- Email: [email protected]
Electrophysiologic mechanism of exercise-induced sustained ventricular tachycardia
Electrophysiologic Mechanism of Exercise-Induced Sustained Ventricular Tachycardia RUEY J. SUNG, MD, EDWARD N. SHEN, MD, FRED MORADY, MD, MELVIN M. SCHEINMAN, MD, DAVID HESS, MD, and ELIAS H. BOTVINICK, MD
To elucidate electrophysi01ogic mechanism of exercise-induced ventricular tachycardia (VT), electrophysiologic studies were performed in 12 patients in whom sustained VT had developed during treadmill exercise testing. Six patients had arteriosclerotic coronary heart disease, 3 had cardiomyopathy, and 3 had no clinical evidence of organic heart disease. All patients had had documented episodes of sustained VT related to exertion and had experienced dizziness, syncope, or both. In addition, 3 patients had had nonfatal cardiac arrest. Electrophysiologic studies provoked paroxysms of sustained VT identical to those observed during treadmill exercise testing in 10 patients and provoked ventricular flutter/fibrillation in 1. Seven patients had VT suggestive of a reentrant mechanism, as the VT could be readily initiated with programmed ven-
tricular extrastimulation or terminated by ventricular overdrive pacing, or both. Three patients had VT suggestive of catecholamine-sensitive automaticity. The VT could not be initiated with programmed electrical stimulation, but it could be provoked by intravenous isoproterenol infusion; furthermore, the VT could not be terminated with ventricular overdrive pacing, but it could be abolished by discontinuing isoproterenol infusion. Reproduction of VT in these 10 patients allowed serial pharmacologic testing in selecting an effective antiarrhythmic regimen. Thus (1) exercise-induced VT can be caused by either reentry or cathecholamine-sensitive automaticity, and (2) electrophysiologic studies are of use in defining the underlying mechanism of exercise-induced sustained VT.
In 1927, B o u r n e 1 suggested the use of exercise in exposing ventricular arrhythmias, particularly in patients with arteriosclerotic coronary heart disease. In 1932 Wilson et ale described a form of paroxysmal V T induced by exertion in patients without clinical evidence of organic heart disease. Several clinical investigators 3-1~ subsequently demonstrated that exercise stress testing may provoke ventricular arrhythmias in normal subjects as well as in those with cardiac disease. Although changing h e a r t rate, enhanced s y m p a t h e t i c nervous activity, increased catecholamine secretion, and development of myocardial ischemia have been implicated as contributing factors, the mechanism by which exercise-induced ventricular a r r h y t h m i a s occur remains poorly understood. In the course of evaluating 12 patients in whom sustained V T developed during tread-
mill exercise testing, we performed electrophysiologic studies to delineate the underlying electrophysiologic mechanism. Our findings suggest t h a t exercise-induced sustained V T can be caused either by r e e n t r y or by catecholamine-sensitive automaticity.
Methods Study patients: The study population consisted of 12 patients who had sustained VT (lasting >30 seconds or requiring pharmacologic or electrical intervention, or both, because of circulatory collapse) during multistaged graded-treadmill stress testing using the Bruce protocol. 12 We selected these patients because electrophysiologic studies are more likely to reproduce the arrhythmia in patients with sustained than those with nonsustained VT. 13 Nine patients had complete cardiac catheterization and coronary angiography before admission. Eleetrephysiologie study: Before the study, antiarrhythmic drugs were withheld for over 5 half-lives. The study was performed with patients in a postabsorptive, nonsedated state. With the conventional method, it a tetrapolar electrode catheter was introduced from the right femoral vein and, under fluoroscopy, placed in the right atrium across the tricuspid valve to record the His bundle potential. Another te•trapolar electrode catheter was also introduced from the right femoral vein and placed in the high right atrium for programmed atrial stimulation or placed in the right ventricle for programmed right ventricular stimulation. Electrocardio-
From the Division of Cardiology, Department of Medicine, and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California. This study was supported in part by Harris R Fund 35835, University of California, San Francisco, California. Manuscript received July 1, 1982; revised manuscript received September 8, 1982, accepted September 17, 1982. Address for reprints: Ruey J. Sung, MD, M-575, Moffitt Hospital, University of California at San Francisco, San Francisco, California 94143.
525
526
EXERCISE-INDUCEDVENTRICULAR TACHYCARDIA
graphic leads V1, I, and III were simultaneously displayed with intracardiac electrograms on a multichannel oscilloscope (Electronics for Medicine, VR-12, White Plains, New York), and recordings were made at a paper speed of 50 to 100 mm/s using filter frequency settings of 30 to 500 Hz. A programmed digital stimulator (Bloom & Associates, Narberth, Pennsylvania) was used to deliver electrical impulses of 2.0 ms duration at approximately twice diastolic threshold. Programmed electrical stimulation consisted of incremental pacing and extrastimulation, 15 and was performed in the right atrium, right ventricle (apex and outflow tract), and, if necessary, in the left ventricle by way of a bipolar electrode catheter placed in the left ventricular apex through the right femoral artery. During programmed ventricular extrastimulation, the ventricle was paced at 2 cycle lengths (usually 500 and 400 ms). If a single ventricular extrastimulus failed to elicit VT, timed double or triple ventricular extrastimuli were delivered until the arrhythmia was provoked or until all extrastimuli failed to evoke ventricular responses. If programmed electrical stimulation could not initiate VT, isoproterenol was infused intravenously at a rate of 1 to 4 #g/min until the sinus rate was accelerated to a maximum of 150 beats/min. If intravenous infusion of isoproterenol alone did not provoke an onset of VT, programmed electrical stimulation was repeated during isoproterenol infusion. 16 After initiation of a sustained paroxysm of VT, timed ventricular premature stimuli, short bursts of rapid (overdrive) ventricular pacing, or both, were delivered to terminate the VT. Classification of mechanisms of VT: Mechanisms of VT can be only presumptive during electrophysiologic studies in humans. 17 The 3 major ones are reentry, abnormal automaticity, and triggered activity. VT of a reentrant mechanism is suggested by the ability to initiate the VT with ventricular extrastimulation, or terminate the VT with ventricular extrastimulation or ventricular overdrive pacing. VT of automaticity is caused by rapid automatic discharge related to spontaneous phase 4 depolarization, is Its presence is suggested by the fact that it can neither be initiated nor terminated by programmed electrical stimulation. 17 In contrast, triggered activity related to delayed afterdepolarizations19,2° does not arise spontaneously and is dependent upon previous depolarizations for its initiation. Clinical electrophysiologic studies 21,22have suggested that this type of VT may he initiated during sinus rhythm or during atrial or ventricular paced rhythm within a critical range of cycle lengths and may be abolished by intravenous infusion of slow channel blockers such as verapamil. TABLE I
Results Clinical observations: T h e r e were 9 men and 3 women aged 18 to 74 years (mean 49). T h e clinical data are summarized in Table I. Six patients had arteriosclerotic coronary heart disease (5 had prior myocardial infarction and 2 had ventricular aneurysm), 3 patients had cardiomyopathy (2 dilated and 1 hypertrophic), and the remaining 3 patients were judged to have no clinically recognizable heart disease except for the r h y t h m disturbance. None had prolongation of the Q-T interval. All 12 patients had a history of recurrent sustained V T t h a t occurred during exertion but not at rest, the duration of which ranged from 3 m o n t h s to 5 years. T h e physical activities t h a t precipitated onset of V T included walking, jogging, house cleaning, and playing golf or tennis. All of t h e m had had palpitations, dizziness, syncope, or a combination of these. T h r e e patients (Cases 2, 8, and 11) also had had nonfatal cardiac arrest, p r e s u m a b l y due to degeneration of V T to ventricular fibrillation. Before electrophysiologic studies, we analyzed the onset of sustained V T induced during treadmill exercise testing: 1 p a t i e n t had V T during stage II, 2 patients during stage III, 4 patients during stage IV, and 1 pat i e n t during stage V of the Bruce protocol; in the remaining 4 patients V T developed during the recovery period after exercise. None of the 12 patients had chest pain or exhibited ischemic S-T segment depression before the onset of VT. T h r e e patients (Cases 1, 4, and 12) received intravenous lidocaine and 2 patients (Cases 2 and 8) required direct-current countershock because of h e m o d y n a m i c deterioration. T h e rates of V T ranged from 150 to 210 beats/min. Seven patients had V T of a right and 5 patients of a left bundle branch block pattern. E l e c t r o p h y s i o l o g i c studies: E x c e p t for 2 patients (Cases 6 and 12), we were able to provoke paroxysms of sustained V T with a QRS morphology identical to that induced with treadmill exercise testing. Based on the mode of initiation and termination of the arrhythmia, we classified the 12 patients into 3 groups: 1. Induction of VT suggestive of reentry. In 7 patients (Cases 1, 2, 4, 8, 9, 10, and 11), the mechanism of V T was considered due to r e e n t r y as the tachycardia
Clinical Observations
Case
Age (yr) & Sex
Type of Cardiac Disease
1 2 3 4 5 6 7 8 9 10 11 12
74F 70M 18M 56M 52M 41M 28F 58M 32M 47M 39F 61M
Coronary (HMI) Coronary (HMI) 0 Cardiomyopathy 0 Cardiomyopathy Cardiomyopathy Coronary (HMI) 0 Coronary (HMI) Coronary (HMI) Coronary
Duration of Symptomatic VT (mo)
VT Stage of TET (VT Induction)
Rate (beats/min)
QRS Morphology BBB Pattern
6 12 24 60 18 3 12 24 12 6 36 6
II Ill IV RP RP IV IV IV V RP III RP
180 200 200 210 150 160 160 190 180 200 160 170
Right Right Left Right Left Left Left Right Left Right Right Right
BBB = bundle branch block; HMI = healed myocardial infarction; RP = recovery period; TET = treadmill exercise testing; VT -- ventricular tachycardia.
February 1983 THE AMERICANJOURNALOF CARDIOLOGY Volume 51
of circulatory collapse in 3 patients (Cases 2, 4, and 11). 2. Induction of VT suggestive of catecholaminesensitive automaticity. In 3 patients (Cases 3, 5, and 7), the mechanism of VT was judged due to automaticity because the tachycardia could not be initiated with programmed electrical stimulation. In each instance, VT was provoked by isoproterenol infusion at a dose of 2 to 4 #g/min. Furthermore, VT could not be terminated with timed ventricular extrastimuli or ventricular overdrive pacing; however, it could be abolished by dis-
could be initiated by programmed ventricular extrastimulation--6 patients from the right ventricle (2 patients with single ventricular extrastimuli, I patient with double ventricular extrastimuli, and 3 patients with triple ventricular extrastimuli) and I patient from the left ventricle with double ventricular extrastimuli. One example to illustrate provocation of the same tachycardia with exercise and with ventricular extrastimulation is shown in Figures 1 to 3. The VT so induced could be terminated by ventricular overdrive pacing in 4 patients and by direct-current countershock because
Recovery
A
2rain.
-I........i-r~-'li---i--i-iq-I-:~'-~~::~i.. '.....'......- ' - ~ ~ ~ r ~
'
"
i,
--
-
,
A~
"
._
" "
-I :.... aVF
l!i
~' . . . .
lii FIGURE 1, Onset of sustained VT during the recovery period after a treadmill exercise testing in a 47-year-old man with arteriosclerotic heart disease. The treadmill test was negative for myocardial ischemia up to a heart rate of 160 beats/min. Tracings A and B are continuous and electrocardiographic leads V5 and aVF were simultaneously recorded. Multiform ventricular extrasystoles appear at 2 minutes into the recovery period and are followed by an onset of sustained VT at a rate of 200 beats/rain.
527
-
I I '- -
I ~l :
,,
ove
,
v~
v4
.:',.t~,: !,!,~ ~ ~i~,,~,~l~
u
,
oV[
[
- -~'l
~ ,
: "i"~1'i
' ' '"
!, !~__ '_-.... :',::~i- ,,.~~ ~ . . _ : ,
.
B
_
~
'_-
,',' _
ovR
,',
.',-
,I -:-
v~
v4
V2
V5
-I-I-.I-!-l-_-I
]i
v2 j
v5
II
aVL
t,
7"
FIGURE 2, Same patient as in Figure 1. Comparison between 12-lead electroCardiogram taken during normal sinus rhythm (A) and that taken during exercise-induced VT (B) as demonstrated in Figure 1. Note that the VT has a positive QRS deflection in leads V~ and I, and a negative QRS deflection in lead III.
II|
aVF
V3
'
V6
g
lit
oVF
V3
V6
:
528
EXERCISE-INDUCED VENTRICULAR TACHYCARDIA
of 6 to 15 months (mean 8 4- 2), 1 patient (Case 5) required addition of oral procainamide (2 g/day) to control exertion-induced palpitations and the remaining 2 patients remained free of symptoms. Amiodarone was given to the 2 patients in whom electrophysiologic studies failed to reproduce the arrhythmia because of a history of failure to respond to conventional drugs. These 2 patients did well without recurrence of symptoms during a follow-up period of 4 and 7 months, respectively.
continuing isoproterenol infusion. One example to illustrate provocation of the same tachycardia with exercise and with isoproterenol infusion is shown in Figures 4 to 6. 3. Failure to reproduce VT. In 2 patients (Cases 6 and 12) exercise-induced VT could not be reproduced during electrophysiologic studies. In 1 (Case 12), programmed right ventricular stimulation provoked ventricular flutter-fibrillation necessitating direct-current countershock. The mechanism of exercise-induced VT could not be classified in this patient. In the remaining patient (Case 6), programmed electrical stimulation and isoproterenol infusion failed to induce ventricular arrhythmia. The mechanism of exercise-induced VT was presumed to be due to automaticity. Pharmacologic testing and subsequent follow-up: In 3 of the 7 patients with VT suggestive of reentry, propranolol was first administered intravenously (0.15 to 0.20 mg/kg) and failed to suppress the inducibility of the arrhythmia. Subsequently, 2 of these 3 patients responded to intravenous infusion of procainamide (15 to 20 mg/kg). In the remaining 4 patients, 2 responded to intravenous infusion of procainamide and 2 did not. Overall, 4 patients (Cases 1, 9, 10, and 11) responded to intravenous infusion of procainmide and were treated with oral procainamide (2 to 6 g/day). The 3 patients (Cases 2, 4, and 8) who did not respond to intravenous procainamide were subsequently treated with oral amiodarone (400 to 600 mg/day) since the arrhythmia was refractory to other antiarrhythmic drugs. In a follow-up period of 5 months to 2 years (mean 14 ± 3 months), 3 patients (Cases 1, 9, and 10) required readjustment of medications because of recurrence of symptoms, but all were clinically improved. In the 3 patients with VT suggestive of catecholamine-sensitive automaticity, intravenous infusion of propranolol (0.15 to 0.20 mg/kg) prevented acceleration of the sinus rate beyond 100 beats/min and suppressed inducibility of VT during isoproterenol infusion in all 3 patients. They were subsequently treated with oral nadolol (120 to 320 mg/day). During a follow-up period
Discussion
Observations made in the present study indicate that electrophysiologic studies can reproduce exercise-induced sustained VT in 10 of the 12 patients, and that the occurrence of exercise-induced sustained VT can be caused either by reentry or by catecholamine-sensitive automaticity. Mechanism of exercise-induced ventricular arrhythmias: Several clinical studies 4,5,7,s have demonstrated that ventricular arrhythmias may be heralded by ischemic S-T segment depression or angina pectoris, particularly in patients with arteriosclerotic coronary heart disease. Development of ischemic S-T segment depression, angina pectoris, or both usually diminishes the duration of exercise and thereby decreases the degree of myocardial stress preventing provocation of ventricular arrhythmias. Several investigators 6 s have noted that exercise-induced ventricular arrhythmias often occur in the absence of ischemic S-T segment depression or angina pectoris. It is postulated that enhanced sympathetic nervous activity or increased secretion of catecholamines may alter electrophysiologic properties of the ventricular myocardium or the subendocardial Purkinje network, thereby enhancing automaticity or favoring the occurrence of reentry, or both. 23 Although myocardial ischemia cannot be completely excluded without perfusion scintigraphy, the results of our study confirmed that either reentry or catecholamine-sensitive automaticity may cause exercise-induced sustained VT.
V1 s,'°° I
FIGURE 3. Same patient as in Figures 1 and 2. Initiation of sustained VT with programmed right ventricular extrastimulation. Electrocardiographic leads V 1, I, and III are simultaneously re-
III
corded with the His bundle electrographic lead (HBE). Right femoral arterial pressure is recorded at the bottom. During right ventricular pacing at
HBE
"+ +;+':'-+'-
--
a cycle length ($1-$1) of 500 ms, a
ventricular premature beat ($2) with a
+ 100 mmHg
---
.
.
',+--+ --"
. .
.
. .
.
.
. .
.
~
. . . . - -
.
.
.
.
~ .
.
__ .
+
-
-
] : L - - ~
~
--
~
-
+
-
premature coupling interval ($1-$2) of 230 ms initiates an onset of VT with a cycle length of 340 ms. Note that the QRS morphology of the VT is identical to that induced during treadmill exercise testing (Fig. 2). The VT could be terminated by overdrive suppression (not shown). A = atrial electrogram.
February 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 51
529
vs
FIGURE 4. Onset of sustained VT at 1.1 minute into stage IV of a treadmill exercise testing in an 18-year-old man without clinical evidence of organic heart disease. The sinus rate is accelerated to 150 beats/rain before the onset of VT at a rate of 190 beats/min. Electrocardiographic leads V5 and aVF are simultaneously recorded•
i
,
!
i J
!
n
*
.
i 4
iij
I
aVF
B
A,IIi
t
aVi
l:
I FIGURE 5. Same patient as in Figure 4. Comparison between 12-lead electrocardiogram taken during sinus rhythm (A) and that taken during exercise-induced VT (B) as demonstrated in Figure 4. Note that the VT has a predominantly negative QRS deflection in leads V1 and I, and a positive QRS deflection in lead II1.
,
*l
I I
v=I
I!i
!
,
I : J I
4 ug/min.
I s o p r o t e r e n o l
420
FIGURE 6. Same patient as in Figures 4 and 5. After failure of programmed electrical stimulation to induce arrhythmia, isoproterenol infusion at 4 /~g/min accelerates the sinus rate (cycle length 420 ms) and provokes an onset of sustained VT with a cycle length of 300 ms. Electrocardiographic leads V1, I, and III, His bundle electrographic lead (HBE), and right ventricular electrogram (RV) are simultaneously recorded. Right femoral arterial pressure is recorded at the bottom. A = atrial electrogram; H = His bundle electrogram. Note that the QRS morPhology of the VT is identical to that induced during treadmill exercise testing (see Fig. 5).
III
300
,, AH
Ls
A
I
AH
+
100 m m H 9 ~Z'~-'-----.~L.~-'~_
--'-~
530
EXERCISE-INDUCEDVENTRtCULAR TACHYCARDIA
Triggered activity related to delayed afterdepolarizations has been raised as a possible mechanism of exercise-induced VT. 24 Based on our recent study, 22 we believe that VT caused by such a mechanism has certain electrophysiologic characteristics: (1) its onset depends on a critical range of cycle lengths; therefore, it may or may not require exercise to induce the arrhythmia; (2) it can be initiated during sinus, atrial, or ventricular paced rhythm within the critical range of cycle lengths; (3) it is more easily triggered with pacing the atrium or ventricle for several beats than with single extrastimuli; (4) the interval between the first beat of tachycardia and the last sinus or paced beat (QRS complex) gradually decreases as the sinus or paced cycle length progressively shortens; and (5) its initiation can be prevented by intravenous infusion of slow channel blockers such as verapamil. In the evaluation of patients with exercise-induced VT, the possibility of having triggered activity as the underlying mechanism should also be considered. Treatment of exercise-induced ventricular arrhythmias: In patients with exercise-induced ventricular arrhythmias related to myocardial ischemia, treatment should be directed toward prevention of the development of myocardial ischemia. This includes the use of nitrates, beta-adrenergic blocking agents, and slow channel blockers in the presence or absence of coronary artery spasm as a contributing factor. 25 In this situation, aortocoronary bypass grafting may be expected to be useful in abolishing the arrhythmia. 26,27 In patients with exercise-induced ventricular arrhythmias not related to myocardial ischemia, the treatment should, however, be directed toward controlling the underlying mechanism. In this series, beta-adrenergic blockade with intravenous propranolol failed to suppress inducibility of VT suggestive of a reentrant mechanism (3 patients), but was effective in preventing induction of VT suggestive of catecholamine-sensitive automaticity (also 3 patients). Overall, amiodarone appeared to be an effective antiarrhythmic agent for cases that are refractory to or intolerant of conventional drugs (5 patients). We realize that the number in each group of patients is small, and further studies are necessary to define the long-term efficacy of various antiarrhythmic agents in the treatment of exercise-induced VT. Myocardial revascularization is not expected to be useful in abolishing ventricular arrhythmias not related to ischemia. 28 Nevertheless, it should be pointed out that VT caused by reentry or automaticity may be corrected by surgical removal of the reentrant pathways or the automatic focus. 29 Clinical implications: Observations made in the present study have the following important clinical implications: (1) Exercise-induced ventricular arrhythmias may or may not be related to myocardial ischemia, and electrophysiologic mechanisms responsible for these arrhythmias vary among patients. Reentry, automaticity, and triggered activity all need to be considered. Understanding of the underlying pathophysiology allows a more rational approach to the treatment. (2) In patients with exercise-induced sustained VT, electrophysiologic studies may be useful in
reproducing the arrhythmia, thereby allowing serial pharmacologic testing for selecting a proper antiarrhythmic regimen. Acknowledgment: We thank Ardith Perry for technical assistance in performing treadmill exercise testing and Lynn Whittier for secretarial assistance in the preparation of this manuscript. References 1. Bourne G. An attempt at the clinical classification of premature ventricular beats. Q J Med 1927;20:219-243 2. Wilson FN, Wishart SW, Macleod AG, Barker PS. A clinical type of paroxysmal tachycardia of ventricular origin in which paroxysms are induced by exertion. Am Heart J 1932;8:155-169. 3. Mann RH, Burchell HB. Premature ventricular contractions and ,exercise Proc Staff Meet Mayo Clinic 1952;27:383-389. 4. Gooch AS, McConnell D. Analysis of transient arrhythmias and conduction disturbances occurring during submaxlmal treadmill exercise. Prog Cardiovasc Dis 1970; 13:293-307. 5. Andrews MT, Lee GB, Campion BC. Cardiac dysrhythmias associated with exercise stress testing. Am J Cardiol 1972;30:763-767. 6. McHenry PL, Fish C, Jordan aw, Corya BR. Cardiac arrhythmias observed during maximal treadmill exercise testing in clinically normal men. Am J Cardiol 1972;29:331-336. 7. Goldschlagar N, Cake D, Cohn K. Exercise-induced ventricular arrhythmJas in patients with coronary artery disease: their relation to angiographlc findings. Am J Cardio11973;31:434-440 8. Jelinek MV, Lown B. Exercise stress testing for exposure of cardiac arrhythmia. Prog Cardiovasc Dis 1974; 16:497-522. 9. Faris JV, McHenry PL, Jordan aw, Morris SN. Prevalence and reproducibility of exercise-induced ventricular arrhythmias during maximal exercise testing in normal men. Am J Cardiol 1976;37:617-622. 10. Mokotoft DM, euinones MA, Miller RR. Exercise-induced ventricular tachycardia. Clinical features, relation to chronic ventricular ectopy, and prognosis. Chest 1980;77:1-16. 11. Codini MA, Sommerfeldt L, Eybel CE, Messer JV. Clinical significance and characteristics of exercise-induced ventricular tachycardia. Cathet Cardiovasc Diagn 1981;7:227-234. 12. Doan AE, Peterson DR, Blackmon JR, Bruce RA. Myocardial Jschemiaafter maximal exercise in healthy men. A method for detecting potential coronary disease. Am Heart J 1965;69:11-20. 13. Denes P, Wu D, Dhingra RC, Amat-y-Leon F, Wyndham C, Mautner R, Rosen KM. Electrophysiological studies in patients with chronic recurrent ventricular tachycardia. Circulation 1976;54:229-236. 14. Scherlag BJ, Lau SH, Helfant RH, Berkowitz WD, Stein E, Damato AN. Catheter technique for recording His bundle activity in man. Circulation 1969;39:13-19 15. Sung RJ, Castellanos A, Mallon SM, Bloom MG, Gelband H, Myerburg RJ. Mode of initiation of reciprocating tachycardia during programmed ventricular stimulation in the Wolff-Parkinson-White syndrome: with reference to various patterns of ventriculoatrial conduction. Am J Cardiol 1977;40: 24-31. 16. Reddy CP, Geltes LS. Use of isoproterenol as an aid to electrical induction of chronic recurrent ventricular tachycardia. Am J Cardiol 1979;44: 705-713. 17. Wellens HJJ. Value and limitations of programmed electrical stimulahon of the heart in the study and treatment of tachycardias. Circulation 1978; 57:845-853. 18. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias Circ Res 1981;49:1-14. 19. Wil AL, Cranefield PF. Triggered activity in cardiac muscle fibers of the simian mitral valve. Circ Res 1976;38:85-98. 20. Rosen MR, Feder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94:794-801. 21. Zipes DP, Foster PR, Troup PJ, Pedersen DH. Atrial induction of ventricular tachycardia: reentry versus triggered automaticity. Am J Cardiol 1979; 44:1-8. 22. Sung RJ, Shen EN, Shapiro W, Morady F, Davis J. Effects of verapamil on ventricular tachycardia of various mechanisms--with special reference to triggered activity in man (abstr). Clin Res 1982;30:224A. 23. Hart J, Moe GK. Nonuniform recovery of excitability of ventricular muscle. Circ Res 1964; 14:44-60. 24. Wu D, Kou H, Hung J. Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization. Ann intern Med 1981;95:410-414. 25. Brodsky SJ, Cutler SS, Weiner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamih a double-blind, placebo-controlled randomized crossover study. Circulation 1982;66:569579. 26. Bryson AL, Parisi AF, Schechter E, Wolfson S. Life-threatening ventricular arrhythmias induced by exercise. Cessation after coronary bypass surgery. Am J Cardiol 1973;32:995-999. 27. Cnne RE, Armstrong RG, Stanford W. Successful myocardial revascularization after ventricular fibrillation induced by treadmill exercise. J. ThoraC Cardiovasc Surg 1973;65:802-805. 28. Lehrman KL, Tilkian AG, Hultgren HN, Fowles RE. Effect of coronary arterial bypass surgery on exercise-induced ventricular arrhvthmias. Long-term follow-up of a prospective randomized study. Am J" Cardiol 1979"44 1056-1061. 29. Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a neW surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:1430-1439.
To elucidate electrophysi01ogic mechanism of exercise-induced ventricular tachycardia (VT), electrophysiologic studies were performed in 12 patients in whom sustained VT had developed during treadmill exercise testing. Six patients had arteriosclerotic coronary heart disease, 3 had cardiomyopathy, and 3 had no clinical evidence of organic heart disease. All patients had had documented episodes of sustained VT related to exertion and had experienced dizziness, syncope, or both. In addition, 3 patients had had nonfatal cardiac arrest. Electrophysiologic studies provoked paroxysms of sustained VT identical to those observed during treadmill exercise testing in 10 patients and provoked ventricular flutter/fibrillation in 1. Seven patients had VT suggestive of a reentrant mechanism, as the VT could be readily initiated with programmed ven-
tricular extrastimulation or terminated by ventricular overdrive pacing, or both. Three patients had VT suggestive of catecholamine-sensitive automaticity. The VT could not be initiated with programmed electrical stimulation, but it could be provoked by intravenous isoproterenol infusion; furthermore, the VT could not be terminated with ventricular overdrive pacing, but it could be abolished by discontinuing isoproterenol infusion. Reproduction of VT in these 10 patients allowed serial pharmacologic testing in selecting an effective antiarrhythmic regimen. Thus (1) exercise-induced VT can be caused by either reentry or cathecholamine-sensitive automaticity, and (2) electrophysiologic studies are of use in defining the underlying mechanism of exercise-induced sustained VT.
In 1927, B o u r n e 1 suggested the use of exercise in exposing ventricular arrhythmias, particularly in patients with arteriosclerotic coronary heart disease. In 1932 Wilson et ale described a form of paroxysmal V T induced by exertion in patients without clinical evidence of organic heart disease. Several clinical investigators 3-1~ subsequently demonstrated that exercise stress testing may provoke ventricular arrhythmias in normal subjects as well as in those with cardiac disease. Although changing h e a r t rate, enhanced s y m p a t h e t i c nervous activity, increased catecholamine secretion, and development of myocardial ischemia have been implicated as contributing factors, the mechanism by which exercise-induced ventricular a r r h y t h m i a s occur remains poorly understood. In the course of evaluating 12 patients in whom sustained V T developed during tread-
mill exercise testing, we performed electrophysiologic studies to delineate the underlying electrophysiologic mechanism. Our findings suggest t h a t exercise-induced sustained V T can be caused either by r e e n t r y or by catecholamine-sensitive automaticity.
Methods Study patients: The study population consisted of 12 patients who had sustained VT (lasting >30 seconds or requiring pharmacologic or electrical intervention, or both, because of circulatory collapse) during multistaged graded-treadmill stress testing using the Bruce protocol. 12 We selected these patients because electrophysiologic studies are more likely to reproduce the arrhythmia in patients with sustained than those with nonsustained VT. 13 Nine patients had complete cardiac catheterization and coronary angiography before admission. Eleetrephysiologie study: Before the study, antiarrhythmic drugs were withheld for over 5 half-lives. The study was performed with patients in a postabsorptive, nonsedated state. With the conventional method, it a tetrapolar electrode catheter was introduced from the right femoral vein and, under fluoroscopy, placed in the right atrium across the tricuspid valve to record the His bundle potential. Another te•trapolar electrode catheter was also introduced from the right femoral vein and placed in the high right atrium for programmed atrial stimulation or placed in the right ventricle for programmed right ventricular stimulation. Electrocardio-
From the Division of Cardiology, Department of Medicine, and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California. This study was supported in part by Harris R Fund 35835, University of California, San Francisco, California. Manuscript received July 1, 1982; revised manuscript received September 8, 1982, accepted September 17, 1982. Address for reprints: Ruey J. Sung, MD, M-575, Moffitt Hospital, University of California at San Francisco, San Francisco, California 94143.
525
526
EXERCISE-INDUCEDVENTRICULAR TACHYCARDIA
graphic leads V1, I, and III were simultaneously displayed with intracardiac electrograms on a multichannel oscilloscope (Electronics for Medicine, VR-12, White Plains, New York), and recordings were made at a paper speed of 50 to 100 mm/s using filter frequency settings of 30 to 500 Hz. A programmed digital stimulator (Bloom & Associates, Narberth, Pennsylvania) was used to deliver electrical impulses of 2.0 ms duration at approximately twice diastolic threshold. Programmed electrical stimulation consisted of incremental pacing and extrastimulation, 15 and was performed in the right atrium, right ventricle (apex and outflow tract), and, if necessary, in the left ventricle by way of a bipolar electrode catheter placed in the left ventricular apex through the right femoral artery. During programmed ventricular extrastimulation, the ventricle was paced at 2 cycle lengths (usually 500 and 400 ms). If a single ventricular extrastimulus failed to elicit VT, timed double or triple ventricular extrastimuli were delivered until the arrhythmia was provoked or until all extrastimuli failed to evoke ventricular responses. If programmed electrical stimulation could not initiate VT, isoproterenol was infused intravenously at a rate of 1 to 4 #g/min until the sinus rate was accelerated to a maximum of 150 beats/min. If intravenous infusion of isoproterenol alone did not provoke an onset of VT, programmed electrical stimulation was repeated during isoproterenol infusion. 16 After initiation of a sustained paroxysm of VT, timed ventricular premature stimuli, short bursts of rapid (overdrive) ventricular pacing, or both, were delivered to terminate the VT. Classification of mechanisms of VT: Mechanisms of VT can be only presumptive during electrophysiologic studies in humans. 17 The 3 major ones are reentry, abnormal automaticity, and triggered activity. VT of a reentrant mechanism is suggested by the ability to initiate the VT with ventricular extrastimulation, or terminate the VT with ventricular extrastimulation or ventricular overdrive pacing. VT of automaticity is caused by rapid automatic discharge related to spontaneous phase 4 depolarization, is Its presence is suggested by the fact that it can neither be initiated nor terminated by programmed electrical stimulation. 17 In contrast, triggered activity related to delayed afterdepolarizations19,2° does not arise spontaneously and is dependent upon previous depolarizations for its initiation. Clinical electrophysiologic studies 21,22have suggested that this type of VT may he initiated during sinus rhythm or during atrial or ventricular paced rhythm within a critical range of cycle lengths and may be abolished by intravenous infusion of slow channel blockers such as verapamil. TABLE I
Results Clinical observations: T h e r e were 9 men and 3 women aged 18 to 74 years (mean 49). T h e clinical data are summarized in Table I. Six patients had arteriosclerotic coronary heart disease (5 had prior myocardial infarction and 2 had ventricular aneurysm), 3 patients had cardiomyopathy (2 dilated and 1 hypertrophic), and the remaining 3 patients were judged to have no clinically recognizable heart disease except for the r h y t h m disturbance. None had prolongation of the Q-T interval. All 12 patients had a history of recurrent sustained V T t h a t occurred during exertion but not at rest, the duration of which ranged from 3 m o n t h s to 5 years. T h e physical activities t h a t precipitated onset of V T included walking, jogging, house cleaning, and playing golf or tennis. All of t h e m had had palpitations, dizziness, syncope, or a combination of these. T h r e e patients (Cases 2, 8, and 11) also had had nonfatal cardiac arrest, p r e s u m a b l y due to degeneration of V T to ventricular fibrillation. Before electrophysiologic studies, we analyzed the onset of sustained V T induced during treadmill exercise testing: 1 p a t i e n t had V T during stage II, 2 patients during stage III, 4 patients during stage IV, and 1 pat i e n t during stage V of the Bruce protocol; in the remaining 4 patients V T developed during the recovery period after exercise. None of the 12 patients had chest pain or exhibited ischemic S-T segment depression before the onset of VT. T h r e e patients (Cases 1, 4, and 12) received intravenous lidocaine and 2 patients (Cases 2 and 8) required direct-current countershock because of h e m o d y n a m i c deterioration. T h e rates of V T ranged from 150 to 210 beats/min. Seven patients had V T of a right and 5 patients of a left bundle branch block pattern. E l e c t r o p h y s i o l o g i c studies: E x c e p t for 2 patients (Cases 6 and 12), we were able to provoke paroxysms of sustained V T with a QRS morphology identical to that induced with treadmill exercise testing. Based on the mode of initiation and termination of the arrhythmia, we classified the 12 patients into 3 groups: 1. Induction of VT suggestive of reentry. In 7 patients (Cases 1, 2, 4, 8, 9, 10, and 11), the mechanism of V T was considered due to r e e n t r y as the tachycardia
Clinical Observations
Case
Age (yr) & Sex
Type of Cardiac Disease
1 2 3 4 5 6 7 8 9 10 11 12
74F 70M 18M 56M 52M 41M 28F 58M 32M 47M 39F 61M
Coronary (HMI) Coronary (HMI) 0 Cardiomyopathy 0 Cardiomyopathy Cardiomyopathy Coronary (HMI) 0 Coronary (HMI) Coronary (HMI) Coronary
Duration of Symptomatic VT (mo)
VT Stage of TET (VT Induction)
Rate (beats/min)
QRS Morphology BBB Pattern
6 12 24 60 18 3 12 24 12 6 36 6
II Ill IV RP RP IV IV IV V RP III RP
180 200 200 210 150 160 160 190 180 200 160 170
Right Right Left Right Left Left Left Right Left Right Right Right
BBB = bundle branch block; HMI = healed myocardial infarction; RP = recovery period; TET = treadmill exercise testing; VT -- ventricular tachycardia.
February 1983 THE AMERICANJOURNALOF CARDIOLOGY Volume 51
of circulatory collapse in 3 patients (Cases 2, 4, and 11). 2. Induction of VT suggestive of catecholaminesensitive automaticity. In 3 patients (Cases 3, 5, and 7), the mechanism of VT was judged due to automaticity because the tachycardia could not be initiated with programmed electrical stimulation. In each instance, VT was provoked by isoproterenol infusion at a dose of 2 to 4 #g/min. Furthermore, VT could not be terminated with timed ventricular extrastimuli or ventricular overdrive pacing; however, it could be abolished by dis-
could be initiated by programmed ventricular extrastimulation--6 patients from the right ventricle (2 patients with single ventricular extrastimuli, I patient with double ventricular extrastimuli, and 3 patients with triple ventricular extrastimuli) and I patient from the left ventricle with double ventricular extrastimuli. One example to illustrate provocation of the same tachycardia with exercise and with ventricular extrastimulation is shown in Figures 1 to 3. The VT so induced could be terminated by ventricular overdrive pacing in 4 patients and by direct-current countershock because
Recovery
A
2rain.
-I........i-r~-'li---i--i-iq-I-:~'-~~::~i.. '.....'......- ' - ~ ~ ~ r ~
'
"
i,
--
-
,
A~
"
._
" "
-I :.... aVF
l!i
~' . . . .
lii FIGURE 1, Onset of sustained VT during the recovery period after a treadmill exercise testing in a 47-year-old man with arteriosclerotic heart disease. The treadmill test was negative for myocardial ischemia up to a heart rate of 160 beats/min. Tracings A and B are continuous and electrocardiographic leads V5 and aVF were simultaneously recorded. Multiform ventricular extrasystoles appear at 2 minutes into the recovery period and are followed by an onset of sustained VT at a rate of 200 beats/rain.
527
-
I I '- -
I ~l :
,,
ove
,
v~
v4
.:',.t~,: !,!,~ ~ ~i~,,~,~l~
u
,
oV[
[
- -~'l
~ ,
: "i"~1'i
' ' '"
!, !~__ '_-.... :',::~i- ,,.~~ ~ . . _ : ,
.
B
_
~
'_-
,',' _
ovR
,',
.',-
,I -:-
v~
v4
V2
V5
-I-I-.I-!-l-_-I
]i
v2 j
v5
II
aVL
t,
7"
FIGURE 2, Same patient as in Figure 1. Comparison between 12-lead electroCardiogram taken during normal sinus rhythm (A) and that taken during exercise-induced VT (B) as demonstrated in Figure 1. Note that the VT has a positive QRS deflection in leads V~ and I, and a negative QRS deflection in lead III.
II|
aVF
V3
'
V6
g
lit
oVF
V3
V6
:
528
EXERCISE-INDUCED VENTRICULAR TACHYCARDIA
of 6 to 15 months (mean 8 4- 2), 1 patient (Case 5) required addition of oral procainamide (2 g/day) to control exertion-induced palpitations and the remaining 2 patients remained free of symptoms. Amiodarone was given to the 2 patients in whom electrophysiologic studies failed to reproduce the arrhythmia because of a history of failure to respond to conventional drugs. These 2 patients did well without recurrence of symptoms during a follow-up period of 4 and 7 months, respectively.
continuing isoproterenol infusion. One example to illustrate provocation of the same tachycardia with exercise and with isoproterenol infusion is shown in Figures 4 to 6. 3. Failure to reproduce VT. In 2 patients (Cases 6 and 12) exercise-induced VT could not be reproduced during electrophysiologic studies. In 1 (Case 12), programmed right ventricular stimulation provoked ventricular flutter-fibrillation necessitating direct-current countershock. The mechanism of exercise-induced VT could not be classified in this patient. In the remaining patient (Case 6), programmed electrical stimulation and isoproterenol infusion failed to induce ventricular arrhythmia. The mechanism of exercise-induced VT was presumed to be due to automaticity. Pharmacologic testing and subsequent follow-up: In 3 of the 7 patients with VT suggestive of reentry, propranolol was first administered intravenously (0.15 to 0.20 mg/kg) and failed to suppress the inducibility of the arrhythmia. Subsequently, 2 of these 3 patients responded to intravenous infusion of procainamide (15 to 20 mg/kg). In the remaining 4 patients, 2 responded to intravenous infusion of procainamide and 2 did not. Overall, 4 patients (Cases 1, 9, 10, and 11) responded to intravenous infusion of procainmide and were treated with oral procainamide (2 to 6 g/day). The 3 patients (Cases 2, 4, and 8) who did not respond to intravenous procainamide were subsequently treated with oral amiodarone (400 to 600 mg/day) since the arrhythmia was refractory to other antiarrhythmic drugs. In a follow-up period of 5 months to 2 years (mean 14 ± 3 months), 3 patients (Cases 1, 9, and 10) required readjustment of medications because of recurrence of symptoms, but all were clinically improved. In the 3 patients with VT suggestive of catecholamine-sensitive automaticity, intravenous infusion of propranolol (0.15 to 0.20 mg/kg) prevented acceleration of the sinus rate beyond 100 beats/min and suppressed inducibility of VT during isoproterenol infusion in all 3 patients. They were subsequently treated with oral nadolol (120 to 320 mg/day). During a follow-up period
Discussion
Observations made in the present study indicate that electrophysiologic studies can reproduce exercise-induced sustained VT in 10 of the 12 patients, and that the occurrence of exercise-induced sustained VT can be caused either by reentry or by catecholamine-sensitive automaticity. Mechanism of exercise-induced ventricular arrhythmias: Several clinical studies 4,5,7,s have demonstrated that ventricular arrhythmias may be heralded by ischemic S-T segment depression or angina pectoris, particularly in patients with arteriosclerotic coronary heart disease. Development of ischemic S-T segment depression, angina pectoris, or both usually diminishes the duration of exercise and thereby decreases the degree of myocardial stress preventing provocation of ventricular arrhythmias. Several investigators 6 s have noted that exercise-induced ventricular arrhythmias often occur in the absence of ischemic S-T segment depression or angina pectoris. It is postulated that enhanced sympathetic nervous activity or increased secretion of catecholamines may alter electrophysiologic properties of the ventricular myocardium or the subendocardial Purkinje network, thereby enhancing automaticity or favoring the occurrence of reentry, or both. 23 Although myocardial ischemia cannot be completely excluded without perfusion scintigraphy, the results of our study confirmed that either reentry or catecholamine-sensitive automaticity may cause exercise-induced sustained VT.
V1 s,'°° I
FIGURE 3. Same patient as in Figures 1 and 2. Initiation of sustained VT with programmed right ventricular extrastimulation. Electrocardiographic leads V 1, I, and III are simultaneously re-
III
corded with the His bundle electrographic lead (HBE). Right femoral arterial pressure is recorded at the bottom. During right ventricular pacing at
HBE
"+ +;+':'-+'-
--
a cycle length ($1-$1) of 500 ms, a
ventricular premature beat ($2) with a
+ 100 mmHg
---
.
.
',+--+ --"
. .
.
. .
.
.
. .
.
~
. . . . - -
.
.
.
.
~ .
.
__ .
+
-
-
] : L - - ~
~
--
~
-
+
-
premature coupling interval ($1-$2) of 230 ms initiates an onset of VT with a cycle length of 340 ms. Note that the QRS morphology of the VT is identical to that induced during treadmill exercise testing (Fig. 2). The VT could be terminated by overdrive suppression (not shown). A = atrial electrogram.
February 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 51
529
vs
FIGURE 4. Onset of sustained VT at 1.1 minute into stage IV of a treadmill exercise testing in an 18-year-old man without clinical evidence of organic heart disease. The sinus rate is accelerated to 150 beats/rain before the onset of VT at a rate of 190 beats/min. Electrocardiographic leads V5 and aVF are simultaneously recorded•
i
,
!
i J
!
n
*
.
i 4
iij
I
aVF
B
A,IIi
t
aVi
l:
I FIGURE 5. Same patient as in Figure 4. Comparison between 12-lead electrocardiogram taken during sinus rhythm (A) and that taken during exercise-induced VT (B) as demonstrated in Figure 4. Note that the VT has a predominantly negative QRS deflection in leads V1 and I, and a positive QRS deflection in lead II1.
,
*l
I I
v=I
I!i
!
,
I : J I
4 ug/min.
I s o p r o t e r e n o l
420
FIGURE 6. Same patient as in Figures 4 and 5. After failure of programmed electrical stimulation to induce arrhythmia, isoproterenol infusion at 4 /~g/min accelerates the sinus rate (cycle length 420 ms) and provokes an onset of sustained VT with a cycle length of 300 ms. Electrocardiographic leads V1, I, and III, His bundle electrographic lead (HBE), and right ventricular electrogram (RV) are simultaneously recorded. Right femoral arterial pressure is recorded at the bottom. A = atrial electrogram; H = His bundle electrogram. Note that the QRS morPhology of the VT is identical to that induced during treadmill exercise testing (see Fig. 5).
III
300
,, AH
Ls
A
I
AH
+
100 m m H 9 ~Z'~-'-----.~L.~-'~_
--'-~
530
EXERCISE-INDUCEDVENTRtCULAR TACHYCARDIA
Triggered activity related to delayed afterdepolarizations has been raised as a possible mechanism of exercise-induced VT. 24 Based on our recent study, 22 we believe that VT caused by such a mechanism has certain electrophysiologic characteristics: (1) its onset depends on a critical range of cycle lengths; therefore, it may or may not require exercise to induce the arrhythmia; (2) it can be initiated during sinus, atrial, or ventricular paced rhythm within the critical range of cycle lengths; (3) it is more easily triggered with pacing the atrium or ventricle for several beats than with single extrastimuli; (4) the interval between the first beat of tachycardia and the last sinus or paced beat (QRS complex) gradually decreases as the sinus or paced cycle length progressively shortens; and (5) its initiation can be prevented by intravenous infusion of slow channel blockers such as verapamil. In the evaluation of patients with exercise-induced VT, the possibility of having triggered activity as the underlying mechanism should also be considered. Treatment of exercise-induced ventricular arrhythmias: In patients with exercise-induced ventricular arrhythmias related to myocardial ischemia, treatment should be directed toward prevention of the development of myocardial ischemia. This includes the use of nitrates, beta-adrenergic blocking agents, and slow channel blockers in the presence or absence of coronary artery spasm as a contributing factor. 25 In this situation, aortocoronary bypass grafting may be expected to be useful in abolishing the arrhythmia. 26,27 In patients with exercise-induced ventricular arrhythmias not related to myocardial ischemia, the treatment should, however, be directed toward controlling the underlying mechanism. In this series, beta-adrenergic blockade with intravenous propranolol failed to suppress inducibility of VT suggestive of a reentrant mechanism (3 patients), but was effective in preventing induction of VT suggestive of catecholamine-sensitive automaticity (also 3 patients). Overall, amiodarone appeared to be an effective antiarrhythmic agent for cases that are refractory to or intolerant of conventional drugs (5 patients). We realize that the number in each group of patients is small, and further studies are necessary to define the long-term efficacy of various antiarrhythmic agents in the treatment of exercise-induced VT. Myocardial revascularization is not expected to be useful in abolishing ventricular arrhythmias not related to ischemia. 28 Nevertheless, it should be pointed out that VT caused by reentry or automaticity may be corrected by surgical removal of the reentrant pathways or the automatic focus. 29 Clinical implications: Observations made in the present study have the following important clinical implications: (1) Exercise-induced ventricular arrhythmias may or may not be related to myocardial ischemia, and electrophysiologic mechanisms responsible for these arrhythmias vary among patients. Reentry, automaticity, and triggered activity all need to be considered. Understanding of the underlying pathophysiology allows a more rational approach to the treatment. (2) In patients with exercise-induced sustained VT, electrophysiologic studies may be useful in
reproducing the arrhythmia, thereby allowing serial pharmacologic testing for selecting a proper antiarrhythmic regimen. Acknowledgment: We thank Ardith Perry for technical assistance in performing treadmill exercise testing and Lynn Whittier for secretarial assistance in the preparation of this manuscript. References 1. Bourne G. An attempt at the clinical classification of premature ventricular beats. Q J Med 1927;20:219-243 2. Wilson FN, Wishart SW, Macleod AG, Barker PS. A clinical type of paroxysmal tachycardia of ventricular origin in which paroxysms are induced by exertion. Am Heart J 1932;8:155-169. 3. Mann RH, Burchell HB. Premature ventricular contractions and ,exercise Proc Staff Meet Mayo Clinic 1952;27:383-389. 4. Gooch AS, McConnell D. Analysis of transient arrhythmias and conduction disturbances occurring during submaxlmal treadmill exercise. Prog Cardiovasc Dis 1970; 13:293-307. 5. Andrews MT, Lee GB, Campion BC. Cardiac dysrhythmias associated with exercise stress testing. Am J Cardiol 1972;30:763-767. 6. McHenry PL, Fish C, Jordan aw, Corya BR. Cardiac arrhythmias observed during maximal treadmill exercise testing in clinically normal men. Am J Cardiol 1972;29:331-336. 7. Goldschlagar N, Cake D, Cohn K. Exercise-induced ventricular arrhythmJas in patients with coronary artery disease: their relation to angiographlc findings. Am J Cardio11973;31:434-440 8. Jelinek MV, Lown B. Exercise stress testing for exposure of cardiac arrhythmia. Prog Cardiovasc Dis 1974; 16:497-522. 9. Faris JV, McHenry PL, Jordan aw, Morris SN. Prevalence and reproducibility of exercise-induced ventricular arrhythmias during maximal exercise testing in normal men. Am J Cardiol 1976;37:617-622. 10. Mokotoft DM, euinones MA, Miller RR. Exercise-induced ventricular tachycardia. Clinical features, relation to chronic ventricular ectopy, and prognosis. Chest 1980;77:1-16. 11. Codini MA, Sommerfeldt L, Eybel CE, Messer JV. Clinical significance and characteristics of exercise-induced ventricular tachycardia. Cathet Cardiovasc Diagn 1981;7:227-234. 12. Doan AE, Peterson DR, Blackmon JR, Bruce RA. Myocardial Jschemiaafter maximal exercise in healthy men. A method for detecting potential coronary disease. Am Heart J 1965;69:11-20. 13. Denes P, Wu D, Dhingra RC, Amat-y-Leon F, Wyndham C, Mautner R, Rosen KM. Electrophysiological studies in patients with chronic recurrent ventricular tachycardia. Circulation 1976;54:229-236. 14. Scherlag BJ, Lau SH, Helfant RH, Berkowitz WD, Stein E, Damato AN. Catheter technique for recording His bundle activity in man. Circulation 1969;39:13-19 15. Sung RJ, Castellanos A, Mallon SM, Bloom MG, Gelband H, Myerburg RJ. Mode of initiation of reciprocating tachycardia during programmed ventricular stimulation in the Wolff-Parkinson-White syndrome: with reference to various patterns of ventriculoatrial conduction. Am J Cardiol 1977;40: 24-31. 16. Reddy CP, Geltes LS. Use of isoproterenol as an aid to electrical induction of chronic recurrent ventricular tachycardia. Am J Cardiol 1979;44: 705-713. 17. Wellens HJJ. Value and limitations of programmed electrical stimulahon of the heart in the study and treatment of tachycardias. Circulation 1978; 57:845-853. 18. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias Circ Res 1981;49:1-14. 19. Wil AL, Cranefield PF. Triggered activity in cardiac muscle fibers of the simian mitral valve. Circ Res 1976;38:85-98. 20. Rosen MR, Feder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94:794-801. 21. Zipes DP, Foster PR, Troup PJ, Pedersen DH. Atrial induction of ventricular tachycardia: reentry versus triggered automaticity. Am J Cardiol 1979; 44:1-8. 22. Sung RJ, Shen EN, Shapiro W, Morady F, Davis J. Effects of verapamil on ventricular tachycardia of various mechanisms--with special reference to triggered activity in man (abstr). Clin Res 1982;30:224A. 23. Hart J, Moe GK. Nonuniform recovery of excitability of ventricular muscle. Circ Res 1964; 14:44-60. 24. Wu D, Kou H, Hung J. Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization. Ann intern Med 1981;95:410-414. 25. Brodsky SJ, Cutler SS, Weiner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamih a double-blind, placebo-controlled randomized crossover study. Circulation 1982;66:569579. 26. Bryson AL, Parisi AF, Schechter E, Wolfson S. Life-threatening ventricular arrhythmias induced by exercise. Cessation after coronary bypass surgery. Am J Cardiol 1973;32:995-999. 27. Cnne RE, Armstrong RG, Stanford W. Successful myocardial revascularization after ventricular fibrillation induced by treadmill exercise. J. ThoraC Cardiovasc Surg 1973;65:802-805. 28. Lehrman KL, Tilkian AG, Hultgren HN, Fowles RE. Effect of coronary arterial bypass surgery on exercise-induced ventricular arrhvthmias. Long-term follow-up of a prospective randomized study. Am J" Cardiol 1979"44 1056-1061. 29. Josephson ME, Harken AH, Horowitz LN. Endocardial excision: a neW surgical technique for the treatment of recurrent ventricular tachycardia. Circulation 1979;60:1430-1439.