CLINICAL RESEARCH
Europace (2013) 15, 582–589
doi:10.1093/europace/eus311
Electrocardiology and risk stratification
T-wave integral: an electrocardiographic marker
discriminating patients with arrhythmogenic
right ventricular cardiomyopathy from patients
with right ventricular outflow tract tachycardia
Alexander Samol 1†, Christian Wollmann 1†‡, Christian Vahlhaus 1}, Joachim Gerss 2,
Hans-Jürgen Bruns 1, Günter Breithardt1, Eric Schulze-Bahr 1,3, Thomas Wichter 1§,
and Matthias Paul 1*
1
Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Münster, Münster, Germany; 2Institute for Biostatistics and Clinical Research, University of
Münster, Münster, Germany; and 3Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany
Received 23 May 2012; accepted after revision 20 August 2012; online publish-ahead-of-print 1 October 2012
Aims
Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study
was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC
and RVOT using a body surface mapping (BSM).
.....................................................................................................................................................................................
Methods
A 120-channel BSM with quantitative signal analysis of the T-wave integral was performed in 10 patients with ARVC.
and results
Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects
(controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups.
Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right
lower anterior region of the torso when compared with RVOT (P , 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of 20.3 mV ms, sensitivity and specificity were 83%
[area under curve (AUC) 0.85 + 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced
in ARVC patients with a plakophlin-2 mutation (P , 0.001).
.....................................................................................................................................................................................
Conclusion
Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from
RVOT patients and controls and may serve as an additional diagnostic tool.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Arrhythmogenic right ventricular cardiomyopathy † Electrocardiography † Body surface mapping † Repolarization
Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is
among the leading causes of ventricular tachyarrhythmias and
†
These authors contributed equally to the manuscript.
‡
Present address: Department of Cardiology, Landesklinikum St. Pölten, St. Pölten, Austria.
sudden cardiac death in the young. Replacement of right ventricular (RV) myocardium by fibrous-fatty tissue provides the structural
basis for ventricular tachycardias (VT) and for typical alterations
detectable on 12-lead surface electrocardiogram (ECG).1 – 3 The
}
Present address: Department of Cardiology and Angiology, Klinikum Leer, Leer, Germany.
§
Present address: Department of Cardiology, Niels-Stensen-Kliniken, Marienhospital Osnabrück, Osnabrück, Germany.
* Corresponding author. Department für Kardiologie und Angiologie, Klinik für Kardiologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149
Münster, Germany. Tel: +49 251 83 49898; fax: +(49) 251 83 43204, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected].
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT
What’s new?
† Body surface potential mapping can be utilized to discriminate patients with arrhythmogenic right ventricular cardiomyopathy and right ventricular outflow-tract tachycardia.
† T-wave integral as measured by body surface potential
imaging identifies repolarization abnormalities in torso
areas outside the standard lead position.
latter may manifest as a prolongation/dispersion of precordial
QRS-complexes, epsilon-potentials, as well as T-wave inversions
in right precordial leads.4,5 Albeit VT arising from the RV frequently
occurs in patients with ARVC, it is also observed in patients
without identifiable structural heart disease, e.g. in idiopathic
right ventricular outflow-tract tachycardia (RVOT), which is one
important differential diagnosis of ARVC. In contrast, patients
with RVOT mostly show a normal surface ECG and have a favourable long-term survival.6 It is essential to establish the correct diagnosis because treatment strategies and long-term prognosis differ
significantly. Intriguingly, typical signs of ARVC on conventional
12-lead surface ECG are often subtle or even absent and, thus,
may hamper diagnosing the underlying disease correctly.7 In addition, right precordial T-wave inversions can be identified in a
smaller portion (14%) of RVOT patients.8
Body surface mapping (BSM) is a dependable tool for the detection of heterogeneities of ventricular repolarization unrevealed by
conventional ECG recording.9 So far, there have been two reports
on repolarization abnormalities detectable by body surface QRST
integral mapping.10,11 Calculation of the QRST integral reflects the
combination of both, the upstroke and downstroke in the action
potential.12 To eliminate potentially confounding effects of the
QRS width, we assessed potential differences in repolarization in
patients with ARVC and RVOT measuring the T-wave integral as
an objective mathematical calculus with the help of a
120-channel BSM recording.
Since mutations in the cardiac plakophilin-2 (PKP2) have been
reported as the most common cause of autosomal-dominant
ARVC (ARVC-9),13 we additionally investigated a possible impact
of the genotype on T-wave integral alterations.
Materials and methods
Study patients
Patients with arrhythmogenic right ventricular
cardiomyopathy and right ventricular outflow-tract
tachycardia
Ten consecutive male patients with ARVC (mean age 45 + 12 years)
and 13 patients with RVOT (mean age 42 + 13 years) were prospectively enrolled in this study after written informed consent was
obtained. All patients underwent detailed investigations including left
ventricular and RV angiography (n ¼ 23), coronary angiography (n ¼
23), and programmed ventricular stimulation (n ¼ 23) according to a
stimulation protocol published earlier.14 In addition, all patients met
the past15 and current criteria for definite ARVC.16 Applying a
scoring system with major criteria counting as 2 and minor criteria
as 1 score point, all patients had at least four points which were
583
required for the diagnosis of ‘definite ARVC’.16 Right ventricular angiograms were evaluated in consensus by two experienced cardiologists
(T.W. and M.P.) as to the extent of global RV dilatation and regional
RV dysfunction (absent, moderate, severe). A moderate regional RV
dysfunction was defined as the presence of severe hypokinesia in up
to two different RV segments (RV outflow-tract, free wall, subtricuspid
area, or apex). Evidence of severe hypokinesia or akinesia in more than
two different RV segments lead to the classification of a severe regional
RV dysfunction. Arrhythmogenic right ventricular cardiomyopathy
patients were regularly followed up to evaluate a potential impact of
T-wave integral on their arrhythmia profile. Follow-up started with
the date of BSM recording and the first occurrence of any sustained
VT/VF (i.e. lasting .30 s or requiring termination due to haemodynamic deterioration, respectively) served as the primary clinical endpoint. Follow-up data were obtained during scheduled visits in our
outpatient clinic, regular telephone calls with patients and/or referring
physicians at regular intervals, and in case of an adverse event (e.g. VT
recurrence). In those patients with an implanted cardioverter defibrillator (ICD), interrogations of the device were scheduled every
3 months. An ICD therapy was classified as appropriate if the stored
ECGs and/or RR intervals retrieved from the ICD confirmed that
the tachyarrhythmia before the first treatment by the device was sustained and of ventricular origin. None of the ICD patients was
pacemaker-dependent, the overall percentage of stimulation within
the month before BSM recording was zero to exclude a potential confounding effect of temporary cardiac pacing (i.e. cardiac memory).
Patients with RVOT had no evidence of any underlying structural
heart disease. Global left ventricular function was normal in all patients
(ARVC and RVOT), and no patient had coronary artery disease.
Control group
Twelve healthy volunteers (mean age 54 + 15 years) with no history,
signs, or symptoms of coronary artery disease or underlying cardiomyopathy served as a control group.
Data acquisition and data analysis
Body surface mapping
Body surface mapping measurements were performed in the absence
of any concomitant antiarrhythmic or sedative medication. In ARVC
patients with an ICD, no stimulated QRS complexes were observed
before or during BSM recording. As reported earlier, BSM electrodes
were applied to the chest in vertical strips (Figure 2A and B).17 Each
electrode (Foxmed GmbH, Idstein, Germany) had a 10 mm diameter
Ag/AgCl sensor embedded in epoxy housing with a 2 mm gel cavity.
In vertical direction, the inter-electrode distance on the strips was
50 mm. The 120 unipolar ECG leads referred to Wilson central terminal and were recorded simultaneously. The ECG signals were amplified, bandpass-filtered (spectrum: 0.16 – 400 Hz), and A/D converted
to 16 bit samples (0.5 mV least significant bit) using a sampling rate of
1 kHz (Mark-6, Biosemi, Amsterdam, Netherlands). Leads that were
excessively noisy or which contained artefacts were excluded from
the data set for further off-line analysis. Measurements were performed during stable sinus rhythm and at resting conditions (5 min).
Recordings with high signal-to-noise ratio and without any offset variation due to respiratory motion were selected for single-beat analysis
as reported before.17 T-wave integral in each channel including standard chest leads V1 – V6 was measured in patients with ARVC and compared with those in RVOT patients and controls. Both the on- and the
offset of the T-wave were manually defined in consensus by three
experienced cardiologists (A.S., C.V., and M.P.) according to
peak-slope-intercept technique,18 marked by digital callipers, and the
PQ-interval served as reference zero.
584
A. Samol et al.
was chosen. To account for variable lengths of follow-up, the probability of remaining arrhythmia/event-free was analysed by the Kaplan–
Meier method, and differences in event-free survival between groups
were evaluated by Cox regression analyses. Statistical analyses were
performed using IBM SPSS Statistics (version 20 for Windows, IBM
Corporation, Somers, NY, USA).
Twelve-lead surface electrocardiogram
A 12-lead surface ECG at a speed of 50 mm/s in the absence of any
concomitant anti-arrhythmic medication at the time of the BSM
recording was available in all patients and controls. Blinded for clinical
details, these ECGs were quantitatively analysed in consensus by two
experienced cardiologists (M.P., C.W.) using a digital calliper. Analyses
comprised the measurement of QRS durations in precordial leads:
maximum (QRSmax), minimum (QRSmin) and average QRS duration
as well as the dispersion of QRS durations across V1-V6 (i.e.
QRSmax – QRSmin), presence/absence of characteristic epsilon potentials, and the presence/extent of T-wave inversions in leads V1-V6.
Results
Clinical characteristics
Demographic characteristics of the study patients are depicted in
Table 1. There were no differences as to the age or body mass
index at BSM recording between the groups (Table 1). Three
patients with ARVC (30%) had received an automatic cardioverterdefibrillator (ICD) 4.6 + 0.2 years prior to the BSM recording.
Among these patients was one patient with a survived episode
of sudden cardiac arrest, one with an extensive disease manifestation and sustained VT; and one patient with moderate RV dysfunction, non-sustained VT, and a highly malignant family history
(two brothers succumbed to sudden cardiac death). During
follow-up of 6.4 + 2.4 years an ICD was implanted in another
three patients after VT recurrences (cycle length 295 + 71 ms)
Statistical analysis
Differences of metric target variables between groups were assessed
by non-parametric ANOVA with post-hoc testing adjusted for multiplicity applying the closed test principle. In the case of binary target variables, the x2 test was used. Results are intended to be exploratory
(hypothesis generating), not confirmatory, and were interpreted accordingly. P values ≤ 0.05 were regarded significant. Receiver operating characteristic (ROC) analysis of the T-wave integral was
performed for each lead. Values for the area under curve (AUC) are
presented as mean + standard error of the mean; all other data are
expressed as mean + standard deviation (where applicable). For correlation of target variables the Spearman’s rank correlation coefficient
Table 1 Clinical characteristics of study patients
ARVC
.................................................
All
PKP2-pos
RVOT
Controls
P value
PKP2-neg
...............................................................................................................................................................................
Clinical characteristics
Patients, n
10
5
5
13
12
Age, years
45 + 12
39 + 12
51 + 11
42 + 13
54 + 15
ns
Sex (M/F)
Body mass index
10/0a
26.4 + 3.3
5/0b
27.9 + 3.0
5/0b
24.9 + 3.3
4/9a,c
25.7 + 4.1
6/6c
26.3 + 3.1
a
,0.01; b,cns
ns
ICD, n (%)
6 (60)a
3 (60)c
3 (60)c
0a
–
a
,0.01; cns
RV dilatation
Normal, n (%)
0a
0c
0c
13 (100)a
ND
a
,0.001; cns
a
,0.001; cns
a
c
c
a
Moderate, n (%)
6 (60)
3 (60)
3 (60)
0
ND
Severe, n (%)
RV wall motion abnormalities
4 (40)a
2 (40)c
2 (40)c
0a
ND
Normal, n (%)
0a
0c
0c
13 (100)a
ND
3 (30)
7 (70)a
c
1 (20)
4 (80)c
2(40)
3 (60)c
0
0a
ND
ND
Patients with PVS, n (%)
Inducible sustained VT, n (%)
10 (100)
6 (60)a
5 (100)
3 (60)c
5 (100)
3 (60)c
13 (100)
0a
ND
ND
Task Force Score
7 + 2a
7 + 2c
7 + 2c
2 + 1a
–
a
,0.001; cns
a
c
c
a
,0.001; cns
,0.01; cns
Moderate, n (%)
Severe, n (%)
a
c
a
Programmed-ventricular stimulation
d
ns
,0.001; cns
a
# major criteria
# minor criteriad
3+1
1 + 1a
3+1
1 + 1c
3+1
1 + 1c
1+0
0 + 1a
–
–
a
Follow-up, years
6.4 + 2.4
5.5 + 3.1c
7.4 + 1.1c
–
–
c
–
–
–
–
c
VT recurrence, n (%)
Time interval between BSM and VT recurrence, year
5 (50)
3.6 + 2.3
c
2 (40)
1.7 + 0.9c
c
3 (60)
4.9 + 2.0c
a
ns
ns
ns
c
Values are expressed as mean + SD where applicable. a,b,cdenote for different levels of significance between the groups compared in the line they appear; dfrom different
diagnostic categories [16].
ARVC, arrhythmogenic right ventricular cardiomyopathy; BSM, body surface mapping; F, female; ICD, implantable cardioverter defibrillator; M, male; n, number; ns not significant;
ND, not done; PKP2, plakophilin-2; pos, positive; PVS, programmed-ventricular stimulation; RVOT, right ventricular outflow-tract tachycardia; VT, ventricular tachycardias; ICD,
implanted cardioverter defibrillator; RV, right ventricular.
585
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT
1.6 + 2.6 years after BSM recording. Overall, five patients experienced life-threatening ventricular tachyarrhythmias 3.6 + 2.3 years
following BSM.
Genetic analyses revealed mutations in the PKP2 encoding gene
in five ARVC patients (50%). However, there were no significant
differences in clinical disease manifestation as reflected in the
Task Force Score between ARVC patients with PKP2-mutations
and those without (PKP2-neg; P ¼ ns; Table 1). In PKP2-neg patients,
additional screening as to potential mutations in other genes
involved in ARVC (desmoglein-2 and desmocolin-2) was negative.
between these groups. In three ARVC patients (30%) with a
severe disease manifestation, epsilon potentials were detectable.
T-wave inversion in precordial leads were present in nine
patients with ARVC (90%), in 8 of 13 patients with RVOT
(62%), and in 6 of 12 controls (50%; P ¼ ns; Table 2). The
number of leads with T-wave inversion yet varied significantly
and was highest in ARVC (2.6 vs. 0.8 vs. 0.5, respectively,
between ARVC, RVOT, and controls; P , 0.01; Table 2). In lead
V1, 9 of 10 ARVC patients (90%), 8 of 13 RVOT patients (62%),
and 6 of 12 controls (50%) had a negative T-wave. In leads V1
and V2, 7 of 10 patients with ARVC (70%), 2 of 13 patients with
RVOT (15%), and none of the controls showed T-wave inversions.
In the ARVC group, 6 of 10 patients (60%) had T-wave inversions
in lead V1 –V3 (n ¼ 4 patients) or beyond (n ¼ 2 patients) compared with no RVOT patient and no control subject. Between
RVOT and controls, the number of leads with T-wave inversion
was comparable (0.8 + 0.7 vs. 0.5 + 0.5; P ¼ ns; Table 2). The
presence of a PKP2 gene mutation made no difference on
QRS-dispersion or the presence of epsilon potentials (Table 2).
Mutation carriers tended to show more leads with T-wave inversions than non-carriers (P ¼ 0.086; Table 2).
Twelve-lead standard surface
electrocardiogram in the study
population
BSM and conventional 12-lead surface ECGs were recorded during
sinus rhythm in all patients. There were no significant differences in
cycle length or QRS-axis between patients with ARVC in comparison with RVOT patients and controls (Table 2). In addition, QRS
durations in leads V1 –V6 and QRS dispersion were comparable
Table 2 Electrocardiographic characteristics of study patients
ARVC
................................................................
All
PKP2-pos
PKP2-neg
10
5
5
RVOT
Controls
P value
...............................................................................................................................................................................
Patients, n
12-lead surface ECG
13
12
Rhythm
SR
SR
SR
SR
SR
Heart rate, bpm
67 + 13
69 + 15
65 + 13
68 + 10
69 + 10
ns
QRS-axis,8
QRS-durations
45.8 + 36.2a
26.5 + 33.8b
65.0 + 29.7b
49.3 + 27.9a
36.2 + 31.1a
a
ns; b ,0.05
QRS-V1, ms
102.3 + 9.6
97.2 + 10.0
107.3 + 6.5
95.7 + 14.2
96.1 + 16.9
ns
QRS-V2, ms
QRS-V3, ms
105.7 + 9.0a
99.0 + 15.8
99.2 + 7.1b
92.7 + 13.5
112.1 + 5.3b
105.4 + 16.6
99.9 + 14.9a
92.9 + 11.6
98.9 + 13.7a
95.2 + 17.7
a
ns; b ,0.05
ns
QRS-V4, ms
93.1 + 12.8
93.4 + 14.0
92.9 + 13.1
83.5 + 13.6
88.2 + 17.2
ns
QRS-V5, ms
QRS-V6, ms
86.3 + 10.0
89.6 + 8.0
90.8 + 6.9
89.3 + 10.5
81.8 + 11.2
89.8 + 5.9
82.2 + 12.8
81.2 + 15.0
84.6 + 14.6
86.7 + 9.5
ns
ns
QRS-dispersion V1 – V6
29.3 + 12.9
22.5 + 9.5
36.2 + 13.0
26.4 + 7.3
24.6 + 12.2
ns
Epsilon potential, n (%)
T-wave inversion V1 –V6
3 (30)a
1 (10)b
2 (20)b
0a
0a
b
Patients with TWI, n (%)
9 (90)
5 (100)
4 (80)
8 (62)
6 (50)
ns
Precordial leads with TWI, n
BSM-ECG and T-wave integrals
2.6 + 1.7a
3.6 + 1.3b
1.6 + 1.5b
0.8 + 0.7a
0.5 + 0.5a
b
ns; a ,0.02
ns; a ,0.01
Lead V1 (mV ms)
24.7 + 31.1
217.9 + 16.1
+8.4 + 38.6
+6.7 + 14.6
+3.8 + 15.3
ns
Lead V2 (mV ms)
Lead V3 (mV ms)
+22.6 + 61.5
+29.2 + 40.6
28.5 + 13.3
+5.3 + 13.7
+53.7 + 77.0
+53.1 + 46.0
+42.5 + 32.0
+45.7 + 32.5
+43.4 + 36.1
+54.2 + 45.8
ns
ns
Lead V4 (mV ms)
+27.0 + 29.7
+8.1 + 13.9
+45.9 + 30.0
+37.2 + 20.6
+47.4 + 38.6
ns
Lead V5 (mV ms)
Lead V6 (mV ms)
+24.9 + 11.1
+23.2 + 9.8
+20.0 + 11.2
+21.0 + 10.2
+30.2 + 8.8
+26.0 + 9.7
+32.4 + 13.8
+24.8 + 11.9
+27.4 + 21.0
+20.0 + 14.1
ns
ns
Values are expressed as mean + SD.
a,b
denote for different levels of significance between the groups compared in the line they appear.
ARVC, arrhythmogenic right ventricular cardiomyopathy; bpm, beats per minute; BSM, body surface mapping; ms, milliseconds; n, number; neg, negative; ns, not significant; PKP2,
plakophilin-2, pos, positive; RVOT, right ventricular outflow-tract tachycardia; SR, sinus rhythm; TWI, T-wave inversion.
586
A. Samol et al.
Body surface mapping in study population
Calculating the T-wave integral in leads V1 –V6, no statistically significant difference between the groups was found (P ¼ ns; Table 2).
However, the values for T-wave integrals were negative in a distinct area in patients with ARVC compared with those with
RVOT and controls (P , 0.001; Table 3). Best results to discriminate between ARVC and RVOT patients were obtained in channel
#6. To account for inter-individual differences in torso shape and
distances from the heart to body surface the four most significant
adjacent channels were picked and the mean values of T-wave integral in this area were calculated for each patient. This area was
located in the right lower anterior region of the torso and
reflected recordings of the BSM channels #6, #7, #13, and #14
(Figure 2A and B). In ROC analyses, the AUC was 0.85 + 0.04
[mean + standard error of the mean (SEM); P , 0.001]. At a
cut-off level of 20.3 mV ms ROC analyses comparing ARVC and
RVOT revealed a sensitivity and specificity of 83% (Table 3). Comparing ARVC with controls, patients with ARVC showed significant
lower T-wave integrals in an adjacent area localized in the right
lower anterior region of the torso reflecting recordings of the
channels #20, #21, #27, and #28. Mean values of T-wave integrals
of these four most significant channels for each patient was calculated and ROC analysis performed [AUC 0.8 + 0.05 (mean +
SEM), sensitivity 73%, specificity 72% at cut-off level of 0.21
mV ms]. In contrast, the value of the T-wave integrals in RVOT
patients and controls was not different (P ¼ ns).
Reciprocal changes were found in the ‘posterior region’ on the
left upper back of the torso comprising the four most significant
adjacent BSM channels #79, #86, #93, and #94 (Figures 1 and
2A, B; Table 3). When compared with both RVOT and controls,
patients with ARVC had a significantly higher mean T-wave integral
of these four adjacent channels resulting in an AUC of 0.87 + 0.04
(compared with RVOT; P , 0.001; Table 3) and 0.84 + 0.04 (compared with controls; P , 0.001; Table 3) with a sensitivity and specificity of 75 of 85% at a cut-off value of 23.1 mV ms (RVOT) and
74 of 85% at a cut-off value of 23.0 mV ms (controls; Table 3), respectively. The difference in T-wave integral between RVOT and
controls remained non-significant (P ¼ ns; Table 3).
Analysing potential differences in T-wave integral in the above
mentioned regions between PKP2-pos and PKP2-neg ARVC
patients in comparison to RVOT and controls, it became apparent
that PKP2-pos patients had the lowest T-wave integral in the anterior region of all groups (P , 0.001). ROC analyses revealed an
AUC for the comparison of PKP2-pos and RVOT of 0.97 + 0.02
(mean + SEM) with a sensitivity of 90% and specificity of 85% at
a cut-off level of 23.9 mV ms. Similar results were obtained
when T-wave integral of PKP2-pos patients were compared to
that of controls [AUC 0.92 + 0.03 (mean + SEM); sensitivity
82%, specificity 85% at cut-off level 23.9 mV ms]. Between
PKP2-neg patients (22.7 + 9.4 mV ms) and RVOT (4.9 +
6.6 mV ms) these differences were less pronounced [AUC
0.74 + 0.07 (mean + SEM); sensitivity 77%, specificity 70% at
cut-off level 0.4 mV ms]. No statistically significant differences in
T-wave integral were found between PKP2-neg patients and controls (22.7 + 9.4 mV ms vs. 20.031 + 8.7 mV ms; mean + SD,
P ¼ 0.28).
In the ‘posterior region’, T-wave integral of both ARVC genetic
subgroups was significantly more positive when compared with
RVOT and controls (P , 0.001) but, different to that in the anterior region, insignificant in the direct comparison of PKP2-pos
and PKP2-neg patients (0.8 + 6.7 mV ms vs. 3.4 + 5.5 mV ms;
P ¼ ns).
Table 3 Receiver operating characteristic analyses of the T-wave integral in the study population
ROC-analyses of T-wave-integral
................................................................................................................................
ARVC vs. RVOT
ARVC vs. controls
RVOT vs. controls
26.9 + 9.6 vs. 20.03 + 8.7
4.9 + 6.6 vs. 20.03 + 8.7
...............................................................................................................................................................................
Anterior region (channels #6, #7, #13, #14)
T-wave integral (mV ms)
26.9 + 9.6 vs. 4.9 + 6.6
Area under curve
0.85 + 0.04
0.71 + 0.05
Cut-off level (mV ms)
20.3
22.6
Sensitivity (%)
Specificity (%)
83
83
64
70
P value
,0.001
,0.001
ns
2.2 + 6.2 vs. 27.6 + 8.8
27.1 + 6.7 vs. 27.6 + 8.8
Posterior region (channels #79, #86, #93, #94)
T-wave integral (mV ms)
2.2 + 6.2 vs. 27.1 + 6.7
Area under curve
0.87 + 0.04
0.84 + 0.04
Cut-off level (mV ms)
Sensitivity (%)
23.1
75
23.0
74
Specificity (%)
85
85
P value
,0.001
,0.04
ns
Values are depicted as mean + standard deviation except for the area under curve which is shown as mean + standard error of the mean.
ARVC, arrhythmogenic right ventricular cardiomyopathy; ms, milliseconds; mV, millivolt; ns, not significant; RVOT, right ventricular outflow-tract tachycardia.
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT
587
Figure 1 Three-dimensional-projection of T-wave integral. Three-dimensional-projections of the T-wave integral distribution on a standard
torso model (frontal view; upper row) with corresponding recordings from the back (lower row) are depicted for the study population.
Impact of body surface mapping findings
on clinical presentation
In patients with ARVC, T-wave integral was significantly correlated
with the angiographic disease extent (anterior region: r ¼ 0.42;
P , 0.044; posterior region: r ¼ 20.51; P , 0.02) and with the
overall inducibility of sustained VT during programmed ventricular
stimulation (n ¼ 6 patients; anterior region: r ¼ 20.49; P , 0.017;
posterior region: r ¼ 0.64; P , 0.001). T-wave integral was not
correlated with age, sex, or BMI. In addition, T-wave integrals in
both regions were not associated with a higher propensity of VT
recurrences during follow-up (P ¼ ns).
Discussion
Electrocardiographic diagnosis of ARVC in delineation to RVOT is
challenging. The present BSM study focussed on repolarization
abnormalities. Apart from the standard ECG leads, novel signal
patterns could be identified which allowed a reliable electrocardiographic differentiation between patients with ARVC and RVOT/
controls. Our results suggest that maximum discrimination
between ARVC- and RVOT-patients using T-wave integral analysis
is localized in an area 10 cm caudal and 10 cm lateral from standard
chest lead V1.
The prevalence of T-wave inversion beyond lead V1 is known to
change from infancy to adolescence and was estimated to be still
present in 1–3% of a healthy population between 19 and 45
years of age.19 In ARVC, divergent figures of T-wave inversion
prevalence in precordial leads have been reported (36;6 47;20
54;21 and 96%;22). In the present study, 6 of 10 patients (60%)
with ARVC showed T-wave inversion in leads V1 –V3 or beyond
which is in line with findings by Piccini et al.23 (63%).
It was hypothesized that characteristic ECG changes in patients
with ARVC due to the progressive nature of the disease will
change over time.24 Different extents of disease manifestation
may therefore contribute to the hitherto published low sensitivity
but good specificity of T-wave inversions as an ECG discriminator
of ARVC from RVOT.20,25 To fill this gap, earlier reports concentrating on QRST-integral mapping with the help of BSM in patients
with ARVC and RVOT identified negative areas on the right anterior and inferior chest independent of the prevalence of T-wave inversion on the corresponding standard 12-lead surface ECG.10,11
Our analysis focussed on the T-wave integral to exclude a potentially confounding influence of the depolarization with an almost
two-fold larger set of BSM-electrodes (120 vs. 62 electrodes10,11)
allowing a higher spatial resolution. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly lower T-wave
integral in a circumscribed region of the right lower anterior
torso when compared with both RVOT and controls with a comparably high sensitivity and specificity (P , 0.001).
The observed significant abnormalities in repolarization in
patients with ARVC may reflect local disturbances in refractoriness
and conduction velocity caused by the interspersed fibro-fatty
tissue. A thereby facilitated susceptibility to ventricular tachyarrhythmias, as indirectly expressed by the inducibility of sustained
VT during programmed ventricular stimulation, could account for
more adverse disease progression.4 In our study, VT inducibility
during programmed-ventricular stimulation was significantly correlated with the T-wave integral both in the anterior and in the posterior region (P , 0.02). Cox-regression analyses yet failed to
show an impact on VT occurrence during follow-up.
Study limitations
This study included a relatively small number of patients with a rare
cardiac disease. The patients are yet well characterized and
588
A. Samol et al.
Figure 2 (A) Original body surface mapping recording in arrhythmogenic right ventricular cardiomyopathy and right ventricular outflow-tract
tachycardia. Depiction of an original body surface mapping recording in a patient with arrhythmogenic right ventricular cardiomyopathy (black
curve) and superimposed that of an right ventricular outflow-tract tachycardia patient (red curve). Each channel is visualized in a 1000 ms
window. The regions of interest are highlighted in yellow and those with optimal discrimination encircled in darker blue. (B) Body surface
mapping recording—zoomed-in display of regions of interest. The region of interest with channel number on the left top of each rectangle,
standard chest leads are marked on the right top where applicable, area-under-curve of the receiver operating characteristic analysis are
listed on the left bottom, and P values are provided on the right bottom. Each channel is visualized in a 1000 ms window.
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT
underwent detailed diagnostic evaluation. However, due to the
sample size, a potentially age- or disease-extent-dependent
cut-off level of T-wave integral remains to be elucidated.
Sensitivity and specificity results as well as ROC areas reported
in this paper have been obtained on the same learning data sets
than the ones that have been used to find the relevant discriminating measurements and to establish the discrimination cut-off
levels. There is no independent test set for assessing the performance of our method.
In addition, since the correlation of BSM parameters and the risk
of sudden cardiac death may change with age, disease manifestation, and progression, variables which did not show a significant
difference in our study could gain a significant and independent
influence.
Gender-specific differences in patients with ARVC could not be
addressed in this study. However, no higher prevalence of T-wave
inversion in leads V1 –V3 were detectable in a large single-centre
study [overall: 60 of 171 patients (45%); male: 44 of 121 patients
(36%); female: 16 of 50 patients (32%); P ¼ ns25].
Changes of T-wave inversion/T-wave integral in the clinical
cause were beyond the aim of our study. In addition, the proposed
cut-off values warrant prospective validation in a larger and independent group of patients. Our findings may yet initiate translation
into a more convenient clinical routine application as standard
ECG recording systems steadily develop and future enhanced software may allow the measurement of T-wave integral in alternative
lead position.
Conclusion
Analysis of T-wave integral discriminates patients with ARVC from
those with RVOT and from controls. Body surface mapping measurements detected torso areas outside the standard lead positions with significantly altered T-wave integral, in particular in the
anterior right lower torso. Further studies using T-wave integral
analysis should address the potential clinical value in identifying
those patients in whom despite detailed invasive investigations
the diagnosis of ARVC otherwise would have remained inconclusive (i.e. ‘borderline ARVC’16).
Acknowledgements
The authors are grateful to Mrs Petra Gerdes, and Thomas Schawe
for their excellent technical support.
Conflict of interest: none declared.
Funding
This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany, Sonderforschungsbereich 656 (Projects C1).
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