A safe and simple approach to avoid fast junctional rhythm during ablation in patients with atrioventricular nodal reentrant tachycardia.

INTRODUCTION: Fast junctional rhythm (JR) during slow pathway modification for atrioventricular nodal reentrant tachycardia (AVNRT) is a predictor of serious atrioventricular block. This study investigated the boundary to avoid fast JR during ablation with three-dimensional (3D) electroanatomical mapping in AVNRT patients. METHODS AND RESULTS: Participants were 129 consecutive patients with common AVNRT who received anatomical ablation to an antegrade slow pathway at our institution between August 2013 and March 2019. Successfully ablated sites with JR were evaluated in terms of distances and angles in the left and right anterior oblique views (LAO and RAO, respectively) to the proximal His bundle (His) site using 3D mapping. We divided JR by heart rate: JR1 ≥150 bpm and JR2 <150 bpm. Average age was 61 ± 16 years; 41.1% of patients were male. The distance from the most proximal His to the JR1 and JR2 site was not significantly different (11.9 ± 4.4 vs 10.7 ± 4.5 mm, P = .24). JR1 predominantly appeared closer to the left ventricle than JR2 in LAO (110.5 ± 19.1° vs 77.5 ± 18.6°, P < .01), and was more posterior from the proximal His in RAO (30.8% vs 6.8%, P < .01). The vertical line drawn down from the proximal His in the LAO view was a good indicator of JR1 appearance (sensitivity and specificity 84.6% and 81.6%, respectively). CONCLUSION: The vertical line drawn down from the proximal His in the LAO view can be employed as a boundary to avoid fast JR during ablation in AVNRT.

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia.

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome.

BACKGROUND: In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle-branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients. METHODS AND RESULTS: In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB. CONCLUSION: Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG.

Change in QRS morphology as a marker of spontaneous elimination in verapamil-sensitive idiopathic left ventricular tachycardia.

BACKGROUND: Verapamil-sensitive idiopathic left ventricular tachycardia (verapamil-ILVT) is thought to be due to a reentry within the LV fascicular system. Radiofrequency catheter ablation (RFCA) is effective for elimination of the VT; however, a long-term prognosis of patients with verapamil-ILVT is still unclear. METHODS AND RESULTS: Eighty consecutive verapamil-ILVT patients (62 men, 31 ± 12 years of age, LVEF: 65 ± 4%) were enrolled. Seventy-six (95%) cases of VT involved right bundle branch block and left axis deviation. We retrospectively analyzed changes in the QRS duration (ΔQRS-d) and QRS axis (ΔQRS-axis) during follow-up and compared them with recurrence of VT. During a mean follow-up period of 10 years (2-32 years), no sudden death or heart failure occurred. Fifty-one (64%) patients underwent RFCA, and 46 (90%) of them had no VT without any medication after RFCA. The ΔQRS-d (16 ± 2 vs. 8 ± 1 ms, P = 0.24) and ΔQRS-axis (20 ± 4 vs. 4 ± 3 degrees, P = 0.23) were not different in patients with no VT (VT[-]) and those with recurrence of VT (VT[+]). However, in the remaining 29 patients without RFCA, VT was spontaneously eliminated in 16 patients. The ΔQRS-d (30 ± 6 vs. 6 ± 1 ms, P = 0.002) and ΔQRS-axis (23 ± 4 vs. 5 ± 2 degrees, P = 0.001) were significantly larger in VT(-) patients compared to VT(+) patients during follow-up. CONCLUSIONS: Some verapamil-ILVT patients who show QRS morphology changes over the follow-up period may become free from VT without any invasive or pharmacological treatments, suggesting that further altered LV fascicular conduction might eliminate the reentry of verapamil-ILVT.

Differences in the onset mode of ventricular tachyarrhythmia between patients with J wave in anterior leads and those with J wave in inferolateral leads.

BACKGROUND: The pathophysiological mechanism of J wave in anterior leads (A-leads) and inferolateral leads (L-leads) remains unclear. OBJECTIVE: We investigated the onset mode and circadian distribution of ventricular tachyarrhythmia (VTA) episodes between patients with early repolarization syndrome (ERS) and Brugada syndrome (BrS). METHODS: The study enrolled 35 patients with ERS and 52 patients with type 1 BrS with spontaneous ventricular fibrillation who were divided into 4 groups: ERS(A+L) (n = 15), patients with ERS who had a non-type 1 Brugada pattern electrocardiogram in any A-leads (second to fourth intercostal spaces) in control and/or after drug provocation tests; ERS(L) (n = 20), patients with ERS with J wave only in L-leads; BrS(A) (n = 24), patients with BrS without J wave in L-leads; and BrS(A+L) (n = 28), patients with BrS with J wave in L-leads. The onset mode of 206 VTAs obtained from electrocardiograms or implantable cardioverter-defibrillators and the circadian distribution of 352 VTAs were investigated in the 4 groups. RESULTS: Three groups with J wave in A-leads, ERS(A+L), BrS(A), and BrS(A+L), had higher incidences of nocturnal (63%, 43%, and 47%, respectively) and sudden onset VTAs (67%, 97%, and 86%, respectively) with longer coupling intervals of premature ventricular contractions (388.8, 397.3, and 385.6 ms, respectively) than the ERS(L) group with J wave only in L-leads (25%, P = .0019; 19%, P < .0001; and 330.6 ms, P = .0004, respectively), the last of which mainly displayed VTAs with a short-long-short sequence. CONCLUSION: The onset mode of VTAs was different between patients with J wave in A-leads and patients with J wave in only L-leads. The underlying mechanism of J wave may differ between A-leads and L-leads.

Enhancement of Spontaneous Activity by HCN4 Overexpression in Mouse Embryonic Stem Cell-Derived Cardiomyocytes - A Possible Biological Pacemaker.

BACKGROUND: Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including the problems of battery life and electromagnetic interference. Enhancement of the funny current (If) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K+ current (IK1) flowing through inward rectifier potassium (Kir) channels are essential for generation of a biological pacemaker. Therefore, we generated HCN4-overexpressing mouse embryonic stem cells (mESCs) and induced cardiomyocytes that originally show poor IK1 currents, and we investigated whether the HCN4-overexpressing mESC-derived cardiomyocytes (mESC-CMs) function as a biological pacemaker in vitro. METHODS AND RESULTS: The rabbit Hcn4 gene was transfected into mESCs, and stable clones were selected. mESC-CMs were generated via embryoid bodies and purified under serum/glucose-free and lactate-supplemented conditions. Approximately 90% of the purified cells were troponin I-positive by immunostaining. In mESC-CMs, expression level of the Kcnj2 gene encoding Kir2.1, which is essential for generation of IK1 currents that are responsible for stabilizing the resting membrane potential, was lower than that in an adult mouse ventricle. HCN4-overexpressing mESC-CMs expressed about a 3-times higher level of the Hcn4 gene than did non-overexpressing mESC-CMs. Expression of the Cacna1h gene, which encodes T-type calcium channel and generates diastolic depolarization in the sinoatrial node, was also confirmed. Additionally, genes required for impulse conduction including Connexin40, Connexin43, and Connexin45 genes, which encode connexins forming gap junctions, and the Scn5a gene, which encodes sodium channels, are expressed in the cells. HCN4-overexpressing mESC-CMs showed significantly larger If currents and more rapid spontaneous beating than did non-overexpressing mESC-CMs. The beating rate of HCN4-overexpressing mESC-CMs responded to ivabradine, an If inhibitor, and to isoproterenol, a beta-adrenergic receptor agonist. Co-culture of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with aggregates composed of mESC-CMs resulted in synchronized contraction of the cells. The beating rate of hiPSC-CMs co-cultured with aggregates of HCN4-overexpressing mESC-CMs was significantly higher than that of non-treated hiPSC-CMs and that of hiPSC-CMs co-cultured with aggregates of non-overexpressing mESC-CMs. CONCLUSIONS: We generated HCN4-overexpresssing mESC-CMs expressing genes required for impulse conduction, showing rapid spontaneous beating, responding to an If inhibitor and beta-adrenergic receptor agonist, and having pacing ability in an in vitro co-culture system with other excitable cells. The results indicated that these cells could be applied to a biological pacemaker.

Atrial electrophysiological and structural remodeling in high-risk patients with Brugada syndrome: assessment with electrophysiology and echocardiography.

BACKGROUND: Atrial fibrillation (AF) often occurs in Brugada syndrome (BrS), and BrS patients with spontaneous AF often experience ventricular fibrillation (VF) attacks. Atrial vulnerability providing a substrate for AF is known to be enhanced in BrS, but there are no data on atrial structural attributes. OBJECTIVE: The objective of this study was to assess atrial electrophysiological and structural characteristics in BrS and their relationships with gene mutations. METHODS: We studied 57 patients with BrS. Intra-atrial conduction time (CT) was defined as the interval from the stimulus at the high right atrium to atrial deflection at the distal portion of the coronary sinus. Left atrial volume index (LAVI) was measured by the modified Simpson method at left ventricular end-systole using echocardiography. SCN5A mutations were analyzed in all patients. RESULTS: In patients with documented VF, spontaneous AF frequently occurred and prolonged CT and increased LAVI were observed compared with those in patients without VF (all P < .05; LAVI: 22 +/- 5 vs. 32 +/- 7 ml/m(2)). Even among patients without AF, CT and LAVI were still increased in patients with VF (all P < .05; LAVI: 22 +/- 5 vs. 29 +/- 5 ml/m(2)). The presence of SCN5A mutation was associated with prolonged CT (P < .05) and increased LAVI (P < .01), but not with arrhythmic episodes. CONCLUSION: Both atrial vulnerability and structural remodeling are enhanced in high-risk patients with BrS, even in those without AF. These morphological characteristics suggest that BrS is a form of genetic myocardial disease.

Abnormal restitution property of action potential duration and conduction delay in Brugada syndrome: both repolarization and depolarization abnormalities.

AIMS: This study sought to examine the action potential duration restitution (APDR) property and conduction delay in Brugada syndrome (BrS) patients. A steeply sloped APDR curve and conduction delay are known to be important determinants for the occurrence of ventricular fibrillation (VF). METHODS AND RESULTS: Endocardial monophasic action potential was obtained from 39 BrS patients and 9 control subjects using the contact electrode method. Maximum slopes of the APDR curve were obtained at both the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA). The onset of activation delay (OAD) after premature stimulation was examined as a marker of conduction delay. Maximum slope of the APDR curve in BrS patients was significantly steeper than that in control subjects at both the RVOT and the RVA (0.77 +/- 0.21 vs. 058 +/- 0.14 at RVOT, P = 0.009; 0.98 +/- 0.23 vs. 0.62 +/- 0.16 at RVA, P = 0.001). The dispersion of maximum slope of the APDR curve between the RVOT and the RVA was also larger in BrS patients than in control subjects. The OAD was significantly longer in BrS patients than in control subjects from the RVOT to RVA and from the RVA to RVOT (from RVOT to RVA: 256 +/- 12 vs. 243 +/- 7 ms, P = 0.003; from RVA to RVOT: 252 +/- 11 vs. 241 +/- 9 ms, P = 0.01). CONCLUSIONS: Abnormal APDR properties and conduction delay were observed in BrS patients. Both repolarization and depolarization abnormalities are thought to be related to the development of VF in BrS patients.

Electrophysiologic characteristics of an Andersen syndrome patient with KCNJ2 mutation.

We report the first case of a patient with Andersen syndrome in whom electrophysiologic study was performed. The patient was a 19-year-old woman with familial periodic paralysis, abnormal QT-U complex, and nonsustained ventricular tachycardia. Mutation analysis revealed a missense mutation in KCNJ2, a component of Kir2.1. Monophasic action potential recordings showed a delayed afterdepolarization (DAD)-like hump in the left ventricle. Initiation of epinephrine-induced premature ventricular contractions always coincided with both the exaggerated DAD-like hump and the U wave. These findings suggest that reduced Kir2.1 current contributes to the development of DAD and ventricular arrhythmias in Andersen syndrome.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome.

OBJECTIVES: We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND: Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS: The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS: Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS: Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.