Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from British Heart Journal, I972, 34) I272-I282.

Effects of new beta-blocking agent (DL-tiprenolol) on conduction within normal and anomalous atrioventricular pathways in Wolff-Parkinson-White syndrome

J. Roelandt, L. Schamroth, and P. G. Hugenholtz From the Thoraxcentre, University Hospital and Medical Faculty, Rotterdam, The Netherlands; and the Baragwanath Hospital and the University of the Witwatersrand, J7ohannesburg, South Africa

The effects of DL-tiprenolol (DU 2I445) - a new beta-receptor blocking agent - and atropine on both normal and abnormal conduction pathways in the Wolff-Parkinson-White (WPW) syn- drome were studied by means of His bundle electrograms and atrial pacing. It was shown that DU 2I445 slows conduction through both pathways significantly (P, o os) and has a potential value in the treatment of symptomatic WPW syndrome and perhaps in other types of re-entrant tachycardias. The effects ofatropine were also studied in 2 patients. Atropine did not affect bypass conduction whereas A V conduction velocity was definitely increased. copyright. The study also shedsfurther light on the mechanism of WPW syndrome. It was found that the bypass had different conducting properties and was most probably a different conducting structure from the normal A V pathway.

Surgical division of the anomalous pathway reason for a surgical approach, virtually as a in the Wolff-Parkinson-White (WPW) syn- measure of desperation. http://heart.bmj.com/ drome has recently been carried out with some Little is known about the conduction success in a few patients with incapacitating properties of, and the influence of drugs on, attacks of tachycardia (Cobb et al., I968; the anomalous bypass. Only a few studies have Sealy, Boineau, and Wallace, I970). Attempts dealt with this problem (Roelandt, Draulans, by others have been unsuccessful (Burchell et and Roos, I970; Agha, Myerburg, and Castel- al., I967; Cole et al., I970; Lindsay et al., lanos, I97I; Roelandt et al., I972). Study of I97I) and in general the results of this surgical the pharmacological action of drugs on both procedure have not, until recently, been par- the normal and the anomalous pathways is now on September 24, 2021 by guest. Protected ticularly encouraging. Conventional medical possible through the analysis of His bundle treatment is therefore still the most widely electrograms and atrial pacing. This method of used method of management, and most gener- study may provide objective data for the ally known antiarrhythmic drugs have, at one rational treatment of a symptomatic patient time or another, been proposed for the pre- (Wallace et al., I971). vention and treatment of the arrhythmias This paper reports the evaluation of DL- associated with this syndrome. tiprenolol (DU 21445) - a new beta-receptor The administration of beta-receptor block- blocking agent - on conduction within the ing agents has been shown to be particularly normal and abnormal pathways of the WPW effective in the prevention and treatment of syndrome, by means of His bundle electro- the attacks of paroxysmal reciprocating tachy- grams and atrial pacing. cardias (Gianelly, Grifin, and Harrison, I967; Gibson and Sowton, I969). Neverthe- less, failures with these agents have occurred Methods in some the most of extensively studied series A multipolar electrode catheter was introduced (Dreifus et al., I968; Sealy et al., I970; Lind- percutaneously into the femoral vein under local say et al., I97I); and this has constituted the anaesthesia. The catheter was fluoroscopically Received 9 June 1972. positioned for the recording of His bundle electro- Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from Effects of new beta-blocking agent (DL-tiprenolol) 1273

grams as described by Scherlag et al. (I969). control 'pace-run' was also studied. In Case 4 This bipolar electrogram was derived from two the effect of atropine was studied the day before adjacent electrodes on the catheter and led into the DU 21445 study. the AC input of a four-channel Elema direct- DL-tiprenolol (DU 21445) is a new beta-block- writing electrocardiograph with an appropriate ing agent (Philips-Dulphar N.V. Weesp, The time constant. Standard lead II and lead Vi were Netherlands) with about the same pharmacologi- recorded simultaneously for reference purposes. cal actions as DL-propranolol, but three times Paper speeds of 50 and ioo mm a second were more active in reducing heart rate during exercise used for reproduction and measurement, respec- (Kesteloot et al., I970). tively. Statistical analysis of the data obtained with All intervals are expressed in milliseconds DU 21445 was executed on an IBM 360 computer. (msec) with an accuracy of ± 5 msec. The values of the intervals at the pacing rates In addition, a bipolar electrode catheter was used for statistical analysis were derived from the introduced percutaneously and positioned against basic data by linear interpolation on the scale of the lateral wall of the right atrium in the region paced heart rates. The statistical test used was of the sinus node for artificial atrial pacing by Wilcoxon's signed rank test for paired differences. means of a suitable variable pacemaker. Great care was taken to ensure proper grounding of all Subjects equipment. The right atrium was usually paced There were 5 patients with WPW syndrome, who at increasing rates until a rate was reached at least volunteered for the study after the procedure had as high as that observed during a clinical attack been fully explained to them and their consent of tachycardia. Recordings for measurements obtained. were taken about 45 to 6o seconds after the rate k was increased, to allow for the attainment of a steady state. After control measurements, 5 mg DL-tiprenolol (DU 2I445) was slowly injected intravenously in Cases I to 4. A second 'pace-run' at nearly identi- cal rate was then after minutes. In repeated I5 copyright. Cases 4 and 5, the effect of atropine administered CONTROt as a 2 mg intravenous dose I5 minutes after the it 1 4 I

PH875 St-H 90 95 105 120 12S

HBE :- v H /.. ' i-4i f I>;=/I H H: FIG. I Case I. the http://heart.bmj.com/ Tracings showing effect of I 1v progressively increasing atrial pacing rates in I.. WPW The His bundle syndrome. electrogram RATE 61 671 901 10 (HBE) is recorded simultaneously with leads St- d 1201 130 1i3 125 st-s 130 130 1301 136 II and VI. As the rate is increasedfrom 67 2201 230 2351 245 -11.255 260 .-, :- -, to a -- "- w 138 beats minute, there is a prolongation It ",-11. ." ".--el. - 1.11' 1. .., ." .I., -II/ of the time intervals between the P waves and ,.:r f I St-H 140 .. His spikes (PH intervals) and between the HtBE *w ,,,o, j pacemaker artefacts and His spikes (StH -. on September 24, 2021 by guest. Protected

intervals) from 75 to 140 msec. At higher f S pacing rates, the His spike is hidden within the ;i i I I ! 'sf QRS complex. The intervals between the pace- vi i maker impulse and the delta wave (Std) do not /: w 5* .S t } change and remain constant at 130 msec. The RATE StS interval (which indirectly reflects the QRS 138 15D, 162 176 180 St-d 130 130 1301 1301 1301 130 duration since the Std interval is constant: St-s 285 275si 2B0 280 280 QRS width (StS)-(Std)) lengthens pro- ,. F gressively until a pacing rate of i5o beats a St ... HOE :. .1.... minute is reached. Pre-excitation becomes .l. .. .I '-progressively greater with increasing heart rates because of the decreasing contribution to ven- i tricular excitation via the normal pathway. At t j. # .- &s pacing rates higher than I62 a minute to 222 s. VI , a minute, the StS interval remains constant at ' 280 msec, and ventricular activation is effected RATE 167 * vkf200| 207 ~ 215~ 222 the St- d 130 exclusively by bypass impulse resulting in l30 130 130! 1301 130 a total pre-excitation complex. St-S 2601 2801 i...... 28asr _, I 280 28 280 Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from 1274 Roelandt, Schamroth, and Hugenholtz

Case i This was a 40-year-old man who suffered AFTER DU 21445 5mg IV from attacks of paroxysmal tachycardia for i8

- "--' years. He had experienced at least one attack a " .' -, ""i'_1 _-e . : 55X -, week during the preceding two years. These PHHB "901 attacks occurred at a rate of about 220 beats a .N- s 12S 140 1 155 HB ...... minute and were accompanied by dizziness and HI,% ; e. faintness. They lasted for periods ranging from I0 to 6o minutes. Clinical and laboratory examina- H f :. t tA tions were entirely normal. The basic electro- VI }, } cardiographic pattern revealed sinus rhythm and ,1 type A, WPW syndrome. ...,.i RATE 64 70 77 84. 88 96 Case 2 A 17-year-old man had complained of St-d 130. 140 140 404 40 135 action St-S 220 230z 250 85 m 280 intermittent attacks of rapid heart during oo, Ab * _. .. .R. s .. M. S .. the preceding three years, the frequency of which .S Ej had increased during the previous few months. w-. Clinical and laboratory examinations were normal. HOE ..*. .n * I, ; The electrocardiogram showed sinus rhythm and t * A '. 1. type A, WPW syndrome. b -? t

_j man who had ! Case 3 This was a 67-year-old VI t 11 :, e. i e. I occasional attacks of rapid heart action for 50 v i.,? years. These had become more frequent and were RATE 100: 107 113 122 136 140 accompanied by angina pectoris during the pre- St-4d 140~ 140 140 13 5SE 1401 145 ceding year. The chest x-ray showed slight cardio- sI-sVI~~~~~~~~~~~~~~ 2801 285 2901 2851 290 megaly. Cine coronary arteriography revealed . ._or ^-,w,< multiple coronary artery narrowing of more than 50 per cent. The electrocardiogram showed sinus

rhythm and a type A, WPW syndrome. copyright. HBE Case 4 A 24-year-old man had 5 attacks of ;, rapid heart action a year during the preceding 5 I P. e years associated with praecordial discomfort. 1IV Clinical examination was entirely normal. The electrocardiogram showed sinus rhythm and a RATE 147 158 167 194 type A, WPW syndrome. St-d 140 145 140 140 140 145

St-s http://heart.bmj.com/ 290 290 290 2901 295 Case 5 A 26-year-old woman with moderate mitral stenosis had had only two short attacks of tachycardia during pregnancy one year before the FIG. 2 Case i. Tracings showing the same study. Her electrocardiogram showed WPW syn- basic phenomena as in Fig. i. After the injec- drome, type B. His bundle electrograms were tion of 5 mg DU 2I445 intravenously the recorded during a catheterization for diagnostic purposes. PH and StH intervals range from 8o to I05 msec at analogous control pacing rates. The Std intervals as well as the StS intervals are on September 24, 2021 by guest. Protected Definitions of intervals and terms also longer compared to control values before PH and StH intervals These are the intervals the administration of DU 21445. measured from the beginning of the P wave (P) or from the stimulus artefact (St) to the rapid deflection of the His bundle spike on the intra- cardiac electrogram. They represent atrial de- StS interval This is the interval measured polarization plus AV nodal conduction. Since from the stimulus artefact to the end of the QRS changes in atrial conduction time are minimal, complex. When the Std interval remains con- changes in these intervals reflect almost exclu- stant, changes in the StS interval represent sively changes in AV nodal conduction time. changes in total QRS duration or ventricular depolarization. Pd interval and Std interval These are the intervals measured from the beginning of the P Normal AV pathway impulse This refers to wave (P) or from the stimulus artefact (St) to the the impulse conducted through the normal AV beginning of the delta wave. These intervals pathway: the AV node, bundle ofHis, and bundle- represent atrial depolarization plus anomalous branches. bypass conduction time. Since changes in atrial conduction time are minimal, changes in these Bypass impulse This refers to the impulse intervals reflect almost exclusively changes in conducted through the anomalous pathway or -bypass conduction time. bypass. Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from Effects of new beta-blocking agent (DL-tiprenolol) 1275

TABLE I Values of measured intervals before and after 5 mg DL-tiprenolol (DU21445) Control After DU 2I445.5 mg IV Rate StH Std StS QRS Rate StH Std StS QRS (b/min) (msec) (msec) (msec) (msec) (b/min) (msec) (msec) (msec) (msec)

Case I NSR 67 75 I20 220 IOO 64 8o I30 220 90 ,APR 8I 90 I30 230 IOO 70 90 140 230 IIO ,, go 95 I30 235 105 77 I25 140 250 IIO ,, IOI 105 I30 245 II5 84 I40 140 265 I25 ,, II3 I20 I30 255 I25 88 I55 140 275 I35 ,, 125 I25 I35 260 I25 96 I65 135 280 I45 ,, I38 I40 I30 265 I35 IOO - I40 280 I40 ,, '43 - 130 275 I45 I07 - I40 285 I45 ,, 150 - I30 275 I45 113 - I40 290 I50 ,, i62 - I30 280 I50 122 - 135 290 I55 *.o.,, I74 I30 280 I50 I36 I40 285 I45 ,, i8o - 130 280 I50 I40 - I45 290 145 . I87 - I30 280 150 147 I40 290 150 I,'93 - 130 280 I50 I56 - 145 290 I45 ,, 200 - I30 280 I50 I67 I40 290 150 ,, 207 - I30 280 150 I75 - I40 290 I50 ,, 2I5 - I30 280 I50 i8o I40 290 I50 3%,, 222 I30 280 I50 I94 I45 295 150

'Zase 2 ,NISR 72 IIO I45 225 80 59 I25 I6o 235 75 -1iPR 78 I35 I50 240 90 70 140 i6o 260 IOO ,, 9I i6o 150 270 I20 78 I65 i6o 275 I15 copyright. ,, I02 I75 145 280 135 92 i8o i6o 300 I40 ,, IIO I90 I50 290 I40 IOO 200 I65 320 155 ,, ii8 - 150 290 I40 III i6o 315 I55 ,, I26 - I50 300 150 I23 I65 320 I55 '..*,, I37 145 300 I55 I34 I65 320 I55 ,, I50 - 150 300 I50 I47 - I60 320 i6o 33, I65 - I50 300 I50 I5 - i65 320 I55 -,, I70 - I50 300 I50 I63 - 170 325 I55 ,, I82 150 300 I50 I72 i65 320 I55 http://heart.bmj.com/ ,, 191 - I50 305 I55 I83 I65 320 155

Case 3 *,NSR 69 IOO 110 240 130 63 120 I15 245 I30 APR 73 IIO I05 250 145 72 125 I15 255 140 ,, 78 II5 IIO 255 I45 76 I35 I15 260 I45 - ,, 87 I25 I05 255 I50 82 140 II5 265 150 _ 94 130 IIO 260 I50 89 145 115 270 I55 ,, I06 145 IIO 270 100 94 I50 I20 275 I55 on September 24, 2021 by guest. Protected ,, II2 I50 IIO 275 I65 100 100 I20 280 I60 ,, 119 I60 IIO 280 I70 I07 I65 115 290 I75 ,, 124 I65 IIO 285 I75 I"4 I90 120 295 '75 ,, I31 I8o 105 290 I85 121 - I20 300 i8o ,, '37 IIO 295 I85 129 I20 305 ,, ' 45 11O 295 I85 I38 120 3IO I90 ,, 152 I05 295 I90 144 115 305 I90 _,, I60 - IIO 295 I85 I53 120 310 Igo ,, I69 - IIO 295 I85 I59 I20 3IO Igo ,, I70 - IIO 295 i85 I65 - 125 310 I85 178 I20 310 Igo

Case 4 NSR 7I I20 135 250 115 54 130 150 260 IIO APR 85 145 I30 265 135 67 I55 150 280 I30 _ ,, 98 130 135 295 I60 90 175 I45 295 150 ,, I13 - I35 305 I70 II6 - I50 310 I60 1 I36 - 135 3IO I75 I33 I50 320 I70 ,, '59 - 135 3I5 I8o 15I I50 325 I75 N SR = normal sinus rhythm; APR = atrial pacing rate. Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from 1276 Roelandt, Schamroth, and Hugenholtz

Pre-excitation fusion complex This refers control *- *St- H to a QRS complex resulting from partial anomal- 0o- StLS activation and normal activation. DU 21445 ous partial n-. St d St S. Total pre-excitation complex This refers to msec a QRS complex resulting from complete ven- tricular activation through the anomalous path- 1310 way - a 'pure' delta wave.

Results and analyses St -d i) Effect of DU 21445 a) The control para- St- H meters The control parameters showing the msec effects of a progressively increasing atrial 200 r pacing rate in Case i are depicted in Fig. i and Table i. A progressive increase in atrial pacing rate results in a progressive prolonga- 180 - tion of the StH interval from 75 to I40 msec. This is due to the increasingly physiological impedance of the AV node to the higher pac- 160 F ing rates. The His spike thus encroaches pro- gressively on the delta wave and is completely hidden within the QRS complex when the 1401- heart rate reaches I43 beats a minute. The Std interval, however, does not change and remains constant at I30 msec. This indicates 120 F that the bypass conduction time is constant, and that the effective atrial impulse bypasses loo L copyright. the AV node to pre-excite the ventricles. Pre- excitation becomes progressively greater with increasing heart rates because of the decreas- ing contribution to ventricular activation through the normal pathway - as a result of increasing delay. This is best seen in lead VI.

The QRS complex widens as the StS interval FIG. 3 Case i. Graphic illustration of all http://heart.bmj.com/ lengthens, while the Std interval remains con- intervals represented in Fig. i and 2, and stant. Furthermore, with pacing rates higher Table i. The diagram shows the behaviour of than I62 beats a minute, ventricular activation the different intervals before (solid lines) and is effected exclusively by the bypass impulse. after (broken lines) the administration of 5 This is because ventricular activation is com- mg DU 2I445 at increasing atrial pacing rates pleted before the arrival of the AV nodal im- (APR). The Std interval, or conduction pulse, thereby resulting in an exclusive or total through the anomalous bypass, lengthens by

pre-excitation complex. This is evident from about IO msec after DU 2I445. The StH on September 24, 2021 by guest. Protected the fact that the QRS complex does not show interval or A V nodal transmission time is any further changes at pacing rates from I62 prolonged after beta-blockade. It is obvious to 222 beats a minute. The StS interval - that DU 2I445 slows conduction both via the reflecting QRS duration - also remains con- normal A V and anomalous pathways. The StS -.- stant at these higher pacing rates. All intervals interval, reflecting QRS duration, parallels are depicted in Table i, Case i. StH prolongation until there is no more con- b) Test parameters The effect I5 minutes tribution to ventricular depolarization by the after the intravenous administration of 5 mg normal A V impulse. When exclusive bypass DU 2I445 is shown in Fig. 2 and Table i. depolarization is present, the StS interval The StH intervals or AV nodal transmission parallels the Std interval. times are lengthened when compared to the control values at the same pacing rates, and now range from 8o to I65 msec (compared pre-excitation complexes prevail at rates of with 75 tO 140 msec). The Std interval or by- 147 to 194 beats a minute. Fig. 3 reflects the pass conduction is also lengthened (by about different intervals measured before (continu- I0 msec) and now measures about 140 msec. ous lines) and after (dashed lines) the ad- DU 21445 slows conduction through both ministration of 5 mg DU 21445. the normal and anomalous pathways. Total Where the end of the P wave could be Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from Effects of new beta-blocking agent (DL-tiprenolol) 1277

defined, the interval from the stimulus artefact - control *pp St -H wave was This to the end of the P measured. DU 21445 ppo St- S represents the atrial activation time. The changes following DU 21445 were not greater St. d than ± 5 msec. This means that changes in St- S the Std intervals are mainly due to changes in msec bypass conduction time. The lengthening of the StS interval (reflecting QRS duration I 330 changes because of the constant Std interval) parallels the lengthening of the StH intervals at lower heart rates. Once a total pre-excitation 320 complex manifests, the StS intervals and QRS St- d duration remain constant. The QRS duration St- H is the same both before and after administra- msec tion of DU 2I445, indicating that intraven- 310 tricular conduction is unaffected. The longer StS interval after DU 2I445 is thus merely 200 r caused by Std prolongation. The interval 300 changes in Cases 2 and 3 are essentially the same as in Case i (Table i). The QRS dura- 180 F tion in Case 2, however, was somewhat longer after DU 21445, probably the result of some 290 intraventricular conduction delay. In Case 4, 160 F DU 21445 was injected the day after the administration of the atropine. The intervals 280 are depicted in Table i. Fig. 4 shows the

results diagrammatically. Conduction through 140 F copyright. the bypass is i5 msec longer after beta- blockade. Conduction through the normal 270 AV pathway is also prolonged. The QRS 120 duration lengthens with increasing heart rate and parallels the StH lengthening, but is 260 also unaffected by the administration of DU 100

2I445. Table 2 shows the main statistical http://heart.bmj.com/ results of the 4 patients studied. Linear 250 interpolation on the scale of paced heart rates was performed in order to obtain the values of the intervals at the rates used for statistical APR I I I I analysis. With respect to the effects of DU * * - 21445 on the various intervals, significant 60 8o 100 120 140 160 180 (min.) differences from premedication values (P

TABLE 2 Values of measured intervals before and after 2 mg atropine IV Control before atropine After atropine 2 mg IV Rate StH Std StS QRS Rate StH Std StS QRS (b/min) (msec) (msec) (msec) (msec) (b/min) (msec) (msec) (msec) (msec) Case 4 NSR 64 125 130 250 I20 95 I25 135 250 II5 APR 8i I50 I35 270 I35 107 I45 I30 265 135 100 200 I30 300 I70 ii8 I50 130 270 I40 II7 I30 3IO i8o I34 I70 130 285 I55 139 I40 320 i8o I52 I90 I30 290 I60 I72 135 320 I85 I67 200 I30 305 I75 Case 5 73 95 IOO 2I5 115 I02 90 100 2IO IIO 84 130 IIO 225 II5 II3 I20 IIO 225 II5 92 I50 110 240 I30 125 130 IIO 235 I25 IOI II5 255 I40 I33 I45 IIO 240 I30 I14 IIO 260 I50 I44 I6o IIO 250 140 126 - IIO 265 I55 158 I05 245 I40 I39 - II5 270 155 171 - IIO 255 I45 I50 - 110 270 i6o I79 IIO 260 150 I74 IIO 270 i6o

control values recorded at the same heart expected deaths have, on rare occasion, been rates. The His spike is always visible. The reported (Dreifus et al., I97i). Life insurance atropine results in enhanced AV conduction statistics also show a slightly increased mor- through the normal AV pathway thereby re- tality rate in WPW patients (Smith, I964). copyright. sulting in lesser degrees of pre-excitation The WPW syndrome could, therefore, be fusion at pacing rates up to I67 beats a min- viewed as a potentially fatal condition, though ute. There is no change in the Std interval or this appears to be very rare indeed. However, bypass conduction time. The QRS duration morbidity secondary to intermittent tachy- is shortened (when compared to the QRS cardias is considerable and treatment directed duration at similar heart rates without atro- to the prevention and management of the pine). This is due to the diminished contribu- complicating tachyarrhythmias is thus strong- http://heart.bmj.com/ tion of the bypass impulse as a result of the ly indicated. faster AV conduction. The results are de- The most attractive basis for the medical picted diagrammatically in Fig. 7. treatment of the supraventricular reciprocat- ing tachycardias appears to be the prevention of re-entry by blocking one or both of the AV Discussion conducting pathways. The re-entry circuit in The prognosis of the WPW syndrome is the majority of patients with the WPW syn- usually considered to be benign (Berkman and drome, however, includes atrial tissue, the on September 24, 2021 by guest. Protected Lamb, I968). Nevertheless, sudden and un- normal AV pathway, ventricular myocardium,

TABLE 3 Average values of heart rate and various intervals at different pacing rates before, and percentage change after, injection of 5 mg DU 21445 IV (4 patients) Normal Atrial pacing rate sinus rhythm Max. 70 80 90 100 110 120 130 140 I50 heart rate Heart rate before DU 70 I87 % change -I4 -6 StH before DU IOI I02 120 134.-- I72 % change 12 25 25 22 6 Std before DU I28 128 130 I30 130 I31 I32 I30 130 130 I31 % change 9 II 9 8 Io 8 8 10 II I0 10 StS before DU 234 234 247 260 27I 280 284 290 294 297 299 % change 3 9 10 10 9 7 7 6 6 5 5 Significant differences from premedication values (P

CONTROL

1I .. .. .' - H P-H 125 St- H154 St-N 20 :. t

HBE .-- I... ", - I H ' H: .. A %-..; IL-I -1...... 1. .I . r i, "I. a, k- .: i i BAE _e 1: 1.

VI ,1 \ I RATE 64 81 100 117 139 172 St-d 130 135 130 130 140 135 St -s 250 270 300 310 320 320

FIG. 5 Case 4. Tracings reflecting the control recordings of the His bundle electrogram (HBE) together with bipolar atrial electrogram (BAE) and leads II and VI at increasing atrial pacing rates before the intravenous injection of 2 mg atropine. As the pacing rate is increasedfrom 64 to I72 a minute the following effects occur: (i) the His spike (H) disappears in the QRS complex because of an increase in atrioventricular conduction time, (ii) the Std interval remains relatively (rather) constant, while (iii) the StS interval lengthens from 250 to 320 msec. A 'full-blown' pre-excitation complex is present at a rate of II7 beats a minute. copyright.

FIG. 6 Case 4. Tracings reflecting the phenomena after the intravenous administration of 2 mg http://heart.bmj.com/ atropine. The resting heart increases to 95 beats a minute. The StH intervals are decreased compared to control values at the same heart rates. The enhanced A V conduction by atropine results in a more effective ventricular depolarization by the impulse conducted through the normal A V pathway. This results in less obvious pre-excitation complexes at heart rates up to 167 a minute. The His spike (H) stays always visible because of the short A V conduction time. The Std interval, however, is unchanged when compared to the control values.

AFTER ATROPINE 2 mg IV on September 24, 2021 by guest. Protected ^

sx, t. ,! P-H 115 St-N 145 5t.H 150 St N170 St-H 190 St-H 200 l, wo/e,; .s H.. iv HBE 2._. H 7.N ,._\ + H -N s.'SS. H ' Xo

IN - Si t t i RSt

; iP_ -i . Q - Ke \ / .

951 107 118 1 34 152 167 St . K f . d . . B ...... -.- -d 135 130 130 130 130 130 St-sSt 250 205 ... +v.270 I 225 290 305 Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from I28o Roelandt, Schamroth, and Hugenholtz and the anomalous pathway, and the ideal control *- *St- H drug should therefore theoretically slow con- _----atropine o-.o St S duction or induce refractoriness at all four -.*St- d of these sites. Furthermore, in order to pre- St-S vent the attacks of reciprocating tachycardia, msec the ideal drug should, in addition, also prevent the occurrence of atrial and ventricular pre- 320 mature beats which can initiate the attacks of St- d tachycardia (Durrer et al., I967). St-H Other approaches for the treatment of m sec 310 WPW tachycardia are surgical transsection of the anomalous pathway (Cobb et al., I968; 200 r Sealy et al., 1970), or the normal pathway fol- 300 lowed by insertion of a pacemaker (Dreifus et al., I968; Edmonds, Ellison, and Crews, 180 F I969). Induced pacemaker stimuli either in 290, the atria or in the ventricles at specific sites can also be used to make one part of the re- 160 F entry circuit refractory, as shown experi- mentally by Moe, Cohen, and Vick (I963). 280 This method was successfully used for the 140 - termination of the episodes of reciprocating tachycardia by Durrer et al. (I967), Massumi, 270 Kistin, and Tawakkol (I967), Ryan et al. -4 (I968), Barold and Linhart (I970), and Wel- 120 F lens, Schuilenburg, and Durrer (I97I). The 260' principle is analogous to the termination of copyright. the reciprocating tachycardias by atrial and/or 100 L ventricular extrasystoles which occur spon- 250 taneously (Schamroth and Yoshonis, I969). Though the action on the normal pathway of most antiarrhythmic drugs is well established, I I I I f I I I APR there is no information, however, about drug 'I.

60 80 100 120 140 160 180 (min) http://heart.bmj.com/ action on the anomalous pathway. While nearly all antiarrhythmic drugs have been FIG. 7 Case 4. Graphic representations - the tried in patients with symptomatic WPW results shown in Fig. 5 and 6 and in Table 3. syndrome, digitalis, quinidine, and procain- Control values are depicted in continuous lines amide continue to be the most widely used and values after atropine are depicted in broken drugs. Digitalis slows AV conduction and lines. The Std interval is the same before and reduces the rate ofventricular response during after atropine, and it can thus be concluded an attack. On the other hand, it shortens the that anomalous bypass conduction is not refractory period of the atria, and there is affected by this drug. The StH intervals are on September 24, 2021 by guest. Protected some indirect evidence that it increases the shorter in contrast to the longer intervals after conductivity of the accessory pathway. The- DU 21445. Here again, the StS interval oretically, this can be dangerous in atrial parallels the StH prolongation but an exclusive fibrillation since it would increase the ven- bypass complex is not reached at a rate of I67 tricular response and could even precipitate a minute. ventricular fibrillation. In practice, however, digitalis has been shown useful though some- times high doses are needed or the combina- quinidine (Hoffman, Abernathy, and Hae- tion with other drugs is necessary (Chung, dicke, I952). Walsh, and Massie, I965). Quinidine has been Combination therapy with digitalis and said to prevent impulse re-entry by increasing quinidine has been used for the management the refractory period of the atria and the ven- of the re-entrant tachycardias; the rationale tricles (Blinder, Burstein, and Smelin, 1952), being that digitalis slows conduction through but it may enhance normal AV conduction. the AV node whereas quinidine prolongs On the other hand, it suppresses the develop- atrial depolarization and depresses conduction ment of the tachycardias by suppressing the within the bypass and the ventricles. These initiating atrial and ventricular extrasystoles. properties are combined in DL-propranolol. Procainamide should act in the same way as Indeed, electrophysiological studies by Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from Effects of new beta-blocking agent (DL-tiprenolol) I28I

Vaughan Williams (I966) and Davis and This is due to an enhancement of normal AV Temte (I968) have shown that DL-propranolol conduction which thereby results in more has a quinidine-like effect which results in complete normal activation. Blinder et al. slower myocardial conduction. This is repre- (1952) reported that the effect of atropine on sented by a reduction in the amplitude and the bypass was negligible. This was also found rate of rise of the action potential and a pro- in Cases 4 and 5 where the Std interval was longation of the effective refractory period. unaffected by atropine. Furthermore, DL-propranolol slows AV con- This study also sheds further light on the duction by its beta-receptor blocking effect mechanism of the WPW syndrome. It indi- (Berkowitz et al., I969; Smithen, Balcon, and cates that the conduction properties of the Sowton, I97I). normal AV nodal pathway and the anomalous Thus, DL-propranolol acts at the four sites pathway are different and unrelated and that of the re-entry pathway and should theoretic- the precise electrocardiographic manifestation ally be an ideal drug in the management and is dependent upon an entirely unpredictable prevention of the reciprocating tachycardias and at times fortuitous relation of these pro- of the WPW syndrome. There is now ample perties. This indicates not only differing evidence that beta-blocking agents are usually physiological properties but also differing successful in the prevention and treatment of anatomical properties. The latter suggests too reciprocating tachycardias of the WPW syn- that the bypass is probably a different con- drome (Gianelly et al., I967; Gibson and ducting structure. Sowton, I969) and DL-propranolol now ap- pears to be the drug of choice, though failures The authors wish to thank Dr. R. van Strik for have been reported (Dreifus et al., I968; his assistance with the statistical work and Dr. A. Sealy et al., I970; Lindsay et al., 197I). Floor-Wieringa for helpful comments. Our study of DL-tiprenolol reveals effects similar to DL-propranolol, though the mechan- copyright. ism of some of the observations with both References drugs is not entirely clear. DU 2I445 has a effect on AV conduc- Agha, A. S., Myerburg, R. J., and Castellanos, A., Jr. beta-receptor blocking (I97i). Functional properties of accessory bypass tion, and in this respect these are quite com- tracts as determined by premature atrial stimula- parable to those obtained by Berkowitz et al. tion. Circulation, 44, Suppl. II, 62. (I969) and Smithen et al. (I97I) with pro- Barold, S. S., and Linhart, J. W. (I970). Recent ad- pranolol. Though in vitro studies with DL- vances in the treatment of ectopic tachycardias by

electrical pacing. American Journal of Cardiology, http://heart.bmj.com/ propranolol reveal a depression in the rate of 25, 698. rise of the action potential of Purkinje and Berkman, N. L., and Lamb, L. E. (I968). The Wolff- muscle fibres, Berkowitz et al. (I969) did not Parkinson-White electrocardiogram: follow-up find a prolongation of intraventricular con- study of five to twenty-eight years. New England journal of Medicine, 278, 492. duction time. In this study too, no QRS pro- Berkowitz, W. D., Wit, A. L., Lau, S. H., Steiner, C., longation was found both before and after the and Damato, A. N. (I969). The effects of proprano- administration of DL-tiprenolol. lol on cardiac conduction. Circulation, 40, 855. There was, however, an effect on bypass Blinder, H., Burstein, J., and Smelin, R. (I952). Drug

effects in Wolff-Parkinson-White syndrome. Ameri- on September 24, 2021 by guest. Protected conduction which was consistently prolonged can Heart Journal, 44, 268. in the four patients whom we studied. This Burchell, J. B., Frye, R. L., Anderson, M. W., and may possibly be due to muscle conduction McGoon, D. C. (i967). Atrioventricular and ven- being more affected than the Purkinje tissue. tricuatrial excitation in Wolff-Parkinson-White syndrome (type B): temporary ablation at surgery. In Cases i and 4, it was possible to induce Circulation, 36, 663. and terminate the attacks of supraventricular Chung, K. Y., Walsh, T. J., and Massie, E. (I965). tachycardia by properly timed atrial stimuli. Wolff-Parkinson-White syndrome. American Heart After DL-tiprenolol, however, it was im- Journal, 69, ii6. Cobb, F. R., Blumenschein, S. D., Sealy, W. C., possible to precipitate any tachycardias in Boineau, J. P., Wagner, G. S., and Wallace, A. G. Case i, and only short self-terminating attacks (I968). Successful surgical interruption of the of tachycardia could be evoked in Case 4. bundle of Kent in a patient with the Wolff- These always terminated with a 'retro- Parkinson-White syndrome. Circulation, 38, ioi8. Cole, J. S., Wills, R. E., Winterscheid, L. C., Reichen- grade' P wave which means that re-entry was bach, D. D., and Blackmon, J. R. (I970). The blocked in the AV node and not in the bypass. Wolff-Parkinson-White syndrome: problems in Perhaps the drug can also be used with suc- evaluation and surgical therapy. Circulation, 42, cess in other types of re-entry tachycardias. III. Davis, L. D., and Temte, J. V. (1968). Effects of pro- Atropine has been used for diagnostic pur- pranolol on the transmembrane potentials of ven- poses in order to diminish or, in some cases, tricular muscle and Purkinje fibers of the dog. abolish the pre-excitation fusion complex. Circulation Research, 22, 66i. Br Heart J: first published as 10.1136/hrt.34.12.1272 on 1 December 1972. Downloaded from I282 Roelandt, Schamroth, and Hugenholtz

Dreifus, L. S., Haiat, R., Watanabe, Y., Arriaga, J., Roelandt, J., Draulans, J., and Roos, J. P. (1970). and Reitman, N. (I97I). Ventricular fibrillation: a Functional characteristics of accessory pathways in possible mechanism of sudden death in patients Wolff-Parkinson-White syndrome (type A) with Wolff-Parkinson-White syndrome. Circula- (abstract). Circulation, 42, Suppl. III, 192. tion, 43, 520. Roelandt, J., Schamroth, L., Draulans, J., and Hugen- Dreifus, L. S., Nichols, H., Morse, D., Watanabe, Y., holtz, P. G. (1972). Functional characteristics of and Truex, R. (I968). Control of recurrent tachy- the Wolff-Parkinson-White bypass. American cardia of Wolff-Parkinson-White syndrome by sur- Heart3Journal. In the press. gical ligature of the A-V bundle. Circulation, 38, Ryan, G. F., Easley, R. M., Jr., Zaroff, L. I., and I030. Goldstein, S. (I968). Paradoxical use of a demand Durrer, D., Schoo, L., Schuilenburg, R. M., and pacemaker in treatment of supraventricular tachy- Wellens, H. J. J. (I967). The role of premature cardia due to the Wolff-Parkinson-White syndrome. beats in the initiation and the termination of supra- Circulation, 38, 1037. ventricular tachycardia in the Wolff-Parkinson- Schamroth, L., and Yoshonis, K. F. (1969). Mechan- White syndrome. Circulation, 36, 644. isms in reciprocal rhythm. American J3ournal of Edmonds, J. H., Ellison, R. G., and Crews, T. L. Cardiology, 24, 224. (I969). Surgically induced atrioventricular block Scherlag, B. J., Lau, S. H., Helfant, R. H., Berkowitz, as treatment for recurrent atrial tachycardia in W. D., Stein, E., and Damato, A. N. (I969). Cathe- Wolff-Parkinson-White syndrome. Circulation, 39, ter technique for recording His bundle activity in Suppl. I, I05. man. Circulation, 39, 13. Gianelly, R., Griffin, J. R., and Harrison, D. C. (I967). Sealy, W. C., Boineau, J. P., and Wallace, A. G. (I970). Propranolol in the treatment and prevention of The identification and division of the bundle of cardiac arrhythmias. Annals of Internal Medicine, Kent for premature ventricular excitation and 66, 667. supraventricular tachycardia. Surgery, 68, I009. Gibson, D., and Sowton, E. (I969). The use of beta- Smith, R. F. (I964). The Wolff-Parkinson-White adrenergic receptor blocking drugs in dysrhyth- syndrome as an aviation risk. Circulation, 29, 672. mias. Progress in Cardiovascular Diseases, 12, I6. Smithen, C. S., Balcon, R., and Sowton, E. (I97I). Hoffman, I., Abernathy, R. S., and Haedicke, T. A. Use of bundle of His potentials to assess changes in (I952). Effect of procaine amide on anomalous con- atrioventricular conduction produced by a series duction and paroxysmal tachycardia in a case re- of beta-adrenergic blocking agents. British Heart sembling the Wolff-Parkinson-White syndrome. Journal, 33, 955. American Heart_Journal, 44, I54. Vaughan Williams, E. M. (I966). Mode of action of

Kesteloot, H., Sluyts, R., Floor-Wieringa, A., and Van beta-receptor antagonists on cardiac muscle. Ameri- copyright. Strik, R. (1970). Effect of beta-receptor blocking can Journal of Cardiology, I8, 399. drugs on the heart rate during submaximal exercise. Wallace, A. G., Boineau, J. P., Davidson, R. M., and European Journal of Pharmacology, 10, 303. Sealy, W. C. (197I). Wolff-Parkinson-White syn- Lindsay, A. E., Nelson, R. M., Abildskov, J. A., and drome. A new look. AmericanJournal ofCardiology, Wyatt, R. (I97i). Attempted surgical division of 28, 509. the pre-excitation pathway in the Wolff-Parkinson- Wellens, H. J. J., Schuilenburg, R. M., and Durrer, D. White syndrome. American Journal of Cardiology, (I97I). Electrical stimulation of the heart in 28, 58i. patients with Wolff-Parkinson-White syndrome

Massumi, R. A., Kistin, A. D., and Tawakkol, A. A. type A. Circulation, 43, 99. http://heart.bmj.com/ (I967). Termination of reciprocating tachycardia by atrial stimulation. Circulation, 36, 637. Moe, G. K., Cohen, W., and Vick, R. L. (I963). Experimentally induced paroxysmal A-V nodal Requests for reprints to Dr. J. Roelandt, Thorax- tachycardia in the dog. American Heart Journal, 65, centre, P.O. Box I738, Rotterdam-3002, The 87. Netherlands. on September 24, 2021 by guest. Protected