Bepridil Inhibits Premature Ventricular Complexes Induced by Cardio-Sympathetic Nerve Stimulation in a Canine Experimental Model.

Sympathetic nerve activity has arrhythmogenic potential for ventricular arrhythmias associated with structural heart diseases. However, a sufficient amount of beta-blockers occasionally cannot be prescribed in some patients.An experimental study was performed to clarify the therapeutic effects of bepridil, a multiple ionic current inhibitor that does not affect beta-adrenergic receptors, for premature beats occurring during enhanced sympathetic nerve activity. Cardio-sympathetic nerve activity was augmented via stellate-ganglion (SG) stimulation in a canine model (n = 8), and the arrhythmogenic potential and anti-arrhythmic effects of bepridil (2 and 4 mg/kg intravenously) were assessed. For safe use, vagal-stimulation-induced slow HR and programmed electrical stimulation were applied to evaluate possible pro-arrhythmic effects of the drug. Heart rate variability (HRV) indexes were used to estimate cardio-autonomic nerve activity.Either side of the SG-stimulation increased BP and HR. Premature beats were induced in 10/16 SG-stimulations and it was more frequent in left (8/8) rather than right stimulation (2/8). Following 2 mg/kg drug administration, premature beats were still inducible in 8/16 stimulations (7/8 in left and 1/8 in right), but burden of the premature beats decreased from 87.1 ± 46.8 to 62.1 ± 42.6 beats. After 4 mg/kg administration, premature beats were inducible in one SG-stimulation. Proarrhythmic effects were not observed in all experiments. Steady-state HRV indexes and percent increases in SG-stimulation-induced BP-elevation and HR-acceleration were similar among the 3 periods (before, 2 and 4 mg/kg of the drug).Bepridil may be an option for ventricular arrhythmias developed during enhanced cardio-sympathetic nerve activity with minimal effect on autonomic nerve responses.

Nifekalant enlarged the transmural activation-recovery interval difference as well as the peak-to-end interval on surface ECG in a patient with short-QT syndrome.

A 38-year-old woman with type 1 short-QT syndrome (SQTS) was referred to our hospital. Her ECG showed short QT/QTc interval and peaked T wave. Activation-recovery intervals (ARIs) were calculated from the intracardiac endocardial and epicardial electrode catheters placed in the left ventricle (LV). Intravenous administration of nifekalant prolonged effective refractory period at multiple ventricular sites as well as the QT/QTc interval (from 260/300 to 364/419 ms) on the surface ECG. Nifekalant also enlarged the transmural ARI dispersion of the ventricular repolarization, which was measured by the difference between the longest endocardial ARI and the shortest epicardial ARI during atrial pacing at 90 bpm, from 73 to 103-105 ms. These values corresponded to the intervals between the peak and end of the T wave on the surface ECG. Nifekalant-induced QT interval prolongation on the surface ECG may not indicate attenuation of the arrhythmogenic potential in the heart of SQTS patients.

Relationship between electroanatomical voltage mapping characteristics and breakout site of ventricular activation in idiopathic ventricular tachyarrhythmia originating from the right ventricular outflow tract septum.

OBJECTIVE: To assess the electrophysiological characteristics of the breakout site of ventricular activation using electroanatomical voltage mapping (EVM) and its relation to the optimal ablation site in idiopathic ventricular tachyarrhythmias originating from the outflow tract of the (RVOT) septum. METHODS: Twenty-eight patients with symptomatic drug-refractory premature ventricular complexes (PVCs) and/or ventricular tachycardia (VT) originating from the RVOT septum and 5 control subjects with WPW syndrome were included. Low-voltage areas (LVAs) were defined as signal amplitudes between 0.1 and 1.5 mV. The borderline between the normal area and the LVA was defined as "border," and the distance from the LVA to the border (length of LVA) was measured. RESULTS: In all 28 patients and control subjects, there was an LVA below the pulmonary valve. There was no significant difference in length of LVA between patients with idiopathic ventricular arrhythmias and control subjects (2.0 ± 0.6 vs. 1.9 ± 0.1 cm). In 19 of the 28 patients, the optimal ablation site was identical to the border area. In all 11 patients who had pre-potentials at the successful ablation site, there were two cases with polymorphic VT and/or ventricular fibrillation associated with PVCs. In these two cases, length of LVA was longer than in other patients (4.0 and 3.9 cm vs. 1.8 ± 0.5 cm (n = 26)), and the optimal ablation site was located at the border area. CONCLUSION: The border area, including the LVA, tends to be the breakout site and/or origin of ventricular arrhythmias in idiopathic ventricular tachyarrhythmia originating from the RVOT septum.

An appropriate defibrillation threshold obtained by the combined connection between two shock leads and ICD generator.

A 60-year-old man with arrhythmogenic right ventricular cardiomyopathy was readmitted for the battery exchange of his implantable cardioverter-defibrillator (ICD). Since (i) he had been treated with a dual-coil shock lead (Sprint Fidelis, Medtronic) and (ii) pre-operative venography showed mild collateral flow to the left subclavian vein, a single-coil lead was additionally implanted. However, the single-coil defibrillation system was unable to terminate the induced ventricular fibrillation (VF), thus dual defibrillation shock pathways were created using the connection to the superior vena cava coil of the Fidelis lead. The combined connections of the two shock leads provided an appropriate margin of the defibrillation threshold.

Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.

BACKGROUND: Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear. METHODS AND RESULTS: This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels. CONCLUSIONS: We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

Effects of bepridil versus E-4031 on transmural ventricular repolarization and inducibility of ventricular tachyarrhythmias in the dog.

BACKGROUND: Bepridil (a multiple channel blocker) may markedly prolong the QT interval and induce polymorphic ventricular tachyarrhythmias (VTA). We compared the transmural ventricular repolarization characteristics and inducibility of polymorphic VTA after administration of bepridil versus the pure I(Kr) blocker, E-4031, each administered to five open-chest dogs. METHODS: We used plunge needle electrode to record transmural left ventricular (LV) repolarization and activation-recovery interval (ARI) to estimate local repolarization. The correlation between paced cycle length and ARI was separately examined in the LV endocardium, mid-myocardium (Mid), and epicardium. Attempts to induce VTA were made during bradycardia and sympathetic stimulation. RESULTS: Bepridil and E-4031 prolonged QT interval and ARI in all LV layers, though the magnitude of prolongation was greatest in Mid, increasing the transmural ARI dispersion, particularly during bradycardia. Compared with E-4031, bepridil caused mild, reverse use-dependent changes in ventricular repolarization, and less ARI dispersion than E-4031 during slow ventricular pacing. Both drugs increased ARI(max) and cycle length at 50% of ARI(max), though the changes were smaller after bepridil than after E-4031 administration. Bradycardia after the administration of each drug induced no VTA; however, sympathetic stimulation induced sustained polymorphic VTA in two of five dogs treated with E-4031 versus no dog treated with bepridil. CONCLUSIONS: Unlike the pure I(kr) blocker, E-4031, bepridil exhibited weak properties of reverse use-dependency and protected against sympathetic stimulation-induced VTA. It may be an effective supplemental treatment for recipients of implantable cardioverter defibrillator.

Non-pharmacological management of ventricular tachycardia.

Ventricular tachyarrhythmias (VTA), a major cause of sudden cardiac death, require meticulous management in order to prevent recurrent episodes. Recently, non-pharmacological interventions, including radiofrequency catheter ablation and implantable cardioverter defibrillators (ICD), have become important treatments of VTA. Catheter ablation is curative in a relatively high percentage of patients presenting with idiopathic monomorphic ventricular tachycardia (VT). For VT associated with structural heart disease, however, the efficacy of catheter ablation remains limited, and ICD is the first-line therapy. In a subset of patients presenting with recurrent episodes of ventricular fibrillation (VF), catheter ablation is a therapeutic option when the VF is triggered by specific premature ventricular complexes. In Japan, unlike in the United States and Europe, ICD have not yet been accepted as first-line prevention of sudden cardiac death caused by VTA. The efficacy of ICD is occasionally limited by intolerable complications, such as electrical storm, inappropriate shock delivery and infection. Catheter ablation and ICD therapy might need to be combined for problematic cases.

Comparison of conduction delay in the right ventricular outflow tract between Brugada syndrome and right ventricular cardiomyopathy: investigation of signal average ECG in the precordial leads.

BACKGROUND: In both Brugada syndrome (BS) and arrhythmogenic right ventricular cardiomyopathy (ARVC), electrical abnormalities in the right ventricular outflow tract (RVOT) are important for arrhythmogenesis. OBJECTIVES: The aim of this study was to compare conduction delay in the right ventricular in BS with that in ARVC using the signal-averaged electrocardiogram. METHODS: Twenty patients with BS (18 men and 2 women; 55 +/- 12 years old; 9 symptomatic and 11 asymptomatic) and eight patients with ARVC (six men and two women; 53 +/- 16 years old) were included. We assessed the presence of late potentials (LPs) and the filtered QRS duration (fQRSd) in V(2) and V(5) using a high-pass filter of 40 Hz (fQRSd:40) and 100 Hz (fQRSd:100). RESULTS: In ARVC, there was no significant difference in fQRSd:40 between V2 and V5 (158 +/- 19 vs. 145 +/- 17 ms, respectively): however, in BS, fQRSd:40 in V2 was significantly longer than fQRSd:40 in V5 (147 +/- 15 vs. 125 +/- 10 ms, P < 0.001). In ARVC, there was no significant difference between fQRSd:40 and fQRSd:100 in V(2) and V(5) (158 +/- 19 vs. 142 +/- 23 ms and 145 +/- 17 vs. 132 +/- 9 ms, respectively). In contrast, in BS, fQRSd:100 was significantly shorter than fQRSd:40 in V2 (110 +/- 8 ms vs. 147 +/- 15, P < 0.001). The relative decrease in fQRSd:100 compared with fQRSd:40 in V2 was significantly greater in BS than in ARVC. CONCLUSION: The dominant prolongation of the fQRSd in the right precordial lead in BS was different from the characteristics of ARVC, which may be caused by the conduction delay due to fibro-fatty replacement in RV.

Incidence and initial characteristics of pilsicainide-induced ventricular arrhythmias in patients with Brugada syndrome.

BACKGROUND: In patients with Brugada syndrome, class I antiarrhythmic drugs can trigger ventricular arrhythmias (VA). The incidence and initial characteristics of VA that developed after pilsicainide was examined in 28 patients with Brugada-type electrocardiographic (ECG) abnormalities and with a positive response in the pilsicainide test. The clinical outcome was also compared between patients with and without pilsicainide-induced VA. METHODS AND RESULTS: In all patients, pilsicainide increased ST segment elevation and accentuated type 1 ECG changes. Ventricular tachycardia (VT) developed in 3 patients and premature ventricular complexes (PVC) in 2 other patients. These 5 patients (group I) had higher ST segment elevation in lead V2 on the ECG at baseline and after pilsicainide and showed a longer QTc interval after pilsicainide than the other 23 patients (group II). However, there was no difference between the 2 groups regarding incidence of prior cardiac events, results of signal-averaged ECG, HV interval, inducibility of ventricular fibrillation by programmed electrical stimulation, or QRS duration. In 1 patient, PVC originated from 3 sites, 2 of which triggered polymorphic VT. The right ventricular (RV) outflow tract was the origin of 2 types of PVC, and other RV sites of 5 other types. During a 45 +/- 37 months follow-up, polymorphic VT recurred in 2 patients in group II. CONCLUSIONS: Pilsicainide induced VA in some patients with Brugada syndrome, but this result may not be used as a parameter of the risk stratification of Brugada syndrome. Multiple PVC induced by pilsicainide and triggering polymorphic VT originated from several RV sites is an important factor when considering patients for treatment with catheter ablation.

Distinct U wave changes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).

Although catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with fatal ventricular arrhythmias and sudden death, the ECG findings are not fully understood. In this paper, we report on alterations in the U-wave. Seven patients from 6 families with CPVT in which bidirectional tachycardia and polymorphic VT were induced by exercise or isoproterenol infusion visited our hospitals. VT was not inducible by programmed electrical stimulation. A novel gene mutation of the ryanodine receptor 2 (RyR2) was confirmed in 2 families. In one of these patients, U-wave alternans was observed following ventricular pacing at 160 beats/min. In the other patient, U-wave alternans was observed during the recovery phase after the exercise stress test, which was terminated because of polymorphic VT. In both cases, leads V3-V5 were the leads showing alternans most clearly. In the third patient, a negative U-wave became positive following a pause from sinus arrest and a change in T-wave was also noted. Since such findings were not found in the other subjects who underwent electrophysiologic study, isoproterenol infusion or exercise stress testing, the phenomenon seems to be relevant to the underlying pathogenesis of CPVT. The genesis and significance of U-wave alteration need to be determined.

Electrophysiologic study-guided therapy with sotalol for life-threatening ventricular tachyarrhythmias.

The aim of this study was to investigate the long-term efficacy and safety of electrophysiologic study (EPS)-guided sotalol administration combined with implantable cardioverter defibrillators (ICD) for ventricular tachyarrhythmias (VTA). This study enrolled 92 patients with both structural heart disease and sustained VTA. Sotalol was administered to 57 patients, and its efficacy was assessed by EPS. Long-term treatment was continued in combination with ICD in 31 patients (57%) whose VTA was no longer inducible (responder group) and in 16 patients whose VTA remained inducible (nonresponder group). The long-term outcomes were compared among the responder group, the nonresponder group, and 35 ICD recipients untreated with antiarrhythmic drugs (ICD-only group). During a mean follow-up of 44 +/- 33 months, the recurrence of VTA was not significantly different between all patients treated with sotalol (30%) and patients in the ICD-only group (46%). However, the recurrence of VTA was significantly lower in the responder (13%) than in the nonresponder (63%) or the ICD-only groups (46%). There was no significant difference in VTA recurrence between the nonresponder and the ICD-only groups. One patient each in the responder and the ICD-only groups died suddenly, and all-cause mortality was similar in the three groups. The incidence of inappropriate ICD discharges was less in the sotalol than in the ICD-only groups. No patient had to discontinue long-term sotalol treatment because of the adverse effects. In conclusion, sotalol reduced VTA recurrence in the responding patients and inappropriate ICD discharge. EPS may predict the efficacy of sotalol for VTA recurrence.

Unsuccessful internal defibrillation in Brugada syndrome: focus on refractoriness and ventricular fibrillation cycle length.

INTRODUCTION: In patients with Brugada syndrome, implantable cardioverter defibrillator (ICD) is the only reliable treatment to prevent sudden death though, in some cases, internal defibrillation may be unsuccessful. The aim of this study was to examine the determinants of defibrillation failure, with a focus on electrophysiologic characteristics. METHODS: The study included 51 patients treated with ICD: 22 with Brugada syndrome and 29 with structural heart disease (SHD). The prevalence of defibrillation energy requirement precluding the programming of a 10-J safety margin, the mean right ventricular effective refractory period (ERP), and mean induced ventricular fibrillation cycle length (VFCL) from the stored ICD electrograms, were compared between the two patient groups. RESULTS: High defibrillation requirements were observed in 18% of patients with Brugada syndrome versus 0% of patients with SHD. However, the patients with SHD had larger heart size than those with Brugada syndrome. Mean VFCL and mean ERP were both significantly shorter in patients with Brugada syndrome than in patients with SHD, and ERP and VFCL were significantly correlated. CONCLUSION: Patients with Brugada syndrome have a high prevalence of high defibrillation energy requirement, and short ventricular ERP and VFCL.

Ventricular tachyarrhythmia associated with cardiac sarcoidosis: its mechanisms and outcome.

BACKGROUND: Cardiac sarcoidosis is increasingly recognized and is associated with poor prognosis. Ventricular tachycardia (VT) associated with cardiac sarcoidosis is the most likely cause of sudden death in most patients, but the mechanism has not been well established. HYPOTHESIS: This study investigated the mechanisms and outcome of VT associated with cardiac sarcoidosis. METHODS: The study included eight consecutive patients (five men, three women, aged 54 +/- 19 years) who had sustained monomorphic VT associated with cardiac sarcoidosis in our hospital. RESULTS: The average ejection fraction was 43 +/- 11%. Twenty-two VTs were observed in these patients, and mean heart rate during VT was 192 +/- 29 beats/min (range 144-259). The phenomenon of transient entrainment was documented in 10 of 22 (45%) VTs by ventricular pacing (eight in the active phase). Another five (23%) VTs could not be entrained, but could be initiated by programmed stimulation and terminated by rapid pacing, reproducibly. In 3 of the 22 (14%) VTs, cardioversion was required urgently because of the fast rate, while the remaining 4 (18%) could be induced during electrophysiologic study. CONCLUSIONS: In this study, there was a high possibility that the mechanism of 15 (68%) VTs was reentry. Reentrant substrate is formed not only in association with the healing of cardiac granulomas in the inactive phase of cardiac sarcoidosis but also in the active phase. Ventricular tachycardia with cardiac sarcoidosis, even if this mechanism is reentry, has different inducibility between the active and inactive phases in an electrophysiologic study. This makes the therapy for cardiac sarcoidosis (e.g., corticosteroids, antiarrhythmic agents, and catheter ablation) difficult. The implantable cardioverter-defibrillator is an effective treatment for ventricular tachyarrythmia with cardiac sarcoidosis.

Mechanism of discordant T wave alternans in the in vivo heart.

INTRODUCTION: Compared to concordant T wave alternans (CA), discordant T wave alternans (DA) may be associated with an increased dispersion of repolarization (DR) and a greater propensity to develop reentrant ventricular tachyarrhythmias. The electrophysiologic mechanisms of DA in the in vivo heart are not well understood. METHODS AND RESULTS: The mechanisms of DA were investigated in the canine anthopleurin-A surrogate model of long QT3 syndrome using tridimensional analysis of activation and repolarization patterns from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. Two mechanisms for the development of DA were observed. (1) Stepwise shortening of cycle length (CL) superimposed on preexisting DR resulted in different diastolic intervals (DI) at midmyocardial sites compared to epicardial and endocardial sites. The dispersion of DI coupled with different restitution kinetics at those sites induced DA. (2) The dependence of conduction velocity on DI as the CL is abruptly shortened could result in differential conduction delays at mid sites. This enhanced the dispersion of DI between sites and, coupled with the different restitution kinetics, induced DA. The critical step for the development of DA in both mechanisms was the occurrence of short ARI in two consecutive beats either at epicardial sites in the first mechanism or at mid sites in the second mechanism. Sites with DA had significantly more DR compared to sites with concordant T wave alternans, and ventricular tachyarrhythmias developed mainly in the presence of DA. CONCLUSION: In the in vivo heart, DA developed due to critical interaction between dispersion of DI and differences in restitution kinetics at different myocardial sites. The dispersion of DI could result from preexisting DR or differential conduction delay at a critical short CL. DA is critically linked to the development of malignant tachyarrhythmias.