REVIEW ARTICLE

Drug Invest. 5 (I): 69-79. 1993 0114-2402/93/000 1-0069/$05.50/0 © Adis International Limited. All rights reserved.

DRI1258

The QT Interval and Drug-Associated Torsades de Pointes

Claude R. Benedict Division of Cardiology, University of Texas Medical School, Houston, Texas, USA

Summary Torsades de pointes is an uncommon form of ventricular tachyarrhythmia, which may occur in the presence or absence of drug the~py. There are several difficulties in establishing a rela­tionship between drug therapy and the induction of this arrhythmia. Drugs for which a definitive association with torsades de pointes are established, Le. class IA and III antiarrhythmics, are known to prolong the QT or QT c interval. However, the definition of significant QT or QT c prolongation is sometimes difficult because there is a significant inter- and intrapatient variability in the observed QT or QT c interval even in the absence of drug therapy. Furthermore, some drugs that induce prolongation of the QT or QT c interval in a given patient do not precipitate torsades de pointes. Recent reports of unexpected drug-induced torsades de pointes by drugs other than class IA or III antiarrhythmics led to the examination of the association between QT interval prolongation and torsades de pointes, and evaluation of the mechanisms for drug-induced tor­sades de pointes by drugs other than class IA or III antiarrhythmic drugs.

Torsades de pointes is an unusual ventricular tachyarrhythmia that is often induced by the administration of a drug (Zipes 1987), although it also occurs in the absence of drug therapy (Finley et al. 1978; Fung et al. 1985; Griffin & Most 1985; Horowitz et aL 1981; Lindpaintner & Kienzle 1987; Przybojewski 1983; Stern et aL 1984; Zilcher et aL 1984). Torsades de pointes has classically been de­fined by two characteristics: QRS morphology changes (twisting of points) during ventricular tachycardia, and a prolonged QT interval. Many investigators have attempted to define this unusual polymorphic ventricular tachycardia more pre­cisely to determine which patients are at risk of its development. Some investigators have reported that drug-induced torsades de pointes is heralded by a heart rate decrease and marked QT interval pro­longation (to a value> 550 msec) [Keren et aL 1981; Raquin & Parizel 1977]. Others have not ob­served marked increases in QT interval preceding

torsades de pointes (Bigger & Sahar 1987; Jackman et al. 1988, 1990; Nguyen et aL 1986). It is clear, however, that no absolute value of prolonged QT interval during uninterrupted rhythm predicts all episodes of the phenomenon (Clark et aL 1982; Ejvinsson & Prinius 1980).

An apparent lack of association between QT in­terval prolongation and torsades de pointes has led some to classify all ventricular tachycardias dem­onstrating an oscillating QRS morphology as tor­sades de poinies, regardless of the QT interval (Ev­ans et aL 1976; Horowitz et al. 1981; Nguyen et aL 1986). Others have defined torsades de pointes as simply polymorphic ventricular tachycardia that occurs in the setting of a prolonged QT interval, often with sustained prominent U waves preceding initiation (Jackman et al. 1988). Confounding the diagnosis, significant changes in QRS morphology are not always present. The one apparently con­sistent finding, pause-dependent torsades de

70

~olk

Quinidine

Fig. 1. Schematic representation of the effects of class I A antiarrhythmic drugs, e.g. quinidine, on the lateral precordial ECG, including mild widening of the QRS complex, sloping ST segment depression, flattened and widened T wave, and the appearance of a new 'slow wave' or 'U wave' beginning near the end of the T wave (after Jackman et al. 1988; re­printed with permission).

pointes, has been reported with virtually every drug known to prolong ventricular repolarisation and, thus, prolong the QT interval (Bauman et al. 1981; Keren et al. 1981),

1. The QT Interval 1.1 Measurement of the QT Interval

The QT interval encompasses the time from the earliest activation of the ventricular myocardium to the latest ventricular repolarisation. It can be prolonged if the process of activation is slowed (an increase in the QRS interval), or if there is pro­longed repolarisation (increase in the ST-T wave interval) in a sufficiently large portion of the myo­cardium. The process of repolarisation is complex and dynamic, and is affected by many factors in­cluding drugs, electrolyte abnormalities, or dis­eases (Ahnve 1985; Elek et al. 1953). Normally, there is a clear T wave corresponding to repolar­isation of the ventricular myocardium. However, the T wave duration can be difficult to measure, and the presence of drugs that alter ventricular re­polarisation may produce abnormalities of the T wave (fig. I).

These abnormalities appear as a sloping depres­sion in the ST segment, and wide, rounded, low amplitude T waves, most marked in the mid to

Drug Im'est. 5 (I) 1993

lateral precordial leads. Also, a low frequency or slow wave beginning shortly before the end of the T wave often becomes prominent. It is uncertain whether this slow wave represents an abnormal in­crease in the normal U wave amplitude (Reynolds & VanderArk 1976; Scherf & Bornemann 1971; Smith & Gallagher 1980), an abnormal distortion of the T wave (reflecting heterogeneity of ventric­ular repolarisation) or a 'diastolic wave' distinct from the normal T and U waves (Ejvinsson & Pri­nius 1980). This slow wave may be generated by different electrophysiological mechanisms. Since the U waves may begin before the downstroke of the T wave is established, it may not always be pos­sible to determine the QT interval with accuracy and precision (Campbell et al. 1985; Lepeschkin & Surawicz 1952).

Traditionally, the best separation of T and U waves may be seen in lead II. The leads that show the largest U waves are the mid-precordial leads (V3, V 4 and V 5). If there is a distinct separation between the T and U wave, the actual QT interval is measured. When the T and U waves are fused together, the QTU interval can be measured. Measurement of the QT interval is even more dif­ficult when there is no c1earcut prolongation of the QT interval but there is a late deflection (bump) or there is a bi-fid form of T wave (fig. 2). When measuring the QT interval the following factors are important: the leads or number of leads selected; the way in which the baseline is defined; and the drawing of the slope at the end of the T wave to determine the end of the QT interval. Variability in heart rate can alter the QT interval and is cor­rected using Bazett's formula (Bazett 1920). This correction is valid only within the normal range of heart rate (American Heart Association 1956).

There is no standard method that is universally accepted to measure QT interval. However, for clinical purposes, in a patient with a normal ECG, lead II should be adequate for routine assessment of changes in the QT interval. If there are abnor­malities in the T wave, precordial leads V3, V 4 and V5 are the best leads to examine the changes in T wave morphology and show the clearest separation of the T and U waves. A complete evaluation of

QT Interval and Drug-Associated Torsades de Pointes

a

b

c

d

Fig. 2. Ambiguities in differentiating T and U waves in the long QT syndrome. All 4 tracings were recorded from the same lateral precordial monitor lead over a 3-day period in a patient receiving quinidine sulfate chronically at a dose of 200mg every 6 hours with no significant change in serum electrolytes. The tracings are not in chronological order. (a) reveals the typical ST segment depression, low amplitude T wave, and moderately low amplitude U wave, beginning after the crest of the T wave. The last QRS complex is aligned in all 4 tracings. (b) and (c): the T wave becomes progressively smaller while the U wave amplitude increases, so that the T wave is not readily identifiable in (c). In the absence of other recordings, the U wave might be mistaken for the T wave and the QT interval falsely measured at 600 msec (d). The T and U waves fuse smoothly, giving the appearance of just a T wave. This tracing would also yield a falsely long QT interval (approximately 700 msec) [after Jackman et al. 1988; reprinted with permission).

the QT interval should include an examination of all 12 leads and the longest measured QT interval should be used.

1.2 Normal Value for the QT Interval

As the heart rate increases, the QT interval shortens. The most frequently used formula for ad-

71

justing the QT interval for variability in heart rate was proposed by Bazett (Bazett 1920): corrected QT or QT c = QT /vR-R. However, the QT c does not remain constant when the heart rate is manipu­lated by atrial or ventricular pacing (Ahnve & Val­lin 1982; Fredlund & Olsson 1985; Milne et al. 1980, 1982), and changes associated with exercise or other physiological manoeuvres (Ahnve & Val­lin 1982; Davidowski & Wolf 1984; Sarma et al. 1984; Staniforth 1983) are inconsistent. Lepesch­kin (1951) analysed 6100 cases to define the nor­mal QT distribution within a wide range of R-R intervals. The normal range of QT c was within ± 15% of the mean value with an upper limit of 460 msec for men and 470 msec for women. The nor­mal upper limit for QT c using Bazett's heart rate correction is often quoted at 440 msec (AHA 1957), although other values have been used.

1.3 QT Interval Variability

There is a marked variability between individ­uals in QT interval measurements and, more im­portantly, within individuals in controlled studies (Morganroth et al. 1991). This variability is illus­trated in figure 3, which depicts mean corrected QT intervals measured from a series of 12-lead ECG recordings made over a 24-hour period in 28 normal subjects and 28 patients with stable cor­onary artery disease or left ventricular dysfunction. The figure shows that the variation in QT interval within individual normal subjects can be as little as 15 msec and as large as 70 msec. Similarly, in patients with cardiovascular disease, the within­patient variability in QT values range from 20 msec to 90 msec. The within-individual standard de­viations calculated using analysis of variance (ANOVA) are approximately 12 msec among nor­mal individuals and 15 msec for patients with stable coronary artery disease or left ventricular dysfunction. The between-individual standard de­viations are approximately 19 msec and 23 msec for normal subjects and cardiac patients, respec­tively.

The within-individual and between-individual variability in QT intervals in 3 different po pula-

72

tions (healthy volunteers, hypercholesterolaemic patients, and patients with heart failure) from an­other study is summarised in table I.

Therefore, when the prolongation in QT inter­val in a given patient is considered, any increase in QT interval is likely to be significant when the increase is beyond two standard deviations of that patient's normal variability. Therefore, the normal variability in QT interval should be taken into con­sideration when assessing the effect of a drug on the QT interval.

These studies (table I) also suggest that between­patient variability within a given patient popula­tion can differ between different disease condi­tions. For example, when compared with normal subjects or hypercholesterolaemic patients, patients with heart failure show a greater prolongation in the mean QT interval and a greater within-patient variability.

Thus, the difficulty in defining the duration of QT interval, the normal variability in QT interval, and the infrequent occurrence oftorsades de pointes make it difficult to establish a quantitative rela­tionship between QT interval prolongation and torsades de pointes.

2. Torsades de Pointes

Torsades de pointes is a rare but potentially life­threatening ventricular tachyarrhythmia. There are

560 a

520

~ 480 (/)

Illlllllllllllllllllllllllll .s 440

" I-400 0

360

320

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Normal subject number

Drug Invest. 5 (1) 1993

congenital forms as well as an acquired form of torsades de pointes (Jackman et al. 1988). Only the acquired form and, in particular, its association with drug administration is considered here.

2.1 Mechanism of Torsades de Pointes

Our understanding of drug-induced torsades de pointes has evolved in the light of recent findings. It was originally believed that the genesis of this arrhythmia was related to marked asynchrony of ventricular repolarisation. This mechanism was based on the finding that torsades de pointes was initiated by a VPC with a short coupling interval in a patient with a long QT interval. For example, if one assumes that: (l) the shortest coupling in­terval at which VPCs occur corresponds to the re­covery of excitability and therefore the end of re­fractoriness, and (2) the end of the total QT on the ECG corresponds to the end of repolarisation in some areas of the ventricle, then the interval be­tween the onset of VPC and the end of the QT interval represents the minimal duration of dis­persion of repolarisation (Surawicz & Knoebel 1984), which can be large in patients with long QT interval syndrome. An analysis of cycle length, im­mediately preceding torsades de pointes, has shown a long-short R-R cycle sequence in many episodes of torsades de pointes. A pause in the supraven­tricular rhythm due to sinus bradycardia, or due

560 b

520

~ 480 'I 111111111111111 11111'11111

(/)

.s 440

~ 0 400

360

320

1 3 5 7 9 11 13 15 17 19 21 23 25 27

Cardiovascular disease patient number

Fig. 3. Within- (a) and between- (b) individual variation in QTc in 2 populations. Centre tic mark is the mean of individual corrected QT interval values. Lower and upper tic marks are the minimum and maximum values of corrected QT interval, respectively.

QT Interval and Drug-Associated Torsades de Pointes 73

Table I. The mean aTe interval and standard deviations (SO) calculated for within-individual and between-individual values recorded in 3 groups of subjects

Group (no. of subjects) ECG recording

Normal males (18) Ambulatory Holter Patients with hypercholesterolaemia (85) Supine, lead II Patients with congestive heart failure (56) Supine, lead II

to the compensatory pause after a VPC, is followed by the next sinus beat with a VPC in its T wave. This appears to initiate torsades de pointes. Such a sequence of changes might increase the degree of dispersion of repolarisation and enhance the pos­sible generation of a ventricular tachycardia (Bau­man et al. 1981; Denes et al. 1981; Keren et al. 1981). Thus, in the presence of greater-than-nor­mal disparity of refractory periods throughout the myocardium, re-entrant excitation would be facil­itated in the event of excitation originating during the relative refractory period. The presence of a prolonged QTU interval and abnormal T and U waves in patients with 'long QT syndromes' was hypothesised to reflect gross and heterogeneous de­lays in repolarisation of ventricular myocardial cells (Keren et al. 1981).

Until recently there was no substantial disa­greement with the above hypothesis, which sug­gests that tachyarrhythmias in the long QT syn­drome are the outcome of re-entrant circuits formed in the environment of greatly prolonged and het­erogenous refractory periods in ventricular myo­cardium. However, this hypothesis does not ex­plain how an initiating impulse that first transgresses into the repolarisation phase (i.e. the first ectopic beat to interrupt the T and U wave of the sinus beat) instigates the process of re-entry. Furthermore, the observation that patients with 'long QT syndromes' are at risk for induction of ventricular tachycardias when stimulated during the T and U waves (Bhandari et al. 1985; Coumel et al. 1985; Hartzler & Osborn 1981; Wellens et al. 1972) is not consistent with this hypothesis.

An alternative hypothesis, which explains not only the occurrence of the long QT syndrome, but

aTe interval (mean ± SO)

within-individual between-individual

406 ± 24 406 ± 37 394 ± 18 405 ± 18 447 ± 38 447 ± 38

also the presence of the abnormal T and U wave, is based on the concept of afterdepolarisations. These are abnormal secondary depolarisations oc­curring before the full completion of repolarisation in myocardial cells. Afterdepolarisations may oc­cur in any phase of repolarisation. Early afterde­polarisations occurring during the plateau phase of the action potential (at low transmembrane poten­tials) may result when inward depolarising currents exceed the outward repolarising currents. These could be due to enhanced Na+ or Ca++ currents, to diminished repolarising outward currents as a result of blocking of the K + channels, or to abnor­malities in intracellular Ca++ handling by the sar­coplasmic reticulum. Late afterdepolarisations ap­pear to be facilitated by slow heart rate, low extracellular K+ and/or Ca++ cOD.centrations, or an increased accumulation of Ca++ in intracellular compartments. A late afterdepolarisation devel­oping at voltage levels sufficient to allow .excita­bility of a channel, may initiate a second action potential. Propagation of the second action poten­tial may produce a ventricular systole or generate a second afterdepolarisation leading to repetitive firing and ventricular tachycardia. In the presence of predisposing conditions, afterdepolarisation may be produced throughout the ventricular myocard­ium producing various forms of tachyarrhythmia, including torsades de pointes (Jackman et al. 1990).

These afterdepolarisations, which may be the mechanism for the production of torsades de pointes, may be explained by the presence of myo­cardial damage. Membrane defects clearly could affect the ability of the K+ channel to function properly and predispose the ventricular myocard­ium to produce various forms of tachyarrhythmia,

74

such as torsades de pointes (Jackman et al. 1990). In addition, the presence of certain drugs may also contribute to a torsades de pointes type arrhythmia by further depressing K+ channels. Patients with severe myocardial damage are easily identifiable as being at risk of developing torsades de pointes. However, there are no markers that allow one to clearly predict those patients with a minimally damaged membrane that will be at risk of devel­oping torsades de pointes following the adminis­tration of a provoking agent.

However, late appearance oftorsades de pointes in patients with heart block or in patients receiving class IA antiarrhythmic agents, with no other ob­vious inciting factors such as hypokalaemia or hy­pomagnesaemia, suggest factors in the genesis of this arrhythmia that are not yet identified. It is not known why a small percentage of patients treated with class IA antiarrhythmic drugs or having elec­trolyte abnormalities seem predisposed to develop torsades de pointes. Additionally, rare patients may

a

b

c

Drug Invest. 5 (I) 1993

present with torsades de pointes without any of the currently appreciated precipitating factors. Thus, although the current hypothesis may partially ex­plain some of the findings with torsades de pointes, they do not explain the genesis of torsades de pointes in all clinical situations. This lack of under­standing of all possible mechanisms makes it dif­ficult to predict the patients that may develop tor­sades de pointes following the administration of a provoking agent.

2.2 Drugs Associated with Torsades de Pointes

Torsades de pointes is closely associated with drugs that prolong the QT interval. However, no significant relationship has been established be­tween the induction of this arrhythmia and either absolute QT value or the increase in QT interval from baseline. Similarly the occurrence of torsades de pointes is not significantly correlated with the

Fig. 4. Features typical of drug-induced torsades de pointes in patients receiving disopyramide (150mg every 6 hours) for atrial fibrillation. (a) Striking postpause U wave accentuation (arrow). The U wave' amplitude decreases progressively over the next 2 cycles. The QT interval (470 msec) is not significantly prolonged, considering the slow ventricular rate. (b) Ven­tricular bigeminy associates with large postpause U waves. (c) Postpause ventricular extrasystoles and torsades de pointes. Same monitor lead as (a) and (b), but gain is reduced. Note the first beat of the tachycardia is widely coupled (650 msec), emerging from the largest U wave. The T wave of that postpause complex is barely perceptible, leaving the impression that the U wave is the T wave (after Jackman et al. 1988; reprinted with permission).

QT Interval and Drug-Associated Torsades de Pointes

dose or plasma concentration of any antiarrhyth­mic drug.

Drug-induced torsades de pointes is frequently an idiosyncratic rather than a dose-related reac­tion, and generally occurs within 2 or 3 days of initiating drug therapy (Keren et al. 1981; Roden et al. 1986). Although once perceived as a compli­cation resulting from drug overdosage or accu­mulation in the plasma (Jackman et al. 1988), tor­sades de pointes has most frequently been documented at therapeutic plasma drug concentra­tions (Bigger & Sahar 1987; Roden et al. 1986; Zipes 1987).

There is no linear relationship between the de­gree of drug-induced QT interval prolongation and the development of torsades de pointes. Thus, the modest (e.g. 80 to 100 msec) increase in QT in­terval produced, for example, by quinidine may well lead to the development of torsades de pointes in susceptible individuals, whereas the marked (> 600 msec) increase in this parameter produced by amiodarone confers minimal risk of torsades de pointes. Moreover, for a given degree of QT inter­val prolongation the incidence of torsades de pointes varies from one drug to another.

Despite this apparent lack of correlation be­tween drug-induced ECG changes and proar­rhythmic risk, patients with moderate pre-existing QT interval prolongation (latent long QT syn­drome) do appear to be at increased risk of devel­opment of torsades de pointes in response to class IA antiarrhythmic agents (Bauman et al. 1981; Big­ger & Sahar 1987; Jackman et al. 1988; Zipes 1987). This might suggest that there is a subset of patients with an inherent or acquired propensity to develop torsades de pointes who are identified by pause­accentuated U waves in the drug-free state (Jack­man et al. 1988).

A wide variety of drugs have been reported to provoke torsades de pointes, but group IA and III antiarrhythmic agents are by far the most common causative agents (Stratmann & Kennedy 1987). Torsades de pointes has been conclusively dem­onstrated in isolated cases of patients administered the group IA antiarrhythmic agents quinidine, di­sopyramide (fig. 4), or procainamide. This group

75

Table II. Drugs (other than antiarrhythmics) having a well­established association with torsades de pointes

Vasodilators

Prenylamine Bepridil

Psychotropics Thioridazine

Miscellaneous drugs

Corticosteroids (e.g. prednisone) Diuretics (e.g. furosemide)

of drugs blocks Na+ (fast) channels, decreases con­duction velocity, and moderately prolongs repo­larisation. Group III agents selectively prolong re­polarisation. Torsades de pointes has been clearly demonstrated for amiodarone and sotalol. Altera­tion of ventricular repolarisation is not a promi­nent electro physiological effect of other classes of antiarrhythmic agents and torsades de pointes has not been conclusively demonstrated in patients ad­ministered these other antiarrhythmics (Stratman & Kennedy 1987).

There are also drugs from other therapeutic classes (other than antiarrhythmics) that can in­duce torsades de pointes (table II). These drugs usually have some group lA-like electrophysiolog­ical activity or induce electrolyte disturbances which can induce QT prolongation similar to that in­duced by class IA antiarrhythmics.

The phenothiazines and tri- and tetracyclic anti­depressants display electrophysiological properties similar to the class IA agents, namely an increase in PR, QRS and QT intervals and U wave ampli­tude (Cassem 1982; Fowler et al. 1976). Of these, the phenothiazines, thioridazine and, less fre­quently, chlorpromazine, and the antidepressants doxepin, maprotiline and amitriptyline have been implicated in the development of torsades de pointes, primarily in patients taking an overdose of these medications (Fowler et al. 1976; Herr­mann et al. 1983; Kemper et al. 1983; Strasberg et al. 1982). However, the incidence of torsades de pointes in patients with an overdose of these psy­chotherapeutic agents is probably lower than that with the class IA agents. Corticosteroids and di-

76

Table III. Agents that are an unconfirmed or rarely reported

cause of torsades de pointes

Vasodilators

Fenoxidil Lidoflazine

Psychotropics

Amitriptyline Chlorpromazine Doxepin Imipramine Maprotiline Trifluoperazine

Antihistamines

Astemizole Diphenhydramine Hydroxyzine Terfenadine

Antibiotics

Erythromycin Trimethoprim/sulfamethoxazole Pentamidine Doxorubicin Tetracycline

Miscellaneous drugs

Amantadine Atropine Chloral hydrate Chloroquine Indoramin Ketanserin Organophosphate insecticides Probucol Suxamethonium Vasopressin Vincamine Terodiline

uretics may, by lowering plasma potassium levels, indirectly precipitate torsades de pointes (Kounis 1979).

Presently, there is also a growing list of agents that have been purported to be associated with tor­sades de pointes as described in isolated patient case report studies (table III). In many cases, how­ever, the lack of consensus in the definition of tor­sades de pointes and the absence of rhythm strips accompanying these reports preclude establishing these drugs as a definite cause of this arrhythmia.

Several cases involving the use of vasopressin

Drug Invest. 5 (I) 1993

(Eden et al. 1983) and atropine (Motte et al. 1982) indicate that these drugs may cause torsades de pointes through their tendency to slow the heart rate. Poisoning with organophosphate insecticides, which inhibit cholinesterase and cause intense va­gal stimulation, have been reported to produce a torsades de pointes similar to that seen in patients with long QT syndrome (Ludomirsky et al. 1982). QT intervals of up to 600 msec (QTc of710 msec) were reported.

The occurrence of QT prolongation and ven­tricular tachycardia has been reported with intra­venous administration of erythromycin in at least 2 well-documented case reports (Guelon et al. 1986; Schoenenberger et al. 1990). Schoenenberger et al. (1990) reported that the phenomenon occurred in I patient 3 separate times, during bolus adminis­tration and also twice during doses given as an in­fusion. These occurred only at the time when peak plasma concentrations would be expected. Simi­larly, Guelon et al. (1986) recorded QT prolonga­tion and self-terminating polymorphic VT during 3 separate infusions of erythromycin during which serum potassium remained normal.

Several cases of pentamidine-associated poly­morphic VT have been reported in patients with AIDS, although the extent to which compromised nutritional status and electrolyte disturbances may have contributed to these events is unclear (Quad­rei et al. 1992; Stein et al. 1990).

Amantadine use has been associated with wid­ened QRS interval (not specified) and QT pro­longation (QTc of 460 msec) [Sartori et al. 1984]. This occurred following ingestion of an extremely high dose of amantadine (2.5g) taken in a suicide attempt.

Reports of torsades de pointes occurring with nonsedating antihistamines are less well-docu­mented. MacConnell and Stanners (1991) reported prolongation of the QT interval (600 msec) with QT c of 560 msec in a patient taking 360mg (3 times the maximum recommended dose) of terfenadine daily for 2 weeks. Although a diagnosis of torsades de pointes was made, the case report did not in­clude rhythm tracings. Davies et al. (1989) re­ported prolonged QTc intervals (up to 0.57 msec)

QT Interval and Drug-Associated Torsades de Pointes

Fig. 5. Hypokalaemia (serum potassium 1.7 mEqjL) pro­ducing the same T and U wave changes as quinidine-induced torsades de pointes, including post pause accentuation of the U wave (arrow) [after Jackman et al. 1988; reprinted with permission).

and ventricular arrhythmias in a patient with sus­pected overdose. Other reported incidents (Mon­ahan et al. 1990; Zimmerman et al. 1992) have been attributed to a drug interaction between terfena­dine and ketoconazole, which resulted in higher than expected serum terfenadine levels from doses in the therapeutic range (Mathews et al. 1991).

Astemizole has also been associated with re­ports of prolonged QT interval and torsades de pointes in cases of overdose (Bishop & Gaudry 1989; Craft 1986) and also at a dose in the thera­peutic range (IOmg daily) for 10 weeks (Simons et al. 1988).

Other case reports have identified vincamine (Duny et al. 1980), the selective serotonin-S2 ant­agonist ketanserin (Aldariz et al. 1986), the anti­malarial chloroquine (Fauchier et al. 1974), and terodiline (McLeod et al. 1991), among others, as possibly related to the onset of prolonged QT in­terval and ventricular arrhythmia, often of tor­sades de pointes morphology.

2.3 Other Risk Factors for Torsades de Pointes

Hypokalaemia and hypomagnesaemia (Jack­man et al. 1988; Zipes 1987) produce QT changes indistinguishable from those produced by quini­dine and other class IA antiarrhythmic agents, in­cluding postpause U wave accentuation as shown in figure 5. Significant depletion of these electro­lytes has been associated with torsades de pointes.

77

Certain altered nutritional states, most notably the liquid protein modified fast diet and anorexia ner­vosa, can produce the characteristic T and U wave changes and torsades de pointes (Isner et al. 1979, 1985; Singh et al. 1978).

Ventricular tachycardia has long been recog­nised as a complication of severe bradyarrhyth­mias (Dessertenne 1966; Schwartz 1936; Schwartz & de Sola Pool 1950). Rapid ventricular tachycar­dia (often clearly torsades de pointes) has been re­ported as the aetiology of syncope in 10 to 68% of patients with Stokes-Adams attacks associated with complete heart block (Dressler 1964; Jensen et al. 1975; Parkinson et al. 1941) and in 7% of patients with such attacks in the presence of sinus node dys­function (Schwartz et al. 1949). As with drug-in­duced torsades de pointes, the prominent post­pause U waves and ventricular tachycardia may not emerge until long after the onset of sinus pauses or complete A V block (Bauman et al. 1981).

There is a question as to whether heart disease, either in general or in certain specific forms, might predispose to this condition. Earlier impressions that torsades de pointes occurred only in patients with rheumatic heart disease have not been sup­ported by continued experience. The. presence of underlying cardiac disease, particularly depressed left ventricular ejection fraction, may be a risk fac­tor. However, it appears that patients with no d~­tectable heart disease may also develop torsades de pointes (Jackman et al. 1988).

3. Conclusions

In summary, no absolute value of QT or QTc

interval during uninterrupted sinus rhythm can be expected to predict all episodes of torsades de pointes. In many patients who develop torsades de pointes, QT values overlap the range of QT inter­vals found in patients who receive the same drugs without developing torsades de pointes. In the ab­sence of a predictable relationship between critical QT or QT c interval prolongation and the devel­opment of torsades de pointes, the abnormal pro­longation in QT interval can be used only as one of the risk factors in the development of torsades

78

de pointes. Excluding the antiarrhythmic drugs and structurally related compounds, the occurrence of drug-associated torsades de pointes with other compounds is rare. Furthermore, the varying de­gree of detail provided in these reports makes it difficult to establish a definitive relationship in many instances or to identify patients at risk. De­velopment of an awareness that drugs other than class IA and III antiarrhythmics can cause torsades de pointes may enhance the identification, inves­tigation and careful reporting of these suspected events, which may lead to an increased under­standing and predictive capability of this rare but life-threatening disorder of cardiac rhythm.

Acknowledgement

This publication reflects the proceedings of a sym­posium entitled 'The Relationship of QT Interval Pro­longation to the Development of Torsades de Pointes', held in April 1991 in Cincinnati, Ohio, USA. The author wishes to acknowledge symposium panelists Drs J. Thomas Bigger, Warren Jackman, Peter Kowey, and Joel Morganroth.

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Correspondence and reprints: Dr Claude Benedict, Associate Pro­

fessor of Medicine, Division of Cardiology, the University of Texas

Medical School, Houston, Texas 77030, USA.