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J Am Coll Cardiol, 2000; 36:167-173
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES: ELECTROPHYSIOLOGY

Electrical behavior of T-Wave polarity alternans in patients with congenital long QT syndrome

Fernando E. S. Cruz Filho, MD, FACCa, Ivan G. Maia, MD, FACCa, M.árcio L. A. Fagundes, MDa, Rosa Celia P. Barbosa, MDa, Paulo A. G. Alves, MDa, Roberto M. S. Sá, MDa, Silvia H. Boghossian, MDa and Jose Carlos Ribeiro, MDa

a Hospital Pró-Cardíaco, Rio de Janeiro, Brazil

Manuscript received December 7, 1998; revised manuscript received January 17, 2000, accepted March 6, 2000.

Reprint requests and correspondence: Dr. Fernando E. S. Cruz Fo, Avenue Canal de Marapendi 2500, Bloco 1, Apartment 503, Barra da Tijuca, Rio de Janeiro, CEP: 22.631-050 Brazil
fcruz{at}ax.apc.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study was designed to evaluate the incidence and characteristics of onset of T-wave polarity alternans (TWPA) in patients with long QT syndrome.

BACKGROUND

The T-wave alternans is a phenomenon that consists of beat-to-beat variability in the amplitude, morphology, and sometimes polarity of the T-wave, and it may trigger life-threatening arrhythmias.

METHODS

The 24-h Holter recordings of 11 patients with congenital long QT syndrome were studied. Episodes of TWPA with 10 or more consecutive cycles were selected and analyzed as follows: 1) mean cycle length (MCL) and QTc interval duration (QTcI) of the episodes of TWPA and the 10 cycles preceding and succeeding the TWPA; 2) MCL and QTcI of the third, second, and first minute before onset (Mn–3, Mn–2, Mn–1); 3) MCL and QTcI from the tenth to the first cycle immediately preceding the onset of TWPA (R–10 to R–1); 4) MCL and QTcI from the first to the fourteenth cycle during alternans (R0 to R14); 5) MCL and QTcI from the first to the tenth cycle immediately succeeding TWPA (R+1 to R+10); 6) linear correlation (Lnc) between QT interval and cycle length (CL) (LncQT/CL) during alternans and for the 10 preceding cycles; 7) Lnc between the first three alternans cycles and episode duration (Lnc 3CL/EpD); and 8) difference between the longest and shortest QTc interval. We also selected episodes consisting of four or more consecutive cycles in order to analyze daily rhythms of the phenomenon.

RESULTS

The TWPA was observed in 5 (45%) out of the 11 patients studied. The alternans process is initiated by a sudden shortening of the first alternans cycle without previous heart rate changes and ends at the moment when prolongation of the cycle tends to occur. LncQT/CL–alternans: r = 0.38 ± 0.2 (p = 0.20); without alternans: r = 0.81 ± 0.06 (p = 0.01). Lnc 3CL/EpD: r = 0.002 (p = 0.992). The QTc difference during alternans: 312.0 ± 52.1 ms; without alternans: 86.0 ± 36.4 ms (p = 0.001). Daily rhythm: 71% of the episodes occurred between 8 AM and 8 PM, with higher incidence during the morning.

CONCLUSIONS

The TWPA was dependent on the cardiac CL; there was loss of the LncQT/CL and an increase in the QT interval variability. Like other biological variables, T-wave polarity alternans has a higher density during the morning.

Abbreviations and Acronyms
  CL = cycle length
  CLQTS = congenital long QT syndrome
  ECG = electrocardiogram
  EpD = episode duration
  Lnc = linear correlation
  MCL = mean cycle length
  QTcI = QTc interval duration
  QTcVr = QTc interval variability
  TWA = T-wave alternans
  TWPA = T-wave polarity alternans

Episodes of T-wave alternans (TWA) are characterized by a cyclic beat-to-beat variation in the amplitude, morphology, or polarity of the T-wave. This phenomenon has been recorded in association with many diseases, and it should be considered as an integral component of the congenital long QT syndrome (1,2) (CLQTS). Several clinical and experimental reports associate TWA with the development of life-threatening ventricular arrhythmias (3,4). Presently, TWA can be quantified by spectral analytical techniques, even low-amplitude invisible alternans (5–8).

In previous studies, 12-lead ECG was used to analyze TWA. This method, however, is limited because of the highly transient and episodic nature of the phenomenon. Assessment by 24-h Holter monitoring would provide more adequate analysis of the electrical characteristics of this peculiar phenomenon.

Therefore, the purpose of the present study was to evaluate by 24-h Holter recording the prevalence and electrical behavior of the TWA in patients with CLQTS. Despite the relevance of the voltage episodes of TWA, we aimed to analyze only T-wave polarity alternans (TWPA) episodes because their incidence could be reliably assessed by visual examination.


   Methods
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 Methods
Results
 Discussion
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Study group.   The study group consisted of 11 patients with clinical and electrocardiogram (ECG) criteria for the diagnosis of CLQTS (9). All patients enrolled in this investigation had a documented QTc (corrected QT interval) interval >480 ms in a 12-lead ECG. A typical clinical history consisting of episodes of sudden loss of consciousness (syncope) under emotional or physical stress was present in five patients. Neurological sequelae developed in two patients after recovery from a cardiac arrest (one occurred outside the hospital, Case 7, and the other after urologic surgery (Case 1). In the asymptomatic patients, the diagnosis of CLQTS was made based not only on a QTc >480 ms but also on the presence of T-wave morphological alterations (bifid or notched), which were particularly evident in the precordial leads (V2 through V4). Because of the presence of auscultatory alteration (murmurs or irregularities in cardiac rhythm), a clinical consultation with the pediatric cardiologist was required, and ECG was performed. Four patients underwent more than one 24-h Holter recording for therapeutic control (Cases 1, 3, 5, and 7). The first recording was used for analysis. Five patients were using propranolol (1.5 mg/kg), one was using captopril, and five patients were without medication at the time of the Holter recording. Clinical characteristics of the patients are presented in Table 1.


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  		Table 1 Clinical Characteristics of the Patients

 
Holter data acquisition and analysis.   Holter recordings were performed on simultaneous two- or three-channel tape recorders with a frequency of response between 0.05 and 100 Hz (AT –3DB), using V2 and V5 or V2 and V5 and modified aVF as monitoring leads. None of the recordings were performed during or soon after hospital admission. The recordings were analyzed in a computer-based operator-interactive system (DMI, Diagnostic Medical Instruments). The signal was digitized at a sampling frequency of 200 Hz and visually analyzed. In a first evaluation we selected all episodes of TWPA with 10 or more successive alternans cycles. The following parameters were assessed: 1) mean cardiac cycle length (MCL) and QTc interval duration (QTcI) of the episodes and the 10 cycles immediately preceding and succeeding (ms) TWPA; 2) MCL and QTcI of the third, second, and first minute before onset (Mn–3, Mn–2, Mn–1); 3) MCL and QT interval from the tenth to the first cycle immediately preceding the TWPA episodes (R–10 to R–1); 4) MCL and QT interval from the first to the fifteenth cycle during alternans (R0 to R14): R0 and R14 represented the first and the last alternans cycles, respectively; 5) MCL and QT interval from the first to the tenth cycle immediately succeeding TWPA (R+1 to R+10); 6) linear correlation between QT interval and cycle length (CL) and between the mean of the first three alternans cycles and duration of the episodes; and 7) difference between the longest and the shortest QTc interval (Bazett’s formula) of the episodes and of the 10 cycles immediately preceding TWPA (QTc variability = QTcVr – ms).

In a second evaluation, we quantified all TWPA episodes with four or more successives alternans cycles to evaluate daily rhythm. We assessed the density of the episodes during daytime/nighttime (8 AM to 8 PM and 8 PM to 8 AM, respectively), every 4 h, and hourly (starting at 8 AM). We also assessed the linear correlation (Lnc) between the TWPA distribution and the MCL.

Statistical analysis.   All results were expressed as mean values ± SD. Differences between groups were assessed by an analysis of variance (ANOVA). Statistical significance was assumed for p values <0.05. Correlation and linear regression analyses were used to determine the association between QT interval and CL during alternans episodes and the 10 preceding cycles, also between the daily rhythm and CL, and between the first three cycles of TWPA and the duration of the episodes.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
We observed T-wave polarity alternans in 5 (45%) out of 11 patients with a total of 121 episodes ≥10 successive cycles. Three of these five patients (Cases 1, 3, and 7) repeated the 24-h Holter, and reproducible recordings of TWPA in different months were registered. In addition, no difference in daily distribution nor significant incidence of alternans was documented. The phenomenon was best seen in lead V2.

Holter data.   A typical episode of TWA is presented in Figure 1. Figure 2 shows the CL and QTc (presented as mean and SD) of the 3-, 2- and 1-min before, as well as the 10 cycles preceding, the alternans cycles, followed by 14 cycles of alternans and the first 10 cycles after alternans. From Figure 2 it becomes very obvious that the CL remains fairly constant during the 3 min preceding the alternans and that a very sharp transient shortening of CL is associated with T-wave alternans. Figure 3 depicts the expression of cycles R–10 to R–1, R0 to R14, and R+1 to R+10. LncQT/CL–alternans: r = 0.38 ± 0.2 (p = 0.20); without alternans: r = 0.81 ± 0.06 (p = 0.01). Lnc 3CL/EpD (episode duration) – r = 0.002 (p = 0.992). QTcVr alternans: 312.0 ± 52.1 ms; without alternans: 86.0 ± 36.4 ms (p = 0.001). During the alternans episodes, the QT interval also showed alternans with short and long values (Fig. 1).



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  		Figure 1 A typical episode of T-wave alternans (Case 1). (A) R(–) refers to the 10 cycles immediately preceding the alternans episode (from R–10 to R–1). R refers to the alternans cycles (R0, onset, and R14, the last measured alternans cycle). R(+) refers to the 10 cycles immediately succeeding alternans episode (R+1, the first, and R+10 the last cycle measured). (B) Graph showing the sequence of these cardiac cycles. Note that the alternans cycles (from R0 to R14) are expressively shorter than the preceding and succeeding cycles. At the bottom (asterisk), a nice demonstration is shown of concomitant great variability of QT intervals, while TWPA is depicted. The transition of the last cycle of alternans and the first cycle after alternans is not continuous.

 


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  		Figure 2 Mean CL and QT intervals before, during, and after alternans. It becomes obvious from the graph that the CL remains fairly constant during the 3 min preceding the alternans and that a very sharp transient shortening of CL is associated with T-wave alternans.

 


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  		Figure 3 Graphic depiction of the mean values of R-R cycles and QT intervals from R–10 to R–1, from R0 to R14, and from R+1 to R+10. The discontinued line between R14 and R+1 refers to the transition of the last cycle of alternans and the first cycle after alternans. These cycles are not always necessarily continuous.

 
Daily rhythm distribution.   The distribution of the TWPA episodes per patient was not proportional (Table 1). Three hundred twenty episodes of TWPA with ≥4 successive cycles were observed. The mean duration of the episodes was 19.3 ± 15.9 s (range: 2.8 to 52.4 s). The episodes of T-wave alternans were not uniformly distributed along the 24-h period: 141 episodes (44%) occurred from 8 AM to noon, 59 episodes (19%) from noon to 4 PM, 28 episodes (9%) from 4 PM to 8 PM, 11 episodes (3%) from 8 PM to midnight, 30 episodes (9%) from midnight to 4 AM, and 51 episodes (16%) from 4 AM to 8 AM (Fig. 4). Linear correlation between hourly distribution and CL: r = 0.309 (p = 0.327).



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  		Figure 4 Graph of hourly distribution of TWPA in a 24-h period. Note that the incidence of such episodes is higher during the daytime period (from 8 AM to 8 PM), with an impressive distribution during the morning (8 AM to noon).

 

   Discussion
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 Methods
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References
 
Prevalence of TWPA.   The prevalence of TWPA in the CLQTS is unknown, although Schwartz et al. (1) suggested the phenomenon is frequently observed. Information on frequencies of TWA in a CLQTS population obtained by analysis of a 12-lead ECG (excluding those occurring after ventricular pacing or premature beats) was previously reported by Zareba et al. (10), who observed alternans in 29 of 1,171 patients (2.5%). However, due to the use of the relatively brief 12-lead ECG recording, quantification of this phenomenon is certainly underestimated with false- negative cases. Using 24-h Holter monitoring we observed that 45% of the studied population had at least six recordings of TWPA. One may argue that this is a small population and that some of these patients were using beta-blocker agents, but we strongly believe that this prevalence seems more reliable for at least one reason: ECG randomly performed is known to underestimate transient repolarization changes. Furthermore, if quantification of the magnitude of TWA voltage was made, prevalence of the phenomenon would probably increase. Recently, Platt et al. (11), using spectral analysis, were able to demonstrate during exercise concealed, visually undetectable forms of TWA in a patient with CLQTS. However, as one of our patients (Patient 5) had predominantly nocturnal symptoms, we cannot rule out the possibility that this patient may have had an event during or close to the Holter recording.

T-wave alternans and abrupt heart rate changes.   There is evidence that repolarization alternans is mostly associated with abrupt rate changes (12,13) and partially modulated by a transient sympathetic activity in the heart (1). As observed in our study, the alternans process is initiated by a sudden shortening of the first alternans cycle without previous heart rate changes and ends when prolongation of the cycle tends to occur (Fig. 1). Compared with the 10 cycles immediately preceding TWPA, the mean duration of episodes was significantly shorter (638.0 ± 73.3 ms vs. 969.3 ± 155.0 ms, p = 0.0001), with a 100% specificity. Significant variations in QT intervals with alternans were also documented (Fig. 1). Using a sophisticated analysis of the relationship between the durations of QT and TQ intervals in recordings of TWPA, researchers (14) suggested that the degrees of "prematurity" of the basic rhythm could produce alternans in the total duration of the action potential that is responsible for the ECG phenomenon of QTVr. Chinushi et al. (15), studying the arrhythmogenicity of TWPA in an experimental model of LQTS, observed differences in the kinetic restitution of the mesocardium in relation to the epicardium and endocardium due to differences in diastolic intervals. Indeed, these factors are at least partially responsible for triggering the TWA process. During alternans episodes there is a greater degree of spatial dispersion of repolarization, which might explain the high arrhythmogenicity of the phenomenon. Thus, TWPA with its arrhythmogenic potential is related to the distinct electrophysiological properties of the different myocardial segments, mesocardium versus epicardium.

Correlation between cardiac cycle and QT interval.   The relation between QT interval and CL can be properly assessed by Lnc (16). The impossibility to adapt QT intervals to different cardiac cycles may represent an independent factor in the development of ventricular arrhythmias (17). Although in CLQTS the progressive shortening of CL produces a correspondent decrease in the values of QT intervals (18), this pattern of response can be altered. This is in accordance with recent clinical data published by Blanche et al. (19), who documented that, during stable cardiac rhythms, the relation between QT interval and cardiac CL was similar in CLQTS and control patients. However, during daily activity variations, there was reduction in the slope of the curve in regard to CL variation. An inverse correlation was observed during nighttime. The same dynamic relationship was observed by other investigators (20).

Our findings demonstrated an important decrease in the correlation between QT interval and cardiac CL during the episodes of TWPA. When comparing the phenomenon with the preceding cardiac cycle, the Lnc showed a reduction in the r values and in the slope of the curve (r = 0.38 ± 0.2 vs. 0.81 ± 0.06; slope: 0.20 vs. 3.47, respectively, p = 0.0001). The clinical implication is significant because this indicates the presence of another factor altering ventricular vulnerability.

The duration of measured episodes of TWPA varied greatly, and there was no correlation between the latter and the value of the MCL of the initial cycles of the phenomenon. This correlation was wisely observed by Locati et al. (21) for the episodes of Torsade de Pointes. Our current understanding regarding the mechanism responsible for the duration of TWA episodes is incomplete, and deserves further investigation.

QTc variability.   In healthy individuals, a circadian variation of QTc intervals over a 24-h period is well demonstrated. These changes occur throughout the day and at night. However, the beat-to-beat QTc interval shows more fluctuations during the morning, specifically at arousal time. In contrast, during sleep, there is much less QTc variability when compared to the daytime period (22). These variabilities occur due to the fluctuation of the cardiac cycles and also to other direct effects upon ventricular repolarization, such as the modulation of the autonomic nervous system. Morganroth et al. (23), using three samples per hour in the 24-h recordings, reported mean fluctuations of 76.0 ± 19.0 ms during the 24 h. Molnar et al. (24) observed mean fluctuations of 95.0 ± 20.0 ms. In accordance with these studies, Singh et al. (22) found values in the same range (i.e., 79.0 ± 28.0 ms). Recently, our group (25) compared QTcVr between patients with CLQTS and a control group in a 24-h period. A significant difference was observed (168.3 ± 70.2 ms vs. 53.3 ± 1.5 ms, respectively, p = 0.001). Certainly, this greater variability represents one of the factors contributing to the existence of a higher degree of dispersion in repolarization found in patients with CLQTS, compared with a control group (26). Our results indicated an expressive increase in QTc variability during episodes of TWPA compared with the values observed in cardiac cycles preceding alternans episodes. The clinical relevance of these findings needs to be further clarified.

Daily rhythm of the TWA.   Nearly all measurable variables in living organisms undergo daily rhythms with maximal and minimal values over a 24-h period. As far as our knowledge is concerned, there are no studies until the present time evaluating the distribution of TWPA in a 24-h period. Like other disorders, such as acute myocardial infarction (27) and sudden cardiac death (28,29), the phenomenon described here occurred more often in some hours of the day, especially in the morning. This rhythmic behavior follows the autonomic nervous system pattern usually observed in human beings, with a predominant sympathetic activity during daytime, a vagal activity during sleep, and higher vulnerability to major cardiac events during the morning. Despite the significant number of TWPA episodes included in the present study, we recognize that further studies with larger samples should be carried out to confirm the results presented here.

Clinical implications.   Previous studies have shown that the presence of TWA correlates with a very long QT interval and with the occurrence of malignant arrhythmias (4,10). The present clinical study corroborates experimental data showing that sudden heart rate acceleration may provoke (or at least facilitate) TWA. It is possible that one of the mechanisms for the well-described beneficial effects of beta-blockers in the CLQTS is to prevent these sudden heart rate accelerations. Of five patients with clinical history of syncope, three (60%) showed episodes of TWPA on Holter recordings, which were underestimated on the ECG recordings. Two patients had neurological sequelae.

Study limitations.   There are some restrictions on the use of conventional tapes for the analysis of T-wave variation, because this type of recording does not adequately reproduce low-frequency signals (6). However, the tape recorders used in the present study seemed to have properly served the purpose of this investigation. In addition, the real value of QT interval by Holter recordings tends to be underestimated (30). Because this method was used in all patients, the possible underestimated values observed had probably a homogeneous distribution.

In the present study, patients with TWA had very long QT intervals (520 to 580 ms). Zareba et al. (10) previously showed that TWA is associated with a very long QT interval. Thus, it is likely that Holter monitoring (for the purpose of demonstrating TWA) will not be of such diagnostic value in patients with less obvious QT prolongation.

In contrast, different CLQTS genotypes have different ECGs, arrhythmia triggers, and different responses to drugs (31–35), and it is therefore logical to assume that the genotype (not evaluated in this study) could affect the prevalence of TWA as well as its characteristics and response to heart rate variations.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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