bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterogeneous Expression of Voltage‐Gated Potassium Channels in the Heart: Roles in Normal Excitation and Arrhythmias
Authors: NERBONNE JEANNE M. , GUO WEINONG
Published: August 2003

Heterogeneities in Ventricular Repolarization. In the mammalian myocardium, there are marked regional differences in action potential waveforms and frequency dependences. This heterogeneity impacts the normal dispersion of ventricular repolarization and appears to reflect the differential expression of voltage‐gated K+ channels. Multiple types of voltage‐gated K+ currents have been distinguished in mammalian ventricles and, in many cases, the K+ (Kv) channel pore‐forming (α) and accessory (β) subunits encoding these channels have been identified. In the diseased myocardium, remodeling of voltage‐gated K+ currents occurs, influencing propagation and rhythmicity, effects that can lead to increased dispersion of ventricular repolarization and create substrates for reentrant arrhythmias. Targeting the K+ channels that function to maintain the normal dispersion of ventricular repolarization could be effective in treating cardiac arrhythmias.
Severity of Cardiac Conduction Involvement and Arrhythmias in Myotonic Dystrophy Type 1 Correlates with Age and CTG Repeat Length
Authors: GROH WILLIAM J. , LOWE MIRIAM R. , ZIPES DOUGLAS P.
Published: August 2003

Cardiac Involvement in Myotonic Dystrophy Type 1.
Introduction: Cardiac myopathy manifesting with conduction disturbances and arrhythmias is common in the neurologic disease myotonic dystrophy. We studied whether the severity of cardiac involvement in myotonic dystrophy correlates with the severity of the genetic abnormality cytosine‐thymine‐guanine (CTG) repeat expansion.

Methods and Results: History, physical examination, ECG evaluation, and genetic testing were performed in patients with a clinical diagnosis of myotonic dystrophy. In 342 of 385 patients, the diagnosis was confirmed by CTG repeat expansion. In these patients, the muscular disability severity correlated with age and CTG repeat length (r = 0.44, P < 0.001). An arrhythmia diagnosis was present in 19 (5.6%) patients with a likelihood of diagnosis correlating with age (relative risk [RR] 2.2 per decade, 95% confidence intervals [CI]1.4 to 3.4, P = 0.001) and CTG repeat length (RR 2.9 per 500 repeats, 95% CI 1.5 to 5.4, P = 0.001). ECGs were abnormal in 222 (64.9%) of the patients. Age, CTG repeat length, and male gender were factors found to correlate with ECG conduction abnormalities quantitated by the PR interval (r = 0.43, P < 0.001) and QRS duration (r = 0.32, P < 0.001). A 24‐hour ambulatory ECG was abnormal in 95 (29.6%) of 321 recordings. The presence of an abnormality correlated with age (RR 1.5 per decade, 95% CI 1.2 to 1.9, P < 0.001) and CTG repeat length (RR 1.6 per 500 repeats, 95% confidence intervals 1.1 to 2.2, P = 0.01).

Conclusion: The severity of skeletal and cardiac myopathy in myotonic dystrophy correlates with age and CTG repeat length, suggesting a similar mechanism causing a time‐dependent degenerative process.
Effects of Thoracic Spinal Cord Stimulation on Cardiac Autonomic Regulation of the Sinus and Atrioventricular Nodes
Authors: OLGIN JEFFREY E. , TAKAHASHI TAMANA , WILSON EMILY , VERECKEI ANDRAS , STEINBERG HELMUT , ZIPES DOUGLAS P.
Published: August 2003

Thoracic Cord Stimulation and Cardiac Autonomics.
Introduction: Thoracic spinal cord stimulation (SCS) has been used to treat angina pectoris and to produce cardiac autonomic control. We studied the effect of thoracic SCS on sinus node and AV nodal function to test the hypothesis that SCS modulated autonomic regulation of the electrophysiology of these structures.

Methods and Results: The effects of thoracic SCS on sinus cycle length and AH interval were studied in 47 dogs in five experimental groups: group 1: intact autonomic nerves; group 2: bilateral ansae subclaviae transection and efferent stellate stimulation; group 3: ansae transection, bilateral vagi transection, and efferent stellate stimulation; group 4: bilateral vagi transection and efferent vagal stimulation; and group 5: bilateral vagal stimulation and bilateral ansae subclaviae transection. Under fluoroscopic guidance, the spinal stimulator electrode was advanced to the T1‐T2 position and threshold determined by adjusting the output to produce muscle contraction. Parameters were measured at baseline prior to SCS and during SCS, at 90% threshold. Ansae subclaviae and vagi nerves were isolated using standard approaches. Stellate and vagal stimulation were each performed using a constant current stimulator and at three different frequencies. Sinus cycle length and AH intervals (the latter at constant right atrial pacing of 400 msec) were measured with and without SCS at baseline and at each level of nerve stimulation. Nitric oxide was measured using the coronary sinus overflow method, from a luminal balloon catheter placed deep in the coronary sinus. SCS resulted in an increase in sinus cycle length from 507 ± 23 msec to 544 ± 22 msec (P = 0.02) and AH interval from 71 ± 4 msec to 74 ± 4 msec (P = 0.03). Ansae subclaviae transection had no effect on this increase, while vagal transection eliminated the increase in sinus cycle length and AH with SCS. The increase in these parameters with SCS was maintained during both stellate stimulation (group 2) and vagal stimulation (group 5) across all three levels of neural stimulation.

Conclusion: SCS appears to enhance parasympathetic activity, mediated via the vagus. This may have implications for use of thoracic SCS to treat chronic angina and perhaps prevent sudden cardiac death.
Electrical Connection Between the Right Atrium and the Superior Vena Cava, and the Extent of Myocardial Sleeve in a Patient with Atrial Fibrillation Originating from the Superior Vena Cava
Authors: OOIE TATSUHIKO , TSUCHIYA TAKESHI , ASHIKAGA KEIICHI , TAKAHASHI NAOHIKO
Published: August 2003

Atrial Fibrillation Originating from the SVC. We describe a case in which the superior vena cava (SVC) was electrically isolated by an application of radiofrequency energy to a point with electrical connection between the right atrium and the SVC in a patient with atrial fibrillation (AF) originating from the SVC. The connection was located in the posteroseptal region between the right atrium and the myocardial sleeve extending into the SVC. Local AF occurred after radiofrequency ablation and rapid activities were recorded all around the SVC, whereas the atrium was still in sinus rhythm. It is suggested that focal AF in the SVC contributes not only to the initiation but also to the maintenance of AF, and the myocardial sleeve extends into the SVC through a connection point to cover the entire internal lumen.
Interpretation and Classification of Microvolt T Wave Alternans Tests
Authors: BLOOMFIELD DANIEL M. , HOHNLOSER STEFAN H. , COHEN RICHARD J.
Published: August 2003

Interpretation of T Wave Alternans Tests. Measurement of microvolt‐level T wave alternans (TWA) during routine exercise stress testing now is possible as a result of sophisticated noise reduction techniques and analytic methods that have become commercially available. Even though this technology is new, the available data suggest that microvolt TWA is a potent predictor of arrhythmia risk in diverse disease states. As this technology becomes more widely available, physicians will be called upon to interpret microvolt TWA tracings. This review seeks to establish uniform standards for the clinical interpretation of microvolt TWA tracings.
What is the Atrioventricular Node? Some Clues in Sorting out its Structure‐Function Relationship
Authors: BILLETTE JACQUES
Published: August 2003

What is the AV Node? The anatomic and functional substrate underlying AV nodal rate‐dependent and dual pathway properties remains highly controversial. This article focuses on some factors that impair the understanding of the AV nodal structure‐function relationship and some clues toward sorting it out. A definition of the AV node that applies to both anatomic and functional studies, an orthogonal topographic representation of nodal structures, and the integration of rate‐dependent and dual pathway behavior of the AV node are proposed as primary steps toward a better understanding of the AV nodal structure‐function relationship. Further fact‐based information is the key to the sorting out of this puzzle.
Quantitative Assessment of the Recovery Property of Atriofascicular/Atrioventricular‐Type Mahaim Fiber
Authors: LEE PI‐CHANG , KANTER RONALD , GOMEZ‐MARIN ORLANDO , WOLFF GRACE S. , YOUNG MING‐LON
Published: August 2003

Recovery Property of Mahaim Fiber.
Introduction: One of the characteristics of the Mahaim fiber is that it possesses a decremental property related to the slow rate of recovery of its excitability similar to that of AV node. The aim of this study was to evaluate the recovery property of the atriofascicular/atrioventricular‐type Mahaim fiber and compare it with that of the AV node.

Methods and Results: Nine patients with a Mahaim fiber were studied; 8 of the patients had atriofascicular/atrioventricular‐type fiber. Different models were used to analyze the relationship between conduction time for the Mahaim fiber and the corresponding coupling intervals. The simplest model with the best fit was found to be the linear regression of the natural log of conduction time on corrected coupling intervals. The individual R2 values ranged between 0.43 and 0.98 for the Mahaim fiber and between 0.79 and 0.98 for AV node. The final model chosen for the log transformed data for the Mahaim fiber and for the AV node was the line with parameter estimates defined as a weighted average, over patients, of the corresponding individual line parameters. The weight used for each parameter was the inverse of its variance. The slopes of the lines of the transformed data were not significantly different between the Mahaim fiber and the AV node. Thus, the best fitting curve for the recovery property of the AF‐type Mahaim fiber is a simple exponential curve similar to that of the AV node.

Conclusion: The atriofascicular/atrioventricular‐type Mahaim fiber has a quantitative recovery property very similar to that of the AV node.
Impaired Negative Chronotropic Response to Adenosine in Patients with Inappropriate Sinus Tachycardia
Authors: STILL AINO‐MAIJA , HUIKURI HEIKKI V. , AIRAKSINEN K.E. JUHANI , KOISTINEN M. JUHANI , KETTUNEN RAIMO , HARTIKAINEN JUHA , MITRANI RAUL D. , CASTELLANOS AGUSTIN , MYERBURG ROBERT J. , RAATIKAINEN M.J. PEKKA
Published: August 2003

Adenosine and Inappropriate Sinus Tachycardia.
Introduction: Adenosine is an endogenous nucleoside that has an important role in the diagnosis and treatment of several cardiac arrhythmias. However, its effects on inappropriate sinus tachycardia (IST) are not well established.

Methods and Results: In this study, the response to intravenous adenosine (0.1 to 0.15 mg/kg) was studied in 18 patients (age 46 ± 15 years) with IST. In a subset of patients (n = 5), the direct effects of adenosine were assessed during pharmacologic beta‐adrenergic and cholinergic blockade. Atrial cycle length (ACL) was measured before adenosine injection, at the time of the greatest cycle length prolongation, and during the maximum rebound acceleration of heart rate. Eighteen subjects (age 46 ± 11 years) with normal sinus rhythm undergoing clinically indicated electrophysiologic study served as controls. Adenosine did not terminate IST in any patient. The maximum dose of adenosine prolonged the sinus interval significantly, from 780 ± 128 msec to 985 ± 225 msec (P < 0.001) in the control subjects. In contrast, adenosine caused no significant lengthening of atrial cycle length (527 ± 69 msec vs 590 ± 148 msec; P = NS) in the patients with IST. Similar difference in the response to adenosine was seen during the pharmacologic autonomic blockade. The reflex increase of the sinus rate (rebound effect) was greater in the control subjects than in the patients with IST (21.2% ± 9.7% vs 8.5% ± 8.8%; P < 0.001).

Conclusion: The usual negative chronotropic effect of adenosine was impaired in the patients with IST. This may have important diagnostic implications and provide new insight into the mechanism(s) of IST.
Microvolt T Wave Alternans Inducibility in Normal Newborn Puppies: Effects of Development
Authors: IDRISS SALIM F. , VAN HARE GEORGE F. , FINK DANIEL , ROSENBAUM DAVID S.
Published: August 2003

T Wave Alternans in Normal Newborn Puppies.
Introduction: The cause of sudden infant death syndrome is unknown, but increased cardiac vulnerability due to repolarization instability may be a contributing factor. The QT interval normally is long at birth and increases further during the first few postnatal months. Although excessive QT intervals indicate increased cardiac vulnerability in the long QT syndrome, the impact of less pronounced QT prolongation during this developmental period is unclear. In adults and older children, the ease of inducing microvolt‐level T wave alternans (TWA) is used as a measure of repolarization instability and arrhythmia vulnerability. The aim of this study was to determine if TWA is inducible in normal newborn puppies.

Methods and Results: Atrial pacing was performed in 15 anesthetized beagle puppies 7 to 35 days old. The pacing drive cycle length was systematically decreased in 20‐msec steps from baseline until AV conduction blocked. Pacing was performed for 8 minutes at each cycle length. Three‐lead ECGs were recorded continuously during the last 5 minutes of pacing at each cycle length. The recordings were analyzed off‐line for the presence of microvolt‐level TWA using a sensitive spectral analysis technique. Microvolt‐level TWA was present in all puppies. TWA was not present at baseline but developed and increased in amplitude as heart rate increased. The threshold heart rate for TWA did not correlate with age. However, due to age‐dependent changes in baseline heart rate, the 7‐ to 14‐day‐old animals needed a 50% to 78% increase in heart rate to reach threshold heart rate, whereas the oldest animals needed only a 5% to 25% increase.

Conclusion: These data suggest that developmentally dependent dynamic repolarization instability exists in puppies as manifest by the inducibility of TWA.
Gender Differences in Various Types of Idiopathic Ventricular Tachycardia
Authors: NAKAGAWA MIKIKO , TAKAHASHI NAOHIKO , NOBE SEIKI , ICHINOSE MASASHI , OOIE TATSUHIKO , YUFU FUMIO , SHIGEMATSU SAKUJI , HARA MASAHIDE , YONEMOCHI HIDETOSHI , SAIKAWA TETSUNORI
Published: August 2003

Gender Differences in Idiopathic VT.
Introduction: The aim of this study was to evaluate gender differences in the incidence and age distribution of various types of idiopathic ventricular tachycardia (VT).

Methods and Results: We conducted a search of the medical literature on idiopathic VT. According to their site of origin, we divided the VTs into three types: right ventricular outflow tract (RVOT‐VT), left ventricular outflow tract (LVOT‐VT), and left ventricular (LV) septum (LV‐VT). We reviewed 68 articles and a total of 748 patients. Among RVOT‐VT patients, there were more females than males (311 vs 153, male/female ratio 0.49). In LV‐VT, males prevailed over females (175 vs 52, male/female ratio 3.37), whereas LVOT‐VT was distributed almost equally between males (n = 33) and females (n = 24). To determine the age distribution, we assessed 419 patients from 51 studies. In both males and females, the highest incidence of RVOT‐VT occurred in the third to fifth decade of life (males, mean 43.5 ± 18.7; females, mean 40.9 ± 13.8 years). LV‐VT occurred at a younger age in both males and females than did RVOT‐VT (mean 33.0 ± 13.9 and 25.7 ± 12.0 years, respectively, P < 0.0001 vs RVOT‐VT). LV‐VT occurred at a younger age in females than males (P < 0.005).

Conclusion: Gender‐specific differences exist in the incidence and age distribution of the various types of idiopathic VT. Studies on gender‐specific differences in arrhythmia will lead to a better understanding of its mechanism(s) and provide valuable information for the development of optimal treatment strategies.
Sustained Inward Current and Pacemaker Activity of Mammalian Sinoatrial Node
Authors: ZHANG HENGGUI , HOLDEN ARUN V. , BOYETT MARK R.
Published: August 2003

Sustained Inward Current in the Sinoatrial Node.
Introduction: A novel sustained inward Na+ current ist, which sensitive to Ca2+‐antagonists and potentiated by beta‐adrenergic stimulation, has been described in pacemaker cells of rabbit, guinea pig, and rat sinoatrial node, as well as rabbit AV node. Although ist has been suggested to be an important pacemaker current, this has never been tested experimentally because of the lack of a specific blocker. In this study, we address the role of ist in the pacemaker activity of the sinoatrial node cell using computer models.

Methods and Results: The newly developed models of Zhang et al. for peripheral and central rabbit sinoatrial node cells and models of Noble and Noble, Demir et al., Wilders et al., and Dokos et al. for typical rabbit sinoatrial node cells were modified to incorporate equations for ist. The conductance gst was chosen to give a current density‐voltage relationship consistent with experimental data. In the models of Zhang et al. (periphery), Noble and Noble, and Dokos et al., in which ist was smaller or about the same amplitude as other inward currents, ist increased the pacemaking rate by 0.6%, 2.2%, and 0.8%, respectively. In the models of Zhang et al. (center), Demir et al., and Wilders et al., in which ist was larger than some other inward ionic currents, ist increased the pacemaking rate by 7%, 20%, and 14%, respectively.

Conclusion: ist has the potential to be a regulator of pacemaker activity, although its importance will depend on the amplitude of ist relative to the amplitude of other inward currents involved in pacemaker activity.
Circular Mapping Catheter Entrapment in the Mitral Valve Apparatus: A Previously Unrecognized Complication of Focal Atrial Fibrillation Ablation
Authors: WU RICHARD C. , BRINKER JEFFREY A. , YUH DAVID D. , BERGER RONALD D. , CALKINS HUGH G.
Published: August 2003

Circular Mapping Catheter Entrapment in MV Apparatus. Radiofrequency catheter ablation of focal atrial fibrillation triggers within the pulmonary veins is a rapidly developing therapy that relies on both recent technologies and evolving techniques. We describe the entrapment of a circular mapping catheter within the mitral valve apparatus after transseptal catheterization and mapping of the left atrium and pulmonary veins. The occurrence of this previously unreported complication stresses the need for continual monitoring and reporting of adverse effects from new devices and procedures to better inform patients and physicians of the benefits and risks of electrophysiologic interventions.
How to Enhance Acute Outcome of Electrical Cardioversion by Drug Therapy: Importance of Immediate Reinitiation of Atrial Fibrillation
Authors: VAN NOORD TRUDEKE , VAN GELDER ISABELLE C. , CRIJNS HARRY J.G.M.
Published: August 2003

Electrical Cardioversion.
Introduction: In almost 20% of patients with persistent atrial fibrillation (AF), electrical cardioversion is unsuccessful because of shock failure (i.e., no single sinus beat) or immediate reinitiation of AF (IRAF; recurrence within 2 min). Relative prevalence of shock failure and IRAF are not well known because data on outcome of electrical cardioversion therapy mostly do not distinguish shock failure from IRAF.

Methods and Results: In this review, the role of pretreatment with antiarrhythmic drugs on prevention of shock failure and total outcome of the cardioversion procedure are investigated. Quinidine and propafenone seem to be effective in preventing IRAF. Verapamil given in addition to Class I or III drugs may strengthen the preventive effects of these drugs than if they were given alone. Ibutilide prevents shock failure, although neither ibutilide nor dofetilide seems to be effective in preventing IRAF.

Conclusion: Pretreatment with antiarrhythmic drugs may enhance cardioversion outcome predominantly by preventing IRAF. Different antiarrhythmic drugs within the same Vaughan‐Williams class have different effects on shock failure and IRAF.
Scaling of Atrioventricular Transmission in Mammalian Species: An Evolutionary Riddle!
Authors: MEIJLER FRITS L. , STRACKEE JAN , STOKHOF ARNOLD A. , WASSENAAR CLAES
Published: August 2003

Scaling of AV Transmission.“Scaling deals with the structural and functional consequences of changes in size or scale among otherwise similar organisms.” It plays a key role in all studies on comparative mammalian physiology and morphology. Heart weight is proportionally related to body weight and can be described by a straightforward, so‐called allometric equation. We studied scaling of AV transmission times (PR intervals on the ECG) in 375 mammals of different dimensions and species. Scaling of AV transmission times versus heart length (third root of weight) is statistically best described by a S‐shaped curve. This implies that AV transmission time in mammals is not linearly related to heart length and does not depend solely on the length of the AV transmission system. The AV node fine‐tunes AV transmission times at rest and during exercise in individuals; it protects the ventricles against high‐rate atrial arrhythmias such as atrial fibrillation; and it regulates basal AV transmission times in mammalian species of varying sizes. We call the “how” and “why” of the scaling of AV transmission time in mammals an evolutionary riddle that deserves further study.
Autonomic Control of the Location and Rate of the Cardiac Pacemaker in the Sinoatrial Fat Pad of Parasympathetically Denervated Dog Hearts
Authors: NAKAJIMA KOICHI , FURUKAWA YASUYUKI , KUROGOUCHI FUMIO , TSUBOI MASATO , CHIBA SHIGETOSHI
Published: August 2003

Autonomic Regulation of Pacemaker Sites.
Introduction: Parasympathetic activity predominates over sympathetic activity not only with respect to heart rate but also with respect to the pacemaker location in the dog heart. After we removed the parasympathetic neural elements in the sinoatrial (SA) fat pad in the right atrium, we observed that cervical vagus stimulation did not decrease the atrial rate, but it did suppress the increase in rate evoked by sympathetic stimulation. We determined whether the pacemaker rate and location were affected by presynaptic or postsynaptic mechanisms.

Methods and Results: We determined the earliest activation site by means of isochronic activation mapping of the right atrium of open chest, anesthetized dog hearts. An electrode array, which consisted of 48 unipolar electrodes, was used to record atrial activation. This array covered the three main pacemaker regions, including the SA node region. After parasympathetic nerve fibers in the SA fat pad had been denervated, vagus stimulation at 10 and 30 Hz did not decrease the heart rate, but it attenuated the increase in heart rate evoked by sympathetic stimulation or isoproterenol. Vagus stimulation at 10 Hz during sympathetic stimulation did not shift the earliest activation site from the superior pacemaker region to the SA node region in 11 of 18 experiments. However, vagus stimulation at 10 Hz during isoproterenol infusion shifted the earliest activation site to the SA node region in 11 of 13 experiments. More intense vagus stimulation during combined sympathetic stimulation or isoproterenol infusion shifted the earliest activation site to the SA node or the inferior pacemaker region in 15 of 18 and in all experiments, respectively.

Conclusion: The results suggest that activation of parasympathetic elements not located in the SA fat pad attenuates the increase in heart rate and the shift in pacemaker location evoked by sympathetic activation. The sympathetic and parasympathetic effects interact at presynaptic and postsynaptic sites in the dog heart.
Restitution Properties and Occurrence of Ventricular Arrhythmia in LQT2 Type of Long QT Syndrome
Authors: YAMAUCHI SOU , YAMAKI MICHIYASU , WATANABE TETSU , YUUKI KOUICHI , KUBOTA ISAO , TOMOIKE HITONOBU
Published: August 2003

Mechanisms of Ventricular Arrhythmia in LQT2 Heart.
Introduction: The aim of this study was to clarify the ventricular tachyarrhythmia mechanism induced by the IKr‐blocking agent E4031, simulating the LQT2 form. Electrophysiologic properties were examined in 13 canines before and after administration of E4031.

Method and Results: Thirty‐six needle electrodes were inserted into the anterior left ventricular wall. From each needle, local unipolar electrograms were obtained from four intramural sites. Activation time (AT) and activation‐recovery interval (ARI) were measured. To evaluate the susceptibility to ventricular arrhythmia, intramural ARI dispersions and the restitution relationship between ARI and diastolic interval were calculated. After E4031 administration, ARI prolonged uniformly in each myocardial layer. However, ARI dispersion was not augmented compared with control. The slope of the ARI restitution curve after E4031 was significantly steeper than control. A steep slope may result from augmented ARI alternans. In 11 of the 13 canines, ventricular tachyarrhythmia was induced by programmed stimulation after E4031, whereas no arrhythmia was induced by the same protocol in control.

Conclusion: Steepness of electrical restitution may play a major role in arrhythmogenicity in LQT2 hearts.
Advanced Rhythm Discrimination for Implantable Cardioverter Defibrillators Using Electrogram Vector Timing and Correlation
Authors: GOLD MICHAEL R. , SHOROFSKY STEPHEN R. , THOMPSON JULIE A. , KIM JAEHO , SCHWARTZ MARK , BOCEK JOE , LOVETT ERIC G. , HSU WILLIAM , MORRIS MILTON M. , LANG DOUGLAS J.
Published: August 2003

Electrogram Vector Timing and Correlation.
Introduction: Discrimination of ventricular and supraventricular arrhythmias remains one of the major challenges for appropriate implantable defibrillator (ICD) therapy delivery. The electrogram vector timing and correlation (VTC) algorithm was developed for such rhythm discrimination. The VTC algorithm differentiates normally conducted supraventricular beats from abnormally conducted ventricular beats by comparing the timing and correlation of rate and shock channel electrograms.

Methods and Results: Rate and shock channel electrograms of sinus rhythm and induced arrhythmias were collected from 93 patients during ICD placement. The algorithm was developed using data from 50 patients and prospectively tested in a software model with the remaining 43 patients. A sinus rhythm reference was formed by averaging complexes of the shock channel signal aligned by the peak amplitude of the rate channel. Eight features measuring the amplitude and timing of shock channel signal characteristics were extracted from the reference for comparison. When a high‐rate rhythm was detected, the VTC algorithm computed the correlation of the arrhythmia complex features with the reference. Rhythms with a sufficient number of uncorrelated beats were classified as ventricular tachycardia (VT). In a dual‐chamber implementation, the VTC algorithm is integrated with ventricular and atrial rate comparison (V > A) and stability above an atrial fibrillation rate threshold. The test set consisted of 117 arrhythmias. Dual‐chamber sensitivity was 100% (81/81 VT) and specificity was 97% (35/36 supraventricular tachycardia). Single‐chamber analysis demonstrated 99% sensitivity and 97% specificity.

Conclusion: The VTC algorithm demonstrated high sensitivity and specificity in discriminating between ventricular and supraventricular arrhythmias.
Inducible Ventricular Flutter and Fibrillation Predict for Arrhythmia Occurrence in Coronary Artery Disease Patients Presenting with Syncope of Unknown Origin
Authors: LINK MARK S. , SAEED MOHAMMAD , GUPTA NEERA , HOMOUD MUNTHER K. , WANG PAUL J. , ESTES N.A. MARK
Published: August 2003

Ventricular Fibrillation and Syncope.
Introduction: Ventricular fibrillation and ventricular flutter (cycle length ≤230 msec) induced at electrophysiologic studies are thought to be nonspecific findings in patients presenting with syncope of unknown origin. However, there are limited data on the prognosis of these patients in long‐term follow‐up.

Methods and Results: We followed 274 consecutive patients with coronary artery disease presenting with syncope or presyncope who underwent electrophysiologic studies from January 1992 to June 1999 and assessed the risk of subsequent arrhythmias stratified by the electrophysiologic result at the time of their presentation with syncope. Ventricular fibrillation was induced in 23 patients (8%); ventricular flutter in 24 (9%), sustained ventricular tachycardia in 41 (15%); and nonsustained ventricular tachycardia 42 (15%). In 37 ± 25 months of follow‐up, there have been ventricular arrhythmias in 34 patients, including 3 (13%) of 23 who had induced ventricular fibrillation, and 7 (30%) of 24 with induced ventricular flutter, compared to 13 (32%) of 41 with sustained ventricular tachycardia, 7 (17%) of 42 with nonsustained ventricular tachycardia, and only 4 (3%) of 144 noninducible patients (P < 0.001 for induced ventricular fibrillation and ventricular flutter vs noninducible patients). The inducibility of ventricular fibrillation and ventricular flutter were independent risk factors for arrhythmia occurrence in follow‐up.

Conclusion: Ventricular fibrillation and ventricular flutter induced at electrophysiologic studies have prognostic significance for arrhythmia occurrence in patients presenting with syncope. These induced arrhythmias may not be as nonspecific as previously thought and treatment should be considered for these patients.
Three‐Dimensional Mapping of Right Atrial Activation During Sinus Rhythm and Its Relationship to Endocardial Architecture
Authors: BETTS TIM R. , HO SIEW YEN , SANCHEZ‐QUINTANA DAMIAN , ROBERTS PAUL R. , ANDERSON ROBERT H. , MORGAN JOHN M.
Published: August 2003

Right Atrial Activation.
Introduction: Previous mapping studies of right atrial (RA) activation during sinus rhythm have been limited by the use of epicardial electrode plaques in open chest subjects or microelectrodes in the excised heart. This study describes global RA endocardial activation patterns using high‐density mapping and compares the results with underlying endocardial architecture.

Methods and Results: Noncontact mapping of the RA was performed in 21 anesthetized swine. Isopotential and isochronal maps were superimposed upon three‐dimensional reconstructions of RA geometry. Hearts were excised and endocardial dissection performed. Two patterns of RA activation were recorded. The site of earliest endocardial activation occurred either laterally at a position consistent with the terminal crest or superiorly at the junction between the superior caval vein and RA appendage. The subsequent spread of depolarization followed the longitudinal orientation of muscle fibers. Areas of conduction delay and block were seen at the junction between the terminal crest and posterior wall, the cavotricuspid isthmus, and around the margins of the triangle of Koch. Endocardial dissection at these sites demonstrated complex fiber orientation. A lateral site of earliest activation demonstrated a more prominent display of conduction delay or block.

Conclusion: The spread of the sinus impulse follows endocardial myofiber orientation and is dictated by the site of earliest activation. Even during sinus rhythm, anisotropic conduction results in areas of conduction block or delay. These findings have implications in the development of reentrant arrhythmias and may influence surgical or electrophysiologic procedures.
FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons
Authors: Gilley Jonathan , Coffer Paul J. , Ham Jonathan
Published: August 2003

Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal–induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation–induced death of sympathetic neurons.
Gene expression during ER stress–induced apoptosis in neurons
Authors: Reimertz Claus , Kögel Donat , Rami Abdelhaq , Chittenden Thomas , Prehn Jochen H.M.
Published: August 2003

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of ischemic and neurodegenerative disorders. Treatment of human SH-SY5Y neuroblastoma cells with tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target genes of the unfolded protein response. However, prolonged treatment also triggered a delayed, caspase-dependent cell death. Microarray analysis of gene expression changes during tunicamycin-induced apoptosis revealed that the Bcl-2 homology domain 3-only family member, Bcl-2 binding component 3/p53 upregulated modulator of apoptosis (Bbc3/PUMA), was the most strongly induced pro-apoptotic gene. Expression of Bbc3/PUMA correlated with a Bcl-xL–sensitive release of cytochrome c and the activation of caspase-9 and -3. Increased expression of Bbc3/PUMA was also observed in p53-deficient human cells, in response to the ER stressor thapsigargin, and in rat hippocampal neurons after transient forebrain ischemia. Overexpression of Bbc3/PUMA was sufficient to trigger apoptosis in SH-SY5Y neuroblastoma cells, and human cells deficient in Bbc3/PUMA showed dramatically reduced apoptosis in response to ER stress. Our data suggest that the transcriptional induction of Bbc3/PUMA may be sufficient and necessary for ER stress–induced apoptosis.
Coupling Between B Cell Receptor and Phospholipase C-γ2 Is Essential for Mature B Cell Development
Authors: Hikida Masaki , Johmura Sachiko , Hashimoto Ari , Takezaki Mayuko , Kurosaki Tomohiro
Published: August 2003

Two signaling pathways known to be essential for progression from immature to mature B cells are BAFF receptor (BAFF-R) and the B cell receptor (BCR). Here, we first show that phospholipase C (PLC)-γ2 is required for a BAFF-R–mediated survival signal. Then, we have examined the question of whether the reduced number of mature B cells in PLC-γ2−/− mice is caused by a defect in either BCR or BAFF-R signaling. We find that a PLC-γ2 SH2 mutant, which inhibits coupling between BCR and PLC-γ2, fails to restore B cell maturation, despite supporting BAFF-dependent survival. Therefore, our data suggest that the BAFF-R–mediated survival signal, provided by PLC-γ2, is not sufficient to promote B cell maturation, and that, in addition, activation of PLC-γ2 by BCR is required for B cell development.
Fractal Properties of Perfusion Heterogeneity in Optimized Arterial Trees
Authors: Karch Rudolf , Neumann Friederike , Podesser Bruno K. , Neumann Martin , Szawlowski Paul , Schreiner Wolfgang
Published: August 2003

Regional blood flows in the heart muscle are remarkably heterogeneous. It is very likely that the most important factor for this heterogeneity is the metabolic need of the tissue rather than flow dispersion by the branching network of the coronary vasculature. To model the contribution of tissue needs to the observed flow heterogeneities we use arterial trees generated on the computer by constrained constructive optimization. This method allows to prescribe terminal flows as independent boundary conditions, rather than obtaining these flows by the dispersive effects of the tree structure. We study two specific cases: equal terminal flows (model 1) and terminal flows set proportional to the volumes of Voronoi polyhedra used as a model for blood supply regions of terminal segments (model 2). Model 1 predicts, depending on the number Nterm of end-points, fractal dimensions D of perfusion heterogeneities in the range 1.20 to 1.40 and positively correlated nearest-neighbor regional flows, in good agreement with experimental data of the normal heart. Although model 2 yields reasonable terminal flows well approximated by a lognormal distribution, it fails to predict D and nearest-neighbor correlation coefficients r1 of regional flows under normal physiologic conditions: model 2 gives D = 1.69 ± 0.02 and r1 = −0.18 ± 0.03 (n = 5), independent of Nterm and consistent with experimental data observed under coronary stenosis and under the reduction of coronary perfusion pressure. In conclusion, flow heterogeneity can be modeled by terminal positions compatible with an existing tree structure without resorting to the flow-dispersive effects of a specific branching tree model to assign terminal flows.
The Role of the Polo Kinase Cdc5 in Controlling Cdc14 Localization
Authors: Visintin Rosella , Stegmeier Frank , Amon Angelika
Published: August 2003

In budding yeast, the protein phosphatase Cdc14 controls exit from mitosis. Its activity is regulated by a competitive inhibitor Cfi1/Net1, which binds to and sequesters Cdc14 in the nucleolus. During anaphase, Cdc14 is released from its inhibitor by the action of two regulatory networks. The Cdc Fourteen Early Anaphase Release (FEAR) network initiates Cdc14 release from Cfi1/Net1 during early anaphase, and the Mitotic Exit Network (MEN) promotes Cdc14 release during late anaphase. Here, we investigate the relationship among FEAR network components and propose an order in which they function to promote Cdc14 release from the nucleolus. Furthermore, we examine the role of the protein kinase Cdc5, which is a component of both the FEAR network and the MEN, in Cdc14 release from the nucleolus. We find that overexpression of CDC5 led to Cdc14 release from the nucleolus in S phase-arrested cells, which correlated with the appearance of phosphorylated forms of Cdc14 and Cfi1/Net1. Cdc5 promotes Cdc14 phosphorylation and, by stimulating the MEN, Cfi1/Net1 phosphorylation. Furthermore, we suggest that Cdc14 release from the nucleolus only occurs when Cdc14 and Cfi1/Net1 are both phosphorylated.
Cyclin Aggregation and Robustness of Bio-switching
Authors: Slepchenko Boris M. , Terasaki Mark
Published: August 2003

During the cell cycle, Cdc2-cyclin B kinase abruptly becomes active and triggers the entry into mitosis/meiosis. Recently, it was found that inactive Cdc2-cyclin B is present in aggregates in immature starfish oocytes and becomes disaggregated at the time of its activation during maturation. We discuss a possible scenario in which aggregation of Cdc2-cyclin B dramatically enhances robustness of this activation. In this scenario, only inactive Cdc2-cyclin B can form aggregates, and the aggregates are in equilibrium with inactive Cdc2-cyclin B in solution. During maturation, the hormone-triggered inactivation of Myt1 depletes the soluble inactive Cdc2-cyclin B and the turnover leads to dissolution of the aggregates. This phase change, when coupled with the instability of the signaling network, provides a robust bio-switch.
Localization and Dynamics of Cdc2-Cyclin B during Meiotic Reinitiation in Starfish Oocytes
Authors: Terasaki Mark , Okumura Ei-ichi , Hinkle Beth , Kishimoto Takeo
Published: August 2003

The Cdc2-cyclin B kinase has a central role in regulating the onset of M phase. In starfish oocytes, Cdc2-cyclin B begins to be activated ∼10 min after application of maturation hormone, followed by accumulation in the nucleus then nuclear envelope breakdown. By immunofluorescence and by expressing a green fluorescent (GFP) chimera of cyclin B, we find that cyclin B is present in aggregates in the cytoplasm of immature oocytes. The aggregates disperse at ∼10 min, suggesting that the dispersal is closely related to the activation of the kinase. Using cyclin B-GFP, the dispersion begins from the region containing the centrosomes. Extractability of Cdc2-cyclin B changes with similar kinetics during maturation. Active Cdc25 phosphatase released Cdc2-cyclin B from the detergent-insoluble fraction independently of its phosphatase activity. Live cell imaging also showed that Cdc2-cyclin B begins to accumulate in the nucleus before changes in nuclear pore permeability, consistent with Cdc2-cyclin B-induced disassembly of the pores.
Schizosaccharomyces pombeRdh54 (TID1) Acts with Rhp54 (RAD54) to Repair Meiotic Double-Strand Breaks
Authors: Catlett Michael G. , Forsburg Susan L.
Published: August 2003

We report the characterization of rdh54+, the second fission yeast Schizosaccharomyces pombe Rad54 homolog. rdh54+shares sequence and functional homology to budding yeast RDH54/TID1. Rdh54p is present during meiosis with appropriate timing for a meiotic recombination factor. It interacts with Rhp51 and the meiotic Rhp51 homolog Dmc1 in yeast two-hybrid assays. Deletion of rdh54+has no effect on DNA damage repair during the haploid vegetative cell cycle. In meiosis, however, rdh54Δ shows decreased spore viability and homologous recombination with a concomitant increase in sister chromatid exchange. The rdh54Δ single mutant repairs meiotic breaks with similar timing to wild type, suggesting redundancy of meiotic recombination factors. Consistent with this, the rdh54Δ rhp54Δ double mutant fails to repair meiotic double strand breaks. Live cell analysis shows that rdh54Δ rhp54Δ asci do not arrest, but undergo both meiotic divisions with near normal timing, suggesting that failure to repair double strand breaks in S. pombe meiosis does not result in checkpoint arrest.
Nod Factor Inhibition of Reactive Oxygen Efflux in a Host Legume
Authors: Shaw Sidney L. , Long Sharon R.
Published: August 2003

Hydrogen peroxide (H2O2) efflux was measured from Medicago truncatula root segments exposed to purified Nod factor and to poly-GalUA (PGA) heptamers. Nod factor, at concentrations > 100 pm, reduced H2O2 efflux rates to 60% of baseline levels beginning 20 to 30 min after exposure, whereas the PGA elicitor, at > 75 nm, caused a rapid increase in H2O2 efflux to >200% of baseline rates. Pretreatment of plants with Nod factor alters the effect of PGA by limiting the maximum H2O2 efflux rate to 125% of that observed for untreated plants. Two Nod factor-related compounds showed no ability to modulate peroxide efflux, and tomato (Lycopersicon esculentum), a nonlegume, showed no response to 1 nm Nod factor. Seven M. truncatula mutants, lacking the ability to make nodules, were tested for Nod factor effects on H2O2 efflux. The nfp mutant was blocked for suppression of peroxide efflux, whereas the dmi1 and dmi2 mutants, previously shown to be blocked for early Nod factor responses, showed a wild-type peroxide efflux modulation. These data demonstrate that exposure to Nod factor suppresses the activity of the reactive oxygen-generating system used for plant defense responses.
Expression Profiling of Cytokinin Action in Arabidopsis
Authors: Rashotte Aaron M. , Carson Susan D.B. , To Jennifer P.C. , Kieber Joseph J.
Published: August 2003

The phytohormone cytokinin is an important regulator of plant growth and development; however, relatively few genes that mediate cytokinin responses have been identified. Genome-wide analyses of Arabidopsis seedlings using the approximately 8,300-element Affymetrix Arabidopsis GeneChips (Affymetrix, Santa Clara, CA) to examine cytokinin-responsive genes were conducted, revealing at least 30 genes whose steady-state level of mRNA was elevated and at least 40 that were down-regulated at multiple time points after application of cytokinin. The cytokinin up-regulated genes include the type-A Arabidopsis response regulators (ARRs), which had been shown previously to be cytokinin primary response genes, cytokinin oxidase, which encodes an enzyme that degrades cytokinins, and several transcription factors. Cytokinin down-regulated genes include several peroxidases and kinases and an E3 ubiquitin ligase. We identified a common sequence motif enriched in the upstream regions of the most consistently cytokinin up-regulated genes. This motif is highly similar to the optimal DNA-binding sites for ARR1/ARR2, type-B ARRs that have been implicated in the transcriptional elevation of the type-A ARRs. Additionally, genome-wide analyses of cytokinin receptor mutants (wol/cre1) revealed large-scale changes in gene expression, including down-regulation of the type-A ARRs and several meristem and cell cycle genes, such as CycD3. Mutations in CRE1 reduced but did not eliminate the effect of cytokinin on gene expression for a subset of cytokinin-responsive genes and had little or no effect on others, suggesting functional redundancy among the cytokinin receptors.
Hyperphosphorylation of a Mitochondrial Protein, Prohibitin, Is Induced by Calyculin A in a Rice Lesion-Mimic Mutant cdr1
Authors: Takahashi Akira , Kawasaki Tsutomu , Wong Hann Ling , Suharsono Utut , Hirano Hisashi , Shimamoto Ko
Published: August 2003

The rice (Oryza sativa) lesion-mimic mutants, cell death and resistance (cdr), show spontaneous cell death on the entire leaf and exhibited significant resistance to the rice blast fungus. Our previous studies showed that CDR1 and CDR2 genes negatively regulated the phosphorylation steps leading to the activation of NADPH oxidase, which is associated with oxidative burst. To identify novel factors involved in the phosphorylation steps, the phosphorylation level of total proteins was compared between cdr mutants and wild type using two-dimensional gel electrophoresis. Here, we show that the phosphorylation level of four proteins in cdr1 was increased as compared with the wild type after calyculin A treatment. Partial amino acid sequences revealed that one of the four proteins is homologous to prohibitin (PHB), which has been shown to be associated with senescence and cell death and to function as a chaperone in the assembly of mitochondrial respiratory chain complex in yeast and mammals. Analysis of green fluorescent protein fusions indicated that rice PHB (OsPHB1) was targeted to mitochondria as found in yeast and mammals, suggesting a possibility that PHB is involved in defense response and/or programmed cell death through the mitochondrial function.