611

Effects of Cardiac Resynchronization Therapy on Ventricular

Repolarization in Patients with Congestive Heart Failure
THOMAS BERGER, M.D., FRIEDRICH HANSER, PH.D., FLORIAN HINTRINGER, M.D.,
GERHARD POELZL, M.D., GERALD FISCHER, PH.D., ROBERT MODRE, PH.D.,
BERNHARD TILG, PH.D., OTMAR PACHINGER, M.D., and FRANZ X. ROITHINGER, M.D.
From the Innsbruck Medical University, Clinical Division of Cardiology; and University for Health Informatics and Technology
Tyrol, Innsbruck, Austria

Biventricular Pacing and Ventricular Repolarization. Introduction: Biventricular pacing has

been shown to improve the clinical status of patients with congestive heart failure, but little is known about
its influence on ventricular repolarization. The aim of our study was to evaluate the effect of biventricular
pacing on ECG markers of ventricular repolarization in patients with congestive heart failure.
Methods and Results: Twenty-five patients with congestive heart failure, sinus rhythm (SR), and complete
LBBB (6 females; age 61 8 years; NYHA class IIIII; echocardiographic ejection fraction 21 5%; QRS
130 ms) underwent permanent biventricular DDDR pacemaker implantation. A high-resolution 65-lead
body-surface ECG recording was performed at baseline and during right-, left-, and biventricular pacing,
and the total 65-lead root mean square curve of the QRST complex and the interlead QT dispersion were
assessed. The QRS duration was increased during right (RV)- and left ventricular (LV) pacing (127 26%
and 117 40%; P < 0.05), as compared to SR (100%) and biventricular pacing (93 16%; ns). The QTc
interval was increased during RV and LV pacing (112 12% and 114 14%; P < 0.05) as compared to SR
(100%) or biventricular pacing (99 12%). There was no effect on JT interval during all pacing modes.
The Tpeakend interval was increased during right (120 34%; P < 0.01) and LV pacing (113 29%; P <
0.05) but decreased during biventricular pacing (81 19%; P < 0.01). A similar effect was found for the
Tpeakend integral and the Tpeak amplitude. QT dispersion was increased during right ventricular (129 16
ms; P < 0.05) and decreased during biventricular pacing (90 12 ms; P < 0.01), as compared to SR (114
22 ms).
Conclusions: Using a high-resolution surface ECG, biventricular pacing resulted in a significant reduction
of ECG markers of ventricular dispersion of repolarization. (J Cardiovasc Electrophysiol, Vol. 16, pp. 611-617,
June 2005)

biventricular pacing, ventricular repolarization, congestive heart failure, body surface electrocardiography

Introduction synchronization, systolic function, and especially exercise

Congestive heart failure affects 12% of the population
and is associated with a considerable morbidity and mor-
tality due to the increased risk for ventricular arrhythmias
and sudden cardiac death.1,2 Approximately one-third of the
patients with congestive heart failure exhibits an interven-
tricular or intraventricular conduction delay with a QRS in-
terval of more than 120 ms, which has been found to be
a harbinger of clinical instability and an increased risk of
death.3,4 In the last years, simultaneous stimulation of both
the right and the left ventricle, via a branch of the coronary
sinus, has been performed as an adjunct to pharmacological
therapy of heart failure patients with ventricular conduction
delay. Several randomized studies demonstrated that biven-
tricular pacing results in an improvement of interventricular
This work was supported in part by the Austrian Science Fund (FWF; grant
START Y-144-N04) and a grant by Medtronic, Inc. Austria.
Address for correspondence: Franz X. Roithinger, M.D., Department of In-
ternal Medicine, Division of Cardiology, Anichstr. 35, A-6020 Innsbruck,
Austria. Fax: +43 512 5043379; E-mail: franz.roithinger@uklibk.ac.at
Manuscript received 5 July 2004; Revised manuscript received 22 November
2004; Accepted for publication 24 November 2004.
doi: 10.1111/j.1540-8167.2005.40496.x
tolerance and quality of life.5-7 However, little is known yet
about the effect of cardiac resynchronization therapy on ven-
tricular repolarization and all-cause mortality.8,9,14 Given the
proposed effect of biventricular pacing on QRS duration,7
one would assume that simultaneous endocardial (right ven-
tricular) and epicardial (left ventricular) pacing might also ex-
ert beneficial effects on ventricular repolarization, especially
on parameters suggested to represent dispersion of ventric-
ular repolarization. However, previous experimental data in
left ventricular (LV) wedge preparations have shown that the
ventricular activation sequence during epicardial pacing may
even augment transmural heterogeneity of repolarization of
the ventricular myocardium and prolong the QT interval on
a surrogate ECG.8,9 Yet, these findings are not supported
by clinical data, where no excess mortality due to arrhyth-
mias could be demonstrated in patients undergoing cardiac
resynchronization therapy.6,7,10-14 Nevertheless, the distinct
effects of biventricular pacing on ventricular repolarization
in humans are still poorly understood.
The aim of our study was to test the hypothesis that biven-
tricular pacing therapy exerts no obvious potentially dele-
terious effects on markers of cardiac repolarization in the
surface ECG. For precise analysis of ventricular repolariza-
tion, additional parameters less dependent on depolarization
alterations, such as the JT interval and the Tpeakend interval,
612 Journal of Cardiovascular Electrophysiology Vol. 16, No. 6, June 2005

were incorporated into our analysis by using a high-resolution Sinus rhythm

65-lead body surface ECG mapping system.
1

Potential / mV
A B
0.8 (150 ms) (231 ms)
Methods
Patients
0.6 C
Twenty-five consecutive patients (6 female, age 61 (98 ms)
8 years) with congestive heart failure (NYHA class IIIII;
echocardiographic ejection fraction 21 5%) due to ischemic 0.4
(N = 11) or nonischemic (N = 14) cardiomyopathy were
studied. All patients were in sinus rhythm (SR) and demon- 0.2 D
strated a left bundle branch block in the standard 12-lead ECG
(QRS duration 130 ms; mean QRS duration 150 24 ms), E
and all patients underwent first time permanent biventricular 0
5300 5400 5500 5600 5700 5800 5900
DDDR pacemaker implantation. In all patients included into Time / ms
evaluation, the LV lead was placed in a posterolateral vein cor-
responding with a position in the LAO 45 projection between Biventricular pacing
1.30 and 3.30 pm. Heart failure medication (ACE-inhibitors, 1

Potential / mV
-blockers, diuretics, digoxin) of the patients remained un-
changed during the previous 8 weeks. None of the patients A B
0.8 (142 ms) (230 ms)
was on class I or III antiarrhythmic drug therapy. Following
pacemaker implantation, a rate below the intrinsic heart rate
(VVI 30) was programmed in order to avoid cardiac mem-
0.6
ory effects on ventricular repolarization. Electrocardiogram
recording was performed 1 or 2 days after pacemaker im- C
plantation and prior to active ventricular pacing. 0.4 (75 ms)
The study was approved by the local ethics committee
and written, informed consent was obtained from all patients
prior to enrollment. 0.2
D
E
0
Data Acquisition 1600 1700 1800 1900 2000 2100 2200
Time / ms
High-resolution 65-lead body-surface ECG recording was
performed, using a 65-channel Mark-8 system (Biosemi Figure 1. A: QRS duration, B: JT interval, C: QT interval (A + B), T peakend
V.O.F., The Netherlands). The leads were placed around the interval, D: T peak amplitude, and E: T peakend integral during sinus rhythm
torso relative to Wilsons central terminal as a reference with (SR) and biventricular pacing.
a higher lead density on the anterior and left lateral chest.15
Recordings were performed during resting tidal volume res-
piration, as the different phases of this breathing pattern have
not been found to exert a significant influence on signal am- Data Analysis
plitude or spatial potential distribution.16 Special attention The 65-lead ECG mapping raw data were preprocessed
was paid to eliminate all correctable causes of noise such as to correct baseline fluctuations by baseline correction, and
muscle tremor and suboptimal electrode contact, and to min- a butterworth filter was used for signal processing, using
imize electromagnetic frequency interference generated by Matlab analyzing software (MathWorks, Inc., Natick, MA).
electrical sources next to the lead array. Recorded data were The leads were excluded from analysis either when the end of
transmitted optically from a preamplifier box to a personal the T-wave was not clearly distinguishable, or the signal qual-
computer (Pentium II, 600 MHz; 256 MB RAM memory) ity was too poor for analysis. A maximum of five leads were
dedicated to online acquisition and storage of data. The sam- excluded during SR or paced rhythm. Manual QT measure-
pling rate was 2048 Hz. Signals were bandpass filtered with a ments were performed using online, digital calipers (Fig. 1).
lower and an upper edge frequency of 0.3 and 400 Hz, respec- For SR and each pacing mode, the 65-lead as well as the pre-
tively. The AC-resolution of the system was 500 nV/bit (16 bit cordial lead (V1V6) total root mean square (RMS) curves
per channel). Sixty-five-lead ECG recording was performed for the total QRST interval were assessed, according to the
during SR, right ventricular, LV, and biventricular pacing in formula
VDD mode (30 bpm; AV delay 150 ms). Each stimulation

was performed for 3 minutes and pacemaker programming N 2
i=1 vi (t)
was performed subsequently after each sequence. Pacing se- RMS(t) =
quences were randomly switched between the patients and N
no effects on the results had been observed. The last 20 sec-
onds were stored, and one representative QRST complex was as previously described.17 N = number of signals included
selected for analysis by visual comparison of all QRST com- in the analysis, vi (t) = the voltage measured in lead i at time-
plexes within the recording (Matlab software). step t.
 Berger et al. Biventricular Pacing and Ventricular Repolarization 613

Definitions
Each patients intrinsic QRST complex during SR was
used as an individual baseline value for comparison and con-
sidered to be 100%. The parameters of depolarization and
repolarization during different pacing modes are presented
as percentage thereof. The QRS duration (ms) was defined
as the interval between the initial deflection of the QRS com-
plex to the J-point. The QT interval was defined as the time
interval between the initial deflection of the QRS complex
to the end of the T-wave. (T-end was defined visually us-
ing the maximum curvature method. Peaks in curvature were
only considered valid if they were three times higher than the
curvature peaks of the RMS noise during the following TP
interval.17 ) JT interval was derived by subtracting the QRS
duration from the QT interval. The Tpeakend interval (ms) was
defined as the interval from the maximum T-wave amplitude
to the end of the T-wave (Fig. 1). QT dispersion was calcu-
lated for each patient during SR and each pacing mode as the
difference between the maximal and the minimal QT value in
all leads.18 Computerized estimation (integral) of the area un-
der the manually determined Tpeakend RMS curve resulted
in values for the areas of the Tpeakend intervals (mVms =
Vs).19 Furthermore, we measured the maximum amplitude
(mV) of the T-waves. Measurements were corrected for heart
rate using Bazetts formula.
Statistical Analysis
Statistical analysis of the data was performed using Stu-
dents t-test for paired data or one-way ANOVA coupled with
LSD test among three or more groups. Data are presented
as mean SD. Differences were considered significant at
P < 0.05.
Results
Influence of Pacing Site on Ventricular Depolarization
Right ventricular and LV pacing increased QRS duration
(127 26% and 117 40%, P < 0.01) as compared to
intrinsic SR (100%), whereas biventricular pacing did not
show a significant effect on QRS duration (93 16%, ns) in
the 65-lead RMS.
Influence of Pacing Site on Ventricular Repolarization
The baseline 65-lead RMS QTc interval was 511 48 ms.
The effects of different pacing modes on 65-lead RMS QTc
interval, JT interval, Tpeakend interval, Tpeak amplitude, and
Tpeakend integral are shown in Figure 2, expressed as per-
centage with respect to SR (100%). The QTc interval during
single right and single LV pacing was significantly increased,
as compared to SR and biventricular pacing. There was no
effect on JT duration during the different pacing modes as
compared to SR. The Tpeakend interval was also significantly
increased during right ventricular and LV pacing, whereas
biventricular pacing significantly decreased the Tpeakend in-
terval (81 17% of SR, P < 0.01; Fig. 2). A similar effect
on Tpeakend integral and Tpeak amplitude was found: right
ventricular and LV pacing both caused a significant increase
of Tpeakend integral and Tpeakend amplitude, whereas biven-
tricular pacing significantly decreased Tpeakend integral and

200 200 200

(A) * (B) (C)
*
150 150
* *
150
% of SR

% of SR

% 0f SR

100 100

100
50 50

0 SR RV LV BiV 0 SR RV LV BiV 50 SR RV LV BiV

250 350 350

(D) (E) (F)
300 300
200 ** ** ** **
* 250 250
**
150
% of SR

% of SR

% of SR

200 200

** 150 150
100
* *
100 100
50
50 50

0 SR RV LV BiV 0 SR RV LV BiV 0 SR RV LV BiV

Figure 2. A: Pacing site dependent changes in QRS interval, B: QTc interval, C: JTc interval, D: T peakend interval, E: T peakend integral, and F: T peak
amplitude during SR, right ventricular (RV), left ventricular (LV), and biventricular (BiV) pacing. Results are expressed as median SD ( = P < 0.05,
= P < 0.01 with respect to the intrinsic QRST complex [SR = 100%]).
614 Journal of Cardiovascular Electrophysiology Vol. 16, No. 6, June 2005

ECG. The results obtained from the standard precordial lead

250 RMS and from the 65-lead RMS are shown in Table 1.

Discussion
200 Main Findings
In the present study, differences in various parameters
of ventricular depolarization and repolarization during right

150 * ventricular (RV), LV, and biventricular pacing in heart fail-

ure patients can be obtained, using high-resolution 65-lead
body-surface ECG measurements. In contrast to biventric-
ms ular pacing, RV, and LV pacing increase QRS duration as

100
**
50
0 SR RV LV BiV
Figure 3. Pacing-site dependent changes in interlead QT dispersion. Results
are expressed as median SD ( = P < 0.05, = P < 0.01).
Tpeak amplitude (71 26% and 84 36% of SR, respectively;
Fig. 2).
Influence of Pacing Site on QT Dispersion
Left ventricular pacing showed no significant effect on
interlead QT dispersion (100 15 ms), whereas right ven-
tricular pacing significantly increased (129 16 ms; P
< 0.05) and biventricular pacing significantly decreased
(90 12 ms; P < 0.01) the interlead QT dispersion, as
compared to SR (114 22 ms; Fig. 3) in the 65-lead
ECG.
Comparison of 65-Lead RMS Versus Precordial
Lead RMS
Using the precordial leads V1V6, the effects on QRS du-
ration, QT, JT interval, Tpeakend integral, and Tpeak amplitude
are similar during all pacing modes, whereas a significant de-
crease in Tpeakend interval was only visible using the 65-lead
well as the QT interval, whereas there was no effect on the
JT interval during all pacing modes. There was no significant
decrease in QRS duration during biventricular pacing. Biven-
tricular pacing results in a decrease of the Tpeakend interval,
Tpeakend integral, Tpeak amplitude, and interlead QT disper-
sion, as compared to SR. There was no significant decrease in
Tpeakend interval in the precordial leads, although Tpeakend
integral and Tpeak amplitude were significantly decreased
corresponding to the results obtained from the 65-lead
ECG.
Previous Studies
Increased JTc, QT interval, and QT dispersion have
been demonstrated in patients with acute myocardial infarc-
tion,20,21 heart failure,22,23 and long QT syndrome.24 Al-
though there are some prospective studies about the prog-
nostic value of QT dispersion as a measure of ventricular
repolarization heterogeneities for cardiac and all-cause mor-
tality,18,25 there is still an ongoing discussion concerning the
validity of QT-dispersion measurements in clinical practice,
especially in patients with prolonged QRS duration.17,26 In a
recent experimental study,17 the RMS curve analysis of the
T-wave provided an accurate method for estimation of the dis-
persion of repolarization from the body surface, as opposed
to standard QT-dispersion analysis.
In our study, we evaluated interlead QT dispersion, RMS
Tpeakend interval, Tpeak amplitude, and the area (integral) of
the Tpeakend curve as further markers of repolarization dis-
persion. Root mean square T-wave amplitude and Tpeakend
integral may be useful for assessment of repolarization dis-
persion, as in case of increased dispersion, the repolarization
vectors of any ECG lead do not add their magnitudes in op-
posite polarity to zero. This results therefore in an increase of
the corresponding RMS T-wave amplitude and in an increase
of the RMS Tpeakend integral.17

TABLE 1
Pacing-Site Dependent Changes in Parameters of Ventricular Repolarization and Depolarization in the 65-Lead and the Precordial RMS Curves

65-lead RMS Precordial RMS (V1-V6)

N = 25 RV (% of SR) LV (% of SR) BiV (% of SR) RV (% of SR) LV (% of SR) BiV (% of SR)

QRSc 127 26% 117 40% 93 16% 128 26% 135 41% 105 16%
QTc 112 12% 114 14% 99 12% 116 11% 118 15% 104 11%
JTc 102 14% 107 17% 102 13% 102 25% 106 29% 100 29%
Tpeakend interval 120 34% 113 29% 81 19% 126 28% 125 27% 100 21%
Tpeakend integral 161 55% 150 64% 71 26% 139 63 163 106 74 39
Tpeak amplitude 156 47% 149 72% 84 36% 143 86 168 124 76 41
P 0.05 versus SR; P 0.01 versus SR.
BiV = biventricular; LV = left ventricular; RMS = root mean square; RV = right ventricular; SR = sinus rhythm.
 Berger et al.
In heart failure patients, an increase of action poten-
tial duration, especially in the midmyocardial cell lay-
ers (M-cells), may result in enhanced transmural electrical
heterogeneities, accounting for QT-interval prolongation and
increased transmural dispersion of ventricular repolarization,
and may therefore cause intramural conduction block and
reentrant polymorphic ventricular tachyarrhythmia.27 The
Tpeakend interval, which encompasses the terminal portion
of the T-wave, closely represents transmural dispersion of re-
polarization in a wedge of myocardium19 and has been sug-
gested to be clinically useful in assessing arrhythmia risk.28,29
Recent experimental studies8,9 suggested a potentially
harmful effect of cardiac resynchronization therapy on ven-
tricular repolarization in ventricular wedge preparations. The
authors found that LV epicardial and biventricular pacing
prolongs QT interval and increases transmural dispersion of
repolarization, which could possibly cause an increased risk
for polymorphic ventricular tachyarrhythmia in heart fail-
ure patients undergoing cardiac resynchronization therapy.8
However, Tpeakend interval was not measured at baseline and
during biventricular pacing due to problems in ECG quality
(low amplitudes). In our study, we were able to obtain that
information, using 65-lead RMS curves, which makes the
analysis robust with respect to a low signal-to-noise ratio
in low amplitude signals.17 Furthermore, we measured the
Tpeakend integral, which might be superior to the Tpeakend
interval, as from a mathematical point of view, this index is
less dependent on the offset of the T-wave due to the low
amplitude values in that part of the curve.17
However, a direct comparison of results obtained from
body surface ECG and data obtained from animal wedge
preparations8,9 might be difficult as the signals investigated
in our study are far field unipolar recordings, whereas in the
wedge model, near field bipolar pseudo ECGs were recorded.
Tpeakend parameters obtained from body surface mapping
may represent heterogeneities in ventricular repolarization,17
although it is unlikely that they closely depict transmural dis-
persion of repolarization as in wedge preparations, due to
differences in spatial resolution. As Tpeak represents the ear-
liest cells to complete repolarization and Tend represents the
latest cells finishing repolarization, it is not likely to provide
spatial information of transmural dispersion in the surface
ECG, especially in the presence of structural abnormalities
and prolongation of action potential duration. Nevertheless,
the Tpeakend interval might be a better predictor than the QT
dispersion for the assessment of ventricular repolarization
heterogeneities in patients with intraventricular conduction
abnormalities,29 as this parameter is less dependent on ven-
tricular depolarization.
Clinical Implications
Ventricular repolarization parameters are not yet widely
used for arrhythmogenic risk stratification due to a consider-
able degree of overlap between healthy subjects and patients
with structural heart disease, as well as due to methodologi-
cal difficulties in assessing the T-wave offset because of low
T-wave amplitudes in the standard 12-lead ECG.26 The use
of a high-resolution body-surface ECG for assessment of the
RMS Tpeakend interval, Tpeakend integral, and Tpeak ampli-
tude, however, may overcome these obstacles and provide
useful information about ventricular repolarization.30,31 Our
data suggest that the QT interval may be an invalid param-
Biventricular Pacing and Ventricular Repolarization 615
eter for exact estimation of ventricular repolarization in pa-
tients with pacemakers and congestive heart failure due to
the impact of the prolonged depolarization interval on the
QT-interval duration.
Although biventricular pacing is widely and successfully
implemented in the therapeutic regimen of heart failure pa-
tients in order to improve exercise capacity and quality of
life, little is known about its influence on ventricular repolar-
ization. In a recent study, biventricular pacing is suggested to
have potential detrimental effects on ventricular repolariza-
tion.8 Nevertheless, prospective, randomized studies did not
find any excess mortality due to sudden death.7,14 In contrast,
possible surrogate parameters for malignant arrhythmia and
sudden death, such as inducibility of ventricular arrhythmias
and appropriate ICD therapy, were even in favor of biventric-
ular pacing therapy.11-13 In fact, data of the COMPANION
trial showed a relative risk reduction in mortality of 24%
during biventricular pacing, as compared to optimal medical
treatment, in patients with congestive heart failure.14
Nevertheless, our results are in accordance with recent ex-
perimental findings,8,9 indicating that single epicardial pac-
ing might have detrimental effects on ventricular repolariza-
tion in a subpopulation of patients with predisposition to QT
prolongation. In contrast, we did not observe any negative ef-
fects of biventricular pacing on parameters of ventricular re-
polarization. Thus, biventricular pacing is noninferior to sin-
gle RV and LV pacing with respect to repolarization alteration
in the surface ECG. Furthermore, sole LV pacing should be
implemented with caution in clinical practice until we know
the exact mechanisms how repolarization is altered and who
is prone to developing torsade de pointes tachyarrhythmias.
Limitations
Acquisition of the ECG data has been performed at the ini-
tial activation of ventricular stimulation in order to avoid any
cardiac memory effects during SR. Therefore, our findings
cannot be extrapolated to chronic pacing. Furthermore, no
prospective evaluation of arrhythmogenic events during dif-
ferent stimulation modes has been performed in our study. QT
parameters have been assessed manually, which may result in
an intraobserver and interobserver variability, especially for
the estimation of the T-wave offset. Nevertheless, especially
the Tpeakend integral and the Tpeak amplitude are in accor-
dance with the Tpeakend interval measurements, which are
less observer-dependent. A direct comparison of results ob-
tained from wedge preparations with clinical results should
be performed with caution, until the reliability of assessment
of transmural dispersion of repolarization in surface ECG
measurements is proven in further studies. Because of the
present study design, this study may be insufficient to re-
veal a clear superiority of the 65-lead ECG, as compared to
the precordial lead RMS. However, as all patients included
in our study had a severe structural heart disease, precordial
leads might not be sensitive to signal components arising, for
example, from areas of injured myocardium in the posterior
wall. Thus, the high-resolution 65-lead ECG may give a more
complete picture of cardiac electric activity.30,31 One might
assume that the changes in QTc and Tpeakend intervals may
be entirely or in large part secondary to pacing-dependent
alterations of the QRS complex. Interestingly, according
to a study by Salim et al.,32 we found no correlation be-
tween the JTc interval and the QRS duration. Furthermore, in
616 Journal of Cardiovascular Electrophysiology Vol. 16, No. 6, June 2005
accordance with other data,33,34 biventricular pacing did not
result in a significant decrease in QRS duration, whereas there
was a significant decrease of Tpeakend parameters. Thus, sim-
ilar to the JT interval, the Tpeakend parameters may be less
dependent on cardiac depolarization alterations than QT mea-
surements, and may therefore provide a more reliable esti-
mation of ventricular dispersion of repolarization in patients
with conduction abnormalities.29 Further studies are needed
to resolve these issues.
Conclusions
Using a high-resolution surface ECG, biventricular pacing
was found to cause a significant reduction of parameters pro-
posed to estimate ventricular dispersion of repolarization, as
compared to SR, whereas both RV and LV pacing caused an
increase in dispersion of repolarization. Although these find-
ings are in accordance with the clinical course of heart failure
patients undergoing cardiac resynchronization therapy, fur-
ther long-term studies have to assess the utility of surrogate
parameters of ventricular dispersion of repolarization.
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