bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Biatrial Computerized Mapping During Permanent Atrial Fibrillation in Patients with Organic Heart Disease
Authors: WU TSU‐JUEY , DOSHI RAHUL N. , HUANG HSUN‐LUN A. , BLANCHE CARLOS , KASS ROBERT M. , TRENTO ALFREDO , CHENG WEN , KARAGUEUZIAN HRAYR S. , PETER C. THOMAS , CHEN PENG‐SHENG
Published: August 2003

Activations in Permanent Atrial Fibrillation.
Introduction: Activation patterns during permanent atrial fibrillation (AF) in patients with organic heart diseases are unclear.

Methods and Results: We studied six patients with permanent AF and organic heart diseases undergoing surgery. The duration of AF averaged 4.9 ± 7.6 years. Computerized epicardial mappings of the right atrial (RA) free wall and the left atrial (LA) posterior wall were simultaneously performed with 224 bipolar electrodes at 3‐mm spatial resolution. In the RA, large wavefronts and conduction blocks were frequently observed. The lines of block correlated with the crista terminalis and large pectinate muscles. In contrast, the LA had rapid repetitive activities originated from corners of the electrode plaque, near the four pulmonary veins (PVs). On average, 2.8 ± 1.2 sites of rapid repetitive activities were identified per patient. They activated continuously, intermittently, or alternately during AF. The mean activation cycle length in the RA (196 ± 22 msec) was significantly longer than that in the LA (179 ± 26 msec; P = 0.004). The maximum dominant frequency in the LA was higher than that in the RA (6.41 ± 1.18 Hz vs 5.66 ± 0.55 Hz; P = 0.049). The maximum dominant frequency was consistently located in areas with rapid repetitive activations near the PVs.

Conclusion: During human permanent AF associated with organic heart diseases, the activation cycle length was shorter in the LA posterior wall than in the RA free wall. Rapid repetitive activities are consistently observed in the LA posterior wall, at or near the PVs.
Survival of Antiarrhythmic or Implantable Cardioverter Defibrillator Treated Patients with Varying Degrees of Left Ventricular Dysfunction Who Survived Malignant Ventricular Arrhythmias
Authors: DOMANSKI MICHAEL J. , EPSTEIN ANDREW , HALLSTROM AL , SAKSENA SANJEEV , ZIPES DOUGLAS P.
Published: August 2003

Survival with ICD or Antiarrhythmic Therapy.
Introduction: The relative effectiveness of the implantable cardioverter defibrillator (ICD) and antiarrhythmic drugs (AADs) varies with left ventricular ejection fraction (LVEF). However, once an ICD or AAD treatment strategy is chosen, the degree to which the LVEF influences survival is unknown. This article addresses that question.

Methods and Results: Using patient data from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, the impact of LVEF on prognosis of patients who were treated with either an ICD or AAD was assessed. Survival within each quintile of LVEF was estimated by the method of Kaplan‐Meier for patients treated with either the ICD or AADs. The Cox proportional hazards model was used to investigate the prognostic value of LVEF for estimating survival after adjustment for other baseline covariates among all patients in the subgroups treated by ICD or AAD. In the highest two quintiles of LVEF, survival was comparable in AAD‐treated and ICD‐treated patients. In the AAD‐treated patients, higher LVEF was significantly and independently associated with survival free of all‐cause mortality and arrhythmic death. In the ICD‐treated patients, however, the statistical significance of the association was lost and only a trend toward greater survival was present. Death due to congestive heart failure remained independently and significantly associated with survival in both AAD‐treated and ICD‐treated patients.

Conclusion: In patients treated with AADs but not patients treated with ICDs, survival is strongly associated with LVEF. The absence of a statistically significant association in the ICD patients is likely related to the effectiveness of the ICD in treating malignant ventricular arrhythmias, but a chance lack of association cannot be excluded.
Arrhythmogenesis of T Wave Alternans Associated with Surface QRS Complex Alternans and the Role of Ventricular Prematurity: Observations from a Canine Model of LQT3 Syndrome
Authors: CHINUSHI MASAOMI , HOSAKA YUKIO , WASHIZUKA TAKASHI , FURUSHIMA HIROSHI , AIZAWA YOSHIFUSA
Published: August 2003

Intramural TWA and Its Arrhythmogenesis.
Introduction: T wave alternans (TWA) is characterized by cycle‐to‐cycle changes in the QT interval and/or T wave morphology. It is believed to amplify the underlying dispersion of ventricular repolarization. The aim of this study was to examine the mechanisms and arrhythmogenesis of TWA accompanied by QRS complex and/or blood pressure (BP) waveform alternans, using transmural ventricular electrogram recordings in an anthopleurin‐A model of long QT syndrome.

Methods and Results: The cardiac cycle length was gradually shortened by interruption of vagal stimulation, and TWA was induced in six canine hearts. Transmural unipolar electrograms were recorded with plunge needle electrodes from endocardial (Endo), mid‐myocardial (Mid), and epicardial (Epi) sites, along with the surface ECG and BP. The activation‐recovery interval (ARI) was measured to estimate local refractoriness. During TWA, ARI alternans was greater at the Mid than the Epi/Endo sites, and it was associated with the development of marked spatial dispersion of ventricular repolarization. As TWA increased, ventricular activation of the cycles associated with shorter QT intervals displayed delayed conduction at the Mid sites as a result of a critically longer ARI of the preceding cycle and longer QT interval, while normal conduction was preserved at the Epi site. Delayed conduction at the Mid sites manifested as surface ECG QRS and BP waveform alternans, and spontaneous ventricular tachyarrhythmias developed in absence of ventricular prematurity. In other instances, in absence of delayed conduction during TWA, ventricular premature complexes infringed on a prominent spatial dispersion of ventricular repolarization of cycles with long QT intervals and initiated ventricular tachyarrhythmia.

Conclusion: TWA accompanied by QRS alternans may signal a greater ventricular electrical instability, since it is associated with intramural delayed conduction, which can initiate ventricular tachyarrhythmia without ventricular premature complexes.
Ectopic Tachycardia Originating from the Superior Vena Cava
Authors: DONG JUN , SCHREIECK JÜRGEN , NDREPEPA GJIN , SCHMITT CLAUS
Published: August 2003

Ectopic Tachycardia from the SVC. We report a 65‐year‐old female patient with a 3‐year history of symptomatic paroxysmal supraventricular tachycardia. Electroanatomic and basket catheter mapping revealed a focal tachycardia originating in the superior vena cava (SVC), 5 cm above the SVC‐right atrium (SVC‐RA) junction. An area of fractionated potentials and slow conduction was found on the anterior wall of the SVC. A line of conduction block extending downwardly and obliquely from the anteroseptal aspect to anterolateral aspect of the SVC forcing the impulse to enter the RA via the posterior aspect of SVC‐RA junction was observed. Entrainment attempts from multiple sites within the SVC failed to demonstrate reentry as a mechanism of arrhythmia. The ablation approach consisted of isolation of the arrhythmogenic area from the rest of the SVC.
T Wave Alternans Threshold Late After Repair of Tetralogy of Fallot
Authors: CHEUNG MICHAEL M.H. , WEINTRAUB ROBERT G. , COHEN RICHARD J. , KARL TOM R. , WILKINSON JAMES L. , DAVIS ANDREW M.
Published: August 2003

TWA Threshold After TOF Repair.
Introduction: Sustained microvolt‐level T wave alternans (TWA) is a marker of increased risk for malignant ventricular arrhythmia. There is a significant risk of arrhythmia and sudden death after repair of congenital heart disease. The aim of this study was to determine the prevalence and characteristics of TWA after repair of tetralogy of Fallot (TOF).

Methods and Results: TWA was evaluated during bicycle exercise in 49 subjects who had consecutively undergone transatrial‐transpulmonary repair. Median values for age, age at repair, and follow‐up duration were 14.9 years (11.5–20.8), 1.6 years (0.2–4.9), and 11.6 years (9.4–17.2), respectively. All patients were in New York Heart Association functional class I and were asymptomatic. Median QRS duration was 120 msec (80–150). Sustained TWA was detected in 7 (23%) of 31 subjects with adequate tests. In these 7 subjects, median onset heart rate (HR) was 120 (98–155). Median HR threshold as a percentage of predicted maximum HR (220 – age) was 58%(48–77). Sustained TWA prevalence was not significantly different compared with normal subjects (7/31 vs 9/83; P = 0.1). Onset HR in the TOF group was significantly lower [mean (SD) of 122 (20) vs 139 (12), P < 0.05]. In the TOF group with sustained TWA, the TWA occurred in 4 of 7 at < 60% predicted maximum HR versus 1 of 9 normal subjects (P < 0.05); 3 of 7 had onset HR < 120 versus 0 of 9 normal subjects (P < 0.03). There was no significant difference in age, gender, transannular patch use, restrictive right ventricular physiology, QRS duration, QTc, QT/QRS dispersion, or nonsustained ventricular tachycardia in subjects with or those without sustained TWA.

Conclusion: The onset HR for sustained TWA is significantly lower after repair of TOF. Further study is required to determine whether this represents an increased risk for arrhythmia in this patient group.
Nonexcitatory Stimulus Delivery Improves Left Ventricular Function in Hearts with Left Bundle Branch Block
Authors: MARROUCHE NASSIR F. , PAVIA STEPHEN V. , ZHUANG SHAOWEI , KIM YUNG‐JIN , TABATA TOMOTSUGU , WALLICK DON , SAAD EDUARDO , ABDUL‐KARIM AHMAD , SCHWEIKERT ROBERT , SALIBA WALID , TCHOU PATRICK , NATALE ANDREA
Published: August 2003

Nonexcitatory Stimulation.
Introduction: Preliminary data in a heart failure animal model and isolated muscle preparation have suggested that nonexcitatory stimulation (NES) improves left ventricular (LV) function.

Methods and Results: We compared biventricular (BV) pacing with NES in an animal model with left bundle branch block (LBBB). The left bundle branch (LBB) was ablated in eight normal heart pigs and led to > 50% increase in QRS duration (mean 100 ± 15 msec). End‐diastolic LV pressure, end‐systolic LV pressure, LV pressure (LV dP/dtmax), aortic pulse pressure, and LV ejection fraction were measured before pre‐LBB ablation and compared with post‐LBB ablation (AAI pacing), BV pacing, NES delivery, and BV + NES. Moreover, to evaluate LV diastolic function, we measured the early (E wave) and late flows (A wave) through the mitral valve using spectral Doppler. Compared with post‐LBB ablation, NES led to a significant increase in LV dP/dtmax (1,047 ± 224 mmHg/sec vs 897 ± 116 mmHg/sec; P < 0.05), LV ejection fraction (64% ± 18% vs 49% ± 17%; P < 0.05), and aortic pulse pressure (18 ± 3.6 mmHg vs 16 ± 2.8 mmHg; P < 0.05). Moreover, improvement in LV hemodynamic parameters was significantly higher during NES delivery when compared with BV pacing. No significant changes in E wave, A wave, and E/A were recorded during NES, NES + BV, and BV pacing.

Conclusion: Our preliminary data demonstrate that NES is superior to BV pacing in improving LV function in an animal model with LBBB. Moreover, we demonstrated that NES does not affect transmitral valve flow and subsequently LV diastolic function.
Scientific Gaps in the Prediction and Prevention of Sudden Cardiac Death
Authors: MYERBURG ROBERT J.
Published: August 2003

Sudden Cardiac Death. The population impact of sudden death remains an unresolved problem despite growing insights into pathophysiologic mechanisms and therapeutic approaches. To make further progress, basic scientists, clinical investigators, and epidemiologists must merge their efforts to achieve better predictive strategies. Better understanding of basic physiologic mechanisms and integration of multiple points of attack in the cascade of coronary atherosclerosis are required. Identification of genetic markers of risk at all levels of the cascade offer one avenue for improving risk predictions. The epidemiologic strategies must go beyond multivariate analysis to the level complex systems analysis of the multiple components of the cascade. Targets for such approaches are discussed.
Identification and Characterization of Atrioventricular Parasympathetic Innervation in Humans
Authors: QUAN KARA J. , LEE JAI H. , VAN HARE GEORGE F. , BIBLO LEE A. , MACKALL JUDITH A. , CARLSON MARK D.
Published: August 2003

AV Parasympathetic Innervation.
Introduction: We hypothesized that in humans there is an epicardial fat pad from which parasympathetic ganglia supply the AV node. We also hypothesized that the parasympathetic nerves innervating the AV node also innervate the right atrium, and the greatest density of innervation is near the AV nodal fat pad.

Methods and Results: An epicardial fat pad near the junction of the left atrium and right inferior pulmonary vein was identified during cardiac surgery in seven patients. A ring electrode was used to stimulate this fat pad intraoperatively during sinus rhythm to produce transient complete heart block. Subsequently, temporary epicardial wire electrodes were sutured in pairs on this epicardial fat pad, the high right atrium, and the right ventricle by direct visualization during coronary artery bypass surgery in seven patients. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1‐cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness at each catheter site was determined in the presence and absence of parasympathetic nerve stimulation (via the epicardial wires). In all seven patients, an AV nodal fat pad was identified. Fat pad stimulation during and after surgery caused complete heart block but no change in sinus rate. Fat pad stimulation decreased the right atrial effective refractory period at 1 cm (280 ± 42 msec to 242 ± 39 msec) and 2 cm (235 ± 21 msec to 201 ± 11 msec) from the fat pad (P = 0.04, compared with baseline). No significant change in atrial refractoriness occurred at distances > 2 cm. The response to stimulation decreased as the distance from the fat pad increased.

Conclusion: For the first time in humans, an epicardial fat pad was identified from which parasympathetic nerve fibers selectively innervate the AV node but not the sinoatrial node. Nerves in this fat pad also innervate the surrounding right atrium.
Characteristics of Right Atrial Activation During Coronary Sinus Pacing
Authors: BETTS TIM R. , HO SIEW YEN , SANCHEZ‐QUINTANA DAMIAN , ROBERTS PAUL R. , ANDERSON ROBERT H. , MORGAN JOHN M.
Published: August 2003

Activation Patterns and Coronary Sinus Pacing.
Introduction: Anatomic and electrical connections between the left atrium and right atrium (RA) have been described. The relationship between coronary sinus (CS) pacing site and RA activation has not been examined.

Methods and Results: Fifteen anesthetized swine underwent high‐density noncontact mapping of the RA during pacing from up to five different sites within the CS. Isopotential mapping identified the site of earliest RA depolarization and the pattern of subsequent activation. Hearts were excised and endocardial dissection performed. Earliest RA activation occurred at the CS os with proximal CS pacing sites and at Bachmann's bundle at distal pacing sites. The mean depth at which a shift in earliest RA activation site occurred was 46 ± 13 mm (range 21 to 63 mm). RA activation times following earliest activation at the CS and Bachmann's bundle were 40 ± 4 msec and 51 ± 6 msec (P < 0.002). Conduction delay or block was recorded at the lateral cavotricuspid isthmus, terminal crest, and tendon of Todaro. Latest RA activation always occurred in the high anterolateral atrium after ascending the anterolateral wall. The lateral RA was activated by the wavefront that traversed the posterior wall rather than by the wavefront crossing the cavotricuspid isthmus, even with earliest RA activation at the CS os.

Conclusion: The site of earliest RA activation during CS pacing is dependent upon the pacing depth within the CS. In the porcine heart, areas of conduction delay influence RA activation patterns and timings. These findings may have implications for patients undergoing assessment of radiofrequency ablation of atrial flutter.
Spontaneous T Wave Alternans and Premature Ventricular Contractions During Febrile Illness in a Patient with Brugada Syndrome
Authors: MORITA HIROSHI , NAGASE SATOSHI , KUSANO KENGO , OHE TOHRU
Published: August 2003

T Wave Alternans in the Brugada Syndrome. A 69‐year‐old man who had experienced syncope and ventricular fibrillation was referred to our hospital. ECG showed a right bundle branch block pattern with ST segment elevation in the right precordial leads. When the patient presented to the hospital with febrile illness, spontaneous T wave alternans and premature ventricular contractions were observed. When the patient became afebrile, ST segment elevation improved, and T wave alternans and premature ventricular contractions disappeared.
Endocardial Mapping of Electrophysiologically Abnormal Substrates and Cardiac Arrhythmias Using a Noncontact Nonexpandable Catheter
Authors: JIA PING , PUNSKE BONNIE , TACCARDI BRUNO , RUDY YORAM
Published: August 2003

Noncontact Mapping of Arrhythmogenic Substrates.
Introduction: In previous studies, we established methodology for reconstructing endocardial potential maps, electrograms, and isochrones from a noncontact intracavitary catheter during a single beat. Recently, we evaluated this approach using a 9‐French (3‐mm) spiral catheter in a normal heart preparation. Here we extend the approach to hearts with structural disease and examine its ability to detect and characterize abnormal electrophysiologic (EP) substrates and to map ventricular arrhythmias on a beat‐by‐beat basis.

Methods and Results: Reconstruction of endocardial potentials from cavity potentials measured with 82 electrodes mounted on a 9‐French spiral catheter was performed in an isolated canine left ventricle (LV). Endocardial potentials were recorded with 91 intramural needles, providing a gold standard for evaluating the noncontact reconstruction. Studies were performed in a normal LV (control) and the same LV 3 hours after left anterior descending coronary artery occlusion and ethanol injection to create an infarct. Abnormal EP characteristics over the infarct were faithfully reconstructed, including (1) low potentials and electrogram derivatives; (2) fractionated electrograms; (3) small deflections on electrograms reflecting local activation; and (4) slow discontinuous conduction transverse to fibers. During arrhythmia, beat‐to‐beat dynamic shifts of initiation site and activation pattern were captured by the reconstruction.

Conclusion: Noncontact, nonexpendable catheter mapping can locate and characterize abnormal EP substrates and can capture the endocardial sequence of an arrhythmia during a single beat.
T Wave Alternans and Torsades de Pointes After the Use of Intravenous Pentamidine
Authors: KROLL CHRISTOPHER R. , GETTES LEONARD S.
Published: August 2003

T Wave Alternans and Pentamidine. We report the case of a patient in whom dramatic T wave alternans with brief bouts of torsades de pointes and QT prolongation occurred in association with intravenously administered pentamidine. This ECG marker of a potentially fatal side effect, although uncommon, should be looked for in patients requiring the use of this drug.
Sudden Death Caused by Cardiac Sarcoidosis in Childhood
Authors: DUKE CHRISTOPHER , ROSENTHAL ERIC
Published: August 2003

Cardiac Sarcoidosis and Sudden Death. This report describes an adolescent who presented with ventricular tachycardia (VT) originating from the right ventricular apex, with no apparent underlying cause. Cardiac sarcoidosis was identified only at postmortem examination after sudden death. There must be a high index of suspicion for subtle forms of primary myocardial abnormalities in such cases. Investigation for VT should include specific investigations for cardiac sarcoidosis when no other pathology has been identified and there are persistent conduction abnormalities on resting ECG.
Effect of Action Potential Duration and Conduction Velocity Restitution and Their Spatial Dispersion on Alternans and the Stability of Arrhythmias
Authors: BANVILLE ISABELLE , GRAY RICHARD A.
Published: August 2003

Restitution and Spatial Heterogeneities vs Arrhythmias.
Introduction: The slope of the action potential duration (APD) restitution curve has been used to explain wavebreaks during arrhythmia initiation and maintenance. This hypothesis remains incomplete to fully describe the experimental data. Other factors contributing to wavebreaks must be studied to further understand arrhythmia dynamics.

Methods and Results: Control APDs were measured from isolated rabbit hearts using a monophasic action potential probe. APD and conduction velocity (CV) restitution were quantified over the heart surface for two drugs, diacetyl monoxime (DAM) and cytochalasin D (CytoD), using a dual camera video imaging system. For all pacing intervals: (1) control APDs were shorter than for CytoD but longer than for DAM; and (2) CV was greater for CytoD compared with DAM. APD dispersion increased as pacing interval decreased for both drugs. For DAM, increased dispersion was due to a difference in APD restitution between the right and left ventricle. For CytoD, increased dispersion was due to discordant alternans, with no significant spatial variation in restitution. Fibrillation was sustained only in the control hearts; with DAM, stable reentry was sustained with shorter APD and cycle length compared with CytoD for which only nonsustained unstable reentry occurred.

Conclusion: Alternans and arrhythmia dynamics are affected by the spatial dispersion of APD restitution as well as CV restitution, not simply the slope of APD restitution. Therefore, a direct link of the APD restitution slope to alternans and arrhythmia dynamics in rabbit heart does not exist. Designing antiarrhythmic drugs to alter only the restitution slope may not be appropriate.
Ablation of Epicardial Macroreentrant Ventricular Tachycardia Associated with Idiopathic Nonischemic Dilated Cardiomyopathy by a Percutaneous Transthoracic Approach
Authors: SWARUP VIJENDRA , MORTON JOSEPH B. , ARRUDA MAURICIO , WILBER DAVID J.
Published: August 2003

Ablation of Epicardial Macroreentry. Characterization of the substrate and mechanism of epicardial ventricular tachycardia (VT) associated with idiopathic nonischemic dilated cardiomyopathy is limited. We report a case of successful mapping and ablation of an epicardial VT by a percutaneous transthoracic approach in a patient with idiopathic dilated cardiomyopathy, frequent VT, and previously unsuccessful endocardial ablation. Evidence of myocardial scar was limited to the epicardium. Electroanatomic and entrainment mapping defined a figure‐of‐eight macroreentrant circuit within the epicardial scar. VT terminated at the onset of low‐power radiofrequency application to the central isthmus of the circuit. VT was no longer induced and did not recur during long‐term follow‐up.
Noninvasive Assessment of Cardiac Resynchronization Therapy for Congestive Heart Failure Using Myocardial Strain and Left Ventricular Peak Power as Parameters of Myocardial Synchrony and Function
Authors: POPOVIĆ ZORAN B. , GRIMM RICHARD A. , PERLIC GEORGE , CHINCHOY EDWARD , GERACI MARIA , SUN JING PING , DONAL ERWAN , XU XIAO‐FANG , GREENBERG NEIL L. , WILKOFF BRUCE L. , THOMAS JAMES D.
Published: August 2003

Resynchronization Therapy for Heart Failure.
Introduction: Although invasive studies have shown that cardiac resynchronization therapy by biventricular pacing improves left ventricular (LV) function in selected heart failure patients, it is impractical to apply such techniques in the clinical setting. The aim of this study was to assess the acute effects of cardiac resynchronization therapy by noninvasive techniques.

Methods and Results: Twenty‐two patients enrolled in the InSync trial (age 64 ± 9 years, 18 men and 4 women; all with ejection fraction <35% and QRS >130 msec) were studied 1 to 12 months after pacemaker implantation during pacing, and while ventricular pacing was inhibited. Regional myocardial strains of the interventricular septum, LV free wall, and right ventricular free wall were derived from color Doppler tissue echocardiography. Peak power index was calculated as a product of simultaneously recorded noninvasive blood pressure and pulse‐wave (PW) Doppler velocity of the LV outflow tract. The Z ratio (sum of LV ejection and filling times divided by RR interval) and tei index were calculated from PW Doppler data. During pacing, overall regional strain improved (P = 0.01), while the LV strain coefficient of variation decreased from 2.7 ± 2.4 to 1.3 ± 0.7 (P = 0.009). Additionally, peak power index improved from 84 ± 24 to 94 ± 27 cm· mmHg/sec (P = 0.004). The Z ratio increased from 0.71 ± 0.08 to 0.78 ± 0.07 (P = 0.0005), while the tei index decreased from 0.86 ± 0.33 to 0.59 ± 0.16 (P = 0.0002).

Conclusion: Using novel noninvasive indices, we demonstrated that cardiac resynchronization therapy improves LV performance.
Accessory Pathway Localization by QRS Polarity in Children with Wolff‐Parkinson‐White Syndrome
Authors: BOERSMA LUCAS , GARCÍA‐MORAN EMILIO , MONT LLUÍS , BRUGADA JOSEP
Published: August 2003

AP Localization by QRS Polarity in Children.
Introductions: Location of the accessory pathway (AP) in Wolff‐Parkinson‐White (WPW) syndrome can be determined accurately by the QRS polarity on resting ECG. These ECG characteristics may be different in children, and no algorithm has yet been tested.

Methods and Results: A total of 153 resting ECGs of symptomatic children with WPW syndrome were retrospectively analyzed. The anatomic AP location had been established fluoroscopically at eight possible sites during radiofrequency catheter ablation. Two independent observers predicted AP location on blinded ECGs with a QRS polarity algorithm for adults using leads II, III, aVL, V1, and V2. Subsequently, the QRS polarity for all individual ECG leads was evaluated and a new algorithm for children was devised. With the adult algorithm, the observers correctly predicted only 55% to 58% of AP locations. The septal and right‐sided pathways often were inseparable, and mid‐septal and parahisian pathways were missed. In the new children's algorithm, left lateral, left posteroseptal, and posteroseptal pathways shared a positive or intermediate QRS polarity on V1, with the left lateral pathway separated by a positive QRS polarity on lead III. Negative QRS polarity on lead V1 and positive QRS polarity on lead V3 were shared by right posteroseptal, mid‐septal, parahisian, and anteroseptal pathways, with the latter two having a positive QRS polarity on lead aVF. Right lateral pathways had negative QRS polarity on lead V1 and negative or intermediate QRS polarity on lead V3. Overall accuracy for these five regions was 90%.

Conclusion: AP characterization by QRS polarity in children with WPW syndrome is more diverse than in adults and requires other ECG leads to establish five AP regions.
Microelectrode Study of the Genesis of the Monophasic Action Potential by Contact Electrode Technique
Authors: KNOLLMANN BJÖRN C. , TRANQUILLO JOSEPH , SIRENKO SYEVDA G. , HENRIQUEZ CRAIG , FRANZ MICHAEL R.
Published: August 2003

Monophasic Action Potential Genesis.
Introduction: Despite widespread use of the contact electrode for recording monophasic action potentials (MAPs) in both clinical and experimental research, the mechanism underlying the genesis of the contact MAP remains unproven. The “Franz hypothesis” assumes that the MAP is driven by a current source originating at the boundary between cells depolarized by the MAP electrode pressure and normal cells immediately adjacent to it. To date, no direct experimental data exist to support this hypothesis.

Methods and Results: In 10 Langendorff‐perfused mouse hearts, a miniaturized MAP probe was inserted into the right ventricle (RV) and gently pressed against the endocardium of the upward‐facing RV free wall. During stable contact and stable MAP recording, KCl‐filled glass microelectrodes were lowered from above the RV to record transmembrane action potentials (TAPs) at the center of and 0.05 and 0.2 mm outside the perimeter of the MAP electrode contact site. TAPs at the center had normal resting potentials (RP) in epicardial layers (−78 ± 4 mV) but showed gradual decrease toward deeper layers, reaching a minimum RP of −23 ± 0.8 mV directly above the MAP electrode surface. RPs at 0.05 mm outside the MAP perimeter were normal at the epicardial surface and with increasing transmural depth showed significantly less decrease than central recordings (min RP −41 ± 0.8 mV, n = 11, P < 0.00001). TAPs at 0.2 mm from the MAP electrode perimeter had normal RPs across the entire RV wall.

Conclusion: These direct data are the first to support the hypothesis that the MAP is generated locally through pressure depolarization of a circumscript volume of cells that (1) has sharp voltage gradients toward normal cells, (2) provides a strong local current source, and (3) when simulated with a circuit model creates the field potential recorded by the contact MAP electrode.
Is There an Optimal Pacing Site to Prevent Atrial Fibrillation?: An Experimental Study in the Chronically Instrumented Goat
Authors: DUYTSCHAEVER MATTIAS , DANSE PETER , EYSBOUTS SABINE , ALLESSIE MAURITS
Published: August 2003

Preventive Atrial Pacing in AF.
Introduction: Atrial pacing can reduce the number of recurrences of atrial fibrillation (AF). It is unclear the extent to which this effect is determined by the site(s) of pacing.

Methods and Results: In six electrically remodeled goats (24‐hour AF), the window of inducibility of AF was determined by applying premature stimuli (S1‐S2) at the right (RA) or left (LA) atrium (baseline values). Determination of the window of inducibility of AF at RA and LA was repeated during preventive pacing at four sites: RA, LA, Bachmann's bundle (BB), and RA + LA (biatrial). Mapping was used to elucidate the mechanisms of prevention of AF. At baseline, the window of inducibility of AF was 49 ± 9 msec at RA and 45 ± 17 msec at LA. Initiation of AF was associated with conduction block of the premature beat at BB. Preventive pacing at BB markedly shortened the window of inducibility of AF at RA (25 ± 11 msec) and LA (17 ± 8 msec, P < 0.01). Pacing at RA only shortened the window of inducibility of AF at LA (23 ± 9 msec, P < 0.01), whereas pacing at LA only shortened the window of inducibility of AF at RA (23 ± 11 msec, P < 0.01). Biatrial pacing failed to shorten the window of inducibility of AF both at RA and LA. Prevention of AF by pacing was due to prolongation of the premature interval at BB.

Conclusion: In the caprine model of AF, BB is a critical area of conduction of premature beats and initiation of AF. Pacing at BB can prevent but not completely abolish the initiation of AF by single premature beats (shortening of the window of inducibility). Prevention of AF by pacing is based on prolongation of the premature interval at BB, thus preventing conduction block and reentry. In general, the optimal site for preventive pacing is close to the area of block and remote from the origin of premature beats.
Partial Vagal Denervation Increases Vulnerability to Vagally Induced Atrial Fibrillation
Authors: HIROSE MASAMICHI , LEATMANORATN ZENG , LAURITA KENNETH R. , CARLSON MARK D.
Published: August 2003

Partial Vagal Denervation on AF.
Introduction: Cervical vagal stimulation shortens the atrial effective refractory period (ERP) primarily in the high right atrium (HRA) and facilitates induction of atrial fibrillation (AF) by single premature HRA extrastimuli. We hypothesized that vagal denervation of the HRA prevents both ERP shortening in the HRA and AF induction during vagal stimulation.

Methods and Results: Vagal denervation of the HRA was achieved using radiofrequency catheter ablation (RFA) of the fat pad at the right pulmonary vein‐atrial junction (RPV fat pad). Programmed stimulation was performed at each of four atrial sites to measure ERP and inducibility of AF during vagal stimulation. RPV fat pad RFA increased only the HRA ERP during vagal stimulation (70 ± 8.7 vs 117 ± 14.8, P < 0.05). RPV fat pad RFA increased measures of dispersion of refractoriness, the standard deviation of ERP (24 ± 2.1 vs 33 ± 2.0, P < 0.01), and the standard deviation of AF cycle length (11 ± 0.8 vs 22 ± 1.7, P < 0.001) during vagal stimulation. RPV fat pad RFA increased the incidence of AF (15/28 vs 24/28, P < 0.05) and the vulnerability (22 ± 4.7 vs 39 ± 5.6, P < 0.01) to AF induction during vagal stimulation, particularly from left atrial premature beats. After RPV fat pad RFA, premature beats induced AF by causing conduction block primarily in the HRA and macroreentrant activation around the block.

Conclusion: Partial right atrial vagal denervation facilitated rather than prevented initiation of vagally mediated AF.
Demonstration of Electrical and Anatomic Connections Between Marshall Bundles and Left Atrium in Dogs: Implications on the Generation of P Waves on Surface Electrocardiogram
Authors: OMICHI CHIKAYA , CHOU CHUNG‐CHUAN , LEE MOON‐HYOUNG , CHANG CHE‐MING , LAI ANGELA C. , HAYASHI HIDEKI , ZHOU SHENGMEI , MIYAUCHI YASUSHI , OKUYAMA YUJI , HAMABE AKIRA , HWANG CHUN , FISHBEIN MICHAEL C. , LIN SHIEN‐FONG , KARAGUEUZIAN HRAYR S. , CHEN PENG‐SHENG
Published: August 2003

Marshall Bundle and P Wave.
Introduction: The muscle bundles within the ligament of Marshall (LOM) are electrically active. The importance of these muscle bundles (Marshall bundle [MB]) to atrial activation and the generation of the ECG P wave is unclear.

Methods and Results: We used optical mapping techniques to study epicardial activation patterns in isolated perfused left atrium in four dogs. In another seven dogs, P waves were studied before and after in vivo radiofrequency (RF) ablation of the connection between coronary sinus (CS) and the LOM. Computerized mapping was performed before and after RF ablation. Optical mapping studies showed that CS pacing resulted in broad wavefronts propagating from the middle and distal LOM directly to the adjacent left atrium (LA). Serial sections showed direct connection between MB and LA near the orifice of the left superior pulmonary vein in two dogs. In vivo studies showed that MB potentials were recorded in three dogs. After ablation, the duration of P waves remained unchanged. In the other four dogs, MB potentials were not recorded. Computerized mapping showed that LA wavefronts propagated to the MB region via LA‐MB connection and then excited the CS. After ablation, the activation of CS muscle sleeves is delayed, and P wave duration increased from 65.3 ± 14.9 msec to 70.5 ± 17.2 msec (P = 0.025).

Conclusion: In about half of the normal dogs, MB provides an electrical conduit between LA free wall and CS. Severing MB alters the atrial activation and lengthens the P wave. MB contributes to generation of the P wave on surface ECG.
Are We Lost in the Labyrinth of the Sinoatrial Node Pacemaker Mechanism?
Authors: KODAMA ITSUO , HONJO HARUO , BOYETT MARK R.
Published: August 2003

SA Node Pacemaker Mechanism. Despite extensive electrophysiologic studies performed to date, the ionic mechanisms of sinoatrial node pacemaker activity are unclear. This article highlights three recent topics associated with this issue: (1) sustained inward current (Ist); (2) the role of Ca2+ release from the sarcoplasmic reticulum; and (3) the role of L‐type Ca2+ current (ICa,L). New observations on these topics seem to make the scenario of the pacemaker mechanism increasingly complex. However, such complexity and diversity of ionic events and their orchestration may be important for the sinoatrial node to perform its robust pacemaking activity under a variety of pathophysiologic circumstances.
Dual recognition of the ribosome and the signal recognition particle by the SRP receptor during protein targeting to the endoplasmic reticulum
Authors: Mandon Elisabet C. , Jiang Ying , Gilmore Reid
Published: August 2003

We have analyzed the interactions between the signal recognition particle (SRP), the SRP receptor (SR), and the ribosome using GTPase assays, biosensor experiments, and ribosome binding assays. Possible mechanisms that could contribute to an enhanced affinity between the SR and the SRP–ribosome nascent chain complex to promote protein translocation under physiological ionic strength conditions have been explored. Ribosomes or 60S large ribosomal subunits activate the GTPase cycle of SRP54 and SRα by providing a platform for assembly of the SRP–SR complex. Biosensor experiments revealed high-affinity, saturable binding of ribosomes or large ribosomal subunits to the SR. Remarkably, the SR has a 100-fold higher affinity for the ribosome than for SRP. Proteoliposomes that contain the SR bind nontranslating ribosomes with an affinity comparable to that shown by the Sec61 complex. An NH2-terminal 319-residue segment of SRα is necessary and sufficient for binding of SR to the ribosome. We propose that the ribosome–SR interaction accelerates targeting of the ribosome nascent chain complex to the RER, while the SRP–SR interaction is crucial for maintaining the fidelity of the targeting reaction.
Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Authors: Cella Marina , Buonsanti Cecilia , Strader Carey , Kondo Takayuki , Salmaggi Andrea , Colonna Marco
Published: August 2003

TREM-2 is an immunoglobulin-like cell surface receptor associated with DAP12/KARAP that activates monocyte-derived dendritic cells (DCs) in vitro. Recently, it has been shown that genetic defects of human DAP12/KARAP and TREM-2 result in a rare syndrome characterized by bone cysts and presenile dementia called Nasu-Hakola disease. This observation suggests that TREM-2 may function in myeloid cells other than DCs, most probably osteoclasts (OCs) and microglial cells, which are involved in bone modeling and brain function. Consistent with this prediction, here we show that OC differentiation is dramatically arrested in TREM-2–deficient patients, resulting in large aggregates of immature OCs that exhibit impaired bone resorptive activity. These results demonstrate a critical role for TREM-2 in the differentiation of mononuclear myeloid precursors into functional multinucleated OCs.
Gating Competence of Constitutively Open CLC-0 Mutants Revealed by the Interaction with a Small Organic Inhibitor
Authors: Traverso Sonia , Elia Laura , Pusch Michael
Published: August 2003

Opening of CLC chloride channels is coupled to the translocation of the permeant anion. From the recent structure determination of bacterial CLC proteins in the closed and open configuration, a glutamate residue was hypothesized to form part of the Cl−-sensitive gate. The negatively charged side-chain of the glutamate was suggested to occlude the permeation pathway in the closed state, while opening of a single protopore of the double-pore channel would reflect mainly a movement of this side-chain toward the extracellular pore vestibule, with little rearrangement of the rest of the channel. Here we show that mutating this critical residue (Glu166) in the prototype Torpedo CLC-0 to alanine, serine, or lysine leads to constitutively open channels, whereas a mutation to aspartate strongly slowed down opening. Furthermore, we investigated the interaction of the small organic channel blocker p-chlorophenoxy-acetic acid (CPA) with the mutants E166A and E166S. Both mutants were strongly inhibited by CPA at negative voltages with a >200-fold larger affinity than for wild-type CLC-0 (apparent KD at −140 mV ∼4 μM). A three-state linear model with an open state, a low-affinity and a high-affinity CPA-bound state can quantitatively describe steady-state and kinetic properties of the CPA block. The parameters of the model and additional mutagenesis suggest that the high-affinity CPA-bound state is similar to the closed configuration of the protopore gate of wild-type CLC-0. In the E166A mutant the glutamate side chain that occludes the permeation pathway is absent. Thus, if gating consists only in movement of this side-chain the mutant E166A should not be able to assume a closed conformation. It may thus be that fast gating in CLC-0 is more complex than anticipated from the bacterial structures.
Conformational Changes in the Pore of CLC-0
Authors: Accardi Alessio , Pusch Michael
Published: August 2003

The Torpedo Cl− channel, CLC-0, is inhibited by clofibric acid derivatives from the intracellular side. We used the slow gate-deficient mutant CLC-0C212S to investigate the mechanism of block by the clofibric acid–derivative p-chlorophenoxy-acetic acid (CPA). CPA blocks open channels with low affinity (KDO= 45 mM at 0 mV) and shows fast dissociation (koff = 490 s−1 at −140 mV). In contrast, the blocker binds to closed channels with higher affinity and with much slower kinetics. This state-dependent block coupled with the voltage dependence of the gating transitions results in a highly voltage-dependent inhibition of macroscopic currents (KD ∼1 mM at −140 mV; KD ∼65 mM at 60 mV). The large difference in CPA affinity of the open and closed state suggests that channel opening involves more than just a local conformational rearrangement. On the other hand, in a recent work (Dutzler, R., E.B. Campbell, and R. MacKinnon. 2003. Science. 300:108–112) it was proposed that the conformational change underlying channel opening is limited to a movement of a single side chain. A prediction of this latter model is that mutations that influence CPA binding to the channel should affect the affinities for an open and closed channel in a similar manner since the general structure of the pore remains largely unchanged. To test this hypothesis we introduced point mutations in four residues (S123, T471, Y512, and K519) that lie close to the intracellular pore mouth or to the putative selectivity filter. Mutation T471S alters CPA binding exclusively to closed channels. Pronounced effects on the open channel block are observed in three other mutants, S123T, Y512A, and K519Q. Together, these results collectively suggest that the structure of the CPA binding site is different in the open and closed state. Finally, replacement of Tyr 512, a residue directly coordinating the central Cl− ion in the crystal structure, with Phe or Ala has very little effect on single channel conductance and selectivity. These observations suggest that channel opening in CLC-0 consists in more than a movement of a side chain and that other parts of the channel and of the selectivity filter are probably involved.
Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis
Authors: Waselle Laurent , Coppola Thierry , Fukuda Mitsunori , Iezzi Mariella , El-Amraoui Aziz , Petit Christine , Regazzi Romano
Published: August 2003

Rab27a is a GTPase associated with insulin-containing secretory granules of pancreatic β-cells. Selective reduction of Rab27a expression by RNA interference did not alter granule distribution and basal secretion but impaired exocytosis triggered by insulin secretagogues. Screening for potential effectors of the GTPase revealed that the Rab27a-binding protein Slac2c/MyRIP is associated with secretory granules of β-cells. Attenuation of Slac2c/MyRIP expression by RNA interference did not modify basal secretion but severely impaired hormone release in response to secretagogues. Although β-cells express Myosin-Va, a potential partner of Slac2c/MyRIP, no functional link between the two proteins could be demonstrated. In fact, overexpression of the Myosin-Va binding domain of Slac2c/MyRIP did not affect granule localization and hormone exocytosis. In contrast, overexpression of the actin-binding domain of Slac2c/MyRIP led to a potent inhibition of exocytosis without detectable alteration in granule distribution. This effect was prevented by point mutations that abolish actin binding. Taken together our data suggest that Rab27a and Slac2c/MyRIP are part of a complex mediating the interaction of secretory granules with cortical actin cytoskeleton and participate to the regulation of the final steps of insulin exocytosis.
Conserved Function of Pex11p and the Novel Pex25p and Pex27p in Peroxisome Biogenesis
Authors: Rottensteiner Hanspeter , Stein Katharina , Sonnenhol Eike , Erdmann Ralf
Published: August 2003

We describe the isolation and characterization of a homologous pair of proteins, Pex25p (YPL112c) and Pex27p (YOR193w), whose C-termini are similar to the entire Pex11p. All three proteins localize to the peroxisomal membrane and are likely to form homo-oligomers. Deletion of any of the three genes resulted in enlarged peroxisomes as revealed by fluorescence and electron microscopy. The partial growth defect on fatty acids of a pex25Δ mutant was not exacerbated by the additional deletion of PEX27; however, when PEX11 was deleted on top of that, growth was abolished on all fatty acids. Moreover, a severe peroxisomal protein import defect was observed in the pex11Δpex25Δpex27Δ triple mutant strain. This import defect was also observed when cells were grown on ethanol-containing medium, where peroxisomes are not required, suggesting that the function of the proteins in peroxisome biogenesis exceeds their role in proliferation. When Pex25p was overexpressed in the triple mutant strain, growth on oleic acid was completely restored and a massive proliferation of laminar membranes and peroxisomes was observed. Our data demonstrate that Pex11p, Pex25p, and Pex27p build a family of proteins whose members are required for peroxisome biogenesis and play a role in the regulation of peroxisome size and number.
Targeted Chemical Disruption of Clathrin Function in Living Cells
Authors: Moskowitz Howard S. , Heuser John , McGraw Timothy E. , Ryan Timothy A.
Published: August 2003

The accurate assignment of molecular roles in membrane traffic is frequently complicated by the lack of specific inhibitors that can work on rapid time scales. Such inhibition schemes would potentially avoid the complications arising from either compensatory gene expression or the complex downstream consequences of inhibition of an important protein over long periods (>12 h). Here, we developed a novel chemical tool to disrupt clathrin function in living cells. We engineered a cross-linkable form of clathrin by using an FK506-binding protein 12 (FKBP)-clathrin fusion protein that is specifically oligomerized upon addition of the cell-permeant cross-linker FK1012-A. This approach interrupts the normal assembly-disassembly cycle of clathrin lattices and results in a specific, rapid, and reversible ∼70% inhibition of clathrin function. This approach should be applicable to a number of proteins that must go through an assembly-disassembly cycle for normal function.