Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity.

The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.

Initial and Secondary ST-T Alternans During Acute Myocardial Ischemia in the In-Situ Pig Heart.

The factors responsible for the ST-T wave alternans (STTA) and associated arrhythmias during acute ischemia have not been clarified.In acutely ischemic porcine myocardium, we recorded transmural unipolar and bipolar electrocardiograms and mid-myocardial extracellular K(+) ([K(+)]e) from the center of the ischemic zone during 8-minute episodes of ischemia. Two different STTAs occurred. The initial STTA, which occurred at 4 minutes 15 seconds ± 12 seconds of ischemia during sinus rhythm, was most prominent in the subendocardium, independent of [K(+)]e and activation block, and heart rate dependent. It occurred in 13/19 (68%) occlusions at heart rates ≤ 100 bpm and in 22/23 (96%) at > 100 bpm. The second STTA was more obvious and greatest in the subepicardium. It began in the later phase of ischemia and was also heart rate dependent (5/19 [26%] occlusions at heart rates ≤ 100 bpm and 10/23 [44%] at > 100 bpm). This STTA was consistently associated with 2:1 change in the bipolar electrogram morphology, possibly due to 2:1 conduction block. Ventricular fibrillation (VF) occurred only at > 100 bpm.The initial STTA may be independent of conduction abnormalities and represent primary repolarization alternans. The second STTA may be secondary to and indicative of 2:1 activation block or marked alternans of the action potential amplitude/duration. The associated VF most likely reflects the underlying conduction abnormality.

Frequency analysis of atrial fibrillation from the specific ECG leads V7-V9: A lower DF in lead V9 is a marker of potential atrial remodeling.

INTRODUCTION: High dominant frequency (DF) sites during atrial fibrillation (AF) play an important role in the perpetuation of AF. We investigated the relationship between the DFs from intracardiac electrograms (iEGM) and the surface electrocardiogram (ECG) during AF, and the relationship between the surface ECG DF and atrial remodeling. METHODS: In 48 patients (57±11 years, 47 males, 20 paroxysmal), the V1-6 precordial leads and specific V7-9 ECG leads were recorded for 8s for an off-line analysis before AF ablation. The QRS-T complex was canceled by a template subtraction algorithm using the CEPAS™ system (Cuoretech Pty Ltd, Sydney, Australia). The iEGM DF maps, reconstructed using the Ensite NavX (St. Jude Medical, Inc., St. Paul, MN, USA) system, were simultaneously created for the right atrium and left atrium (LA) during AF. RESULTS: The DF in leads V8 and V9 correlated well with the DF in the LA floor (R=0.55, p<0.01; R=0.68, p<0.01, respectively), and that in V1 with the right inferior pulmonary vein (R=0.45, p=0.01). Persistent AF patients had a significantly lower DF in lead V9 (5.7±1.0Hz vs. 6.7±1.5Hz, p=0.02) than paroxysmal AF patients. CONCLUSIONS: A frequency analysis from lead V9 reflects the LA electrical activity.

Relation Between Left Atrial Wall Thickness in Patients with Atrial Fibrillation and Intracardiac Electrogram Characteristics and ATP-Provoked Dormant Pulmonary Vein Conduction.

INTRODUCTION: Atrial remodeling plays a key role in development of the substrate for atrial fibrillation (AF). Whether the wall thicknesses of the left atrium (LA) and pulmonary vein (PV)-LA junction affect remodeling and AF ablation is unknown. We investigated the relationship between wall thicknesses, electrogram characteristics, and adenosine triphosphate (ATP)-provoked dormant PV conduction as they pertain to AF. METHODS: In 50 patients with AF and 25 patients without AF, wall thicknesses of the LA and PV-LA junction were measured on 320-slice computed tomography images. For the AF patients, NavX-based voltage maps generated during sinus rhythm were obtained, and ATP-provoked dormant PV conduction after PV isolation was evaluated. RESULTS: Walls of the LA and PV-LA junction were significantly thicker in the AF patients than in the control patients (1.83 ± 0.29 mm vs. 1.59 ± 0.28 mm, respectively; P = 0.0010; and 0.88 ± 0.14 mm vs. 0.65 ± 0.11 mm, P<0.0001, respectively). Wall thickness at the PV-LA junction was independently associated with AF (ß = 0.40, P = 0.0002). In AF patients, the walls of the PV-LA junction showed stepwise thickening across bipolar voltages indicative of severe (bipolar voltage <33rd percentile) to moderate (33rd-66th percentiles) to mild fibrosis/scarring (≥66th percentile). Walls of the PV-LA junction with dormant PV conduction were significantly thicker than those without it (0.94 ± 0.19 mm vs. 0.86 ± 0.21 mm, respectively; P = 0.0025). CONCLUSIONS: Together, the association between thickened PV-LA junction walls and AF and the increased bipolar voltage suggests that such wall thickening increases PV electrical activities, leading to initiation and maintenance of AF and perhaps to ATP-provoked dormant PV conduction.

Epicardial adipose tissue-based defragmentation approach to persistent atrial fibrillation: its impact on complex fractionated electrograms and ablation outcome.

BACKGROUND: Increased epicardial adipose tissue (EAT) volume is associated with atrial fibrillation (AF). However, the efficacy of EAT-based left atrial (LA) ablation for persistent AF (PsAF) is unclear. OBJECTIVE: The purpose of this study was to assess whether EAT-based LA ablation is effective for PsAF. METHODS: In 60 PsAF patients (group I), 3-dimensional reconstructed computed tomography images depicting EAT were merged with NavX-based dominant-frequency (DF) and complex fractionated electrogram (CFE) maps obtained during AF. Pulmonary vein antrum isolation (PVAI) was followed by map-guided EAT-based ablation. Results were compared to those in a historical control group (group II, case-matched patients who underwent generalized stepwise ablation including linear plus CFE-targeted ablation). RESULTS: In 70% (n = 42) of group I patients, the LA-EAT was located at the pulmonary vein antra; anterior and inferior surfaces, roof, septum, and mitral annulus; and left atrial appendage. EAT was at or near (<3 mm) 71% (390/550) of high-DF (> -8 Hz) sites. In 41 patients with persistent AF despite EAT-targeted ablation, CFE burden decreased significantly (from 96% to 13%, P < .0001), and DF decreased within the coronary sinus (6.9 ± 0.7 Hz vs 5.9 ± 0.7 Hz, P < .0001). Radiofrequency energy duration was significantly less in group I than in group II (25 ± 6 minutes vs 31 ± 12 minutes, P < .05). During 16-month follow-up, freedom from AF on antiarrhythmic drugs was 78% vs 60% (P < .05). CONCLUSION: PVAI plus EAT-based ablation efficiently eliminates high-frequency sources and yields relatively high success. EAT-based LA ablation is a simple, clinically feasible PsAF ablation strategy.

Three-dimensional high-density bipolar contact mapping of left atrial endocardial activation during sinus rhythm in patients with atrial fibrillation.

Non-contact array mapping studies have demonstrated the existence of a line of conduction block along the septopulmonary bundle area and the posterior left atrial (LA) roof during sinus rhythm (SR). However, little is known of the global LA activation pattern during SR using a high-density contact bipolar mapping system. High-density contact bipolar isochronal mapping (bipolar mapping sites: 292 [IQR 250-348] points) of the LA was performed during SR with the NavX mapping system in 20 patients with paroxysmal atrial fibrillation (AF) and 11 patients with non-paroxysmal AF. The earliest endocardial breakthrough in the the LA from the right atrium (RA) during SR occurred in the anterosuperior LA (77%) or anterior to the right pulmonary veins (23%), and the breakthrough site did not differ between patients with paroxysmal and non-paroxysmal AF. Regardless of the site of breakthrough, the LA activation pattern was homogeneous, and no line of functional block was observed in any patient. Total LA activation time was significantly longer in non-paroxysmal AF patients than in paroxysmal AF patients (95.1 ± 4.3 ms versus 78.3 ± 3.2 ms, P = 0.0040). Contact-based bipolar LA endocardial activation mapping revealed a homogeneous LA activation pattern during SR, regardless of the between-group difference in activation time and the between-patient difference in sites of earliest LA endocardial breakthrough from the RA.

Effect of catheter tip-tissue surface contact on three-dimensional left atrial and pulmonary vein geometries: potential anatomic distortion of 3D ultrasound, fast anatomical mapping, and merged 3D CT-derived images.

UNLABELLED: Anatomic Distortion of 3D Mapping. BACKGROUND: Although catheter tip-tissue contact is known as a reliable basis for mapping and ablation of atrial fibrillation (AF), the effects of different mapping methods on 3-dimensional (3D) map configuration remain unknown. METHODS AND RESULTS: Twenty AF patients underwent Carto-based 3D ultrasound (US) evaluation. Left atrium (LA)/pulmonary vein (PV) geometry was constructed with the 3D US system. The resulting geometry was compared to geometries created with a fast electroanatomical mapping (FAM) algorithm and 3D US merged with computed tomography (merged 3D US-CT). The 3D US-derived LA volumes were smaller than the FAM- and merged 3D US-CT-derived volumes (75 ± 21 cm(3) vs 120 ± 20 cm(3) and 125 ± 25 cm(3) , P < 0.0001 for both). Differences in anatomic PV orifice fiducials between 3D US- and FAM- and merged 3D US-CT-derived geometries were 6.0 (interquartile range 0-9.3) mm and 4.1 (0-7.0) mm, respectively. Extensive encircling PV isolation guided by 3D US images with real-time 2D intracardiac echocardiography-based visualization of catheter tip-tissue contact generated ablation point (n = 983) drop-out at 1.9 ± 3.8 mm beyond the surface of the 3D US-derived LA/PV geometry. However, these same points were located 1.5 ± 5.4 and 0.4 ± 4.1 mm below the FAM- and merged 3D US-CT-derived surfaces. CONCLUSIONS: Different mapping methods yield different 3D geometries. When AF ablation is guided by 3D US-derived images, ablation points fall beyond the 3D US surface but below the FAM- or merged 3D US-CT-derived surface. Our data reveal anatomic distortion of 3D images, providing important information for improving the safety and efficacy of 3D mapping-guided AF ablation. (J Cardiovasc Electrophysiol, Vol. 24, pp. 259-266, March 2013).

Linear catheter ablation of the right atrium for rapid atrial pacing-induced sustained atrial fibrillation in dogs.

Catheter ablation of persistent/long-persistent atrial fibrillation (AF) has been shown to be less effective by pulmonary vein isolation (PVI) and additional left atrial (LA) complex fractionated atrial electrograms and long linear lesions are often required. Recent reports have demonstrated right atrial (RA) ablation increases the success rate of maintaining sinus rhythm in persistent/long-persistent AF. The aim of this study was to investigate whether effective RA linear lesions can terminate AF and render it noninducible in a canine model of rapid atrial pacing-induced sustained AF. Sustained AF was induced by rapid atrial pacing in 20 dogs. AF duration was 21-126 days (median, 50 days). Four RA linear lesions (superior vena cava-inferior vena cava, septal line, transverse line, and cavo-tricuspid line) were created with the use of 1 of 3 different ablation catheters (large-tip [8-mm tip], coil-tip, and cooled-tip catheters). AF was terminated with the large-tip catheter in 4/7 dogs (1 dog died of ventricular fibrillation [VF]), with the coil-tip catheter in 3/7 dogs (1 dog died of VF), and with the cooled-tip catheter in 1/6 dogs. In 6 dogs in which AF could not be terminated acutely by RA ablation, AF terminated spontaneously at 7-78 days (median, 14 days) after ablation. RA linear ablation terminated AF with limited success in our dog model of rapid atrial pacing-induced AF, but late AF termination was noted in the surviving dogs. Therefore, RA linear lesions in addition to the PVI and LA lesions may have additional effects on the catheter ablation for the persistent AF.

Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation?

BACKGROUND: Although increased epicardial adipose tissue (EAT) volume is known to be associated with increased prevalence of atrial fibrillation (AF), the exact mechanisms are unclear. Therefore, we investigated whether EAT locations were associated with high dominant frequency (DF) sites or complicated fractionated atrial electrogram sites during AF. METHODS AND RESULTS: Three-dimensional reconstruction computed tomography images depicting EAT volumes (obtained by 320-detector-row multislice computed tomography) were merged with NavX-based DF and complicated fractionated atrial electrogram maps obtained during AF for 16 patients with paroxysmal AF and for 18 patients with persistent AF. Agreement between locations of the EAT, especially EAT surrounding the left atrium, and of high DF or complicated fractionated atrial electrogram sites was quantified. In addition, serum biomarker levels were determined. EAT surrounding the left atrium volumes was significantly greater in patients with persistent AF than in patients with paroxysmal AF (52.9 cm(3) [95% CI, 44.2-61.5] versus 34.8 cm(3) [95% CI, 26.6-43.0]; P=0.007). Serum high-sensitivity C-reactive protein and interleukin-6 levels were significantly higher in persistent AF patients than in paroxysmal AF patients (median high-sensitivity C-reactive protein, 969 ng/mL [interquartile range, 307-1678] versus 320 ng/mL [interquartile range, 120-660]; P=0.008; median interleukin-6, 2.4 pg/mL [interquartile range, 1.7-3.2] versus 1.3 [interquartile range, 0.8-2.4] pg/mL; P=0.017). EAT locations were in excellent agreement with high DF sites (κ=0.77 [95% CI, 0.71-0.82]) but in poor agreement with complicated fractionated atrial electrogram sites (κ=0.22 [95% CI, 0.13-0.31]). CONCLUSIONS: Increased EAT volume and elevation of inflammatory biomarkers are noted in persistent AF rather than paroxysmal AF patients. High DF sites are located adjacent to EAT sites. Thus, EAT may be involved in the maintenance of AF.

Characteristics and distribution of complex fractionated atrial electrograms and the dominant frequency during atrial fibrillation: relationship to the response and outcome of circumferential pulmonary vein isolation.

BACKGROUND: Although sites of complex fractionated electrograms (CFAEs) and dominant frequency (DF) are known to be critical for the maintenance of atrial fibrillation (AF), spatial distribution of CFAEs and DF and their impact on the outcome of AF ablation remain unclear. METHODS: We created CFAE and DF maps of the left atrium (LA), right atrium, and pulmonary veins (PVs) with a NavX mapping system and simultaneously calculated the DF values with a Bard LabSystem Pro in 40 patients with AF (nonparoxysmal, n = 16). RESULTS: In 19 patients in whom circumferential PV isolation (CPVI) terminated AF, there was a high DF in the PVs (Bard-based DF value, 6.70 ± 1.01 Hz), low DF in the LA body (5.94 ± 0.75 Hz), and a significant PV-to-LA body DF gradient (0.76 ± 0.65 Hz), and the CFAEs were located mainly in the PV antrum. In the 21 patients not responding to CPVI, a high DF was located in both the PVs (7.04 ± 0.81 Hz) and LA body (6.75 ± 0.81 Hz), and therefore, the PV-to-LA body DF gradient was smaller than that in the CPVI responders (0.29 ± 0.52 Hz, P = 0.0160), and the CFAEs extended to the LA body. The higher DF in the LA body, nonparoxysmal AF, and longer AF duration remained as independent predictors of a post-ablation AF recurrence by using a multivariate analysis. CONCLUSIONS: A higher LA-DF value, smaller PV-to-LA DF gradient, and wider LA-CFAE distribution were noted more often in the nonresponders to CPVI than in the responders. This suggested the presence of an arrhythmogenic substrate in the LA beyond the PVs in patients whose AF persisted after CPVI, which was further associated with post-ablation AF recurrence.

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.

Clarifying the arrhythmogenic substrate for Brugada syndrome.

The right ventricular outflow tract (RVOT) is considered the arrhythmogenic region that gives rise to Brugada syndrome. To obtain a better understanding of this substrate, we performed electroanatomic mapping of the right ventricle (RV) in patients with Brugada syndrome. The RV was mapped electroanatomically with the CARTO system in 11 patients with asymptomatic Brugada syndrome but in whom ventricular fibrillation was induced by programmed ventricular stimulation, and in 5 control patients. The low voltage zone area (< 1.5 mV) was larger (16.1% versus 7.8%, P < 0.01) and the bipolar electrogram duration was greater (81.6 ± 7.8 ms versus 53.4 ± 5.6 ms, P < 0.01) in the patients with Brugada syndrome versus the control patients; the bipolar electrogram duration was greater in the septal portion and free wall of the RVOT. Our data suggest that regional endocardial conduction slowing based on structural abnormalities exists at the RVOT in Brugada syndrome.

Functional atrioventricular conduction block in an elderly patient with acquired long QT syndrome: elucidation of the mechanism of block.

The long QT syndrome (LQTS) is occasionally complicated by impaired atrioventricular (AV) conduction. This form of LQTS can manifest before birth or during neonatal life, and no previous report has demonstrated LQTS complicated by impaired AV conduction in elderly patient. This case report describes an elderly patient with an acquired form of LQTS who developed ventricular fibrillation that was successfully defibrillated during admission to the hospital. Electrophysiologic study demonstrated that HV interval was 38 milliseconds and QT interval was 635 milliseconds during sinus rhythm cycle length of 1167 milliseconds. 1:1 AV conduction was maintained to a pacing cycle length of 545 milliseconds with an AH interval of 144 milliseconds, HV interval of 44 milliseconds, and right ventricular monophasic action potential duration of 360 milliseconds. However, 2:1 HV block developed at a pacing cycle length of 500 milliseconds. Intravenous administration of mexiletine decreased the cycle length of developing HV block to 360 milliseconds.

Upper turnaround point of the reentry circuit of common atrial flutter--three-dimensional mapping and entrainment study.

BACKGROUND: Although the anterior and posterior boundaries of cavotricuspid isthmus-dependent atrial flutter (AFL) are reported to be located at the tricuspid annulus and sinus venosa region or crista terminalis, the exact upper turnaround point of the AFL circuit remains unclear. The aim of this study was to determine the upper turnaround site of the AFL circuit by means of three-dimensional (3D) mapping and entrainment pacing. METHODS: Subjects were 21 patients with counter-clockwise AFL in whom high-density mapping of the high right atrium (RA) and superior vena cava (SVC) orifice was performed with an electroanatomical or non-contact mapping system. Entrainment pacing was performed around the SVC-RA junction. RESULTS: In 20 of the 21 patients, the wavefront from the septal RA split into two wavefronts: one that traveled anterior to the SVC and another that traveled to the posterior RA where it was blocked. In the remaining patient, the wavefront from the septal RA split into two wavefronts: one that propagated through the anterior portion of the SVC orifice and another that propagated transversely across the posterior portion of the SVC orifice. The two wavefronts joined in the lateral RA. Entrainment pacing from the SVC-RA junction demonstrated that the anterior boundary was within the circuit in all patients, but the posterior boundary also constituted a circuit in four patients. CONCLUSIONS: We surmise that the upper turnaround site of the AFL circuit is located in the anterior portion of the SVC-RA junction in the majority of patients with AFL.

Electrical remodeling in fibrillating canine atrium: action potential alternans during rapid atrial pacing and late phase 3 early afterdepolarization after cessation of rapid atrial pacing.

Sustained atrial fibrillation (AF) was induced by atrial burst pacing, and monophasic action potentials (MAPs) were recorded. MAP alternans was observed at a cycle length (CL) of 167.5 ± 28.2 msec before burst pacing and 201.3 ± 40.2 msec after burst pacing. AF > 5 minutes duration was induced in 1 dog in the control condition but in all 8 dogs after burst pacing. The difference in RA MAPD(80) of the first spontaneous beat and steady-state sinus rhythm was significantly larger after atrial burst pacing than before atrial burst pacing (31.5 ± 15.9 msec versus 8.2 ± 9.0 msec) In 4 dogs, late phase 3 early after depolarization was observed after rapid atrial pacing. Rapid atrial pacing-induced electrical remodeling includes APD alternans during rapid atrial pacing and also causes an increase in the MAPD of the initial several beats and the development of late phase 3 early afterdepolarizations after a sudden increase in CL.

Surface ECG characteristics of ventricular tachyarrhythmias before degeneration into ventricular fibrillation in patients with Brugada-type ECG.

This study was designed to evaluate whether the right ventricular outflow tract (RVOT) is the arrhythmogenic focus in Brugada syndrome. We enrolled 45 patients with Brugada-type ECG who underwent programmed ventricular stimulation and inducible ventricular fibrillation (VF). In 25 of these 32 patients, repetitive VT was observed before degeneration into VF. The QRS morphology of surface ECG and intracardiac electrograms were evaluated to determine the origin of the ventricular tachycardia (VT) that degenerated into VF. The VT morphology was a left bundle branch block pattern with an inferior axis in 22 of 28 VTs and the intracardiac conduction sequence during VT revealed activation from the RVOT to the RV apex in these 22 VTs. The majority of the patients with Brugada syndrome showed repetitive VT originating from the RVOT that degenerated into VF. The RVOT may be an arrhythmogenic focus in patients with Brugada syndrome.

Novel SCN5A mutation (Q55X) associated with age-dependent expression of Brugada syndrome presenting as neurally mediated syncope.

BACKGROUND: An association between Brugada syndrome and neurally mediated syncope has been described. Although mutations in SCN5A have been identified in Brugada syndrome, the genetic link between Brugada syndrome and neurally mediated syncope has not been determined. OBJECTIVES: The purpose of the study was to clinically and genetically characterize a man with recurrent syncope that originally was diagnosed as neurally mediated syncope at age 8 years but subsequently manifested as Brugada syndrome at age 17 years. METHODS: The proband underwent clinical examination, which included head-up tilt test, sodium channel provocation test, and electrophysiologic study. Genetic screening of SCN5A was performed for the proband and his family members. The biophysical properties of a mutant SCN5A channel in a heterologous expression system were studied using whole-cell, patch clamp technique. RESULTS: The proband showed positive head-up tilt test, coved-type ST elevation recorded from the third intercostal space, and positive pilsicainide provocation test. Ventricular fibrillation was inducible at programmed electrical stimulation, consistent with characteristics of both Brugada syndrome and neurally mediated syncope. A novel nonsense SCN5A mutation (Q55X) was identified in the proband, his mother, and his asymptomatic brother. The heterologously expressed mutant channel was nonfunctional. CONCLUSION: We genetically determined an SCN5A mutation in a patient showing the combined phenotype of neurally mediated syncope and Brugada syndrome. Neurally mediated syncope and Brugada syndrome may share, at least in part, a common pathophysiologic mechanism.

Atrial electrophysiological abnormality in patients with Brugada syndrome assessed by P-wave signal-averaged ECG and programmed atrial stimulation.

BACKGROUND: There is evidence that some patients with Brugada syndrome (BS) exhibit atrial tachyarrhythmias including paroxysmal atrial fibrillation. We investigated whether BS associated not only with vulnerability to ventricular fibrillation, but also with vulnerability to atrial fibrillation. METHODS AND RESULTS: In 15 patients with BS and Brugada-type electrocardiogram (ECG) (14 men, 1 woman; age 52.8+/-12.9 years) and 15 age-matched control patients (12 men, 3 women; age 50.9+/-18.9 years), the P-wave signal-averaged ECG was recorded, and the filtered P-wave duration was derived from the vector magnitude obtained by X, Y, Z leads. In 11 of the 15 patients with BS and Brugada-type ECG, invasive electrophysiologic testing was conducted. Filtered P-wave duration was significantly increased in patients with BS and Brugada-type ECG in comparison with control subjects (143.2+/-12.9 vs 129.6+/-10.1 ms, p<0.001). Ventricular late potential (root mean square voltage <20 muV in the last 40 ms and <40 muV at a low amplitude signal duration >38 ms) was present in 10 of the 12 BS patients in whom a QRS wave signal-averaged electrogram was also recorded. In all 11 patients with Brugada-type ECG who underwent electrophysiologic testing, sustained atrial fibrillation (>5 min) was induced by 1 or 2 atrial extrastimuli. In 10 of these 11 patients, ventricular fibrillation was also induced by 2 or 3 right ventricular extrastimuli. CONCLUSIONS: The electrical abnormality in BS is not limited to the ventricular level; similar changes occur in the atria. Such abnormal conduction properties could be a substrate for re-entrant atrial tachyarrhythmias.

Idiopathic left ventricular tachycardia with a change from left to right axis deviation during radiofrequency catheter ablation.

A 62 year-old-woman presented with a right bundle branch block (RBBB) and left axis deviation (LAD) tachycardia. Radiofrequency (RF) energy was delivered to the left posterior fascicle (LPF) where 2 presystolic Purkinje potentials (P1 and P2) preceding onset of the QRS complex were recorded. During RF energy applications, the QRS morphology of the tachycardia changed from RBBB and LAD to RBBB and right axis deviation without termination of the tachycardia. The Purkinje potential was observed following the QRS complex during the tachycardia because of conduction block of the LPF distal to the reentry circuit due to RF catheter ablation.

Usefulness of the polarity in high-density wide range-filtered bipolar mapping to detect isthmus block during radiofrequency ablation of typical atrial flutter.

BACKGROUND: The atrial activation sequence around the tricuspid annulus (TA) cannot always be used to establish whether complete block has been achieved across the cavotricuspid isthmus (CTI) during radiofrequency ablation (RFCA) for typical counterclockwise atrial flutter (CCW-AFL). AIM: We examined whether a change in the polarity of the atrial high-density wide range-filtered bipolar electrograms recorded near the ablation line is an accurate indicator of complete CTI block. METHODS: Nineteen patients with CCW-AFL underwent RFCA. Electrograms were recorded around the TA with duodecapolar conventional (2mm x 8mm x 2mm spacing) and high-density (2-mm spacing) Halo catheters. The bipolar electrograms on the high-density Halo catheter recorded from a series of adjacent electrode pairs positioned just lateral to the ablation line were filtered at a bandpass setting of 0.05-500 Hz. The activation sequence on the conventional Halo catheter during coronary sinus pacing (CSp) and inferolateral TA pacing, and the bipolar electrograms on the high-density Halo catheter during CSp were determined before and after RFCA. The final complete CTI block was verified by the presence of widely split double electrograms > or =100 msec along the ablation line. RESULTS: The final complete CTI block was achieved in all the 19 patients. Before RFCA, the polarity of bipolar electrograms was predominantly negative during CCW-AFL and positive during CSp. In 18 of the 19 patients, the bipolar electrograms exhibited the CCW activation and a negative polarity during CSp only after complete CTI block. In one of those 18 patients, additional applications of RFCA changed the polarity of bipolar electrograms positive to negative although the conventional Halo electrogram activation sequence suggested complete CTI block during CSp. In seven patients, who had transverse conduction across the crista terminalis during CSp, the conventional Halo electrogram activation sequence suggested an incomplete CTI block. However, in six of those seven patients, the CCW activation had a predominantly negative polarity of the bipolar electrograms. In one of those seven patients, complete CTI block was unable to be detected even using the high-density Halo catheter. CONCLUSIONS: These data demonstrate that the high-density wide range-filtered mapping can identify the CTI block in undetectable cases of complete CTI block or incomplete CTI block by the conventional method. The polarity of the bipolar electrograms recorded just lateral to the ablation line during CSp after RFCA of AFL may be used as a simple and an accurate indicator of complete CTI block.