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(Circulation. 1995;91:715-721.)
© 1995 American Heart Association, Inc.

Articles

Time- and Frequency-Domain Analyses of the Signal-Averaged ECG in Patients With Arrhythmogenic Right Ventricular Dysplasia

Osamu Kinoshita, MD; Guy Fontaine, MD, PhD; Fernando Rosas, MD; Jorge Elias, MD; Toru Iwa, MD; Joelci Tonet, MD; Gilles Lascault, MD; Robert Frank, MD

From the Center de Stimulation Cardiaque et de Rythmologie, Hopital Jean Rostand, Ivry, France.

	Abstract

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Background Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by recurrent ventricular tachycardia of right ventricular origin and a cardiomyopathy with hypokinetic areas involving the free wall of the right ventricle. Subjects have a risk of sudden cardiac death, particularly during sports and strenuous exercise. Routine clinical examinations may be normal, but fragmented or delayed electrograms are usually recorded in the right ventricle of these patients. However, the frequency with which late potentials are detected by conventional time-domain analysis of the signal-averaged ECG (SAECG) is not high. This study evaluated the usefulness of the frequency-domain analysis of the SAECG in addition to the conventional time-domain analysis for a screening test to detect patients with ARVD.

Methods and Results SAECG was recorded by using a bipolar X, Y, and Z lead system in 28 patients with ARVD (mean age, 38±13 years) and 35 age-matched normal subjects (mean age, 35±11 years). The conventional time-domain analysis of the SAECG was performed at two different high-pass filter settings, 25 and 40 Hz, and the low-pass cutoff frequency was fixed at 250 Hz. The fast-Fourier transform analysis of SAECG was performed using a Blackman-Harris window. Area ratio 1 (area of 20 to 50 Hz)/(area of 0 to 20 Hz) and area ratio 2 (area of 40 to 100 Hz)/(area of 0 to 40 Hz) were calculated. In the conventional time-domain analysis, 20 (71%) and 18 (64%) patients had positive criteria at filter settings of 25 and 40 Hz, respectively. In the frequency-domain analysis, 18 (64%) and 20 (71%) patients had abnormal values in area ratios 1 and 2, respectively. Combining the time- and frequency-domain analyses, all patients were judged positive, with a sensitivity of 100% and a specificity of 94%.

Conclusions Each result of the time- and frequency-domain analyses revealed that both methods had equivalent value. Combining the two domain analyses improved the sensitivity without reducing the specificity. These findings suggest that combining the time- and frequency-domain analyses of the SAECG may be useful as a screening test to detect patients with ARVD.

Key Words: tachycardia • cardiomyopathy • Fourier analysis • electrocardiography • potentials

	Introduction

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Arrhythmogenic right ventricular dysplasia (ARVD) is clinically recognized by recurrent ventricular tachycardia of right ventricular origin and a cardiomyopathy with hypokinetic areas involving the free wall of the right ventricle.^{1 2 3 4 5 6 7 8 9 10 11} Ventricular tachycardia showing a left bundle branch block pattern is observed in relatively young adults, and subjects have a risk of sudden cardiac death, particularly during sports and strenuous exercise.² However, routine clinical examination may be normal, and the patient may have no complaint other than palpitations.³ Specific changes on the ECG in sinus rhythm, such as ventricular postexcitation waves ("epsilon waves") occurring after the QRS complex at the beginning of the ST segment, are recorded in only 30% of these cases.⁴

The signal-averaged ECG (SAECG) has been used to detect low-amplitude, high-frequency, and altered frequency components in the terminal QRS complex.^{12 13 14 15 16 17 18 19 20 21} These signals are called late potentials and are considered a noninvasive marker for areas of slow conduction that are a prerequisite for reentrant arrhythmias. Delayed or fragmented electrograms are usually recorded during endomyocardial mapping in the right ventricle in patients with ARVD.^{4 5} The reported prevalence of late potentials has ranged from 50% to 80%.^{22 23}

Fast-Fourier transform analysis is a powerful analytic method for signal processing in the frequency domain.^{24 25 26 27 28 29 30 31 32 33 34} Cain et al^{24 25 26} report that frequency analysis offers potential advantages for the identification and characterization of signals that differentiate patients with from those without sustained ventricular tachycardia. Haberl et al²⁷ found frequency analysis to be more specific than time-domain analysis without loss of sensitivity. Lindsay et al^{28 29 30} have demonstrated that differentiation of patients with and without ventricular tachycardia by frequency-domain analysis is possible in the presence of bundle branch block. Pierce et al³¹ report that high frequencies in late potentials most usefully identify patients with coronary artery disease and ventricular tachycardia from patients without tachycardia. However, there is no established report regarding frequency-domain analysis of SAECG in patients with ARVD. The purpose of this study was to estimate the validity of frequency-domain analysis of the SAECG in addition to the conventional time-domain analysis as a screening test to detect patients with ARVD.

	Methods

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Study Population
The study included 28 patients with ARVD, 19 men and 9 women (mean age, 38±13 years) and 35 healthy age-matched volunteers, 30 men and 5 women (mean age, 35±11 years). Informed consent was obtained from all subjects. Patients with complete bundle branch block were not included in this study. ECGs obtained during clinical ventricular tachycardia showed left bundle branch block pattern in all patients. Diagnosis of ARVD was established by echocardiograms, right and left ventricular angiograms, coronary angiograms, and electrophysiological studies. Echocardiograms and right ventricular angiograms showed dilated or local wall-motion abnormality, but left ventricular angiograms and coronary angiograms were normal in all patients. A detailed description of the protocol of electrophysiological study in our department has been reported.^{5 6} Prior to the procedure, antiarrhythmic drugs are withheld for a period equivalent to five half-lives. The stimulation protocol includes the introduction of one to three progressively more premature stimuli after pacing at a progressively increasing rate. When ventricular tachycardia was not induced by stimulation, isoproterenol was injected to facilitate ventricular tachycardia induction. The site of origin of ventricular tachycardia was determined by recording the site of earliest activation during ventricular tachycardia and by pace mapping. Comparison of QRS morphologies was performed by using the standard 12-lead recorder. Special attention was paid to identifying the area of slow conduction. The site of origin of induced ventricular tachycardia was the right ventricle in all patients.

SAECG
Silver–silver chloride electrodes were used. The subject's skin was thoroughly cleansed with alcohol and abraded to decrease impedance. Signal averaging was performed by using the LVP-1200 EPX (Arrhythmia Research Technology) before electrophysiological evaluation. SAECGs were recorded during sinus rhythm using a standard bipolar X, Y, and Z lead system. The X lead was positioned at the fourth intercostal space in both midaxillary lines, the Y lead was positioned on the superior aspect of the manubrium and on the left iliac crest, and the Z lead was positioned at the fourth intercostal space, with the second electrode directly posterior on the left side of the vertebral column. More than 200 beats were averaged to obtain a noise level of <0.3 µV (mean, 0.22 µV) at 40 Hz.

Time-Domain Analysis
The time-domain analysis was performed with two high-pass bidirectional (Butterworth) filters (25 and 40 Hz), and the low-pass cutoff frequency was fixed at 250 Hz. For each filter setting, three conventional indexes were computed: the duration of the total filtered QRS (fQRS) complex, the duration of the low-amplitude signal (LAS) after the voltage decreased to less than 40 µV, and the root-mean-square (RMS) of the amplitude of signals in the last 40 ms of the fQRS complex. Late potentials were considered to be present if any two of the following three criteria at each filter setting were met: fQRS >120 ms, LAS >40 ms, or RMS <25 µV at a 25-Hz filter setting (according to Simson's¹³ criteria); or fQRS >114 ms, LAS >38 ms, or RMS <20 µV at a 40-Hz filter setting.³²

Frequency-Domain Analysis
Fast-Fourier transform analysis was performed on the terminal 20 ms of the QRS complex and ST segment of each signal-averaged X, Y, and Z lead. For each region of interest, a 120-ms interval was calculated with a four-term Blackman-Harris window to reduce spectral leakage. Before Fourier transform, the mean of all data values was subtracted after windowing. The data were plotted on a high-resolution plotter and expressed as a ratio of the area under the spectral plot between 20 Hz and 50 Hz divided by the area under the spectral plot between 0 Hz and 20 Hz (area ratio 1=20 to 50/0 to 20 Hz) and a ratio of the area under the spectral plot between 40 Hz and 100 Hz divided by the area under the spectral plot between 0 Hz and 40 Hz (area ratio 2=40 to 100/0 to 40 Hz).

Statistical Analysis
Data are presented as mean±SD. To compare SAECG parameters in patients with ARVD and in normal subjects, the unpaired t test was selected. A probability of P<.05 was considered significant.

The following definitions were used for calculating the sensitivity, specificity, and predictive accuracy of the SAECG for ARVD: (1) true positive (patients with abnormal SAECG criteria), (2) true negative (normal subjects with normal SAECG criteria), (3) false positive (normal subjects with abnormal SAECG criteria), and (4) false negative (patients with normal SAECG criteria). Receiver operating characteristic curves were constructed comparing the true positive rate (sensitivity) to the false positive rate.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Time-Domain Analysis
The mean values of the time-domain analysis for the two filter settings are shown in Table 1 and Fig 1. The fQRS duration was significantly prolonged in patients with ARVD in both filters. The mean duration of LAS was also significantly prolonged in patients with ARVD in both filter settings. RMS voltage of the terminal 40 ms of the QRS complex was significantly lower in patients with ARVD compared with normal subjects in both filter settings. Late potentials were considered to be present in 20 (71%) of 28 patients with ARVD, who had positive criteria in two or three parameters at the 25-Hz filter setting, and 18 (64%) of 28 patients with ARVD were judged as having late potentials at the 40-Hz filter setting. None of the normal subjects had abnormal values at either the 25- or 40-Hz high-pass filter settings.

View this table: [in this window] [in a new window]   Table 1. Results of Time-Domain Analysis of Signal-Averaged ECG

View larger version (16K): [in this window] [in a new window]   Figure 1. Plots of the filtered QRS duration (fQRS; left), the duration of low-amplitude signal of the fQRS complex that remains below 40 µV (LAS; middle), and root-mean-square voltage of the terminal 40 ms of the fQRS (RMS; right) using a 25-Hz high-pass filter for patients with arrhythmogenic right ventricular dysplasia (ARVD; n=28) and normal subjects (Normal; n=35). The size of the circles indicates the number of subjects with the same values.

Frequency-Domain Analysis
The mean values of the frequency-domain analysis for area ratio 1 (20 to 50/0 to 20 Hz) and area ratio 2 (40 to 100/0 to 40 Hz) are shown in Table 2 and Fig 2. The mean value of the mean X, Y, and Z leads of area ratio 1 in patients with ARVD was significantly higher than that of normal subjects (410±340 versus 186±28, P<.001). The mean value at mean X, Y, and Z leads of area ratio 2 in patients with ARVD was also significantly higher than that of normal subjects (174±143 versus 41±16, P<.001). The mean value of each lead was also significantly higher in patients with ARVD.

View this table: [in this window] [in a new window]   Table 2. Results of Frequency-Domain Analysis of Signal-Averaged ECG

View larger version (18K): [in this window] [in a new window]   Figure 2. Plots of comparison of values for the area ratios in patients with arrhythmogenic right ventricular dysplasia (ARVD; n=28) and normal subjects (Normal; n=35). Left, Results of area ratio 1 (20-50/0-20 Hz); right, results of area ratio 2 (40-100/0-40 Hz). The size of the circles indicates the number of subjects with the same values.

Receiver Operating Characteristic Curves and Combined Analysis
Fig 3 shows receiver operating characteristic curves for fQRS duration at both 25- and 40-Hz high-pass filter settings and area ratios 1 and 2, plotting true positive against false positive rates. The curves are convex to the upper left (high sensitivity with low false positive rate), indicating that fQRS duration at a 25-Hz high-pass filter setting and area ratio 2 are relatively useful tests.

View larger version (23K): [in this window] [in a new window]   Figure 3. Line graph of receiver operating characteristic curves of filtered QRS (fQRS) duration at both 25-Hz and 40-Hz filter settings and area ratio 1 (20-50/0-20 Hz) and area ratio 2 (40-100/0-40 Hz).

Fig 4 shows receiver operating curves for leads X, Y, and Z at area ratio 2, plotting true positive against false positive rates. The curves indicate that lead Z is relatively useful. This finding was also seen at area ratio 1.

View larger version (21K): [in this window] [in a new window]   Figure 4. Line graph of receiver operating characteristic curves of the frequency-domain analysis of individual leads X, Y, and Z.

Combining the time- and frequency-domain analyses of the SAECG improved the sensitivity (Table 3). We selected fQRS duration using 25-Hz high-pass filter and area ratio 2 for combined variables based on receiver operating characteristic curves. Defining a positive test as fQRS duration >120 ms or area ratio 2 >75 yielded 82% sensitivity and 97% specificity. Defining a positive test as fQRS duration >120 ms or area ratio 2 >100 yielded 78% sensitivity and 100% specificity. Defining a positive test as fQRS duration >110 ms or area ratio 2 >75 yielded 100% sensitivity and 94% specificity. Defining a positive test as fQRS duration >110 ms or area ratio 2 >100 yielded 96% sensitivity, 97% specificity, and 97% total predictive accuracy.

View this table: [in this window] [in a new window]   Table 3. Sensitivity, Specificity, and Predictive Accuracy of Signal-Averaged ECG Criteria in 28 Patients With ARVD

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
ARVD is recognized clinically by recurrent ventricular tachycardia of right ventricular origin and by cardiomyopathy limited to the right ventricle.^{1 2 3 4 5 6 7} A review of our original experience of 24 cases of supposed right ventricular dysplasia has been reported by Marcus et al.¹ Localized hypokinesis in the right ventricle is usually demonstrated angiographically, and the right ventricle may be dilated. There is excessive adipose tissue in the subepicardium. Patients with ARVD have recurrent episodes of ventricular tachycardia with a left bundle branch block–like pattern that can usually be induced by electrical stimulation, suggesting a reentrant mechanism. Fragmented or delayed potentials are often recorded during endocardial mapping in the right ventricle.^{4 5} These areas of slow conduction, in conjunction with endomyocardial biopsy findings of fatty infiltration, a decrease in myocardial fibers, and intramyocardial fibrosis in the dysplastic right ventricle, may cause inhomogeneity of activation and recovery and thus promote reentry.⁴ There is a risk of cardiac sudden death, generally observed during sports and strenuous exercise, in young adults^{2 3} ; this may be the first episode of ventricular arrhythmia. Routine clinical examination is often normal.^{3 4} Because the standard 12-lead ECG in sinus rhythm may show so-called "epsilon waves" in only 30% of cases,⁴ we developed screening tests for detecting patients with ARVD.

Time-Domain Analysis
SAECG has been used as a screening test to predict arrhythmia events in patients with old myocardial infarction, and it correlates with inducibility of ventricular tachycardia.^{12 13 14 15 16 17 18 19 20 21} A Task Force Committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology recently established standards for data acquisition and analysis of SAECGs.³² They recommended that the SAECG should be considered abnormal (using 40-Hz high-pass bidirectional filtering) when (1) the fQRS complex is greater than 114 ms, (2) there is less than 20 µV of signal in the last 40 ms of the vector magnitude complex, and (3) the terminal vector magnitude complex remains below 40 µV for more than 38 ms. In addition to these criteria at a 40-Hz high-pass filter setting, we used Simson's¹³ criteria at 25 Hz, ie, total fQRS duration >120 ms, terminal fQRS duration below 40 µV >40 ms, and RMS voltage of the terminal 40 ms <25 µV. The effect of the bandpass filter for SAECG to detect late potentials was assessed by Gomes et al³³ and Caref et al³⁴ in patients with ventricular tachycardia associated with coronary artery disease. Gomes et al³³ reported that a level of 25 Hz provided a low sensitivity but the best specificity, whereas 80 Hz provided the best sensitivity but a low specificity, and a filter of 40 Hz provided sensitivity and specificity intermediate between those at 25 and 80 Hz. Caref et al³⁴ reported that the SAECG parameters analyzed at 40 Hz were most frequently represented in the top predictive combinations. There were few reports of SAECG in patients with ARVD. Blomström-Lundqvist et al²² reported results from 16 patients with ARVD and 16 healthy volunteers that the sensitivity was 81%, 75%, and 75% in fQRS duration >120 ms, late potential duration >40 ms, and RMS <25 µV, respectively, using 25-Hz high-pass filter settings. Wichter et al²³ recently reported that late potentials were present in only 50% of patients with arrhythmogenic right ventricular cardiomyopathy using a 40-Hz high-pass filter and the criteria proposed by the Task Force Committee.³² In our present study, late potentials were present in 20 of 28 patients (71%) at the 25-Hz high-pass filter setting and in 18 patient (64%) at 40 Hz. These results suggest that the 25-Hz high-pass filter setting might be favorable for detecting patients with ARVD.

Frequency-Domain Analysis
Fast-Fourier transform analysis of the SAECG has been proposed as a means of identifying patients who are likely to develop sustained ventricular tachycardia after myocardial infarction.^{24 25 26 27 28 29 30 31 35 36 37} Cain et al^{24 25 26} showed a high-frequency content of the terminal QRS segment with an SAECG frequency-domain analysis. Frequency-domain analysis of the SAECG offers several advantages compared with time-domain analysis. First, complex high-pass filtering is not necessary. This is important because the frequency content of late potentials is low, and cutoff frequencies may abolish late potentials. Second, the definition of the end of the QRS complex is not a crucial factor in frequency-domain analysis, and patients with bundle branch block need not be excluded. Lindsay et al^{28 29 30} have demonstrated that differentiation of patients with and without ventricular tachycardia by frequency-domain analysis is possible even in the presence of complete bundle branch block. Haberl et al²⁷ and Pierce et al³¹ emphasize the significance of subtracting mean voltage before applying the Fourier transform. Kinoshita et al^{38 39} report that the frequency analysis of the SAECG might be able to detect late potentials that had short duration or were concealed within the QRS wave. However, there have been no established reports concerning the validity of frequency-domain analysis in patients with ARVD. In this study, we used two different area ratios, 20 to 50/0 to 20 Hz and 40 to 100/0 to 40 Hz. Eighteen (64%) and 20 (71%) of 28 patients with ARVD had abnormal values (>mean+2 SD) in area ratios 1 and 2, respectively. These results revealed that the time- and frequency-domain analyses of the SAECG were relatively equivalent in the identification of patients with ARVD.

Recording Leads
Late potentials of right ventricular origin may be detected in leads Z or V₁, which reflect vector for the anterior chest. Receiver operating characteristic curves indicated that lead Z was a relatively useful test in patients with ARVD. Kulakowski et al⁴⁰ report that lead X had abnormal values in the frequency analysis in patients with hypertrophic cardiomyopathy and ventricular tachycardia. Ohe et al⁴¹ report that late potentials of right ventricular origin were detected predominantly in lead V₁ and those of left ventricular origin in lead V₅ using a time-domain analysis. Blomström-Lundqvist et al²² have demonstrated that the ratio of the late potential duration/fQRS duration was significantly higher in V₁ than V₃ and V₅ in the ARVD group. In frequency-domain analysis, Lindsay et al^{28 29 30} report that analysis of the individual X, Y, and Z leads differentiated patients with myocardial infarction and ventricular tachycardia, providing sensitivities of 67%, 63%, and 63%, respectively. Further studies using multiple lead systems (such as late potential mapping) are needed for determining which leads are useful for differentiating patients with ARVD.

Combining Time- and Frequency-Domain Analyses
Combining the time-domain and frequency-domain analyses increased the sensitivity without diminution of the specificity. We would like to propose a criteria, fQRS duration >110 ms or area ratio 2 (40 to 100/0 to 40 Hz) >75, as a screening test for detecting patients with ARVD. This criteria provided a diagnostic sensitivity of 100%, specificity of 94%, positive predictive value of 93%, negative predictive value of 100%, and total predictive accuracy of 97%.

Study Limitations
The major limitation of this study may be the absence of patients with ARVD but without ventricular tachycardia. Our study was quite different from those studies that include patients with myocardial infarction with and without ventricular tachycardia. To discriminate between patients with and without tachycardia, these other studies generally relied on conventional time-domain criteria that were chiefly based on patients with myocardial infarction, using patients with old myocardial infarction without ventricular tachycardia as a control group. In contrast, the present study adopted healthy normal volunteers as a control group, ie, as a means of discriminating between patients with ARVD and normal subjects.

The proposal criteria of time-domain analysis, ie, fQRS duration >110 ms (25 Hz), is looser than Simson's criteria (fQRS duration >120 ms).¹³ This may depend on our small normal control group (n=35). Normal values (mean±SD) reported by Caref et al³⁴ using a larger group (n=100) were 94.4±10.3 ms. They defined normal values of fQRS duration as <115 ms at a 25-Hz high-pass filter setting. The conventional criteria of time-domain analysis have been used for patients with myocardial infarction, who may have a dilated left ventricle and whose standard 12-lead ECG findings generally show abnormal Q waves and longer QRS duration. Thus, conventional time-domain analysis criteria might not be appropriate for patients with ARVD. Optimal criteria and filter settings to identify patients with ARVD should be established from larger study groups.

There are no well-defined criteria for frequency-domain analysis of the SAECG for choice of the window function, the segment length of the window, or the area ratio. We used only two area ratios (20 to 50/0 to 20 and 40 to 100/0 to 40 Hz). Other area ratios should be analyzed to improve detectability of frequency-domain analysis.

Contamination with 60-Hz line voltage was not excluded by a 60-Hz filter. This may represent one limitation of the present study. However, no patients had spectral peaks repeated at 60, 120, and 180 Hz, and we did not observe a relative increase at 60 Hz that was consistent in all three X, Y, and Z leads. These findings were also described by Pierce et al.³¹

Lindsay et al³⁰ has shown that frequency-domain analysis does not need to exclude patients with bundle branch block. Two additional ARVD patients with complete right bundle branch block visited our hospital during the evaluation period, one of whom had atrial fibrillation. They had extensively dilated right ventricles and abnormal frequency-domain analysis values. Although these patients were not included in the present study, the inclusion of similar patients in future studies might improve the usefulness of frequency-domain analysis. We believe that patients with complete bundle branch block should be also evaluated by echocardiogram.

Conclusions
Late potentials were present in 20 (71%) and 18 (64%) of 28 patients with ARVD at 25-Hz and 40-Hz high-pass filter settings, respectively, in conventional time-domain analysis. In frequency analysis, 18 (64%) and 20 (71%) patients with ARVD had abnormal values in area ratio 1 (20 to 50/0 to 20 Hz) and area ratio 2 (40 to 100/0 to 40 Hz). Combining the time- and frequency-domain analyses, ie, fQRS duration >110 ms or area ratio 2 >75, yielded an improved sensitivity (100%) with specificity of 94%. These results suggest that combination of the time- and frequency-domain analyses of the SAECG may be useful as a screening test for detecting patients with ARVD.

	Footnotes

 
Reprint requests to Guy Fontaine, MD, Center de Stimulation Cardiaque et de Rythmologie, Hopital Jean Rostand, 39-41, rue Jean Le Galleu, 94200 Ivry-Sur-Seine, France.

Received April 6, 1994; accepted August 29, 1994.

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