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Reproducibility and treatment of exercise-induced ventricular tachycardia
Reproducibilityand Treatment of Exercise-Induced Ventricular Tachycardia ALAN WOELFEL, MD, JAMES R. FOSTER, MD, ROSS J. SIMPSON, Jr., MD, and LEONARD S. GETTES, MD
Fourteen patients with exercise-induced ventricular tachycardia (VT) underwent serial treadmill testing, and those with reproducible arrhythmia were treated with a fl-adrenergic blocking agent. In 11 patients (79 % ), VT of similar rate, morphologic characteristics and duration was reproduced on 2 consecutive treadmill tests performed 1 to 14 days apart. Beta blockade prevented recurrent VT during acute testing in 10 of 11 patients and during chronic therapy in 9. Eight patients had a consistent relation between a critlcal sinus rate and the onset of VT. In
these patlents, successful therapy correlated with preventing achievement of the critical sinus rate during maximal exercise. Thus, serial exercise testing is an appropriate means of assessing efficacy of therapy in patients with exercise-induced VT, provided that reproducibility is established on 2 control tests before beginning treatment. Therapy with &blocking agents is effective, especially when guided by the presence of a critical sinus rate-VT relation. (Am J Cardiol 1984;53:75 l-756)
In 1932, Wilson et all described 3 patients in whom ventricular tachycardia (VT) was provoked by exertion. Subsequent reports2-7 have further delineated the clinical features of exercise-induced VT, but less attention has been given to the therapy of this arrhythmia. Successful treatment, usually with ,L3-adrenergic blocking agents, 7-11 has been reported in only a small number of patients. In addition, it is not clear whether this arrhythmia is sufficiently reproducible2J2J3 to permit the use of exercise testing to assess treatment efficacy. We report our experience with serial treadmill tests and P-blockade therapy in 14 patients with exercise-induced VT.
treadmill exercise test. Two of the 16 patients were not entered into the study: In 1, VT degenerated into ventricular fibrillation requiring cardioversion and in 1, VT occurred during severe exercise-induced ischemia and was treated with coronary bypass grafting. The remaining 14 patients comprised the study group. In each patient a complete history was taken and a physical examination, ECG, chest radiograph, echocardiogram and 24-hour Holter monitor recording was performed. Six patients underwent cardiac catheterization and coronary angiography. Treadmill exercise testing: Exercise testing was performed on a motor-driven treadmill (Model 18-60, Quinton) according to the standard Bruce protocol.14 The ECG was displayed on a multichannel oscilloscope (Model 6500, Marquette) and recorded on a 3-channel electrocardiograph (Model MAC-I, Marquette). Twelve-lead ECGs and cuff determinations of blood pressure were performed with the patient in the supine and upright positions before exercise, at 3-minute intervals during exercise and immediately after exercise. Leads II, V4 and V5 were continuously monitored during the exercise and for 10 minutes after exercise. A 6second delay circuit permitted recording of the electrocardiographic events immediately preceding the onset of VT in all patients. Criteria for terminating exercise included occurrence of VT, presence of horizontal or downsloping STsegment depression 2 mm or greater in any lead, and inability to perform further exercise because of fatigue or dyspnea. The exercise tests were analyzed for exercise duration, peak exercise heart rate, presence of VT, sinus rate at the onset of VT and ST-segment change. After the initial treadmill test on which the diagnosis of exercise-induced VT was made, each patient underwent an-
Methods Patients: Sixteen consecutive patients with exercise-induced VT were evaluated at the University of North Carolina between February 1980 and February 1982. Exercise-induced VT was defined as 5 or more sequential ectopic ventricular beats during or within 5 minutes after termination of a
From the Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. This study was supported by Grants HL 27430, HL 26464-02 and HL 07470 from the National Institutes of Health, Bethesda, Maryland. Manuscript received September 8, 1983; revised manuscript received October 28, 1983. accepted October 3 1, 1983. Address for reprints: Alan Woelfel, MD, 349 Clinical Sciences Building 229H, University of North Carolina School of Medicine, Chapel Hill, Ndrth Carolina 27514.
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TABLE I
1 3’ s 6 : 9 10 :: 13 14
TACHYCARDIA
Clinical and Electrophysiologic Observations Age (yr)
Case
VENTRICULAR
& Sex 54M 38M 23M 32M 25F 44M 51M 66M 66M 49M 68M 60M 61F 43M
Cardiac Disease
8
0
0” 0 Coronary Coronary Coronary Coronary Coronary Coronary LA myxoma Cardiomyopathy
Indication for ETT Exertional syncope Exertional presyncope Exertional syncope Exertional presyncope Exertional syncope Exertional syncope Routine post-Ml Spontaneous VT Spontaneous VT Spontaneous VT Spontaneous VT Spontaneous VT Dyspnea Spontaneous VT
Stage of ETT (VT induction)
VT Rate (beats/min)
IP IV II III II II II Ill RP II II
Cardioverted. t Multiple episodes of VT. ETT = exercise tolerance test; LA = left atrial; LBBB = left bundle branch block; P = pleomorphic, branch block; VT = ventricular tachycardia.
190 140 200 250 170 160 170 130 180 140 165 160 215 220
VT Duration 10 beats+ 4 min 20 beats+ 5 beats.7 7 beats+ 7 beats? 2 min 45 set 5 beats 1 min 10 beats 30 minx 9 beats 15 beats
VT Morphology LBBB LBBB RBBB LBBB ; PBBB LBBB RBBB RBBB LBBB RBBB RBBB
l
other exercise test 1 to 14 days (mean 6.1) later. Both exercise tests were performed after all ant&rhythmic drugs had been discontinued for at least 5 drug half-lives. The patients with reproducible VT were then treated with an orally administered P-adrenergic blocking agent and the exercise test was repeated after 4 or more doses of the medication. If VT recurred, exercise testing was repeated on a higher dosage of drug. Prevention of VT on 2 consecutive exercise tests or the occurrence of side effects constituted the end point of therapy. Six patients received propranolol, 20 to 100 mg 4 times daily; 4 received nadolol, 60 to 80 mg twice daily; and 1 patient re-
RP = recovery period; RBBB = right bundle
ceived metoprolol, 50 mg twice daily. Each patient in whom VT was prevented during acute testing of a P-adrenergic blocking agent continued to take the same drug. Efficacy of chronic therapy was assessed by monitoring clinical symptoms and by performing additional exercise testing in all patients. When reproducible exercise-induced VT and spontaneous VT unrelated to exercise occurred in the same patient, each arrhythmia was evaluated independently. Electrophysiologic testing with serial programmed electrical stimulation was performed to assess efficacy of drug regimens for the spontaneous arrhythmia, but only after the evaluation of the exercise-induced arrhythmia was complete. The effect of p blockade on the spontaneous VT was not assessed, nor was the effect of the drug used to treat the spontaneous arrhythmia on the VT induced by exercise. Results
VT. I70/nin
FIGURE 1. A, onset of sustained ventricular tachycardia (VT) at 3.5 minutes of exercise in a 5 l-year-old man with a prior myocardial infarction. B, multiple runs of nonscistainedVT interrupted by occasional sinus beats (arrows) in a 44-year-old man without diagnosed heart disease.
Clinical observations (Table I): The patients included 12 men and 2 women, aged 23 to 66 years (mean 46). Six patients, 2 of whom underwent cardiac catheterization, had no evident heart disease. All 6 gave a history of exertional symptoms, which prompted the initial exercise test. None had symptoms suggestive of arrhythmia unrelated to exercise or had VT during 24-hour Holter monitoring. Six patients had coronary artery disease documented by cardiac catheterization or by evidence of a prior myocardial infarction. None had symptoms of arrhythmia related to exercise. The initial treadmill tests were performed as part of routine protocols for evaluating patients with documented VT or recent myocardial infarction. Five of these 6 patients had documented sustained VT (duration 230 seconds) that was unrelated to exercise: Four had infrequent VT (52 episodes/year) and 1 had an average of 2 to 3 episodes/ week. None of the 6 had either sustained or nonsustained VT during 24-hour Holter monitoring. Characteristics of ventricular tachycardia (Table I): VT appeared during exercise in 12 patients and within 4 minutes of complete exercise in 2 patients. VT was sustained in 5 patients (Fig. 1A); it terminated spontaneously in 4 and required electrical cardioversion
March 1, 1984
in 1 patient. VT was nonsustained in 9 patients, but 5 of these patients had multiple episodes (Fig. 1B). The rates of VT ranged from 130 to 250 beats/min (mean 180). The QRS morphology during VT was of a right bundle branch block configuration in 7 patients, a left bundle branch block configuration in 5 and was pleomorphic in 2. No patient had chest pain, ST-segment changes or a decrease in blood pressure before the onset of VT. Repeat treadmill testing: Three of the 14 patients who had VT on the qualifying exercise test did not have VT on the repeat test, even though they achieved exercise durations and maximal heart rates at least as great as those on their initial tests. All 3 patients had only a single episode of nonsustained VT on the initial exercise test. Two of these patient were known to have spontaneous VT unrelated to exercise, but this VT was infrequent and sustained in both patients. In the other 11 patients, VT was reproduced on the repeat exercise test. In each case, VT on the second test was similar in rate, duration and morphologic characteristics to the VT on the initial test. The sinus rates at the onset of VT in these patients with reproducible arrhythmia ranged from 105 to 190 beats/min. In 8 patients (4 with coronary disease and 4 without evident heart disease) there was a consistent relation between sinus rate and onset of VT: The sinus rate at the onset of VT in the second test was within 5 beatslmin of that on the first test (Fig. 2). Patients who received additional exercise tests had this relation in as many as 4 successive tests performed within a period of 10 months. In 3 patients, the sinus rates at the onset of VT differed
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
TABLE
753
Response of Patient 4 to Beta-Adrenergic Blockade
II
Date
Medication
Ex Duration
(min)
Max Ex HR (beatslmin)
VT
2114 2125 2/27 2/28 2/29
0 Propranolol, 60 mg q.i.d Propranolol, 60 mg q.i.d. Propranolol, 100 mg q.i.d.
6 10 12 13
154 152 127 154 133
: + -
Ex = exercise; HR = heart rate; Max = maximal; VT = ventricular tachycardia.
by at least 25 beats/min. Both patients with VT during the recovery period were in this latter group. Acute therapy: Administration of a (3-adrenergic blocking agent prevented recurrence of VT during acute treadmill testing in 10 of the 11 patients with reproducible arrhythmia. Therapy was effective in all 8 patients with and in 2 of 3 patients without a consistent sinus rate-VT relation. In each patient treated successfully, exercise duration on therapy equalled or exceeded that before treatment. In the patients with a consistent sinus rate-VT relation, the efficacy of p blockade correlated with the sinus rate response to exercise: VT was prevented only when the dosage of drug was sufficient to prevent the sinus rate from reaching the critical rate identified on the pretreatment tests (Fig. 3). Table II shows the response of a patient in whom VT developed during both pretreatment tests at 6 minutes of exercise when the sinus rate was 153 beats/min. After 2 days of propranolol therapy at a dosage of 240 mg/day,
200 200 1
b\
I
------l
160-
01
I #I PRETREATMENT
I EXERCISE
#2 TESTS
FIGURE 2. Sinus rate at onset of ventricular tachycardia (VT) in the 11 patients with reproducible VT. In 8 patients (closed circles), the sinus rates were within 5 beats/min of each other on the 2 tests. In 3 patients (open circles), the sinus rates differed by more than 25 beats/min.
#I
PRETREATMENT
#2 EXERCISE
EXERCISE ON BETA BLOCKADE
FIGURE 3. Sinus rate during exercise before therapy and during successful @-blockade therapy in the 8 patients with a consistent sinus rate-ventricular tachycardia relation. In each patient, the maximal sinus rate during therapy is below the critical rate at which ventricular tachycardia occurred on the pretreatment tests.
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TACHYCARDIA
rhythma. An additional patient underwent excision of a left atria1 myxoma. All 3 patients remained free of subsequent VT, but no additional exercise tests were performed.
he exercised for 10 minutes and achieved a maximal heart rate of 127 beats/min without VT. However, this was a submaximal test. The next day, while receiving the same amount of propranolol, he underwent a maximal test. Exercise duration was extended to 12 minutes, when the sinus rate reached the critical rate of 153 beats/min and VT occurred. The dosage of propranolol was then increased to 400 mglday and the exercise test repeated. With this dosage, maximal exercise tolerance was 13 minutes, the maximal sinus rate was 133 beats/ min-well short of the critical rate-and there was no VT. This response illustrates the value of the critical sinus rate in guiding the dosage of p blockers, and the necessity of performing maximal exercise to document inability to achieve the critical rate. Chronic therapy: The 10 acute responders to P-blocking agents continued to receive the same drug. Seven patients had only exercise-induced VT and received a P-blocking agent alone. Three also had VT unrelated to exercise and received an additional drug selected by electrophysiologic testing. After 12 to 32 months (mean 18) of follow-up with therapy, 9 patients remained asymptomatic, and all 9 completed exercise testing during therapy without VT. One patient had recurrent, exercise-induced VT during the third month of treatment. In 1 of the long-term responders, fatigue prompted a change in therapy from propranolol to verapamil after 18 months. No other side effects of treatment were observed during the study. The overall response rate to P-adrenergic blockade, combining the results of acute and chronic therapy, was 82% (9 of 11 patients). Beta-blocking agents were comparably effective in patients with coronary disease (4 of 5 patients) and in those without evident heart disease (5 of 6 patients). However, the drugs failed only in patients without a consistent sinus rate-VT relation (Fig. 4). The 3 patients with nonreproducible exercise-related arrhythmia did not receive specific therapy for exercise-induced VT. Two had effective therapy of spontaneous VT selected by serial electrophysiologic testing, and did not have VT on repeat exercise testing while receiving dosage used to treat the spontaneous ar-
PRIOR
TO
Discussion Reproducibility: Our results demonstrate that exercise-induced VT in unselected patients is highly, although not uniformly, reproducible. Eleven of our 14 patients (79%) had VT similar in rate and morphology initiated on 2 consecutive treadmill tests performed 1 to 14 days apart. Reproducibility was high in patients without cardiac disease (6 of 6 patients) and in those with coronary disease (5 of 6). However, reproducibility was greater in patients with either sustained VT or multiple episodes of nonsustained VT (10 of 10) than in patients with a single episode of nonsustained VT (1 of 4). The rate of reproducibility in the present study is considerably higher than that reported in other studies. This difference is most likely explained by the failure of some studiesls-18 to separate VT from less severe grades of ventricular arrhythmias, and by differences in patient population, diagnostic method and definition of VT. The figure most often quoted for the reproducibility rate of exercise-induced VT is 50%, from the study of Jelinek and Lown.‘s However, this figure was determined from the results of 12 exercise tests performed in only 3 patients, and includes the reproducibility of couplets as well as VT. Mokotoff et al2 demonstrated reproducibility in 2 of 8 patients with exercise-induced VT. In their study, 50% of the patients had only 3 beats of VT, and the mean intertest interval was 4.8 months. DeBacker et al’s reported a reproducibility of only 17%. However, they studied only healthy, asymptomatic male volunteers, and determined reproducibility by comparing results of treadmill exercise to those of isometric exercise in each patient. The high rate of reproducibility in our study probably reflects the combination of a relatively brief intertest interval (mean 6 days), a restrictive definition of VT (25 beats), and a study group that consisted of patients with either exertional symptoms or known heart disease.
ON BETA
TREATMENT
8-CONSISTENT AT ONSET
BLOCKERS
SR OF
FIGURE 4. Results of P-adrenergic blockade in 11 patients with reproducible ventricular tachycardia (VT), showing uniform success in patients with a consistent sinus rate-VT relation. One of the failures in the other group occurred during acute testing and 1 during chronic therapy.
VT O-VT
I I-REPRODUCIBLE
VT
I-NO
-: \
3-NO AT
CONSISTENT ONSET
OF
SR VT 2-VT
VT
March 1. 1984
The reproducibility of exercise-induced VT has important therapeutic implications. Serial exercise testing is used11Jg,20 to test efficacy of drug treatment of this arrhythmia. The presence of arrhythmia on 1 test and its absence on a repeat test after beginning medication is interpreted as a therapeutic success. However, reproducibility of the arrhythmia before therapy is crucial to the validity of this approach. Although our results confirm the validity of the technique in most patients with exercise-induced VT, they indicate that false conclusions of drug efficacy could be reached in approximately 20% if duplicate tests before therapy are not performed to exclude patients with nonreproducible arrhythmia. Beta-blockade therapy: Treatment with (3-adrenergic blocking drugs was highly effective in preventing recurrent exercise-induced VT. Short-term therapy was successful in 10 of our 11 patients with reproducible arrhythmia, and 9 of these patients remained free of VT on long-term follow-up. These results confirm the responsiveness to p blockade suggested in previous reports7-‘l of smaller numbers of patients with this arrhythmia. A surprising finding was the consistent relation between a critical sinus rate and the onset of VT in 8 of our patients. This relation occurred in different clinical settings and was stable over prolonged periods. Beta blockade was uniformly effective in these 8 patients, but did not alter the sinus rate-VT relation: Patients who reached their critical sinus rates during exercise while receiving therapy still had VT. Successful therapy required dosages of P-blocking agents sufficient to prevent the sinus rate from reaching the critical rate during maximal exercise. Talbot et al4 also found that padrenergic blocking drugs prevented exercise-induced VT only when they decreased the maximal heart rate reached during exercise. However, these investigators did not perform duplicate control tests necessary to establish the specific rate associated with the onset of VT. Pathophysiology: The similarities in arrhythmia behavior and therapeutic response in our patients with a consistent sinus rate-VT relation suggest that the arrhythmias in this group share a common pathophysiologic mechanism. In these patients, the occurrence of VT may depend only on the rate increase per se. This would be analogous to the initiation of VT by atria1 pacing at a critical cycle length,2l and would suggest that the arrhythmia is generated by triggered delayed afterpotentials.21-23 The efficacy of P-blocking agents could thus be explained by a decrease in the magnitude of the delayed afterpotentials produced by slowing of the heart rate.zs Suppression of exercise-induced VT by verapamil,5 a drug known to suppress delayed afterpotentials,24 is also consistent with this mechanism. It is also possible that the rate increase does not initiate VT, but instead simply identifies the exerciseinduced adrenergic state necessary for VT induction. The importance of P-adrenergic influence in the generation of this arrhythmia is suggested by several studies5-7J5 in which exercise-induced VT was induced by isoproterenol infusion. Sung et a16 concluded that
THE AMERICAN JOURNAL OF CARDIOLOGY
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isoproterenol and, by implication, exercise, produce VT by enhancing the spontaneous discharge of a catecholamine-sensitive automatic focus. However, the multiplicity of electrophysiologic effects of ,L3-adrenergic stimulation make it difficult to exclude other mechanisms that might facilitate the occurrence of VT.25 Increased fl-adrenergic tone could produce reentry by shortening ventricular refractoriness and increasing the nonuniformity of recovery of excitability,“” or facilitate arrhythmias due to triggered activity by increasing the magnitude of afterpotentials.z7 Unfortunately, the limitations of current electrophysiologic techniques may preclude reliable differentiation of these mechanisms.‘l:( Although acute ischemia may sometimes be responsible for exercise-induced ventricular arrhythmias,28,2g there was no evidence that it was present in our patients. The only patient who had chest pain or ST-segment changes at the onset of VT was not included in the study. Ischemia was especially unlikely in the 4 patients with angiographically normal coronary arteries and in the 3 patients younger than 35 years. Goldschlager et alSo also report the frequent absence of demonstrable ischemia in patients with exercise-induced ventricular arrhythmias and coronary artery disease, although it is difficult to exclude the presence of subclinical ischemia in this group. Clinical implications: Our findings demonstrate that repetitive exercise testing is an appropriate means of assessing drug therapy in most patients with exercise-induced VT. Because effective therapy can be reliably designed using this relatively simple and noninvasive technique, it appears to be unnecessary to perform invasive programmed electrical stimulation for this purpose unless VT has also occurred at rest. However, to identify patients with nonreproducible VT and thus prevent erroneous conclusions regarding efficacy of therapy, reproducibility must be established from 2 control exercise tests before drug testing is begun. The second control exercise test may also permit identification of patients with a consistent relation between sinus rate and onset of VT who are especially likely to respond to fi-adrenergic blockade. Success of therapy in these patients depends on preventing the sinus rate during maximally tolerated exercise from reaching the critical rate associated with the onset of VT. Acknowledgment: We gratefully acknowledge the assistance of Rosalie Olsen in the preparation of’ this manuscript.
References 1. Wilson FN, Wishart SW, Macleod AG, Barker PS. A chnical type of tachycardia of ventncular origin in which paroxysms are induced by exertion Am Heart J 1932;8:155-169. 2. Mokotoff DM. Guinones MA. Miller RR. Exercise-Induced ventricular tachycardia: dlinical features.‘relation to chronic ventricular ectopy. and prognosis. Chest 1980;77:10-16. 3. Condini MA, Sommerfeldt L, Eybet CE, Messer JV. Cllnical significance and characteristics of exercise-induced ventricular tachycardia Cathet Cardiovasc Diagn 1981;7:227-234. 4. Talbot S, Kilpatrick D, Krikler D, Oakley CM. Ventricular tachycardia due to cardiac ischemia: assessment by exercise electrocardiography. Br Med J 1978;2:733-736. 5. Wu D, Kou H, Hung J. Exercise-triggered paroxysmal ventricular tachycardia: a repetitive rhythmic activity possibilityrelated to after&polarization. Ann Intern Med 1981:95:410-414. 6. Sung RJ, Shen EN, Morady F, Scheinman MM, Hess D, Botvinfck Eli. Electrophysiologic mechanism of exercise-induced sustained ventricular
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tachycardia. Am J Cardiol 1983;51.525-530. 7. Palileo EV, Ashley WW, Swiryn S, Bauernfeind RA, Strasberg B, Petropoulos Al, Rosen KM. Exercise provocable right ventricular outflow tract tachycardia. Am Heart J 1982,104-185-193 6. Taylor RR, Halllday EJ. Beta-adrenergic blockade In the treatment of ex;y;T;;;duced paroxysmal ventricular tachycardia Circulation 1965;32:
19. 20. 21.
9. Gettes LS, Surawicz B. Long-term preventlon of paroxysmal arrhythmias with propranolol therapy. Am J Med Sci 1967;254:257-65 10. Gettes LS. Beta adrenergic blocklng drugs in the treatment of cardiac arrhythmias Cardiovasc Clin 1972;2:21 l-237 11. Nixon JV, Pennington W, Ritter W, Shapiro W. Efficacy of propranolol in the control of exercise-induced or augmented ventricular arrhythmias Circulation 1978;57:115-122 12. Jelinek MV, Lown 8. Exercise stress testing for exposure of cardiac arrhythmia. Prog Cardiovasc Dis 1974;16:497-522 13. DeBacker G, Jacobs D, Prlneas R, Crow R, Vilandre J, Blackburn H. Ventricular premature beats. Reliability in various measurement methods at rest and during exercise. Cardiology 1978;63:53-63 14. Doan AE, Peterson DR, Blackman JR, Bruce RA. Myocardlal lschemia after maximal exercise in healthy men A method for detecting potenbal coronary disease Am Heart J 1965;69:1 I-20. 15. Blackburn H, Taylor HL, Hamrell B, Bushkirk E, Nicholas EC, Thorsen RD. Premature ventricular complexes induced by stress testing: their frequency and response to physical conditioning. Am J Cardiol 1973;31:441-449. 16. Faris JV, McHenry PL, Jordan JW, Morris SN. Prevalence and reproducibility of exercise-induced ventricular arrhythmias during maximal exercise testing in normal men. Am J Cardiol 1976;37:617-622. 17. Sheps DS, Ernst JC, Briese FR, Lopez LV, Conde CA, Castellanos A, Meyerburg RJ. Decreased frequency of exercise-induced ventricular ectopy In the second of two consecutive treadmill tests Circulabon 1977;55: 892-895 16. Sann M, Kraemer H, DeBush RF. Reproduclbtllty of exercise-induced
22. 23. 24. 25.
26. 27. 26.
29. 30.
ventricular arrhythmia after myocardial Infarction. Am J Cardiol 1979;43: 724-730. Lown B, Graboys TB. Management of patients with malignant ventricular arrhythmias. Am J Cardlol 1977;39.910-918. Podrid PJ, Lown B. Mexiletine for ventricular arrhythmias Am J Cardiol 1981:47~895-902. Zipes DP, Foster PR, Troup PJ, Pedersen DH. Atrial induction of ventricular tachycardia. reentry versus triggered automaticity. Am J Cardiol 1979; 44.1-11 Sini RJ, Shen EN, Shapiro W, Morady F, Davis J. Effects of verapamil on ventricular tachvcardia of various mechanisms-with soecial reference to triggered actlvit$ in man (abstr). Clin Res 1982;30:224’A. Rosen MR, Reder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94:794-801. Rosen MR, llvento JP, Gelband H, Merker C. Effects of veraoamil on electrophysiologic properties of canine cardiac Purkinje fibers’ J Pharmacdvn EXD Ther 1974:189:414-422 Reddy CP, ‘Getles LS. Use of isoproterenol as an ald to electrical induction of chronic recurrent ventricular tachycardia Am J Cardiol 1979;44: 705-713. Han J, Moe GK. Nonuniform recovery of excitability of ventricular muscle. Circ Res 1964,14:44-60 Cranefield PF. The conducbon of the cardiac impulse: The slow response and cardiac arrhythmias. Mount Kisco, NY: Futura, 1975:123-25. Bryson AL, Parlsi AF, Schecter E, Wolfson S. Life-threatening ventricular arrhythmias induced by exercise. Cessation after coronary bypass surgery. Am J Cardiol 1973;32:995-999. Cline RE, Armstrong RG, Stanford W. Successful myocardial revascularization after ventricular fibrillation induced by treadmill exercise J Thorac Cardiovasc Sura 1973:85:802-805. Goldschlager N,-Cake b, Cohn K. Exercise-induced ventricular arrhvthmias In patients with coronary artery disease: their relation to angiobraphic findings Am J Cardiol 1973;31:434-440
Fourteen patients with exercise-induced ventricular tachycardia (VT) underwent serial treadmill testing, and those with reproducible arrhythmia were treated with a fl-adrenergic blocking agent. In 11 patients (79 % ), VT of similar rate, morphologic characteristics and duration was reproduced on 2 consecutive treadmill tests performed 1 to 14 days apart. Beta blockade prevented recurrent VT during acute testing in 10 of 11 patients and during chronic therapy in 9. Eight patients had a consistent relation between a critlcal sinus rate and the onset of VT. In
these patlents, successful therapy correlated with preventing achievement of the critical sinus rate during maximal exercise. Thus, serial exercise testing is an appropriate means of assessing efficacy of therapy in patients with exercise-induced VT, provided that reproducibility is established on 2 control tests before beginning treatment. Therapy with &blocking agents is effective, especially when guided by the presence of a critical sinus rate-VT relation. (Am J Cardiol 1984;53:75 l-756)
In 1932, Wilson et all described 3 patients in whom ventricular tachycardia (VT) was provoked by exertion. Subsequent reports2-7 have further delineated the clinical features of exercise-induced VT, but less attention has been given to the therapy of this arrhythmia. Successful treatment, usually with ,L3-adrenergic blocking agents, 7-11 has been reported in only a small number of patients. In addition, it is not clear whether this arrhythmia is sufficiently reproducible2J2J3 to permit the use of exercise testing to assess treatment efficacy. We report our experience with serial treadmill tests and P-blockade therapy in 14 patients with exercise-induced VT.
treadmill exercise test. Two of the 16 patients were not entered into the study: In 1, VT degenerated into ventricular fibrillation requiring cardioversion and in 1, VT occurred during severe exercise-induced ischemia and was treated with coronary bypass grafting. The remaining 14 patients comprised the study group. In each patient a complete history was taken and a physical examination, ECG, chest radiograph, echocardiogram and 24-hour Holter monitor recording was performed. Six patients underwent cardiac catheterization and coronary angiography. Treadmill exercise testing: Exercise testing was performed on a motor-driven treadmill (Model 18-60, Quinton) according to the standard Bruce protocol.14 The ECG was displayed on a multichannel oscilloscope (Model 6500, Marquette) and recorded on a 3-channel electrocardiograph (Model MAC-I, Marquette). Twelve-lead ECGs and cuff determinations of blood pressure were performed with the patient in the supine and upright positions before exercise, at 3-minute intervals during exercise and immediately after exercise. Leads II, V4 and V5 were continuously monitored during the exercise and for 10 minutes after exercise. A 6second delay circuit permitted recording of the electrocardiographic events immediately preceding the onset of VT in all patients. Criteria for terminating exercise included occurrence of VT, presence of horizontal or downsloping STsegment depression 2 mm or greater in any lead, and inability to perform further exercise because of fatigue or dyspnea. The exercise tests were analyzed for exercise duration, peak exercise heart rate, presence of VT, sinus rate at the onset of VT and ST-segment change. After the initial treadmill test on which the diagnosis of exercise-induced VT was made, each patient underwent an-
Methods Patients: Sixteen consecutive patients with exercise-induced VT were evaluated at the University of North Carolina between February 1980 and February 1982. Exercise-induced VT was defined as 5 or more sequential ectopic ventricular beats during or within 5 minutes after termination of a
From the Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. This study was supported by Grants HL 27430, HL 26464-02 and HL 07470 from the National Institutes of Health, Bethesda, Maryland. Manuscript received September 8, 1983; revised manuscript received October 28, 1983. accepted October 3 1, 1983. Address for reprints: Alan Woelfel, MD, 349 Clinical Sciences Building 229H, University of North Carolina School of Medicine, Chapel Hill, Ndrth Carolina 27514.
751
752
EXERCISE-INDUCED
TABLE I
1 3’ s 6 : 9 10 :: 13 14
TACHYCARDIA
Clinical and Electrophysiologic Observations Age (yr)
Case
VENTRICULAR
& Sex 54M 38M 23M 32M 25F 44M 51M 66M 66M 49M 68M 60M 61F 43M
Cardiac Disease
8
0
0” 0 Coronary Coronary Coronary Coronary Coronary Coronary LA myxoma Cardiomyopathy
Indication for ETT Exertional syncope Exertional presyncope Exertional syncope Exertional presyncope Exertional syncope Exertional syncope Routine post-Ml Spontaneous VT Spontaneous VT Spontaneous VT Spontaneous VT Spontaneous VT Dyspnea Spontaneous VT
Stage of ETT (VT induction)
VT Rate (beats/min)
IP IV II III II II II Ill RP II II
Cardioverted. t Multiple episodes of VT. ETT = exercise tolerance test; LA = left atrial; LBBB = left bundle branch block; P = pleomorphic, branch block; VT = ventricular tachycardia.
190 140 200 250 170 160 170 130 180 140 165 160 215 220
VT Duration 10 beats+ 4 min 20 beats+ 5 beats.7 7 beats+ 7 beats? 2 min 45 set 5 beats 1 min 10 beats 30 minx 9 beats 15 beats
VT Morphology LBBB LBBB RBBB LBBB ; PBBB LBBB RBBB RBBB LBBB RBBB RBBB
l
other exercise test 1 to 14 days (mean 6.1) later. Both exercise tests were performed after all ant&rhythmic drugs had been discontinued for at least 5 drug half-lives. The patients with reproducible VT were then treated with an orally administered P-adrenergic blocking agent and the exercise test was repeated after 4 or more doses of the medication. If VT recurred, exercise testing was repeated on a higher dosage of drug. Prevention of VT on 2 consecutive exercise tests or the occurrence of side effects constituted the end point of therapy. Six patients received propranolol, 20 to 100 mg 4 times daily; 4 received nadolol, 60 to 80 mg twice daily; and 1 patient re-
RP = recovery period; RBBB = right bundle
ceived metoprolol, 50 mg twice daily. Each patient in whom VT was prevented during acute testing of a P-adrenergic blocking agent continued to take the same drug. Efficacy of chronic therapy was assessed by monitoring clinical symptoms and by performing additional exercise testing in all patients. When reproducible exercise-induced VT and spontaneous VT unrelated to exercise occurred in the same patient, each arrhythmia was evaluated independently. Electrophysiologic testing with serial programmed electrical stimulation was performed to assess efficacy of drug regimens for the spontaneous arrhythmia, but only after the evaluation of the exercise-induced arrhythmia was complete. The effect of p blockade on the spontaneous VT was not assessed, nor was the effect of the drug used to treat the spontaneous arrhythmia on the VT induced by exercise. Results
VT. I70/nin
FIGURE 1. A, onset of sustained ventricular tachycardia (VT) at 3.5 minutes of exercise in a 5 l-year-old man with a prior myocardial infarction. B, multiple runs of nonscistainedVT interrupted by occasional sinus beats (arrows) in a 44-year-old man without diagnosed heart disease.
Clinical observations (Table I): The patients included 12 men and 2 women, aged 23 to 66 years (mean 46). Six patients, 2 of whom underwent cardiac catheterization, had no evident heart disease. All 6 gave a history of exertional symptoms, which prompted the initial exercise test. None had symptoms suggestive of arrhythmia unrelated to exercise or had VT during 24-hour Holter monitoring. Six patients had coronary artery disease documented by cardiac catheterization or by evidence of a prior myocardial infarction. None had symptoms of arrhythmia related to exercise. The initial treadmill tests were performed as part of routine protocols for evaluating patients with documented VT or recent myocardial infarction. Five of these 6 patients had documented sustained VT (duration 230 seconds) that was unrelated to exercise: Four had infrequent VT (52 episodes/year) and 1 had an average of 2 to 3 episodes/ week. None of the 6 had either sustained or nonsustained VT during 24-hour Holter monitoring. Characteristics of ventricular tachycardia (Table I): VT appeared during exercise in 12 patients and within 4 minutes of complete exercise in 2 patients. VT was sustained in 5 patients (Fig. 1A); it terminated spontaneously in 4 and required electrical cardioversion
March 1, 1984
in 1 patient. VT was nonsustained in 9 patients, but 5 of these patients had multiple episodes (Fig. 1B). The rates of VT ranged from 130 to 250 beats/min (mean 180). The QRS morphology during VT was of a right bundle branch block configuration in 7 patients, a left bundle branch block configuration in 5 and was pleomorphic in 2. No patient had chest pain, ST-segment changes or a decrease in blood pressure before the onset of VT. Repeat treadmill testing: Three of the 14 patients who had VT on the qualifying exercise test did not have VT on the repeat test, even though they achieved exercise durations and maximal heart rates at least as great as those on their initial tests. All 3 patients had only a single episode of nonsustained VT on the initial exercise test. Two of these patient were known to have spontaneous VT unrelated to exercise, but this VT was infrequent and sustained in both patients. In the other 11 patients, VT was reproduced on the repeat exercise test. In each case, VT on the second test was similar in rate, duration and morphologic characteristics to the VT on the initial test. The sinus rates at the onset of VT in these patients with reproducible arrhythmia ranged from 105 to 190 beats/min. In 8 patients (4 with coronary disease and 4 without evident heart disease) there was a consistent relation between sinus rate and onset of VT: The sinus rate at the onset of VT in the second test was within 5 beatslmin of that on the first test (Fig. 2). Patients who received additional exercise tests had this relation in as many as 4 successive tests performed within a period of 10 months. In 3 patients, the sinus rates at the onset of VT differed
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
TABLE
753
Response of Patient 4 to Beta-Adrenergic Blockade
II
Date
Medication
Ex Duration
(min)
Max Ex HR (beatslmin)
VT
2114 2125 2/27 2/28 2/29
0 Propranolol, 60 mg q.i.d Propranolol, 60 mg q.i.d. Propranolol, 100 mg q.i.d.
6 10 12 13
154 152 127 154 133
: + -
Ex = exercise; HR = heart rate; Max = maximal; VT = ventricular tachycardia.
by at least 25 beats/min. Both patients with VT during the recovery period were in this latter group. Acute therapy: Administration of a (3-adrenergic blocking agent prevented recurrence of VT during acute treadmill testing in 10 of the 11 patients with reproducible arrhythmia. Therapy was effective in all 8 patients with and in 2 of 3 patients without a consistent sinus rate-VT relation. In each patient treated successfully, exercise duration on therapy equalled or exceeded that before treatment. In the patients with a consistent sinus rate-VT relation, the efficacy of p blockade correlated with the sinus rate response to exercise: VT was prevented only when the dosage of drug was sufficient to prevent the sinus rate from reaching the critical rate identified on the pretreatment tests (Fig. 3). Table II shows the response of a patient in whom VT developed during both pretreatment tests at 6 minutes of exercise when the sinus rate was 153 beats/min. After 2 days of propranolol therapy at a dosage of 240 mg/day,
200 200 1
b\
I
------l
160-
01
I #I PRETREATMENT
I EXERCISE
#2 TESTS
FIGURE 2. Sinus rate at onset of ventricular tachycardia (VT) in the 11 patients with reproducible VT. In 8 patients (closed circles), the sinus rates were within 5 beats/min of each other on the 2 tests. In 3 patients (open circles), the sinus rates differed by more than 25 beats/min.
#I
PRETREATMENT
#2 EXERCISE
EXERCISE ON BETA BLOCKADE
FIGURE 3. Sinus rate during exercise before therapy and during successful @-blockade therapy in the 8 patients with a consistent sinus rate-ventricular tachycardia relation. In each patient, the maximal sinus rate during therapy is below the critical rate at which ventricular tachycardia occurred on the pretreatment tests.
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EXERCISE-INDUCED
VENTRICULAR
TACHYCARDIA
rhythma. An additional patient underwent excision of a left atria1 myxoma. All 3 patients remained free of subsequent VT, but no additional exercise tests were performed.
he exercised for 10 minutes and achieved a maximal heart rate of 127 beats/min without VT. However, this was a submaximal test. The next day, while receiving the same amount of propranolol, he underwent a maximal test. Exercise duration was extended to 12 minutes, when the sinus rate reached the critical rate of 153 beats/min and VT occurred. The dosage of propranolol was then increased to 400 mglday and the exercise test repeated. With this dosage, maximal exercise tolerance was 13 minutes, the maximal sinus rate was 133 beats/ min-well short of the critical rate-and there was no VT. This response illustrates the value of the critical sinus rate in guiding the dosage of p blockers, and the necessity of performing maximal exercise to document inability to achieve the critical rate. Chronic therapy: The 10 acute responders to P-blocking agents continued to receive the same drug. Seven patients had only exercise-induced VT and received a P-blocking agent alone. Three also had VT unrelated to exercise and received an additional drug selected by electrophysiologic testing. After 12 to 32 months (mean 18) of follow-up with therapy, 9 patients remained asymptomatic, and all 9 completed exercise testing during therapy without VT. One patient had recurrent, exercise-induced VT during the third month of treatment. In 1 of the long-term responders, fatigue prompted a change in therapy from propranolol to verapamil after 18 months. No other side effects of treatment were observed during the study. The overall response rate to P-adrenergic blockade, combining the results of acute and chronic therapy, was 82% (9 of 11 patients). Beta-blocking agents were comparably effective in patients with coronary disease (4 of 5 patients) and in those without evident heart disease (5 of 6 patients). However, the drugs failed only in patients without a consistent sinus rate-VT relation (Fig. 4). The 3 patients with nonreproducible exercise-related arrhythmia did not receive specific therapy for exercise-induced VT. Two had effective therapy of spontaneous VT selected by serial electrophysiologic testing, and did not have VT on repeat exercise testing while receiving dosage used to treat the spontaneous ar-
PRIOR
TO
Discussion Reproducibility: Our results demonstrate that exercise-induced VT in unselected patients is highly, although not uniformly, reproducible. Eleven of our 14 patients (79%) had VT similar in rate and morphology initiated on 2 consecutive treadmill tests performed 1 to 14 days apart. Reproducibility was high in patients without cardiac disease (6 of 6 patients) and in those with coronary disease (5 of 6). However, reproducibility was greater in patients with either sustained VT or multiple episodes of nonsustained VT (10 of 10) than in patients with a single episode of nonsustained VT (1 of 4). The rate of reproducibility in the present study is considerably higher than that reported in other studies. This difference is most likely explained by the failure of some studiesls-18 to separate VT from less severe grades of ventricular arrhythmias, and by differences in patient population, diagnostic method and definition of VT. The figure most often quoted for the reproducibility rate of exercise-induced VT is 50%, from the study of Jelinek and Lown.‘s However, this figure was determined from the results of 12 exercise tests performed in only 3 patients, and includes the reproducibility of couplets as well as VT. Mokotoff et al2 demonstrated reproducibility in 2 of 8 patients with exercise-induced VT. In their study, 50% of the patients had only 3 beats of VT, and the mean intertest interval was 4.8 months. DeBacker et al’s reported a reproducibility of only 17%. However, they studied only healthy, asymptomatic male volunteers, and determined reproducibility by comparing results of treadmill exercise to those of isometric exercise in each patient. The high rate of reproducibility in our study probably reflects the combination of a relatively brief intertest interval (mean 6 days), a restrictive definition of VT (25 beats), and a study group that consisted of patients with either exertional symptoms or known heart disease.
ON BETA
TREATMENT
8-CONSISTENT AT ONSET
BLOCKERS
SR OF
FIGURE 4. Results of P-adrenergic blockade in 11 patients with reproducible ventricular tachycardia (VT), showing uniform success in patients with a consistent sinus rate-VT relation. One of the failures in the other group occurred during acute testing and 1 during chronic therapy.
VT O-VT
I I-REPRODUCIBLE
VT
I-NO
-: \
3-NO AT
CONSISTENT ONSET
OF
SR VT 2-VT
VT
March 1. 1984
The reproducibility of exercise-induced VT has important therapeutic implications. Serial exercise testing is used11Jg,20 to test efficacy of drug treatment of this arrhythmia. The presence of arrhythmia on 1 test and its absence on a repeat test after beginning medication is interpreted as a therapeutic success. However, reproducibility of the arrhythmia before therapy is crucial to the validity of this approach. Although our results confirm the validity of the technique in most patients with exercise-induced VT, they indicate that false conclusions of drug efficacy could be reached in approximately 20% if duplicate tests before therapy are not performed to exclude patients with nonreproducible arrhythmia. Beta-blockade therapy: Treatment with (3-adrenergic blocking drugs was highly effective in preventing recurrent exercise-induced VT. Short-term therapy was successful in 10 of our 11 patients with reproducible arrhythmia, and 9 of these patients remained free of VT on long-term follow-up. These results confirm the responsiveness to p blockade suggested in previous reports7-‘l of smaller numbers of patients with this arrhythmia. A surprising finding was the consistent relation between a critical sinus rate and the onset of VT in 8 of our patients. This relation occurred in different clinical settings and was stable over prolonged periods. Beta blockade was uniformly effective in these 8 patients, but did not alter the sinus rate-VT relation: Patients who reached their critical sinus rates during exercise while receiving therapy still had VT. Successful therapy required dosages of P-blocking agents sufficient to prevent the sinus rate from reaching the critical rate during maximal exercise. Talbot et al4 also found that padrenergic blocking drugs prevented exercise-induced VT only when they decreased the maximal heart rate reached during exercise. However, these investigators did not perform duplicate control tests necessary to establish the specific rate associated with the onset of VT. Pathophysiology: The similarities in arrhythmia behavior and therapeutic response in our patients with a consistent sinus rate-VT relation suggest that the arrhythmias in this group share a common pathophysiologic mechanism. In these patients, the occurrence of VT may depend only on the rate increase per se. This would be analogous to the initiation of VT by atria1 pacing at a critical cycle length,2l and would suggest that the arrhythmia is generated by triggered delayed afterpotentials.21-23 The efficacy of P-blocking agents could thus be explained by a decrease in the magnitude of the delayed afterpotentials produced by slowing of the heart rate.zs Suppression of exercise-induced VT by verapamil,5 a drug known to suppress delayed afterpotentials,24 is also consistent with this mechanism. It is also possible that the rate increase does not initiate VT, but instead simply identifies the exerciseinduced adrenergic state necessary for VT induction. The importance of P-adrenergic influence in the generation of this arrhythmia is suggested by several studies5-7J5 in which exercise-induced VT was induced by isoproterenol infusion. Sung et a16 concluded that
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isoproterenol and, by implication, exercise, produce VT by enhancing the spontaneous discharge of a catecholamine-sensitive automatic focus. However, the multiplicity of electrophysiologic effects of ,L3-adrenergic stimulation make it difficult to exclude other mechanisms that might facilitate the occurrence of VT.25 Increased fl-adrenergic tone could produce reentry by shortening ventricular refractoriness and increasing the nonuniformity of recovery of excitability,“” or facilitate arrhythmias due to triggered activity by increasing the magnitude of afterpotentials.z7 Unfortunately, the limitations of current electrophysiologic techniques may preclude reliable differentiation of these mechanisms.‘l:( Although acute ischemia may sometimes be responsible for exercise-induced ventricular arrhythmias,28,2g there was no evidence that it was present in our patients. The only patient who had chest pain or ST-segment changes at the onset of VT was not included in the study. Ischemia was especially unlikely in the 4 patients with angiographically normal coronary arteries and in the 3 patients younger than 35 years. Goldschlager et alSo also report the frequent absence of demonstrable ischemia in patients with exercise-induced ventricular arrhythmias and coronary artery disease, although it is difficult to exclude the presence of subclinical ischemia in this group. Clinical implications: Our findings demonstrate that repetitive exercise testing is an appropriate means of assessing drug therapy in most patients with exercise-induced VT. Because effective therapy can be reliably designed using this relatively simple and noninvasive technique, it appears to be unnecessary to perform invasive programmed electrical stimulation for this purpose unless VT has also occurred at rest. However, to identify patients with nonreproducible VT and thus prevent erroneous conclusions regarding efficacy of therapy, reproducibility must be established from 2 control exercise tests before drug testing is begun. The second control exercise test may also permit identification of patients with a consistent relation between sinus rate and onset of VT who are especially likely to respond to fi-adrenergic blockade. Success of therapy in these patients depends on preventing the sinus rate during maximally tolerated exercise from reaching the critical rate associated with the onset of VT. Acknowledgment: We gratefully acknowledge the assistance of Rosalie Olsen in the preparation of’ this manuscript.
References 1. Wilson FN, Wishart SW, Macleod AG, Barker PS. A chnical type of tachycardia of ventncular origin in which paroxysms are induced by exertion Am Heart J 1932;8:155-169. 2. Mokotoff DM. Guinones MA. Miller RR. Exercise-Induced ventricular tachycardia: dlinical features.‘relation to chronic ventricular ectopy. and prognosis. Chest 1980;77:10-16. 3. Condini MA, Sommerfeldt L, Eybet CE, Messer JV. Cllnical significance and characteristics of exercise-induced ventricular tachycardia Cathet Cardiovasc Diagn 1981;7:227-234. 4. Talbot S, Kilpatrick D, Krikler D, Oakley CM. Ventricular tachycardia due to cardiac ischemia: assessment by exercise electrocardiography. Br Med J 1978;2:733-736. 5. Wu D, Kou H, Hung J. Exercise-triggered paroxysmal ventricular tachycardia: a repetitive rhythmic activity possibilityrelated to after&polarization. Ann Intern Med 1981:95:410-414. 6. Sung RJ, Shen EN, Morady F, Scheinman MM, Hess D, Botvinfck Eli. Electrophysiologic mechanism of exercise-induced sustained ventricular
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tachycardia. Am J Cardiol 1983;51.525-530. 7. Palileo EV, Ashley WW, Swiryn S, Bauernfeind RA, Strasberg B, Petropoulos Al, Rosen KM. Exercise provocable right ventricular outflow tract tachycardia. Am Heart J 1982,104-185-193 6. Taylor RR, Halllday EJ. Beta-adrenergic blockade In the treatment of ex;y;T;;;duced paroxysmal ventricular tachycardia Circulation 1965;32:
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9. Gettes LS, Surawicz B. Long-term preventlon of paroxysmal arrhythmias with propranolol therapy. Am J Med Sci 1967;254:257-65 10. Gettes LS. Beta adrenergic blocklng drugs in the treatment of cardiac arrhythmias Cardiovasc Clin 1972;2:21 l-237 11. Nixon JV, Pennington W, Ritter W, Shapiro W. Efficacy of propranolol in the control of exercise-induced or augmented ventricular arrhythmias Circulation 1978;57:115-122 12. Jelinek MV, Lown 8. Exercise stress testing for exposure of cardiac arrhythmia. Prog Cardiovasc Dis 1974;16:497-522 13. DeBacker G, Jacobs D, Prlneas R, Crow R, Vilandre J, Blackburn H. Ventricular premature beats. Reliability in various measurement methods at rest and during exercise. Cardiology 1978;63:53-63 14. Doan AE, Peterson DR, Blackman JR, Bruce RA. Myocardlal lschemia after maximal exercise in healthy men A method for detecting potenbal coronary disease Am Heart J 1965;69:1 I-20. 15. Blackburn H, Taylor HL, Hamrell B, Bushkirk E, Nicholas EC, Thorsen RD. Premature ventricular complexes induced by stress testing: their frequency and response to physical conditioning. Am J Cardiol 1973;31:441-449. 16. Faris JV, McHenry PL, Jordan JW, Morris SN. Prevalence and reproducibility of exercise-induced ventricular arrhythmias during maximal exercise testing in normal men. Am J Cardiol 1976;37:617-622. 17. Sheps DS, Ernst JC, Briese FR, Lopez LV, Conde CA, Castellanos A, Meyerburg RJ. Decreased frequency of exercise-induced ventricular ectopy In the second of two consecutive treadmill tests Circulabon 1977;55: 892-895 16. Sann M, Kraemer H, DeBush RF. Reproduclbtllty of exercise-induced
22. 23. 24. 25.
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ventricular arrhythmia after myocardial Infarction. Am J Cardiol 1979;43: 724-730. Lown B, Graboys TB. Management of patients with malignant ventricular arrhythmias. Am J Cardlol 1977;39.910-918. Podrid PJ, Lown B. Mexiletine for ventricular arrhythmias Am J Cardiol 1981:47~895-902. Zipes DP, Foster PR, Troup PJ, Pedersen DH. Atrial induction of ventricular tachycardia. reentry versus triggered automaticity. Am J Cardiol 1979; 44.1-11 Sini RJ, Shen EN, Shapiro W, Morady F, Davis J. Effects of verapamil on ventricular tachvcardia of various mechanisms-with soecial reference to triggered actlvit$ in man (abstr). Clin Res 1982;30:224’A. Rosen MR, Reder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94:794-801. Rosen MR, llvento JP, Gelband H, Merker C. Effects of veraoamil on electrophysiologic properties of canine cardiac Purkinje fibers’ J Pharmacdvn EXD Ther 1974:189:414-422 Reddy CP, ‘Getles LS. Use of isoproterenol as an ald to electrical induction of chronic recurrent ventricular tachycardia Am J Cardiol 1979;44: 705-713. Han J, Moe GK. Nonuniform recovery of excitability of ventricular muscle. Circ Res 1964,14:44-60 Cranefield PF. The conducbon of the cardiac impulse: The slow response and cardiac arrhythmias. Mount Kisco, NY: Futura, 1975:123-25. Bryson AL, Parlsi AF, Schecter E, Wolfson S. Life-threatening ventricular arrhythmias induced by exercise. Cessation after coronary bypass surgery. Am J Cardiol 1973;32:995-999. Cline RE, Armstrong RG, Stanford W. Successful myocardial revascularization after ventricular fibrillation induced by treadmill exercise J Thorac Cardiovasc Sura 1973:85:802-805. Goldschlager N,-Cake b, Cohn K. Exercise-induced ventricular arrhvthmias In patients with coronary artery disease: their relation to angiobraphic findings Am J Cardiol 1973;31:434-440