Investigating the effect of sotalol on the repolarization intervals in healthy young individuals

Heart Research Follow-up Program, Cardiology Department, University of Rochester, Rochester, NY, USA.
Journal of electrocardiology (Impact Factor: 1.36). 10/2008; 41(6):595-602. DOI: 10.1016/j.jelectrocard.2008.06.013
Source: PubMed
ABSTRACT
Background:
The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals.

Methods:
We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings.

Results:
The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, rho = 0.9, P < .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: DeltaERD(50%) = 23 +/- 6 msec, P < .05; DeltaLRD(50%) = 8 +/- 3 msec, P = .05) and day 2 (peak effect of sotalol: DeltaERD(50%) = 51 +/- 14 msec, P < .05; DeltaLRD(50%) = 20 +/- 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (> or = 3.5 hours after dosing) and QTc/QTc apex profiles (< 3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization.

Conclusion:
This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.

Full-text

Available from: Jean-Philippe Couderc, Jan 09, 2015
Investigating the effect of sotalol on the repolarization intervals in
healthy young individuals
Jean-Philippe Couderc, PhD,
a,
Meijian Zhou, PhD,
b
Nenad Sarapa, MD,
c
Wojciech Zareba, MD, PhD
a
a
Heart Research Follow-up Program, Cardiology Department, University of Rochester, Rochester, NY, USA
b
iCardiac Technologies Inc., Global Research and Development Department, Rochester, NY, USA
c
Johnson & Johnson Inc., Experimental Medicine, Raritan, NJ, USA
Received 8 May 2008; revised 24 June 2008; accepted 25 June 2008
Abstract Background: The dissociation between a drug-induced increase of the QT interval prolongation and
an increased risk for ventricular arrhythmias has been suggested by academic investigators and
regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG)
techniques available for assessing the cardiotoxicity of novel compounds. In this study, we
investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of
healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced
prolongations of the QTc, QTc apex and T-peak to T-end intervals.
Methods: We implemented a set of parameters describing the morphology of the T loop in its
preferential plane. These parameters measure the time interval needed for the heart vector amplitude
to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%,
and 70%. These measurements are called early repolarization duration (ERD) when they are
located before the T-wave apex and late repolarization duration (LRD) when measured after the
apex. They depend on both the speed of the repolarization process and the morphology of the
T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen
ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of
sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The
plasma concentration of the drug was measured just before the ECG recordings.
Results: The values of all investigated parameters revealed a dose-dependent effect of sotalol (in
average between parameters, ρ = 0.9, P b .001). Our investigations described profound and
statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of
sotalol: ΔERD
50%
= 23 ± 6 msec, P b .05; ΔLRD
50%
= 8 ± 3 msec, P = .05) and day 2 (peak effect
of sotalol: ΔERD
50%
= 51 ± 14 msec, P b .05; ΔLRD
50%
= 20 ± 12 msec, P = .05). When
investigating the timing of peak drug concentration and peak effect of the drug on the various
repolarization parameters, we found asynchrony between ERDs/LRDs (3.5 hours after dosing) and
QTc/QTc apex profiles (b3.5 hours after dosing), suggesting that the time of maximum prolongation
on the repolarization process was not synchronized with the time of maximum drug-induced
heterogeneity of repolarization.
Conclusion: This study describes the sotalol-induced changes of the T-loop morphology in healthy
individuals based on novel vectocardiographic parameters. These observations might help in
improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.
© 2008 Elsevier Inc. All rights reserved.
Keywords: QT interval; Torsades de pointes; Long QT syndrome; Sotalol; Vectocardiography; ECG
Introduction
While the association of increased arrhythmia risk with
QTc prolongation is well established,
1
the association
between a rate-corrected QT prolongation and the presence
A
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doi:10.1016/j.jelectrocard.2008.06.013
Page 1
of an arrhythmogenic substrate has been strongly questioned.
Indeed, the releases of several postmarketing reports have
described noncardiac drugs with small QTc prolonging effect
associated with significant torsadogenic properties,
2,3
whereas other drugs that have no history of cardiac events
were significantly prolonging the QTc interval.
4,5
Conse-
quently, one faces a challenging exercise related to the design
and validation of a more reliable ECG surrogate marker of
drug cardiotoxi city than QTc prolongation.
The mechanisms involved in the triggering of drug-induced
arrhythmias remain to be fully elucidated, yet one recognizes
the role of the repolarization heterogeneity as a required
arrhythmogenic substrate.
6,7
For instance, the TriAd concept
suggests the importance of the combined roles of action
potential triangulation, reverse use dependency of the drug,
and repolarization instability. An unbalanced contribution of
these factors could lead to an increased ventricular hetero-
geneity and an increased propensity to torsades de pointes
(TdPs).
7
Another concept, mainly based on in vitro experi-
ments, emphasizes the association between ventricular
transmural heterogeneity and the promoting role of early
after-depolarization as primary factors triggering ventricular
tachyarrhythmias.
8,9
In the arena of development of novel ECG markers,
different techniques are currently investigated; they include
T-wave and T-loop morphologies
10,11
as well as time intervals
such as the T-peak to T-end (TpTe) interval. TpTe interval has
been suggested to be a predictor of ventricular arrhythmias in
an increasing number of studies involving animal and human
data.
12-15
However, its association with transmural dispersion
and/or apicobasal ventricular heterogeneity is actively debated.
In this work, we will consider the duration of this interval as an
index of global ventricular repolarization heterogeneity.
12,13
We investigated the effects of dl-sotalol, a class III
antiarrhythmic agent with strong I
Kr
inhibitory properties
and associated with numerous cases of TdPs, on the
morphology of the T-loop.
16,17
Our objective was to describe
the sotalol-induced changes of QTc and TpTe intervals and
compare them with the changes of novel computerized
indices quantifying the morphology of the T loop. As noted
above, the dissociation between the level of QT/QTc
prolongation and the propensity to arrhythmic events may
suggest the existence of malignant and benign QT/QTc
prolongations; the level of ventricular heterogeneity may
help distinguish them.
Method
Study populatio ns and ECG recordings
A group of 38 healthy individuals were enrolled (28 men;
28 ± 8 years; body mass index, 24.4 ± 3.4 kg/m
2
) and
underwent repeated digital 12-lead ECG recordings during a
3-day protocol. The first day of the experiment was the
baseline. During the second day, patients were exposed to a
single dose of sotalol (160 mg); and during the third day, a
double dose of 320 mg of sotalol was used. All recordings
were preceded by a 5-minute resting period in supine position.
Standard 12-lead ECGs were recorded for 10 seconds using a
commercial equipment (Mortara Instruments, Milwaukee,
WI). Sixteen recordings were done at identical times each day,
first during baseline (day 0) and then immediately after
the dosing (at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 13, 16,
and 22.5 hours after dosing during day 1 and day 2).
The recordings were sampled at 500 Hz with a 16-bit
amplitude resolution.
Sotalol blood plasma concentration was measured
before each ECG. The protocol is described in details
elsewhere.
18
The interval measurements: QT, QT apex, and TpTe intervals
In this analysis, the repolarization interval (RI) is
defined between the J point and the p oint located
220 milliseconds before the next R peak. Such approach
requires that the patients remain at rest during the ECG
recording to avoid high heart rates, that is, short RR
intervals in which 220 milliseconds before the next R peak
would encompass the beginning of the P wave. All
measurements of RIs are based on the singular value
decomposition (SVD) from the 12-lead signals. The SVD is
used to reduce the dimension of the ECG lead systems from
12 leads to 2 leads.
19
We refer to the resulting 2 leads as the
eigenvectors 1 (ev
1
) and 2 (ev
2
).
We measured the QT, QT apex, and TpTe intervals (TpTe =
QT QT apex) from ev
1
. The software
20
was used to
automatically measure the QT interval in all available cardiac
beats in sinus rhythm. The median values from all measured
beats are reported. The apex and the end of the T wave were
identified in a fully computerized manner.
ERD and LRD parameters
ERD
%
and LRD
%
are measurements of interval durations
based on the T loop. The starting point of these intervals is
the time at which the length (magnitude) of the repolarization
vector is maxi mized (Vmax in the lower panel of Fig. 1). The
ending point of these intervals is identified by a circle of
diameter equal to 30% of Vmax (Fig. 1 illustrates ERD
30%
and LRD
30%
). Consequently, these parameters measure the
time needed for the repolarization vector to vary from its
maximum length to a time point corresponding to a 30%
reduction of its maximum length. The LRD
%
is a measure
toward the end of the RI, and the ERD
%
is directed toward
the J point (Fig. 1, lower panel). The durations of these
intervals increase when the electrical vector slows down or/
and the roundness of the T loop increases. Consequently,
these parameters measure time interval duration reflecting
both the velocity of the repolarization vector and the
repolarization heterogeneity.
The SVD and the repolarization measurements were
computed in each cardiac beat, and we reported the average
values from all beats for a given ECG tracing.
Heart rate correction
All repolarization measurements were heart-rate corrected
using a pooled technique. A linear regression analysis was
used to m odel the relationship between repolarization
measurements and RR intervals during baseline periods.
For a given parameter, we pooled all data from the overall
596 J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 2
population, merging data from and between individuals. The
slope (β) characterizing this relationship was used to correct
the repolarization measurements such as QTc = QT + β(1
RR). The same heart-rate correction technique was applied to
all other measurements.
Statistical analysis
We reported the median values and their 95%
confidence inte rvals for each time point describing the
drug effect profile on the repolarization parameters. When
comparing 2 parameters at a given time point or when
assessing if a drug effect was different from 0, a t-test with
appropriate testing hypotheses was used. When comparing
the profiles of curves describing the evolution of
parameters over time, we used the Pearson product moment
correlation coefficient (ρ) to measure the degree of linear
relationship between the 2 variables. For a 2-tailed test of
the correlation, H
0
: ρ = 0 vs H
1
: ρ 0, where ρ is the
correlation between a pair of variables. For all implemented
tests, a P value inferior or equal to .05 was considered
statistically significant.
Results
Profiles of sotalol-induced prolongation of the QT, QT apex,
and TpTe intervals
Fig. 2 describes the profile of the sotalol plasma
concentration based on the average v alue b etween all
individuals at each time point and their 95% confidence
interval. It reveals a maximum plasma concentration recorded
on average between 2.5 and 3 hours after dosing. Fig. 3
illustrates the profile for the sotalol-induced prolongation of
QTc, QTc apex, and TpTe intervals (corrected for heart rate).
The upper panel corresponds to changes during day 1 in
reference to baseline, and the changes between the second
day and baseline are described in the lower panel. Each time
point is the median value and its 95% confidence interval
across the study population.
The QTc, QTc apex, and TpTe intervals were significantly
correlated (P b .001) with the sotalol plasma concentration
(QTc: ρ = 0.97, QTc apex: ρ = 0.94, and TpTe: ρ = 0.89); but
Fig. 3 suggests t hat th e effect of th e drug on the
repolarization segment is not evenly distributed across the
QT interval. First, the profile computed from day 1 reveals
that the drug primarily prolongs the QT apex interval
(corrected for heart rate). The profiles of the QTc and QTc
apex are almost superimposed from hour 0 to hour 2.5.
During this period, sotalol does not induce any prolongation
of the TpTe interval (nearly equal to 0). During and after
2.5 hours after dosing, one can note that QTc apex has
reached a maximum, where as QTc interval continues to be
prolonged by the effect of the drug; this increase is the
contribution of the TpTe prolongation to the overall changes
of the QTc interval. During day 2, one can note a similar
development of the various interval prolongations with a
higher contribution of the TpTe interval during the period
between 1 and 2.5 hours after the dosing. As a note, there is a
Fig. 1. Illustration of the ERD and LRD (for a detection threshold equal to 30% of Vmax); ERD measures the time needed for the cardiac vector magnitude to be
reduced by 30% when following a clockwise rotation (opposite to time direction), whereas LRD is the time needed for the heart vector magnitude to be reduced
by 30% when following an anticlockwise rotation (toward the end of the T wave). The ERD and LRD parameters are reported on ev
1
in the lower panel (see text
for more detailed description).
Fig. 2. The curves provide the mean values and corresponding 95%
confidence intervals of level of sotalol plasma concentration within the study
population for the 2 days of the protocol. A single dose of 160 mg of sotalol
was given at time 0 of day 1, and a double dose (320 mg) was given at
time 0 of day 2.
597J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 3
carryover effect of the drug at the beginning of day 2 (Fig. 2)
leading to a slight but significant (P = .05) prolongation of
the QTc and QTc apex intervals at time 0. This carryover
effect might explain the slight contribution of the TpTe
interval during the first 2 hours of day 2 that does not exist
during day 1.
Profiles of sotalol-induced prolongation of the ERDs and
LRDs parameters
The average values of sotalol-induced changes of
ERD
70%
and LRD
70%
across day 1 and day 2 are presented
in Fig. 4. The figure is limited to these 2 parameters (70%)
for the clarity of purpose, but all other ERD and LRD
parameters (30% and 50%) have similar profiles. The ERD
and LRD parameters reflect dose-dependent prolongation
during day 1 and day 2. The drug effect profiles of ERDs
(ERD
30%
: ρ = 0.90, ERD
50%
: ρ = 0.93, and ERD
70%
: ρ =
0.96) and LRDs (LRD
30%
: ρ = 0.79, LRD
50%
: ρ = 0.81,
and LRD
70%
: ρ = 0.90) were highly correlated (P b .001
for all).
Comparing the profiles of sotalol-induced prolongation
measured by QTc apex and ERDs
Fig. 5 describes the superimposition of the sotalol-
induced changes of ERD
70%
and QTc apex.
During the first 3 hours after dosing, the QTc apex
prolongation is fully superimposed with the ERD
70%
,reveal-
ing that all the sotalol-induced prolongation of the QTc apex
interval is also captured by the ERD parameter. This state of the
repolarization is similar to the one we have observed while
studying the effect of moxifloxacin on the ventricular
repolarization process.
21
The portion of the signal encompassed by ERD
70%
is nested
inside the QT apex interval; it is noteworthy that sotalol-
induced repolarization prolongation measured by ERD
70%
continues to increase, whereas the prolongation of the QT apex
diminished. Indeed, at 6 hours after dosing, ERD
70%
measured
a prolongation twice that of QTc apex interval during day 2.
Based on this observation, one could suggest that the
heterogeneity is, in this specific example, dissociated from
the sotalol-induced prolongation of the ventricular repolariza-
tion process.
Timing of the sotalol-induced changes of the surface
repolarization parameter
As shown in Fig. 2 , the maximum plasma concentration
of sotalol occurred at 2.5 and 3 hours after dosing for day 1
Fig. 4. Profiles of the ERD and LRD parameters (for the 70% threshold)
during day 1 (upper panel) and day 2 (lower panel). The figures reveal that
the ERD and LRD parameters present a dose-response to sotalol.
Fig. 3. Sotalol-induced evolution of QTc, QTc apex, and TpTe intervals
across time for the 2 days of the study. The upper panel describes these
curves for day 1 (single dose), whereas the lower panel is for day 2 (double
dose). For each time point, we reported the median values among the
population and its 95% confidence interval. These measurements were fully
computerized. Apart from the first 3 and the last 3 time points from TpTe
interval of day 1, all sotalol-induced changes are significantly different from
0(P b .05).
598 J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 4
and day 2, respectively. Table 1 provides the values of the
maximum changes of sotalol on QTc, QTc apex, TpTe,
ERD
30%
, and LRD
30%
parameters and their associated time
of occurrence. The table reveals the presence of time shifting
of the peak effects of the drug between the various
repolarization parameters. For instance, QTc and QTc apex
show a peak effect occurring between 2.5 and 4 hours after
dosing, whereas the TpTe, ERDs, and LRDs were, on
average, at or beyond 4 hours after dosing.
These results suggest again the presence of an asynchrony
between the levels of drug effect on the early and late part of
the QT interval.
Interestingly, the sotalol-induced peak prolongation of the
QTc apex interval occurs much earlier than the peak
prolongation measured by the ERD parameters suggesting
that the morphology of the T-loop still changes while the QT
apex stop prolonging.
Discussion
This study describes the sotalol-induced changes of the
T-loop morphology in healthy individuals. We compare these
changes to the drug-induced prolongation of the QTc, QTc
apex, and TpTe intervals. All parameters reveal a dose-
dependent effect of sotalol on their values. The study is
consistent with the resul ts from the previous report describing
the effect of dl-sotalol on the QT measurements realized
using different recording and measurement techniques.
22
In addition, the study provides new insights into the
sotalol-induced changes of the morphology of the T loop and
their timing. Our discussion provides speculative explana-
tions for the dissociation observed between drug-induced
interval prolongation and loop morphology changes.
Assessment of abnormal T morphology in the congenital
long QT syndrome
The investigation of the T morphology has been primarily
used for characterizing individuals with the congenital form
of the long QT syndrome (LQTS) in whom specific T-wave
morphology has been linked to specific type of genetic
mutations.
23-29
The pioneering work related to T-wave
morphology analysis suggested that symptomatic LQTS
patients present a significantly higher percentage of notched
T waves than asymptomatic patients (81% vs 19%,
respectively).
25
Lehman et al
24
compared the prevalence of
T-wave humps (double-peaked T w aves: T2) in 254
members of 13 (diagnosed) LQTS families with 2900
healthy control subjects. In the group of patients with a
prolonged QT interval, T2 waves were present in 53% of
individuals, but only in 16% of those with borderline QTc. In
healthy volunteers, these numbers were less than 1%.
Thereafter, quantitative indices capturing T-wave morphol-
ogy were developed by Padrini et al
30
and were successful at
discriminating symptomatic patient s from age-matched
healthy subjects (n = 14). These preliminary works suggest
that T morphology bring s supplemental information to QTc
prolongation in such patients. More recently, our group
confirmed these observations; we investigated T morpho-
logy as a phenotypic expression of LQTS mutations when
Fig. 5. Differences in the pattern of the profile of sotalol-induced changes of
the ventricular repolarization process when quantified using the QTc apex
and ERD
70%
parameters. The 2 curves present different patterns being fully
synchronized during hour 0 and hour 2 and showing very different amplitude
between hour 3 and hour 10.
Table 1
Average timing and values and their 95% confidence interval for the repolarization indices
Unit Peak effect value
(day 1 day 0) (ms)
Peak effect time
(day 1 day 0) (h)
Peak effect value
(day 2 day 0) (ms)
Peak effect time
(day 2 day 0) (h)
QT apex (ev
1
) 38 ± 9 2.5 61 ± 9 2.5
QTc (ev
1
) 52 ± 19 3 83 ± 10 4
TpTe (ev
1
) 15 ± 6 4.5 34 ± 24 5
ERD
30%
15 ± 4 5 25 ± 9 5
ERD
50%
23 ± 6 4.5 51 ± 14 4
ERD
70%
42 ± 10 3.5 80 ± 17 3.5
LRD
30%
7 ± 3 4.5 14 ± 8 5
LRD
50%
8 ± 3 3.5 20 ± 12 5
LRD
70%
12 ± 8 4.5 41 ± 15 5
599J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 5
considering the two most spread forms of the syndrome
(whereas the QTc prolongation could not).
31
Based on Holter
technology and relying on an RR bin technique, the
repolarization indices ba sed on Principal Comp onents
Analysis (PCA), revealed their ability to separate patients
carrying KvLQT1 and KCNH2 mutations.
31,32
All these
reports consistently support the role of T morpholog y as a
phenotypic expression of the LQTS mutation by bringing
information complementary to the QT/QTc prolongation.
Assessment of abnormal T morphology in the acquired LQTS
In the acquired form of this syndrome or in patients with
drug-induced QT prolongation, ERD and LRD parameters
were compared with QTc prolongation for detecting the effect
of moxifloxacin. This antibiotic compound is a subtle I
Kr
inhibitor used as a positive control substance in drug safety
trial. It can trigger ventricular arrythmias but at very high
dose. Based on logistic models, we tried to separate the ECG
tracings on vs off drug. The ERD
30%
was selected as the
most relevant index to identify the presence of moxifloxacin.
Afterward, based on receiver operating characteristic analy-
sis, we compared 3 statistical models: (1) QTc; (2) ERD
30%
;
and (3) ERD
30%
, QTc apex, and TpTe intervals. First, the
results revealed that only the early part of the T wave was
prolonged and the TpTe interval was not affected by the drug.
Second, the receiver operating characteristic analysis demon-
strated that the combination of information about both
morphology and QTc prolongation maximized the ability of
the logistic method to separate the group of ECGs on and
off moxifloxacin.
21
The role of ERD, LRD, TpTe, and QTc intervals as
potential markers of the presence of an arrhythmogenic
substrate has been further investigated by comparing their
values in 2 groups of cardiac patients with and without a
history of drug-induced TdPs.
33
This work revealed that
baseline ECGs present specific T-loop morphology and
abnormal ERD values characterizing patients with a
predisposition to TdPs. The ERD
30%
and the ERD
50%
were
significantly higher in patients with a history of TdPs in
comparison with patients without such history (35 ± 8 vs
44 ± 13 msec, respectively; P = .03), yet the QTc apex was
not prolonged in these patients (350 ± 19 vs 358 ± 23 msec,
P = .3). Such observation suggests that the patients with a
predisposition to drug-induced TdPs could present higher
repolarization heterogeneity at baseline captured by our
novel ECG markers (ERDS).
TpTe interval and T-loop morphology
Heterogeneity of ventricular repolarization is known to
underlie arrhythmogenesis.
6,34
TheTpTeintervalwas
introduced as a marker of transmural dispersion in the
wedge preparation from dog by Watanabe et al
14
; and
subsequently, it was described as an independent predictor of
TdPs in several human studies: Takenaka et al
13
have shown
that, during exercise, ECG tracings from LQT1 patients have
a prolonged TpTe interval, whereas the ECGs from LQT2
patients do not. Because LQT1 patients are prone to cardiac
events under exercise, this study would support the link
between an increased TpTe interval and the presence of an
arrhythmogenic substrate. In addition, clinical observations
have emphasized the presence of TpTe prolongation in
patients with TdPs
35
and have presented the TpTe prolonga-
tion as a marker of arrhythmia inducibility.
14
In animal
studies, this concept has been strengthened further in
experiments involving nontorsadogenic drugs (amiodarone
36
and pentobarbital sodium
37
) prolonging the QTc interval but
reducing the transmural dispersion.
Additional studies are needed to better understand the
meaning of an abnormal prolongation of the TpTe interval
when measured from the surface ECGs. Xia and Yuan
15
and
Opthof et al
12
investigated the correlation between TpTe and
transmural dispersion in animals (swine and dogs), but they did
not find any relation. Clearly, there is a lack of understanding
around the respective contributions of transmural dispersion
and apicobasal heterogeneity of repolarization to the inscrip-
tion of the TpTe interval on the body surface ECGs.
Our study compares the dose-response of parameters
designed to measure both repolarization prolongation/short-
ening and heterogeneity from the vectorial loop. First , the
results show that the sotalol-induced changes of ERDs are
correlated with QTc apex interval during the first 2 hours
after dosing but they become dissociated from QTc apex
beyond 2 hours after dosing. Because ERD prolongs whereas
QT apex (measured from first eigenvector) starts decreasing,
one would expect the repolarization changes captured by
ERD to be issued from the second eigenvector (defining the
second axis of the T loop) and thus to correspond to changes
in T-loop morphology reflecting an increased heterogeneity
of the ventricular repolarization . Second, the LRD para-
meters represent the same measurements as ERDs but are
located in the late part of the T-wave apex. Interestingly, the
LRD parameters are not dissociated with sotalol-induced
TpTe prolongation, suggesting that TpTe and LRD might
measure the same information. Therefore, our analysis
enriches our current effort to better understand how the
morphology of the T wave may help us to better separate
dangerous from safe QT-prolonging drugs. Based on our
current observations, (1) moxifloxacin is associated with
ventricular repolarization heterogeneity mainly located in the
early portion o f the T wave (in healthy individuals),
21
(2)
patients with a history of drug-induced TdPs have longer
sotalol-induced QT prolongation than patient without a
history of TdPs (in addition, they present more pronounced
sotalol-induced changes in the late portion of the T wave
[TpTe interval and LRDs]),
33
and (3) we suggest in this
study that sotal ol produces large QT prolongatio n and
profound increased heterogeneity detected in both the early
and late portion of the T wave of healthy individuals; more
importantly, (4) the time of peak sotalol-induced QT
prolongation was not synchronized with the time of
maximum ventricular heterog eneity.
To conclude, one can speculate that non-torsadogenic drugs
could provoke smaller ventricular heterogeneity than torsado-
genic drugs. In sotalol, the overall T-wave/T-loop morphology
is affected (early and late portion of the T wave), whereas in
moxifloxacin, only the early portion of the T wave is changed.
This observation is consistent with the description of
repolarization heterogeneity reported in patients with the
600 J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 6
congenital LQTS
38
showing large interlead disparity in T-wave
morphology (increased repolarization heterogeneity). Such
hypothesis about the predominant role of the repolarization
morphology in predicting an individual predisposition to
ventricular arrythmias should be challenged by studying
torsadogenic drugs with small QT prolongation effect.
Limitations
A prior work investigated the robustness of the T-loop
indices to slight shifts of QT interval definition; the authors
suggested that such transformation was robust to such
variation.
39
In our study, we lack such investigation; and the
reproducibility and robustness of our repol arization indices
should be demon strated in future works. Second, we opted to
use a pooled technique to correct our parameters for heart
rate. Such stra tegy generates an opportunity for a biased
estimation of the drug effect on the repolarization indices.
Indeed, we used the baseline data to estimate these
relationships, although we have shown that sotalol modifies
this relationship.
20
However, as of today, the authors do not
believe there is a more appropriate alternative to such
method when using 10-second ECG tracings.
Conclusions
The study presents a description of the effect of sotalol on
the T wave and the T loop and the effect of the changes in
plasma concentration of the drug on various repolarization
quantifiers. The study suggests that the peak plasma
concentration is synchronized with its peak effect on QT
interval but not with its peak effect on ventricular h etero-
geneity. These observations require confirmation in a larger
set of data; but today, they clearly reveal that drug-induced
QT prolongation represents only one aspect of the effect of
sotalol to the repol arization intervals from surface ECGs.
These observations might help design the next generation of
ECG markers for the e valuation of drug cardiotoxicity.
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Paper drag mimicking sinus tachycardia
Two simultaneously recorded rhythm strips are shown. The rhythm begins as normal sinus with ventricular bigeminy, as each sinus-stimulated QRS
complex is followed by a premature ventricular complex (asterisks). After the third premature ventricular complex (gray box), the rhythm appears to
become more rapid, eventually coming to resemble sinus tachycardia at a ventricular rate close to 200 beats per minute. The premature ventricular
complexes are also becoming more narrow than at the beginning of the rhythm strip. Upon careful inspection, some of the PR intervals are clearly
measured to be physiologically impossible (some are as short as 40 milliseconds), as are some QT intervals (some are as short as 120 milliseconds); and PR
intervals, QRS durations, and QT intervals are varying. Apparent rapid rates which are accompanied by physiologically impossible conduction times and
compressed PQRST complexes represent paper drag (in older Holter recordings which employed reel-to-reel tape, tape drag resulted in the same
phenomenon.) In this case, the paper drag occurred at the central telemetry write-out unit in the nursing station. Paper drag can be present anywhere that
printer paper is used, such as analog electrocardiogram machines and telemetry units.
Kurt S. Hoffmayer, PharmD, MD, and Nora Goldschlager, MD
San Francisco, CA, USA
doi:10.1016/j.jelectrocard.2008.07.014
602 J.-P. Couderc et al. / Journal of Electrocardiology 41 (2008) 595602
Page 8
  • Source
    • "The QT interval and its correction for heart rate (HR), QTc, are the most extensively used indices of ventricular Available online at www.sciencedirect.com repolarization, but other T-wave-based electrocardiogram (ECG) indices have also been investigated, including the interval between the T-wave peak and the T-wave end (Tpe) [3]. The Tpe interval has been proposed by recent studies to reflect differences in the time for completion of repolarization of different ventricular regions [4,5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Previous studies investigated the QT/RR relationship by linear regressions of QT and RR intervals. However, the pattern of the QT/RR relationship is not necessarily linear. This study investigated the QT/RR and T-peak-to-end (Tpe)/RR curvatures and corresponding slopes in chronic heart failure (CHF) patients, and studied their differences between sudden cardiac death (SCD) victims and others. Methods Holter ECG recordings of 650 CHF patients were analyzed. RR, QT and Tpe series were obtained and for each patient, the data of each subject were fitted with a non-linear regression function of the form: QT = χ + φ(1-RRγ), where γ is the QT/RR curvature . The same regression formula was applied to the Tpe interval series. The slopes (dimensionless units) were calculated at the averaged RR intervals and at RR of 1 second. Results The median (difference between 75th and 25th percentile) of the curvature parameter was 0.226 (2.39) for QT/RR and -0.002 (3.64) for Tpe/RR in the overall sample. For the QT/RR slope, these values were 0.170 (0.12) and 0.190 (0.10) when evaluated at RR = 1 and at the averaged RR, respectively, while for the Tpe/RR slope the values were 0.016 (0.04) and 0.020 (0.04), respectively. The Tpe/RR slope showed high statistical significance for separation of SCD victims and others, particularly when evaluated at the averaged RR (median values of 0.040 vs 0.020, p = 0.002), but also when evaluated at RR = 1 second (0.026 vs 0.015, p = 0.023). Patients with values of Tpe/RR slope above 0.042 had double incidence of SCD, for the case of the slope being evaluated at RR = 1 second, and triple incidence for the case of the slope being evaluated at the averaged RR. The QT/RR slope and curvature, as well as the Tpe/RR curvature, were not different in SCD victims and in others. Conclusions Non-linear regression models based on curvature and slope characteristics, individually obtained for each patient, were used to characterize the QT/RR and Tpe/RR relationships. Steeper Tpe/RR slopes, obtained after adjusting for the curvature parameter, were associated with higher incidence of SCD. The curvature parameter itself did not show SCD predictive value.
    Full-text · Article · Nov 2014 · Journal of Electrocardiology
  • Source
    • "The QT interval and its correction for heart rate (HR), QT c, are the most extensively used indices of ventricular repolarization, but other T-wave-based electrocardiogram (ECG) indices have been investigated, including the interval between the T-wave peak and the T-wave end (T pe ) [1]. Increased QT /RR and T pe /RR slopes have been shown to be independent predictors of sudden cardiac death (SCD) in patients with chronic heart failure (CHF) [2, 3] . "
    [Show abstract] [Hide abstract] ABSTRACT: Increased QT /RR and Tpe /RR slopes have been shown to be independent predictors of sudden cardiac death (SCD) when analyzed over a 24-hour ECG recording. The circadian influence on the QT /RR slope is well-known but it has never been tested on the Tpe /RR slope. This work studied the inter-individual variability of the curvature and slope of QT /RR and Tpe /RR, as well as their circadian pattern in women and men. Holter ECG recordings of 385 patients with chronic heart failure (CHF) from the " MUSIC " database were analyzed. ECGs were delineated using a single-lead procedure over the first principal component lead derived to emphasize the T-wave. RR, QT and Tpe series were obtained and for each patient, a regression equation was fitted, where γ is the QT /RR or Tpe /RR curvature , and Δ is the slope of the regression pattern evaluated at the medium RR value. The median (IQR) slope was Δ QT = 0.194 (0.11), and Δ Tpe = 0.018 (0.04). The median (IQR) curvature was γ QT = 0.993 (0.17) and γ Tpe = 1.000 (0.04), respectively. The circadian pattern modulated the QT /RR and Tpe /RR curvature and slope, with statistically significant differences between day and night for QT /RR slope. No statistically significant differences in gender were found in this study. According to the results in this work, the time of the day should be considered when using QT /RR slope for SCD risk prediction, but the Tpe /RR slope is less sensitive to the circadian pattern.
    Full-text · Conference Paper · Sep 2014
  • Source
    • "Clinical and experimental studies have suggested that abnormalities of ventricular repolarization play a role in the genesis of ventricular arrythmias [1] . The QT interval of the electrocardiogram (ECG) is the most extensively used index of repolarization, but other ECG indices related to the T wave have been proposed in the last years, including the interval between the T wave peak and the T wave end (T pe ) [2]. The T pe interval is generally accepted to reflect differences in the time for completion of repolarization of different ventricular regions and has been proposed as a measure of dispersion of repolarization [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: In predicting the risk of suffering from ventricular arrhythmias, the dynamics of QT and T-peak-to-T-end (Tpe) intervals after changes in heart rate (HR) provide richer information than their values themselves. In this study, QT/RR and Tpe/RR dynamics were investigated. Electrocardiogram (ECG) recordings of healthy subjects were analyzed during a head-up tilt test. ECGs were delineated using multi-lead (ML) and single-lead (SL) techniques and the QT and Tpe intervals series were obtained. QT/RR and Tpe/RR dynamics were modeled using a nonlinear system, from which the time constant of adaptation t90 was derived. QT/RR dynamics is similar using SL or ML delineation, with adaptation times being: tSL90[s] = 49.7 +/-29.0, tML90 [s] = 47.1 +/- 20.1. The Tpe interval responded more abruptly to HR when calculated using SL as compared to ML. Consequently, Tpe/RR dynamics were characterized by different adaptation time constants depending on whether SL or ML was used: tSL90 [s] = 25.6 +/- 37.3, tSL90 [s] = 56.4 +/- 48.3. QT dynamics can be invariantly characterized using either SL or ML delineation, while Tpe dynamics are highly sensitive to the delineation method. Differences arise from the way SL and ML delineation are affected by T-wave loop rotation. Care should be taken when electrophysiological interpretation is provided to measurements obtained from one or the other delineation methods.
    Full-text · Conference Paper · Jan 2012
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