bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of K+ Currents by Homocysteine in Rat Ventricular Myocytes
Authors: SHONTZ ROBERT D. , XU ZHI , PATEL KAUSHIK P. , ROZANSKI GEORGE J. 
Published: August 2003

Homocysteine Inhibition of K+ Channels in Rat Cardiomyocytes.
Introduction: Clinical evidence suggests that increased blood levels of homocysteine may be an independent risk factor for the development of cardiovascular disease, but the functional effects of this sulfhydryl amino acid on the myocardium are poorly understood. The present study was conducted to determine the direct effects of homocysteine on the electrophysiologic properties of the heart. Methods and Results: Whole‐cell voltage‐clamp recordings were made in ventricular myocytes isolated from normal rat hearts to analyze the Ca2+‐independent, transient outward K+ current (Ito), a major repolarizing current in these cells. Maximum Ito density (measured at + 60 mV) was decreased ˜ 47% from baseline in the presence of 500 μM homocysteine (P < 0.05), but the amount of block varied in a frequency‐ and voltage‐dependent manner. Decreased Ito density was not accompanied by significant changes in voltage‐ or time‐dependent properties of the current, nor was it affected by pretreating myocytes with the protein kinase inhibitor staurosporine. Because a portion of total extracellular homocysteine is oxidized, we examined the response to homocystine, the oxidized form of homocysteine. In myocytes superfused with 500 μM homocystine, maximum Ito density was decreased by ˜ 40% from baseline (P < 0.05). In contrast, the thiolactone form of homocysteine did not alter Ito amplitude. Conclusion: These data suggest that homocysteine and its oxidized form homocystine acutely inhibit Ito channels in ventricular myocytes by mechanisms involving the free thiol or disulfide moieties of these compounds. High homocysteine or homocystine levels may contribute to abnormal repolarization and arrhythmogenic conditions in the intact heart.
Electrophysiologic Perturbations and Arrhythmogenic Activity Caused by Activation of the Fas Receptor in Murine Ventricular Myocytes: Role of the Inositol Trisphosphate Pathway
Authors: SHILKRUT MARK , GEALEKMAN OLGA , ROSEN DALIA , BERKE GIDEON , WOODCOCK ELIZABETH , BINAH OFER 
Published: August 2003

Ionic Basis of Fas Receptor Effects on Ventricular Myocytes.
Introduction: Experimental evidence suggests a major role for Fas receptor activation in a wide range of myocardial pathologies. Because clinical situations, which are likely to be associated with Fas activation, are accompanied by a variety of ventricular arrhythmias, the major goal of this study was to investigate the ionic mechanisms responsible for these phenomena. Methods and Results: To delineate the origin of Fas‐mediated electrophysiologic perturbations, the transient outward K+ current Ito and the L‐type Ca2+ current ICa,L were studied in murine ventricular myocytes treated with the Fas‐activating monoclonal antibody Jo2. Jo2 decreased Ito (4.36 ± 1.2 pA/pF vs 17.48 ± 2.36 pA/pF in control, VM=+50 mV; P < 0.001) and increased ICa,L (− 13.17 ± 1.38 pA/pF vs − 3.94 ± 0.78 pA/pF in control, VM= 0 mV; P < 0.001). Pretreatment of ventricular myocytes with ryanodine or thapsigargin prevented the electrophysiologic effects of Jo2, suggesting that [Ca2+]i elevation is important for Fas‐mediated action. In agreement with our previous studies demonstrating dependence of Fas‐based myocyte dysfunction on an intact inositol trisphosphate (1,4,5‐IP3) pathway, the effects of Jo2 on Ito and ICa,L were prevented by the phospholipase C (generates 1,4,5‐IP3) blocker U73122, and by xestospongin C (tested with Ito), a specific blocker of IP3‐operated sarcoplasmic reticulum Ca2+ release channels. Furthermore, intracellular perfusion with 1,4,5‐IP3, but not with 1,3,4‐IP3, caused electrophysiologic effects resembling those of Jo2. Conclusion: Decreased Ito and increased ICa,L underlie Fas‐induced action potential alterations and arrhythmias in murine ventricular myocytes, effects that appear to be mediated by 1,4,5‐IP3‐induced intracellular calcium release.
Mechanisms for Discordant Alternans
Authors: WATANABE MARI A. , FENTON FLAVIO H. , EVANS STEVEN J. , HASTINGS HAROLD M. , KARMA ALAIN 
Published: August 2003

Discordant Alternans Mechanism.
Introduction: Discordant alternans has the potential to produce larger alternans of the ECG T wave than concordant alternans, but its mechanism is unknown. Methods and Results: We demonstrate by one‐ and two‐dimensional simulation of action potential propagation models that discordant alternans can form spontaneously in spatially homogeneous tissue through one of two mechanisms, due to the interaction of conduction velocity and action potential duration restitution at high pacing frequencies or through the dispersion of diastolic interval produced by ectopic foci. In discordant alternans due to the first mechanism, the boundaries marking regions of alternans with opposite phase arise far from the stimulus site, move toward the stimulus site, and stabilize. Dynamic splitting of action potential duration restitution curves due to electrotonic coupling plays a crucial role in this stability. Larger tissues and faster pacing rates are conducive to multiple boundaries, and inhomogeneities of tissue properties facilitate or inhibit formation of boundaries. Conclusion: Spatial inhomogeneities of electrical restitution properties are not required to produce discordant alternans.
Topographic Anatomy of the Inferior Pyramidal Space: Relevance to Radiofrequency Catheter Ablation
Authors: SÁNCHEZ‐QUINTANA DAMIÁN , HO SIEW YEN , CABRERA JOSÉ A. , FARRÉ JERÓNIMO , ANDERSON ROBERT H. 
Published: August 2003

Inferior Pyramidal Space and Ablation.
Introduction: Radiofrequency catheter ablation carried out in the vicinity of the triangle of Koch risks damaging not only the AV conduction tissues but also their arterial supply. The aim of this study was to examine the relationship of the AV nodal artery to the inferior pyramidal space, the triangle of Koch, and the right atrial endocardial surface. Methods and Results: We studied 41 heart specimens, 24 by gross dissections and 17 by histologic sections. The proximity of the AV nodal artery to the surface landmarks of the triangle of Koch was variable, but it was notable that in 75% of specimens the artery passed close to the endocardial surface of the right atrium and within 0.5 to 5 mm of the mouth of the coronary sinus. In all specimens, the mean distance of the artery to the endocardial surface was 3.5 ± 1.5 mm at the base of Koch's triangle. The location of the compact AV node and its inferior extensions varied within the landmarks of the triangle. At the mid‐level of Koch's triangle, the compact node was medially situated in 82% of specimens, but it was closer to the hinge of the tricuspid valve in the remaining 18% of specimens. In 12% of specimens, the inferior parts of the node extended to the level of the mouth of the coronary sinus. Conclusion: The nodal artery runs close to the orifice of the coronary sinus, the endocardial surface of the right atrium, the middle cardiac vein, and the specialized conduction tissues in most hearts. The nodal artery and/or the AV conduction tissues can be at risk of damage when ablative procedures are carried out at the base of the triangle of Koch.
Alterations of Sodium Channel Kinetics and Gene Expression in the Postinfarction Remodeled Myocardium
Authors: HUANG BOYU , EL‐SHERIF TAREK , GIDH‐JAIN MADHAVI , QIN DAYI , EL‐SHERIF NABIL 
Published: August 2003

Postinfarction Changes in Cardiac Na+ Channel.
Introduction: After a myocardial infarction (MI), the heart undergoes a remodeling process that includes hypertrophy of noninfarcted left ventricular myocytes. Alterations in the genetic expression, including reexpression of fetal isogene patterns, can result in electrophysiologic changes that contribute to the arrhythmogenicity of post‐MI heart. The present study investigated possible alterations in gene expression of Na+ channel subtypes, as well as the kinetics of the Na+ current (INa), in 3‐ to 4‐week‐old post‐MI rat remodeled left ventricular myocardium. Methods and Results: Using a macropatch technique, we showed increased Na + channel bursting activity during sustained depolarization in post‐MI remodeled myocytes resulting in a large slow component of the INa decay. A tetrodotoxin‐sensitive current contributed 18% to the prolonged APD90 of isolated post‐MI myocytes compared with 6% in control myocytes. Our molecular studies revealed that, in addition to the rat heart I (rH I) subtype, thought to be the predominant subtype that encodes a tetrodotoxin‐resistant isoform, the brain subtypes NaCh I and NaCh Ia also are expressed in the rat myocytes. Post‐MI remodeled myocardium showed increased expression of NaCh I protein with reversion of the NaCh Ia/NaCh I isoform ratio toward the fetal phenotype. Conclusion: Our findings raise the possibility that the increase in the slow component of INa in post‐MI remodeled myocytes is secondary to the increased expression of NaCh I. Additional studies are required to address these questions and to characterize the functional role of the NaCh I subtypes in cardiac myocytes.
Electrocardiographic Imaging: I. Effect of Torso Inhomogeneities on Body Surface Electrocardiographic Potentials
Authors: RAMANATHAN CHARULATHA , RUDY YORAM 
Published: August 2003

Effect of Inhomogeneities on Body Surface.
Introduction: Body surface potential maps (BSPMs) and conventional ECG reflect electrical sources generated by cardiac excitation and repolarization and noninvasively provide important diagnostic information about the electrical state of the heart. Because the heart is located within the torso volume conductor, body surface potentials also reflect the effects of torso inhomogeneities, which include blood, lungs, bone, muscle, fat, and fluid. It is necessary to characterize and understand these effects in order to interpret BSPM and ECG in terms of cardiac activity without “contamination” from the inhomogeneous volume conductor. Methods and Results: Actual measured epicardial and body surface potentials were obtained during normal sinus rhythm and for different pacing protocols from a Langendorff‐perfused dog heart suspended in a human‐shaped torso tank. Accurate geometry of the torso inhomogeneities was digitized from the Visual Human Project and appropriately introduced into a computer model of the tank setup. The geometry and electrical properties of the volume conductor could be varied. Both homogeneous and inhomogeneous torsos have major smoothing effects on BSPM, which is of very low resolution compared with its corresponding epicardial potential pattern. Relative to a homogeneous torso, the inhomogeneities have only a minor effect on BSPM patterns. They augment potential magnitudes depending on the pattern of epicardial activation. Variations of geometry and electrical properties within the normal physiologic range have minimal effects. Conclusion: Effects of torso inhomogeneities on 12‐lead ECGs are minimal, and the associated ECG changes fall within the range of normal interindividual variations.
Electrocardiographic Imaging: II. Effect of Torso Inhomogeneities on Noninvasive Reconstruction of Epicardial Potentials, Electrograms, and Isochrones
Authors: RAMANATHAN CHARULATHA , RUDY YORAM 
Published: August 2003

Torso Effects on Reconstructed Epicardial Potentials.
Introduction: Noninvasive electrocardiographic imaging (ECGI) involves inverse reconstruction of epicardial potentials, electrograms (EGMs), and isochrones from body surface potential maps (BSPMs). The heart lies in a volume conductor that includes lungs, blood, bone, muscle, and fluid. We investigate the effects of these torso inhomogeneities on reconstructed epicardial potentials, EGMs, and isochrones to address the issue of whether they should be included in clinical ECGI methodology. Methods and Results: Potential data were obtained for different pacing protocols from a dog heart suspended in a human‐shaped torso tank. Accurate geometry of torso inhomogeneities was digitized from the Visual Human Project and appropriately introduced into a computer model of the torso. Three models were used: accurate inhomogeneous torso, homogeneous torso, and a torso with stylized lungs (to generate an approximate model). The inhomogeneous model was used to compute BSPMs from the measured epicardial potentials. These BSPMs were the starting point for inverse computations in the different torso models. Epicardial potential maps, EGMs, and isochrones were computed. The homogeneous model produced slightly less accurate epicardial potential reconstructions than the inhomogeneous model and stylized lung model, but epicardial potential patterns, EGMs, isochrones, and locations of pacing sites were reconstructed with comparable accuracy when torso inhomogeneities were ignored. Conclusion: The results demonstrate that, in the clinical application, it is not necessary to include torso inhomogeneities for noninvasive reconstructions of epicardial potentials, EGMs, and activation sequences.
Roles of Line Stimulation‐Induced Virtual Electrodes and Action Potential Prolongation in Arrhythmic Propagation
Authors: BAYNHAM TAMARA C. , KNISLEY STEPHEN B. 
Published: August 2003

Arrhythmias During Line Stimulation.
Introduction: Line stimulation across fibers generates a virtual electrode (VE) pattern that consists of adjacent + Vm and − Vm regions. In this study, we evaluated Vm at the break of line stimulation pulses to determine where arrhythmias arise and their propagation direction relative to +Vm and −Vm regions. Methods and Results: We optically mapped the anterior left ventricular epicardium of isolated rabbit hearts (n = 9). Monophasic line stimuli were applied across fibers at various coupling intervals. In 18 of 24 break arrhythmias, i.e., arrhythmias in which propagation occurred after the break but ≤ 30 msec postshock, excitation propagated from the border between +Vm and −Vm regions toward the −Vm region (P < 0.05) for either shock polarity, even though locations of positive and negative Vm changed with shock polarity. In 13 of 18 make arrhythmias, i.e., arrhythmias in which propagation occurred before the break, the excitation propagated from the center of the + Vm region toward the − Vm regions (P < 0.05). For late arrhythmias, i.e., arrhythmias in which propagation was found > 30 msec postshock, propagation was reversed, i.e., toward the + Vm region (P < 0.01), which was where the positive VE produced action potential prolongation. Conclusion: The propagation of break, make, and late arrhythmias is spatially related to VEs. The different direction of propagation of late arrhythmias relative to the VEs is explained by the delayed recovery of Vm due to VE‐induced action potential prolongation.
Electrogram Polarity and Cavotricuspid Isthmus Block During Ablation of Typical Atrial Flutter
Authors: TADA HIROSHI , ORAL HAKAN , STICHERLING CHRISTIAN , CHOUGH STEVEN P. , BAKER ROBERT L. , WASMER KRISTINA , KIM MICHAEL H. , PELOSI FRANK , MICHAUD GREGORY F. , KNIGHT BRADLEY P. , STRICKBERGER S. ADAM , MORADY FRED 
Published: August 2003

Electrogram Polarity in Atrial Flutter Ablation.
Introduction: The atrial activation sequence around the tricuspid annulus has been used to assess whether complete block has been achieved across the cavotricuspid isthmus during radiofrequency ablation of typical atrial flutter. However, sometimes the atrial activation sequence does not clearly establish the presence or absence of complete block. The purpose of this study was to determine whether a change in the polarity of atrial electrograms recorded near the ablation line is an accurate indicator of complete isthmus block. Methods and Results: Radiofrequency ablation was performed in 34 men and 10 women (age 60 ± 13 years [mean ± SD]) with isthmus‐dependent, counterclockwise atrial flutter. Electrograms were recorded around the tricuspid annulus using a duodecapolar halo catheter. Electrograms recorded from two distal electrode pairs (E1 and E2) positioned just anterior to the ablation line were analyzed during atrial flutter and during coronary sinus pacing, before and after ablation. Complete isthmus block was verified by the presence of widely split double electrograms along the entire ablation line. Complete bidirectional isthmus block was achieved in 39 (89%) of 44 patients. Before ablation, the initial polarity of E1 and E2 was predominantly negative during atrial flutter and predominantly positive during coronary sinus pacing. During incomplete isthmus block, the electrogram polarity became reversed either only at E2, or at neither E1 nor E2. In every patient, the polarity of E1 and E2 became negative during coronary sinus pacing only after complete isthmus block was achieved. In 4 patients (10%), the atrial activation sequence recorded with the halo catheter was consistent with complete isthmus block, but the presence of incomplete block was accurately detected by inspection of the polarity of E1 and E2. Conclusion: Reversal of polarity in bipolar electrograms recorded just anterior to the line of isthmus block during coronary sinus pacing after ablation of atrial flutter is a simple, quick, and accurate indicator of complete isthmus block.
Provoked and Spontaneous High‐Frequency, Low‐Amplitude, Respirophasic Noise Transients in Patients with Implantable Cardioverter Defibrillators
Authors: SWEENEY MICHAEL O. , ELLISON KRISTIN E. , SHEA JULIE B. , NEWELL JOHN B. 
Published: August 2003

Respirophasic Noise Transients in ICD Patients. Introduction: Ventricular oversensing (OS) of respirophasic noise transients may cause spurious detections and therapies and pacing inhibition among patients with implantable cardioverter defibrillators (ICDs). The incidence of OS and its relationship to clinical variables and ICD system design are unknown. Methods and Results: Three hundred twenty‐nine patients performed provocative respiratory maneuvers at rest during intrinsic rhythm and continuous ventricular pacing. OS resulting in spurious ventricular detections was provoked in 3 (0.9%) of 329 patients during intrinsic rhythm and 34 (10.3%) of 329 during pacing. Noise transients not recognized and marked as sensed events, but visually evident on the local endocardial ventricular electrogram, were provoked in an additional 23 (7.0%) of 329 patients. Multivariate logistic regression identified history of spontaneous OS (P < 0.0005, odds ratio 9.7, 95% confidence interval [CI] 1.9 to 50.0), automatic gain control device (P < 0.0005, odds ratio 5.3, 95% CI 2.6 to 10.8) or integrated bipolar lead (P = 0.05, odds ratio 2.6, 95% CI 1.0 to 7.25), and male gender (P = 0.008, odds ratio 3.7, 95% CI 1.2 to 11.1) as predictive of provocable OS. Spontaneous OS resulting in spurious ventricular detections and therapies occurred in 12 (3.6%) patients during follow‐up. Eleven of 12 spontaneous episodes occurred in male patients during ventricular pacing; 11 of 12 patients had automatic gain control devices and integrated bipolar leads. Conclusion: OS is commonly provoked in ICD patients during ventricular pacing and may occur spontaneously, causing spurious tachyarrhythmia therapies and pacing inhibition. Differences in the incidence of spontaneous and provoked OS between ICD systems can be explained on the basis of unique features of automatic sensing systems and sensing lead design.
Problems of Heart Rate Correction in Assessment of Drug‐Induced QT Interval Prolongation
Authors: MALIK MAREK 
Published: August 2003

Problems of Drug‐Prolonged QTc Assessment.
Introduction: Estimation of QT interval prolongation belongs to safety assessment of every drug. Among unresolved issues, heart rate correction of the QT interval may be problematic. This article proposes a strategy for heart rate correction in drug safety studies and demonstrates the strategy using a study of ebastine, a nonsedating antihistamine. Methods and Results: Four‐way cross‐over Phase I study investigated 32 subjects on placebo, ebastine 60 mg once a day, 100 mg once a day, and terfenadine 180 mg twice a day. Repeated ECGs were obtained before each arm and after 7 days of treatment. The changes in heart rate‐corrected QTc interval were investigated using (A) 20 published heart rate correction formulas, (B) a correction formula optimized by QT/RR regression modeling in all baseline data, and (C) individual corrections optimized for each subject by drug‐free QT/RR regression modeling. (A) Previously published correction formulas found QTc interval increases on terfenadine. The results with ebastine were inconsistent. For instance, Bazett's and Lecocq's correction found significant QTc increase and decrease on ebastine, respectively. The results were related (|r| > 0.95) to the success of each formula (independence of drug‐free QTc and RR intervals). (B) The pooled drug‐free QT/RR regression found an optimized correction QTc = QT/RR0.314. QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were − 1.95 ± 6.87 msec (P = 0.18), − 3.91 ± 9.38 msec (P = 0.053), 0.75 ± 8.23 msec (P = 0.66), and 12.95 ± 14.64 msec (P = 0.00025), respectively. (C) Individual QT/RR regressions were significantly different between subjects and found optimized corrections QTc = QT/RRα with α= 0.161 to 0.417. Individualized QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were − 2.76 ± 5.51 msec (P = 0.022), − 3.15 ± 9.17 msec (P = 0.11), − 2.61 ± 9.55 msec (P = 0.19), and 12.43 ± 15.25 msec (P = 0.00057), respectively. Drug‐unrelated QTc changes up to 4.70 ± 8.92 msec reflected measurement variability. Conclusion: Use of published heart rate correction formulas in the assessment of drug‐induced QTc prolongation is inappropriate, especially when the drug might induce heart rate changes. Correction formulas optimized for pooled drug‐free data are inferior to the formulas individualized for each subject. Measurement imprecision and natural variability can lead to mean QTc interval changes of 4 to 5 msec in the absence of drug treatment.
T Wave Alternans Threshold in Normal Children
Authors: CHEUNG MICHAEL M.H. , DAVIS ANDREW M. , COHEN RICHARD J. , WILKINSON JAMES L. 
Published: August 2003

T Wave Alternans in Children.
Introduction: Sustained microvolt‐level T wave alternans (TWA) during exercise is a predictor of ventricular arrhythmia propensity in adult populations. TWA occurs in normal adults, but it is rare at < 70% of predicted maximum heart rate. An onset heart rate ≤ 110 is believed to be significant. The aim of this study was to examine the feasibility of performing the test in children and to determine the normal heart rate threshold for sustained TWA in children. Methods and Results: Alternans was evaluated during bicycle exercise in 100 normal volunteers aged 8 to 17 years. Adequate resting data were obtained in 76 of 100 children and was negative in all. Exercise data from 16 of 100 was excluded due to excessive noise. Median maximum heart rate was 192 (range 140 to 214). Sustained alternans was absent in 75 (89%) of 84. In the nine children with sustained alternans, median onset heart rate was 138 (range 120 to 158), and 7 of 9 had an onset heart rate ≤ 135. Median heart rate threshold as a percentage of predicted maximum heart rate (220 – age) was 67% (range 58% to 76%). Only 1 subject (1.2%) had an onset heart rate < 60% of predicted maximum. There was no significant difference between age, gender, endurance, maximum heart rate, QRS duration, QT interval, or QTc in those with and those without sustained TWA. Conclusion: Noninvasive assessment of TWA is feasible at ≤ 8 years of age. Sustained TWA was present in 11% of normal children, but was absent at heart rates below 120 and rare (1.2%) below 60% of predicted maximum heart rate.