Download Dispersion of Ventricular Depolarization-Repolarization

Dispersion of Ventricular Depolarization-Repolarization
A Noninvasive Marker for Risk Stratification in Arrhythmogenic Right
Ventricular Cardiomyopathy
Pietro Turrini, MD, PhD; Domenico Corrado, MD; Cristina Basso, MD, PhD; Andrea Nava, MD;
Barbara Bauce, MD; Gaetano Thiene, MD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—We retrospectively investigated the value of clinical and ECG findings as well as QT-QRS dispersion in
predicting the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).
Methods and Results—Duration and interlead variability of the QT interval and QRS complex were measured
manually from standard ECGs in 20 sudden death victims with ARVC diagnosed at autopsy (group I), in 20 living
ARVC patients with sustained ventricular tachycardia (group II), in 20 living ARVC patients with ⱕ3 consecutive
premature ventricular beats (group III), and in 20 control subjects (group IV). QT and QRS dispersions were
greater in group I (77.5⫾10.6 ms for QT and 45.7⫾8.1 ms for QRS) compared with group II (64.5⫾13.9 ms for
QT [P⫽0.001] and 33.5⫾8.7 ms for QRS [P⫽0.0004]) and in group II compared with group III (48⫾8.9 ms for
QT [P⬍0.0001] and 28⫾5.2 ms for QRS [P⬍0.0001]) and group IV (33.5⫾4.8 ms for QT [P⬍0.0001] and
18.5⫾3.6 ms for QRS [P⬍0.0001]). Negative T wave beyond V1 and syncope were statistically more frequent in
group I (P⫽0.02 and P⫽0.007, respectively). On multivariate analysis, QRS dispersion remained an independent
predictor of sudden death (P⬍0.0001), followed by syncope (P⫽0.09). In assessing risk of sudden death, QRS
dispersion ⱖ40 ms had a sensitivity and specificity of 90% and 77%, respectively; QT dispersion ⬎65 ms, 85%
and 75%, respectively; negative T wave beyond V1, 85% and 42%, respectively; and syncope, 40% and 90%,
respectively.
Conclusions—QRS dispersion (ⱖ40 ms) was the strongest independent predictor of sudden death in ARVC. Syncope, QT
dispersion ⬎65 ms, and negative T wave beyond V1 refined arrhythmic risk stratification in these patients. (Circulation.
2001;103:3075-3080.)
Key Words: cardiomyopathy 䡲 death, sudden 䡲 electrocardiography
T
dispersion, has been proposed as a simple noninvasive
method for detecting regional differences in ventricular
recovery times of excitability.13 In ARVC, body-surface
QRST integral mapping revealed the presence of repolarization abnormalities,14 which might be correlated with
vulnerability to malignant ventricular arrhythmias.15 Benn
et al16 measured an increased QT dispersion in ARVC
patients, without significant differences between individuals considered at low and high risk for life-threatening
arrhythmias. Peters et al8 demonstrated that an increased
dispersion of QRS complex in precordial leads was a
noninvasive predictor of recurrent arrhythmic events.
However, these ECG markers have never been evaluated in
patients who died suddenly with ARVC proven at autopsy.
The present study was designed to investigate the value of
clinical and ECG findings as well as QT-QRS dispersion in
predicting the risk of sudden death in a large group of ARVC
patients.
he natural history of arrhythmogenic right ventricular
(RV) cardiomyopathy (ARVC) is a function of both
the electrical instability of dystrophic myocardium, which
can precipitate sudden death any time during the disease
course, and the progressive myocardial loss that results in
ventricular dysfunction and heart failure.1–5 Sudden death
accounts for the majority of the fatal events, and it is more
common in adolescents and young adults.6 Invasive markers for unfavorable outcome in ARVC include inducible
ventricular tachycardia (VT), drug failure during serial
electrophysiological studies, RV dilatation, and left ventricular involvement.7,8 In contrast, there is still limited
clinical information on noninvasive risk stratification,
especially when no sustained VT has been documented.9
Patients with a history of syncope,10,11 familial sudden
death,12 and precordial T-wave inversion beyond V38 seem
to have a worse prognosis.
Measurement of the interlead variability in QT-interval
duration on the standard 12-lead ECG, known as QT
Received January 18, 2001; revision received April 6, 2001; accepted April 6, 2001.
From the Departments of Pathology (P.T., C.B., G.T.) and Cardiology (D.C., A.N., B.B.), University of Padua Medical School, Padua, Italy.
Correspondence to Gaetano Thiene, MD, FESC, Istituto di Anatomia Patologica, Via A. Gabelli, 61, 35121 Padua, Italy. E-mail cardpath@
unipd.it
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
3075
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June 26, 2001
TABLE 1.
Comparison of Clinical and ECG Data in the 4 Groups
Group I
(20 Pts)
Age, y
24.8⫾6.5
Sex (male/female), n
Group III
(20 Pts)
Group IV
(20 Pts)
26.4⫾6.2
22.4⫾7.4
25.9⫾5.4
16/4
16/4
975⫾136
982⫾117
943⫾117
935⫾139
Isolated complete RBBB, n (%)
3 (15)
3 (15)
1 (5)
0
Isolated ST-segment elevation on right precordial
leads, n (%)
7 (35)
8 (40)
3 (15)
0
Complete RBBB and ST-segment elevation on right
precordial leads, n (%)
1 (5)
0
0
0
RR interval, ms
␧ wave, n (%)
Negative T-wave beyond V1, n (%)
Syncope, n (%)
Left ventricular involvement, n (%)
Diffuse RV involvement, n (%)
17/3
Group II
(20 Pts)
18/2
7 (35)
5 (25)
6 (30)
0
17 (85)*
14 (70)
9 (45)
0
8 (40)†
4 (20)
0
0
7 (35)‡
6 (30)
6 (30)
0
16 (80)‡
20 (100)
20 (100)
0
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Pts indicates patients. Values are mean⫾1 SD or number (percentage).
*P⫽0.02 vs groups II and III; †P⫽0.007 vs groups II and III.
‡Postmortem evaluation.
Methods
Patient Population
We examined 12-lead ECGs in 4 different groups of patients, for
whom Table 1 gives the main clinical and ECG data. Group I
included 20 consecutive patients with ARVC and available ECG
who died suddenly. The pathological diagnosis was proven at
autopsy in all and was based on the finding of gross and/or
histological evidence of transmural loss of myocardium with fibrofatty replacement of the RV free wall myocardium, either regional or
diffuse, in the absence of valve, coronary, and pericardial disease or
other known cardiac or noncardiac causes of death.1,3,6 Groups II and
III included 20 age- and sex-matched living patients, each with an
overt form of ARVC. All the patients fulfilled the diagnostic criteria
of ARVC recommended by the Task Force of the European Society
of Cardiology.17 According to these criteria, ARVC was defined to
be diffuse when imaging techniques such as echocardiography,
angiography, MRI, or radionuclide scintigraphy showed a widespread RV involvement with a global RV dilatation and ejection
fraction reduction. Localized RV disease was diagnosed in the
presence of regional RV lesions, such as segmental RV wall motion
abnormalities (hypo-akinetic or dyskinetic areas), with mild or no
ejection fraction reduction. At postmortem examination, RV involvement was defined as diffuse or regional when fibrofatty
replacement of the RV was found to be widespread or segmental,
respectively. Left ventricular involvement was diagnosed in the
presence of either localized or diffuse pathological lesions/wall
motion abnormalities of the left ventricular free wall, with or without
septal involvement. Endomyocardial biopsy was available for all
patients from group II and for 14 of 20 patients from group III. The
extent of RV disease and incidence of left ventricular involvement
were comparable in the 3 ARVC groups (Table 1). Patients of group
II experienced spontaneous sustained (ⱖ30-second) monomorphic
VT (mean rate 210⫾37 bpm), whereas patients of group III had ⱕ3
consecutive premature ventricular beats at ECG and/or Holter
monitoring. Group IV consisted of 20 age- and sex-matched healthy
control subjects with no history of arrhythmia or syncope and normal
ECG patterns.
ECG Features
Analysis of ECG focused on the following parameters: ⑀ waves,
defined according to Fontaine et al18 as distinct waves of small
amplitude that occupy the QT segment in the right precordial leads;
negative T wave beyond V1; ST-segment elevation, defined as
maximal displacement of ST segment with upward convexity
ⱖ0.5 mm from the isoelectric line; and complete right bundle-branch
block (RBBB), defined as a prolonged QRS complex ⱖ120 ms.
Patients with a Brugada-like ECG pattern (Brugada and Brugada19)
characterized by high take-off ST-segment elevation ⱖ1 mm of
“coved” or “saddle-back” type were excluded.
ECG Measurements
No patients were on antiarrhythmic drugs or other drugs known to
affect the QRS complex and/or the QT interval during or before
acquisition of the ECG tracings analyzed in the present study. All
patients were in sinus rhythm. The 12-lead ECGs were obtained in
the traditional lead position and recorded at 25 mm/s. To increase the
accuracy of measurements, all the ECGs were enlarged ⫻2 to obtain
for all a format comparable to 50 mm/s. The QT interval and
QRS-complex duration were measured manually at each lead by
means of a method previously described.20,21 The QT interval was
measured from the onset of the QRS complex to the end of the T
wave, ie, return to the T-P baseline. When U waves were present, the
QT interval was measured to the nadir of the curve between the T
and U waves. The QRS-complex duration was measured from the
beginning of the QRS complex to its end. When the offset of QRS
complex was difficult to define because of a gradual slope toward a
plateau, it was measured at the intersection of the S wave with the
isoelectric baseline. The JT interval was calculated by subtracting
QRS duration from QT (means) interval in individual leads. Whenever possible, 3 consecutive cycles were measured in each of 12
leads to calculate a mean value of RR from these 3 values. When the
end of the QRS complex or T wave could not be identified, the lead
was not included. Three precordial leads at least and a minimum of
7 leads were required for QT/QRS/JT dispersion. The QT, QRS, and
JT dispersions were defined as the difference between the maximum
and minimum QT, QRS, and JT values occurring in any of the 12
ECG leads, respectively.
The percentage of missing leads for determination of QT dispersion
and QRS dispersion was 8.7% and 4.2%, respectively, for group I; 9.2%
and 5%, respectively, for group II; 7.9% and 4.6%, respectively, for
group III; and 6.2% and 2%, respectively, for group IV.
Cutoff values and correlations between dispersions of QT, QRS,
and JT intervals were assessed by using uncorrected values. In
addition, we provide rate-corrected values of QT and JT intervals
and dispersions with the use of Bazett’s formula.
Two independent observers, blinded as to the clinical data, tested
the repeatability of these measurements in a random sample of 20
ECGs. For the same ECG tracings, the percentage differences in
QT/QRS/JT dispersion measurements ranged from 2% to 6% for
Turrini et al
TABLE 2.
Dispersion of Ventricular Depolarization in ARVC
3077
Comparison of QT/QRS/JT Interval in the 4 Groups
QT Max, ms
Group I
(20 Pts)
P*
Group II
(20 Pts)
P†
Group III
(20 Pts)
445⫾30.7
NS
433⫾36.5
NS
410⫾30.7
QT Min, ms
367⫾31.3
NS
QTc Max, ms
453⫾16.5
0.04
QTc Min, ms
374⫾18.3
QRS Max, ms
125.2⫾18.3
366⫾30.2
436.9⫾20
NS
NS
362⫾29.8
422.9⫾20
P‡
Group IV
(20 Pts)
⬍0.0001
387.5⫾25.7
NS
354⫾24.5
⬍0.0001
402.5⫾16.4
366.5⫾18.1
NS
371.4⫾20.2
NS
373.2⫾20.6
NS
0.08
113⫾21
NS
106.5⫾9.8
⬍0.0001
88⫾8.9
QRS Min, ms
79.5⫾15.7
NS
78.7⫾14.6
NS
78.5⫾8.7
NS
JT Max, ms
320.7⫾28.1
NS
319⫾34.1
NS
307⫾26.9
NS
69.6⫾9.4
300⫾19.1
JT Min, ms
287.5⫾27.8
NS
287⫾30.5
NS
280⫾27.7
NS
279⫾17.1
Max indicates maximum; min, minimum. Values are mean⫾1 SD.
*Group I vs group II; †Group II vs group III; and ‡group II vs group IV.
within-observer variability and 2% to 7% for between-observer
variability.
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Statistical Analysis
All analyses were performed with STATA, version 6.0 (STATA
Corp, 1999). All continuous variable values are reported as mean⫾1
SD. Continuous variables were analyzed by use of ANOVA with the
Bonferroni correction for multiple comparisons or by use of the
Spearman correlation of ranks when appropriate. Categorical variables were analyzed by use of contingency tables and the Pearson ␹2
method. The independent correlation of clinico-ECG variables with
sudden death was determined by means of multivariate logistic
regression analysis, with sudden death as a dependent variable.
Variables with a value of Pⱕ0.1 in the univariate analysis (maximum QT interval [both uncorrected and rate-corrected] and QRS
complex, QT/QRS/JT dispersion, rate-corrected QT and JT dispersions, negative T wave beyond V1, syncope, ST-segment elevation in
right precordial leads, and RBBB) were considered candidates for
multivariable analysis. We estimated the odds ratio and 95% CIs of
the variables independently associated with sudden death. A value
Pⱕ0.05 was considered statistically significant.
Results
Clinical and ECG Findings
History of syncope was statistically more frequent in group I
than in groups II and III (Table 1). RR intervals were similar
in the 4 groups. The incidence of negative T wave beyond V1
was higher in group I than in groups II and III.
There was no significant difference in ⑀ waves as well as
ST-segment elevation among the ARVC groups. Isolated
complete RBBB was found in 3 patients each in groups I and
II and in 1 patient in group III. Only 1 patient of group I
TABLE 3.
showed complete RBBB with coexistent ST-segment
elevation.
QT/QRS/JT Interval
Table 2 reports maximum and minimum QT, QRS, and JT
intervals in the 4 groups. QT and QRS intervals tended to be
higher in group I. Maximum values of QRS and QT intervals
were measured in the right precordial leads in all the patients
of groups I, II, and III. In group IV, maximum QT interval
and QRS duration were found in the right precordial leads in
10 and 8 subjects, respectively.
QT/QRS/JT Dispersion
QT and QRS dispersions (Table 3) were greater in group I
than in group II and greater in group II than in groups III and
IV. JT dispersion did not differ significantly in the 3 ARVC
groups. In group I, the subgroup of 4 patients with RBBB had
similar values of QT, QRS, and JT dispersions compared with
values in the subgroup of patients without RBBB (with
RBBB versus without RBBB, respectively: 81.2⫾3 versus
76.8⫾11.9 ms [P⫽NS] for QT, 50⫾8.1 versus 44.6⫾8 ms
[P⫽NS] for QRS, and 35⫾5.7 versus 32.8⫾4.4 ms [P⫽NS]
for JT). Also, in group II, the subgroup of 3 patients with
RBBB had similar values of QT, QRS, and JT dispersions
compared with the subgroup of patients without RBBB (with
RBBB versus without RBBB, respectively: 73.3⫾11.5 versus
62.9⫾14 ms [P⫽NS] for QT, 43.3⫾11.5 versus 31.1⫾7.2 ms
[P⫽NS] for QRS, and 33.3⫾5.7 versus 32.3⫾8.3 ms
[P⫽NS] for JT).
Comparison of QT/QRS/JT Dispersion in the 4 Groups
Group I
(20 Pts)
P*
Group II
(20 Pts)
P†
QTD, ms
77.5⫾10.6
0.001
64.5⫾13.9
⬍0.0001
QTDc, ms
78.5⫾10.4
⬍0.0001
65⫾12.4
⬍0.0001
QRSD, ms
45.7⫾8.1
⬍0.0001
33.5⫾8.7
0.07
JTD, ms
33.2⫾4.6
NS
32.5⫾7.8
JTDc, ms
34.5⫾4.6
NS
31.7⫾7.9
Group III
(20 Pts)
P‡
Group IV
(20 Pts)
48⫾8.9
⬍0.0001
33.5⫾4.8
49.6⫾8.6
⬍0.0001
34.8⫾4.4
28⫾5.2
⬍0.0001
18.5⫾3.6
0.08
27.5⫾6.3
⬍0.0001
21⫾5.5
NS
29.3⫾6.7
⬍0.0001
21.7⫾5.3
QTD indicates QT dispersion; QTDc, rate-corrected QTD; QRSD, QRS dispersion; JTD, JT dispersion; and JTDc,
rate-corrected JTD.
*Group I vs group II; †group II vs group III; and ‡group II vs group IV.
3078
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June 26, 2001
30% and 72%, respectively. When these parameters were
used in combination, there was an increased in specificity for
QRS plus QT dispersion (82%) and for QT plus QRS plus JT
dispersions (85%) associated with a reduction of sensitivity
(85% and 30%, respectively).
Multivariate Analysis of Risk Factors for
Sudden Death
Figure 1. QT dispersion in 3 ARVC groups. Cutoff values are
indicated by horizontal lines.
We performed a stepwise logistic regression analysis incorporating all the clinical and ECG-derived variables to determine independent predictors of sudden death. Only QRS
dispersion remained an independent predictor of sudden
death (odds ratio 1.22, CI 1.11 to 1.35; P⬍0.0001), followed
by history of syncope (odds ratio 5.9, CI 0.71 to 49.44;
P⫽0.09).
Figures 1 and 2 provide the individual values of QT and
QRS dispersions, respectively, in the 3 ARVC groups.
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Correlations Between Intervals and Dispersions
There were significant correlations between QRS duration or
QT interval and the dispersions of QT/QRS/JT when all the
ARVC patients were considered as a single group (Table 4).
QT dispersion correlated strongly with QRS dispersion and
JT dispersion. There was a particularly close correlation
between QRS dispersion and maximal QRS duration. QT
dispersion had a significant relationship with maximum QT
interval.
Accuracy of Clinico-ECG Variables in Predicting
the Risk of Sudden Death
A history of syncope had a sensitivity and specificity in
predicting the occurrence of sudden death of 40% and 90%,
respectively; a negative T wave beyond V1 had a sensitivity
and specificity in predicting the occurrence of sudden death
of 85% and 42%, respectively.
For QT, QRS, and JT dispersions, we considered as the
upper limit of low arrhythmic risk the 99% tolerance limits
(mean⫾2 SD) of the values of group III. The following cutoff
values were indicative of high risk: QT dispersion ⬎65 ms,
QRS dispersion ⱖ40 ms, and JT dispersion ⱖ40 ms.
A QRS dispersion ⱖ40 ms showed a sensitivity and a
specificity in identifying patients at risk of sudden death of
90% and 77%, respectively (Figure 2); a QT dispersion ⬎65
ms, 85% and 75%, respectively (Figure 1); and a JT ⱖ40 ms,
Discussion
The main findings of the present study were that QRS
dispersion (ⱖ40 ms) was the strongest independent predictor
of sudden death in ARVC patients; increased QRS dispersion
resulted mainly from localized prolongation of the QRS
complex in the right precordial leads; syncope, QT dispersion
⬎65 ms, and negative T wave beyond V1 refined noninvasive
risk stratification for sudden death.
Pathophysiology of Ventricular Arrhythmias
in ARVC
VT and fibrillation are well-documented causes of sudden
death in ARVC.1,2,4,8 The peculiar histopathology of the
disease predisposes the patient to malignant ventricular arrhythmias.18,22 In ARVC, VT is generally believed to be
reentrant4,9 and is usually accompanied by abnormalities of
ventricular activation.4,23 Localized prolongation of QRS
duration in the right precordial leads is a well-recognized
feature of ARVC, and a duration of ⱖ110 ms is considered a
main diagnostic criterion.17 A reentry mechanism is suggested by the inducibility of VT by programmed ventricular
stimulation,4,18,22 together with a high frequency of late
potentials,24,25 and by the finding of areas of slow conduction
during endocardial mapping of the RV.4,26,27 Recently, it has
been hypothesized that repolarization abnormalities in ARVC
may facilitate the occurrence of ventricular arrhythmias15
with a mechanism that can be modulated by autonomic
nervous system activity.24
QT Dispersion
Figure 2. QRS dispersion in 3 ARVC groups. Cutoff values are
indicated by horizontal lines.
Experimental studies have provided powerful evidence that
nonuniform recovery of ventricular excitability plays an
important role in the mechanism of ventricular arrhythmias.28
Potentially arrhythmogenic nonuniform recovery of excitability is the result of either dispersion of refractoriness or
activation times depending on the underlying pathophysiological substrate.29 The interlead variability in QT-interval
duration on the standard 12-lead ECG, the so-called QT
dispersion, is a noninvasive method for detecting regional
differences in ventricular recovery time.13 Experimental studies confirmed that QT dispersion is significantly correlated
with dispersion of ventricular recovery time, measured directly from myocardium.30 The studies on QT dispersion have
Turrini et al
TABLE 4.
QRS Max
JT Max
3079
Correlations in Total Patients With ARVC
QT Max
QT Max
Dispersion of Ventricular Depolarization in ARVC
QRS Max
QRSD
QTD
JTD
䡠䡠䡠
r⫽0.60
r⫽0.60
r⫽0.64
r⫽0.42
䡠䡠䡠
P⬍0.0001
P⬍0.0001
P⬍0.0001
P⫽0.0008
䡠䡠䡠
䡠䡠䡠
r⫽0.77
r⫽0.67
r⫽0.40
P⫽0.001
䡠䡠䡠
r⫽0.76
䡠䡠䡠
r⫽0.09
P⬍0.0001
P⬍0.0001
r⫽0.21
r⫽0.33
r⫽0.29
P⬍0.0001
P⫽NS
P⫽NS
P⫽0.009
P⫽0.02
䡠䡠䡠
䡠䡠䡠
r⫽0.33
䡠䡠䡠
P⫽0.008
QRSD
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
QTD
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
r⫽0.83
䡠䡠䡠
P⬍0.0001
䡠䡠䡠
Abbreviations as in Table 3.
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provided information about regional variations in ventricular
repolarization in many diseases characterized by malignant
ventricular arrhythmias, such as myocardial infarction,31
coronary artery disease,32 long-QT syndrome,13 hypertrophic
cardiomyopathy,33 chronic heart failure,34 and repaired tetralogy of Fallot.35
In our ARVC patient population, QT dispersion was
significantly greater in the patients who died suddenly compared with living patients with different arrhythmic profiles.
Our cutoff value for QT dispersion, ⬎65 ms, is similar to that
reported by Surawicz.36 Also, Benn et al16 measured an
increased QT dispersion in ARVC patients, but they did not
find significant differences between individuals considered at
low and high risk for life-threatening arrhythmias. However,
patients who died suddenly were only 5 of 11 high-risk
patients (45%), and the mean QRS duration of the whole
high-risk group was smaller than that of our victims of
sudden death. Peeters et al,15 analyzing ARVC patients with
sustained VT and overt forms of the disease, did not find an
increased QT dispersion, although they demonstrated that
repolarization abnormalities were present at body surface
mapping and might have been related to the occurrence of
ventricular arrhythmias. A smaller mean QRS duration and a
lower number of patients could explain the discrepancy with
the present findings.
It has been recently advanced that QT dispersion may be an
index of general repolarization abnormalities instead of an
expression of regional heterogeneity of myocardial refractoriness. Accordingly, T-wave loop dynamics and the variable
projections of the loop into individual ECG leads has been
proposed to be the true mechanistic background of QT
dispersion.37 This concept was in keeping with our finding
that in victims of sudden death, a negative T wave beyond V1,
which is another marker of repolarization abnormalities,
showed approximately the same sensitivity of QT dispersion
but less specificity.
QRS Dispersion
Because QT dispersion has been taken to represent regional
inhomogeneity of repolarization times, QRS dispersion is
likely to represent regional inhomogeneity of depolarization
times, as a consequence of a ventricular conduction defect.
QRS dispersion was closely correlated with maximal QRS
䡠䡠䡠
r⫽0.67
䡠䡠䡠
P⬍0.0001
duration in total patients with ARVC. This finding suggests
the major role of localized prolongation of QRS complex in
determining the increased QRS dispersion. Such an increased
QRS dispersion has many parallels with the revisited definition of ⑀ waves, which are now considered by Fontaine et al38
as “any potential in V1-V3 exceeding the QRS duration in lead
V6 by more than 25 ms” and regarded as a diagnostic marker
for ARVC. The present study further demonstrated that an
increased QRS dispersion is the strongest independent predictor of sudden death. A cutoff value ⱖ40 ms had a good
sensitivity and specificity in predicting the occurrence of
sudden death. Also, Peters et al8 demonstrated that increased
QRS dispersion ⱖ50 ms was a strong predictive factor of
recurrent malignant arrhythmic events.
Two mechanisms leading to sudden death in ARVC have
been proposed by Fontaine et al,39 ie, depolarization abnormalities mediated by a sympathetic mechanism and repolarization abnormalities facilitated by parasympathetic drive.
Our data confirm that both depolarization and repolarization
abnormalities do exist in patients at risk for sudden death.
However, depolarization abnormalities are most commonly
associated with cardiac arrest.
Study Limitations
This is a retrospective study that was carried out in a young
population of ARVC patients with comparable clinical characteristics. Therefore, the ability to transfer our results to
ARVC patients older or with different clinical picture remains to be elucidated. The correlation between ECG parameters and the risk of sudden death may change with age,
extent, and progression of ARVC and severity of left ventricular involvement, all variables that may have a significant
and independent influence on the proposed ECG parameters
and may affect the correlation with sudden death risk.
The present study investigated the ECG features of ARVC
patients, either living or experiencing sudden death, before
starting antiarrhythmic drug therapy. The subsequent
follow-up of these patients on antiarrhythmic drug treatment
or after implantation of cardioverter defibrillator was not
addressed. Whether pharmacological or nonpharmacological
therapy modifies ARVC natural history by preventing sudden
death cannot be derived from the present data and needs to be
evaluated by prospective studies.40
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June 26, 2001
Conclusions
This was the first study to address the prognostic value of
clinical and ECG variables in ARVC patients who died
suddenly compared with living patients with different degrees
of arrhythmic risk. Our data indicate that QRS dispersion
(ⱖ40 ms) is the strongest independent predictive marker of
sudden death in ARVC patients and that syncope as well as
QT dispersion (⬎65 ms) and negative T wave beyond V1
refine noninvasive arrhythmic risk stratification. Because
maximum QRS complex and QT interval were found in the
right precordial leads, these leads appear to be crucial in the
diagnosis and risk stratification of ARVC.
Acknowledgments
This study was supported by Veneto Region, Venice; Fondazione
Cassa di Risparmio, Padua; and Murst, Rome, Italy.
References
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
1. Thiene G, Nava A, Corrado D, et al. Right ventricular cardiomyopathy
and sudden death in young people. N Engl J Med. 1988;318:129 –133.
2. Corrado D, Thiene G, Nava A, et al. Sudden death in young competitive
athletes: clinicopathologic correlations in 22 cases. Am J Med. 1990;89:
588 –596.
3. Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular
cardiomyopathy: dysplasia, dystrophy, or myocarditis? Circulation.
1996;94:983–991.
4. Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia:
a report of 24 adult cases. Circulation. 1982;65:384 –398.
5. Daliento L, Turrini P, Nava A, et al. Arrhythmogenic right ventricular
cardiomyopathy in young versus adult patients: similarities and differences. J Am Coll Cardiol. 1995;25:655– 664.
6. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic
manifestations of arrhythmogenic right ventricular cardiomyopathy/
dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30:1512–1520.
7. Nava A, Rossi L, Thiene G, eds. Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia. Amsterdam, the Netherlands: Elsevier; 1997.
8. Peters S, Peters H, Thierfelder L. Risk stratification of sudden cardiac
death and malignant ventricular arrhythmias in right ventricular
dysplasia-cardiomyopathy. Int J Cardiol. 1999;71:243–250.
9. Leclercq JF, Coumel P. Characteristics, prognosis, and treatment of the
ventricular arrhythmias of right ventricular dysplasia. Eur Heart J. 1989;
10(suppl D):61– 67.
10. Blomstrom-Lundqvist C, Sabel KG, Olsson SB. A long term follow-up of
15 patients with arrhythmogenic right ventricular dysplasia. Br Heart J.
1987;58:477– 488.
11. Marcus FI, Fontaine GH, Frank R, et al. Long term follow-up in patients
with arrhythmogenic right ventricular disease. Eur Heart J. 1989;
10(suppl D):68 –73.
12. Nava A, Thiene G, Canciani B, et al. Familial occurrence of right
ventricular dysplasia: a study involving nine families. J Am Coll Cardiol.
1988;12:1222–1228.
13. Day CP, McComb JM, Campbell RWF. QT dispersion: an indication of
arrhythmia risk in patients with long QT intervals. Br Heart J. 1990;63:
342–344.
14. De Ambroggi L, Aimè E, Ceriotti C, et al. Mapping of ventricular
repolarization potentials in patients with arrhythmogenic right ventricular
dysplasia: principal component analysis of the ST-T waves. Circulation.
1997;96:4314 – 4318.
15. Peeters HAP, SippensGroenewegen A, Schoonderwoerd BA, et al. Bodysurface QRST integral mapping: arrhythmogenic right ventricular dysplasia versus idiopathic right ventricular tachycardia. Circulation. 1997;
95:2668 –2676.
16. Benn M, Hansen PS, Pedersen AK. QT dispersion in patients with
arrhythmogenic right ventricular dysplasia. Eur Heart J. 1999;20:
764 –770.
17. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic
right ventricular dysplasia/cardiomyopathy. Br Heart J. 1994;71:
215–218.
18. Fontaine G, Fontaliran F, Lascault G, et al. Arrhythmogenic right ventricular dysplasia. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology:
From Cell to Bedside. Philadelphia, Pa: WB Saunders; 1994:754 –768.
19. Brugada P, Brugada J. Right bundle branch block, persistent ST segment
elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol. 1992;20:
1391–1396.
20. Higham PD, Furniss SS, Campbell RW. QT dispersion and components
of the QT interval in ischaemia and infarction. Br Heart J. 1995;73:
32–36.
21. Gatzoulis MA, Till JA, Somerville J, et al. Mechanoelectrical interaction
in tetralogy of Fallot: QRS prolongation relates to right ventricular size
and predicts malignant ventricular arrhythmias and sudden death. Circulation. 1995;92:231–237.
22. Fontaine G, Frank R, Tonet JL, et al. Arrhythmogenic right ventricular
dysplasia: a clinical model for the study of chronic ventricular
tachycardia. Jpn Circ J. 1984;48:515–538.
23. Fontaine G, Frank R, Gallais-Hamonno F, et al. Electrocardiographie des
potentiels tardifs du syndrome de post-excitation. Arch Mal Coeur Vaiss.
1978;8:854 – 864.
24. Wichter T, Hindricks G, Lerch H, et al. Regional myocardial sympathetic
dysinnervation in arrhythmogenic right ventricular cardiomyopathy: an
analysis using 123I-meta-iodobenzylguanidine scintigraphy. Circulation.
1994;89:667– 683.
25. Turrini P, Angelini A, Thiene G, et al. Late potentials and ventricular
arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Am J
Cardiol. 1999;83:1214 –1219.
26. Fontaine G, Guiraudon G, Frank R, et al. Stimulation studies and epicardial mapping in ventricular tachycardia: study of mechanism and
selection for surgery. In: Kulbertus HE, ed. Reentrant Arrhythmias. Lancaster, Pa: MTP Press Limited; 1977:334 –350.
27. Fontaine G, Guiraudon G, Frank R. Intramyocardial conduction defects in
patients prone to ventricular tachycardia, parts I–III. In: Sandoe E, Julian
DG, Bell JW, eds. Management of Ventricular Tachycardia: Role of
Mexiletine. Amsterdam, the Netherlands: Excerpta Medica Publications;
1978:39 –79.
28. Han J, Moe GK. Nonuniform recovery of excitability in ventricular
muscle. Circ Res. 1964;14:44 – 60.
29. Vassallo JA, Cassidy DM, Kindwall KE, et al. Nonuniform recovery of
excitability in the left ventricle. Circulation. 1988;78:1365–1372.
30. Zabel M, Portnoy S, Franz MR. Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study.
J Am Coll Cardiol. 1995;25:746 –752.
31. Perkiomaki JS, Koistinen MJ, Yli-Mayry S, et al. Dispersion of QT
interval in patients with and without susceptibility to ventricular
tachyarrhythmias after previous myocardial infarction. J Am Coll
Cardiol. 1995;26:174 –179.
32. Zareba W, Moss AJ, le Cessie S. Dispersion of ventricular repolarization
and arrhythmic cardiac death in coronary artery disease. Am J Cardiol.
1994;74:550 –553.
33. Buja G, Miorelli M, Turrini P, et al. Comparison of QT dispersion in
hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol. 1993;72:973–976.
34. Barr CS, Naas A, Freeman M, et al. QT dispersion and sudden unexpected death in chronic heart failure. Lancet. 1994;343:327–329.
35. Gatzoulis MA, Till JA, Redington AN. Depolarization-repolarization
inhomogeneity after repair of tetralogy of Fallot: the substrate for
malignant ventricular tachycardia? Circulation. 1997;95:401– 404.
36. Surawicz B. Will QT dispersion play a role in clinical decision-making?
J Cardiovasc Electrophysiol. 1996;7:777–784.
37. Malik M, Batchvarov VN. Measurements, interpretation, and clinical
potential of QT dispersion. J Am Coll Cardiol. 2000;36:1749 –1766.
38. Fontaine G, Fontaliran F, Hebert JL, et al. Arrhythmogenic right ventricular dysplasia. Annu Rev Med. 1999;50:17–35.
39. Fontaine G, Aouate P, Fontaliran F. Repolarization and the genesis of
cardiac arrhythmias: role of body surface mapping. Circulation. 1997;95:
2600 –2602.
40. Corrado D, Fontaine G, Marcus FI, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Circulation. 2000;101:e101– e106.
Dispersion of Ventricular Depolarization-Repolarization: A Noninvasive Marker for Risk
Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy
Pietro Turrini, Domenico Corrado, Cristina Basso, Andrea Nava, Barbara Bauce and Gaetano Thiene
Circulation. 2001;103:3075-3080
doi: 10.1161/01.CIR.103.25.3075
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