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Received 23 May 2012; accepted after revision 20 August 2012; online publish-ahead-of-print 1 October 2012
†
These authors contributed equally to the manuscript.
‡
Present address: Department of Cardiology, Landesklinikum St. Pölten, St. Pölten, Austria.
}
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: Matthias.Paul@ukmuenster.de
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com.
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT 583
Twelve-lead surface electrocardiogram was chosen. To account for variable lengths of follow-up, the probabil-
A 12-lead surface ECG at a speed of 50 mm/s in the absence of any ity of remaining arrhythmia/event-free was analysed by the Kaplan–
concomitant anti-arrhythmic medication at the time of the BSM Meier method, and differences in event-free survival between groups
recording was available in all patients and controls. Blinded for clinical were evaluated by Cox regression analyses. Statistical analyses were
details, these ECGs were quantitatively analysed in consensus by two performed using IBM SPSS Statistics (version 20 for Windows, IBM
experienced cardiologists (M.P., C.W.) using a digital calliper. Analyses Corporation, Somers, NY, USA).
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. Results
QRSmax – QRSmin), presence/absence of characteristic epsilon poten-
tials, and the presence/extent of T-wave inversions in leads V1-V6. Clinical characteristics
Demographic characteristics of the study patients are depicted in
Statistical analysis Table 1. There were no differences as to the age or body mass
Differences of metric target variables between groups were assessed index at BSM recording between the groups (Table 1). Three
by non-parametric ANOVA with post-hoc testing adjusted for multipli- patients with ARVC (30%) had received an automatic cardioverter-
city applying the closed test principle. In the case of binary target vari- defibrillator (ICD) 4.6 + 0.2 years prior to the BSM recording.
ables, the x2 test was used. Results are intended to be exploratory
Among these patients was one patient with a survived episode
(hypothesis generating), not confirmatory, and were interpreted ac-
of sudden cardiac arrest, one with an extensive disease manifest-
cordingly. P values ≤ 0.05 were regarded significant. Receiver operat-
ing characteristic (ROC) analysis of the T-wave integral was ation and sustained VT; and one patient with moderate RV dys-
performed for each lead. Values for the area under curve (AUC) are function, non-sustained VT, and a highly malignant family history
presented as mean + standard error of the mean; all other data are (two brothers succumbed to sudden cardiac death). During
expressed as mean + standard deviation (where applicable). For cor- follow-up of 6.4 + 2.4 years an ICD was implanted in another
relation of target variables the Spearman’s rank correlation coefficient three patients after VT recurrences (cycle length 295 + 71 ms)
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.
T-wave integral: an ECG marker discriminating patients with ARVC from patients with RVOT 585
1.6 + 2.6 years after BSM recording. Overall, five patients experi- between these groups. In three ARVC patients (30%) with a
enced life-threatening ventricular tachyarrhythmias 3.6 + 2.3 years severe disease manifestation, epsilon potentials were detectable.
following BSM. T-wave inversion in precordial leads were present in nine
Genetic analyses revealed mutations in the PKP2 encoding gene patients with ARVC (90%), in 8 of 13 patients with RVOT
in five ARVC patients (50%). However, there were no significant (62%), and in 6 of 12 controls (50%; P ¼ ns; Table 2). The
differences in clinical disease manifestation as reflected in the number of leads with T-wave inversion yet varied significantly
Task Force Score between ARVC patients with PKP2-mutations and was highest in ARVC (2.6 vs. 0.8 vs. 0.5, respectively,
and those without (PKP2-neg; P ¼ ns; Table 1). In PKP2-neg patients, between ARVC, RVOT, and controls; P , 0.01; Table 2). In lead
additional screening as to potential mutations in other genes V1, 9 of 10 ARVC patients (90%), 8 of 13 RVOT patients (62%),
involved in ARVC (desmoglein-2 and desmocolin-2) was negative. 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
Twelve-lead standard surface in lead V1 –V3 (n ¼ 4 patients) or beyond (n ¼ 2 patients) com-
electrocardiogram in the study pared with no RVOT patient and no control subject. Between
population RVOT and controls, the number of leads with T-wave inversion
BSM and conventional 12-lead surface ECGs were recorded during was comparable (0.8 + 0.7 vs. 0.5 + 0.5; P ¼ ns; Table 2). The
sinus rhythm in all patients. There were no significant differences in presence of a PKP2 gene mutation made no difference on
cycle length or QRS-axis between patients with ARVC in compari- QRS-dispersion or the presence of epsilon potentials (Table 2).
son with RVOT patients and controls (Table 2). In addition, QRS Mutation carriers tended to show more leads with T-wave inver-
durations in leads V1 –V6 and QRS dispersion were comparable sions than non-carriers (P ¼ 0.086; Table 2).
Body surface mapping in study population of these four adjacent channels resulting in an AUC of 0.87 + 0.04
Calculating the T-wave integral in leads V1 –V6, no statistically sig- (compared with RVOT; P , 0.001; Table 3) and 0.84 + 0.04 (com-
nificant difference between the groups was found (P ¼ ns; Table 2). pared with controls; P , 0.001; Table 3) with a sensitivity and spe-
However, the values for T-wave integrals were negative in a dis- cificity of 75 of 85% at a cut-off value of 23.1 mV ms (RVOT) and
tinct area in patients with ARVC compared with those with 74 of 85% at a cut-off value of 23.0 mV ms (controls; Table 3), re-
RVOT and controls (P , 0.001; Table 3). Best results to discrimin- spectively. The difference in T-wave integral between RVOT and
ate between ARVC and RVOT patients were obtained in channel controls remained non-significant (P ¼ ns; Table 3).
#6. To account for inter-individual differences in torso shape and Analysing potential differences in T-wave integral in the above
distances from the heart to body surface the four most significant mentioned regions between PKP2-pos and PKP2-neg ARVC
adjacent channels were picked and the mean values of T-wave in- patients in comparison to RVOT and controls, it became apparent
tegral in this area were calculated for each patient. This area was that PKP2-pos patients had the lowest T-wave integral in the anter-
located in the right lower anterior region of the torso and ior region of all groups (P , 0.001). ROC analyses revealed an
reflected recordings of the BSM channels #6, #7, #13, and #14 AUC for the comparison of PKP2-pos and RVOT of 0.97 + 0.02
(Figure 2A and B). In ROC analyses, the AUC was 0.85 + 0.04 (mean + SEM) with a sensitivity of 90% and specificity of 85% at
[mean + standard error of the mean (SEM); P , 0.001]. At a a cut-off level of 23.9 mV ms. Similar results were obtained
cut-off level of 20.3 mV ms ROC analyses comparing ARVC and when T-wave integral of PKP2-pos patients were compared to
RVOT revealed a sensitivity and specificity of 83% (Table 3). Com- that of controls [AUC 0.92 + 0.03 (mean + SEM); sensitivity
paring ARVC with controls, patients with ARVC showed significant 82%, specificity 85% at cut-off level 23.9 mV ms]. Between
lower T-wave integrals in an adjacent area localized in the right PKP2-neg patients (22.7 + 9.4 mV ms) and RVOT (4.9 +
lower anterior region of the torso reflecting recordings of the 6.6 mV ms) these differences were less pronounced [AUC
channels #20, #21, #27, and #28. Mean values of T-wave integrals 0.74 + 0.07 (mean + SEM); sensitivity 77%, specificity 70% at
of these four most significant channels for each patient was calcu- cut-off level 0.4 mV ms]. No statistically significant differences in
lated and ROC analysis performed [AUC 0.8 + 0.05 (mean + T-wave integral were found between PKP2-neg patients and con-
SEM), sensitivity 73%, specificity 72% at cut-off level of 0.21 trols (22.7 + 9.4 mV ms vs. 20.031 + 8.7 mV ms; mean + SD,
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
...............................................................................................................................................................................
Anterior region (channels #6, #7, #13, #14)
T-wave integral (mV ms) 26.9 + 9.6 vs. 4.9 + 6.6 26.9 + 9.6 vs. 20.03 + 8.7 4.9 + 6.6 vs. 20.03 + 8.7
Area under curve 0.85 + 0.04 0.71 + 0.05
Cut-off level (mV ms) 20.3 22.6
Sensitivity (%) 83 64
Specificity (%) 83 70
P value ,0.001 ,0.001 ns
Posterior region (channels #79, #86, #93, #94)
T-wave integral (mV ms) 2.2 + 6.2 vs. 27.1 + 6.7 2.2 + 6.2 vs. 27.6 + 8.8 27.1 + 6.7 vs. 27.6 + 8.8
Area under curve 0.87 + 0.04 0.84 + 0.04
Cut-off level (mV ms) 23.1 23.0
Sensitivity (%) 75 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.
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 589
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