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Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent?
  1. S Viskina,
  2. R Fisha,
  3. D Zeltsera,
  4. B Belhassena,
  5. K Hellera,
  6. D Brosha,
  7. S Laniadoa,
  8. H V Barronb
  1. aDepartment of Cardiology, Sourasky-Tel Aviv Medical Center, Sackler-School of Medicine, Tel Aviv University, Israel, bCardiovascular Research Institute, University of California, San Francisco, California, USA
  1. Dr S Viskin, Department of Cardiology, Tel Aviv Medical Center, Weizman 6, Tel Aviv 64239, Israel email: viskin_s{at}netvision.net.il

Abstract

OBJECTIVE To determine the frequency and predictors of pause dependent torsade de pointes among patients with the congenital long QT syndrome and spontaneous ventricular tachyarrhythmias.

DESIGN The literature on the “congenital long QT” was reviewed. Articles with illustrations demonstrating the onset of spontaneous polymorphic ventricular arrhythmias in the absence of arrhythmogenic drugs were included.

RESULTS Illustrations of 62 spontaneous episodes of torsade de pointes among patients with congenital long QT syndrome were found in the literature. The majority (74%) of documented arrhythmias were “pause dependent”; 82% of these pauses were longer than the basic cycle length by > 100 ms. Age and sex correlated with the mode of arrhythmia initiation. Arrhythmias in infants (⩽ 3 years old) were not pause dependent, while female sex correlated with pause dependent torsade. Using multivariate analysis, age was the only independent predictor of the mode of onset of torsade de pointes.

CONCLUSION Available data suggest that the majority of spontaneous arrhythmias in the congenital long QT syndrome are pause dependent. Torsade de pointes that is not preceded by pauses appears to be limited to patient subgroups with severe forms of the disease, like symptomatic infants. These findings have important implications regarding the use of cardiac pacing for arrhythmia prevention.

  • long QT
  • congenital long QT syndrome
  • torsade de pointes
  • ventricular tachycardia

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Characterisation of the mode of onset of spontaneous ventricular arrhythmias in the long QT syndrome has important clinical implications.1 2Specifically, the frequency by which torsade de pointes is preceded by sudden decrements in cycle length—that is, is “pause dependent”—could affect the role of cardiac pacing for arrhythmia prevention.3 4

We recently evaluated the frequency of “pause dependent” torsade de pointes in patients with congenital long QT syndrome who had documented spontaneous arrhythmias.2 In our original series,2 the majority of arrhythmic episodes (in 14 of 15 patients) were preceded by pauses (either sinus pauses or post-extrasystolic pauses). These results, however, deviated from the prevailing view in the literature, which equated “pause dependent torsade de pointes” with the acquired, rather than the congenital long QT syndrome.5-8 Moreover, our study had important limitations (like the limited number of documented arrhythmias), which precluded generalisation of our findings. We therefore reviewed the literature of the congenital long QT syndrome, searching for additional illustrations of spontaneous arrhythmias, to identify clinical predictors of the mode of onset of torsade de pointes.

Methods

We reviewed the English literature on “torsade de pointes” and the “congenital long QT”. All published articles, with illustrations demonstrating the onset of spontaneous arrhythmias in patients with a congenital long QT, were included. Reports were excluded if: (1) the documented arrhythmias occurred in the setting of potentially torsadogenic metabolic abnormalities or drug treatment; (2) the poor quality of the illustrations, or the absence of at least three complexes before arrhythmia initiation, precluded classification of the arrhythmia as “pause dependent” or “non-pause dependent”. Reports from the University of California San Francisco,9-12 which included patients also reported in our original series describing the mode of onset of torsade de pointes,2 were not included in the present study in order to avoid potential double counting.

Torsade de pointes was defined as a polymorphic ventricular tachycardia lasting > 3 beats (all but six episodes lasted ⩾ 10 beats) and was considered to be pause dependent when the arrhythmia was immediately preceded by a pause that was longer than the basic cycle length by at least 40 ms. Also, if torsade followed a period of ventricular bigeminy, it was considered to be pause dependent (even if the undisturbed basic cycle length was unknown) as long as the post-extrasystolic interval was longer than the coupling interval of the preceding extrasystole by at least 40 ms. The 40 ms value was chosen because this was the smallest interval increment that could be reproducibly recognised. As in a previous study,2 the identified pauses were, in fact, considerably longer than the basic cycle length (see below).

Results

In addition to the 15 patients with congenital long QT syndrome reported in our original series,2 we found 62 illustrations of torsade de pointes in 54 articles published by others.3 6 13-51 52 53-64 Fifteen of these patients were excluded for the following reasons. Five patients with a congenital long QT syndrome and pause dependent torsade were excluded because the illustrated arrhythmias occurred during hypokalaemia,52 hypomagnesaemia53 or during treatment with imipramine,54 astemizole59 or after amiodarone discontinuation.61 One patient with non-pause dependent tachycardia was excluded because the arrhythmia appeared to be related to an old myocardial infarction.55Five patients were excluded because the poor quality of the ECG or the absence of ⩾ 3 complexes before arrhythmia initiation precluded classification of the arrhythmia.51 56-58 60 In addition, four arrhythmia illustrations that were repeatedly published—first in original articles15 20 36 38 and later in reviews6 45 64—were included only once. Thus, the present report includes 62 patients with documented torsade de pointes, including 15 patients reported in our original series2 and 47 patients reported by others.3 6 13-20 22-37 39-50 62

The majority of arrhythmia illustrations, in patients with congenital long QT syndrome reported by others, also demonstrated pause related arrhythmias (table 1, fig 1). However, the percentage of arrhythmias preceded by pauses among patients reported by others (68%) was less than the preponderance of pause dependent arrhythmias (93%) observed in our original series.2 Based on all available data (62 patients), it appears that torsade de pointes is pause dependent in roughly three out of four symptomatic patients with congenital long QT syndrome (table 1). Only two patients15 36 demonstrated both type of arrhythmias (fig2).

Table 1

Patients with congenital long QT syndrome and documented torsade de pointes reported in the literature

Figure 1

Spontaneous torsade de pointes in a 25 year old female with congenital LQTS reported by Benhorin and Medina.46This Holter recording shows the sequence of events that is typical of pause dependent torsade de pointes. Sinus tachycardia is followed by a sudden decrement in sinus rate (A) with concomitant augmentation of the U wave amplitude (arrow). Eventually, an extrasystole (arrowhead) is followed by a long post-extrasystolic pause. The sinus complex that follows the pause shows further U wave augmentation and is followed by more extrasystoles (arrowhead), which in turn, trigger a new pause. This creates a series of short (s) and long (l) cycles that culminate in torsade de pointes. Reproduced with permission from the authors and the Massachusetts Medical Society (copyright© 1997 Massachusetts Medical Society).

Figure 2

The top trace shows what is probably the most famous example of non-pause dependent torsade de pointes. It was originally published by Malfatto and colleagues36 and is commonly cited as a typical example of adrenergic dependent torsade de pointes.45 The preceding sinus rate is 90 beats per minute and there is no pause before the onset of the arrhythmia. This 11 year old female patient also had documented pause dependent torsade de pointes (middle and bottom panels): Sudden sinus pauses (*) are followed by sinus complexes with tall bizarre TU waves (arrows) from which short bursts of torsade de pointes originate. Reproduced with permission from the authors and Futura Publishing Company Inc, publisher of the Journal of Cardiovascular Electrophysiology.

The R-R cycles that preceded the onset of pause dependent arrhythmias are shown in fig 3. The ratio between the short cycle and the long cycle immediately leading to torsade was large enough to make the diagnosis of “pause dependent” arrhythmias evident (figs 1, 2, and 3). Although a 40 ms increment in cycle length was used as a definition of “pause” (see Methods), in fact 85% and 82% of the “pauses” preceding torsade were longer than the basic cycle length by > 60 ms or by > 100 ms, respectively. Moreover, a “short-long-short” sequence (an extrasystole, followed by a post-extrasystolic pause) immediately preceded the onset of torsade de pointes in most arrhythmic events (see below). In such cases, the post-extrasystolic “long cycle” leading to torsade was longer than the previous “short cycle” (created by the extrasystole) by more than 200 ms in 84% of events. Finally, electrocardiographic features supporting the causative role of pauses—like observation of “post-pause U wave augmentation”,6 reproducible arrhythmia initiation after pauses, or an escalating sequence of events (in which longer pauses are followed by faster bursts of ventricular tachycardia)65—were common among our patients2 and were seen in the majority of illustrations reported by others.3 6 15 17 18 22 25 28 30 32 33 35-37 44 46 62 63The pauses eventually leading to torsade de pointes were mainly “compensatory pauses” following extrasystoles. These post-extrasystolic pauses were observed in 28 patients reported by others3 6 7 13 15 18 19 21-23 25 26 28 30-33 35 37 42-46 48-50 62and in all but two of the patients reported by us.2 In all, post-extrasystolic pauses, sudden sinus pauses, or both, preceded the onset of torsade de pointes in 73%, 14%, and 15% of all patients with pause dependent arrhythmias, respectively.

Figure 3

R-R intervals preceding the onset of arrhythmias in patients with pause dependent torsade de pointes. BCL, basic cycle length; short and long, short cycle and long cycle immediately preceding the onset of torsade.

COMPARISON OF PATIENTS WITH PAUSE DEPENDENT VERSUS NON-PAUSE DEPENDENT ARRHYTHMIAS

Age and sex correlated with the mode of onset of torsade de pointes (table 2). Arrhythmias in newborns and infants (⩽ 3 years old) were predominantly not pause dependent (fig 4), whereas female sex correlated with pause dependent arrhythmias. Using multivariate analysis, age was the only independent predictor of the mode of onset of torsade de pointes.

Table 2

Mode of onset of torsade de pointes in patients with congenital long QT syndrome and documented arrhythmias2-151

Figure 4

(A) Non-pause dependent torsade de pointes in a neonate.47 There is sinus tachycardia with marked T wave alternans. Although there appears to be some R-R alternans (the R-R intervals are shown in milliseconds), the interval immediately preceding the sinus complex from which torsade originates, which would be expected to be the longest interval if this was a pause dependent arrhythmia (*), is actually short (420 ms). Reproduced with permission from the authors and Futura Publishing Company Inc, publisher of the Journal of Cardiovascular Electrophysiology. (B) One of the first cases of congenital long QT syndrome and deafness described.16The QT interval is giant and bizarre. Torsade de pointes is not preceded by a pause. Reproduced with permission from Mosby Inc, publisher of Advances in Internal Medicine.

It is difficult to assess the importance of “stress” as a precipitating factor of arrhythmias not preceded by pauses, because the majority of such arrhythmias were recorded in hospitalised newborns. Nevertheless, 76% of patients with documented pause dependent torsade de pointes had a history of syncope or cardiac arrest preceded by physical or emotional stress.

Discussion

This review supports our observations regarding the mode of onset of torsade de pointes in the congenital long QT syndrome.2 Although the predominance of pause dependent arrhythmias was not as pronounced as originally reported in our series,2 the majority of spontaneous arrhythmias documented in the literature were also pause dependent (table 1, figs1, 2, and 3). Most patients with congenital long QT syndrome and pause dependent arrhythmias had a history of stress related arrhythmias (table 2). This implies that the terms “adrenergic dependent” and “pause dependent” torsade de pointes, which are too often equated with the congenital and the acquired long QT syndrome, respectively, are not mutually exclusive.

PAUSE DEPENDENT TORSADE DE POINTES

The fact that arrhythmias were preceded by pauses does not prove cause and effect. It could be argued that torsade de pointes should be labelled “pause related” rather than “pause dependent”. However, the marked QTU changes, that become apparent immediately after pauses, appear to represent enhanced early after depolarisations (or increased dispersion of repolarisation) following sudden increments in cycle length.5 6 37 66 67Furthermore, the escalating sequence of events, in which longer pauses are followed by faster runs of torsade de pointes,65supports the notion that pauses indeed favour the onset of torsade de pointes. In contrast, idiopathic polymorphic ventricular tachyarrhythmias in patients without a long QT syndrome are generally not preceded by pauses.1 68

The univariate association between female sex and pause dependent torsade de pointes is of interest because acquired forms of the long QT syndrome, which are essentially always pause dependent, are also more common in women.69 70 However, this association was not confirmed by multivariate analysis in our series.

NON-PAUSE DEPENDENT TORSADE DE POINTES

Torsade de pointes that was not pause dependent was seen predominantly in infants (table 2). Typically, infants would develop torsade following periods of sinus tachycardia (mean (SD) heart rate 107 (21) bpm) with marked T wave alternans or ventricular bigeminy. In the last case, the coupling interval of the extrasystole and the post-extrasystolic interval were of similar duration. Thus, the “short-long” sequence of pause dependent arrhythmias was not identifiable. This could be related to our methodology in several ways. First, our definition of “pause” could have been too strict. However, most investigators will argue that our 40 ms cut off value was “too lenient” rather than “too strict”. Second, the huge and bizarre TU waves, commonly seen in symptomatic infants, probably made defining the onset of extrasystoles less accurate (fig 4). This could result in imprecise estimation of the intervals preceding the arrhythmias. Alternatively, the absence of pause dependent arrhythmias in infants could reflect a more severe disease. Onset of symptomatic arrhythmias at infancy denotes a rather malignant course.9 47 71 Sudden decrements in cycle length—“pauses”—merely facilitate the onset of torsade via two mechanisms: (1) cycle length dependent augmentation of ensuing early afterdepolarisations (which triggers more extrasystoles); and (2) differential prolongation of repolarisation (with greater prolongation in mid/endocardial zones), which worsens the dispersion of repolarisation and facilitates re-entry.5 66 72 Indeed, it is possible that patients with more severe forms of the disease (like infants), can develop torsade even without the aid of pauses. In this regard, it is interesting that deafness (indicating homozygote inheritance of a long QT syndrome73 and a more severe disease), also seemed to be more common among patients with torsade not preceded by pauses (21% v 7%). The last difference, however,did not reach significance, probably because of the small number of patients with deafness.

LIMITATIONS

A computerised literature search cannot be customised to find arrhythmia illustrations. This was an “old fashioned” non-automatic search and we probably overlooked more than one report. Also, genotype analysis of the patients with documented arrhythmias is lacking. Since the response of the QT interval to changes in heart rate varies considerably among genotypes,74 it is likely that sudden pauses are not equally arrhythmogenic for all genotypes. Finally, case reports tend to include illustrations of arrhythmias more often than large series. Thus, serial studies were under represented in our review. However, since the prevailing view in the literature has been that torsade de pointes in the congenital long QT syndrome is generally not pause dependent,5-8 there is no reason to believe that the authors of the articles reviewed opted for presenting only illustrations of arrhythmias preceded by pauses. Nevertheless, these limitations could have biased our results.

CLINICAL IMPLICATIONS

Some data suggest that cardiac pacing reduces the arrhythmic risk in the long QT syndrome.11 12 75 However, arrhythmias may recur despite treatment with β blockers and pacing. Unfortunately, these rare recurrences may be lethal.75 76Our data suggest that sudden pauses, especially post-extrasystolic pauses, play a major role in the genesis of torsade de pointes. Post-extrasystolic pauses are not entirely prevented by cardiac pacing. Whenever an extrasystole occurs, the premature event is sensed by the pacemaker, resetting the escape interval. Although this represents normal pacemaker behaviour, it perpetuates the “short-long” sequence that we ought to interrupt. This is because the coupling interval of the extrasystole (a short cycle) is immediately followed by the escape interval, which is a relatively long cycle determined by the programmed lower rate limit. In contrast, post-extrasystolic pauses may be significantly shortened with specific pause-prevention pacing algorithms. Our clinical experience with the use of one such algorithm for preventing torsade de pointes has been rewarding, but is very limited.3 4 The results of the present study support the rationale for further careful evaluation of pause-prevention pacing algorithms to prevent torsade de pointes.

References

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