Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome

Takashi Noda, Wataru Shimizu*,1, Kazuhiro Satomi, Kazuhiro Suyama, Takashi Kurita, Naohiko Aihara and Shiro Kamakura

Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita 565-8565, Japan

Received March 30, 2004; revised August 3, 2004; accepted August 26, 2004 * Corresponding author. Tel.: 81 6 6833 5012; fax: 81 6 6872 7486 (E-mail: wshimizu{at}hsp.ncvc.go.jp).


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 References
 
AIMS: To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS).

METHODS AND RESULTS: We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C2, C1, and C0, the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short–long cardiac cycles followed by an initiating short-coupled PVC (C1>C2 and C0), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C2≥C1≥C0), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C0 was shorter in ISR than SLS and CD (mean C0: 488 vs. 587 and 603 ms, respectively; P<0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P<0.05).

CONCLUSIONS: Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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 References
 
Torsade de Pointes (TdP) is a distinct polymorphic ventricular tachycardia appearing as a twist around the isoelectric line.1 TdP occurs under various pathophysiological states including either acquired or congenital, long QT syndrome (LQTS), which sometimes degenerates into ventricular fibrillation and results in sudden cardiac death.2–6

Previous experimental observations suggest several hypotheses about the mechanism responsible for TdP. TdP is proposed to arise from premature ventricular contraction (PVC) due to triggered activity, especially early after depolarization (EAD) and to be perpetuated by a re-entrant mechanism as a result of the increased dispersion of repolarization.7,8

In the clinic, some reports have described a typical mode of onset of TdP in patients with acquired LQTS as a "short-long-short sequence" (SLS), a so-called "pause dependent" phenomenon, which shows RR interval oscillations. With regard to the initiating mode of TdP in patients with congenital LQTS, Viskin et al.,9 suggested that SLS plays a major role in the genesis of TdP. However, data from the Registry of LQTS shows that SLS occurs as the mode of onset in half of all patients with congenital LQTS.10

The present study was designed to classify the initiating mode of TdP, the timing of the initiating PVC, and the cycle length (CL) of TdP in patients with congenital LQTS at a single centre.


    Methods
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 Abstract
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 Methods
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 Discussion
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 References
 
Patient characteristics
We reviewed the medical records of consecutive 24 patients affected with congenital LQTS in whom one or more episodes of TdP were recorded at the National Cardiovascular Center, Suita, Japan. They were composed of 4 males and 20 females ranging in age from 1 to 60 years (mean of 28±17 years). All patients had a history of syncope and were diagnosed with congenital LQTS based on the diagnostic criteria of Schwartz et al (score ≥4).11

Definition of arrhythmia and analysis parameters
TdP was defined as a polymorphic ventricular tachycardia consisting of more than five consecutive beats during which the peaks of QRS complexes twisted above and below the isoelectric line.4,9 Measurements were taken from Holter electrocardiograms, or monitoring electrocardiograms which detected the onset of TdP. We defined the three consecutive preceding RR intervals before the onset of TdP as C2, C1, and C0; C2=the second preceding RR interval before onset, C1=the first preceding RR interval before onset, C0=the coupling interval of the initiating PVC. The CL of TdP was calculated by averaging 10 beats of TdP. When the TdP did not last more than 10 beats, all of the beats were averaged. The QT intervals were measured by the tangential method, and bifurcated T-waves and pathological U waves were included as part of the measurements of QT intervals. If the initiating PVC appeared before the peak of the T-wave so that we could not measure the QT intervals, the previous QT intervals were referred to. The values of the absolute QT intervals (QTe) and the preceding RR intervals that could be precisely measured were used for the analysis. The Q–T peak interval (QTp) was defined as the interval between the QRS onset and the peak of the T-wave at the last beat before the onset of TdP. The corrected QT interval (QTc) was defined as the QT interval divided by the square root of the preceding RR intervals.

We evaluated the initiating mode of TdP on the basis of the relationship between the preceding RR intervals (C2, C1, and C0), the timing of initiating PVC, and the CL of TdP.

Classification of the initiation mode of TdP
The initiating mode of TdP was classified into three different patterns: an SLS pattern, an "increased sinus rate" (ISR) pattern and a "changed depolarization" (CD) pattern. The SLS pattern was defined as one or more short–long cardiac cycles followed by an initiating short-coupled PVC, and the relationship between the three consecutive preceding RR intervals was C1>C2 and C0. Fig. 1(a) shows that a PVC led to a post-extrasystolic pause (C1=920 ms), which changed the QTU of the following beat and culminated in TdP. The preceding RR intervals of TdP fulfilled the criteria of C1 (920 ms)>C2 (540 ms) and C0 (580 ms). The ISR pattern was defined as a gradual increase in the sinus rate with or without T-wave alternans, and the relationship between the preceding RR intervals was C2≥C1≥C0. Fig. 2(a) illustrates a gradual increase in the sinus rate with T-wave alternans resulting in TdP. The preceding RR intervals of TdP fulfilled the criteria for C2 (520 ms)≥C1 (520 ms)≥C0 (360 ms). The CD pattern was defined as a sudden long-coupled PVC or fusion beat followed by a short-coupled PVC, and the relationship between the preceding RR intervals was C1≥C2>C0. This pattern was different from the SLS pattern, in that the last beat before the onset of TdP was PVC or a fusion beat, and resulted in a change of repolarization (QT interval) of the last beat.12 Fig. 3(a) represents a sudden long-coupled PVC as the last preceding beat of TdP, resulting in marked QT prolongation and subsequent TdP. The preceding RR intervals of TdP fulfilled the criteria for C1 (820 ms)≥C2 (760 ms)>C0 (560 ms).



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Fig. 1 The "short-long-short sequence" (SLS) pattern as an initiating mode of Torsade de Pointes (TdP). (a) The monitoring electrocardiogram shows that TdP is induced by the short-long cardiac cycles followed by an initiating short-coupled premature ventricular contraction (PVC). The relationship between the 3 consecutive preceding RR intervals fulfills the criteria for C1 (920 ms)>C2 (540 ms) and C0 (580 ms). (b) The initiating PVC appears after the T-wave peak of the last beat before the onset of TdP.

 


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Fig. 2 The "Increased sinus rate" (ISR) pattern as an initiating mode of Torsade de Pointes (TdP). (a) The monitoring electrocardiogram indicates that TdP is induced by a gradual increase in the sinus rate with T-wave alternans, and that the relationship between the preceding RR intervals fulfills the criteria for C2 (520 ms)≥C1 (520 ms)≥C0 (360 ms). (b) The initiating premature ventricular contraction occurs before the T-wave peak of the last beat before the onset of TdP.

 


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Fig. 3 The "changed depolarization" (CD) pattern as an initiating mode of Torsade de Pointes (TdP). (a) The monitoring electrocardiogram shows that TdP is induced by a sudden long-coupled premature ventricular contraction (PVC) followed by a short-coupled PVC. The relationship between the 3 consecutive preceding RR intervals fulfills the criteria for C1 (820 ms)≥C2 (760 ms)>C0 (560 ms). (b) The initiating PVC appears after the T-wave peak of the last beat before the onset of TdP.

 
Statistical analysis
We took possible correlations between a patient's different episodes into account. Therefore, when a patient had more than two episodes with the same initiation mode, we adopted mean values of the parameters in all episodes of each mode as a representation of each patient, and performed statistical analyses using these values. Continuous variables were expressed as the group mean value±SD. We used two-sided tests and compared using one-way ANOVA followed by Scheffe's test. A value of p<0.05 was regarded as being significant.


    Results
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 Abstract
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Clinical characteristics
Table 1 shows the clinical characteristics of the 24 patients with congenital LQTS. Molecular screening showed that three patients were affected with the LQT1 syndrome, and 10 patients with the LQT2 syndrome. Seven patients had a familial history of sudden death. The episodes of TdP occurred while on β-blockers in 11 patients, while 13 patients had TdP episodes while off β-blockers. Eight patients had a serum potassium concentration of less than 3.5 mEq/litre during the TdP episodes.


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Table 1. Clinical characteristics of 24 patients with congenital long QT syndrome
 
Initiating mode of TdP
A total of 111 episodes of TdP were observed with a median of three episodes. Seventy-two TdP events (65%) in 23 patients showed an SLS pattern as the initiating mode, 28 TdP events (25%) in nine patients exhibited an ISR pattern, and 11 TdP events (10%) in five patients exhibited a CD pattern. All three initiating mode patterns were observed in three patients, and two patterns were observed in seven patients. The initiating modes of TdP were not correlated with age, gender, genotype, or the level of serum potassium. However, the CD pattern was only observed in five patients while on β-blockers.

Table 2 represents comparisons of the ECG parameter between the three initiating patterns. There were no significant differences in the QTp, QTe, and QTc between the three initiating patterns.


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Table 2. Comparisons of ECG parameters between three initiating patterns
 
Timing of initiating PVC
The coupling intervals of the initiating PVC (C0) were significantly shorter in the ISR pattern than in the SLS and CD patterns (488±72 ms vs. 587±65 ms and 603±24 ms; p=0.010 and 0.035, respectively). The C1 was significantly longer in the SLS pattern than in the ISR pattern (1038±188 ms vs. 634±146 ms, p=0.001), while the C2 was significantly shorter in the SLS pattern than in the ISR pattern (582±65 ms vs. 732±176 ms, p=0.016). The initiating PVC appeared before or near the T-wave peak of the last beat before the onset of the ISR pattern (Fig. 2(b)), while it occurred after the T-wave peak for the SLS pattern (Fig. 1(b)) and CD pattern (Fig. 3(b)). Fig. 4(a) illustrates a comparison of the values of C0-QTp between the three patterns. The C0-QTp was significantly smaller in the ISR pattern than in the SLS pattern (9±38 ms vs. 60±34 ms; p=0.040). It was also smaller in the ISR pattern compared with the CD pattern, but this difference was not significant (9±38 ms vs. 53±8 ms; p=0.219).



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Fig. 4 Comparison of the values of the subtraction of Q-T peak intervals (QTp) from C0 at the last beat before the onset of Torsade de pointes (TdP) (a) and the cycle length (CL) of TdP (b) between the "short-long-short sequence" (SLS), "increased sinus rate" (ISR), and "changed depolarization" (CD) patterns. The C0-QTp values were significantly smaller in the ISR pattern than in the SLS pattern. The CL of TdP was also significantly shorter in the ISR pattern than in the SLS pattern.

 
CL of TdP
Fig. 4(b) shows a comparison of the CL of TdP between the three patterns. The CL was significantly shorter in the ISR pattern compared with the SLS pattern (256±25 ms vs. 295±36 ms; p=0.042). It was also shorter in the ISR pattern compared with the CD pattern, but this difference was not significant (256±25 ms vs. 279±10 ms; p=0.547). The CL of TdP was not correlated with age, gender, or genotype.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 References
 
Classification of the initiating mode of TdP
TdP is a distinct polymorphic ventricular tachycardia with a twisting QRS morphology most often associated with QT prolongation in congenital and acquired forms of LQTS. The initiating mode of TdP in the congenital form of LQTS is still unclear. While the SLS pattern was reported to be predominant in congenital LQTS,9 an investigation of the LQTS Registry showed that this pattern appeared as the mode of TdP onset in 20 out of 44 patients with congenital LQTS (45%).10 The present study of a single centre showed that the SLS pattern appeared in 72 (65%) out of 111 TdP episodes, the ISR pattern in 28 (25%), and the CD pattern in 11 (10%), which is in agreement with the latter report. Viskin et al., recently suggested the difference in the clinical characteristics between "pause dependent" and "non-pause dependent" TdP. "Pause dependent" TdP was associated with females, and "non-pause dependent" TdP, especially after sinus tachycardia, with T wave alternans and was seen predominantly in infants.13 In our study, the initiating mode of TdP and the CL of TdP were not correlated with age, gender, or genotype. In fact, three patients (pts No. 1, No. 4, and No. 21) affected with LQT2 had all three patterns of TdP. However, the present study examined a small number of patients, especially a small number of infants or genotyped patients. Furthermore, the deviation of gender could have biased our results. Therefore, larger study populations are needed to make a definitive conclusion about the relation between the initiating mode of TdP and age, gender, or genotype.

We classified the initiating mode of the TdP into three patterns based on the relationships with the preceding RR intervals and the supposed mechanisms of TdP. The CD pattern seems another variation of the SLS pattern from a point of preceding RR patterns. However, the TdP in the CD pattern was always preceded by long-coupled PVC or fusion beats and was only observed in five patients on β-blockers. We speculate that beta-blocker-induced sinus bradycardia may produce long-coupled PVC or fusion beats, leading to TdP in the CD pattern, and this mechanism may be different from that in the SLS pattern.

Possible mechanisms of TdP in the three initiating patterns
Previous experimental observations suggested that the initiating PVC of TdP is due to triggered activity arising from phase 2 or phase 3 EADs.14–18 Clinical observations using monophasic action potential recordings indicated phase 3 EADs during the SLS sequence as a mechanism responsible for initiating PVC of TdP.19–22 Burashnikov et al., suggested that phase 2 EADs were predominantly induced during a transient acceleration of the pacing rate, but that phase 3 EADs developed as the rate of stimulation was slowed.23 The present study showed that the coupling interval of initiating PVC of TdP was significantly shorter in the ISR pattern than in the SLS pattern. Therefore, it is reasonable that the initiating PVC of TdP is related to phase 2 EADs in the ISR pattern and phase 3 EADs in the SLS pattern. On the other hand, experimental studies employing whole heart24–26 and arterially perfused wedge preparations27–29 presented evidence in support of the hypothesis that TdP is maintained by a re-entrant mechanism. El-Sherif and co-workers used tridimensional analysis of the kinetics of cardiac repolarization and showed that an increased transmural dispersion of repolarization (TDR), due to a more prominent prolongation of local repolarization in M regions than in epicardial or endocardial regions, resulted in functional block and slow conduction. This leads to re-entry in the "SLS" initiating pattern of TdP. 24,25 Shimizu et al., used LQTS models employing wedges and also showed that the increase in TDR was mainly due to the prolongation of action potential duration (APD) of M cells in the initiation of TdP associated with the "SLS" pattern.27,28 They also found that the large fluctuations of TDR were mainly due to the oscillation of APD in the M regions during T-wave alternans, which were induced by an abrupt acceleration in rate similar to the "ISR" pattern, and were associated with the induction of TdP.29 Based on these observations, we believe that TdP is at least maintained by a re-entrant mechanism resulting from increased TDR of the two initiating modes of the SLS and ISR patterns. On the other hand, these experimental studies using whole heart26 and perfused wedge preparations29 also showed that the initiating PVC due to triggered activity is not always required for the initiation of TdP. In other words, TdP may occur as a result of large fluctuations in the transmural and spatial dispersion of repolarization of the preceding beat, leading to local functional block and circulating wave fronts inducing the first re-entrant excitation at the fast pacing rate similar to the "ISR" initiation pattern.

Costard–Jackle et al., reported that the short-term change in ventricular activation did not allow for the accurate adaptation of ventricular APD. It produced a dispersion of repolarization, leading to TdP.30 Kurita et al.,12 also reported that a sudden change in the depolarization pattern was related to marked QT prolongation and the induction of TdP in a patient with a pacemaker implantation. These observations could explain a possible mechanism of TdP seen in the CD pattern. The change in the depolarization pattern of the last beat before the onset of TdP (i.e., PVC or fusion beat) resulted in the increased dispersion of repolarization, thus possibly leading to TdP due to a re-entrant mechanism.


    Limitations
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 Abstract
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 Methods
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 Limitations
 References
 
Our study included two 60-year-old patients, in whom their arrhythmias might be polymorphic ventricular arrhythmias rather than TdP. However, we believe that the episodes of our patients were due to TdP because these two patients had QT prolongation and prior episodes of syncope suggesting TdP in their young age. In addition, all patients showed no structural heart disease in their echocardiogram and no ischaemic ST changes during exercise testing.

We adopted mean values of the parameters in all episodes of each mode as a representation of each patient. When a patient has episodes in different initiation modes, the underlying assumption of independence is violated. However, it is clinically important to report the fact that the different initiating patterns exist in the same patient. Therefore, we performed the statistical analyses using these values.


    Footnotes
 
1 Dr. Shimizu was supported in part by the Vehicle Racing Commemorative Foundation, Kanahara Ichiro Memorial Foundation, Mochida Memorial Foundation, and Health Sciences Research Grants from the Ministry of Health, Labor, and Welfare, and Research Grants for Cardiovascular Diseases (15C-6) from the Ministry of Health, Labor and Welfare, Japan. Back


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 References
 

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