Akiko Ueda

Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR

Phenobarbital (PB) increases hepatic drug/steroid-metabolic capability by coordinately activating transcription of the genes encoding various metabolizing enzymes. The nuclear receptor CAR was first implicated as a transcription factor that activates the cytochrome P450 Cyp2b10 gene. In response to PB, CAR forms a heterodimer with the retinoid X receptor (RXR), binds to a PB response element (typified by DR-4 motif), and activates transcription of the gene. In the CAR-null mouse, PB does not only induce the Cyp2b10 gene, but also induces genes encoding various metabolizing enzymes. Thus, CAR is a general nuclear receptor that is essential for PB induction of drug/steroid metabolizing enzymes. PB also induces amino levulinate synthase 1 (ALAS-1), the rate-limiting enzyme in heme biosynthesis, to increase heme supply. However, PB induction of the synthase occurs in CAR-null mice, suggesting that CAR does not coordinate the heme synthesis for the induction of drug/steroid metabolism.

Contemporary outcomes of supraventricular tachycardia ablation in congenital heart disease: a single-center experience in 116 patients.

Background—Remote magnetic navigation–guided ablation with 3-dimensional (3D)-image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies. Methods and Results—One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation–guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation–guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra-atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P<0.001). Acute success was 91.5%, 83.7%, and 82.2%, respectively (P=0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P<0.001) despite the longer procedure duration (median, 253 min; P<0.001). SVTs free rates were 80.4%, 82.4%, and 75.8%, respectively (P=0.787) during a mean 20-months follow-up period. Conclusions—The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies.

Magnetic navigation in adults with atrial isomerism (heterotaxy syndrome) and supraventricular arrhythmias

AIMSnWe analysed the type and mechanism of supraventricular arrhythmias encountered in a series of symptomatic adults with atrial isomerism undergoing catheter ablation procedures.nnnMETHODS AND RESULTSnThe study population included consecutive adults with atrial isomerism who had previously undergone surgical repair or palliation of the associated anomalies. Patients underwent electrophysiological study for symptomatic arrhythmia in our institution between 2010 and 2012 using magnetic navigation in conjunction with CARTO RMT and three-dimensional (3D) image integration. Eight patients (five females) with a median age of 33 years [interquartile range (IQR) 24-39] were studied. Access to the cardiac chambers of interest was obtained retrogradely via the aorta using remotely navigated magnetic catheters in six patients. Radiofrequency ablation successfully targeted twin atrioventricular (AV) nodal reentrant tachycardia in two patients, atrial fibrillation (AF) in three, focal atrial tachycardia (AT) mainly originating in the left-sided atrium in four patients, and macro-reentrant AT dependent on a right-sided inferior isthmus in three patients. The median fluoroscopy time was 3.0 min (IQR 2-11). After a median follow-up of 10 months (IQR 6-21), five of the ablated patients are free from arrhythmia; two patients experienced episodes of self-terminated AF and AT, respectively, within one month post-ablation; the remaining patient had only non-sustained AT during the electrophysiological study and was managed medically.nnnCONCLUSIONnVarious supraventricular tachycardia mechanisms are possible in adults with heterotaxy syndrome, all potentially amenable to radiofrequency ablation. The use of remote magnetic navigation along with 3D mapping facilitated the procedures and resulted in a short radiation time.

Thr176 regulates the activity of the mouse nuclear receptor CAR and is conserved in the NR1I subfamily members PXR and VDR

The mouse nuclear receptor CAR (constitutively active receptor) is a transcription factor that is activated by phenobarbital-type inducers such as TCPOBOP {1,4 bis[2-(3,5-dichloropyridyloxy)]benzene} in liver in vivo. However, CAR is constitutively active in cell-based transfection assays, the molecular mechanism for which has not been elucidated yet. In the model structure of CAR, Thr176 constitutes a part of the ligand-binding surface, but its side chain is not directed toward the surface, instead it forms a hydrogen bond with Thr350 in the AF2 (activation function 2) domain of CAR. Thr350 is known to regulate CAR activity [Ueda, Kakizaki, Negishi, and Sueyoshi (2002) Mol. Pharmacol. 61, 1284-1288]. Thr176 was mutated to various amino acids to examine whether this interaction played a role in conferring the constitutive activity. Hydrophobic and positively charged amino acids at position 176 abrogated the constitutive activity, whereas polar and negatively charged amino acids retained it. When one of the small hydrophobic amino acids, such as alanine or valine, was substituted for threonine, the mutants were fully activated by TCPOBOP. The co-activator SRC-1 (steroid receptor co-activator-1) regulated the activity changes associated with the mutations. Thr248 and Ser230 are the Thr176-corresponding residues in human pregnane X receptor and mouse vitamin D3 receptor respectively, interacting directly with the conserved threonine in the AF2 domains. Thr248 and Ser230 also regulated the ligand-dependent activity of these receptors by augmenting binding of the receptors to SRC-1. Thr176, Thr248 and Ser230 are conserved residues in the NR1I (nuclear receptor 1I) subfamily members and determine their activity.

Reaching the ventricular aspect of the inferior isthmus in a Fontan patient using magnetic navigation

e r After classic Fontan operation, that is, atriopulmonary onnection, up to 50% of the patients develop atrial tachyardia (AT) during long-term follow-up. The majority of trial arrhythmias following the Fontan procedure are ATs elated to surgical incision or inferior isthmus-dependent utter. We report a 44-year-old man with recurrent AT. His original diagnosis was double inlet left ventricle with discordant ventricular arterial connection and pulmonary stenosis. At age 21 years, he underwent a Fontan operation with an atriopulmonary connection (using a homograft) and patch closure of the AV valve connecting the right atrium (RA) to the left ventricle following a palliative left BlalockTaussig shunt at the age of 12 years. In addition, 2 device closures (Amplatzer, 6 and 15 mm, respectively) were performed for residual patch leaks. (The dotted red line in Figure A depicts the patch across the right-sided AV valve. Note the 2 closure devices.) A single-lead atrial pacemaker had also been implanted for sinus node dysfunction. A 3-dimensional electroanatomic mapping system (Carto-RMT, Biosense-Webster, Diamond Bar, CA) was used in combination with the remote magnetic navigation system (Niobe, Stereotaxis Inc, St Louis, MO) for mapping and ablation of AT. The activation in the electroanatomic apping and entrainment mapping demonstrated that the achycardia was isthmus dependent. Radiofrequency energy as delivered to the RA-sided inferior isthmus (the blue line n Figure 1) without effect, and hence the decision to aproach the ventricular side of the inferior isthmus (the arrow n Figure 1; the remaining myocardium excluded from the

Clinical and electrophysiological characteristics in patients with sustained monomorphic reentrant ventricular tachycardia associated with dilated-phase hypertrophic cardiomyopathy.

AIMSnLittle is known about sustained monomorphic ventricular tachycardia (SMVT) associated with dilated-phase hypertrophic cardiomyopathy (DHCM). The purpose of this study was to clarify the clinical characteristics and effectiveness of catheter ablation for SMVTs in DHCM patients.nnnMETHODS AND RESULTSnFive patients with DHCM (mean age; 67.0 years old, five males) who underwent catheter ablation for drug-refractory SMVTs were included the study. Four of five patients suffered from electrical storm. When the endocardial ablation failed, epicardial and/or intracoronary ethanol ablation, or surgical cryoablation was performed. We reviewed all ablation procedures and electrocardiogram (ECG) of targeted SMVTs. A total of 13 SMVTs were targeted for ablation. Mechanism of all ventricular tachycardias (VTs) was diagnosed as reentry. Endocardial ablation successfully eliminated all VTs in two patients. The remaining three patients needed epicardial ablation, intracoronary ethanol ablation, and surgical cryoablation. All but one VT arose from the basal septum, basal anterior to anterolateral left ventricle (LV). Although the ECGs demonstrated similar features of idiopathic outflow or mitral annulus VTs reflecting the origins, there were characteristic multiple QRS deflections. Following the ablation, four (80%) of the five patients are free from VT recurrence during 18 months of the follow-up period.nnnCONCLUSIONSnIn DHCM patients, VT circuits predominantly distributed in the basal septum and the basal anterior to anterolateral LV. In addition to the endocardial ablation, alternative approaches were required in some patients.

Anatomic Assessment of Variations in Myocardial Approaches to the Atrioventricular Node

Atrial Septum, Coronary Sinus, and Atrioventricular Node.

Case ReportEpicardial access and ventricular tachycardia ablation in a postmyocarditis patient using a nonfluoroscopic catheter visualization system

Introduction The efficacy of catheter ablation for scar-related ventricular tachycardia (VT) has significantly improved since the introduction of percutaneous epicardial access by Sosa in 1996. Percutaneous epicardial ablation has been used in approximately 30% of VT ablation cases associated with nonischemic cardiomyopathy. However, complications such as cardiac tamponade, coronary artery laceration, or occlusion develop in approximately 4% of the procedures. Epicardial puncture and ablation are indicated after coronary angiogram (CAG) so as to avoid damage to the coronary arteries. Prior to the ablation, a CAG must be repeated, and fluoroscopy is often used during the puncture while the operator’s hands are in the field. As a result, these procedures increase fluoroscopy time and radiation exposure for both the patient and the operator. MediGuide (St. Jude Medical [SJM], St. Paul, MN) is a sensor-based, electromagnetic, nonfluoroscopic catheter visualization system. The system tracks dedicated sensorembedded catheters and guidewires directly on fluoroscopy or cine-loop images acquired at the beginning of the ablation procedure. To reduce radiation exposure during the access and mapping, the MediGuide system has been used for epicardial access and ablation in our institution. In this report, we present a patient with postmyocarditis scar-related VT who underwent an ablation procedure using this technology.

Contemporary Outcomes of Supraventricular Tachycardia Ablation in Congenital Heart DiseaseClinical Perspective: A Single-Center Experience in 116 Patients

Background—Remote magnetic navigation–guided ablation with 3-dimensional (3D)-image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies. Methods and Results—One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation–guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation–guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra-atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P<0.001). Acute success was 91.5%, 83.7%, and 82.2%, respectively (P=0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P<0.001) despite the longer procedure duration (median, 253 min; P<0.001). SVTs free rates were 80.4%, 82.4%, and 75.8%, respectively (P=0.787) during a mean 20-months follow-up period. Conclusions—The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies.

Contemporary Outcomes of Supraventricular Tachycardia Ablation in Congenital Heart DiseaseClinical Perspective

Background—Remote magnetic navigation–guided ablation with 3-dimensional (3D)-image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies. Methods and Results—One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation–guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation–guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra-atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P<0.001). Acute success was 91.5%, 83.7%, and 82.2%, respectively (P=0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P<0.001) despite the longer procedure duration (median, 253 min; P<0.001). SVTs free rates were 80.4%, 82.4%, and 75.8%, respectively (P=0.787) during a mean 20-months follow-up period. Conclusions—The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies.