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Am J Physiol Heart Circ Physiol 286: H131-H136, 2004. First published August 28, 2003; doi:10.1152/ajpheart.00479.2003
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Ventricular gradient and nondipolar repolarization components increase at higher heart rate

Peter Smetana, Velislav N. Batchvarov, Katerina Hnatkova, A. John Camm, and Marek Malik

Department of Cardiological Sciences, St. George's Hospital Medical School, London SW17 0RE, United Kingdom

Submitted 22 May 2003 ; accepted in final form 31 July 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Differences in action potential duration reflect differences in ion channel properties. These properties also determine rate dependence of action potential duration, and transmural dispersion was confirmed experimentally to increase with cycle length. While several electrocardiographic indexes characterizing repolarization abnormalities have been proposed, studies of their heart rate dependence are missing. This study therefore investigated rate relationship of two repolarization descriptors, namely, the so-called total cosine of the QRS-T angle (TCRT), proposed to characterize global repolarization heterogeneity, and the so-called relative T wave residuum (TWR), linked to regional repolarization dispersion. During 24-h holter recordings in 60 healthy subjects (27 males), a 12-lead ECG was obtained every 30 s. RR intervals, QT intervals, and TCRT and TWR were calculated in each ECG and averaged over RR interval bins ranging from 550 to 1,150 ms in 10-ms steps. Women had uniformly greater TCRT and TWR values than men did over the entire range of investigated RR intervals. Whereas the TCRT in both sexes showed marked rate dependence with higher values at long RR intervals (550 vs. 1,150 ms: women, 0.46 ± 0.31 vs. 0.76 ± 0.18, P = 9 x 10–7; men, 0.08 ± 0.45 vs. 0.49 ± 0.35, P = 9 x 10–8), the rate dependence of TWR was more marked in women than in men, showing higher values at shorter RR intervals (550 ms vs. 1,150 ms: women: 0.29 ± 0.14% vs. 0.08 ± 0.06%, P = 2 x 10–8; men: 0.14 ± 0.12% vs. 0.04 ± 0.02%, P = 2 x 10–15). This suggests that both global and regional repolarization heterogeneity are increased at faster heart rates. Whereas in women at all heart rates the sequence of repolarization more closely replicates the sequence of depolarization, localized repolarization is more heterogeneous than in men especially at fast heart rates.

repolarization heterogeneity; electrocardiogram; rate dependence; gender difference

ACTION POTENTIAL DURATION (APD) differs not only between myocytes of different ventricular layers (35) but also between the cardiac apex and base (25), posterior and anterior endocardial surfaces (4), and right and left ventricle (8). This APD dispersion is potentially arrhytmogenic, especially when increased by ion channel mutations in congenital and drug-induced long QT syndrome (3) or by abrupt changes in cycle length (17).

Differences in APD reflect differences in ion channel properties (13, 35). Because these properties also determine the rate dependence of APD (13, 35, 42), heart rate likely influences APD dispersion across the heart. However, experimental studies confirmed significant increase with cycle length prolongation for transmural dispersion (35) that was linked to the occurrence of torsades de pointes and QT interval prolongation at slow heart rates (3). Electrocardiographic investigations of heart rate dependence of other facets of repolarization heterogeneity are missing.

Several electrocardiographic indexes have recently been proposed to characterize repolarization abnormalities (1, 22, 27, 32, 45). Among these, the so-called total cosine of the QRS-T angles (TCRT) that rekindles the concept of ventricular gradient has been proposed to characterize global repolarization heterogeneity, and the so-called relative T wave residuum (TWR) that has been linked to regional repolarization dispersion (37).

Studies of heart rate dependence of these electrocardiographic repolarization indexes are also missing. We have therefore investigated the rate relationship of TCRT and TWR in a population of healthy young women and men. On purpose, we have selected these two repolarization descriptors among the large spectrum of proposed T wave and QRS-T characteristics because both TCRT and TWR have been previously shown to carry strong and independent predictive clinical information (46, 47).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population

The study investigated 60 healthy volunteers, 27 men aged 26.7 ± 7.3 yr, and 33 women aged 27.1 ± 9.6 yr, recruited among employees and students of St. George's Hospital Medical School. All subjects had negative medical histories, normal physical examination, and a normal 12-lead ECG. During the study, participants were not taking any medication. The study was approved by the local ethics committee, and all subjects gave a written informed consent.

Data Acquisition

Twenty-four-hour 12-lead digital ECGs were obtained in each subject with the use of SEER MC recorders (GE Medical Systems; Milwaukee, WI) and repeated after 1, 7, and 30 days. During each 24-h recording, standard 10-s 12-lead ECG samples were obtained every 30 s.

ECG Measurements

Within each ECG sample, individual cardiac cycles were identified to obtain a mean RR interval by averaging all individual RR intervals within the 10 s. With the use of linear regressions between RR interval durations and their consecutive order, slope values were calculated quantifying systematic acceleration or deceleration of heart rate within the ECG sample.

With the use of the research version of ECG software by GE Medical Systems median beats of all leads of each ECG sample were constructed and processed with 6 different algorithms for the QT interval measurement (least-square line fitting with 6 and 12 samples around the maximum T wave downslope, and the threshold method based on 5% and 15% of the maximum T peak, and on 5% and 15% of the maximum T wave differential). For each of these methods, the median QT interval of all measurable leads was calculated, and the results of the six methods were averaged to obtain the representative QT interval.

The median beats of the eight independent leads of each ECG sample (I, II, V1–V6) of each 10-s ECG were processed by singular value decomposition. With the use of a previously described technology (1), TCRT was computed from the decomposition of the entire QRS-T pattern and TWR was computed from the decomposition of the T wave signal. Because TWR measures the so-called nondipolar repolarization component (i.e., the part of the T wave signal that cannot be explained by a movement of a single three-dimensional repolarization vector), the assessment of TWR might be influenced by the noise in the recordings. Therefore, we also calculated the nondipolar components of the QRS complex (termed QRS residua or QRSR) using the same algorithm when restricting the singular value decomposition to the QRS complex signal. QRSR values were used both to characterize the depolarization heterogeneity (measuring the extent of the QRS signal that cannot be explained by a single depolarization vector) and to provide control data to eliminate the possibility of noise influence on the heart rate dependence of TWR.

Exclusion Criteria

Stability of computerized QT measurement was used as a surrogate of data quality. ECGs in which the QT interval was measurable in less than six leads or in which the results of the six different algorithms differed >40 ms were excluded. ECGs were also excluded if recorded from episodes of nonstable heart rate (systematic and statistically significant acceleration or deceleration >5 ms per RR interval through the whole 10-s sample). Finally, only subjects with >500 valid ECG samples in each of the repeated 24-h recordings were considered.

Statistical Analysis

Because only ECGs with stable heart rates were considered, the so-called RR interval bin approach (38) was used to evaluate the rate dependency. Specifically, to compare QT, TCRT, TWR, and QRSR occurring at the same heart rate, values derived from separate ECG samples were averaged over RR interval bins ranging from 550 to 1,150 ms in 10-ms steps. This sorting according to RR interval bins was performed separately for each recording. In each subject, repeated recordings were pooled together and subject-specific data obtained. These were grouped for women and men.

In each 10-ms RR bin, data in women and men were compared with a two-sample Student's t-test assuming different variances. Data are presented as means ± SD unless otherwise stated. A P value <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Data Availability

After all the exclusion criteria were applied, two female subjects aged 49 and 59 yr were additionally excluded to obtain a comparable age distribution of both sex groups. The investigated population finally consisted of 25 women (aged 25.9 ± 6.8 yr, range 18–45) and 25 men (aged 26.5 ± 7.5 years, range 18–41). There were no statistical differences between the age distribution in women and men. In accepted recordings, the mean number of analyzable ECG samples was 1,453 ± 377 (women, 1,450 ± 295; men, 1,456 ± 459, P = 0.462).

The differences in the rate relationship of QT, TCRT, TWR, and QRSR in women and men are shown in Figs. 1, 2, 3, 4. Table 1 compares QT, TCRT, TWR, and QRSR in women and men at two RR interval bins of 540–550 and 1,140–1,150 ms.



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  		Fig. 1. Uncorrected QT intervals at the same RR interval in women ({circ}) and men ({bullet}). Values are shown as means ± SE.

 


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  		Fig. 2. Total cosine of QRS-T angle (TCRT) at the same RR interval in women ({circ}) and men ({bullet}). Values are shown as means ± SE.

 


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  		Fig. 3. T wave residuum (TWR) at the same RR interval in women ({circ}) and men ({bullet}). Values are shown as means ± 95% cardiac interval (CI) (%).

 


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  		Fig. 4. Relative QRS residuum (QRSR) at the same RR interval in women ({circ}) and men ({bullet}). Values are shown as means ± SE (%).

 

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  		Table 1. Uncorrected QT interval, TCRT, TWR, and QRSR in women and men at two heart rate bins

 

QT Interval

As described previously (40), uncorrected QT intervals in women were longer than in men at all investigated RR intervals. This difference was significantly more marked at slower heart rates (Fig. 2).

TCRT

TCRT was greater (and thus the "global" repolarization heterogeneity less pronounced) in women than in men over the whole range of investigated RR intervals and showed marked rate dependence with an increase at longer RR intervals in both sexes. The difference between both sexes was statistically stronger at faster heart rates (Fig. 3).

TWR

TWR values were higher (and thus the "localized" repolarization heterogeneity more pronounced) in women than in men at all investigated RR intervals. However, whereas the sex difference was relatively constant at longer RR intervals, it increased significantly when RR intervals became shorter due to a steeper increase in women (Fig. 4).

QRSR

QRSR values were higher in men than in women at all RR intervals. However, whereas QRSR did not show any rate dependence in men, it significantly decreased with lengthening of the RR interval in women; thus the sex difference became more marked at slow heart rates. Hence, despite similarly small absolute values (<1%), the very different patterns of TWR/RR and QRSR/RR relationship and their opposite sex difference showed that these phenomena are not driven by artificial recording properties, such as increased electrocardiographic noise at faster heart rates.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We described a distinct rate dependence of both TCRT as well as TWR, suggesting that both global and regional repolarization heterogeneity are increased at faster heart rates. Whereas the sequence of repolarization more closely replicated the sequence of depolarization in women at all heart rates, localized repolarization was more heterogeneous than in men, especially at fast heart rates. This rate relationship and its sex difference significantly differed from that of the QT interval.

Physiological and Technical Considerations

TCRT. Under physiological conditions, the sequences of depolarization and repolarization are of approximately opposite directions with cells that depolarize first repolarizing last as reflected in the differences of APD throughout the heart (9). For this reason, as already observed by Wilson in the 1930s (44), the overall dipoles of depolarization and repolarization are oriented in approximately the same direction. Because it is an integral of cosines of the angles between QRS and T wave dipoles, TCRT reflects the angle between overall depolarization and repolarization. TCRT values close to one indicate no orientation difference between the dipoles, values ~0 correspond to 90° differences and values close to –1 correspond to the very opposite direction. Negative values of TCRT are usually found in cardiac disease with nonlocalized pathologies, e.g., in hypertrophic cardiomyopathy and ischemic heart disease (1, 26, 46) when T waves are more likely to be inverted (6).

TWR. TWR has been proposed in an attempt to quantify the proportion of the ECG signal contents that cannot be explained by a single moving repolarization dipole. Localized recovery dipoles, which are canceled when integrated into the overall dipole of the T wave, reflect localized differences in APD. The calculation of TWR attempts to find the overall T wave dipole that would explain (in the 8 independent leads of the standard 12-lead ECG) as much of the T wave signal as possible. Thus the concept of TWR is actually likely underestimating the localized APD heterogeneities. Nevertheless, the greater TWR the greater proportion of the T wave signal beyond a single moving dipole and thus the greater localized heterogeneities. These localized heterogeneities were significantly increased in cardiovascular disease (22, 47) similar to the increased multipolarity of body surface maps (10).

Finding decreased values of TCRT and increased values of TWR at higher heart rates, our study suggests that both global and localized repolarization heterogeneity increases with increasing heart rate. Although the proportions between the global and localized heterogeneity are difficult to quantify, our observations also indicate that in women, the increase in repolarization heterogeneity at faster heart rates mainly concerns the localized dispersion, whereas in men, both components of heterogeneity increase similarly.

Relations to Previous Studies

APD dispersion and rate dependence. Dispersion of APD within the heart reflects differences in repolarizing ionic currents (13). These differences have been confirmed repeatedly for several currents in cells of different myocardial layers (17, 18, 30, 35). There are also reports of significant differences in ion channel properties between cells of the left and right ventricle (8) and between the ventricular apex and base (7).

The differences in ion channel properties determine not only APD, but because of the differences in restitution kinetics of different channels, also its rate dependence (8, 18, 35, 36, 42). However, whereas gradients generated by the differences in APD were confirmed repeatedly in intact hearts (9, 16, 25, 33, 43, 48), reports on rate-dependent changes of these gradients are limited. Weissenburger et al. (43) described the transmural gradient as significantly increased with the slowing of the heart rate (43). Dispersion of APD between the left and right ventricular endocardium (48) or between the apex and base (16, 33) showed only a tendency to decrease at higher rates.

Extrapolation of these findings into a clinical setting is problematic. Findings from isolated cells or tissue slab models might not reflect in vivo relations (3), and intact hearts are often deprived of physiological conditions, e.g., autonomic tone or mechanical loading (16, 33, 48). Finally, due to technical reasons, in vivo studies normally focus on selected gradients (23, 43) and thus do not provide a comprehensive image of cardiac repolarization heterogeneity. Relative contributions of ion channels and their activation and deactivation kinetics in ventricular myocytes are also substantially species dependent (7), further complicating the extrapolation of the laboratory findings to humans.

Nevertheless, our findings are, in principle, in agreement with those from experimental studies. Reflecting the trend toward reduced global APD dispersion at higher heart rates observed experimentally (16, 33, 43, 48), TCRT values decreased at higher heart rates. This translates into smaller differences between APDs and increased spatial deviation between the repolarization and depolarization wavefronts.

In ischemic heart disease, an increased rather than decreased angle between QRS complex and T wave was found to be a marker of an increased risk (1, 46, 47). This suggests that TCRT is a broad descriptor with changes in different directions indicating different pathologies. A too-close angle between QRS complex and T wave may indicate accentuation of normal intraventricular APD gradients leading to the propensity of repolarization-driven tachycardia, such as torsades de pointes appearing at slow heart rates in the long QT syndrome (3). In contrast, a too-broad angle between depolarization and repolarization wavefront may indicate gross regional APD dispersion due to diseased myocardium (6, 24) with a propensity to reentry-driven tachycardia (15, 16, 28), such as that appearing in ischemic heart disease without slowing of heart rate or QT prolongation. The observed sex differences in this study seem also to replicate the different propensity to these types of tachycardia between women and men (14, 34).

Significant localized differences in myocardial repolarization in addition to the global distribution of APDs were confirmed repeatedly (4, 9, 23). This suggests an even more complex pattern in the distribution of repolarization properties as supported by the recent finding in canine wedge preparations of a nonuniform cluster-like appearance of midmyocardial cells within the ventricular wall (2). In the present study, local repolarization heterogeneities were increased at higher heart rates. Although this observation does not have a direct experimental correlate, it agrees with the finding of increased TWR during bicycle exercise test in healthy subjects (5).

Indirect correlates of our observation exist. Beat-to-beat alternation of APD was found to be rate dependent (11). Above a critical heart rate threshold, reported to vary substantially across the epicardial surface (29), beat-to-beat changes occur in membrane and intracellular processes that determine APD (11, 29). Regional differences in these fluctuations may lead to increased APD dispersion and, consequently, to changes in gradients up to a unidirectional block and functional reentry (29). Hence, although speculative, it seems plausible to suggest that the increase in the nondipolar component expressed by TWR reflects higher localized repolarization heterogeneity due to similar though physiological changes and their nonuniformity within the myocardium.

Sex difference. Women are more prone to arrhythmic events in both acquired (14, 21) and congenital long QT syndrome (20). However, although sex differences in the ECG manifestation of ventricular repolarization have been reported, repeatedly including a more complex T wave morphology in women partly attributable to lower T wave amplitudes and T wave areas (27), they do not fully explain the higher arrhythmic risk in women.

The finding of a significant sex difference in TCRT suggests a marked disparity in the geometry of repolarization sequence between women and men (37). Independent of heart rate, the repolarization sequence in women replicates the opposite direction of the depolarization sequence more than in men. In both sexes, the deviation between repolarization and depolarization dipole was increasing with heart rate. This means that the differences between APDs are increased at slow heart rates and that this increase in the differences is expressed more in women than in men. This is in a good agreement with the observation of increased repolarization heterogeneity at very slow cycle lengths (35) as well as with reports of higher female arrhythmic risk at slow heart rates (14).

The sex differences observed in this study have also indirect experimental correlates. Animal models have recently suggested that sex hormones may influence cardiac repolarization. The rapidly activating delayed-rectifier K+ current (IKr) and inward rectifier K+ current were reported to be smaller in female rabbits (19), and expression of Kv1.5 and of its corresponding ultrarapidly activating K+ current, IKur, was described to be significantly lower in female mice (41). Transmural inward L-type Ca2+ current gradients were observed only in female rabbit hearts (30), and testosterone levels were described to have a modulating effect on proarrhythmic response to IKr blockers in rabbit hearts (31). Finally, estradiol was shown to influence significantly the transient outward current gene expression in women (39). Differences also exist in autonomic tone between women and men (12), and sympathetic activation of ion channels has been described repeatedly (3).

Despite the broad range of these experimental studies, there are no clear experimental explanations for the sex differences in TWR. By assuming that TWR is at least in part related to a canine-like nonuniformity of the distribution of islands of midmyocardial cells in human hearts, and by considering all of the sex differences in repolarization patterns, it seems logical to suggest that the nonuniformity of different myocardial layers and regions is different between women and men. Our observation suggests that it is greater in women.

Limitations. The physiology of TCRT and TWR has not yet been investigated in experimental models, and thus the relevant mechanisms can only be discussed theoretically.

Although the comparison with QRSR shows that our TWR related observations are not a simple artifact due to recording noise and signal quality, phase-locked mechanical influences cannot be excluded. Mechanical systole occurs during electrical repolarization, and sex differences can be expected in the mechanical influence of the beating heart on the ECG electrodes. However, it is not obvious how such an explanation of TWR would account for the sex differences in rate dependence. Besides, mechanoelectrical feedback was also shown to modulate APD in a heart rate-dependent fashion. When combined with known sex differences in left ventricular mass and functioning, it may actually contribute to the observed electrophysiological differences.

The recording mode of one 10-s ECG sample taken twice a minute did not allow a sensible measurement of heart rate variability. We were therefore not able to correlate our findings with differences in heart rate variability based assessment of the cardiac autonomic status.

The study involved ~700,000 individual 10-s ECGs. It was therefore not possible to review all recordings visually and/or to check them manually. To optimize the accuracy of the automatic computations used, we had to introduce some arbitrary limits based on our previous experience with the ECG processing software. It is unlikely that the particular settings (e.g., QT interval measured in >6 leads) had any impact on the findings of the study.

In conclusion, the finding of a marked difference in the rate relationship of the spatial repolarization patterns between women and men seems to add a new facet to the complex issues of sex difference in arrhythmic risk. Because the understanding of the pathophysiological background of the observation is mostly theoretical, experimental studies are needed to substantiate our findings as well as to provide appropriate detailed models. Nevertheless, because both TCRT and TWR have been shown to be strong risk factors, their marked rate dependence shows that in future clinical studies, these parameters should be corrected for the underlying heart rate.


   ACKNOWLEDGMENTS
 
GRANTS

This study was supported by the Primarärzteverein des Wilhelminenspitals (Vienna, Austria), The Wellcome Trust (London), and The British Heart Foundation (London).


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Malik, Dept. of Cardiological Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK (E-mail: m.malik{at}sghms.ac.uk).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 METHODS
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 DISCUSSION
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