Cees A Swenne

Laura Burattini

Sumche Man

CiteSeerX

Exercise-Induced Repolarization Alternans Heterogeneity in Patients with an 
Implanted Cardiac Defibrillator 
Laura Burattini1, Sumche Man2, Cees A Swenne2 
1Department of Information Engineering, Polytechnic University of Marche, Ancona, Italy 
2Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands 
 
 
Abstract 
    Repolarization alternans (RA), generally recognized as 
a promising noninvasive index for risk stratification, is 
often measured under exercise conditions, since RA 
increases its amplitude with heart rate. Instead, the effect 
of exercise on the RA location along the JT interval is still 
unknown. Aim of the present study was to evaluate 
exercise-induced RA heterogeneity in terms of both 
amplitude and location. To this aim, we analyzed the 
ECG precordial leads of 36 patients with an implanted 
cardiac defibrillator (ICD) who underwent a bicycle 
ergometer test during which the working load was 
increased from zero (NoWL) to the patient’s maximum 
capacity (MaxWL). RA was analyzed using our heart-rate 
adaptive match filter method, which provides an RA 
parameterization in terms of its amplitude (RAA, µV) and 
location, the latter measured as time-delay (RAD, ms) 
with respect to the T-wave apex, so that positive values of 
RAD indicate RA occurring in the T-wave right side and 
vice versa. According to our results, during MaxWL, RAA 
was higher than during NoWL (34±21 µV vs. 16±10 µV; 
P<10-5), whereas RAD was shorter (26±29 ms vs. 69±45 
ms; P<10-4). Thus, in ICD patients, exercise not only 
induced a significant increment of RA amplitude, but also 
caused RA location to move from very late in the 
repolarization segment toward the T-wave apex.  
 
 
1. Introduction 
Repolarization alternans (RA) is an 
electrophysiological phenomenon consisting in every-
other-beat subtle fluctuations of either amplitude and/or 
shape of the electrocardiographic (ECG) JT segment at 
fixed heart rate. Macroscopic RA is quite rare and has 
been recognized as a harbinger of malignant ventricular 
arrhythmias [1]. Instead, microvolt RA is much more 
common, requires specifically designed algorithms for its 
automatic identification [2-3] and is also generally 
recognized as a promising noninvasive index for risk 
stratification [4-10]. Although characterized by its 
amplitude and time-instant of occurrence along the JT 
segment, RA is usually described by providing only its 
amplitude. Still, heterogeneity in the temporal location of 
RA along the JT segment has recently became a matter of 
major interest, and the identification of an association 
between RA location along the JT segment with diseases 
has been attempted [11-15].  
Even though microvolt RA has been also observed in 
resting conditions [11, 16], it is well known that its 
amplitude increases at higher heart rates [17] so that RA 
is often detected from exercise ECG recordings [4, 17]. 
Instead, the effect of heart rate on the RA location along 
the JT interval is still unknown. Thus, aim of the present 
study was to analyze exercise ECG recordings from 
patients with an implanted cardio-defibrillator to evaluate 
the effect of heart rate on RA heterogeneity in terms of 
both its amplitude and location. 
 
2. Methods 
2.1. Study population and clinical data 
Our study population consisted of 36 subjects from the 
Leiden University Medical Center (The Netherlands) 
collection of routine clinical data from patients with an 
implanted cardio defibrillator (ICD) for primary 
prevention because of a depressed left ventricular ejection 
fraction (LVEF<0.35). Each patient underwent a bicycle 
ergometer test, during which the working load was 
increased from zero (NoWL) to the patient’s maximal 
capacity (MaxWL), by applying load-increments of 10% 
of the expected maximal capacity every minute. Thus, 
each exercise test was approximately 10 minutes long.  
During the bicycle ergometer test, the ECG precordial 
leads (V1 to V6) were obtained using a CASE 8000 stress 
test recorder (GE Healthcare, Freiburg, Germany; 
sampling frequency: 500 Hz; resolution: 4.88 μV/LSB).  
After the exercise test, the patients underwent a 4-years 
follow-up during which they all developed ventricular 
tachycardia or fibrillation (VT/VF).  
441cinc.org Computing in Cardiology 2012; 39:441-444.
2.2. RA characterization by heart-rate 
adaptive match filter 
RA was identified and characterized using our heart-
rate adaptive match filter (AMF) method [18], a 
technique previously tested and prospectively validated in 
both clinical [11, 16] and simulated settings [2, 19]. More 
specifically, two windows of 64 consecutive beats were 
extracted from each lead of the ECG tracing during the 
NoWL and the MaxWL phases of the exercise test, 
respectively. For a patient to be enrolled in the study, 
both NoWL and MaxWL ECG windows had to be 
characterized by stable heart-rate (NN standard deviation, 
in s, less than 10% of mean NN, in s). Each one of these 
windows was then analyzed independently.  
After being preprocessed for noise and baseline 
removal, and for noisy and ectopic beats replacement 
(patients whose ECG leads showed five or more replaced 
beats were rejected), each ECG window was submitted to 
our AMF for RA identification and characterization. At 
first, the typical RA frequency (fRA) was estimated as half 
the mean heart rate. Then, the filter was designed as a 6th 
order bidirectional Butterworth band-pass filter (0.12 Hz 
wide passing band centered in fRA) and implemented as a 
cascade of a low-pass filter (LPF; cut-off frequency 
fLPF=fRA+dfRA, with dfRA=0.06 Hz) and a high-pass filter 
(HPF; cut-off frequency fHPF=fRA-dfRA). The squared 
module of the AMF is expressed by the following 
equation: 
 
 
. 
f
f1
f
f
f
f1
1)f(H)f(H)f(H 6
HPF
6
HPF
6
LPF
2
HPF
2
LPF
2
AMF






+






⋅






+
=⋅=
 
(1) 
 
 
Thus, the AMF was expected to detect RA by filtering out 
noise and any other ECG component but the RA typical 
one. Indeed, the output of the AMF was the RA signal, an 
amplitude-modulated sinusoidal signal, whose frequency 
is fRA and characterized by the same length of the input 
ECG. The RA signal maxima and minima had to fall 
inside the JT intervals to pertain to RA (Fig. 1). The local 
amplitude of the RA signal (i.e. its absolute amplitude in 
correspondence of a maximum or a minimum; Fig.1) 
provided a measure of the RA amplitude (RAA, in µV) 
characterizing the corresponding beat [11]. Instead, the 
time occurrence of a RA signal maximum or minimum 
represented the center of mass of the alternations, and 
thus provided information about RA localization along 
repolarization in the beat [11] (Fig. 1). More specifically, 
after having identified a reference point (Tref) inside the 
repolarization segment as the T-wave apex for 
monophasic T waves, or as the amplitude-weighted mean 
point between T apexes for biphasic T waves, the RA 
delay (RAD, in ms) parameter was defined as the signed 
time interval between the instant at which Tref occurred 
and the instant at which the RA signal maximum or 
minimum occurred. Thus, a negative value of RAD 
indicated the presence of an RA occurring before the T-
wave apex (i.e. along the ST segment or the T-wave left 
side), whereas a positive value of RAD indicated an RA 
occurring late in the repolarization segment (T-wave right 
side). Eventually, a RAD equal to zero indicated that the 
T-wave apex was alternating.  
In the case of an ECG tracing not affected by RA, the 
RA signal at the output of the AMF reduced to a zero 
constant signal. Consequently, the values of RAA were 
equal to zero whereas the values of RAD remained 
undetermined. 
 
 
 
Figure 1. ECG signal (upper panel) and relative RA 
signal (lower panel) at the output of the AMF from which 
the RA amplitude (RAA) and delay (RAD) parameters 
are estimated.  
 
 
The RAA and RAD values computed from each T 
wave were averaged over the 64 analyzed beats to 
provide a characterization of each ECG window. The 
RAA and RAD values measured in the six precordial 
leads were then averaged (mean RAA and mean RAD) to 
provide an overall lead-independent characterization of 
the RA phenomenon during the NoWL and the MaxWL 
phases of the bicycle test.  
 
2.3. Statistics 
To be independent of normal distributions, non-
parametric tests were used to perform comparisons 
among quantities. More specifically, comparisons 
between the distributions of the heart rate, and single as 
well as mean RAA and RAD parameters measured from 
the NoWL and MaxWL ECG windows were performed 
using the Wilcoxon rank sum test for equal medians. The 
statistical significance level was set at 5%.  
442
3. Results 
    Going from the NoWL to the MaxWL phases of the 
bicycle test, heart rate increased from 81±10 bpm to 
121±13 bpm (P<10-12). Accordingly, mean RAA 
significantly increased in all leads but V6 (Table 1), 
whereas RAD significantly decreased in all leads (Table 
2). Analogously, an increment of mean RAA and a 
decrement of mean RAD were observed (Table 1, Table 2 
and Fig. 2). 
 
 
Table 1. RAA values (mean±sd over the ICD population) 
during the NoWL and MaxWL phases of the bicycle test.  
Lead MaxWL 
(µV) 
NoWL 
(µV) 
p 
V1 19±9 12±7 <10-3 
V2 30±20 19±15 <0.01 
V3 35±35 18±15 <0.01 
V4 35±30 17±13 <0.01 
V5 39±23 19±13 <10-3 
V6 37±28 17±13 NS 
Mean V1-V6 34±21 16±10 <10-5 
 
 
Table 2. RAD values (mean±sd over the ICD population) 
during the NoWL and MaxWL phases of the bicycle test.  
Lead MaxWL 
(ms) 
NoWL 
(ms) 
p 
V1 33±31 80±54 <0.01 
V2 29±34 56±61 <0.05 
V3 22±31 70±52 <10-3 
V4 21±28 57±55 <0.01 
V5 19±38 77±40 <10-3 
V6 6±27 43±49 <0.05 
Mean V1-V6  26±29 69±45 <10-4 
 
 
 
Figure 2. Histograms of mean RAA (panels a and b) and 
mean RAD (panels c and d) distributions during the 
NoWL (panels a and c) and the MaxWL (panels b and d) 
phases of the bicycle test.  
 
4. Discussion  
The present study represents, as far as we know,  the 
first attempt to evaluate the effect of high heart rate, 
reached through exercise, on the RA localization along 
the JT interval. To this aim ECG tracings of 36 ICD 
patients, recorded during the NoWL and MaxWL phases 
of a bicycle test, were analyzed by means of our AMF 
method. Compared to other RA identification techniques 
proposed in the literature, the AMF, although requiring a 
certain heart-rate stability, is more robust to small heart-
rate variations [19] which are likely to occur during an 
exercise test with increasing workload. This properties is 
due to the fact that the AMF assumes RA to be 
characterized not only by a single frequency, fRA, defined 
as half heart rate but, rather, by a small frequency band 
(0.12 Hz) centered in fRA. In addition, the AMF provides 
an RA characterization in terms of both amplitude (RAA) 
and localization, the latter defined as the signed time-
delay with respect to the T-wave apex (RAD). Only the 
six precordial ECG leads were analyzed, since they were 
previously found to provide analogous information of the 
twelve standard leads in these kind of patients [20]. 
As expected, both heart rate and mean RAA were 
significantly higher during MaxWL than during NoWL 
(heart rate: 121 bpm vs. 81 bpm; mean RAA: 16 µV vs. 
34 µV), confirming the well known dependency of RA 
amplitude on heart rate [17]. Of major interest, because 
more innovative, are the results relative to the RA 
location. The ICD patients were characterized by an RA 
generally distributed late in the repolarization segment 
(over the T-wave right hand side, as indicated by positive 
values of RAD) during both NoWL and MaxWL. This 
kind of RA is the one that Narayan [13] indicates as the 
most specific for inducible ventricular tachycardia, which 
is in agreement with the fact that all ICD patients 
developed VT/VF during the 4-year follow-up. During 
MaxWL, however, mean RAD was found to be 
significantly lower than during NoWL (26 ms vs. 69 ms). 
Such difference should not be attributed to the shortening 
of the ECG beat due to the increased heart rate, since RA 
location is identified with respect to the T-wave peak and 
not R peak, as in other techniques [12]. This finding 
rather indicates that the heart-rate increment caused an 
anticipation of the RA occurrence, which moved from the 
very late portion of the repolarization segment toward the 
T-wave apex, as graphically represented in Fig. 3.   
 
5.  Conclusion 
In our ICD patients RA was generally localized late in 
the repolarization segment (T-wave right hand side). The 
exercise induced increment of heart rate caused RA to 
move toward the T-wave apex, beside increasing its 
amplitude.  
443
 
Figure 3. Mean (over the V1-V6 leads) RAD vs. mean 
RAD observed in the ICD population during NoWL and 
MaxWL (panel a), and their averaged value (over the 36 
ICD patients) indicating the RA center of mass along 
repolarization (panel b).  
 
 
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Address for correspondence. 
 
Laura Burattini 
Department of Information Engineering 
Polytechnic University of Marche  
60131 Ancona, Italy 
l.burattini@univpm.it. 
444


Exercise-Induced Repolarization Alternans Heterogeneity in Patients with an Implanted Cardiac Defibrillator

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Exercise-Induced Repolarization Alternans Heterogeneity in Patients with an Implanted Cardiac Defibrillator

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