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Value of the ajmaline-procainamide test to predict the effect of long-term oral amiodarone on the anterograde effective refractory period of the accessory pathway in the Wolff-Parkinson-White Syndrome
Value of the Ajmaline-Procainamide Test to Predict the Effect of Long-Term Oral Amiodarone on the Anterograde Effective Refractory Period of the Accessory Pathway in the Wolff-Parkinson-White Syndrome PEDRO BRUGADA, MD, WILLEM R. DASSEN, PhD, SIMON BRAAT, MD, ANTON P. GORGELS, MD, and HEIN J. J. WELLENS, MD
In patients with the Wolff-Parkinson-White syndrome, intravenous ajmaline (50 mg administered over 3 minutes) or procainamlde (10 mg/kg body weight administered over 10 minutes) is helpful in defining the duration of the anterograde effective refractory period of the accessory pathway. In this study the value of the ajmallne-procatnamlde test to predict the effects on the anterograde effective refractory period of the accessory pathway of long-term oral amiodarone were assessed. Thirty-six patients with the Wolff-Parkinson-White syndrome were studied. Twenty-four (Group A) had a negative result of the ajmaline-procalnamkle test and a mean duration of the anterograde effective refractory period of the accessory pathway of 237 f 24 ms. Twelve (Group B) had a positive result in the ajmaline-procainamide test (disappearance of preexcitatlon during sinus rhythm after administration of ajmaline and procainamide) and a duration
of the anterograde effective refractory period of the accessory pathway of 284 f 25 ms (p X0.05 versus values in Group A). Amiodarone prolonged the anterograde effective refractory period of the accessory pathway by 53 f 35 ms in patients in Group A to 290 f 37 ms (p
In patients with the Wolff-Parkinson-White (WPW) syndrome, the intravenous administration of 50 mg of ajmaline over 3 minutes or 10 mg/kg body weight of procainamide over 10 minutes during sinus rhythm gives information about the duration of the anterograde effective refractory period of the accessory pathway. In most patients with the WPW syndrome with a duration of the anterograde effective refractory period of the accessory pathway 1270 ms, both ajmalinei and pro-
cainamides block anterograde conduction over the accessory pathway during sinus rhythm (a positive test). In most patients in whom the anterograde effective refractory period of the accessory pathway is <270 ms, ajmaline and procainamide fail to block anterograde conduction over the accessory pathway during sinus rhythm (a negative test) .ls2 Ajmaline is a class I antiarrhythmic agent not available in the United States. We have previously shown a good correlation between the effects of ajmaline and procainamide to block anterograde conduction over the accessory pathway in patients with the WPW syndrome.2 Roughly 10 mg of ajmaline is equivalent to 100 mg of procainamide. Amiodarone is now being evaluated as an antiarrhythmic agent in the United States. Several studies have shown that it is of value in preventing both supraventricular and ven-
From the Department of Cardiology, University of Limburg, Annadal Hospital, Maastricht, The Netherlands. Manuscript received November 29,1982; revised manuscript received March 18.1983. accepted March 18, 1983. Address for reprints: Pedro Brugada, MD, Clinical Electrophysiology Laboratory, Department of Cardiology, University of Limburg, Annadal Hospital, Maastricht, The Netherlands.
July 1983
tricular arrhythmias.3-g In patients with WPW syndrome, amiodarone prolo:ngs the anterograde effective refractory period of the accessory pathway more than other antiarrhythmic agents such as procainamide, ajmaline, and quinidine. lo At present accurate assessment of the effect of an antiarrhythmic drug on the length of the anterograde effective refractory period of the accessory pathway in patients with the WPW syndrome requires an invasive electrophysiologic investigation. In this study we evaluated the value of the ajmaline-procainamide test in predicting the effects of oral amiodarone on the duration of the anterograde effective refractory period of the accessory pathway. We wanted to know to what extent oral amiodarone was able to lengthen the anterograde effective refractory period of the accessory pathway in patients with both positive and negative results of the ajmaline-procainamide test. The results of such a study could be of value in providing noninvasive information about the effect of amiodarone on the anterogralde effective refractory period of the accessory pathway in patients with the WPW syndrome.
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52
Results A summary of the duration of the anterograde effective refractory period of the accessory pathway before and after administration of amiodarone is shown in Table I. In patients in Group A (with negative results of the ajmaline-procainamide test), the mean duration of the anterograde effective refractory period of the accessory pathway before administration of amiodarone was 237 f 24 ms. This value was significantly different from the duration of the anterograde effective refractory period of the accessory pathway in patients in Group B (290 f 37 ms) (p <0.05). One patient (Patient 20) in Group A had an anterograde effective refractory period of the accessory pathway >270 ms (290 ms). One patient (Patient 35) in Group B had an anterograde effective refractory period of the accessory pathway <270 ms (230 ms). Amiodarone prolonged the duration of the anterograde effective refractory period of the accessory
TABLE I
Duration (ms) of Anterograde Effective Refractory Period of the Accessory Pathway Before and During Oral Administration of Amiodarone in the 36 Patients Studied
Methods Patients: Thirty-six patients (28 male and 8 female) with the WPW syndrome were retrospectively studied. Their ages ranged from 16 to 62 years. Four patients had a right-sided, 6 a sept& and 26 a left-sided accessory pathway. Patients were classified into 2 groups according to the results of the ajmaline and procainamide tests, which were performed as previously described.ly2 Twenty-four patients had a negative ajmaline test result (Group A) and 12 patients a positive test result (Group B). Eleven patients in Group A and 7 in Group B also had a procainamide test performed, with results identical to those of the ajmaline test. Twenty-four to 48 hours after the last test (ajmaline or procainamide), an electroph:ysiologic study was performed to determine the duration of the anterograde effective refractory period of the accessory pathway. The extrastimulus technique was used during atria1 stimulation at at least 3 different basic cycle lengths of pacing, usually 600, 500, and 430 ms. The anterograde effective refractory period of the accessory pathway was defined as the longest Al-A2 interval not followed by anterograde conduction over the accessory pathway. The shortest measured anterograde effective refractory period of the accessory pathway at any cycle length of pacing from the atria1 site closest to the atria1 end of the accessory pathway was used. Patients were not included in this study when atria1 refractoriness prevented accurate measurement of the duration of the anterograde effective refractory period of the accessory pathway during the control or repeat study on oral amiodarone. After the control study, patients were given amiodarone orally starting at a dose of 600 mg/day for 7 days followed by 200 mg/day for an additional 3 to 5 weeks. The total oral dose of amiodarone at the time of examination varied individually from 8,400 to 11,200 mg. During reexamination the same protocol was followed as during the initial electrophysiologic examination. The shortest value of the anterograde effective refractory period of the accessory pathway was used for analysis. Plasma levels of ajmaline, procainamide, and amiodarone were not determined. Statistical analysis was performed using the paired and unpaired Student’s t test, and the chi-square test.
71
Amiodarone Patient
Before
During
Increase
Group A (Negative Ajmaline-Procainamide Test) 245 245 260 260 240 230 250 240 200 230 240 240 200 250 260 220 250 240
270 310 285 295 300 290 400 270 220 320 260 300 260 290 270 280 310 290
19
240 290 260
290 360 260
22 ;: Mean f SD
210 210 180 237 f 24
300 300 230 290 f 37
:
I.5
is ;:
3: tz 150 30 :8 t8 60 40 10 60 40 70 50 70 0 1;: 53 2035
Group B (Positive Ajmaline-Procainamide Test)
z: ;: 8: :: 35 36 Mean f SD
270 300 270 310 280 290 270 270 330 300 230 290 284 f 25
SD = standard deviation.
450 350 400 500 350 340 280 270 400 340 330 600 384 f 95
180 50 130 190 ;z 10 0 70 40 100 310 100 f 85
72
AJMALINE-PROCAINAMIDE TEST AND AMIODARONE IN WOLFF-PARKINSON-WHITE
pathway in both groups: in Group A by a mean of 53 f 35 ms, and in Group B by a mean of 100 f 85 ms. These results were statistically significant (p0.05). When individual data were analyzed, it was observed that in 10 (83%) of 12 patients in Group B, amiodarone prolonged the anterograde effective refractory period of the accessory pathway to a value 2330 ms; in 5 of these 10 patients it was 2400 ms. In patients in Group A a duration of the anterograde effective refractory period of the accessory pathway 1330 ms after administration of amiodarone was obtained only in Patients 7 and 20 (400 and 360 ms, respectively). In 20 of the remaining 22 patients the anterograde effective refractory period of the accessory pathway was 260 to 320 ms, and in the remaining 2 patients it was 220 and 230 ms. In this group, 20 (83%) of 24 patients had an anterograde effective refractory period of the accessory pathway of 260 to 330 ms during administration of amiodarone (p
Discussion In this study patients with the WPW syndrome were classified into 2 groups on the basis of the results of the ajmaline-procainamide test. The duration of the anterograde effective refractory period of the accessory pathway as shown previously was significantly different in the 2 groups during the c,ontrol study.lt2 Amiodarone brought the anterograde effective refractory period of the accessory pathway to a duration of 260 to 330 ms in the majority of patients (83%) in Group A, and to a duration 2330 ms in 83% of patients in Group B. We and other+l3 found a relation between the duration of the anterograde refractory period of the accessory pathway in the WPW syndrome and the shortest preexcitated R-R interval during atrial fibrillation. One might assume therefore that in a majority of Group A patients (83’S), the shortest R-R interval during atria1 fibrillation will not be <260 ms during amiodarone administration (corresponding to a ventricular rate of 240 beats/min). In 83% of Group B patients the shortest R-R interval will not be <330 ms (corresponding to a ventricular rate of 170 beats/min) during administration
SYNDROME
of amiodarone. In our patients, however, atria1 fibrillation was not systematically initiated during the study before and after administration of amiodarone, and these considerations should be made with caution. The results of our study show that an ajmaline-procainamide test performed before antiarrhythmic therapy is helpful in predicting the results of oral administration of amiodarone and will help to avoid a repeat electrophysiologic investigation. We recently showed that beta-adrenergic stimulation shortens the duration of the effective refractory period of the accessory pathway in patients with the WPW syndrome.‘4 The results of that study indicate that the properties of the accessory pathway are dynamic, and they change with changes in autonomic tone. At present the behavior of the properties of the accessory pathway with time are unknown, and it is possible that they are not stable. The results of this study, therefore, have to be considered with caution in light of these observations.
References 1. Wellens HJJ, B&r FW, Gorgele AP, Vanagf EJ. Use of ajmaline in patients with the Wolff-Parkinson-White syndrome to disclose a short refractory period of the accessory pathway. Am J Cardiol 1980;45:130-133. 2. Wellem HJJ, Braat S, Brugada P, Gorgelo AP, Bier FW. Use of procainamide in,pabents with the Wolff-Parkinson-White syndrome to disclose a short refractory period of the accessory pathway. Am J Cardiol 1982;50: 1087-1089. 3. Rosenbaum MB, Chlale PA, Rljba D, Ellzarl MV. Control of tachyarmythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 1974:34:215-223. 4. Wellena HJJ, Lie KI, Bier FW, We&p JC, Dobmen HJ, Duren DR. Durrer 0. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 1978;36:189-194. 5. Waleffe A, Brunninx P, Kulbertus HE. Effects of amiodarone studied by programmed electrical stimulation of the heart in patients with paroxysmal m-entrant supraventricular tachycardia. J Electrocardiol 1978;11:253260. 8. Pockfd PJ, Lawn B. Amiodarone therapy in symptomatic sustained refractory atrial and ventricular tachyarrhythmias. Am Heart J 1981;101:374-379. 7. Nademanee K, Hendrlckaon JA, Cannom OS, Goldreyer BN, Slngh BN. Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. Am Heart J 1981;101:759-768. 8. Heger JJ, Pryatowsky EN, Jackman WM, Nacarelll GV, Warfel KA, Rlnkenberger RL, Zlpea DP. Amiodarone. Clinicafefficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-544. 9. Hamer AW, Flnerman WB Jr, Peter T, Man&l WJ. Disparity between the clinical and electrophysiologic effects of amiodarone in the treatment of recurrent ventricular tachyarrhythmias. Am Heart J 1981;102:992innn .-__. 10. Weffens HJJ, B&r FW, Dasaen WRY, Brugada P, Vanagt EJ, Fati, J. Effect of drugs in tfm Wolff-Parkinson-Whiie syndrome. lmpmtamx of initial length of effective refractory period of the accessory pathway. Am J Cardiol 1980;46:665-689. 11. Caatellanoa A, Myerburg NJ, Craparo K, Befeler B, Agha AS. Factors regulating ventricular rates during atrial flutter and fibrillation in preexcitation. Br Heart J 1973;35:811-817. 12. Wellens HJJ, Durrer D. Wolff-Parkinson-White syndrome and atrial fibrillation. Relation between refractory period of the accessory pathway and ventricular rate during atrial fibrillation. Am J Cardiol 1974;34:777-782. 13. Campbell RWF, Smith RA, Gallagher J.J. Atrial fibrillation in the pre-excitation syndrome. Am J Cardiol 1977;40:514-520. 14. Wellena HJJ. Brugada P, Roy 0, Weirs J, B&r FW. Effect of isoproterenol on the anterograde refractory period of the accessory pathway in patients with the Wolff-Parkinson-White syndrome. Am J Cardiol 1982;50:160184.
In patients with the Wolff-Parkinson-White syndrome, intravenous ajmaline (50 mg administered over 3 minutes) or procainamlde (10 mg/kg body weight administered over 10 minutes) is helpful in defining the duration of the anterograde effective refractory period of the accessory pathway. In this study the value of the ajmallne-procatnamlde test to predict the effects on the anterograde effective refractory period of the accessory pathway of long-term oral amiodarone were assessed. Thirty-six patients with the Wolff-Parkinson-White syndrome were studied. Twenty-four (Group A) had a negative result of the ajmaline-procalnamkle test and a mean duration of the anterograde effective refractory period of the accessory pathway of 237 f 24 ms. Twelve (Group B) had a positive result in the ajmaline-procainamide test (disappearance of preexcitatlon during sinus rhythm after administration of ajmaline and procainamide) and a duration
of the anterograde effective refractory period of the accessory pathway of 284 f 25 ms (p X0.05 versus values in Group A). Amiodarone prolonged the anterograde effective refractory period of the accessory pathway by 53 f 35 ms in patients in Group A to 290 f 37 ms (p
In patients with the Wolff-Parkinson-White (WPW) syndrome, the intravenous administration of 50 mg of ajmaline over 3 minutes or 10 mg/kg body weight of procainamide over 10 minutes during sinus rhythm gives information about the duration of the anterograde effective refractory period of the accessory pathway. In most patients with the WPW syndrome with a duration of the anterograde effective refractory period of the accessory pathway 1270 ms, both ajmalinei and pro-
cainamides block anterograde conduction over the accessory pathway during sinus rhythm (a positive test). In most patients in whom the anterograde effective refractory period of the accessory pathway is <270 ms, ajmaline and procainamide fail to block anterograde conduction over the accessory pathway during sinus rhythm (a negative test) .ls2 Ajmaline is a class I antiarrhythmic agent not available in the United States. We have previously shown a good correlation between the effects of ajmaline and procainamide to block anterograde conduction over the accessory pathway in patients with the WPW syndrome.2 Roughly 10 mg of ajmaline is equivalent to 100 mg of procainamide. Amiodarone is now being evaluated as an antiarrhythmic agent in the United States. Several studies have shown that it is of value in preventing both supraventricular and ven-
From the Department of Cardiology, University of Limburg, Annadal Hospital, Maastricht, The Netherlands. Manuscript received November 29,1982; revised manuscript received March 18.1983. accepted March 18, 1983. Address for reprints: Pedro Brugada, MD, Clinical Electrophysiology Laboratory, Department of Cardiology, University of Limburg, Annadal Hospital, Maastricht, The Netherlands.
July 1983
tricular arrhythmias.3-g In patients with WPW syndrome, amiodarone prolo:ngs the anterograde effective refractory period of the accessory pathway more than other antiarrhythmic agents such as procainamide, ajmaline, and quinidine. lo At present accurate assessment of the effect of an antiarrhythmic drug on the length of the anterograde effective refractory period of the accessory pathway in patients with the WPW syndrome requires an invasive electrophysiologic investigation. In this study we evaluated the value of the ajmaline-procainamide test in predicting the effects of oral amiodarone on the duration of the anterograde effective refractory period of the accessory pathway. We wanted to know to what extent oral amiodarone was able to lengthen the anterograde effective refractory period of the accessory pathway in patients with both positive and negative results of the ajmaline-procainamide test. The results of such a study could be of value in providing noninvasive information about the effect of amiodarone on the anterogralde effective refractory period of the accessory pathway in patients with the WPW syndrome.
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52
Results A summary of the duration of the anterograde effective refractory period of the accessory pathway before and after administration of amiodarone is shown in Table I. In patients in Group A (with negative results of the ajmaline-procainamide test), the mean duration of the anterograde effective refractory period of the accessory pathway before administration of amiodarone was 237 f 24 ms. This value was significantly different from the duration of the anterograde effective refractory period of the accessory pathway in patients in Group B (290 f 37 ms) (p <0.05). One patient (Patient 20) in Group A had an anterograde effective refractory period of the accessory pathway >270 ms (290 ms). One patient (Patient 35) in Group B had an anterograde effective refractory period of the accessory pathway <270 ms (230 ms). Amiodarone prolonged the duration of the anterograde effective refractory period of the accessory
TABLE I
Duration (ms) of Anterograde Effective Refractory Period of the Accessory Pathway Before and During Oral Administration of Amiodarone in the 36 Patients Studied
Methods Patients: Thirty-six patients (28 male and 8 female) with the WPW syndrome were retrospectively studied. Their ages ranged from 16 to 62 years. Four patients had a right-sided, 6 a sept& and 26 a left-sided accessory pathway. Patients were classified into 2 groups according to the results of the ajmaline and procainamide tests, which were performed as previously described.ly2 Twenty-four patients had a negative ajmaline test result (Group A) and 12 patients a positive test result (Group B). Eleven patients in Group A and 7 in Group B also had a procainamide test performed, with results identical to those of the ajmaline test. Twenty-four to 48 hours after the last test (ajmaline or procainamide), an electroph:ysiologic study was performed to determine the duration of the anterograde effective refractory period of the accessory pathway. The extrastimulus technique was used during atria1 stimulation at at least 3 different basic cycle lengths of pacing, usually 600, 500, and 430 ms. The anterograde effective refractory period of the accessory pathway was defined as the longest Al-A2 interval not followed by anterograde conduction over the accessory pathway. The shortest measured anterograde effective refractory period of the accessory pathway at any cycle length of pacing from the atria1 site closest to the atria1 end of the accessory pathway was used. Patients were not included in this study when atria1 refractoriness prevented accurate measurement of the duration of the anterograde effective refractory period of the accessory pathway during the control or repeat study on oral amiodarone. After the control study, patients were given amiodarone orally starting at a dose of 600 mg/day for 7 days followed by 200 mg/day for an additional 3 to 5 weeks. The total oral dose of amiodarone at the time of examination varied individually from 8,400 to 11,200 mg. During reexamination the same protocol was followed as during the initial electrophysiologic examination. The shortest value of the anterograde effective refractory period of the accessory pathway was used for analysis. Plasma levels of ajmaline, procainamide, and amiodarone were not determined. Statistical analysis was performed using the paired and unpaired Student’s t test, and the chi-square test.
71
Amiodarone Patient
Before
During
Increase
Group A (Negative Ajmaline-Procainamide Test) 245 245 260 260 240 230 250 240 200 230 240 240 200 250 260 220 250 240
270 310 285 295 300 290 400 270 220 320 260 300 260 290 270 280 310 290
19
240 290 260
290 360 260
22 ;: Mean f SD
210 210 180 237 f 24
300 300 230 290 f 37
:
I.5
is ;:
3: tz 150 30 :8 t8 60 40 10 60 40 70 50 70 0 1;: 53 2035
Group B (Positive Ajmaline-Procainamide Test)
z: ;: 8: :: 35 36 Mean f SD
270 300 270 310 280 290 270 270 330 300 230 290 284 f 25
SD = standard deviation.
450 350 400 500 350 340 280 270 400 340 330 600 384 f 95
180 50 130 190 ;z 10 0 70 40 100 310 100 f 85
72
AJMALINE-PROCAINAMIDE TEST AND AMIODARONE IN WOLFF-PARKINSON-WHITE
pathway in both groups: in Group A by a mean of 53 f 35 ms, and in Group B by a mean of 100 f 85 ms. These results were statistically significant (p
Discussion In this study patients with the WPW syndrome were classified into 2 groups on the basis of the results of the ajmaline-procainamide test. The duration of the anterograde effective refractory period of the accessory pathway as shown previously was significantly different in the 2 groups during the c,ontrol study.lt2 Amiodarone brought the anterograde effective refractory period of the accessory pathway to a duration of 260 to 330 ms in the majority of patients (83%) in Group A, and to a duration 2330 ms in 83% of patients in Group B. We and other+l3 found a relation between the duration of the anterograde refractory period of the accessory pathway in the WPW syndrome and the shortest preexcitated R-R interval during atrial fibrillation. One might assume therefore that in a majority of Group A patients (83’S), the shortest R-R interval during atria1 fibrillation will not be <260 ms during amiodarone administration (corresponding to a ventricular rate of 240 beats/min). In 83% of Group B patients the shortest R-R interval will not be <330 ms (corresponding to a ventricular rate of 170 beats/min) during administration
SYNDROME
of amiodarone. In our patients, however, atria1 fibrillation was not systematically initiated during the study before and after administration of amiodarone, and these considerations should be made with caution. The results of our study show that an ajmaline-procainamide test performed before antiarrhythmic therapy is helpful in predicting the results of oral administration of amiodarone and will help to avoid a repeat electrophysiologic investigation. We recently showed that beta-adrenergic stimulation shortens the duration of the effective refractory period of the accessory pathway in patients with the WPW syndrome.‘4 The results of that study indicate that the properties of the accessory pathway are dynamic, and they change with changes in autonomic tone. At present the behavior of the properties of the accessory pathway with time are unknown, and it is possible that they are not stable. The results of this study, therefore, have to be considered with caution in light of these observations.
References 1. Wellens HJJ, B&r FW, Gorgele AP, Vanagf EJ. Use of ajmaline in patients with the Wolff-Parkinson-White syndrome to disclose a short refractory period of the accessory pathway. Am J Cardiol 1980;45:130-133. 2. Wellem HJJ, Braat S, Brugada P, Gorgelo AP, Bier FW. Use of procainamide in,pabents with the Wolff-Parkinson-White syndrome to disclose a short refractory period of the accessory pathway. Am J Cardiol 1982;50: 1087-1089. 3. Rosenbaum MB, Chlale PA, Rljba D, Ellzarl MV. Control of tachyarmythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 1974:34:215-223. 4. Wellena HJJ, Lie KI, Bier FW, We&p JC, Dobmen HJ, Duren DR. Durrer 0. Effect of amiodarone in the Wolff-Parkinson-White syndrome. Am J Cardiol 1978;36:189-194. 5. Waleffe A, Brunninx P, Kulbertus HE. Effects of amiodarone studied by programmed electrical stimulation of the heart in patients with paroxysmal m-entrant supraventricular tachycardia. J Electrocardiol 1978;11:253260. 8. Pockfd PJ, Lawn B. Amiodarone therapy in symptomatic sustained refractory atrial and ventricular tachyarrhythmias. Am Heart J 1981;101:374-379. 7. Nademanee K, Hendrlckaon JA, Cannom OS, Goldreyer BN, Slngh BN. Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. Am Heart J 1981;101:759-768. 8. Heger JJ, Pryatowsky EN, Jackman WM, Nacarelll GV, Warfel KA, Rlnkenberger RL, Zlpea DP. Amiodarone. Clinicafefficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-544. 9. Hamer AW, Flnerman WB Jr, Peter T, Man&l WJ. Disparity between the clinical and electrophysiologic effects of amiodarone in the treatment of recurrent ventricular tachyarrhythmias. Am Heart J 1981;102:992innn .-__. 10. Weffens HJJ, B&r FW, Dasaen WRY, Brugada P, Vanagt EJ, Fati, J. Effect of drugs in tfm Wolff-Parkinson-Whiie syndrome. lmpmtamx of initial length of effective refractory period of the accessory pathway. Am J Cardiol 1980;46:665-689. 11. Caatellanoa A, Myerburg NJ, Craparo K, Befeler B, Agha AS. Factors regulating ventricular rates during atrial flutter and fibrillation in preexcitation. Br Heart J 1973;35:811-817. 12. Wellens HJJ, Durrer D. Wolff-Parkinson-White syndrome and atrial fibrillation. Relation between refractory period of the accessory pathway and ventricular rate during atrial fibrillation. Am J Cardiol 1974;34:777-782. 13. Campbell RWF, Smith RA, Gallagher J.J. Atrial fibrillation in the pre-excitation syndrome. Am J Cardiol 1977;40:514-520. 14. Wellena HJJ. Brugada P, Roy 0, Weirs J, B&r FW. Effect of isoproterenol on the anterograde refractory period of the accessory pathway in patients with the Wolff-Parkinson-White syndrome. Am J Cardiol 1982;50:160184.