Idiopathic ventricular fibrillation (IVF) has been recognized as a cause of unexplained, nocturnal sudden death in middle-aged men, especially in Asian countries.1,2 In some of these patients with IVF, high-takeoff ST-segment and prominent J wave in the right precordial leads have been reported.3 Furthermore, IVF patients without this specific ECG pattern have been reported, and some of them have a prominent J wave in the inferior leads.4 In these IVF patients, the most reliable therapy for prevention of sudden death is implantation of an implantable cardioverter defibrillator (ICD). However, frequent episodes of VF reduce quality of life because of frequent shock therapy from ICD. Recently, Belhassen et al reported that quinidine is effective for prevention of spontaneous episodes of VF in Brugada syndrome, but it was associated with a 36% incidence of side effects.5 In IVF patients including Brugada and non-Brugada ECG patterns, we have found a lower slope of the QT-RR relation and shorter QT interval at slow heart rates compared with age-matched healthy subjects.6 Hence, we evaluated efficacy of pharmacological therapy with antiarrhythmic drugs prolonging QT interval (bepridil and disopyramide) in patients with IVF with respect to the 24-hour QT-RR relationship.
The study group consisted of 8 men ranging in age from 33 to 53 years (43.6 ± 9.1 years) including 5 subjects with Brugada type and 3 subjects with non-Brugada type (prominent J wave in the inferior leads) who had documented spontaneous episodes of VF. All patients underwent physical examination, 12-lead ECG, 24-hour Holter ECG, treadmill exercise testing, and biochemical and hematological testing. None had a prolonged QT interval during the course of syncopal episodes or had cardiovascular disease including hypertension, coronary artery disease, or congestive heart disease. All IVF patients underwent implantation of an ICD except one patient, who had refused. After informed consent was obtained, patients were followed without pharmacological therapy at least 6 months, and then all patients received antiarrhythmic drug therapy (bepridil 200 mg/d or disopyramide 300 mg/d).
Analysis of RR and QT Interval
QT and RR intervals were determined from 24-hour Holter ECG data within 2 weeks after VF episodes before drug administration, and during pharmacological therapy without VF episodes at least 6 months. Using an automatic measurement system (SCM6000 Fukuda Denshi, Tokyo, Japan), signal-averaged waves from CM5 lead were obtained by the summation of consecutive sinus beats during each 15-second period throughout 24 hours. The end of the T wave was determined automatically according to the following algorithm (HPS-QTM Fukuda Denshi, Tokyo, Japan). The top of the T wave was determined as the point where the first derivative (dv/dt) of the T wave changed from positive to negative. The endpoint of the T wave was determined as the point where the first derivative of the T wave became undetectable after the top of T wave. In each case, detection level of the first derivative of T wave was set as the average level of ST segment.
We confirmed the accuracy of the automatic measurement of QT intervals manually. For the averaged period of 15 seconds, a corresponding mean RR interval was calculated, and measured QT interval was plotted against the corresponding mean RR interval. For the analyses of the QT-RR relationship, a regression line was used, and QT at RR intervals of 0.6, 1.0, and 1.2 seconds were calculated.
Results are presented as mean ± SD. The dependence of QT interval on the RR interval was analyzed by linear regression using the entire 24-hour tracing in each patient (QT = A[RR] + B, where A is the slope and B is the intercept). The differences in continuous variables between groups were analyzed by Student t test for paired and unpaired data. Statistical significance was set at P < 0.05.
QT-RR Relation Before and After Pharmacological Therapy
Representative 12-lead ECG recordings and QT-RR relations from a Brugada type IVF patient before and after bepridil therapy (200 mg/d) are shown in Figures 1 and 2. After bepridil treatment, the slope of QT-RR regression line became steeper compared with control state.
Values of slope and intercept of QT-RR linear regression lines and QT intervals at preselected RR intervals for each IVF patient before and after pharmacological therapy are summarized in Tables 1 and 2. Bepridil and disopyramide increased the slope of QT-RR relations from 0.105 ± 0.020 to 0.144 ± 0.037 (P < 0.05). Drug administration also increased QT intervals at RR intervals of 1.0 second and 1.2 seconds [QT(1.0), 0.382 ± 0.016 seconds vs 0.414 ± 0.016 seconds, P < 0.01; QT(1.2), 0.403 ± 0.017 seconds vs 0.442 ± 0.021 seconds, P < 0.01]. However, QT at an RR interval of 0.6 second did not change with drug administration.
Follow-up With Bepridil and Disopyramide
Effects of pharmacological therapy on VF episodes are summarized in Table 3. Before drug therapy, the average observation period was 19.3 ± 17.6 months (range 6 to 60 months), and the average episodes of VF were 5.5 ± 5.8 (range 1 to 17). All patients received either bepridil or disopyramide for 52.5 ± 41.0 months (range 12 to 120 months). Six patients had no episode of VF for 24 to 120 months (66.0 ± 38.5 months). However, 2 patients had a single VF episode treated with ICD. The first patient (case 1) with Brugada syndrome had 17 episodes of VF during a 28-month follow-up period before drug therapy, and he suffered from frequent ICD shocks. After starting bepridil (200 mg/d), he had only 1 episode of VF during 12 months of follow-up. The second patient (case 7) with J wave elevation in the inferior leads had 11 nocturnal episodes of VF before drug administration. During 96 months of follow-up after starting disopyramide (300 mg/d), he had only 1 episode of VF treated with ICD. No adverse effect of drug administration was observed during follow-up periods.
The major findings of the present study were as follows: (1) Pharmacological therapy with bepridil and disopyramide significantly reduced frequency of VF episodes in patients with prominent J wave and ST segment elevation. (2) In patients with IVF who had had recent VF episodes, the slope of QT-RR regression line was lower, and QT intervals at RR intervals of 1.0 and 1.2 seconds were shorter than those obtained after successful treatment with bepridil and disopyramide for at least 6 months. These results suggest that failure of prolongation of QT interval (shorter QT interval) at slower heart rates may play an important role for spontaneous occurrence of VF episodes,6,7 and both bepridil and disopyramide are effective for reducing frequency of VF episodes through modification of repolarization dynamics.
Repolarization Dynamics in IVF Patients
In our previous study, we analyzed Holter ECGs recorded just after VF episodes and found that IVF patients had lower slopes of the QT-RR relation and impaired prolongation of QT interval at longer RR intervals compared with control healthy subjects.6 It is possible that repolarization dynamics in patients with IVF might be variable depending on pharmacological therapy. Hence, in the present study, we determined QT-RR relations before and after antiarrhythmic drug therapy.
Our observations indicate that IVF patients with episodes of VF may have unique repolarization dynamics, ie, impaired prolongation of QT intervals at longer RR intervals.6,7 Smaller QT prolongation at longer RR intervals results in a lower slope of the QT-RR relation. These repolarization characteristics in IVF patients during sinus bradycardia may be related to the nocturnal occurrence of VF episodes.2 Both bepridil and disopyramide increased the slope of the QT-RR relation along with prolongation of QT interval and successfully suppressed VF episode.
Although the mechanism of VF is still unclear, and heterogeneity of mechanisms may contribute to differences in ECG features in patients with IVF, these patients have a prominent J wave and ST elevation in either the precordial or the inferior leads. In the present study, IVF patients without Brugada-like ECG showed a similar relationship of QT with RR intervals as patients with Brugada type ECG. It is therefore possible that a combination of characteristic J wave and ST elevation with abnormal repolarization dynamics could reflect a common underlying mechanism in IVF patients irrespective of the site of ECG leads having a specific J wave or ST segment elevation pattern.
Mechanism of Lower Slope of QT-RR Relation and Short QT Interval at Slower Heart Rates
Recent studies suggested that the presence of a prominent transient outward current (Ito) in the right ventricular epicardial layer and genetic abnormalities of the sodium channel gene (SCN5A) may play a key role in the characteristic ECG pattern in Brugada syndrome.8-10 Experiments using wedge preparations of canine heart revealed that a down-sloping ST-segment elevation may be caused by an earlier repolarization of the epicardial action potential because of a more intense Ito.11,12 Na channel blocking agents induced a coved type of ST elevation in the precordial leads13 because they accentuated Ito-mediated notch and failed to develop the action potential plateau (loss of dome). We hypothesized that these abnormalities of ionic currents might affect not only configuration of ST segment pattern but also ventricular repolarization dynamics.
Either reduction of inward currents (INa or ICa) or increase in outward currents (IK or Ito) causes early repolarization, resulting in shortening of the QT interval. At rest, an increase in Ito may limit the prolongation of action potential duration, especially at slower heart rates, and also produce prominent J wave in surface ECG. During exercise, both faster heart rates and an increase in adrenergic tone may offset the excessive Ito current14 and make a difference in QT interval at higher heart rates (for instance, RR interval of 0.6 seconds) insignificant compared with healthy subjects.
Bepridil and Disopyramide
Bepridil hydrochloride, a diarylaminopropylamine derivative, was introduced as a Ca antagonist affecting both L and T type Ca channels with a lidocaine-like fast kinetic block of Na current.15 Bepridil also has unique electrophysiological properties to inhibit outward currents including most types of K current (IKr, IKs, IKur, IK1, IKAch, IKATP) and Ito.16 In Figure 1, bepridil prolonged QT interval and decreased J wave amplitude in V2 but increased the late component of the ST segment. Disopyramide possesses intermediate kinetics of Na channel blocking effect and suppresses several types of K current (IKr, IKACh, IKATP) and Ito.17 Both drugs increased the slopes of QT-RR regression lines and reduced frequency of spontaneous VF episodes in the present study. Suppression of not only Ito but also other K channels may contribute to prolongation of QT interval in IVF patients and benefit for prevention of VF episodes. The prolonged QT interval at RR intervals of 1.0 second and 1.2 seconds after drug therapy became similar to the values in the healthy controls in our previous paper.6 The underlying mechanisms of effects of multichannel blocking drugs on suppression of phase 2 reentry should be investigated further.18 Although bepridil and disopyramide are effective in decreasing VF episodes in IVF patients, the most reliable therapy for prevention of sudden death is ICD. These antiarrhythmic drugs may improve quality of life after ICD implantation through decreasing frequency of shock therapy.
In the present study the number of IVF patients was small, and ECG patterns were heterogeneous: 5 patients had Brugada-type and 3 had non-Brugada-type ECG. However, they showed the similar repolarization abnormality, a finding suggesting the presence of a common underlying electrophysiological abnormality. In patients with Brugada type ECG, precordial leads close to the anterior right ventricular wall may be appropriate for the measurement of QT intervals, but we analyzed QT in CM5 lead because of higher reliability of automatic QT measurement. Abnormality in ventricular repolarization dynamics observed in CM5 lead suggests that not only the J wave and ST segment elevation but also the abnormal relationship of QT with RR may be useful for evaluation of efficacy of antiarrhythmic drugs. Although cardioversion of VF in itself may affect the repolarization pattern, Holter ECG recordings were done at least a few days after an episode of VF, and we believe it is quite unlikely. The unique repolarization dynamics in IVF may be regulated by several other factors including autonomic nervous system, electrolyte balance, and glucose-induced insulin secretion19 and may contribute to spontaneous onset of VF episodes. The relation between these factors and repolarization dynamics in IVF patients should be evaluated further.
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