International Journal of ,Cardiology, 36 (1992) 69-19 0 1992 Elsevier Science Publishers B.V. All rights reserved 0167-5273/92/$05.00
69
CARD10 01475
Electrophysiology and long-term efficacy of pentisomide in patients with supraventricular tachycardia Volker Kiihlkamp, Christian Mewis and Ludger Seipel Medizinische Klinik Abteilung III, Tiibingen, Germany
(Received 18 October 1991; revision accepted 5 February 1992)
Kiihlkamp V, Mewis C, Seipel L. Electrophysiology and long-term efficacy of pentisomide with supraventricular tachycardia. Int J Cardiol 1992;36:69-79.
in patients
The electrophysiologic effects of pentisomide were investigated after intravenous (5 mg/kg) and oral (900-1200 mg three times a day) application in 9 patients with drug refractory atrioventricular nodal tachycardia and 6 patients with orthodromic atrioventricular re-entrant tachycardia. Pentisomide did not change sinus cycle length, effective refractory period of the right ventricle and the atrioventricular node. AH, HV interval, effective refractory period of the right atrium, QRS duration and QTc duration were (p I 0.01) increased. Tachycardia cycle length was only increased after intravenous application of pentisomide, antegrade effective refractory periods of the accessory pathways and shortest fully pre-excited R-R intervals during atria1 fibrillation were increased after the oral treatment phase (p = 0.054). Intravenous pentisomide prevented tachycardia in 6/9 patients with atrioventricular nodal tachycardia and in 2/6 patients with atrioventricular re-entrant tachycardia. If intravenous pentisomide did not prevent induction of the tachycardia, oral pentisomide was not effective either. During long-term follow-up 2/7 patients with atrioventricular nodal tachycardia and l/4 patient with atrioventricular re-entrant tachycardia had a recurrence. Long-term treatment with pentisomide had to be discontinued because of possible side effects in 2 patients. It is concluded, that the electrophysiological effects of pentisomide are similar to those of flecainide and propafenone. Key words: Pentisomide;
Supraventricular
tachycardia; Medical treatment
of arrhythmia
Introduction
is a new class under investigation
[l], drug currently
M.D., Medizinische III, Otfried Miiller Str.
that its action is the inhibition fast sodium channel [4-61, whereas its calcium-blocking effects are probably [7]. The information concerning the effects pentisomide with supraventricular [3]. No information oral treatment with
70
currence of supraventricular tachycardia and its general tolerance in the long-term follow-up. Hence we performed a study in patients with drug refractory supraventricular tachycardia.
Methods The study group consisted of 15 patients (9 men and 6 women, 22 to 65 yr) with drug refractory supraventricular tachycardia (Table 1). The study protocol was approved by the local commit-
tee on human research. All patients gave informed written consent. Antiarrhythmic drugs including cardiac glycosides were withdrawn for at least five drug halflives. After the washout period, a 1Zlead surface electrocardiogram, a bicycle exercise stress test and a baseline electrophysiologic study were performed. The electrophysiologic study was repeated after intravenous administration of pentisomide (4 mg/kg in 10 min, maintenance dose 1 mg/kg in 60 min). A further electrophysiologic
TABLE 1 Patient characteristics and ineffective anti-arrhythmic drugs. No.
Age (yr)
Sex
Cardiac disease
Tachycardia
Ineffective antiarrhythmic drugs
1
53
M
None
AVRT
2 3
3.5 65
M F
None None
AVRT AVRT
4
58
F
None
AVRT
5 6 7
22 22 49
M M M
AVRT AVRT AVNT
8
56
F
Ebstein’s anomaly Ebstein’s anomaly Arterial hypertension None
9
56
M
AVNT
10
54
F
Coronary artery disease None
Propranolol 120 mg Verapamh 240 mg Ajmaline 200 mg Propafenone 450 mg Metoprolol200 mg Propafenone 900 mg Flecainide 300 mg Propafenone 900 mg Quinidine 600 mg BetaxoloI20 mg Sotalol 160 mg Flecainide 200 mg Metoprolol200 mg Verapamil240 mg Propranolol 160 mg Verapamil240 mg Quinidine 600 mg Flecainide 200 mg Betaxolol 10 mg
11
64
M
AVNT
12 13
59 54
M F
14
46
F
Aortic valve insufficiency Diabetes Arterial hypertension None
15
26
M
AVRT =atrioventricular
Aortic valve insufficiency
AVNT
AVNT
AVNT AVNT AVNT
AVNT
Verapamil240 mg Propafenone 450 mg Flecainide 300 mg Disopyramide 500 mg Verapamil240 mg Verapamil240 mg Propranolol 120 mg Sotalol 160 mg Propranolol 120 mg Verapamil360 mg Propafenone 450 mg Propranolol 160 mg
re-entrant tachycardia; AVNT = atrioventricular nodal re-entrant tachycardia.
71
study was performed after an oral treatment phase with pentisomide for 5 days (900 mg in patients with a body weight 5 80 kg and 1200 mg in patients with a body weight > 80 kg) in 12 patients. Prior to this electrophysiologic study a second 1Zlead surface electrocardiogram and a second exercise stress test were obtained. The electrophysiologic study was performed with the usual technique [8]: 4 multipolar electrode catheters were advanced under fluoroscopic control to the high right atrium, the coronary sinus, His-position and the right ventricular apex. A quadripolar catheter (10 mm interelectrode distance) was positioned in the high right atrium, atria1 stimulation was performed via the distal electrode pair, and the proximal electrode pair was used to record the high right atria1 electrogram. The electrode catheter in the coronary sinus (quadripolar, 5 mm interelectrode distance) was used to record retrograde atria1 activation during re-entrant tachycardia and ventricular stimulation. If necessary right atria1 mapping for localization or exclusion of a right-sided accessory pathway was performed. The electrophysiologic study after the oral treatment phase was performed using 3 electrode catheters. Programmed atria1 (driving frequency lOO/min) and ventricular stimulation (driving frequency 120/min to 180/min, up to 2 extrastimuli) using the extrastimulus technique as well as continuous atria1 stimulation with paced rates between lOO/min and 200/min were performed. The surface electrocardiogram (leads I, III, V, and V,) as well as the intracardiac signals were recorded simultaneously on a Siemens Elema Mingograf 62 at a paper speed between 50 mm/s and 100 mm/s. Pacing stimuli were provided by a digital stimulator (Medtronic 5328), with a pulse duration of 2 ms and approximately twice diastolic strength. Blood for pentisomide serum levels was drawn 15 min and 30 min after the end of the pentisomide infusion and at the electrophysiologic study after the oral treatment phase and determined by high pressure liquid chromatography. The following parameters were determined: P wave, PR, QRS, QT and QTc duration, cycle length during sinus rhythm, sinus node recovery time, frequency corrected sinus node recovery
time, effective and functional refractory period of the atrioventricular node, Wenckebach cycle length, intra-atria1 conduction time during sinus rhythm, intranodal (AI-I interval) and infranodal (HV interval) conduction time during sinus rhythm and a paced cycle length of 600 ms, effective refractory period of the right atrium at a paced cycle length of 600 ms, effective refractory period of the right ventricle at a paced cycle length of 500 ms, effective antegrade and retrograde refractory period of the accessory pathway, shortest fully pre-excited R-R interval during atria1 fibrillation in patients with an accessory pathway. P wave, PR, QRS, QT and QTc duration were determined in lead V, of the surface electrocardiogram. Sinus node recovery time was measured from the last paced atria1 beat to the first beat of sinus origin. Frequency corrected sinus node recovery time was calculated by the difference between sinus node recovery time and sinus cycle length [9]. Intra-atria1 conduction time was defined as the time interval from the onset of high right atria1 activation to the deflection of the basal right atria1 electrogram (A wave). Shortest ventricular cycle length during atria1 fibrillation was the shortest fully pre-excited R-R interval within the first 30 s after the onset of the atria1 tachyarrhythmia. Atrioventricular nodal re-entrant tachycardia (slow-fast) was diagnosed in 9 patients based on the following criteria [lO,ll]: - demonstration of dual atrioventricular nodal pathways by programmed atria1 stimulation; - induction of the tachycardia after reaching the effective refractory period of the fast atrioventricular nodal pathway; - recording of the signal from the high right atrium at a maximum of 90 ms after earliest recording of ventricular activation during tachycardia; - documentation of retrograde atria1 activation via the atrioventricular node during programmed ventricular stimulation. In 6 patients the mechanism of the tachycardia was orthodromic atrioventricular re-entrance using an extranodal pathway for retrograde conduction, 2 patients having concealed and 4 patients manifest Wolff-Parkinson-White syndrome. The
72
presence of an accessory pathway was diagnosed if: - retrograde atria1 depolarization during tachycardia and programmed ventricular stimulation was not compatible with retrograde conduction via the atrioventricular node; - premature atria1 depolarization was elicited by a paced single premature ventricular contraction occurring during refractoriness of the HisPurkinje system 1121. All data are expressed as mean value -tstandard deviation, and the Wilcoxon test was used for statistical analysis of paired data. Elec-
trophysiologic data after intravenous and oral application of pentisomide were compared to electrophysiologic data obtained at the baseline electrophysiologic study. Results Sinus cycle length and sinus node function (Table 2) Although sinus cycle length was not significantly affected by intravenous pentisomide there was a significant decrease in heart rate after oral
TABLE 2 Electrophysiologic
data (ms) obtained under baseline conditions and after intravenous and oral application of pentisomide.
Sinus cycle length (R-R) Sinus node recovery time Frequency corrected sinus node recovery time Effective refractory period of the right atrium Effective refractory period of the right ventricle Intranodal conduction time (AI-I, sinus rhythm) Intranodal conduction time (AH, paced rate lOO/min) Infranodal conduction time (HV, sinus rhythm) Infranodal conduction time (HV, paced rate lOO/minI Intra-atrial conduction time (HRA-A, sinus rhythm) Wenckebach cycle length P-wave duration PR interval
Baseline n = 15
Intravenous pentisomide n = 15
731 f 109
696 f 111 p = 0.134 995 f 130 p = 0.487 314& 71 p = 0.129 225 k 30 p = 0.011 225 + 17 p = 0.046 103k 36 p = 0.008 120* 39 p = 0.025 54+ 8 p = 0.001 53+ 11 p = 0.006 30+ 14 p = 0.002 335 f 44 p = 0.026 94& 13 p = 0.001 186* 45 p < 0.001 97* 14 p = 0,001 372 + 29 p = 0.295 461 f 51 p = 0.018
999 f 155 275 f 118 210*
25
234 + 25 94 f .33 113f
63
45+
9
46+
8
23 f
10
319, 84+
46 11
155 + 43 85f
13
QT interval
367*
34
QTc interval
430+
27
QRS duration
n = number of patients.
Oral pentisomide n = 12 822 + 174
p = 0.014 1185 + 254
p = 0.01 365 + 107 p = 0.046 232* 31 p = 0.004 234 + 15 p = 0.239 12Ok 67 p = 0.002 165 f 124 p = 0.001 55 * 10 p = 0.008 54* 9 p = 0.023 33+ 9 p = 0.005 377 f 72 p = 0.006 90* 13 p = 0.006 196* 62 p = 0.003 94+ 16 p = 0.009 383 + 38 p = 0.073 427 f 41 p = 0.319
73
pentisomide (p = 0.014). Sinus node recovery time was also not significantly affected by intravenous pentisomide; it was, however, increased by oral pentisomide (p = 0.01). In accordance with these findings is a significant increase (p = 0.046) in the frequency corrected sinus node recovery time only after the oral treatment phase with pentisomide. Conduction times in the surface electrocardiogram (Table 2) P-wave duration, PR interval and QRS duration were significantly increased by intravenous and oral pentisomide. Although the QT interval was not significantly affected, the QTc interval was increased from 430 5 27 ms to 461 t- 51 ms (p = 0.018) after intravenous pentisomide. However, there was no significant increase in the QTc interval after oral pentisomide in comparison to the baseline value. Effective refractory period of atrium and ventricle There was a small but significant increase in the effective refractory period of the right atrium by intravenous and oral pentisomide. In contrast, the effective refractory period of the right ventricle was decreased by intravenous pentisomide (p = 0.046), an effect that was not seen with oral pentisomide ( p = 0.239). Atrioventricular node and extranodal pathway The effective refractory period of the atrioventricular node could be determined in only 3 patients at the baseline electrophysiologic study (293 f 31 ms), after intravenous (287 f 33 ms) and oral (347 + 80 ms) pentisomide. In all other patients measurement of the effective refractory periods of the atrioventricular node was limited by the effective refractory period of the atrium or the accessory pathway (Tables 3A and 3B). The functional and the effective refractory periods of the slow atrioventricular nodal pathway in patients with atrioventricular nodal re-entrant tachycardia were not significantly affected by intravenous and oral pentisomide (Table 3B). The
functional refractory periods of the fast atrioventricular nodal pathway, not significantly increased by intravenous pentisomide, increased from 382 + 28 ms to 468 f 53 ms (p = 0.014, Table 3B) after oral application of pentisomide. A small increase in Wenckebach cycle length was noted after intravenous (p = 0.026) and oral (p = 0.006) application of pentisomide (Table 2). Measurement of the retrograde effective refractory periods of the atrioventricular node was limited by the effective refractory periods of the right ventricle or by conduction via an extranodal pathway (Tables 3A and 3B). Intravenous and oral pentisomide prevented retrograde conduction via the atrioventricular node in 5 of 9 and 6 of 8 patients with atrioventricular nodal tachycardia, respectively, and in 2 of 6 and 2 of 4 patients with atrioventricular reentrant tachycardia. Neither the antegrade nor the retrograde effective refractory periods of the accessory pathway were significantly increased by intravenous or oral pentisomide (Table 4). The shortest fully pre-excited R-R intervals during atria1 fibrillation in patients with manifest Wolff-Parkinson-White syndrome were also not significantly prolonged by pentisomide (Table 4). However, the increase in the antegrade effective refractory period of the accessory pathway (p = 0.054) as well as the increase in the shortest fully pre-excited R-R interval during atria1 fibrillation (p = 0.054) both just failed to reach statistical significance (Table 4). Intranodal (AI-I) as well as infranodal (HV) conduction time were both significantly prolonged by intravenous and oral pentisomide (Table 2). Induction of tachycardia At the baseline study a sustained (> 30 s) tachycardia could be induced by programmed atria1 stimulation in all patients. Intravenous pentisomide prevented re-induction of the tachycardia in 6 of 9 patients with atrioventricular nodal tachycardia (Fig. 1) and in 2 of 6 patients with atrioventricular tachycardia (Fig. 2). If tachycardia was still inducible after intravenous application of pentisomide the cycle length of the tachycardia was significantly increased. This increase
74
TABLE 3 Antegrade effective (ERP-AVN) and functional (FRP-AVN) refractory period of the atrioventricular node in patients with atrioventricular re-entrant tachycardia (Table 3A, patients 1 to 6) and antegrade effective (ERP) and functional (FRP) refractory period of the slow (AVN,,,,) and fast (AVN,,,,) atrioventricular nodal pathway in patients with atrioventricular nodal re-entrant tachycardia (Table 3B, patients J to 1.5). Furthermore the retrograde effective refractory period of the atrioventricular node (ERP-VA,,) is given for both patient groups (C = baseline electrophysiologic study, i.v. = intravenous application of pentisomide, p.o. = oral application of pentisomide, data’are given in ms). For calculation of the mean values, only those data were taken into account that were available in the baseline electrophysiologic study and after intravenous and oral pentisomide. TABLE 3A Atrioventricular
re-entrant tachycardia.
Pt. no.
ERP-AVN C
i.v.
p.0.
C
i.v.
p.0.
C
i.v.
p.0.
1 2
380 (1) (1)
I:RA
370
360
430
69
CARD10 01475
Electrophysiology and long-term efficacy of pentisomide in patients with supraventricular tachycardia Volker Kiihlkamp, Christian Mewis and Ludger Seipel Medizinische Klinik Abteilung III, Tiibingen, Germany
(Received 18 October 1991; revision accepted 5 February 1992)
Kiihlkamp V, Mewis C, Seipel L. Electrophysiology and long-term efficacy of pentisomide with supraventricular tachycardia. Int J Cardiol 1992;36:69-79.
in patients
The electrophysiologic effects of pentisomide were investigated after intravenous (5 mg/kg) and oral (900-1200 mg three times a day) application in 9 patients with drug refractory atrioventricular nodal tachycardia and 6 patients with orthodromic atrioventricular re-entrant tachycardia. Pentisomide did not change sinus cycle length, effective refractory period of the right ventricle and the atrioventricular node. AH, HV interval, effective refractory period of the right atrium, QRS duration and QTc duration were (p I 0.01) increased. Tachycardia cycle length was only increased after intravenous application of pentisomide, antegrade effective refractory periods of the accessory pathways and shortest fully pre-excited R-R intervals during atria1 fibrillation were increased after the oral treatment phase (p = 0.054). Intravenous pentisomide prevented tachycardia in 6/9 patients with atrioventricular nodal tachycardia and in 2/6 patients with atrioventricular re-entrant tachycardia. If intravenous pentisomide did not prevent induction of the tachycardia, oral pentisomide was not effective either. During long-term follow-up 2/7 patients with atrioventricular nodal tachycardia and l/4 patient with atrioventricular re-entrant tachycardia had a recurrence. Long-term treatment with pentisomide had to be discontinued because of possible side effects in 2 patients. It is concluded, that the electrophysiological effects of pentisomide are similar to those of flecainide and propafenone. Key words: Pentisomide;
Supraventricular
tachycardia; Medical treatment
of arrhythmia
Introduction
is a new class under investigation
[l], drug currently
M.D., Medizinische III, Otfried Miiller Str.
that its action is the inhibition fast sodium channel [4-61, whereas its calcium-blocking effects are probably [7]. The information concerning the effects pentisomide with supraventricular [3]. No information oral treatment with
70
currence of supraventricular tachycardia and its general tolerance in the long-term follow-up. Hence we performed a study in patients with drug refractory supraventricular tachycardia.
Methods The study group consisted of 15 patients (9 men and 6 women, 22 to 65 yr) with drug refractory supraventricular tachycardia (Table 1). The study protocol was approved by the local commit-
tee on human research. All patients gave informed written consent. Antiarrhythmic drugs including cardiac glycosides were withdrawn for at least five drug halflives. After the washout period, a 1Zlead surface electrocardiogram, a bicycle exercise stress test and a baseline electrophysiologic study were performed. The electrophysiologic study was repeated after intravenous administration of pentisomide (4 mg/kg in 10 min, maintenance dose 1 mg/kg in 60 min). A further electrophysiologic
TABLE 1 Patient characteristics and ineffective anti-arrhythmic drugs. No.
Age (yr)
Sex
Cardiac disease
Tachycardia
Ineffective antiarrhythmic drugs
1
53
M
None
AVRT
2 3
3.5 65
M F
None None
AVRT AVRT
4
58
F
None
AVRT
5 6 7
22 22 49
M M M
AVRT AVRT AVNT
8
56
F
Ebstein’s anomaly Ebstein’s anomaly Arterial hypertension None
9
56
M
AVNT
10
54
F
Coronary artery disease None
Propranolol 120 mg Verapamh 240 mg Ajmaline 200 mg Propafenone 450 mg Metoprolol200 mg Propafenone 900 mg Flecainide 300 mg Propafenone 900 mg Quinidine 600 mg BetaxoloI20 mg Sotalol 160 mg Flecainide 200 mg Metoprolol200 mg Verapamil240 mg Propranolol 160 mg Verapamil240 mg Quinidine 600 mg Flecainide 200 mg Betaxolol 10 mg
11
64
M
AVNT
12 13
59 54
M F
14
46
F
Aortic valve insufficiency Diabetes Arterial hypertension None
15
26
M
AVRT =atrioventricular
Aortic valve insufficiency
AVNT
AVNT
AVNT AVNT AVNT
AVNT
Verapamil240 mg Propafenone 450 mg Flecainide 300 mg Disopyramide 500 mg Verapamil240 mg Verapamil240 mg Propranolol 120 mg Sotalol 160 mg Propranolol 120 mg Verapamil360 mg Propafenone 450 mg Propranolol 160 mg
re-entrant tachycardia; AVNT = atrioventricular nodal re-entrant tachycardia.
71
study was performed after an oral treatment phase with pentisomide for 5 days (900 mg in patients with a body weight 5 80 kg and 1200 mg in patients with a body weight > 80 kg) in 12 patients. Prior to this electrophysiologic study a second 1Zlead surface electrocardiogram and a second exercise stress test were obtained. The electrophysiologic study was performed with the usual technique [8]: 4 multipolar electrode catheters were advanced under fluoroscopic control to the high right atrium, the coronary sinus, His-position and the right ventricular apex. A quadripolar catheter (10 mm interelectrode distance) was positioned in the high right atrium, atria1 stimulation was performed via the distal electrode pair, and the proximal electrode pair was used to record the high right atria1 electrogram. The electrode catheter in the coronary sinus (quadripolar, 5 mm interelectrode distance) was used to record retrograde atria1 activation during re-entrant tachycardia and ventricular stimulation. If necessary right atria1 mapping for localization or exclusion of a right-sided accessory pathway was performed. The electrophysiologic study after the oral treatment phase was performed using 3 electrode catheters. Programmed atria1 (driving frequency lOO/min) and ventricular stimulation (driving frequency 120/min to 180/min, up to 2 extrastimuli) using the extrastimulus technique as well as continuous atria1 stimulation with paced rates between lOO/min and 200/min were performed. The surface electrocardiogram (leads I, III, V, and V,) as well as the intracardiac signals were recorded simultaneously on a Siemens Elema Mingograf 62 at a paper speed between 50 mm/s and 100 mm/s. Pacing stimuli were provided by a digital stimulator (Medtronic 5328), with a pulse duration of 2 ms and approximately twice diastolic strength. Blood for pentisomide serum levels was drawn 15 min and 30 min after the end of the pentisomide infusion and at the electrophysiologic study after the oral treatment phase and determined by high pressure liquid chromatography. The following parameters were determined: P wave, PR, QRS, QT and QTc duration, cycle length during sinus rhythm, sinus node recovery time, frequency corrected sinus node recovery
time, effective and functional refractory period of the atrioventricular node, Wenckebach cycle length, intra-atria1 conduction time during sinus rhythm, intranodal (AI-I interval) and infranodal (HV interval) conduction time during sinus rhythm and a paced cycle length of 600 ms, effective refractory period of the right atrium at a paced cycle length of 600 ms, effective refractory period of the right ventricle at a paced cycle length of 500 ms, effective antegrade and retrograde refractory period of the accessory pathway, shortest fully pre-excited R-R interval during atria1 fibrillation in patients with an accessory pathway. P wave, PR, QRS, QT and QTc duration were determined in lead V, of the surface electrocardiogram. Sinus node recovery time was measured from the last paced atria1 beat to the first beat of sinus origin. Frequency corrected sinus node recovery time was calculated by the difference between sinus node recovery time and sinus cycle length [9]. Intra-atria1 conduction time was defined as the time interval from the onset of high right atria1 activation to the deflection of the basal right atria1 electrogram (A wave). Shortest ventricular cycle length during atria1 fibrillation was the shortest fully pre-excited R-R interval within the first 30 s after the onset of the atria1 tachyarrhythmia. Atrioventricular nodal re-entrant tachycardia (slow-fast) was diagnosed in 9 patients based on the following criteria [lO,ll]: - demonstration of dual atrioventricular nodal pathways by programmed atria1 stimulation; - induction of the tachycardia after reaching the effective refractory period of the fast atrioventricular nodal pathway; - recording of the signal from the high right atrium at a maximum of 90 ms after earliest recording of ventricular activation during tachycardia; - documentation of retrograde atria1 activation via the atrioventricular node during programmed ventricular stimulation. In 6 patients the mechanism of the tachycardia was orthodromic atrioventricular re-entrance using an extranodal pathway for retrograde conduction, 2 patients having concealed and 4 patients manifest Wolff-Parkinson-White syndrome. The
72
presence of an accessory pathway was diagnosed if: - retrograde atria1 depolarization during tachycardia and programmed ventricular stimulation was not compatible with retrograde conduction via the atrioventricular node; - premature atria1 depolarization was elicited by a paced single premature ventricular contraction occurring during refractoriness of the HisPurkinje system 1121. All data are expressed as mean value -tstandard deviation, and the Wilcoxon test was used for statistical analysis of paired data. Elec-
trophysiologic data after intravenous and oral application of pentisomide were compared to electrophysiologic data obtained at the baseline electrophysiologic study. Results Sinus cycle length and sinus node function (Table 2) Although sinus cycle length was not significantly affected by intravenous pentisomide there was a significant decrease in heart rate after oral
TABLE 2 Electrophysiologic
data (ms) obtained under baseline conditions and after intravenous and oral application of pentisomide.
Sinus cycle length (R-R) Sinus node recovery time Frequency corrected sinus node recovery time Effective refractory period of the right atrium Effective refractory period of the right ventricle Intranodal conduction time (AI-I, sinus rhythm) Intranodal conduction time (AH, paced rate lOO/min) Infranodal conduction time (HV, sinus rhythm) Infranodal conduction time (HV, paced rate lOO/minI Intra-atrial conduction time (HRA-A, sinus rhythm) Wenckebach cycle length P-wave duration PR interval
Baseline n = 15
Intravenous pentisomide n = 15
731 f 109
696 f 111 p = 0.134 995 f 130 p = 0.487 314& 71 p = 0.129 225 k 30 p = 0.011 225 + 17 p = 0.046 103k 36 p = 0.008 120* 39 p = 0.025 54+ 8 p = 0.001 53+ 11 p = 0.006 30+ 14 p = 0.002 335 f 44 p = 0.026 94& 13 p = 0.001 186* 45 p < 0.001 97* 14 p = 0,001 372 + 29 p = 0.295 461 f 51 p = 0.018
999 f 155 275 f 118 210*
25
234 + 25 94 f .33 113f
63
45+
9
46+
8
23 f
10
319, 84+
46 11
155 + 43 85f
13
QT interval
367*
34
QTc interval
430+
27
QRS duration
n = number of patients.
Oral pentisomide n = 12 822 + 174
p = 0.014 1185 + 254
p = 0.01 365 + 107 p = 0.046 232* 31 p = 0.004 234 + 15 p = 0.239 12Ok 67 p = 0.002 165 f 124 p = 0.001 55 * 10 p = 0.008 54* 9 p = 0.023 33+ 9 p = 0.005 377 f 72 p = 0.006 90* 13 p = 0.006 196* 62 p = 0.003 94+ 16 p = 0.009 383 + 38 p = 0.073 427 f 41 p = 0.319
73
pentisomide (p = 0.014). Sinus node recovery time was also not significantly affected by intravenous pentisomide; it was, however, increased by oral pentisomide (p = 0.01). In accordance with these findings is a significant increase (p = 0.046) in the frequency corrected sinus node recovery time only after the oral treatment phase with pentisomide. Conduction times in the surface electrocardiogram (Table 2) P-wave duration, PR interval and QRS duration were significantly increased by intravenous and oral pentisomide. Although the QT interval was not significantly affected, the QTc interval was increased from 430 5 27 ms to 461 t- 51 ms (p = 0.018) after intravenous pentisomide. However, there was no significant increase in the QTc interval after oral pentisomide in comparison to the baseline value. Effective refractory period of atrium and ventricle There was a small but significant increase in the effective refractory period of the right atrium by intravenous and oral pentisomide. In contrast, the effective refractory period of the right ventricle was decreased by intravenous pentisomide (p = 0.046), an effect that was not seen with oral pentisomide ( p = 0.239). Atrioventricular node and extranodal pathway The effective refractory period of the atrioventricular node could be determined in only 3 patients at the baseline electrophysiologic study (293 f 31 ms), after intravenous (287 f 33 ms) and oral (347 + 80 ms) pentisomide. In all other patients measurement of the effective refractory periods of the atrioventricular node was limited by the effective refractory period of the atrium or the accessory pathway (Tables 3A and 3B). The functional and the effective refractory periods of the slow atrioventricular nodal pathway in patients with atrioventricular nodal re-entrant tachycardia were not significantly affected by intravenous and oral pentisomide (Table 3B). The
functional refractory periods of the fast atrioventricular nodal pathway, not significantly increased by intravenous pentisomide, increased from 382 + 28 ms to 468 f 53 ms (p = 0.014, Table 3B) after oral application of pentisomide. A small increase in Wenckebach cycle length was noted after intravenous (p = 0.026) and oral (p = 0.006) application of pentisomide (Table 2). Measurement of the retrograde effective refractory periods of the atrioventricular node was limited by the effective refractory periods of the right ventricle or by conduction via an extranodal pathway (Tables 3A and 3B). Intravenous and oral pentisomide prevented retrograde conduction via the atrioventricular node in 5 of 9 and 6 of 8 patients with atrioventricular nodal tachycardia, respectively, and in 2 of 6 and 2 of 4 patients with atrioventricular reentrant tachycardia. Neither the antegrade nor the retrograde effective refractory periods of the accessory pathway were significantly increased by intravenous or oral pentisomide (Table 4). The shortest fully pre-excited R-R intervals during atria1 fibrillation in patients with manifest Wolff-Parkinson-White syndrome were also not significantly prolonged by pentisomide (Table 4). However, the increase in the antegrade effective refractory period of the accessory pathway (p = 0.054) as well as the increase in the shortest fully pre-excited R-R interval during atria1 fibrillation (p = 0.054) both just failed to reach statistical significance (Table 4). Intranodal (AI-I) as well as infranodal (HV) conduction time were both significantly prolonged by intravenous and oral pentisomide (Table 2). Induction of tachycardia At the baseline study a sustained (> 30 s) tachycardia could be induced by programmed atria1 stimulation in all patients. Intravenous pentisomide prevented re-induction of the tachycardia in 6 of 9 patients with atrioventricular nodal tachycardia (Fig. 1) and in 2 of 6 patients with atrioventricular tachycardia (Fig. 2). If tachycardia was still inducible after intravenous application of pentisomide the cycle length of the tachycardia was significantly increased. This increase
74
TABLE 3 Antegrade effective (ERP-AVN) and functional (FRP-AVN) refractory period of the atrioventricular node in patients with atrioventricular re-entrant tachycardia (Table 3A, patients 1 to 6) and antegrade effective (ERP) and functional (FRP) refractory period of the slow (AVN,,,,) and fast (AVN,,,,) atrioventricular nodal pathway in patients with atrioventricular nodal re-entrant tachycardia (Table 3B, patients J to 1.5). Furthermore the retrograde effective refractory period of the atrioventricular node (ERP-VA,,) is given for both patient groups (C = baseline electrophysiologic study, i.v. = intravenous application of pentisomide, p.o. = oral application of pentisomide, data’are given in ms). For calculation of the mean values, only those data were taken into account that were available in the baseline electrophysiologic study and after intravenous and oral pentisomide. TABLE 3A Atrioventricular
re-entrant tachycardia.
Pt. no.
ERP-AVN C
i.v.
p.0.
C
i.v.
p.0.
C
i.v.
p.0.
1 2
380 (1) (1)
I:RA
370
360
430
