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Drug conversion of nonsustained ventricular tachycardia to sustained ventricular tachycardia during serial electrophysiologic studies: Identification of drugs that exacerbate tachycardia and potential mechanisms
Drug conversrion of nonsustained ventricular tachycardia to sustained ventricular tachycardia during serial etectrophysiologic studies: Identification of drugs that exacerbate tachycardla and potential mechanisms Eleven of 83 patients who had ventricular tachycardia (VT) and underwent serial electrophysiologic study (EPS) had a more severe VT induced while receiving a particular antiarrhythmic drug as compared to control study. For all patients only nonsustained VT was initiated during control study, while sustained VT occurred during drug testing with disopyramlde (2 patients), quinidine (2 patients), amiodarone (4 patients), and encainide (7 patients), although spontaneous arrhythmias appeared well-controlled prior to repeat testing. Pacing techniques used to induce sustained VT were the same as those used in the control study in eight patients and “less aggressive” in three patients. Almost all episodes of sustained VT resulted in substantial hypotension, especially in patients who were taking encainide. Drugs associated with sustained VT increased the median tachycardia cycle length by 112 msec (p < 0.005) but increased the median ventricular effective refractory period by only 30 msec @ < 0.02). Assuming re-entry was responsible for VT, we postulate that drugs facilitated initiation of sustained VT by prolonging activation time but only minimally increasing refractoriness of the tachycardia circuit. (AM HEART J 103:177, 1982.)
Robert L. Rinkenberger, M.D., Eric N. Prystowsky, M.D., Warren M. Jackman, Gerald V. Naccarelli, M.D., James J. Heger, M.D., and Douglas P. Zipes, M.D. Indianapolis, Ind.
Programmed electrical stimulation (PES) of the heart is a useful method to test drug effectiveness in patients who have recurrent ventricular tachycardia (VT).ls3 Published data2g3 suggest that patients who have inducible VT before but not after drug therapy usually do not have recurrence of VT while taking that drug. In contrast, induction of VT during drug therapy does not always indicate that the patient will have spontaneous recurrence of the arrhyth-
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, and the Veterans Administration Hospital. Supported in part by the Herman C. Krannert Fund, hy Grants HL-06306 and HL-07182 and from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, and by the American Heart Association, Indiana Afiliate, Inc. Received for publication Sept. 23, 1981; accepted Sept. 26, 1981. Reprint requests: Eric N. Pry&why, M.D., Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, IN 46223. 0002~8703/82/020177
+ 08$00.80/O
@ 1982 The
C. V. Mosby
Co.
M.D.,
mia.4 It is well known that some antiarrhythmic drugs also can be arrhythmogenic.5.’ However, in the patient experiencing infrequent arrhythmic episodes, it is difficult to predict who may develop an adverse electrophysiologic or hemodynamic response while receiving a particular drug. If VT is induced by PES, the characteristics of the tachycardia and the patient’s hemodynamic response can be analyzed. In this report we demonstrate the induction by PES of sustained VT during drug therapy in 11 patients who only had nonsustained VT induced while receiving no drug therapy. This finding has not been stressed in previous studies1-3 and is important, since it is equally necessary to avoid selecting a potentially harmful ant&rhythmic agent as it is to select an efficacious one. In this study, we also examined possible electrophysiologic parameters that may have influenced induction of sustained VT. 177
178
Rinkenberger
et al.
American
I. Clinical features and spontaneousventricular tachyarrhythmias of patients studied
Table
Patient NO.
Cardiovascular disease
Age/Sex
1
27/M
CAD
VT-VF
2
52/M
CAD
VT-VF
3
45/F
Cardiomyopathy
VT-VF
4
69/M
CAD
Sustained VT
5
34/F
Cardiomyopathy
VT-VF
6 8
52/M 48/M 51/M
CAD CAD CAD
Nonsustained VT Sustained VT Sustained VT
9
62/M
CAD
Sustained VT
10
69/F
MVP
VT-VF
11
63/M
CAD
Sustained VT
7
Abbreviations:
CAD = coronary
artery
disease; MVP = mitral
valve prolapse;
Il. Control electrophysiologic study: Methods and results Table
Patient
No.
Method
of induction*
21
V,V, (700 msec) V,V,V, (700 msec-LV,) RV burst (350 msec) V,V, (700,500 msec)
3
V,V, (780 msec)
4
V,V,V, (500 msec) V,V,V, (400 msec) V,V,V, (500 msec)
8 9 10 11
Result?
5 episodes complexes
12
4 episodes 6 complexes 5 episodes 16 complexes 1 episodes 17 complexes 2 episodes 6 complexes 5 episodes 3 complexes
episodes complexes episodes
V,V,V, (700,600,500 msec) RV burst (300 msec) V,V,V, (600,500 msec)
5 32 8
V,V,V, (400 msec) RV burst (290 msec) V,V,V, (400 msec) RV burst (270 msec) V,V,V, (700,600 msec)
8 complexes 3 episodes 11 complexes 10 episodes 10 complexes 6 episodes 17
complexes
Abbreviations: LV, = left ventricular apex; V,V, = single vetltricular extrastimulation during ventricular pacing; V,V,V, = double ventricular extrastimulation during ventricular pacing; RV burst = right ventrimdar burst pacing. *Ventricular pacing cycle length. tNumber of episodes of ventricular tachycardia at study and longest episode. fPatient was taking propranolol, 20 mg four times daily for all studies.
VF = ventricular
__-~---
Symptoms.. No. electrical cardioversions
Clinical arrhythmias
February, 1992 Heart Journal
of
Syncope: DC cardioversion ~2 Syncope: DC cardioversion ~3 Syncope: DC cardioversion Xl Palpitations, presyncope: DC cardioversion ~5 Syncope: DC cardioversion ~2 Palpitations Syncope Presyncope: DC cardioversion ~1 Syncope: DC cardioversion ~3 Syncope: DC cardioversion Xl Syncope: DC cardioversion Xl fibrillation;
VT = ventricular
tachycardia.
METHODS Patient selection. A total of 170 patients who had a history of symptomatic recurrent VT underwent electrophysiologic study (EPS) in the clinical electrophysiology laboratory at the Krannert Institute of Cardiology. Serial EPS to evaluate drug efficacy wasperformed in83 of these patients. A more severe VT during drug therapy, as compared to control study, occurred in 11 patients and data from these patients form the basisof this report. EPS technique. Patients were studied in the postabsorptive, nonsedatedstate using two to five intracardiac electrode catheters.8Tracings were recorded on a multichannel oscilloscopicrecorder (Electronics for Medicine VR-12) at paper speedof 100 mm/set using filter settings of 30 to 500 Hz for intracardiac electrogramaLLnd0.1 to 20 Hz for surface ECGs. The heart waspaced by meansof a programmable stimulator (Medtronic Mode1 53%) that delivered square wave stimuli of 1.8 msec duration and 2-times late diastolic threshold. EPS protocol. The following pacing protocql was useed in an attempt to initiate VT: (1) Incremental left (LA) and/or right atria1 (RA) pacing at progressively shorter pacing cycle lengths until AV nodal block occurred. (2) Premature LA and/or RA stimulation at two or more pacing cycle lengths. Premature stimuli were introduced beginning late in diastole and at 10 to 20 msecdecrements until atriai refractariness was obtained, (3) Premature right ventricular (RV) stimulation during rainus rhythm and ventricular pacing. Premature stimuli ($2) were ini-
tiated after every eighth paced or sinuscomplex beginning in late diastole and at progressively shorter coupling intervals until ventricular refractoriness was reached.
Volume Number
103 2
EPS-sustained
VT hazardous antiarrhythmic
exam/reentry
traits
179
Ill. Serial drug electrophysiologic study: Methods and results
Table
Patient NO.
1
2
3
Drug
Method
Disopyramide (300 mg q 6 hr) Aprindine (60 mg bid)
V,Vy, (700 msec) V,V1 (600 msec) V,V, (700 msec) V,V,V, (700 msec, 500 msec)
Encainide
(25 mg q 4 hr)
V,V, (700 msec, 600 msec)
Aprindine
(60 mg bid)
V,V, (700,600,500 msec)
Disopyramide
(250 mg q 6 hr)
Amiodarone (400 mg bid) Amiodarone + Quinidine (300 mg q 6 hr) Encainide (25 mg q 6 hr) Amiodarone (400 mg bid)
RV, C V,V, (780 msec) V,V, (780 msec) V,V,V, (780 msec) V,V, (606 msec) RV, V,V,V, (500 msec)
5
Encainide (25 mg q 4 br) Amiodarone (400 mg bid) Aprindine (75 mg bid) Amiodarone (300 mg bid) Aprindine (50 mg q 6 br)
RV,
6
Encainide (75 mg q 6 hr) Amiodarone (400 mg bid)
V,V,V, (500 msec) RV,V,
Clofilium (50 fig/kg iv)
V,V,V, (700 msec)
Encainide Encainide Quinidine Encainide Amiodarone
RV burst (310 msec) V,V,V, (500 msec) V,V,V, (600 msec) V,V,V, (600 msec) V,V,V, (600, 500 msec)
4
7
8 9
V,V,V, (500 msec)
(50 mg q 6 hr) (50 mg q 6 hr) (400 mg q 6 hr) (35 mg q 6 hr) (400 mg bid)
Result
of induction
episodes complexes Sustained VT 4 episodes 14 complexes 5 episodes 6 complexes 14 episodes 8 complexes VTNF VTNF Sustained VT 5 episodes 19 complexes Sustained VT Sustained VT 1 episode 9 complexes Sustained VT 9 episodes 20 complexes Sustained VT 3 episodes 11 complexes 2 episodes 4 complexes Sustained VT Sustained VT Sustained VT Sustained VT 9 episodes 4 7
18 complexes 10
Amiodarone Amiodarone
(400 mg bid) + Quinidine (400 mg q 6 hr) (400 mg bid) + Disopyramide (150 mg q 6 hr)
11
Disopyramide (200 mg q 6 hr) Encainide (50 mg q 6 hr)
V,V*V, (600 msec) V,V, (400 msec) V,V,V, (600,500,400 msec) V,V,V, (700 msec) V,V,V, (600 msec)
Sustained VT 15 episodes 49 complexes Sustained VT Sustained VT
Abbreviations: RV, = single ventricular extrastimulation during normal sinus rhythm; RV,V, = double ventricular extrastimulation during normal rhythm; C = catheter insertion; VT = ventricular tachycardia; VF = ventricular fibrillation. (For other abbreviations and format see Table II.)
Then, if VT was not reproducibly initiated, the shortest coupling interval (S,SJ resulting in consistent ventricular capture was chosenand a secondpremature stimulus (S,) was introduced beginning at an SzSsinterval 100 msec longer than the S,S, interval. The S,S, interval was shortened by 10 to 20 msecdecrementsuntil SI no longer resulted in ventricular depolarization. If VT was not reproducibly induced, the S,S, interval was increased by 50 msecand the S,S, interval was set at 100 mseclonger than the SS, interval. The S,S, interval was shortened until the ventricle wasrefractory to Sa,at which time the S,S, interval was decreasedby 10 msecintervals until S, again resulted in ventricular depolarization. This pacing sequencewasrepeated until the ventricle wasrefractory to S,. (4) RV burst pacing using three to eight complexesat cycle lengths L 250 msec. For all patients, premature ventricular stimulation was
sinus
performed at two or more pacing cycle lengths. If tachycardia wasnot reproducibly initiated at the first ventricular site (usually apex) tested, both premature ventricular stimulation and burst pacing were performed at a second RV site (usually outflow tract). Patient 1 also had PES performed at the left ventricular apex. Sustained VT was defined as tachycardia lasting 30 seconds or more or tachycardia requiring termination before 30 seconds becauseof symptoms. Nonsustained VT was defined as tachycardia > 3 consecutiveventricular complexeslasting I 29 seconds. Drug studies. After the initial control EPS, patients weretreated with oral antiarrhythmic drugs and observed in a unit where their rhythms weremonitored continuously. Investigational drugs were given in divided doses: aprindine 120to 200 mg/day, encainide 150to 300 mgjday and amiodarone600 to 800 mg/day; clofilium wasgiven as
February.
180
Rinkenberger et al.
American
Heart
1992 Journal
#< RV
I
,
1
1. I* .. -.- 1. . ’
.
,
4OOJ
Fig. 1. Ventricular tachycardia induced with one premature ventricular complex during normal sinus rhythm (Patient 2). Tachycardia degeneratedinto ventricular fibrillation within seconds(not shown),and 400joules (J) successfullydefibriilated the patient. Top and bottom tracings are continuous; for each, the first four lines are ECG leads I, II, III, and V,, and the last line is an intracardiac electrogram recorded from the right ventricle (RV).
a single intravenous doseof 50 &kg body weight. For all 11 patients, no VT was recorded during 48 hours of continuous monitoring prior to restudy and during a 24-hour ECG Holter recording the day prior to restudy. Patients were restudied 10 to 18 days after beginning amiodarone therapy and 4 to 7 days after beginning therapy with the other antiarrhythmic agents. Statistics. Comparison of VT cycle length and RV effective refractory period (ERP) between control and drug studies was done by meansof the Wilcoxon signed rank test for paired data.9 RESULTS Patient characteristics. The clinical features of the patients are described in Table I. All patients had recurrent ventricular fibrillation and/or VT prior to study, and in eight patients the arrhythmia was resistant to, or the patient did not tolerate, conventional antiarrhythmic drugs. Eight patients had coronary artery disease, two had cardiomyopathy, and one had mitral valve prolapse. Control PES. PES initiated two or more episodes of nonsustained VT in all but Patient 4 (Table II). In Patient 4, one episode of nonsustained VT was initiated only after prolonged PES attempts at stimulating a second RV site. Attempts to reproduce the arrhythmia were unsuccessful. VT could not be initiated by single or double premature ventricular stimuli delivered during RA pacing or normal sinus rhythm in any patient. serial drug f!pS. In eight patients nonsustained VT was initiated during repeat EPS while the patient received an a&&rhythmic drug other than the one that induced sustained VT. In addition, Patient 1
had nonsustained VT induced during disepyramide therapy only at the lower dose. Patient 8 had only one drug study performed and developed sustained VT during the study. Induction of sustained VT occurred in all 11 patients while they were receiving a specific ant&rhythmic agent (Table- III). No episode of nonsustained VT preceded initiation of sustained VT in 9 of 11 patients. In Patient 11 during encainide therapy, and in patient one during disopyramide therapy, one and two episodes, respectively, of nonsustained VT occurred prior to induction of sustained VT. It is important to stress that pacing techniques used to induce sustained VT in eight patients were the same as those techniques that induced only nonsustained VT in their control study. In the remaining three patients sustained VT wasinitiated during drug study by means of pacing techniiues “less aggressive” than those used at control study, that is, a single premature ventricular stimulus induced after a conducted sinus impulse. Fig. 1 demonstrates induction of sustained VT in Patient 2. During the final study of this patient (m&&own), ventricular
fibrillation
(VF) resulted merely upon
introduction of the catheter electrode into the RV. No patient required a “more aggressive” pacing technique to initiate sustained VT t&-n that used in the control study. Terminat@n of suaver VT. Induced VT within seconds spontaneously transformed to W in Patient 2 before pa&g procedures could be in&&&d to terminate it (Fi. I), and the patient was d&brillated successfully. Sustained VT resulted in presyn-
Volume Number
Table
103 2
EPS-sustained
IV. Comparison
of nonsustained
Patient No.
3 4 5 6
7 8 9
10
11
electrical
stimulation;
ERP
RV = effective
cope in Patients 1, 3, and 7 to 10, and RV burst pacing terminated VT in all except Patient 1 in whom burst pacing induced an unstable rhythm requiring electrical cardioversion (Table IV). VT during encainide therapy in Patients 4,6, and 11 and during disopyramide therapy in Patient 11 caused severe hypotension and syncope necessitating immediate electrical DC cardioversion. Patients 4 and 5 tolerated sustained VT well during amiodarone treatment and burst pacing stopped VT. Difference
during
nonsustained
and
ERP
240 270 320 260 300 340 300 320 430-550 440 470-610 270 400 350 225 305 380 270 270 270 280 240 265 370 240 280 265 425 370 320 170-300 340 330-470 250 390 390 refractory
sustained
VT.
The morphology of induced sustained and nonsustained VT was similar in all patients (Table IV). Comparison of VT cycle length was made between control and drug studies for all but Patients 3 and 10. A comparison was not possible in these two patients due to variability of VT cycle lengths.
period
exam/reentry
traits
181
tachycardia
Tachycarciia cycle length
Control Disopyramide (250 mg) Disopyramide (300 mg) Aprindine Control Encainide Aprindine Amiodarone Control Encainide Amiodarone Control Encainide Amiodarone Control Aprindine Amiodarone Control Aprindine Encainide Amiodarone Control Clofilium Encainide Control Encainide Control Quinidine Encainide Amiodarone Control Quinidine + amiodarone Disopyramide + amiodarone Control Disopyramide Encainide
2
programmed
ventricular
Drug
1
PES =
and sustained
VT hazardous antiarrhythmic
of the right
RV
240 250 280 240 250 260 280 NM 320 NM 320 280 NM NM 250 290 270 235 230 235 240 275 280 320 210 240 270 330 300 280 230 NM 300 230 260 260 ventricle;
NM
Termination
Spontaneous Spontaneous DC cardioversion Spontaneous Spontaneous Spontaneous Spontaneous DC cardioversion Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion RV pacing Spontaneous Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion Spontaneous Spontaneous Spontaneous RV pacing Spontaneous RV pacing Spontaneous RV pacing RV pacing Spontaneous Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion DC cardioversion
= not measured.
During drug therapy that resulted in induced sustained VT, the median VT cycle length substantially increased from a control value of 257.5 msec (range 225 to 300 msec) (Fig. 2, A) to 370 msec (range 270 to 425 msec) 03 < 0.005) (Fig. 2, B). In contrast, the median VT cycle length minimally increased from a control value of 265 msec (range 225 to 300 msec) to 280 msec (range 260 to 340 msec) (p < 0.02) during drug therapy associated with the initiation of nonsustained VT. To determine if changes in ventricular refractoriness correlated with the development of sustained VT, RV ERP was compared prior to and during drug therapy when possible (Table IV). For each patient, the site of RV stimulation was the same and the pacing cycle length was identical for each study. The median RV ERP increased from control value of 240
182
Rinkenberger
et al.
February, American
Heart
Fig. 2. Ventricular tachycardia before and during encainide therapy (Patient 4). A, Nonsustained (16 complexes) ventricular tachycardia (CL = 270 msec) occurred during premature ventricular stimulation prior to drug therapy. B, During encainide therapy, sustained ventriculer tachyardia (CL = 400 meet) occurred. Morphology of the ventricular ttwhycardia wee &niIar exmpt for a minor &sift in axis. fn both A and B, the tracings are continuous. HBE = His bundle electrogram. See Fig. 1 for other abbreviations.
19132 Journal
Volume Number
103 2
EPS-sustained
msec (range 210 to 275 msec) to 270 msec (range 235 to 300 msec) (p < 0.02) during therapy with the drug that facilitated the development of sustained VT. Drug studies in which nonsustained VT was induced demonstrated an increase from control value in the median RV ERP of only 10 msec, from 250 msec (range 235 to 275 msec) to 260 msec (range 230 to 290 msec) (p < 0.03). DISCUSSION Identification of potentially hazardous antiarrhythmic drugs by PES in the absence of spontaneous VT recorded by continuous ECG. Drug efficacy in
patients who have VT often is judged by noninvasive studies such as prolonged ECG monitoring and/or ambulatory recording. However, it is well known that some antiarrhythmic drugs are arrhythmogenic,5-7 and this adverse response to therapy may not be predictable and may occur days to weeks after initiation of drug therapy. It is important to stress that none of the 11 patients receiving drugs that led to induction of sustained VT during EPS had VT detected during 2 48 hours of continuous ECG monitoring and during a 24-hour ECG Holter recording performed the day before EPS. Thus, for all patients noninvasive testing suggested that antiarrhythmic therapy was effective. Since induction of VT at EPS appears to correlate with subsequent spontaneous recurrence of VT? 3 we show that EPS can be used to identify drugs that are potentially life threatening to the patient. Comparable PES technique for initiation of nonsustained VT during control study and sustained VT during drug study. The reproducibility of inducing nonsus-
tained VT needs to be addressed, particularly since 10 of 11 patients had sustained VT spontaneously prior to the control EPS. We induced multiple episodes of nonsustained VT during the initial EPS in all except Patient 4 who had only one episode induced. In eight patients we also reproducibly induced episodes of nonsustained VT during serial drug EPS. Therefore, the induction of nonsustained VT in almost all of our patients was performed repeatedly and on more than one day. It can be argued that if we had been more aggressive we might have induced sustained VT in all patients. While this may be true, the fact remains that the pacing technique used to induce sustained VT in eight patients was the same as the technique that repeatedly induced nonsustained VT, and in three patients “less aggressive” pacing techniques than those used in the control study induced sustained VT (Table III). Thus, specific antiarrhythmic drugs were arrhythmogenic in se-
VT hazardous
antiarrhythmic
exam/reentry
traits
183
lected patients and facilitated the conversion of nonsustained to sustained VT by PES. Propensity of sustained VT induced during drug therapy to develop VF or hypotension. The patients re-
sponded poorly to most episodes of induced sustained VT, and in one patient the arrhythmia quickly progressed to VF. Of note are the results with encainide therapy. Seven patients had sustained VT induced during encainide therapy, including Patient 6 who had a history of only nonsustained VT. Marked hypotension occurred in all seven patients and three patients required immediate electrical DC cardioversion. It appears that encainide may affect adversely myocardial contractility in patients who have depressed myocardialfunction, in contrast to minimal effects on ventricular function reported in patients who have relatively normal hearts.‘O For example, Patient 4 had sustained VT while receiving both encainide and amiodarone. The tachycardia rate was slower during encainide treatment but resulted in rapid loss of consciousness; tachycardia during amiodarone therapy was tolerated well and caused only palpitations. Potential electrophysiologic mechanisms for druginduced conversion of nonsustained to sustained VT.
We considered that investigation of this group of patients represented an opportunity to explore and contrast the electrophysiologic characteristics present during nonsustained and sustained VT, and by so doing to gain insight into electrophysiologic mechanisms possibly responsible for the latter. Assuming that re-entry was responsible for VT in our patients, one can postulate a potential mechanism by which a drug converts nonsustained VT to sustained VT. To extinguish a re-entrant tachycardia, the optimal electrophysiologic alteration would be to increase refractoriness in one or more limbs of the re-entrant pathway without prolonging activation time. The returning wavefront would encroach on refractory tissue and conduction would cease. A substantial increase in activation time with small increase in refractoriness allows fibers in the reentrant pathway sufficient time to repolarize in advance of the returning wavefront and thus perpetuate the re-entrant circuit. The markedly slower rate of the sustained VT in our patients implies prolonged activation time in the circuit (also assuming that the circuit did not change, a likely assumption since all patients had a similar QRS contour during sustained VT). Naturally, it is impossible to determine the refractory period of individual elements in the reentrant loop and this mechanism remains speculative.
February,
184
Rinkenberger
et al.
The authors thank Elizabeth Darling, R.N., for assistance during electrophysiologic studies, Naomi Fineberg, Ph.D., for performing statistical analyses, and Nancy Perkins for manuscript preparation. REFERENCES
1. Fisher JD, Cohen HL, Mehra R, Altachuler H, Escher DJW, Furman S: Cardiac pacing and pacemakers. II. Serial electrophysiologic-pharmacologic testing for control of recurrent tachyarrhythmias. AM HEART J 93:658, 1977. 2. Mason JW, Winkle RA: Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy in recurrent ventricular tachycardia. Circulation 58:971, 1978. 3. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 58:986, 1978. 4. Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, Zipes DP: Amiodarone: Clini-
American
Heart
1982 Journal
cal efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or fibrillation. N Engl d Med 305:539, 1981. 5. Seizer A, Wray HW: Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atria1 arrhythmias. Circulation 30:17, 1964. 6. Nicholson WJ, Martin CE, Gracey JG, Knoch HR: Disopyramide-induced ventricular fibrillation. Am J Cardiol43:1053, 1979. 7. Meltzer RS, Robert EW, McMorrow M, Martin RP: Atypical ventricular tachycardia as a manifestation of disopyramide toxicity. Am J Cardiol 42:1049, 1978. 8. Pederson DH, Zipes DP, Foster PR, Troup PJ: Ventricular tachycardia and ventricular fibrillation in a young population. Circulation 60:988, 1979. 9. Snedecor GW, Cochran WG: Statistical methods. Ames, Iowa, 1967, Iowa State IJniversity Press. LO. DiBianco R, Gottdiener JS, Fletcher RD, Singh S, Katz RJ, Sauerbrunn B: Effects of encainide on left ventricular function: Assessment with treadmill exercise and radionuclide ventriculography. Circulation 62(111):182, 1980.
Robert L. Rinkenberger, M.D., Eric N. Prystowsky, M.D., Warren M. Jackman, Gerald V. Naccarelli, M.D., James J. Heger, M.D., and Douglas P. Zipes, M.D. Indianapolis, Ind.
Programmed electrical stimulation (PES) of the heart is a useful method to test drug effectiveness in patients who have recurrent ventricular tachycardia (VT).ls3 Published data2g3 suggest that patients who have inducible VT before but not after drug therapy usually do not have recurrence of VT while taking that drug. In contrast, induction of VT during drug therapy does not always indicate that the patient will have spontaneous recurrence of the arrhyth-
From the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, and the Veterans Administration Hospital. Supported in part by the Herman C. Krannert Fund, hy Grants HL-06306 and HL-07182 and from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, and by the American Heart Association, Indiana Afiliate, Inc. Received for publication Sept. 23, 1981; accepted Sept. 26, 1981. Reprint requests: Eric N. Pry&why, M.D., Indiana University School of Medicine, 1100 West Michigan St., Indianapolis, IN 46223. 0002~8703/82/020177
+ 08$00.80/O
@ 1982 The
C. V. Mosby
Co.
M.D.,
mia.4 It is well known that some antiarrhythmic drugs also can be arrhythmogenic.5.’ However, in the patient experiencing infrequent arrhythmic episodes, it is difficult to predict who may develop an adverse electrophysiologic or hemodynamic response while receiving a particular drug. If VT is induced by PES, the characteristics of the tachycardia and the patient’s hemodynamic response can be analyzed. In this report we demonstrate the induction by PES of sustained VT during drug therapy in 11 patients who only had nonsustained VT induced while receiving no drug therapy. This finding has not been stressed in previous studies1-3 and is important, since it is equally necessary to avoid selecting a potentially harmful ant&rhythmic agent as it is to select an efficacious one. In this study, we also examined possible electrophysiologic parameters that may have influenced induction of sustained VT. 177
178
Rinkenberger
et al.
American
I. Clinical features and spontaneousventricular tachyarrhythmias of patients studied
Table
Patient NO.
Cardiovascular disease
Age/Sex
1
27/M
CAD
VT-VF
2
52/M
CAD
VT-VF
3
45/F
Cardiomyopathy
VT-VF
4
69/M
CAD
Sustained VT
5
34/F
Cardiomyopathy
VT-VF
6 8
52/M 48/M 51/M
CAD CAD CAD
Nonsustained VT Sustained VT Sustained VT
9
62/M
CAD
Sustained VT
10
69/F
MVP
VT-VF
11
63/M
CAD
Sustained VT
7
Abbreviations:
CAD = coronary
artery
disease; MVP = mitral
valve prolapse;
Il. Control electrophysiologic study: Methods and results Table
Patient
No.
Method
of induction*
21
V,V, (700 msec) V,V,V, (700 msec-LV,) RV burst (350 msec) V,V, (700,500 msec)
3
V,V, (780 msec)
4
V,V,V, (500 msec) V,V,V, (400 msec) V,V,V, (500 msec)
8 9 10 11
Result?
5 episodes complexes
12
4 episodes 6 complexes 5 episodes 16 complexes 1 episodes 17 complexes 2 episodes 6 complexes 5 episodes 3 complexes
episodes complexes episodes
V,V,V, (700,600,500 msec) RV burst (300 msec) V,V,V, (600,500 msec)
5 32 8
V,V,V, (400 msec) RV burst (290 msec) V,V,V, (400 msec) RV burst (270 msec) V,V,V, (700,600 msec)
8 complexes 3 episodes 11 complexes 10 episodes 10 complexes 6 episodes 17
complexes
Abbreviations: LV, = left ventricular apex; V,V, = single vetltricular extrastimulation during ventricular pacing; V,V,V, = double ventricular extrastimulation during ventricular pacing; RV burst = right ventrimdar burst pacing. *Ventricular pacing cycle length. tNumber of episodes of ventricular tachycardia at study and longest episode. fPatient was taking propranolol, 20 mg four times daily for all studies.
VF = ventricular
__-~---
Symptoms.. No. electrical cardioversions
Clinical arrhythmias
February, 1992 Heart Journal
of
Syncope: DC cardioversion ~2 Syncope: DC cardioversion ~3 Syncope: DC cardioversion Xl Palpitations, presyncope: DC cardioversion ~5 Syncope: DC cardioversion ~2 Palpitations Syncope Presyncope: DC cardioversion ~1 Syncope: DC cardioversion ~3 Syncope: DC cardioversion Xl Syncope: DC cardioversion Xl fibrillation;
VT = ventricular
tachycardia.
METHODS Patient selection. A total of 170 patients who had a history of symptomatic recurrent VT underwent electrophysiologic study (EPS) in the clinical electrophysiology laboratory at the Krannert Institute of Cardiology. Serial EPS to evaluate drug efficacy wasperformed in83 of these patients. A more severe VT during drug therapy, as compared to control study, occurred in 11 patients and data from these patients form the basisof this report. EPS technique. Patients were studied in the postabsorptive, nonsedatedstate using two to five intracardiac electrode catheters.8Tracings were recorded on a multichannel oscilloscopicrecorder (Electronics for Medicine VR-12) at paper speedof 100 mm/set using filter settings of 30 to 500 Hz for intracardiac electrogramaLLnd0.1 to 20 Hz for surface ECGs. The heart waspaced by meansof a programmable stimulator (Medtronic Mode1 53%) that delivered square wave stimuli of 1.8 msec duration and 2-times late diastolic threshold. EPS protocol. The following pacing protocql was useed in an attempt to initiate VT: (1) Incremental left (LA) and/or right atria1 (RA) pacing at progressively shorter pacing cycle lengths until AV nodal block occurred. (2) Premature LA and/or RA stimulation at two or more pacing cycle lengths. Premature stimuli were introduced beginning late in diastole and at 10 to 20 msecdecrements until atriai refractariness was obtained, (3) Premature right ventricular (RV) stimulation during rainus rhythm and ventricular pacing. Premature stimuli ($2) were ini-
tiated after every eighth paced or sinuscomplex beginning in late diastole and at progressively shorter coupling intervals until ventricular refractoriness was reached.
Volume Number
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Ill. Serial drug electrophysiologic study: Methods and results
Table
Patient NO.
1
2
3
Drug
Method
Disopyramide (300 mg q 6 hr) Aprindine (60 mg bid)
V,Vy, (700 msec) V,V1 (600 msec) V,V, (700 msec) V,V,V, (700 msec, 500 msec)
Encainide
(25 mg q 4 hr)
V,V, (700 msec, 600 msec)
Aprindine
(60 mg bid)
V,V, (700,600,500 msec)
Disopyramide
(250 mg q 6 hr)
Amiodarone (400 mg bid) Amiodarone + Quinidine (300 mg q 6 hr) Encainide (25 mg q 6 hr) Amiodarone (400 mg bid)
RV, C V,V, (780 msec) V,V, (780 msec) V,V,V, (780 msec) V,V, (606 msec) RV, V,V,V, (500 msec)
5
Encainide (25 mg q 4 br) Amiodarone (400 mg bid) Aprindine (75 mg bid) Amiodarone (300 mg bid) Aprindine (50 mg q 6 br)
RV,
6
Encainide (75 mg q 6 hr) Amiodarone (400 mg bid)
V,V,V, (500 msec) RV,V,
Clofilium (50 fig/kg iv)
V,V,V, (700 msec)
Encainide Encainide Quinidine Encainide Amiodarone
RV burst (310 msec) V,V,V, (500 msec) V,V,V, (600 msec) V,V,V, (600 msec) V,V,V, (600, 500 msec)
4
7
8 9
V,V,V, (500 msec)
(50 mg q 6 hr) (50 mg q 6 hr) (400 mg q 6 hr) (35 mg q 6 hr) (400 mg bid)
Result
of induction
episodes complexes Sustained VT 4 episodes 14 complexes 5 episodes 6 complexes 14 episodes 8 complexes VTNF VTNF Sustained VT 5 episodes 19 complexes Sustained VT Sustained VT 1 episode 9 complexes Sustained VT 9 episodes 20 complexes Sustained VT 3 episodes 11 complexes 2 episodes 4 complexes Sustained VT Sustained VT Sustained VT Sustained VT 9 episodes 4 7
18 complexes 10
Amiodarone Amiodarone
(400 mg bid) + Quinidine (400 mg q 6 hr) (400 mg bid) + Disopyramide (150 mg q 6 hr)
11
Disopyramide (200 mg q 6 hr) Encainide (50 mg q 6 hr)
V,V*V, (600 msec) V,V, (400 msec) V,V,V, (600,500,400 msec) V,V,V, (700 msec) V,V,V, (600 msec)
Sustained VT 15 episodes 49 complexes Sustained VT Sustained VT
Abbreviations: RV, = single ventricular extrastimulation during normal sinus rhythm; RV,V, = double ventricular extrastimulation during normal rhythm; C = catheter insertion; VT = ventricular tachycardia; VF = ventricular fibrillation. (For other abbreviations and format see Table II.)
Then, if VT was not reproducibly initiated, the shortest coupling interval (S,SJ resulting in consistent ventricular capture was chosenand a secondpremature stimulus (S,) was introduced beginning at an SzSsinterval 100 msec longer than the S,S, interval. The S,S, interval was shortened by 10 to 20 msecdecrementsuntil SI no longer resulted in ventricular depolarization. If VT was not reproducibly induced, the S,S, interval was increased by 50 msecand the S,S, interval was set at 100 mseclonger than the SS, interval. The S,S, interval was shortened until the ventricle wasrefractory to Sa,at which time the S,S, interval was decreasedby 10 msecintervals until S, again resulted in ventricular depolarization. This pacing sequencewasrepeated until the ventricle wasrefractory to S,. (4) RV burst pacing using three to eight complexesat cycle lengths L 250 msec. For all patients, premature ventricular stimulation was
sinus
performed at two or more pacing cycle lengths. If tachycardia wasnot reproducibly initiated at the first ventricular site (usually apex) tested, both premature ventricular stimulation and burst pacing were performed at a second RV site (usually outflow tract). Patient 1 also had PES performed at the left ventricular apex. Sustained VT was defined as tachycardia lasting 30 seconds or more or tachycardia requiring termination before 30 seconds becauseof symptoms. Nonsustained VT was defined as tachycardia > 3 consecutiveventricular complexeslasting I 29 seconds. Drug studies. After the initial control EPS, patients weretreated with oral antiarrhythmic drugs and observed in a unit where their rhythms weremonitored continuously. Investigational drugs were given in divided doses: aprindine 120to 200 mg/day, encainide 150to 300 mgjday and amiodarone600 to 800 mg/day; clofilium wasgiven as
February.
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Rinkenberger et al.
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1992 Journal
#< RV
I
,
1
1. I* .. -.- 1. . ’
.
,
4OOJ
Fig. 1. Ventricular tachycardia induced with one premature ventricular complex during normal sinus rhythm (Patient 2). Tachycardia degeneratedinto ventricular fibrillation within seconds(not shown),and 400joules (J) successfullydefibriilated the patient. Top and bottom tracings are continuous; for each, the first four lines are ECG leads I, II, III, and V,, and the last line is an intracardiac electrogram recorded from the right ventricle (RV).
a single intravenous doseof 50 &kg body weight. For all 11 patients, no VT was recorded during 48 hours of continuous monitoring prior to restudy and during a 24-hour ECG Holter recording the day prior to restudy. Patients were restudied 10 to 18 days after beginning amiodarone therapy and 4 to 7 days after beginning therapy with the other antiarrhythmic agents. Statistics. Comparison of VT cycle length and RV effective refractory period (ERP) between control and drug studies was done by meansof the Wilcoxon signed rank test for paired data.9 RESULTS Patient characteristics. The clinical features of the patients are described in Table I. All patients had recurrent ventricular fibrillation and/or VT prior to study, and in eight patients the arrhythmia was resistant to, or the patient did not tolerate, conventional antiarrhythmic drugs. Eight patients had coronary artery disease, two had cardiomyopathy, and one had mitral valve prolapse. Control PES. PES initiated two or more episodes of nonsustained VT in all but Patient 4 (Table II). In Patient 4, one episode of nonsustained VT was initiated only after prolonged PES attempts at stimulating a second RV site. Attempts to reproduce the arrhythmia were unsuccessful. VT could not be initiated by single or double premature ventricular stimuli delivered during RA pacing or normal sinus rhythm in any patient. serial drug f!pS. In eight patients nonsustained VT was initiated during repeat EPS while the patient received an a&&rhythmic drug other than the one that induced sustained VT. In addition, Patient 1
had nonsustained VT induced during disepyramide therapy only at the lower dose. Patient 8 had only one drug study performed and developed sustained VT during the study. Induction of sustained VT occurred in all 11 patients while they were receiving a specific ant&rhythmic agent (Table- III). No episode of nonsustained VT preceded initiation of sustained VT in 9 of 11 patients. In Patient 11 during encainide therapy, and in patient one during disopyramide therapy, one and two episodes, respectively, of nonsustained VT occurred prior to induction of sustained VT. It is important to stress that pacing techniques used to induce sustained VT in eight patients were the same as those techniques that induced only nonsustained VT in their control study. In the remaining three patients sustained VT wasinitiated during drug study by means of pacing techniiues “less aggressive” than those used at control study, that is, a single premature ventricular stimulus induced after a conducted sinus impulse. Fig. 1 demonstrates induction of sustained VT in Patient 2. During the final study of this patient (m&&own), ventricular
fibrillation
(VF) resulted merely upon
introduction of the catheter electrode into the RV. No patient required a “more aggressive” pacing technique to initiate sustained VT t&-n that used in the control study. Terminat@n of suaver VT. Induced VT within seconds spontaneously transformed to W in Patient 2 before pa&g procedures could be in&&&d to terminate it (Fi. I), and the patient was d&brillated successfully. Sustained VT resulted in presyn-
Volume Number
Table
103 2
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IV. Comparison
of nonsustained
Patient No.
3 4 5 6
7 8 9
10
11
electrical
stimulation;
ERP
RV = effective
cope in Patients 1, 3, and 7 to 10, and RV burst pacing terminated VT in all except Patient 1 in whom burst pacing induced an unstable rhythm requiring electrical cardioversion (Table IV). VT during encainide therapy in Patients 4,6, and 11 and during disopyramide therapy in Patient 11 caused severe hypotension and syncope necessitating immediate electrical DC cardioversion. Patients 4 and 5 tolerated sustained VT well during amiodarone treatment and burst pacing stopped VT. Difference
during
nonsustained
and
ERP
240 270 320 260 300 340 300 320 430-550 440 470-610 270 400 350 225 305 380 270 270 270 280 240 265 370 240 280 265 425 370 320 170-300 340 330-470 250 390 390 refractory
sustained
VT.
The morphology of induced sustained and nonsustained VT was similar in all patients (Table IV). Comparison of VT cycle length was made between control and drug studies for all but Patients 3 and 10. A comparison was not possible in these two patients due to variability of VT cycle lengths.
period
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traits
181
tachycardia
Tachycarciia cycle length
Control Disopyramide (250 mg) Disopyramide (300 mg) Aprindine Control Encainide Aprindine Amiodarone Control Encainide Amiodarone Control Encainide Amiodarone Control Aprindine Amiodarone Control Aprindine Encainide Amiodarone Control Clofilium Encainide Control Encainide Control Quinidine Encainide Amiodarone Control Quinidine + amiodarone Disopyramide + amiodarone Control Disopyramide Encainide
2
programmed
ventricular
Drug
1
PES =
and sustained
VT hazardous antiarrhythmic
of the right
RV
240 250 280 240 250 260 280 NM 320 NM 320 280 NM NM 250 290 270 235 230 235 240 275 280 320 210 240 270 330 300 280 230 NM 300 230 260 260 ventricle;
NM
Termination
Spontaneous Spontaneous DC cardioversion Spontaneous Spontaneous Spontaneous Spontaneous DC cardioversion Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion RV pacing Spontaneous Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion Spontaneous Spontaneous Spontaneous RV pacing Spontaneous RV pacing Spontaneous RV pacing RV pacing Spontaneous Spontaneous RV pacing Spontaneous Spontaneous DC cardioversion DC cardioversion
= not measured.
During drug therapy that resulted in induced sustained VT, the median VT cycle length substantially increased from a control value of 257.5 msec (range 225 to 300 msec) (Fig. 2, A) to 370 msec (range 270 to 425 msec) 03 < 0.005) (Fig. 2, B). In contrast, the median VT cycle length minimally increased from a control value of 265 msec (range 225 to 300 msec) to 280 msec (range 260 to 340 msec) (p < 0.02) during drug therapy associated with the initiation of nonsustained VT. To determine if changes in ventricular refractoriness correlated with the development of sustained VT, RV ERP was compared prior to and during drug therapy when possible (Table IV). For each patient, the site of RV stimulation was the same and the pacing cycle length was identical for each study. The median RV ERP increased from control value of 240
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Heart
Fig. 2. Ventricular tachycardia before and during encainide therapy (Patient 4). A, Nonsustained (16 complexes) ventricular tachycardia (CL = 270 msec) occurred during premature ventricular stimulation prior to drug therapy. B, During encainide therapy, sustained ventriculer tachyardia (CL = 400 meet) occurred. Morphology of the ventricular ttwhycardia wee &niIar exmpt for a minor &sift in axis. fn both A and B, the tracings are continuous. HBE = His bundle electrogram. See Fig. 1 for other abbreviations.
19132 Journal
Volume Number
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EPS-sustained
msec (range 210 to 275 msec) to 270 msec (range 235 to 300 msec) (p < 0.02) during therapy with the drug that facilitated the development of sustained VT. Drug studies in which nonsustained VT was induced demonstrated an increase from control value in the median RV ERP of only 10 msec, from 250 msec (range 235 to 275 msec) to 260 msec (range 230 to 290 msec) (p < 0.03). DISCUSSION Identification of potentially hazardous antiarrhythmic drugs by PES in the absence of spontaneous VT recorded by continuous ECG. Drug efficacy in
patients who have VT often is judged by noninvasive studies such as prolonged ECG monitoring and/or ambulatory recording. However, it is well known that some antiarrhythmic drugs are arrhythmogenic,5-7 and this adverse response to therapy may not be predictable and may occur days to weeks after initiation of drug therapy. It is important to stress that none of the 11 patients receiving drugs that led to induction of sustained VT during EPS had VT detected during 2 48 hours of continuous ECG monitoring and during a 24-hour ECG Holter recording performed the day before EPS. Thus, for all patients noninvasive testing suggested that antiarrhythmic therapy was effective. Since induction of VT at EPS appears to correlate with subsequent spontaneous recurrence of VT? 3 we show that EPS can be used to identify drugs that are potentially life threatening to the patient. Comparable PES technique for initiation of nonsustained VT during control study and sustained VT during drug study. The reproducibility of inducing nonsus-
tained VT needs to be addressed, particularly since 10 of 11 patients had sustained VT spontaneously prior to the control EPS. We induced multiple episodes of nonsustained VT during the initial EPS in all except Patient 4 who had only one episode induced. In eight patients we also reproducibly induced episodes of nonsustained VT during serial drug EPS. Therefore, the induction of nonsustained VT in almost all of our patients was performed repeatedly and on more than one day. It can be argued that if we had been more aggressive we might have induced sustained VT in all patients. While this may be true, the fact remains that the pacing technique used to induce sustained VT in eight patients was the same as the technique that repeatedly induced nonsustained VT, and in three patients “less aggressive” pacing techniques than those used in the control study induced sustained VT (Table III). Thus, specific antiarrhythmic drugs were arrhythmogenic in se-
VT hazardous
antiarrhythmic
exam/reentry
traits
183
lected patients and facilitated the conversion of nonsustained to sustained VT by PES. Propensity of sustained VT induced during drug therapy to develop VF or hypotension. The patients re-
sponded poorly to most episodes of induced sustained VT, and in one patient the arrhythmia quickly progressed to VF. Of note are the results with encainide therapy. Seven patients had sustained VT induced during encainide therapy, including Patient 6 who had a history of only nonsustained VT. Marked hypotension occurred in all seven patients and three patients required immediate electrical DC cardioversion. It appears that encainide may affect adversely myocardial contractility in patients who have depressed myocardialfunction, in contrast to minimal effects on ventricular function reported in patients who have relatively normal hearts.‘O For example, Patient 4 had sustained VT while receiving both encainide and amiodarone. The tachycardia rate was slower during encainide treatment but resulted in rapid loss of consciousness; tachycardia during amiodarone therapy was tolerated well and caused only palpitations. Potential electrophysiologic mechanisms for druginduced conversion of nonsustained to sustained VT.
We considered that investigation of this group of patients represented an opportunity to explore and contrast the electrophysiologic characteristics present during nonsustained and sustained VT, and by so doing to gain insight into electrophysiologic mechanisms possibly responsible for the latter. Assuming that re-entry was responsible for VT in our patients, one can postulate a potential mechanism by which a drug converts nonsustained VT to sustained VT. To extinguish a re-entrant tachycardia, the optimal electrophysiologic alteration would be to increase refractoriness in one or more limbs of the re-entrant pathway without prolonging activation time. The returning wavefront would encroach on refractory tissue and conduction would cease. A substantial increase in activation time with small increase in refractoriness allows fibers in the reentrant pathway sufficient time to repolarize in advance of the returning wavefront and thus perpetuate the re-entrant circuit. The markedly slower rate of the sustained VT in our patients implies prolonged activation time in the circuit (also assuming that the circuit did not change, a likely assumption since all patients had a similar QRS contour during sustained VT). Naturally, it is impossible to determine the refractory period of individual elements in the reentrant loop and this mechanism remains speculative.
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Rinkenberger
et al.
The authors thank Elizabeth Darling, R.N., for assistance during electrophysiologic studies, Naomi Fineberg, Ph.D., for performing statistical analyses, and Nancy Perkins for manuscript preparation. REFERENCES
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