Circadian variation of late potentials in idiopathic ventricular fibrillation associated with J waves: Insights into alternative pathophysiology and risk stratification

Circadian variation of late potentials in idiopathic ventricular fibrillation associated with J waves: Insights into alternative pathophysiology and risk stratification Atsuko Abe, MD, Takanori Ikeda, MD, FACC, Takehiro Tsukada, MD, Haruhisa Ishiguro, MD, Yosuke Miwa, MD, Mutsumi Miyakoshi, MD, Hisaaki Mera, MD, Satoru Yusu, MD, Hideaki Yoshino, MD From the Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan. BACKGROUND The presence of J waves on ECGs is related to idiopathic ventricular fibrillation (VF). OBJECTIVE The purpose of this study was to investigate the pathophysiology of J waves by assessing risk markers that reflect electrophysiologic abnormalities. METHODS The study enrolled 22 idiopathic VF patients (17 men and 5 women; mean age 36 ⫾ 13 years). Patients were divided into two groups according to the presence or absence of J waves. The following risk stratifiers were assessed: late potentials (LPs; depolarization abnormality marker) for 24 hours using a newly developed signal-averaging system, and T-wave alternans and QT dispersion (repolarization abnormality markers). Frequency-domain heart rate variability (HRV), which reflects autonomic modulation, also was assessed. The results were compared to those of 30 control subjects with J waves and 30 with no J wave, matched for age and gender to the idiopathic VF patients. RESULTS J waves were present in 7 (32%) idiopathic VF patients. The incidence of LP in the idiopathic VF J-wave group was higher than in the idiopathic VF non–J-wave group (86% vs 27%, P ⫽ .02). In contrast, repolarization abnormality markers did not differ between the two groups. In the idiopathic VF J-wave group, dynamic changes in LP parameters (fQRS, RMS40, LAS40) were

Introduction Idiopathic ventricular fibrillation (VF) is a disease that causes unexpected cardiac death in adults with structurally normal hearts, particularly young men.1– 4 Recently, the presence of J waves (notches after the QRS complex) on 12-lead ECG has been reported to be associated with idiopathic VF5–9 and atypical Brugada syndrome.10 –12 Although the mechanism responsible for arrhythmogenesis in

This manuscript was supported in part by Grants-in-Aid 18300157 and 21590909 for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by a grant for Scientific Research from Kyorin University School of Medicine to Dr. Ikeda. Address reprint requests and correspondence: Dr. Takanori Ikeda, Second Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. E-mail address: [email protected]. (Received November 26, 2009; accepted January 8, 2010.)

observed and were pronounced at nighttime; this was not the case in the idiopathic VF non–J-wave group and the control J-wave group. High-frequency components (vagal tone index) on frequency-domain HRV analysis were associated with J waves in idiopathic VF patients (P ⬍ .05). CONCLUSION Idiopathic VF patients with J waves had a high incidence of LP showing circadian variation with night ascendancy. J waves may be more closely associated with depolarization abnormality and autonomic modulation than with repolarization abnormality. KEYWORDS Circadian variation; Depolarization abnormality; Idiopathic ventricular fibrillation; J wave; Late potential ABBREVIATIONS fQRS ⫽ filtered QRS duration; HF ⫽ high frequency; HRV ⫽ heart rate variability; LAS40 ⫽ duration of low-amplitude signals (⬍40 ␮V) in terminal filtered QRS complex; LF ⫽ low frequency; LP ⫽ late potential; QTD ⫽ QT dispersion; RMS40 ⫽ root mean square voltage of terminal 40 ms of filtered QRS complex; TWA ⫽ T-wave alternans; VF ⫽ ventricular fibrillation (Heart Rhythm 2010;7:675– 682) © 2010 Heart Rhythm Society. All rights reserved.

idiopathic VF is unknown, most investigators have used the term early repolarization abnormality in describing J waves, which are seen in the inferior and/or lateral leads but not in the precordial leads.8,13,14 Some studies support this proposal, showing the presence of a prominent action potential notch15 mediated by a transient outward current (Ito) and the effectiveness of antiarrhythmic drug therapy. such as isoproterenol, quinidine, disopyramide, and bepridil.16 –18 Conversely, several clinical studies with small patient numbers support the idea that J waves may be more strongly associated with a depolarization abnormality (conduction disturbance) because patients with idiopathic VF frequently have ventricular late potentials (LPs) detected by signalaveraged ECGs.19,20 LPs have been used widely to detect high-risk individuals among patients with cardiac disorders, such as myocardial infarction, arrhythmogenic right ventricular cardiomyopathy, and Brugada syndrome.21,22 Recently,

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doi:10.1016/j.hrthm.2010.01.023

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it has become possible to monitor LPs continuously for 24 hours using a newly developed signal-averaging system that is applied to Holter ECG recordings. In the present study, we assessed the value of risk stratification markers that reflect depolarization abnormality (i.e., LP) and repolarization abnormalities (i.e., T-wave alternans [TWA]23 and QT dispersion [QTD]24) in order to investigate the pathophysiology of J waves in patients with idiopathic VF. These data were compared with values from healthy control subjects matched for age and gender. In addition, we assessed the relationship between the amplitude of J waves and daily variation in autonomic indices by analyzing frequency-domain heart rate variability (HRV)25 of the 24-hour Holter ECG in idiopathic VF patients and selected healthy control subjects.

Methods Idiopathic VF patients The study enrolled 22 consecutive idiopathic VF patients (17 men and 5 women; mean age 36 ⫾ 13 years) who had a ventricular fibrillation (VF) event and were admitted to Kyorin University Hospital between December 2005 and August 2009. All patients were younger than 60 years. VF was defined as a polymorphic ventricular tachyarrhythmia with RR interval ⬎260 bpm and hemodynamic decompensation that required electrical defibrillation. Before enrollment into the study, informed consent was obtained from each patient. The study was approved by the institutional ethics committee. Characteristics of the idiopathic VF patients are listed in Table 1. All patients had a history of at least one syncopal episode before the VF event, and 2 (9%) patients had a family history of sudden death. Twelve (55%) patients had a VF event during the day (08:00 –22:00) and the remaining 10 (45%) patients at night (22:00 – 08:00). Idiopathic VF was diagnosed by echocardiography, coronary angiography

with acetylcholine, cardiac scintigraphy, exercise testing, helical computed tomographic scan, and magnetic resonance imaging to exclude organic heart diseases such as arrhythmogenic right ventricular cardiomyopathy, myocardial ischemia, and other infiltrative cardiomyopathies. As a result, all idiopathic VF patients were believed to have structurally normal hearts. In addition, no patient had a Brugada-type ECG (either coved or saddle-back type), QTinterval prolongation, or bundle branch block. To exclude patients with Brugada syndrome, all patients underwent a pharmacologic challenge test with oral administration of pilsicainide (100 mg). None of the patients had ECG changes consistent with Brugada syndrome. Patients with catecholaminergic ventricular tachyarrhythmia as confirmed by catecholamine infusion test and/or exercise stress testing also were excluded from the study. Based on the presence of J waves on 12-lead ECGs during sinus rhythm, idiopathic VF patients were divided into two groups: J-wave group and non–J-wave group. Measurement and definition of J waves are described later.

Control subjects A total of 6,657 healthy control subjects (3,399 men and 3,258 women; mean age 45 ⫾ 22 years) who had routine health care examinations (12-leads ECG, blood test, chest X-ray film) at our hospital health care center between April 2006 and August 2008 were included in the study. Subjects with abnormal 12-lead ECG (i.e., wide QRS complex, STsegment elevation, T-wave inversion, QT-interval prolongation), blood test results, or chest X-ray films were excluded. After all ECGs were checked for the presence of J waves, 30 consecutive subjects with J waves and 30 subjects with no J wave who were matched for age and gender to idiopathic VF patients underwent assessment of markers of subsequent depolarization and repolarization abnormalities.

Measurement and definition of J waves Table 1 Characteristics of idiopathic VF patients enrolled in the study No. of patients Age (years) Male gender Documented VF History of syncope Family history of sudden death Time of VF events Daytime Nighttime Situation at VF events* During exercise or physical effort During sleeping or just after getting up After meals or drinking During driving During standing At rest Values are given as number (percent) or mean ⫾ SD. VF ⫽ ventricular fibrillation. *Some overlap.

22 36 17 22 22 2

⫾ 13 (77%) (100%) (100%) (9%)

12 (55%) 10 (45%) 7 7 5 2 2 2

(32%) (32%) (23%) (9%) (9%) (9%)

All 12-lead ECGs were analyzed using a computerized ECG system (ECAPS 12C, Nihon Kohden Co., Tokyo, Japan) that can measure J-point elevation. First, the system was used to detect the J-point elevation automatically. Two cardiologists then confirmed the detection of J-point elevation by checking each ECG recorded in the study population. The J wave (i.e., J-point elevation) was defined as ⱖ1.0 mm elevation at the J point compared to baseline in at least two leads within either the inferior leads (II, III, aVF) or the left lateral leads (I, aVL, V5, V6; Figure 1).

Measurements of risk stratification makers LP by signal-averaged ECG In this study, LPs (marker of abnormal depolarization) were analyzed for 24 hours using a newly developed signalaveraging system (SCM-6600, Fukuda Denshi Co., Tokyo, Japan) that is capable of analyzing LPs automatically every 30 minutes using data from a digital Holter ECG recorder (FM-180). This system was developed using the same al-

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677 rected QT intervals in any of the 12 ECG leads in which it could be reliably determined. In this study, QTD was considered increased when dispersion was ⬎65 ms.28

Measurements of frequency-domain-HRV

Figure 1 Twelve-lead ECG of an idiopathic ventricular fibrillation patient with a prominent J wave. The arrows on ECGs indicate J waves.

gorithm as that used in the FDX series from Fukuda Denshi and now is available commercially in Japan. The analysis is based on quantitative time-domain measurements of the filtered vector magnitude of the orthogonal X, Y, and Z leads.26,27 QRS complexes (⬎200 beats) were amplified, digitized, averaged, and filtered with a high-pass filter (40 Hz). Three parameters were assessed every 30 minutes by computer algorithm: (1) filtered QRS duration (fQRS); (2) root mean square voltage of terminal 40 ms of filtered QRS complex (RMS40); and (3) duration of low-amplitude signals (⬍40 ␮V) in the terminal filtered QRS complex (LAS40). LPs were considered positive when two of three criteria (fQRS ⬎135 ms, RMS40⬍15 ␮V, LAS40 ⬎39 ms) were met.26,27 Changes in LP parameters were presented as a trend graph over 24 hours. Using this system, we assessed circadian variation in LP parameters in 22 idiopathic VF patients and 60 selected control subjects matched for age and gender with idiopathic VF patients. TWA and QTD TWA (repolarization abnormality marker)23 was assessed using HeartWave (Cambridge Heart, Bedford, MA, USA), which allows detection of microvolt electrical alternans of the T wave using spectral analysis. For TWA analysis, treadmill exercise testing was applied to increase the heart rate to 110 bpm because most patients have a patientspecific heart rate threshold for the development of TWA. TWA was considered positive if sustained alternans (i.e., duration ⬎1 minute) occurred at a heart rate ⬍110 beats/ min with alternans voltage ⬎1.9 ␮V and alternans ratio ⬎3.0 in single orthogonal leads or two adjacent precordial leads during exercise.28 QTD was automatically measured using the FDX6521 ECG system (Fukuda Denshi Co.). QT intervals corrected for heart rate were used in this study. QTD was defined as the difference between the minimum and maximum cor-

Frequency-domain HRV was analyzed using the same ECG system (SCM-6600) that was used for detection of LP over 24 hours, based on Holter ECG recordings. Fluctuations in consecutive RR intervals were converted into time-based connected functions, which then were processed via fast Fourier transformation. Resulting power spectra were segmented into two components: a low-frequency (LF) component (0.04 – 0.15 Hz) and a high-frequency (HF) component (0.15– 0.40 Hz). Each component was quantified for display as the square root of the area under the respective power spectrum. HF, LF, and LF/HF ratio were calculated every hour. The HF component levels, which are a reliable method for assessing vagal nerve activity,29 and LF/HF ratio levels, which are a global method for assessing sympathetic nerve activity,29 were compared to the amplitudes of J waves in idiopathic VF patients.

Statistical analysis Data are expressed as mean ⫾ SD. The incidences of J waves between 22 idiopathic VF patients and 6,657 control subjects were compared using a logistic regression model. Differences in rates of LP, TWA, and QTD between the J-wave group and the non–J-wave group of 22 idiopathic VF patients and 60 selected control subjects were examined by Chi-square contingency test and Fisher exact probability test. A logistic model (binary outcome variables) was used for comparison between J-wave groups of idiopathic VF patients and selected control subjects, and correlation among the matched subjects was adjusted for this model. Differences in fQRS (ms), RMS40 (␮V), LAS40 (ms), alternans voltage (␮V), mean corrected QT (ms), QTD (QTmax ⫺ QTmin; ms), HF, LF, and LF/HF between the two groups were examined by unpaired t-test. P ⬍ .05 was considered significant.

Results Incidence of J waves in idiopathic VF patients and control subjects Among the idiopathic VF patients, 7 (32%) had J waves on 12-lead ECG: 6 (86%) in the inferior leads, 4 (57%) in the lateral leads, and 2 (29%) in both leads. In contrast, 127 (1.9%) of 6,657 control subjects had J waves: 118 (93%) in the inferior leads, 27 (21%) in the lateral leads, and 18 (14%) in both leads. The incidence of J waves was higher in idiopathic VF patients than in control subjects (P ⬍ .0001). Among idiopathic VF patients, age, gender, history of syncope, and family history of sudden death did not differ upon comparison of J-wave and non–J-wave groups. A significant difference was seen for the time of VF events (Table 2). The J-wave group had VF events mainly at night (6/7 [86%] patients), whereas the non–J-wave group had events mainly during the day (11/15 [73%] patients). VF

678 Table 2

Heart Rhythm, Vol 7, No 5, May 2010 Comparison of idiopathic VF patients and control subjects according to presence or absence of J waves Idiopathic VF patients

Variable Age (years) Male gender History of syncope Family history of sudden death Time of VF events Daytime Nighttime Presence of J wave Inferior leads (II, III, aVF) Lateral leads (I, aVL,V5,V6) Determinate LP fQRS (ms) RMS40 (␮V) LAS40 (ms) Determinate TWA Alternans voltage (␮V) Determinate QTD Mean corrected QT (ms) QTD (ms) Frequency-domain HRV HF (ms2) LF (ms2) LF/HF

Control subjects

J-wave group (n ⫽ 7)

Non–J-wave group (n ⫽ 15)

P value

J-wave group (n ⫽ 30)

Non–J-wave group (n ⫽ 30)

P value

35 ⫾ 8 6 (86%) 7 (100%) 1 (14%)

37 ⫾ 15 11 (73%) 15 (100%) 1 (7%)

NS NS NS NS

34 ⫾ 12 24 (80%)

36 ⫾ 13 21 (70%)

NS NS

1 (14%) 6 (86%)

11 (73%) 4 (27%)

.02 .02

.02 .005 .02 .04 NS NS NS NS NS

26 (87%) 7 (23%) 3 (10%)** 118 ⫾ 8## 34 ⫾ 19†† 30 ⫾ 6‡‡ 1 (3%) 1.0 ⫾ 1.2 2 (7%) 406 ⫾ 12 46 ⫾ 16

1 (3%) 119 ⫾ 7 33 ⫾ 20 31 ⫾ 6 1 (3%) 1.0 ⫾ 1.8 1 (3%) 410 ⫾ 12 46 ⫾ 12

NS NS NS NS NS NS NS NS NS

NS NS NS

840 ⫾ 1146 1,021 ⫾ 69 2.1 ⫾ 1.1

966 ⫾ 1522 833 ⫾ 688 2.0 ⫾ 1.3

NS NS NS

5 (71%) 4 (57%) 6 (86%)* 145 ⫾ 10# 14 ⫾ 4† 40 ⫾ 6‡ 1 (14%) 1.0 ⫾ 0.4 1 (14%) 405 ⫾ 19 50 ⫾ 18

4 (27%) 127 ⫾ 12 34 ⫾ 20 31 ⫾ 11 1 (7%) 1.1 ⫾ 0.2 2 (13%) 416 ⫾ 18 47 ⫾ 17

825 ⫾ 822 917 ⫾ 797 1.9 ⫾ 1.5

1,037 ⫾ 1,264 827 ⫾ 807 2.2 ⫾ 1.7

Values are given as number (percent) or mean ⫾ SD. P ⫽ .002 in comparison of values between ⴱ and ⴱⴱ; P ⫽ .04 between # and ##; P ⫽ .04 between † and ††; P ⫽ .01 between ‡ and ‡‡. fQRS ⫽ filtered QRS duration; HF ⫽ high frequency; HRV ⫽ heart rate variability; LAS40 ⫽ duration of low-amplitude signals (⬍40 ␮V) in terminal filtered QRS complex; LF ⫽ low frequency; LP ⫽ late potential; QTD ⫽ QT duration; RMS40 ⫽ root mean square voltage of terminal 40 ms of filtered QRS complex; TWA ⫽ T-wave alternans; VF ⫽ ventricular fibrillation.

events at night were more numerous in the J-wave group than in the non–J-wave group (P ⫽ .02).

Comparison of risk stratification markers Test results of risk stratification markers in the 22 idiopathic VF patients and 60 selected control subjects (30 with J waves, 30 without J waves), matched for age and gender with idiopathic VF patients, are listed in Table 2. Among the 22 idiopathic VF patients, the mean values of fQRS, RMS40, and LAS40 were 133 ⫾ 14 ms, 27 ⫾ 19 ␮V, and 34 ⫾ 10 ms, respectively. LPs were identified in 10 (45%) patients. In the J-wave group, 6 (86%) patients had LPs. In contrast, LPs were identified in only 4 (27%) patients in the non–J-wave group. The incidence of LPs identified in the J-wave group was higher than in the non–Jwave group (P ⫽ .02). Among the 60 control subjects, the mean values of fQRS, RMS40, and LAS40 were 118 ⫾ 7 ms, 34 ⫾ 20 ␮V, and 31 ⫾ 6 ms, respectively. LPs were found in 4 (7%) subjects. The incidence of LPs did not differ between the J-wave group and non–J-wave group in control subjects. All values of LP parameters were lower in control subjects than in the J-wave group of idiopathic VF patients. The incidence of LPs in the idiopathic VF J-wave group (n ⫽ 7) was higher than in the control J-wave group (n ⫽ 30; P ⫽ .002). Similarly, values of fQRS, RMS40, and LAS40 for LP determination in the idiopathic VF J-wave group

were greater than in the control J-wave group (P ⫽ .04, P ⫽ .04, and P ⫽ .01, respectively). With regard to TWA and QTD, a significant difference was not seen between idiopathic VF patients and control subjects or between the J-wave group and non–J-wave group in either idiopathic VF patients or control subjects. Similarly, components of frequency-domain HRV did not differ between idiopathic VF patients and control subjects or between the two groups in either population.

Circadian variation of LP parameters Circadian variation of LP parameters was observed in all seven idiopathic VF patients with J waves. Figure 2 shows a representative example of trend graphs of each LP parameter (fQRS, RMS40, LAS40) in an idiopathic VF patient with J waves. All parameters fluctuated for 24 hours, and measured values of LP parameters increased at night and decreased during the day. In this patient, maximum LP values were recorded at 3:30 – 4:30 (midnight) and minimum values at 12:30 –13:00 (noon). In 6 (86%) of 7 idiopathic VF patients with J waves, similar trend graphs were recorded, and LPs were identified in all. These six patients had VF events at night. The one (14%) remaining idiopathic VF patient with J waves had the highest measured LP values during the day, but LPs were indeterminate. In this patient, a VF event was documented during the day. In control

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679

Figure 2 Circadian variation of the late potential parameters of filtered QRS duration (fQRS; A), root mean square voltage of terminal 40 ms of filtered QRS complex (RMS40; B), and duration of low-amplitude signals (⬍40 ␮V) in terminal, filtered QRS complex (LAS40; C), and minimum (D) and maximum (E) values of filtered QRS complexes used for late potential determination in an idiopathic ventricular fibrillation patient with J waves. Note that the maximum value used for identification of late potentials was recorded at night. The arrows in Panels A, B, and C indicate times that recorded the highest measured LP values. The arrow in Panel E demonstrates significant LP.

subjects with J waves, significant circadian variation in LP parameters was not seen. Because LP parameters showed circadian variation in idiopathic VF patients with J waves, we measured differences between maximum and minimum values (fQRS max– min, RMS40 max–min, LAS40 max–min) and compared them in the J-wave group and non-J-wave group in both idiopathic VF patients and the control group (Table 3). The two groups of idiopathic VF patients differed significantly in all parameters, whereas control subjects did not show differences in any of the parameters between the two groups. Figure 3 shows differences between maximum and minimum values of three LP parameters in all seven idiopathic VF patients with J waves. fQRS, RMS40, and LAS40

all changed markedly. When these changes are compared in the J-wave groups of idiopathic VF patients and control subjects, the former had more significant values than the latter.

Relationship between frequency-domain-HRV components and maximal amplitudes of J waves In general, the components on frequency-domain HRV analysis show circadian variation. HF components (vagal nerve activity index) increase at night and decrease during the day; LF components or LF/HF ratios (sympathetic nerve activity indices) show inverse patterns. Therefore, we evaluated the relationship between these components and Jwave amplitude. Figure 4A shows circadian variation of HF

Table 3 Comparison of differences between maximal and minimal values in J-wave group and non–J-wave group of idiopathic VF patients and control subjects Idiopathic VF patients

fQRS max–min (ms) RMS40 max–min (␮V) LAS40 max–min (ms)

Control subjects

J-wave group (n ⫽ 7)

Non–J-wave group (n ⫽ 15)

P value

J-wave group (n ⫽ 30)

Non–J-wave group (n ⫽ 30)

P value

18.6 ⫾ 3.7# 10.4 ⫾ 3.1† 9.3 ⫾ 2.4‡

6.0 ⫾ 3.4 3.5 ⫾ 1.6 4.0 ⫾ 2.3

⬍.001 ⬍.001 ⬍.001

5.0 ⫾ 2.0## 4.4 ⫾ 1.9†† 4.3 ⫾ 2.1‡‡

6.1 ⫾ 2.3 4.0 ⫾ 1.3 3.6 ⫾ 1.5

NS NS NS

P ⬍ .001 in comparison of values between # and ##; P ⬍ .001 between † and ††; P ⬍ .001 between ‡ and ‡‡. fQRS ⫽ filtered QRS duration; LAS40 ⫽ duration of low-amplitude signals (⬍40 ␮V) in terminal filtered QRS complex; RMS40 ⫽ root mean square voltage of terminal 40 ms of filtered QRS complex.

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components and LF/HF ratios on frequency-domain HRV analysis. Figure 4B shows the maximum amplitude of J waves and heart rate in an idiopathic VF patient with J waves. When the maximum amplitude of J waves increased at nighttime, HF components also increased. HF components and amplitude of J waves had a parallel circadian variation. Figure 5 shows the difference in HF components between maximum and minimum amplitudes of J waves in seven idiopathic VF patients with J waves. There was a relationship between HF components and amplitude of J waves in idiopathic VF patients with J waves (P ⬍ .05) but no such relationship in control subjects with J waves.

Discussion This is the first report showing a relationship between LPs detected with a signal-averaging system and idiopathic VF associated with J waves. The main finding of this study is that idiopathic VF patients with J waves had a high incidence of LPs with circadian variation and night ascendancy. There was no association between J waves and TWA or QTD. Detection of LPs by signal-averaged ECG using 24hour Holter ECG could be useful for risk stratification of subjects with J waves.

Figure 3 Differences in three parameters of late potentials between maximum and minimum amplitudes of J waves in seven idiopathic ventricular fibrillation patients with J waves. fQRS ⫽ filtered QRS duration; LAS40 ⫽ duration of low-amplitude signals (⬍40 ␮V) in terminal filtered QRS complex; RMS40 ⫽ root mean square voltage of terminal 40 ms of filtered QRS complex.

Figure 4 Relationship between high-frequency (HF) components and J-wave amplitude in an idiopathic ventricular fibrillation patient with J waves. HR ⫽ heart rate; LF ⫽ low frequency.

Recent clinical reports have shown that J waves are often encountered in idiopathic VF patients.5– 8,10 Although the electrophysiologic mechanisms of arrhythmogenesis related to J waves have not been established, the term repolarization abnormality has been used to describe J waves when they are associated with malignant ventricular tachyarrhythmias in idiopathic VF patients.8,13,14 Theoretical considerations and some experiments support this description. Yan and Antzelevitch15,30 have proposed that epicardial– endocardial heterogeneity of repolarization is responsible for J-point elevation (i.e., J wave) observed in patients with idiopathic VF as well as Brugada syndrome. In this study, we assessed the relationship between LPs on signal-averaged ECG and J waves in idiopathic VF patients, using healthy subjects as controls. LPs are abnormal low-amplitude signals in the terminal portion of the QRS complex that reflect delayed conduction (i.e., depolarization abnormality) of the ventricle. As a result, J waves were significantly associated with all LP parameters, but

Figure 5 Difference in high-frequency (HF) components between maximum and minimum amplitudes of J waves in seven idiopathic ventricular fibrillation patients with J waves.

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TWA and QTD, which are markers of repolarization abnormality, were not. Recently, the presence of TWA has been reported to be associated with increased risk for ventricular arrhythmias in several clinical settings.28,31 In this study, no significant association was seen between TWA and the presence of J waves in either idiopathic VF patients or control subjects. TWA is not useful for identifying high-risk patients in the setting of idiopathic VF. This finding may support the idea that J waves are more strongly associated with depolarization abnormality than with repolarization abnormality. The presence of LP is an established marker that is useful for risk stratification of patients with structurally abnormal hearts, for example, following myocardial infarction.21,28 Several clinical studies support a strong relationship between LP and Brugada syndrome, and this marker currently is being used to identify high-risk patients with Brugadatype ECG.22,32 Thus, the pathophysiology of idiopathic VF with J waves resembles that of Brugada syndrome, including the pharmacologic reaction to J waves.16 –18 Sarkozy et al33 recently reported that J waves in the inferior and lateral leads are frequently recorded spontaneously in patients with typical Brugada syndrome. There may be some overlap between Brugada syndrome and idiopathic VF in the pathophysiology. However, as previously mentioned, patients with Brugada-type ECG were excluded from this study. Therefore, LP not only is associated with Brugada syndrome but also with idiopathic VF in the presence of J waves. In this study, we used a new signal-averaging system that can measure LPs over 24 hours. Consequently, LPs were identified in 45% of all cases of idiopathic VF and 86% of those with J waves. In contrast, LPs were found in 7% of all control subjects and 10% of those with J waves. The incidence was lower in control subjects than in idiopathic VF patients. In addition, LP showed circadian variation in idiopathic VF patients with J waves but not in control subjects with J waves. In the majority of idiopathic VF patients with J waves and positive LP (86%), the highest LP values occurred at night. This finding reveals that, in idiopathic VF, dynamic changes in LP are associated with J waves and with autonomic imbalance of night ascendancy. Because VF events occurred at night in 86% of idiopathic VF patients with J waves and during the day in 73% of idiopathic VF patients without J waves, the presence of dynamic changes in LP with night ascendancy may be a useful marker for identifying patients with J waves at risk for sudden death due to idiopathic VF. Correlation between the amplitude of J waves and the occurrence of VF in idiopathic VF patients has been reported.8,13 These reports indicated that the J-point amplitude increased just before the occurrence of VF. In this study, the amplitude of J waves was highly associated with HF components (vagal activity index) on frequency-domain HRV analysis. Most idiopathic VF patients (86%) with J waves had VF events at nighttime (i.e., circadian variation of vagal

681 activity with night ascendancy) in this study. In contrast, the amplitude of J waves did not change in control subjects with J waves. This finding reveals that high vagal activity affects pathophysiology in idiopathic VF patients with J waves. In fact, some clinical reports support the role of high vagal activity in idiopathic VF patients.6,34 Vagally mediated idiopathic VF was seen at nighttime in these cases. Furthermore, previous reports demonstrated that intravenous injection of isoproterenol (a sympathetic agonist) eliminated J wave in idiopathic VF patients.17,18 Similarly, previous studies in a subgroup of patients with Brugada syndrome reported that a relationship between high vagal tone and characteristic ST-segment elevation.19,35 Thus, high vagal activity accelerates characteristic ECG abnormalities in idiopathic VF as well as Brugada syndrome. Sympathetic activity may decrease the chances of VF occurrence. J waves may be observed in a healthy young population. In this study of a large number (n ⫽ 6,657) of healthy control subjects (mean age 45 ⫾ 22 years), the incidence of J waves was 1.9% when J waves were defined as ⱖ1.0-mm elevation at the J point compared to baseline. Haïssaguerre et al8 reported an incidence of 5% in 412 control subjects (mean age 36 years), and Rosso et al9 reported an incidence was 9% in 124 control subjects (mean age 38 years) using the same definition of J waves. The incidence of J waves varies greatly among reports. The definition of J waves in this study appears to be stricter than that used in other studies, with J waves analyzed using a computerized ECG system that can measure J-point elevation. In control healthy subjects with J waves, identification of LPs by a signal-averaging system with 24-hour Holter ECG could be useful for screening to assess whether the presence of J waves is associated with future arrhythmic events.

Study limitations In this study, only noninvasive risk stratification markers was used to identify electrophysiologic abnormalities. We did not include electrophysiologic testing, drug infusion tests, and genetic analysis, which were used in previous studies.8,16 –18,36 In this study, TWA and QTD were used for assessment of repolarization abnormalities. However, these selections may not be appropriate for idiopathic VF patients because other indices, such as QT-RR slope, have been used to explain repolarization abnormalities in the setting of idiopathic VF.37

Clinical implications In identifying patients with J waves at high risk for sudden cardiac death due to VF, noninvasive measurements are more desirable than invasive or genetic methods. Our study shows that in patients with J waves and structurally normal hearts, detection of LPs by a signal-averaged system using 24-hour Holter ECG is a useful technique for identifying a group at high risk for arrhythmic events. If such patients have dynamic changes in LP over 24 hours with night ascendancy, they may be considered candidates for an implantable defibrillator. Concerning the mechanism of ar-

682 rhythmogenesis of J waves, our clinical results may support the hypothesis of conduction abnormality.

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