Provocative Testing and Drug Response in a Patient with the Long QT Syndrome

Home , Cardiovascular centre, Isoprenaline, Torsades de pointes

Br Heart3t 1995;74:67-70 67 Provocative testing and drug response in a patient with the long QT syndrome

Mayumi Kawade, Tohru Ohe, Tetsuro Kamiya

Abstract Case report A girl of 14 with the long QT syndrome A 14 year old girl was admitted to the (LQTS) and torsades de pointes is National Cardiovascular Centre because she reported. Isoprenaline or adrenaline has had syncopal episodes. She fainted at the infusions induced torsades de pointes and age of 13 while being questioned by a teacher inversion of the TU wave. Changes in the at school. She had a second syncopal episode TU wave during isoprenaline infusion at the same age at school while being scolded were used to select effective drugs to treat by her teacher. She had no neurological this patient. A /1 blocker and calcium abnormality, including deafness. She had channel blocker were selected and the never received medical treatment. She had no patient had no episodes of syncope for family history of QT prolongation, syncope, Department of two years. This electrocardiographically or sudden death. Paediatrics, Gifu guided method may be useful for select- Physical examination, including neurologi- University School of Medicine, Gifu, Japan ing effective drugs in patients with the cal examination, on admission showed no M Kawade LQTS. abnormal findings. The chest x ray, cross sec- Department of tional echocardiogram, and serum electrolyte Cardiovascular (Br HeartJ 1995;74:67-70) concentrations were normal. The electrocar- Medicine, Okayama diogram was obtained on a 6 channel University School of Fukuda Medicine, Okayama, Keywords: long QT syndrome, torsades de pointes, Denshi FD-63 at a paper speed of 25 mm/s Japan isoprenaline. with a calibration of 10 mm/mV. The QT T Ohe interval was measured by hand in lead II at Department of The idiopathic long QT syndrome (LQTS) is rest and during the interventions. The QT Paediatrics, National Cardiovascular characterised by a prolonged QT interval in interval was corrected for heart rate using Centre, Osaka, Japan the surface electrocardiogram, syncopal Bazzett's formula. The end of the T wave was T Kamiya episodes, and sudden death caused by ventric- defined as the return to the baseline. When Correspondence to: ular tachyarrhythmia.1-3 We describe a patient the first component of the T wave and the Dr M Kawade, Department of Paediatrics, Gifu with LQTS and torsades de pointes. Infusion second component of the T wave (U wave) University School of of isoprenaline or adrenaline induced TU fused, making it impossible to distinguish two Medicine, 40 Tsukasa machi, Gifu, Japan, 500. changes and torsades de pointes. We used TU types of waves, the QT interval was measured Accepted for publication wave changes during isoprenaline infusion to to the time of final return to the baseline. The 2 November 1994 select an effective drug for this patient. QT interval of the resting ECG was 450 ms at a heart rate of 64 beats/min (QTc = 460 ms).

EXERCISE TESTING Treadmill testing was performed according to a modified Bruce protocol (fig 1). The protocol Before exercise 1 min after exercise stopped when the patient became exhausted. ECG was obtained on a six channel Marquette CASE 12 at a paper speed of 25 I =="V=V1! I _ vi mm/s with a calibration of 10 mm/mV. The QT intervals were measured in lead II. Heart

X rate increased from 70 to 143 beats/min with IJJVV2 exercise. QTc was prolonged from 460 ms to * I,:A''1 550 ms. 111 ~V3 tE -IIIV3 RESPONSES TO ADRENALINE, ISOPRENALINE AND METHOXAMINE INFUSION To examine the influence of alpha and/or beta aVR V4e adrenoreceptor stimulation, adrenaline, iso- aVR__ V4 prenaline, and methoxamine were adminis- tered by infusion after we had obtained -1._I,-, aV = .. informed consent from her parents (fig 2). aVLF V5e During adrenaline infusion at 0 4 ,ug/kg/min (alpha and beta stimulation) the QTc interval V6 was prolonged (from 470 ms to 600 ms) and u i aVF i-V6 1 mV prominent U waves developed especially in lead V3. A bolus injection of adrenaline (0-8 1|~~~~~~V2 induced inversion of the TU wave in Figure 1 Effects oftreadmill testing. One minute after exercise the QTc interval had pg/kg) increasedfrom 460 ms to 550 ms.[t the left precordial leads, multiform premature 68 Kawade, Ohe, Kamiya

Figure 2 Responses to Adrenaline Isoprenaline Methoxamine adrenaline, isoprenaline, and methoxamine infusion. 0.4 jg/kg/min 0.8 jg/kg iv 0.02 ig/kg/min 0.06 ig/kg iv 40 ig/kg iv Administration of L:~~T.. adrenaline or isoprenaline was associated with the prolongation ofthe QT interval, the development ofprominent U waves, and slow VT. Methoxamine increased U wave ~ ~ vI amplitude. The changes V3V3~~~~~~~~~~ were less pronounced than those produced by ... v i;il adrenaline or isoprenaline...... -fl tX t 44...... A._ .v

V55 l t t $ i ] I 1mV

ventricular contractions (PVCs), and slow sedated. Monophasic action potentials ventricular tachycardia. Infusion of adrenaline (MAPs) were recorded as previously (beta stimulation) at the rate of 0-02 reported.45 MAPs were recorded from the ,ug/kg/min, prolonged the QTc interval (from right ventricular septum (RVS) and the right 480 ms to 590 ms) and induced large U ventricular anterior wall (RVA). The duration waves. A bolus injection of adrenaline (0-06 of MAPs was measured at 90% repolarisation p,g/kg) was associated with inversion of the (MAPD9O). Adrenaline was infused at the TU wave in the left precordial leads and mul- same protocol as described. After drip infu- tiform PVCs. After bolus injection of methox- sion, the U wave became larger than the T amine (40 pig/kg, alpha stimulation) there wave and the QT interval was prolonged. were increases in blood pressure (from 105/60 MAPD9O increased from 280 ms to 420 ms at mm Hg to 128/82 mm Hg), in QTc interval the RVS and from 290 ms to 350 ms at the (from 470 ms to 560 ms), and in U wave RVA. During drip infusion of adrenaline the amplitude. patient became uncomfortable. Rapid injection of adrenaline induced torsades de ELECTROPHYSIOLOGICAL STUDY pointes. Humps, which were probably consis- After informed consent was obtained from her tent with early afterdepolarisations, were seen parents, we performed an electrophysiological immediately before the onset of torsades de study with the patient fasting, and not pointes (fig 3).

Figure 3 Recording of Adrenaline 0-4 jg/kg/min -*O0.8g/kg iv monophasic action potential after drip infusion and additional injection of adrenaline. The bolus injection ofadrenaline was II associated with torsades de pointes. The inversion of TU wave, the QT prolongation, and humps Ill appeared immediately before the onset oftorsades de pointes. MAP, vi monophasic action potential. V3

RVS MAP

RVA MAP Provocative testing and drug response in a patient with the long QTsyndrome 69

Before isoprenaline Isoprenaline Isoprenaline was difficult to estimate the effects of these 0.02 g/kgmin iv 0.06 /kg iv drugs by the change in QTc interval or the configuration of TU waves. This patient continued to receive propra- Baseline nolol and verapamil and has not had a syncope attack for 2 years.

Discussion Propranolol In this patient prominent U waves, inversion (2 mg/kg) of the TU wave, PVCs, and non-sustained VT were reproducibly induced by administration of adrenaline or isoprenaline. Beta blockers are effective in 75%-80% of sympto- Propranolol matic patients with idiopathic long QT syn- (2 mg/kg) + verapamil drome.P8 Previously, the effect of drugs has (5-5 mg/kg) been estimated by their clinical effects. However, in this patient, it was difficult to estimate the drug effect before discharge. Figure 4 Effects ofpropranolol and verapamil on preventing the changes in TUproduced Therefore, we used the TU changes to select by isoprenaline. Without such medication QTc was prolonged and U wave amplitude was much increased during isoprenaline infusion. An additional bolus injection ofisoprenaline an effective drug. During drip infusion of iso- resulted in the inversion of TU waves and premature ventricular contractions. Propranolol prenaline, propranolol suppressed the TU prevented the TU alternans waves and suppressed the increase in U wave amplitude changes, but propranolol and verapamil pre- during drip infusion ofisoprenaline. After bolus injection ofisoprenaline premature ventricular contractions were prevented but prominent U waves were observed. Propranolol vented the augmentation of the U wave more with verapamil suppressed the TU changes and ventricular extrasystoles more effectively effectively. than propranolol alone. Figure 3 shows early afterdepolarisations immediately before the onset of torsades de pointes. This suggests a correlation between these two features. When each afterdepolarisations appeared the TU wave became signifi- EFFECTS OF PROPRANOLOL AND VERAPAMIL ON cantly inverted. Morganroth suggested that U TU WAVES waves may represent a summation of early We examined the effects of propranolol and afterdepolarisations occurring throughout the verapamil on the changes in TU induced by myocardium.9 Moore reported that early isoprenaline (fig 4). Infusion of isoprenaline afterdepolarisations may stem from increased (0 02 ug/kg/min) induced an increase in U inward calcium or sodium currents or from wave amplitude. An additional bolus injection decreased outward potassium current. Early of isoprenaline resulted in the inversion of the afterdepolarisations may occur when inward TU wave and PVCs. Propranolol (2 mg/kg depolarising currents exceed outward repolar- per day) was given by mouth for 5 days. Two ising currents. In contrast to the normal hours after a dose ofpropranolol the inversion recovery process, early afterdepolarisations of the TU waves was prevented and the aug- are associated with additional action poten- mentation of the U wave amplitude sup- tials occurring during the repolarisation pressed during the drip infusion of process; the rapidly occurring early afterdepo- isoprenaline. Administration of propranolol larisations may trigger malignant arrhythmias. prevented PVCs but not prominent U waves These findings suggest that by blocking the after a bolus injection of isoprenaline. Next, in calcium current during the repolarisation addition to propranolol (daily dose of 2 process, verapamil can suppress the formation mg/kg), we studied the effect of verapamil of early afterdepolarisations and so abolish (5 5 mg/kg per day). After 5 days of combined TU changes. treatment the effects of the drugs were tested. A limitation of this report is that we could The prominent U waves and PVCs after the not document spontaneous torsades de bolus injection of isoprenaline were signifi- pointes in this patient. We had evidence of cantly reduced. only two episodes of syncope, both after The effects of propranolol and verapamil emotional stress. We have no evidence that on the TU changes induced by treadmill test- the syncope was caused by torsades de ing were also investigated. Without medica- pointes. However, we could induce multiple tion the heart rate was increased from 70 premature ventricular contractions and TU beats per minute to 143 beats per minute with changes with isoprenaline or adrenaline infu- exercise. QTc was increased from 460 ms to sions. Furthermore, propranolol and vera- 550 ms. After propranolol was given by pamil prevented multiple premature mouth the heart rate increased from 55 beats ventricular contractions and the TU changes per minute to 137 beats per minute with exer- induced by isoprenaline or adrenaline infu- cise. QTc increased from 500 ms to 550 ms. sion. When propranolol and verapamil were given After starting treatment with propranolol by mouth the heart rate increased from 54 and verapamil she has been free of attack for beats per minute to 128 beats per minute with two years. The electrocardiographically guided exercise. QTc was prolonged from 460 ms to selection of the effective drugs may be useful 610 ms. The duration of exercise did not for patients with idiopathic long QT syn- change with administration of these drugs. It drome. 70 Kawade, Ohe, Kamiya

1 Jervell A, Lange-Nielse F. Congenital deaf-mutism, func- 6 Jackman WM, Friday KJ, Anderson JL. The long QT syn- tional heart disease with prolongation of the QT interval dromes: a critical review, new clinical observations and a and sudden death. Am Hearty 1957;54:59-68. unifying hypothesis. Prog Cardiovasc Dis 1988;31: 2 Schwartz PJ. Idiopathic long QT syndrome: Progress and 115-72. questions. Am Hearty 1985;109:399-41 1. 7 Schwartz PJ, Locati E. The idiopathic long QT syndrome. 3 Gillette PC, Garson A. Ventricular arrhythmias. Pediatric Pathogenetic mechanisms and therapy. Eur Heart J arrhythmias: electrophysiology and pacing. Philadelphia: 1985;6(suppl.D): 103-14. WB Saunders, 1990:468-72. 8 Emanuela HL, Schwartz PJ. The idiopathic long QT syn- 4 Ohe T, Kurita T, Aihara N, et al. Electrocardiographic and drome: therapeutic management. PACE 1992;15: electrophysiologic studies in patients with torsades de 1374-9. pointe. Role of monophasic action potentials. 3mpn Circ J 9 Morganroth J. Relations of QTc prolongation on the elec- 1990;54: 1323-30. trocardiogram to torsades de pointes: Definitions and 5 Shimizu W, Ohe T, Kurita T, et al. Early afterdepolariza- mechanisms. Am J Cardiol 1993;72: 1OB-13B. tions induced by isoproterenol in patients with congenital 10 Moore EN. Mechanisms and models to predict a QTc long QT syndrome. Circulation 1991;84:1915-23. effect. Am J Cardiol 1993;72:4B-9B.

IMAGES IN CARDIOLOGY "Sago" in a saphenous vein graft

A 65 year old man was free of angina after coronary artery bypass grafting. Angina recurred 57 months later and rapidly wors- ened over the next 3 months. Coronary and graft angiography was performed and selective angiography of a reversed saphenous vein graft to the obtuse marginal branch of the circumflex showed severe stenoses in the proximal and middle segments of the graft (arrows). The segment between the stenoses contained multiple, mobile, oscillating filling defects suggestive of thrombus (large arrow- heads). There are clips on the left internal

...... -mammary artery graft (small arrowhead). JANE S SKINNER ...... _.. PHILIP C ADAMS

Figure 1 Left anterior oblique view ofthe proximal part ofthe circumflex graft (digitally magnified x 2).

Figure 2 Anteropostenior view ofthe graft, unmagnified, showing the distal anastomosis.