs. At least in our experience, amiodaroneappearsto be the only drug where that is clearly the case. Dr. Wellens: Concerningyour protocol, do you consider IVR only when you can bring it out during ventricular pacing by a single ventricular premature beat? Dr. Horowitz: No. I think some of the difference between our studiesand those of other laboratories is that our particular protocol considers IVR inducible by any method of programmed stimulation, which includes one and two premature stimuli during sinus rhythm and a variety of paced cycle lengths and at multiple sites. We specifically do not limit ourselves to single premature beats either in sinusrhythm or at one paced cycle length. If we did, the incidence of IVR would be lower. I do not think that would improve its sensitivity. If anything, it might improve its specificity. Dr. Zipes: We have data to support the amiodarone experience that Dr. Wellens indicated (Heger et al: Circulation 62(suppl III):321, 1980). In addition, we have studied the importance of repetitive ventricular responses (RVRs), both prospectively and retrospectively in patients who have VT (Naccarelli et al: In press). We found that if the ventricle is paced for the basic beatsand is prematurely stimulated, the frequency of both nonbundle and bundle branch reentry is increased significantly compared with premature ventricular stimulation during atrial pacing. Furthermore, although sensitivity is gained with one pacing mode, specificity is gainedwith the other, but neither has a really significant predictive accuracy prospectively. Many problemsremain regarding reproducibility of the RVRs. Also, if more sitesare stimulated and at more cycle lengths, the prevalence of RVRs may increase.
Assessment
of
ventricular
vulnerability
609
On another point, the usefulnessof inducing VT to distinguish a patient who may develop it clinically is really basedon the fact that VT is generally not induced in other patients undergoing electrophysiologic study. However, the real control group-patients with comparable coronary disease who do not have VT-has not been studied. Dr. Horowitz: Well, actually, I would go one step farther. The only way to know that a test is, in fact, useful prospectively is to do a prospective study. To answeryour question, in the 500 or sopatients that we have studied, a little over half have had organic heart diseaseof all types. In our laboratory, that means 80% coronary disease.I can’t give you an exact number, but my guessis that we have done programmed stimulation in somewhere between 150 and 200 patients with coronary disease, although they have not all beenverified by an angiogram. VT is not inducible in that population. I agree, that is all retrospective, but a prospective study is difficult to do. That is why there are not many data of this sort. However, all our information to date indicates that induction of sustained tachyarrhythmia in the laboratory correlates with its clinical occurrence. Dr. Sobel: Because(1) VT is not inducible in someof these patients, whatever the number is; (2) patients who undergo these long and arduous studies are experiencing changes in their metabolic, respiratory, and hormonal status; and (3) people with ischemicheart diseaseconstitute an ever changing substrate of factors influencing. ventricular function and electrophysiologic stability, how large are the errors that we should anticipate on either a priori or a posteriori grounds with observations made at one point in time under one set of conditions with respect to the longitudinal issue? Dr. Horowitz: That is clearly a consideration. It turns out that many patients with sustained VT, whether it causescardiac arrest or not, if they survive, have the same arrhythmia for many years. Certainly, a new infarction or some other insult to ventricular function can change things, and there is no doubt that coronary diseaseis a changing disease.But our observation is that radical changesin arrhythmias do not happen very frequently. I know of only a couple of patients studied over several years in whom there was a distinct change in the clinical course, with respect to VT, because of a subsequent myocardial infarction. Dr. Sobel: You do not mean the primary fibrillators when you say that, nor the postmyocardial infarction population? Dr. Horowitz: That’s right. Dr. Zipes: The patient’s responseto premature stimulation may change. For example, if you investigate some patients at 1 week and others at 4 weeksafter a myocardial infarction, the anatomic substrate may be different at 1 and 4 weeks, and so may the response to a single premature stimulus. Dr. Horowitz: That’s right. If you considerpatients who were referred becausethey had recurrent VT, most of
April,
Horowitz
et al.
American
them are beyond 2 months of infarction; presumably moat of the healing has taken place and the electrophysiologic findings are stable. We have studied patients for 6 months and some for several years, and VT is just as inducible years later as during the initial study. Coupling intervals and refractory periods are different, but if VT was induced with programmed stimulation on the first study, it was also induced in the second study, and if it wasn’t inducible the first time, it usually is not inducible the next time. Dr. Conti: In your laboratory or in other laboratories, what are the complications of the procedure in those who fibrillate? Stroke, myocardial infarction, or death? Dr. Horowitz: I am aware of only two deaths that have occurred during serial studies for the evaluation of therapy for VT in all laboratories worldwide; both patients had VT. That doesnot mean, of course,that there have been no other deaths. In our laboratory, the complications of venous catheterization are about the same as those reported from large catheterization series;i.e., about 5% of the patients have local complications. Arterial catheter-
Heart
1992
Journal
ization used to be done by arteriotomy, but we use arteriotomy now only if we can’t get in percutaneously. We have had two significant complications with percutaneous left ventricular catheterization; both patients required cardioversion, and when they moved, their arteries were torn, but later were repaired. We have had no other serious arterial complications. One patient had a transient neurologic event, presumably due to a plaque that was knocked off, but the deficit cleared within 30 minutes. There have been no myocardial infarctions. We have performed approximately 200 left ventricular catheterizations, and I would say that the complications are comparableto those of angiographic catheterization. I am aware of a few deaths worldwide, and I cannot even guess the number of patients who have been studied. We evaluate about 200 patients a year and probably do 750 studies a year. The complications are low, but there is a risk, and patients are made aware of that. I believe that the risk-to-benefit ratio is still on the side of doing the studies in the population at risk of VT or VF.
of
The purpose of these studies is to ilfustrate that the time of drug admin#Wation in expertmental animals subjected to coronary artery occlusion Is an impor@&t infiuetrca on the myocardfal distribution of the drug as well as its electrophysiologic and arrhythmogenlc effacts. Also, because several drugs have active metabolites, some stud&as qust be done after oral administration. Finally, electrophysiologic testing to determine drug effkacy may give misleading results with some drugs. (AM HEART J 103:610, 1982.)
Douglas P. Zipes, M.D., E. N. Prystowsky, Indianapolis, Ind.
M.D., and J. J. Heger, M.D.
Several factors that may influence the results obtained and conclusions drawn from testing the effects of antiarrhythmic agents clinically and in animals are discussed here.
From the K.rannert Indiana University tion Hospital. Supported HL-07182, Institute, Association, Reprint Medicine,
610
Institute of Cardiology, the Department School of Medicine, and from the Veterans
of Medicine, Administra-
in part by the Herman C. Krannert Fund; by grants HL-06308, and HL-18795 from the National Heart, Lung and Blood National Institutes of Health; and by the American Heart Indiana Affiliate, Inc. requests: Douglas I?. Zipes, M.D., Indiana University 1100 West Michigan St., Indianapolis, IN 46202.
School
of
APRINDINE
An early question of ours concerned the influence of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. Accordingly, we examined the effecta of administrating aprindine to five groups of open-cheat dogs.’ Group 1 (35 dogs) received aprindine immediately before one-stage left ant&or descending coronary artery (LAl% occlusion; group 2 (34 dogs) received wine 5 minutes after LAD occlusion; group 3 (16 dogs) was administered aprindine without LAQ oc&sion; group 4 (10 dog%) underw&nt, LAD occlu&on but received no aprindine; and group 5 (10 dogs) was administered aprindine 24 hours after LAD occlu0002-8703/82/040610
+ 06$00.60/O
‘?’ 1982
The
C. V.
MosbyCo.
Leonard N. Horowitz, M.D., Scott R. Spielman, Mark E. Josephson, M.D. Philadelphia, Pa.
M.D., Allan M. Greenspan,
Sudden cardiac death accounts for approximately 500,000 deaths yearly in the United States, the majority of which are nearly instantaneous and without warning. Since 1940, many attempts have been made to assess vulnerability to ventricular arrhythmias by using electrical stimulation of the heart. Recently, however, because of increased survival from sudden cardiac arrest, a group of patients now exists that can be studied to develop techniques for predicting vulnerability to ventricular arrhythmias and to test newer methods of therapy. The use of programmed electrical stimulation in the human heart to assess vulnerability to arrhythmias and the effect of antiarrhythmic therapy are discussed here. The protocols discussed have been approved by The Committee for Human Studies of The University of and all patients gave written Pennsylvania, informed consent. From the Clinical Electrophysiology Laboratory, Cardiovascular Department of Medicine, University of Pennsylvania School and Hospital of the University of Pennsylvania.
Section, of Medicine,
Supported in part by grants from the American Heart Association, Southeastern Pennsylvania Chapter, Philadelphia, and from the National Heart, Lung and Blood Institute. Dr. Horowitz is supported by the Young Investigator Award from the National Heart, Lung and Blood Institute (R23 HL21292). Dr. Greenspan is supported by the Special Investigatorship Award from the American Heart Association, Southeastern Pennsylvania Affiliate. Dr. Josephson is supported by the Research Career Development Award from the National Heart, Lung and Blood Institute (K04 HLOO361). Reprint requests: Leonard N. Horowitz, M.D., Director, Clinical Electrophysiology Laboratory, Likoff Cardiovascular Institute, mann Medical College & Hospital, 230 N. Broad St., Philadelphia, 19102.
604
Cardiac HabnePA
M.D., and
TECHNtQUE
Programmed electrical stimulation is performed with electrode catheters that have been inserted percutaneously and advanced into the heart under fluoroecopic guidance. Our stimulation protocoP2 includes rapid ventricular pacing at cycle lengths of 600 to 250 msec for 15 to 60 seconds and premature ventricular stimulation, includii single and double extrastimuli, at two or more paced cycle lengths. In selected patients, triple extrastimuli are also used. Stimulation is performed at the right ventricular apex in all patients and at other right and left ventricular sites in selected patients. Stimuli are 1 msec in duration and twice diastolic threshold in intensity. We wish to emphasize that the data discussed here are derived from studies in which the stimulation protocol was rigorously applied. All observations are reproducible and not chance occurrences. Reproducibility is particularly important when electrophysiologic studies are used for choosing antiarrhythmic therapye2 A standardized protocol is important because experience with it in a large group of patients allows signi&ance to be assigned to an individual observation in a specific patient. RESPONSES
TO PFt00iRAMf6ED
STWLATION
Programmed ventricular stimulation can produce repetitive ventricular responses, ventricular tachycardia (VT), and ventricular fibrillation. Repetitive ventricular response(s), are defined as single or multiple extra ventricular complexes that are reproducibly induced by one or more ventricular 0002-8703/82/040604
+ 07$00.70/O
‘3 1982
The
C. V. Mosby
Co.
Volume
103
Number
4, part 2
Assessment
of ventricular
vulnerability
605
BLbDLE BRANCH RE-ENTRY
INlRAVENTRlCULAR RE-ENTRYw~ A-
1. Repetitive ventricular responses.In both panels,ECG leads2 and V, are shownwith a His bundle electrogram (HBE) and time lines (TL) (10 msec). Upper panel: During ventricular pacing (5’3, a premature stimulus (SJ was introduced, followed by the V, responseand an extra response(VA due to BBR. Note the similarity of the BBR responseto the paced complexesand the preceding His bundle potential (23). Bottom panel: A premature stimulus (S,, was introduced and followed by the V, response and an extra response(VJ, which, in this example, was due to IVR. Note that the IVR responseis dissimilar in QRS morphology from the paced complexesand is not preceded by a His potential (No HI. Fig.
extrastimuli.3s4 There are two types of repetitive ventricular responses: bundle branch reentry (BBR) and intraventricular reentry (IVR) (Fig. 1). BBR is
recognized by the appearance of an extra ventricular depolarization, which is dependent on the creation of a critical degree of retrograde His-Purkinje conduction delay in response to a premature stimulus. The QRS morphology of this type of repetitive response typically has a configuration similar to that of the paced complex and is preceded by a His bundle potential with an HV interval equal to or greater than that of a normally conducted antegrade complex. IVR responses are extra complexes that are independent of retrograde His-Purkinje delay and that take place either in the absence of His potentials or with a His potential occurring before the repetitive response with an HV interval less than that observed during sinus rhythm in that particular patient. Other ventricular responses due to AV nodal reentrant echoes are not considered repetitive ventricular responses. The second class of responses to programmed ventricular stimulation includes ventricular tachycardia (VT) and ventricular fibrillation (VF). Several groups have studied the predictive value of the repetitive ventricular response in selecting
patients at risk for ventricular arrhythmias.‘-7 The BBR response is considered by most investigators to be a normal physiologic occurrence. It is observed in 50% or more of patients, with or without heart disease. IVR, on the other hand, is seen in less than 10% of normal patients and is considered a pathologic response. We have, therefore, analyzed the repetitive response by grouping patients by the presence or absence of IVR during programmed stimulation. The group with no IVR may have either no repetitive ventricular response or BBR only. We have correlated the clinical occurrence of ventricular tachyarrhythmias with the results of programmed ventricular stimulation in 424 consecutive patients undergoing elsctrophysiologic study for a variety of clinical indications.4 It should be emphasized in this study that we used both single and double premature stimuli delivered during ventricular pacing. The results are shown in Table I. Seventy-eight patients with IVR during programmed electrical stimulation had clinically documented VT or VF, and 253 patients who had no IVR were clinically free of ventricular tachyarrhythmias. This relationship was statistically significant. When the clinical usefulness of the test is assessed by analyzing the sensitivity, however, the IVR response was only 65 %
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1. Relationship of the results of programmed ventricular stimulation and the clinical occurrence of VT/ VF Table
Ii. Relationship of laboratory inducibility of sustained VT to clinical occurrence of arrhythmia Table
Electrophysiologj laboratory stud.v
Programmed ventricular stimulation IVR Clinical VT/VF No clinical VT/VF Sensitivity Specificity
78 52 = 78 = 6576 ii9 = 253 = 83% 305
1982
Heart Journal
VT
No VT
48 3
9 109
No IVR 41 253
Study population included patients in whom ventricular stimulation was performed at the right ventricular apex using single and double extrastimuli. IVR, intraventricular reentry.
sensitive in this population in identifying those patients who have ventricular tachyarrhythmias clinically. Its specificity is somewhat higher. Thus, although it appears that IVR is a pathologic phenomenon related to ventricular arrhythmias, it would not be a useful predictive marker in large population studies. The other type of response to programmed stimulation is the initiation of a ventricular tachyarrhythmia, i.e., VT or VF. The use of programmed stimulation to determine vulnerability to arrhythmias and the efficacy of antiarrhythmic drugs is baaed on the assumptions that an arrhythmia can be initiated only in susceptible patients and that the arrhythmia produced by programmed stimulation is identical to the clinical arrhythmia. The first assumption is supported by the results of programmed ventricular stimulation in 527 patients undergoing electrophysiologic study.8 Fifty-seven patients had spontaneously occurring sustained VT, 29 had nonsustained VT clinically, and 441 had no VT. Among the patients with sustained VT, the arrhythmia was inducible in the laboratory in 95 % . Left ventricular stimulation was necessary to induce VT in six patients. Even if left ventricular stimulation were not included, inducibility of VT in patients with sustained VT clinically would be 84 % (Table II). VT was induced in only three patients in whom it had not occurred clinically, and in those three, the induced VT was nonsustained. In patients with nonsustained VT clinically, the rate of inducibility was 62%. Thus ventricular arrhythmias are rarely induced by programmed ventricular stimulation in patients without clinical ventricular tachyarrhythmiss, and conversely, in tbose patienta witi sustained VT clinically, the arrhythmias are very frequently inducible in the electrophysiology laboratory.
Clinical VT No clinical VT Sensitivity
Specificity Predictive value of a positive test
= 84% = 97% = 94 “;,
Predictivevalue
= 926 of a negative test Overall accuracy = 93%
Study included a group of patients who underwent electrophysiologic study for a variety of clinical indications. In all patients, single and double premature stimuli were delivered to the right ventricular apex. Right ventricular outflow tract and left ventricular pacing were discounted for this analysis because not all patients underwent stimulation at these latter sites.
The second assumption-that the arrhythmia initiated by programmed electrical stimulation is identical to the clinical arrhythmia and repruduces its effects-is also supported by our data. We were able to compare the QRS morphologies and cycle len@hs of clinical and induced VT in 43 patienthi. Eightyseven percent of the induced tachycardia morphologies were documented to occur spontaneously. The difference in cycle lengths between clinical and induced VT was less than 10 msec in 50% of- the episodes and ranged from 10 to 80 msec in the remaining episodes of tachycardia. SERIAL ELECTROPHYSNXQOIC EVALUATE MUG EFFICACY
STUWS
TO
Programmed ventricular stimulation can reproduce clinical sustained VT in most patients susceptible to it, and this observation can be u&d to devise antiarrhytbmic therapy. Our protocol for selecting antiarrhythmic therapy by electrophysiologic testing is as follows. Control programmed ventricular stimulation is performed to demonstrate reproducible initiation of ventricular tachyarrhythmia. Drugs are administered intravenously when possible, although certain agents must be given orally. Programmed stimulation is then repeated. Plasma concentrations are measured at the time of the study. After acute testing has been completed, the best regimen is selected for long-term therapy. After 48 to 72 hours of this regimen, programmed sti-mnulation is done again to confirm the effect of the regimen. An exam&e of such a serial eleetrophysi&gic study performed for selecting an antiarrhythmic drug for VT is shown in Fig. 2. In evaluating serial electrophysiologic studies to
Volume Number
103 4, part 2
Assessment
III. Relationship of laboratory electrophysiologic testing results with clinical outcome in selecting antiarrhythmic regimensfor recurrent sustainedVT
Table
Laboratory
electrophysiologic
Success (no VT with drug)
of
ventricular
uukzerability
607
CONThtX
testing
Failure (VT induced with drug)
4 Clinical success 61 Clinical failure 4 42 Predictive value of successful test = 93% Predictive value of unsuccessful test = 90% Overall accuracy = 92% In this study, antiarrhythmic regimens used for chronic outpatient therapy were classified as successful if the oral regimen prevented initiation of VT by programmed stimulation and as unsuccessful (failure) if it did not prevent initiation of sustained VT. Clinical success was defined as prevention of palpitations, syncopa, documented sustained VT, and sudden death; failure was the occurrence of any of these. This analysis included patients receiving only standard, commonly available antiarrhythmic agents; experimental agents were specifically excluded. Clinical failure of these regimens was evaluated by retrospective as well as prospective follow-up.
select antiarrhythmic therapy, several potential measures of drua efficacy are available. We have found that the only reliable end point is prevention of initiation of VT. Changes in the width of the tachycardia zone, ease of inducibility of the tachycardia, and rate of the induced tachycardia are unreliable in predicting long-term efficacy. In addition to identifying effective antiarrhythmic drugs, the necessary concentration of the specific drug can testbe determined by the acute electrophysiologic ing. Antiarrhythmic drug concentrations can be increased in a stepwise fashion with electrophysiologic testing at each drug level until the concentration that prevents induction of the tachycardia is found. The plasma concentrations produced by
acute administration of antiarrhythmic drugs can be used to devise oral regimens2ss The results of our previous studies have shown that the levels achieved during acute testing accurately predict successful
chronic levels. The average plasma concentrations of antiarrhythmic drugs, particularly procainamide, that are required to prevent initiation of VT are higher than have been previously considered acceptable.2vgs lo
We have analyzed the clinical
results of antiar-
D/sOPYUAME
8.4 mg/L.
L&t/N/D/NE
48 mg/L.
QUSWXNE
q7 mg/L
600mg
q6h
Fig. 2. Serial drug study for recurrent sustainedVT. In
eachpanel, ECG lead V, is shownwith a right ventricular apical electrogram. Ten-millisecond time lines (T) are shown at the bottom. The numbers at the right are the cycle lengths of the induced VT. During the control study, programmed stimulation reproducibly induced sustained VT with a cycle length of 260 msec. Lidocaine at a concentration of 5.1 mg/L did not prevent induction of VT. Phenytoin at a concentration of 17.8 mg/L alsofailed to prevent initiation of VT. Neither lidocaine nor phenytoin significantly changedthe cycle length of the induced VT. Procainamide at a concentration of 14.8 mg/L prevented the initiation of sustained VT. However, note a single extra response,which was identical in morphology to the VT that occurred. Disopyramide at a level of 8.4 mg/L did not prevent initiation of sustainedVT, although the drug prolonged the cycle length to 310 msec.Intravenous quinidine that produced a blood level of 4.8 mg/L prevented initiation of VT. Oral quinidine (600mg every 6 hours) administered for 72 hours reproduced this same effect.
rhythmic regimens for recurrent sustained VT that
were devised evaluated in 111 patients.
by electrophysiologic
testing
This analysis was restricted
to
patients treated with currently available nonexperimental drugs. Average follow-up in this group of patients was 18 months (9 to 54 months) (Table III). Sixty-one patients in whom a regimen was evaluated during electrophysiologic studies that was judged to be successful (prevention of the initiation of VT)
had a clinical success. Clinical success was defined as no sustained or symptomatic tachyarrhythmias during chronic treatment with the testing drug. In four patients, these regimens, which were predicted to prevent VT, failed to do so. Forty-two patients in whom the laboratory studies predicted failure indeed had clinical failure (recurrence of VT) while taking the tested regimen, either prior to study or
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following discharge on the evaluated regimen which was predicted to fail. Only four patients who were predicted to have recurrences of VT actually had a successful outcome. The predictive value of the electrophysiologic study for selecting antiarrhythmic regimens for sustained VT is quite good. The predictive value of a laboratory success is 93%) that of a laboratory failure is 90%, and the overall accuracy of the test is 92 % . If we select for evaluation only those patients in this group who had suffered a cardiac arrest, the results are similar. Thirty patients in this group suffered out-of-hospital cardiac arrest, and among them, the predictive value of either a successful or an unsuccessful test was 87 % , with an overall accuracy for the test of 87%. These values are not significantly different from those recently reported by others.sr”-13 Experience with electrophysiologic drug testing for recurrent sustained VT is extensive, and many groups are in substantial agreement regarding its utility. On the other hand, data on the use of programmed stimulation for selecting treatment of other recurrent ventricular tachyarrhythmias or in patients who are at high risk of suffering sudden cardiac death are rudimentary. Serial electrophysiologic studies can be performed in patients with recurrent VF, although these studies are significantly more difficult because the arrhythmia cannot be terminated by programmed electrical stimulation and cardioversion is frequently necessary. Spontaneous conversion to normal sinus rhythm occasionally occurs.14,15 The results of provocative electrophysiologic study in this group of patients appears promising, but only a small number of such patients have been studied.gr 14+15Furthermore, provocative electrophysiologic testing in patients potentially at risk of sudden death (e.g., those with frequent multiform premature ventricular depolarizations or survivors of recent myocardial infarction) has been largely unstudied. Initiation of sustained tachyarrhythmia in this group of patients, who have never had a clinically observed sustained episode of VT or VF, may be predictive of subsequent clinical events, but this possibility requires prospective evaluation. CONCLUSIONS
An association exists between the pathologic phenomenon of IVR and sustained ventricular tachyarrhythmias. However, its value in predicting the occurrence of VT or VF in a homogeneous population at risk is controversial. On the other hand, the induction of sustained VT with programmed ven-
American
Heart
t982
Journal
tricular stimulation in patients suspected clinically of having ventricular tachyarrhythmias correlates closely with the spontaneous occurrence of the arrhythmia, and the prediction of therapy based on the results of programmed stimulation appears to be highly accurate for that group. We wish to thank Ms. Helaine Corr for secretarial assistance in preparation of the manuscript, Dr. David McCarthy for assistance in statistical evaluation and editorial review, and Dr. John A. Kastor, Chief of the Cardiovascular Section, for continued enthuasiastic support. REFERENCES
1. Josephson ME, Horowitz LN, Farshidi A, Kastor JA: Recurrent sustained ventricular tachycardia. I. Mechanisms. Circulation 57:431, 1978. 2. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM Recurrent sustained ventricular tachycardia. III. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 58:986, 1978. 3. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogrenkelu JB, Vargas G: Demonstration of reentry within the HisPurkinje system in man. Circulation 49:1150, 1974. 4. Farshidi A, Michelson EL, Greenspan AM, Spielman SR, Horowitz LN, Josephson ME: Repetitive responses to ventricular extrastimuli: Incidence, mechanism and significance. AM HEART J 199:59, 1980. 5. Greene HL, Reid PR, Schaeffer AH: The repetitive ventricular response in man: A predictor of sudden death. N Engl J Med 299:729, 1978. 6. Troup PJ, Pederson DN, Zipes DP: Effects of premature ventricular stimulation in patients with ventricular tachycardia. Circulation 58(suppl II):154, 1978. (Abst.1 7. Mason JW: Repetitive beating after single ventricular extrastimuli: Incidence and prognostic significance in patients with recurrent ventricular tachycardia. Am J Cardiol45407, 1980. (abst.1 8. VandePol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME: The incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 45:725, 1980. 9. Horowitz LN, Josephson ME, and Kastor JA: Intracardiac electrophysiologic studies aa a method for the optimization of drug therapy in chronic ventricular arrhythmia. Progr Cardiovasc Dis 23:81, 1930. 10. Greenspan AM, Horowitz LN, Spielman SR, Josephson ME: Large dose procainamide therapy for ventricular tachyarrhythmia. Am J Cardiol 46:453, 1980. 11. Mason JW, Winkle RA: Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circuiation 583971, 1978. 12. Mason JW, Winkle R: Arrhythmic induction in patients with recurrent ventricular tachycardia: New findings. Circulation 69(suppl 11):24, 1979. 13. Ruskin JN, DiMarco JP, Garan H: Out-of-hospital cardiac arrest: Electrophysiologic observations and selection of longterm antiarrhythmic therapy. N Engl J Med 303:607, 1980. 14. Spielman SR, Farshidi A, Horowitz LN, Josephson ME: Ventricular fibrillation during programmed ventricular stimulation: Incidence and clinical implications. Am J Cardiol 42:918, 1978. 15. Josephson ME, Horowitz LN, Spielman SR, Greenspan AM: Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardiol 46:948, 1980.
Volume Number
103 4, pari
2
DISCUSSION Dr. Wellens: I think I would agreewith you about the predictive value of serial drug testing, except that with certain drugs, asyou know, there is no correlation between the effects during programmed stimulation and the clinical course of a particular patient. When you talk about predictive value, you have to take into account the type of drug you are studying. A typical example is amiodarone.If you give amiodarone to patients with sustained VT in whom you can induce an arrhythmia during the stimulation study and then you study them again after 4 weeks,it becomeseasier to initiate VT in nearly all of them. In some patients, it even becomespossible to initiate a tachycardia with one rather than two premature beats. Dr. Horowitz: I completely agree. The data I showed were generated from drugs that are available for routine use in this country. No patients taking amiodaronewere included in this study. We do, however, have about 40 patients taking amiodarone and can induce VT in more than half of them, yet many, if not most, of them have a successful outcome. We have seen some failures with amiodarone, as you know, but there appears to be no correlation between the laboratory results and the clinical results with that drug. We have not seenthat samelack of correlation with other experimental antiarrhythmic drugs. At least in our experience, amiodaroneappearsto be the only drug where that is clearly the case. Dr. Wellens: Concerningyour protocol, do you consider IVR only when you can bring it out during ventricular pacing by a single ventricular premature beat? Dr. Horowitz: No. I think some of the difference between our studiesand those of other laboratories is that our particular protocol considers IVR inducible by any method of programmed stimulation, which includes one and two premature stimuli during sinus rhythm and a variety of paced cycle lengths and at multiple sites. We specifically do not limit ourselves to single premature beats either in sinusrhythm or at one paced cycle length. If we did, the incidence of IVR would be lower. I do not think that would improve its sensitivity. If anything, it might improve its specificity. Dr. Zipes: We have data to support the amiodarone experience that Dr. Wellens indicated (Heger et al: Circulation 62(suppl III):321, 1980). In addition, we have studied the importance of repetitive ventricular responses (RVRs), both prospectively and retrospectively in patients who have VT (Naccarelli et al: In press). We found that if the ventricle is paced for the basic beatsand is prematurely stimulated, the frequency of both nonbundle and bundle branch reentry is increased significantly compared with premature ventricular stimulation during atrial pacing. Furthermore, although sensitivity is gained with one pacing mode, specificity is gainedwith the other, but neither has a really significant predictive accuracy prospectively. Many problemsremain regarding reproducibility of the RVRs. Also, if more sitesare stimulated and at more cycle lengths, the prevalence of RVRs may increase.
Assessment
of
ventricular
vulnerability
609
On another point, the usefulnessof inducing VT to distinguish a patient who may develop it clinically is really basedon the fact that VT is generally not induced in other patients undergoing electrophysiologic study. However, the real control group-patients with comparable coronary disease who do not have VT-has not been studied. Dr. Horowitz: Well, actually, I would go one step farther. The only way to know that a test is, in fact, useful prospectively is to do a prospective study. To answeryour question, in the 500 or sopatients that we have studied, a little over half have had organic heart diseaseof all types. In our laboratory, that means 80% coronary disease.I can’t give you an exact number, but my guessis that we have done programmed stimulation in somewhere between 150 and 200 patients with coronary disease, although they have not all beenverified by an angiogram. VT is not inducible in that population. I agree, that is all retrospective, but a prospective study is difficult to do. That is why there are not many data of this sort. However, all our information to date indicates that induction of sustained tachyarrhythmia in the laboratory correlates with its clinical occurrence. Dr. Sobel: Because(1) VT is not inducible in someof these patients, whatever the number is; (2) patients who undergo these long and arduous studies are experiencing changes in their metabolic, respiratory, and hormonal status; and (3) people with ischemicheart diseaseconstitute an ever changing substrate of factors influencing. ventricular function and electrophysiologic stability, how large are the errors that we should anticipate on either a priori or a posteriori grounds with observations made at one point in time under one set of conditions with respect to the longitudinal issue? Dr. Horowitz: That is clearly a consideration. It turns out that many patients with sustained VT, whether it causescardiac arrest or not, if they survive, have the same arrhythmia for many years. Certainly, a new infarction or some other insult to ventricular function can change things, and there is no doubt that coronary diseaseis a changing disease.But our observation is that radical changesin arrhythmias do not happen very frequently. I know of only a couple of patients studied over several years in whom there was a distinct change in the clinical course, with respect to VT, because of a subsequent myocardial infarction. Dr. Sobel: You do not mean the primary fibrillators when you say that, nor the postmyocardial infarction population? Dr. Horowitz: That’s right. Dr. Zipes: The patient’s responseto premature stimulation may change. For example, if you investigate some patients at 1 week and others at 4 weeksafter a myocardial infarction, the anatomic substrate may be different at 1 and 4 weeks, and so may the response to a single premature stimulus. Dr. Horowitz: That’s right. If you considerpatients who were referred becausethey had recurrent VT, most of
April,
Horowitz
et al.
American
them are beyond 2 months of infarction; presumably moat of the healing has taken place and the electrophysiologic findings are stable. We have studied patients for 6 months and some for several years, and VT is just as inducible years later as during the initial study. Coupling intervals and refractory periods are different, but if VT was induced with programmed stimulation on the first study, it was also induced in the second study, and if it wasn’t inducible the first time, it usually is not inducible the next time. Dr. Conti: In your laboratory or in other laboratories, what are the complications of the procedure in those who fibrillate? Stroke, myocardial infarction, or death? Dr. Horowitz: I am aware of only two deaths that have occurred during serial studies for the evaluation of therapy for VT in all laboratories worldwide; both patients had VT. That doesnot mean, of course,that there have been no other deaths. In our laboratory, the complications of venous catheterization are about the same as those reported from large catheterization series;i.e., about 5% of the patients have local complications. Arterial catheter-
Heart
1992
Journal
ization used to be done by arteriotomy, but we use arteriotomy now only if we can’t get in percutaneously. We have had two significant complications with percutaneous left ventricular catheterization; both patients required cardioversion, and when they moved, their arteries were torn, but later were repaired. We have had no other serious arterial complications. One patient had a transient neurologic event, presumably due to a plaque that was knocked off, but the deficit cleared within 30 minutes. There have been no myocardial infarctions. We have performed approximately 200 left ventricular catheterizations, and I would say that the complications are comparableto those of angiographic catheterization. I am aware of a few deaths worldwide, and I cannot even guess the number of patients who have been studied. We evaluate about 200 patients a year and probably do 750 studies a year. The complications are low, but there is a risk, and patients are made aware of that. I believe that the risk-to-benefit ratio is still on the side of doing the studies in the population at risk of VT or VF.
of
The purpose of these studies is to ilfustrate that the time of drug admin#Wation in expertmental animals subjected to coronary artery occlusion Is an impor@&t infiuetrca on the myocardfal distribution of the drug as well as its electrophysiologic and arrhythmogenlc effacts. Also, because several drugs have active metabolites, some stud&as qust be done after oral administration. Finally, electrophysiologic testing to determine drug effkacy may give misleading results with some drugs. (AM HEART J 103:610, 1982.)
Douglas P. Zipes, M.D., E. N. Prystowsky, Indianapolis, Ind.
M.D., and J. J. Heger, M.D.
Several factors that may influence the results obtained and conclusions drawn from testing the effects of antiarrhythmic agents clinically and in animals are discussed here.
From the K.rannert Indiana University tion Hospital. Supported HL-07182, Institute, Association, Reprint Medicine,
610
Institute of Cardiology, the Department School of Medicine, and from the Veterans
of Medicine, Administra-
in part by the Herman C. Krannert Fund; by grants HL-06308, and HL-18795 from the National Heart, Lung and Blood National Institutes of Health; and by the American Heart Indiana Affiliate, Inc. requests: Douglas I?. Zipes, M.D., Indiana University 1100 West Michigan St., Indianapolis, IN 46202.
School
of
APRINDINE
An early question of ours concerned the influence of coronary artery occlusion on the distribution and actions of antiarrhythmic agents. Accordingly, we examined the effecta of administrating aprindine to five groups of open-cheat dogs.’ Group 1 (35 dogs) received aprindine immediately before one-stage left ant&or descending coronary artery (LAl% occlusion; group 2 (34 dogs) received wine 5 minutes after LAD occlusion; group 3 (16 dogs) was administered aprindine without LAQ oc&sion; group 4 (10 dog%) underw&nt, LAD occlu&on but received no aprindine; and group 5 (10 dogs) was administered aprindine 24 hours after LAD occlu0002-8703/82/040610
+ 06$00.60/O
‘?’ 1982
The
C. V.
MosbyCo.