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Department of Cardiological Sciences, St. George's Hospital Medical School, London SW17 0RE, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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The reason for sex differences in arrhythmic risk remains unclear. Heterogeneity of ventricular repolarization is directly linked to arrhythmogenesis; thus we investigated repolarization homogeneity and its circadian pattern in men and women. During 24-h Holter recordings in 60 healthy subjects (27 males), a 12-lead electrocardiogram (ECG) was obtained every 30 s. RR and QT intervals, and, after singular-value decomposition, two characteristics of repolarization homogeneity were calculated in each ECG. Corrected QT (QTc) values were obtained using an individually optimized heart rate (HR) correction formula. All values were averaged over 10-min time bands from 0000 to 2400. There were substantial sex differences in both global repolarization homogeneity (measured by the total cosine of the angle between QRS and T wave vectors) and regional homogeneity of repolarization (quantified independently by the relative T wave residuum). Whereas women throughout the 24 h followed more closely the pattern of inverse sequence between depolarization and repolarization, they also showed much higher localized repolarization heterogeneity than men. In both women and men, repolarization irregularity was greatest during morning hours. A sex difference was also observed for HR and QTc interval; however, the circadian patterns of the repolarization homogeneity descriptors were different from those of HR and QTc intervals.
arrhythmic risk; electrocardiogram; Holter recording; gender
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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NUMEROUS PHYSIOLOGICAL DIFFERENCES between the human sexes have been previously described. Among other cardiovascular differences such as the lower incidence of atherosclerotic coronary artery disease in premenopausal women (20), different prevalences of some arrhythmias in women and men have been repeatedly confirmed. Atrial fibrillation is more common in men (11). Women have a lower incidence of sudden cardiac death (36) but are more prone to develop bradycardia-related torsades de pointes (16) and more frequently experience acquired (23) and clinically manifested congenital long QT syndrome (LQTS; Ref. 22). Differences in risk factors and the effects of estrogen on serum lipid concentrations and atherosclerosis (28) do not completely explain this sexual disparity.
Heterogeneity of ventricular repolarization is linked to an increased arrhythmic risk (17). Consequently, sex differences in cardiac electrophysiology and particularly in repolarization properties have been recently addressed. Gender differences in cardiac autonomic tone (14) and the QT-RR relation (15) have also been described. Reports on sex differences in QT dispersion exist (10), although the concept of QT dispersion as a marker of regional heterogeneity of repolarization has been recently discredited (25, 49). Thus a direct evidence of differences in repolarization homogeneity between women and men is missing.
Recently (2, 25), several new morphological descriptors of the electrocardiogram (ECG) repolarization pattern have been proposed. Although most of them can separate normal and abnormal ECGs, only some of these measures have been shown to have clinical value. Namely, the vectorial deviation between the depolarization and repolarization wavefront, which is expressed by the so-called total cosine R to T (TCRT) that rekindles some aspects of the concept of ventricular gradient, was shown to provide independent information on arrhythmic risk in patients surviving myocardial infarction (48). The nondipolar component of the T wave signal, i.e., the so-called T wave residuum (TWR) that reflects regional repolarization heterogeneities, was shown to predict all-cause mortality independently of clinical and other ECG variables in a large cohort of US male veterans with cardiac disease (50). We have therefore investigated the sex differences of TCRT and TWR as well as the circadian pattern of the characteristics in healthy women and men.
As described in more detail in METHODS, the TCRT and TWR parameters characterize two different facets of repolarization homogeneity. TCRT is dependent on the global distribution of action potential durations that determine the overall spatial T wave orientation. On the contrary, TWR depends on the existence of localized differences in action potential durations and is not influenced by the global action potential distribution.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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The study population consisted of 60 healthy volunteers: 27 men age 26.7 ± 7.3 yr, and 33 women age 27.1 ± 9.6 yr, that were recruited from within St. George's Hospital Medical School. All subjects had normal medical histories, normal physical examination, and a normal 12-lead ECG. During the study, participants were not taking any medication. All subjects were healthcare professionals and had a normal day-night activity profile without any workload in unusual hours of the day. The study was approved by the local Ethics Committee, and all subjects gave written informed consent.
Data Acquisition
Digital ECGs (24-h, 12-lead) were obtained in each subject using SEER MC recorders (GE Marquette Medical Systems; Milwaukee, WI) and were repeated after 1 day, 1 wk, and 1 mo. During each 24-h recording, 10-s, 12-lead ECG samples were obtained every 30 s. Subjects were instructed to adhere to a standard daily routine without any physical or mental excesses during the recording days.ECG Analysis
RR intervals. Individual cardiac cycles within each ECG sample were identified, and RR intervals were computed by cross correlating the image of a representative cardiac beat with the native ECG signal (27). For each ECG sample, a mean RR interval was obtained in this way. With the use of linear regressions between RR interval durations and the consecutive order, slope values were also obtained quantifying the systematic acceleration or deceleration of the heart rate within the ECG sample.
QT intervals. The research version of ECG software by GE Marquette was used to construct median beats in all leads of each 10-s ECG (45). To improve the automatic measurement of QT intervals, the median beat of each lead of the ECG sample was processed with six different algorithms for computerized QT interval measurement: least-square line fitting with 6 (method 1) and 12 (method 2) points around the maximum downslope of the T wave and the threshold method, which is based on 5% (method 3) and 15% (method 4) of the maximum T peak and on 5% (method 5) and 15% (method 6) of the maximum T wave differential (45). For each of these methods, the median QT interval of all measurable leads was obtained, and the results provided by the six methods were averaged.
It has been recently shown that the QT-RR relationship is very significantly different in different subjects (26). Therefore any ad hoc selected heart rate correction formula overcorrects in some subjects and undercorrects in others. For this reason, we used individually optimized heart rate correction formulas. For each subject, a correction parameter designated as
was
identified that ensured that the corrected QT (QTc) interval values,
which were obtained as QTc = QT/RR
, were not
correlated with RR intervals, as the correlation coefficient between
QTc and RR interval durations was zero in each subject (24).
TCRT. With the use of a previously described technology (1, 2), eight independent leads of each median beat of an ECG sample (I, II, V1 through V6) were subjected to singular-value decomposition. The decomposed ECG signal was transformed and reconstructed in an algebraic eight-dimensional space based on the distribution of energy. It has been shown previously (1) that 99% of the ECG energy is represented in the first three orthogonal leads of this space. From these, the three-dimensional QRS and T vector loops were reconstructed corresponding to the dipolar component of the total energy.
TCRT was defined as an integrated cosine of the angle between the three-dimensional QRS and T vector within the decomposition space. (See the APPENDIX for computational details.) Thus it measures the difference between the directions of depolarization and repolarization propagation. If this difference is close to zero (TCRT is close to 1), the repolarization sequence broadly replicates the depolarization sequence in the opposite direction (the upstroke and downslope of the action potential have opposite directions). Thus high values of TCRT indicate a global distribution (e.g., endo-epicardial and apex-base) of action potential durations in which the cells that depolarize last repolarize first. On the contrary, TCRT values close to
1 broadly indicate an overall minimum difference in action potential
durations among ventricular myocytes. The concept of TCRT
mathematically redefines and computationally improves the concept of
the so-called ventricular gradient proposed by Wilson et al. in 1931 (44).
TWR. By its principle, singular-value decomposition organizes the signal in such a way that the first three components contain the maximum energy that can be explained by a moving dipole. TWR is based on singular-value decomposition of the T wave signal only and quantifies the proportion of the signal contents that exists beyond the maximum moving dipole. (See the APPENDIX for computational details.) Computed in this way, TWR is not influenced by the global distribution of action potential durations and by the global orientation of the repolarization sequence; rather, it reflects localized heterogeneities in action potential duration. Because the moving cardiac dipole represents only the vectorial sum of all action potential dipoles, it does not reflect the heterogeneity of action potentials through the myocardium. Localized dipoles that are mutually cancelled when summed into the total cardiac dipole influence various ECG leads differently. Consequently, the distribution of the signal energy in the individual leads of a 12-lead ECG cannot be entirely accounted for solely by the movement of the global cardiac dipole. Those parts of the ECG energy that cannot be attributed to the global dipole represent an ECG expression of the local myocardial heterogeneity. TWR measures this heterogeneity within the T wave and thus quantifies the localized repolarization inhomogeneity in the ventricular myocardium (25).
Schematically, we may imagine the repolarization process as represented by a plane. In such a representation, the TCRT parameter indicates by how much such a plane is tilted compared to the QRS complex orientation, whereas the TWR parameter characterizes how much the repolarization plane is irregularly creased.Data Organization
Repeated 24-h recordings were pooled in each subject and in each individual. The measurements of RR, uncorrected QT, and QTc intervals; TCRT; and TWR obtained in separate ECG samples were correlated, and the values of Pearson correlation coefficients were compared for women and men.For the investigation of the circadian profile, RR and QTc intervals and TCRT and TWR values were calculated for each 10-s ECG sample and were averaged over 10-min time bands from 0000 to 2400. 24-h recordings were grouped in women and men.
Exclusion Criteria
Stability of the automatic measurement of the QT interval was taken as a surrogate for data quality. Those 10-s ECG samples in which the QT interval was measurable in fewer than six leads or in which the results of the six different algorithms differed by >40 ms were excluded. These limits were based on previous experience with the QT Guard package (4). ECGs were also excluded if recorded from episodes of unstable heart rate (systematic significant acceleration or deceleration by >5 ms per RR interval through the whole 10-s sample). Finally, to ensure a reliable representation of the circadian pattern, only those 24-h recordings with acceptable ECG samples in
90% of 10-min intervals were considered.
Statistics
Identical steps of data analysis were used to elaborate sex differences of RR and QTc intervals and TCRT and TWR values. Averages of individual measures [24 h, day (9 AM to 8 PM), and night (1 AM to 5 AM)] were calculated from the averaged values within the 10-min bands.To investigate circadian pattern, the averaged values of individual measures in women and men were compared within individual 10-min bands. Early morning dynamics were characterized by linear slope of the values between 6 AM and 9:30 AM.
Intersex comparisons were performed by Student's t-test. Unless specified otherwise, data are presented as means ± SD. In figures, data are presented as means ± SE. Statistical significance was considered as P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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Data Availability
Of the 240 recordings, 59 were excluded because of an insufficient number of acceptable samples over 24 h. The investigated population finally consisted of 25 male (age 27.0 ± 7.3 yr, range 18-41 yr) and 26 female (age 26.8 ± 8.0 yr, range 18-49 yr) subjects. After the exclusion criteria were applied, the mean number of analyzable ECG samples was 1,075 ± 391/recording, which corresponds to 23.3 ± 0.7 h.Heart Rate Correction
As previously observed in independent populations (24, 26), the individual heart rate correction coefficient used
in QTc interval computations differed substantially between subjects and ranged from 0.319 to 0.492 and 0.322 to 0.427 in women and men,
respectively. Moreover, these values where highly significantly different in women (0.424 ± 0.04) and in men (0.368 ± 0.03;
P = 3.5 × 10
6).
Intermeasurement Correlation
The correlation coefficients between individual measurements are shown in Table 1. Although both TCRT and TWR were correlated with RR intervals, the relationship to RR intervals was much weaker than that of uncorrected QT intervals and also highly variable between subjects. The correlations of TCRT and TWR with QTc intervals were very weak. The QT-RR and TWR-QTc correlation coefficients were significantly different in women and men.
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Circadian Pattern and Sex Differences
The differences in circadian pattern in women and men are shown in Figs. 1-4. The averaged data are shown in Table 2 and the day-night differences as well as the slopes of morning changes are shown in Table 3.
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RR interval. In accordance with previous studies (5), we observed shorter RR intervals (higher heart rates) in women than in men. In both sexes, and more pronounced in men, the RR interval values showed a distinct circadian pattern (Fig. 1) with the gap between the values for women and men almost disappearing during the day.
QTc interval. The known sex difference (29) in the QTc interval (which was longer in women) was observed throughout the day. However, by eliminating the under- and overcorrection in the QTc computation, the circadian fluctuations of QTc were much less marked than previously described (31). The circadian patterns in women and in men were practically parallel, and the sex difference remained almost constant over the entire 24-h period (Fig. 2).
TCRT. A striking difference between women and men was found with the highest TCRT values at night and a steep decrease in early morning hours in both sexes. In contrast to RR and QTc intervals, the difference was more marked during the day than at night, and the circadian pattern was more pronounced in men (Fig. 3).
TWR. We observed not only a marked sex difference but also a significant difference in the extent of the circadian pattern between women and men as shown in Fig. 4. Lowest values during the night in both sexes were followed by a steep increase in the early morning in women but not in men.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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The results of this study show that there are substantial differences between women and men in both global and regional homogeneity of myocardial repolarization. Women more closely follow the pattern of inverse sequence between depolarization and repolarization (that is, in women more than in men, the cells that depolarize last repolarize first). However, repolarization is much more locally heterogeneous in women than in men, especially during the day. Both in women and men, the largest increase of repolarization heterogeneity occurs during morning hours.
Relationship Between Repolarization Parameters and RR and QTc Intervals
As previously reported (5, 29, 31, 40), we observed substantial differences between women and men in both RR and QTc intervals. However, the sex differences in the circadian pattern of TCRT and TWR were different than those of RR and QTc intervals. Although the sex differences in RR intervals diminished during the day and the differences in QTc intervals remained practically constant through the entire 24-h period, the TCRT and TWR differences between men and women increased during the day.This is in good agreement with TCRT and TWR expressing repolarization qualities different from the duration of the QT interval. Although the QT interval represents the overall duration of action potentials in the ventricular myocardium (together with the duration of the excitation sequence), TCRT and TWR characterize the distribution of action potential durations and morphologies on both a global (TCRT) and a local (TWR) basis. Thus women have not only longer action potentials than men do, but also differently distributed action potential durations and shapes.
Relation to Previous Studies
Sex differences have been repeatedly described in various ECG and vectorcardiogram parameters. Besides having longer QTc intervals and a steeper QT-RR relation (15), women were reported to have QRS complex and T wave loops of smaller magnitude than men (39, 46) and a smaller T wave amplitude in the surface ECG (38). Consistently, the magnitude of the ventricular gradient (3) and T potentials in body-surface maps (12) were also reported to be smaller in women. The clinical value of these amplitude differences was never established, and they either remained unexplained (12, 39) or were attributed to a smaller average heart size in women (3), differences in thoracic muscle mass and fat content (46), or to the shape of the female torso (42). These anatomical and geometrical aspects might, at least in part, explain differences in the vectorcardiographic and electrocardiographic patterns as well as the difference in the magnitude of the ventricular gradient. However, they cannot explain the substantial difference in TCRT (angle of the ventricular gradient) and TWR. Indeed, these repolarization quantifiers have not only been designed to be independent of the size and anatomical orientation of the heart but have also been shown to carry prognostic information that is unlikely to be related to anatomical and geometrical aspects.Both global and regional repolarization heterogeneity is caused by differences in the action potential duration within the myocardium due to differences in ion channel density and expression (8, 19, 37). These properties do not differ only between different muscle layers (endocardium, midmyocardium, epicardium) of the ventricular wall (37) but also within a single layer (19) and between right and left ventricle (8).
Increasing evidence has been recently obtained from animal models that sex hormones may influence repolarization properties (9, 21, 33, 41). Drici et al. (9) tested the effects of estradiol and dihydrotestosterone treatment on K+ channel mRNA levels in isolated hearts of ovariectomized rabbits. Both sex hormones were shown to downregulate mRNA levels for these channels and to prolong the QT interval. Liu et al. (21) described significantly lower rapidly activating delayed rectifier K+ current (IKr) and outward current (IKl) densities in female rabbit ventricular myocytes, and Pham et al. (33) showed the modulating effect of testosterone levels on proarrhythmic response to IKr blockers in rabbit hearts. Most recently, Trépanier-Boulay et al. (41) demonstrated that the expression of Kv1.5 and its corresponding K+ current, IKur, is significantly lower in female mice. Although these reports are supported by findings in humans describing a possible influence of sex hormones on QT interval (7), the arrhythmic risk in congenital LQTS (34), and drug-related QT prolongation (35), the results in humans are inconsistent (18) and there are significant species-dependent differences in ion channel expression. Nevertheless, it is tempting to hypothesize that gender differences in regional ion channel pattern may cause differences in transmural gradients between men and women and thus be responsible for the sex differences in repolarization homogeneity found in our study. The larger localized repolarization heterogeneity in women, when eventually increased by drugs interfering with ion channel properties, might be responsible for the higher female susceptibility for torsades de pointes arrhythmias despite the more uniform global repolarization.
Circadian Pattern
A circadian pattern, and particularly a morning peak, in cardiovascular (32) and arrhythmic (43) events has been reported repeatedly. Our findings suggest a morning peak in repolarization heterogeneity in both sexes. The decrease in TCRT and increase in TWR in the early morning hours reflects an increase in both global and regional repolarization heterogeneity and implies a higher susceptibility to arrhythmic events. Generally, these diurnal changes were previously explained by the circadian pattern of the autonomic tone. This is supported by a blunted pattern in survivors of sudden cardiac death (30), after heart transplantation, in diabetic patients (6), and in patients after myocardial infarction (13, 47). The differences in circadian patterns of RR and QTc interval, and of TCRT and TWR not only confirm that TCRT, TWR, and QTc characterize repolarization differently but also suggest that the circadian patterns of TCRT and TWR and those of RR and QTc intervals might be influenced by different regulatory mechanisms.The short-term changes in repolarization homogeneity might be the consequence of changes in action potential duration due to the differences in ion channel activity caused by circulating hormones. Because most hormones as well as cellular hormone receptors are known to exhibit a circadian pattern, the combination of varying concentrations of sex, stress, growth, and other hormones may, in addition to autonomic tone, have a substantial impact on myocardial ion channel activity and contribute to the sex difference throughout the day.
Limitations of the Study
The recording mode of one 10-s ECG sample taken twice a minute did not allow a sensible measurement of heart rate variability. We are therefore not able to correlate our findings with differences in heart rate variability based on assessment of the cardiac autonomic status.We also did not collect any data on hormone levels and on menstrual cycle phases. The influence of plasma sex-hormone levels on myocardial repolarization deserves a separate study.
Because we analyzed ambulatory rather than strictly supine recordings, the ECG noise levels were likely to be increased and the technical ECG settings were likely different from recordings obtained with a stationary electrocardiograph. This may partially explain the higher TWR values observed in our study compared with normal subjects reported by Malik et al. (25). Although this requires further technical studies, the same conceptual differences in ECG recording apply to both women and men in our study, and the sex-related difference remains uninfluenced.
The mean age of our study population was 27 yr, and we were therefore unable to investigate the effect of aging on the descriptors of repolarization homogeneity.
The analysis of circadian pattern in an uncontrolled setting is known to be problematic. Although we are unaware of any changes in the daily routines of the studied subjects, the possibility of behavioral influence cannot be excluded.
Because the study involved almost 700,000 ECG samples, it was not possible to review all ECGs visually and/or to check them manually. To optimize the accuracy of the automatic measurements used, we had to introduce some arbitrary limits, which we based on former 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 summary, we observed substantial differences in both global and regional repolarization homogeneity between men and women. Whereas the global pattern of repolarization was more homogeneous in women, women also showed much higher localized repolarization heterogeneity. In both sexes, characteristics of repolarization morphology exhibited a marked circadian pattern with a steep increase of repolarization heterogeneity during morning hours. This pattern significantly differed from the pattern of the RR intervals as well as from the pattern of the individually corrected QT intervals, which confirms the independence of the morphological descriptors.
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APPENDIX |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
REFERENCES
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To calculate TCRT and TWR from a 12-lead ECG sample, the eight algebraically independent leads (I, II, V1 through V6) are subjected to the singular-value decomposition (2) and reconstructed in an orthogonal eight-lead system. In such a system, the first lead contains the maximum energy in one single direction, the second lead the maximum energy perpendicular to the first two leads, etc. The energy embedded in the first three orthogonal leads corresponds to the energy of the ECG vector, and the energy of the remaining five leads corresponds to nondipolar components summed over all 12 leads of the original ECG.
In formal terms, if E is an 8 × n matrix, where each
column corresponds to a successive sampling-time instant and each row corresponds to an ECG lead, there exist two orthogonal matrices: L = [l1,
l2,...,l8]
8×8 and R = [r1, r2,...,
rn]n×n
such that 
= LTER = diag (
1,
2,...,
8)8×n, where
1 2 ... 8 0. That is, columns L and R are left and right singular vectors,
respectively, and i are singular values of
matrix E.
TCRT Parameter
The TCRT parameter measures the difference between the dominant orientation of the QRS and T wave loops. In formal terms, let us denote
8×3, and let P be a projection of E onto
![TCRT = <FR><NU>1</NU><DE><IT>t</IT><SUB>RE</SUB> − t<SUB>RS</SUB></DE></FR> <LIM><OP>∫</OP><LL><IT>i=t</IT><SUB>RS</SUB></LL><UL><IT>t</IT><SUB>RE</SUB></UL></LIM> cos {ang[u<SUB>T</SUB>, P<SUB>QRS</SUB>(<IT>i</IT>)]}](/content/vol282/issue5/fulltext/H1889/img002.gif)
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TWR Parameter
The TWR parameter is defined using the singular values calculated from the decomposition of the repolarization wave. The QRS complex and T wave are separated (2) and the T wave range is used to restrict the scope for the singular-value decomposition. Resulting singular values
1 2 ... 8 0 are used for the calculation of TWR as a proportion between the nondipolar and 3-D
vector components (25)
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ACKNOWLEDGEMENTS |
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This work is supported in part by Primarärzteverein des Wilhelminenspitals, Vienna, Austria; the Wellcome Trust, London; and the British Heart Foundation, London, UK.
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FOOTNOTES |
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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: p.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.
First published January 10, 2002;10.1152/ajpheart.00962.2001
Received 2 November 2001; accepted in final form 4 January 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
APPENDIX
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