bluuebunny/crossref_metadata_2025 huggingface dataset:
Tight Mechanism Correlation Between Heart Rate Turbulence and Baroreflex Sensitivity: Sequential Autonomic Blockade Analysis
Authors: LIN LIAN‐YU , LAI LING‐PING , LIN JIUNN‐LEE , DU CHAO‐CHENG , SHAU WEN‐YI , CHAN HSIAO‐LUNG , TSENG YUNG‐ZU , HUANG SHOEI K. STEPHEN
Published: August 2003

Heart Rate Turbulence and Baroreflex Sensitivity.
Introduction: Heart rate turbulence is a powerful de novo risk predictor for patients surviving acute myocardial infarction. However, little is known about its underlying physiologic mechanism.

Methods and Results: Hypothesizing that heart rate turbulence is barorceptor reflex related, we studied heart rate and blood pressure fluctuations at rest and after systematically introduced ventricular premature beats in 16 patients without structural heart disease (10 men and 6 women; mean age 45 ± 17 years) before and after sequential sympathetic (esmolol 4‐mg bolus followed by 120 μg/kg/min intravenously), parasympathetic (atropine 0.04 mg/kg intravenously), and combined autonomic blockade (esmolol plus atropine). Turbulence onset (%) and turbulence slope (msec/beat) were averaged from 10 respective ventricular premature beats. Spontaneous baroreflex sensitivity (msec/mmHg) was calculated from 5 minutes of sinus rhythm recording. The results showed that turbulence slope decreased after atropine (0.71 ± 0.50 msec/beat vs 5.17 ± 3.96 msec/beat at baseline; P < 0.01) and combined autonomic blockade (1.23 ± 1.02 msec/beat; P < 0.01) but was unchanged after esmolol (4.53 ± 3.30 msec/beat; P > 0.05). Turbulence onset increased after atropine (0.32% ± 0.35% vs −0.45 ± 0.94 at baseline; P < 0.05) and combined sympathetic and parasympathetic blockade (0.58% ± 0.86%; P < 0.05) but was unchanged after esmolol (−0.62% ± 1.33%; P > 0.05). Turbulence slope was positively correlated with baroreflex sensitivity at baseline (r = 0.78, P < 0.01) and after esmolol (r = 0.8, P < 0.01), but dissociated after atropine (r = 0.16, P > 0.05) and combined autonomic blockade (r = 0.31, P > 0.05). Turbulence onset was negatively correlated with baroreflex sensitivity at baseline (r =−0.61, P < 0.05), after esmolol (r =−0.80, P < 0.01), and after atropine (r =−0.53, P < 0.05).

Conclusion: Heart rate turbulence of turbulence onset and turbulence slope is critically vagal dependent and highly correlated with spontaneous baroreflex sensitivity, which underscores its clinical importance in cardiovascular risk stratification.
Discrimination of Ventricular Tachycardia from Supraventricular Tachycardia by a Downloaded Wavelet‐Transform Morphology Algorithm: A Paradigm for Development of Implantable Cardioverter Defibrillator Detection Algorithms
Authors: SWERDLOW CHARLES D. , BROWN MARK L. , LURIE KEITH , ZHANG JIANXIN , WOOD NICOLE M. , OLSON WALTER H. , GILLBERG JEFFREY M.
Published: August 2003

Morphology Download.
Introduction: Present implantable cardioverter defibrillators (ICDs) have algorithms that discriminate supraventricular tachycardia (SVT) from ventricular tachycardia (VT). One type of algorithm is based on differences in morphology of ventricular electrograms during VT and SVT. Prior SVT‐VT discrimination algorithms have not undergone real‐time evaluation in ambulatory patients until they were incorporated permanently into ICDs. This approach may result in incomplete testing of electrogram morphology algorithms because they are influenced by posture, activity, and electrogram maturation. We downloaded software into implanted ICDs to study a novel algorithm that compares morphologies of baseline and tachycardia electrograms based on differences between corresponding coefficients of their wavelet transforms. This comparison is expressed as a match‐percent score.

Methods and Results: In 23 patients, we downloaded the wavelet algorithm into implanted ICDs to assess the temporal and postural stability of baseline electrograms as measured by this algorithm and its accuracy for SVT‐VT discrimination. Median follow‐up was 6 months. Software was downloaded into all ICDs without altering other device functions. With few exceptions, percent template match in baseline rhythm was stable with changes in body position, rest versus walking, isometric exercise, and over time (1 and 3 months). Using the nominal match‐percent threshold of 70%, sensitivity for detection of 38 VTs was 100%. Specificity for rejection of 65 SVTs was 78%. SVTs were rejected for a total of 2.7 hours. Inappropriate detections of SVT as VT were caused by electrogram truncation, myopotential interference with low‐amplitude electrograms, waveform alignment error, and rate‐dependent aberrancy. The first three accounted for 69% of inappropriate detections and could have been prevented by optimal programming. The optimal match‐percent threshold was 60% to 70% based on a receiver‐operator characteristic curve. After shocks, the median time for baseline electrogram morphology to normalize was 85 seconds.

Conclusion: The wavelet morphology algorithm has high sensitivity for VT detection. Inappropriate detections of SVT as VT may be reduced by optimal programming. Downloadable software permits evaluation of new algorithms in implanted ICDs.
Analysis of the Chronotropic Effect of Acetylcholine on Sinoatrial Node Cells
Authors: ZHANG HENGGUI , HOLDEN ARUN V. , NOBLE DENIS , BOYETT MARK R.
Published: August 2003

Analysis of Chronotropic Effect of ACh.
Introduction: The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue.

Methods and Results: The known concentration‐dependent effects of ACh on iK,ACh, iCa,L, and if were introduced into models of rabbit central and peripheral SA node cells. In the central and peripheral models, 9 × 10−8 and 14 × 10−8 M ACh, respectively, caused a 50% decrease in pacemaking rate, whereas in rabbit SA node ˜ 7.4 × 10−8 M ACh caused such a decrease. In the models, iK,ACh was primarily responsible for the decrease and actions of ACh on iCa,L or if alone caused a negligible effect. Although the inhibition of if did not directly contribute to the chronotropic effect, it was indirectly important, because it minimized the opposition by if to the decrease of rate caused by activation of iK,ACh. The central model was more sensitive to ACh than the peripheral model.

Conclusion: The chronotropic effect of ACh is principally the result of activation of iK,ACh, and inhibition of iCa,L plays little or no role. Inhibition of if and possible inhibition of ib,Na play an important facilitative role by reducing the ability of if and ib,Na to curtail the chronotropic effect caused by activation of iK,ACh.
Osborn Waves Associated with Ventricular Fibrillation in a Patient with Vasospastic Angina
Authors: MARUYAMA MITSUNORI , ATARASHI HIROTSUGU , INO TAKESHI , KISHIDA HIROSHI
Published: August 2003

Osborn Waves in Ischemic Heart Disease. A 52‐year‐old man with a history of vasospastic angina experienced a severe ischemic episode accompanied by a non‐Q wave myocardial infarction. Two episodes of ventricular fibrillation (VF) occurred during the acute phase of the event. Osborn waves were observed on the ECG preceding each episode of VF. In the second episode, the gradual development of Osborn waves until VF occurred was confirmed on ECG. The Osborn waves appeared to be related to the occurrence of VF. This case may provide clinical evidence that a prominent Ito participates in the development of VF during myocardial ischemia.
Electrical Connection Between Left Superior and Inferior Pulmonary Veins in a Patient with Paroxysmal Atrial Fibrillation
Authors: TAKAHASHI YOSHIHIDE , IESAKA YOSHITO , TAKAHASHI ATSUSHI , HIRAOKA MASAYASU
Published: August 2003

Electrical Connection Between Pulmonary Veins. We report the case of a patient with paroxysmal atrial fibrillation, who underwent pulmonary vein (PV) electrical isolation from the left atrium (LA). Prior to achieving isolation of the left superior PV (LSPV) from the LA, earlier PV potentials were recorded inside the left inferior PV (LIPV) than LA activity during pacing at the distal LSPV. The LSPV finally was isolated by radiofrequency applications at the ostium of the LIPV. The patient had electrical connection between the LSPV and LIPV, and required radiofrequency ablation of the breakthroughs from the LA to LIPV for complete isolation of the LSPV.
Atrial Fibrillation After DDDR Pacemaker Implantation
Authors: GILLIS ANNE M. , MORCK MARGARET
Published: August 2003

AF After Pacemaker Implantation.
Introduction: Newer implantable pulse generators have data storage capabilities that permit detection of multiple episodes of atrial fibrillation (AF). This study evaluated the clinical predictors and time course of AF development in a general pacemaker population.

Methods and Results: Patients (n = 231) received DDDR pacemakers with features that permit detection and storage of information about the date, time of onset, and duration of multiple, sequential episodes of AF. Patients were followed for 718 ± 383 days. Time to first occurrence of AF, interval between first and second episode of AF, and total AF burden were determined at each follow‐up visit. AF occurred more often in patients (68%) with sinus node disease than in patients with AV block (37%; P < 0.001). Time to first occurrence of AF was 21.2 days (95% confidence interval [CI] 14.7 to 30.6 days) after pacemaker implantation. AF burden initially decreased significantly in patients (0.8 hours/day, 95% CI 0.7 to 0.9 at 8 weeks after implant vs 0.6 hours/day, 95% CI 0.4 to 0.8 at 12 months after implant; P = 0.005) but then increased significantly during long‐term follow‐up (2.0 hours/day, 95% CI 1.0 to 3.7 at 48 months after implant; P = 0.008). The long‐term increase in AF burden was seen predominantly in patients with sinus node disease. A prior history of AF and the duration of follow‐up were independent predictors of AF occurrence.

Conclusion: AF develops frequently after dual‐chamber pacemaker implantation. AF burden increases progressively over the long term.
Outcome of Women Versus Men with Ventricular Tachyarrhythmias Treated with the Implantable Cardioverter Defibrillator
Authors: PIRES LUIS A. , SETHURAMAN BARATHI , GUDUGUNTLA VAMSHIDHAR D. , TODD KATRINA M. , YAMASAKI HIROSHI , RAVI SRIHARI
Published: August 2003

Gender and ICD Therapy.
Introduction: Important sex differences in the incidence and outcome of patients with ischemic heart disease, the leading cause of ventricular tachyarrhythmias, have been identified. Implantable cardioverter defibrillator (ICD) therapy has become the treatment of choice for patients with ventricular tachycardia (VT) and ventricular fibrillation (VF), but little is known about gender differences in the outcome of ICD‐treated patients.

Methods and Results: In this retrospective study, we compared arrhythmic events and survival of 376 women and 1,654 men treated with an ICD as part of prospective evaluations of transvenous devices or lead systems. Women were younger (62 ± 14 years vs 65 ± 12 years, P = 0.0005), had higher left ventricular ejection fraction (0.36 ± 0.15 vs 0.32 ± 0.13, P < 0.0001), were more likely to present with VF (34% vs 19%, P < 0.001), and had lower implantation defibrillation threshold (11 ± 6 vs 13 ± 6 J, P < 0.0001). Implant complication rates were similar in men and women (2.6% vs 3.5%, P = 0.46). The 1‐year and 2‐year cumulative rates of appropriate ICD therapies were 31.4% and 38.4% for men and 32.6% and 40.8% for women, respectively (P = 0.63). The unadjusted 1‐year and 2‐year cumulative survival rates were 95.6% and 93.7% for men and 95.7% and 94.3% for women, respectively (P = 0.98). Adjusted total (P = 0.61), sudden (P = 0.82), and cardiac (P = 0.34) death‐free survivals also were similar in men and women.

Conclusion: Despite clinical differences suggesting women are at lower risk than men, men and women with VT/VF who are treated with an ICD have similar arrhythmic event and survival rates. These factors should be considered when determining risk and prescription of ICD therapy for women.
Short‐Term Rapid Atrial Pacing Produces Electrical Remodeling of Sinus Node Function in Humans
Authors: HADIAN DJAVID , ZIPES DOUGLAS P. , OLGIN JEFFREY E. , MILLER JOHN M.
Published: August 2003

Sinus Node Remodeling in Man.
Introduction: Depression of sinus node function occurs in dogs and in patients after cessation of atrial flutter and fibrillation. We tested whether transient atrial pacing might produce similar changes in humans.

Methods and Results: We studied the impact of short‐term rapid atrial pacing, simulating atrial tachyarrhythmias, on sinoatrial conduction time (SACT) and corrected sinus node recovery time (CSNRT) in 10 patients undergoing electrophysiologic study. None had recognizable structural heart disease, history of atrial fibrillation or flutter, autonomic dysfunction, or any tachycardia for at least 24 hours before study. All cardiac drugs were discontinued > 5 half‐lives prior to study. No patient had significant hypotension during atrial stimulation. SACT and CSNRT were measured at baseline, and sinus node reset zone was determined. Right atrial pacing was performed for 10 to 15 minutes, after which SACT and CSNRT were measured again. Both parameters increased significantly, from 423 ± 208 msec to 491 ± 214 msec and from 80 ± 50 msec to 96 ± 53 msec, respectively (P = 0.02 and P < 0.001, respectively).

Conclusion: Rapid atrial pacing for only 10 to 15 minutes, simulating transient atrial tachyarrhythmias, alters sinus node function in humans. Additional studies are needed to evaluate the mechanism, but the clinical implication is that even transient episodes of atrial tachyarrhythmias can cause sinus node remodeling in patients.
Intrapericardial Therapeutics: A Pharmacodynamic and Pharmacokinetic Comparison Between Pericardial and Intravenous Procainamide Delivery
Authors: UJHELYI MICHAEL R. , HADSALL KELLY Z. , EULER DAVID E. , MEHRA RAHUL
Published: August 2003

Pericardial Procainamide Delivery.
Introduction: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery.

Methods and Results: Swine were randomized to sequential procainamide doses delivered intravenously (n = 6) or into the pericardial space (n = 7). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% (P < 0.01) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% (P < 0.05) and raised atrial fibrillation threshold by 70 mA (P < 0.05). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% (P < 0.01), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial‐ventricular conduction times by 27% and 17%, respectively (P < 0.05), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% (P < 0.05). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 μg/mL, but plasma concentrations were < 1 μg/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 μg/mL.

Conclusion: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.
Novel Cause of Spurious Mode Switching in Dual‐Chamber Pacemakers: Atrioventricular Desynchronization Arrhythmia
Authors: SWEENEY MICHAEL O.
Published: August 2003

Spurious Mode Switching. Spurious mode switching is a common problem in DDDR pacing and implantable cardioverter defibrillator systems. It may produce symptoms indistinguishable from classic pacemaker syndrome or paroxysmal atrial arrhythmias due to loss of AV synchrony. The dominant cause of spurious mode switching is oversensing of far‐field R waves. This report describes a novel cause of spurious mode switching, AV desynchronization arrhythmia. Clinical manifestations, recognition, and management are discussed.
Short‐Term Reproducibility of T Wave Alternans Measurement
Authors: TURITTO GIOIA , MIRANDI ANTHONY P. , PEDALINO RONALD P. , URETSKY SCOTT , EL‐SHERIF NABIL
Published: August 2003

T Wave Alternans Reproducibility.
Introduction: Microvolt T wave alternans (TWA) has been proposed as a strong independent predictor of malignant ventricular tachyarrhythmias and sudden cardiac death. TWA reproducibility during bicycle stress test has not been previously investigated. We sought to assess the short‐term reproducibility of TWA, as well as heart rate (HR) threshold for TWA, and its spatial distribution and magnitude.

Methods and Results: The study enrolled 42 patients who were able to complete two bicycle stress tests with HR at peak exercise > 110 beats/min within 4 hours of each other and who had technically adequate recordings for TWA analysis during both tests. Concordant results for TWA determination were obtained in 39 (93%) of 42 cases. TWA was present during both tests in 23 patients and was absent during both tests in 16 patients. In the 23 patients with two positive tests, HR at the onset of TWA was not significantly different during the two tests. Further, the number of leads showing TWA and the magnitude of TWA were not significantly different between the two tests.

Conclusion: TWA is characterized by satisfactory short‐term reproducibility and, when present, by high temporal and spatial stability.
Repolarization Dynamics in Patients with Long QT Syndrome
Authors: PERKIÖMÄKI JUHA S. , ZAREBA WOJCIECH , NOMURA ATSUNOBU , ANDREWS MARK , KAUFMAN ELIZABETH S. , MOSS ARTHUR J.
Published: August 2003

Repolarization Dynamics in LQTS.
Introduction: Dynamics of ventricular repolarization may contribute to cardiac arrhythmias in subjects with the long QT syndrome (LQTS). The aim of the present study was to assess the dynamics of repolarization duration and the dynamics of repolarization complexity in LQTS patients and their unaffected family members.

Methods and Results: Twelve‐lead 24‐hour ambulatory ECG recordings were obtained from LQTS patients (n = 38) and unaffected family members (n = 20). The 24‐hour dynamics of the QT interval, T wave complexity (TWC) index measured by principal component analysis, and the RR interval were analyzed using standard deviation (SD) and square root of the mean squared differences of successive values of the parameters (RMSSD). QT variability, mean TWC, and TWC variability were increased in the LQTS patients compared with unaffected family members (QT‐SD: 38 ± 20 msec vs 19 ± 7 msec, P = 0.0001; QT‐RMSSD: 36 ± 20 msec vs 14 ± 8 msec, P = 0.0001; TWC: 27.7% ± 11.1% vs 20.4% ± 6.7%, P = 0.003; TWC‐SD: 6.7% ± 2.8% vs 4.6% ± 1.8%, P = 0.003; TWC‐RMSSD: 5.3% ± 2.8% vs 3.7% ± 1.2%, P = 0.004, respectively). At the same time, the measures of heart rate variability were similar between the affected and unaffected LQTS subjects (SD of normal‐to‐normal RR intervals [SDNN]: 94 ± 25 msec vs 89 ± 37 ms, P = 0.56; RMSSD: 49 ± 26 msec vs 49 ± 34 ms, P = 0.97, respectively).

Conclusion: Despite similar heart rate variability, QT variability and the variability of TWC are significantly increased in LQTS patients compared with unaffected family members, suggesting that disturbances in temporal dynamics of repolarization and repolarization complexity in LQTS patients possibly increase vulnerability to arrhythmias.
Randomized Comparison of Anatomic and Electrogram Mapping Approaches to Ablation of Typical Atrial Flutter
Authors: TADA HIROSHI , ORAL HAKAN , OZAYDIN MEHMET , CHUGH AMAN , SCHARF CHRISTOPH , HASSAN SOHAIL , GREENSTEIN RADMIRA , PELOSI FRANK , KNIGHT BRADLEY P. , STRICKBERGER S. ADAM , MORADY FRED
Published: August 2003

Isthmus Ablation.
Introduction: The cavotricuspid isthmus can be ablated using an anatomic approach or an electrogram mapping approach in which sites at which there is a gap in the line of block are targeted. The aim of this study was to compare the anatomic and electrogram mapping approaches for creating a line of block in the cavotricuspid isthmus after an initial, unsuccessful anatomically directed ablation line.

Methods and Results: The subjects of this study were 63 patients with isthmus‐dependent atrial flutter in whom a single series of contiguous applications of radiofrequency energy guided by fluoroscopy in the cavotricuspid isthmus did not result in complete block. The patients were randomly assigned to additional ablation on an anatomic basis (n = 31) or guided by single potentials or narrowly split double potentials during coronary sinus pacing (n = 32). After every 15 applications of radiofrequency energy, the alternate approach was used until complete block was achieved. Before cross‐over, complete block was achieved in 6 patients (19%) with the anatomic approach compared with 19 patients (59%) with the electrogram mapping approach (P < 0.005). The electrogram mapping approach also was more effective than the anatomic approach in achieving complete isthmus block after the first cross‐over (72% vs 23%, P < 0.005) and after the second cross‐over (80% vs 42%, P < 0.05).

Conclusion: When there is incomplete block after an initial series of applications of radiofrequency energy in the cavotricuspid isthmus, complete block is achieved more efficiently with an electrogram mapping approach than with an anatomic approach.
Frequency of Symptomatic Atrial Fibrillation in Patients Enrolled in the Atrial Fibrillation Follow‐up Investigation of Rhythm Management (AFFIRM) Study
Authors: EPSTEIN ANDREW E. , VIDAILLET HUMBERTO , GREENE H. LEON , CURTIS ANNE B. , ELLENBOGEN KENNETH A. , SIMMONS TODD , MICKEL MARY
Published: August 2003

AF Frequency.
Introduction: The frequency of symptomatic paroxysmal atrial fibrillation (AF) may identify subsets with different characteristics. Because the approach to AF now is so varied, ranging from drug therapy to surgery and catheter ablation, the frequency of AF may have important therapeutic implications if the frequency identifies subsets with distinguishing features.

Methods and Results: The Atrial Fibrillation Follow‐up Investigation of Rhythm Management (AFFIRM) Study is evaluating patients with AF who are at high risk for stroke. We evaluated the clinical characteristics of the patients in the AFFIRM Study in an attempt to identify features that might distinguish patients with infrequent and frequent AF occurrences. Patients were divided into five groups, based upon the historic frequency of occurrence of AF at the time the patients were enrolled in the study. Although statistically significant differences were present among the groups, no important differences were noted in clinical or echocardiographic characteristics that could differentiate patients with frequent episodes of AF from other patients in the AFFIRM population.

Conclusion: In a large population of patients with AF at high risk for stroke, individual historic and echocardiographic characteristics failed to distinguish patients based on the frequency of AF. Those with frequent and infrequent AF were similar. Although AF frequency has been suggested as a marker of a focal etiology in young populations with little overt heart disease, it does not seem to be a distinguishing characteristic in older populations at high risk for stroke.
Phase Singularities and Termination of Spiral Wave Reentry
Authors: EASON JAMES , TRAYANOVA NATALIA
Published: August 2003

Phase Singularities and Termination of Reentry.
Introduction: Recent defibrillation studies show that electric fields interact with reentrant activity in myocardial tissue through virtual electrode polarization (VEP). This study focuses on determining how VEP relates to the creation and survival of postshock phase singularities in cardiac tissue and demonstrating that interactions between VEP and preshock tissue state engender the probabilistic nature of defibrillation.

Methods and Results: We constructed a two‐dimensional tissue model representing a ventricular cross‐section with fiber architecture and surrounding bath. We initiated spiral wave reentry and subjected the tissue to a monophasic shock. We estimated the shock success probability for a given strength by testing 16 coupling intervals throughout a single rotation of the wavefront. Over a range of shock strengths, our model exhibits dose‐response behavior similar to experimental defibrillation efficacy curves. At the 50% effective strength (ED50), successful termination of reentry depends upon the interaction between preshock excitable gap and postshock phase singularities. We also found that increasing the stimulus strength toward ED50 increases the number of postshock singularities, whereas further strength increases above ED50 decrease the number of singularities.

Conclusion: Our results show for the first time that a computational model can account for the probabilistic nature of defibrillation as VEP interacts with the dynamics of an ongoing reentrant wavefront. Further, we demonstrate that success of a shock depends on the annihilation of the phase singularities that arise after any strong stimulus. Our findings imply that VEP completely overrides the preshock tissue state in shocks that are highly likely to defibrillate (ED95).
Developmentally Modulated Cardiac Conduction Failure in Transgenic Mice with Fetal or Postnatal Overexpression of DNA Nonbinding Mutant Nkx2.5
Authors: WAKIMOTO HIROKO , KASAHARA HIDEKO , MAGUIRE COLIN T. , IZUMO SEIGO , BERUL CHARLES I.
Published: August 2003

Conduction Failure in Mutant Nkx2.5 Overexpression Mice.
Introduction: Nkx2.5 is a conserved homeodomain (HD) containing transcription factor essential for early cardiac development. We generated a DNA nonbinding missense mutation, I183P in the HD, similar to the missense HD mutation found in patients. Transgenic mice expressing this mutation under β‐MHC promoter [β‐MHC(I183P)] showed a postnatal lethal phenotype with heart failure. In contrast, mice expressing the mutation under α‐MHC promoter [α‐MHC(I183P)] survive, with later onset heart failure. The aim of this study was to investigate the interrelationship between lethal cardiac failure and the electrophysiologic (EP) phenotypes using cardiac‐specific promoters with mutant gene expression at different stages of development and maturation.

Methods and Results: In‐MHC(I183P) and wild‐type littermates, six‐lead ECG and in vivo endocardial EP studies were performed at 2.5, 3, 4, and 5 weeks of age. In α‐MHC(I183P) and their wild‐type controls, ECGs were acquired at 3, 19, 31, and 64 weeks and in vivo EP studies assssed at 19 ± 4 weeks of age. β‐MHC(I183P) mice display AV nodal, atrial, and ventricular EP dysfunction by 3 weeks of age. Bradycardia and PR prolongation were evident on telemetered ambulatory ECG of β‐MHC(I183P) mice. In contrast, α‐MHC(I183P) mice had no abnormalities on serial ECG through 31 weeks or EP findings at 19 weeks, except increased myocardial tissue refractoriness. However, by 64 weeks, PR intervals lengthened in α‐MHC(I183P) mice.

Conclusion: Both prenatal and postnatal overexpression of DNA nonbinding mutant Nkx2.5 are associated with AV conduction malfunction and heart failure; however, more profound progressive EP defects are seen when this mutation expresses during fetal and neonatal periods. These conduction abnormalities may contribute to the lethal heart failure and early mortality evident in DNA nonbinding mutant Nkx2.5 mice.
Influence of QRS Duration on the Prognostic Value of T Wave Alternans
Authors: RASHBA ERIC J. , OSMAN AHMED F. , MACMURDY KAREN , KIRK MALCOLM M. , SARANG SAMANTHA , PETERS ROBERT W. , SHOROFSKY STEPHEN R. , GOLD MICHAEL R.
Published: August 2003

T Wave Alternans and QRS Duration.
Introduction: T wave alternans (TWA) is a promising new noninvasive marker of arrhythmia vulnerability that quantifies beat‐to‐beat changes in ventricular repolarization. Secondary repolarization abnormalities are common in subjects with wide QRS complexes. However, the relationship between TWA and QRS prolongation has not been evaluated. The goal of this study was to determine if QRS prolongation influences the prevalence or prognostic value of TWA.

Methods and Results: The study consisted of 108 consecutive patients with coronary artery disease and left ventricular ejection fraction ≤40% who were referred for electrophysiologic studies. Patients underwent TWA testing using bicycle ergometry in the absence of beta‐blockers or antiarrhythmic drugs. The primary endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator therapy. The prognostic value of TWA was assessed in the entire cohort and in two subgroups: QRS < 120 msec (normal, n = 62) and QRS ≥ 120 msec (prolonged, n = 46). TWA (hazard ratio 2.2, P = 0.03) and QRS prolongation (hazard ratio 2.2, P = 0.01) were both significant and independent predictors of arrhythmic events. QRS prolongation had no effect on the prevalence of positive TWA tests (QRS < 120 msec: 48%, QRS ≥ 120 msec: 50%, P = NS). TWA was a highly significant predictor of events in patients with a normal QRS (hazard ratio 5.8, P = 0.02). In contrast, TWA was not useful for risk stratification in subjects with QRS prolongation (hazard ratio 1.1, P = 0.8).

Conclusion: TWA is useful only for risk stratification in the absence of QRS prolongation. The presence of QRS prolongation and left ventricular ejection fraction ≤40% may be sufficient evidence of an adverse prognosis that additional risk stratification is not useful or necessary.
Aging‐Related Increase to Inducible Atrial Fibrillation in the Rat Model
Authors: HAYASHI HIDEKI , WANG CHARLES , MIYAUCHI YASUSHI , OMICHI CHIKAYA , PAK HUI‐NAM , ZHOU SHENGMEI , OHARA TOSHIHIKO , MANDEL WILLIAM J. , LIN SHIEN‐FONG , FISHBEIN MICHAEL C. , CHEN PENG‐SHENG , KARAGUEUZIAN HRAYR S.
Published: August 2003

Aging and Atrial Fibrillation.
Introduction: Aging is associated with atrial interstitial fibrosis and increased incidence of atrial fibrillation (AF). We hypothesized that aged rats are suitable for study of aging‐related AF and that partial atrial cellular uncoupling induced with heptanol in young rats mimics aging‐related AF.

Methods and Results: Interatrial conduction time and atrial response to burst atrial pacing were evaluated in 11 young (2–3 months) and 12 old (22–24 months) male rats (Fisher 344) in the Langendorff‐perfused setting. At baseline, sustained (>30 sec) atrial tachycardia (AT) and AF were induced in 10 of 12 and in 7 of 12 old rats, respectively. No such arrhythmias could be induced in the young rats. Old rats had significantly (P < 0.01) longer interatrial conduction time and P wave durations than the young rats. Burst pacing failed to induce AT and AF in all 11 young rats studied. The effects of heptanol 2 to 10 μM were studied in both groups. Heptanol 2 to 5 μM promoted inducible AT in all 5 young rats studied; however, when its concentration was raised to 10 μM, AT could no longer be induced in any of the 5 young rats. No AF could be induced in any of the 5 young rats at heptanol concentrations of 2 to 10 μM. In the old rats, AF could still be induced during perfusion of 2 μM heptanol. However, when its concentration was raised to 5 and 10 μM, AF could not be induced in any of the 6 old rats studied. Optical mapping using a potentiometric dye showed a periodic single wavefront of activation during AT in both groups and 2 to 4 independent wavefronts propagating in different directions during AF in the old rats. Histology revealed a significant increase in interstitial atrial fibrosis (P < 0.01), atrial cell size (P < 0.05), and heart weight in old versus young rats. Fibrosis in the old rats was highly heterogeneous.

Conclusion: The rat model is suitable for study of aging‐related AF. Uniform partial atrial cellular uncoupling with heptanol perfusion in the young rats, although promoting inducible AT, does not mimic aging‐related AF. The results suggest that heterogeneous atrial interstitial fibrosis and atrial cell hypertrophy might contribute to the aging‐related increase in atrial conduction slowing, conduction block, and inducible AF in the old rat model.
Exercise is Superior to Pacing for T Wave Alternans Measurement in Subjects with Chronic Coronary Artery Disease and Left Ventricular Dysfunction
Authors: RASHBA ERIC J. , OSMAN AHMED F. , MACMURDY KAREN , KIRK MALCOLM M. , SARANG SAMANTHA , PETERS ROBERT W. , SHOROFSKY STEPHEN R. , GOLD MICHAEL R.
Published: August 2003

Exercise vs Pacing for TWA Measurement.
Introduction: T wave alternans (TWA) is a heart rate‐dependent marker of vulnerability to ventricular arrhythmias. Atrial pacing and exercise both are used as provocative stimuli to elicit TWA. However, the prognostic value of the two testing methods has not been compared. The aim of this prospective study was to compare the prognostic value of TWA measured during bicycle exercise and atrial pacing in a large cohort of high‐risk patients with ischemic heart disease and left ventricular dysfunction.

Methods and Results: This was a prospective study of 251 patients with coronary artery disease and left ventricular dysfunction who were referred for electrophysiologic studies (EPS) for standard clinical indications. Patients underwent TWA testing using bicycle ergometry (exercise TWA, n = 144) and/or atrial pacing (pacing TWA, n = 178). The primary endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator therapy. The predictive value of exercise and pacing TWA for EPS results and for endpoint events was determined. Exercise and pacing TWA both were significant predictors of EPS results (odds ratios 3.0 and 2.9 respectively, P < 0.02). Kaplan‐Meier survival analysis of the primary endpoint revealed that exercise TWA was a significant predictor of events (hazard ratio 2.2, P = 0.03). In contrast, pacing TWA had no prognostic value for endpoint events (hazard ratio 1.1, P = 0.8).

Conclusion: TWA should be measured during exercise when it is used for clinical risk stratification. EPS results may not be an adequate surrogate for spontaneous events when evaluating new risk stratification tests.
Randomized Comparison of Bipolar versus Unipolar Plus Bipolar Recordings During Segmental Ostial Ablation of Pulmonary Veins
Authors: TADA HIROSHI , ORAL HAKAN , KNIGHT BRADLEY P. , OZAYDIN MEHMET , CHUGH AMAN , SCHARF CHRISTOPH , HASSAN SOHAIL , GREENSTEIN RADMIRA , PELOSI FRANK , STRICKBERGER S. ADAM , MORADY FRED
Published: August 2003

Unipolar vs Bipolar Electrograms.
Introduction: Segmental ostial ablation to isolate pulmonary veins is guided by pulmonary vein potentials. The aim of this prospective randomized study was to compare the utility of unipolar plus bipolar electrograms versus only bipolar electrograms as a guide for segmental ablation to isolate the pulmonary veins in patients with atrial fibrillation.

Methods and Results: Isolation of the left superior, right superior, and left inferior pulmonary veins was attempted in 44 patients (35 men and 9 women; mean age 54 ± 10 years) with paroxysmal atrial fibrillation. A decapolar Lasso catheter was positioned in the pulmonary veins, near the ostium, and a conventional ablation catheter was used for segmental ablation aimed at elimination of all pulmonary vein potentials. One hundred fourteen pulmonary veins were randomly assigned for ostial ablation guided by either bipolar or unipolar plus bipolar recordings. Electrical isolation was achieved in 51 (96%) of 53 pulmonary veins randomized to the bipolar approach, and 57 (93%) of 61 pulmonary veins randomized to the unipolar plus bipolar approach (P = 0.7). In the unipolar plus bipolar group, the total duration of radiofrequency energy needed to achieve isolation, 5.5 ± 2.8 minutes/vein, was significant shorter than in the bipolar group, 7.6 ± 4.1 minutes/vein (P < 0.01). Mean procedure and fluoroscopy durations per vein were 19% to 28% shorter in the unipolar plus bipolar group.

Conclusion: Segmental ostial ablation to isolate the pulmonary veins can be achieved more efficiently and with less radiofrequency energy when guided by both unipolar and bipolar recordings than by bipolar recordings alone.
Conduction Delay Within the Coronary Sinus in Humans: Implications for Atrial Arrhythmias
Authors: KATRITSIS DEMOSTHENES , IOANNIDIS JOHN P.A. , GIAZITZOGLOU ELEFTHERIOS , KOROVESIS SOCRATES , ANAGNOSTOPOULOS CONSTANTINE E. , CAMM A. JOHN
Published: August 2003

Coronary Sinus Mapping.
Introduction: Striated myocardial connections between the venous wall of the coronary sinus (CS) and the left atrium have been described in humans. This aim of this study was to investigate the conduction properties and potential arrhythmogenicity of CS and left atrial myocardial connections in patients with and patients without paroxysmal atrial fibrillation (PAF).

Methods and Results: Thirty‐eight patients with PAF, 52 patients with other arrhythmias, and 44 patients without arrhythmia underwent catheter mapping of the CS from the distal superoposterior part to the ostium. Catheterization of the superoposterior CS was feasible in 21, 32, and 25 subjects in the three groups, respectively (P = 0.82). Discrete double potentials or fractionated electrograms were recorded during proximal CS or right atrial pacing in 14 (66.7%), 11 (34.4%), and 5 (20.0%) patients, respectively (P = 0.004). In 29 patients, double or fractionated potentials were recorded at the distal superoposterior CS, in 3 at the mid‐CS, and in 4 at the ostium. Spontaneous or induced atrial ectopy and/or tachyarrhythmias were recorded in 18 (85.7%), 12 (37.5%), and 2 (8.0%) patients in the three groups, respectively (P < 0.001) and originated from the CS in 6, 3, and 0 patients, respectively (P = 0.010).

Conclusion: Recording of double potentials is possible within the CS, particularly at its distal superoposterior part, near the left superior pulmonary vein. Their prevalence is higher in patients with PAF than in subjects with other or no arrhythmias, and their presence denotes possible sources or substrate for atrial arrhythmia.
Heterogeneous Loss of Connexin43 Protein in Nonischemic Dilated Cardiomyopathy with Ventricular Tachycardia
Authors: KITAMURA HIDETSUNA , OHNISHI YOSHIO , YOSHIDA AKIHIRO , OKAJIMA KATSUNORI , AZUMI HIROSHI , ISHIDA AKIHIKO , GALEANO ERDULFO J. , KUBO SHINYA , HAYASHI YOSHITAKE , ITOH HIROSHI , YOKOYAMA MITSUHIRO
Published: August 2003

Connexin43 Expression in DCM.
Introduction: Gap junction alterations recently have been implicated in chronic heart failure, but direct evidence between gap junction manifestation in nonischemic dilated cardiomyopathy (DCM) is lacking. The current study examines whether qualitative changes or altered distribution of gap junctional connexin43 (Cx43) are related to global ventricular function and ventricular arrhythmia in DCM.

Methods and Results: We investigated 31 DCM patients (52 ± 15 years) and 5 control subjects (55 ± 10 years). Expression of Cx43 proteins was qualitatively and quantitatively determined using immunoconfocal microscopy in right ventricular biopsy specimens from each patient. The expression level of Cx43 protein was defined as the proportion of tissue area occupied by Cx43 (percent tissue area) in each test area. Cx43 immunoreactive signal expressed as percent tissue area was not correlated with the change in left ventricular ejection fraction (P = 0.17). Of 31 DCM patients, 23% subsequently developed sustained ventricular tachycardia (VT), which allowed retrospective division of the samples into two groups: non‐VT and VT. Left ventricular ejection fraction was comparable in both groups, but the percent tissue area in the VT groups was significantly decreased compared with that of the non‐VT groups (P = 0.03). Furthermore, Cx43 protein was distributed heterogeneously in the VT groups (P < 0.0001).

Conclusion: Heterogeneous reduction of Cx43 protein may result in development of malignant ventricular arrhythmia in DCM.
Phased‐Array Intracardiac Echocardiography During Pulmonary Vein Isolation and Linear Ablation for Atrial Fibrillation
Authors: MARTIN ROBERT E. , ELLENBOGEN KENNETH A. , LAU YUNG R. , HALL JEFF A. , KAY G. NEAL , SHEPARD RICHARD K. , NIXON J.V. , WOOD MARK A.
Published: August 2003

Phased‐Array Intracardiac Echocardiography for AF Ablation.
Introduction: Fluoroscopic imaging provides limited anatomic guidance for left atrial structures. The aim of this study was to determine the utility of real‐time, phased‐array intracardiac echocardiography during radiofrequency ablation for atrial fibrillation.

Methods and Results: In 29 patients undergoing pulmonary vein isolation (n = 16) or linear (n = 13) left atrial radiofrequency ablation for atrial fibrillation, intracardiac phased‐array echocardiography was used to visualize left atrial anatomy and the pulmonary veins, as well as ablation and mapping catheters during ablation procedures. In the 16 pulmonary vein isolation patients, the mean pulmonary vein ostial diameters measured by venography and intracardiac echocardiography were similar for all veins positions, except that left common pulmonary vein diameters were larger as measured by echocardiography (2.50 ± 0.29 cm) than by venography (1.79 ± 0.50 cm, P = 0.001). The ostial diameters measured by echocardiography and venography were not correlated, however (r = 0.23, P = 0.19). As directed by echocardiography, only 1 of 25 circular mapping catheters (4%) used in 16 patients was replaced due to inappropriate sizing of the pulmonary veins. Mean pulmonary vein Doppler flow velocities increased after ablation for left‐sided veins but ostial diameters were unchanged. In the linear ablation patients, the entire extent of the linear electrode array could be visualized in only 3 of 52 of catheter positions (6%) in the 13 patients. A portion of the catheter could be seen in only 50% of all target catheter positions.

Conclusion: Phased‐array intracardiac echocardiography (1) allows sizing and positioning of pulmonary vein mapping catheters, (2) provides measures of pulmonary vein ostial diameters, (3) continuously monitors pulmonary vein Doppler flow velocities, and (4) has limited use in positioning linear ablation catheters in the left atrium.
Programmed Electrical Stimulation in Brugada Syndrome: How Reproducible Are the Results?
Authors: GASPARINI MAURIZIO , PRIORI SILVIA G. , MANTICA MASSIMO , COLTORTI FERNANDO , NAPOLITANO CARLO , GALIMBERTI PAOLA , BLOISE RAFFAELLA , CERIOTTI CARLO
Published: August 2003

PES in Brugada Syndrome.
Introduction: Inducibility of ventricular arrhythmias at programmed electrical stimulation (PES) ranges between 50% and 80% of patients with Brugada syndrome. However, the variety of PES protocols and the lack of data relative to a control group or to ventricular arrhythmia reproducibility contribute to a still undefined interpretation of PES outcome in Brugada syndrome.

Methods and Results: Twenty‐one patients with Brugada syndrome (18 men and 3 women; mean age 34 years; 9/21 symptomatic; 8/21 with SCN5A gene mutation) underwent a PES protocol from two right ventricular sites. The endpoint was PES protocol completion or induction of sustained or reproducible (> 6 consecutive inductions) nonsustained (> 6 beats) fast ventricular arrhythmia. In 17 of 21 patients with Brugada syndrome, PES was repeated 2 months later to test ventricular arrhythmia reproducibility. Twenty‐five healthy patients (17 men; mean age 36 years) formed the control group. In patients with Brugada syndrome, ventricular arrhythmia inducibility rate at PES was high (18/21 patients [85%]) and increased with protocol aggressiveness, independent of clinical presentation. In control subjects, no ventricular arrhythmias were induced. Among patients with Brugada syndrome, 14 (82%) of 17 patients remained inducible at a second PES.

Conclusion: In our experience, ventricular arrhythmia inducibility in patients with Brugada syndrome, at variance with healthy controls, is high and does not correlate with clinical presentation. PES inducibility is deeply influenced by the protocol used. PES outcome is reproducible at a mid‐term follow‐up mainly if a categorical endpoint (inducible vs noninducible) is used. The need to assess the predictive value of specific PES protocols in targeted studies is widely emerging and is confirmed by our results.
Cellular Mechanisms of Vagally Mediated Atrial Tachyarrhythmia in Isolated Arterially Perfused Canine Right Atria
Authors: HIROSE MASAMICHI , CARLSON MARK D. , LAURITA KENNETH R.
Published: August 2003

Mechanism of Vagally Mediated AT.
Introduction: Increased vagal tone significantly enhances susceptibility to atrial fibrillation (AF); however, the cellular mechanisms responsible for vagally mediated AF are not completely understood.

Methods and Results: In 12 isolated arterially perfused canine right atria, high‐resolution optical mapping techniques were used to measure action potentials during control conditions, during intracardiac parasympathetic nerve stimulation (IPS; 30 to 50 Hz) as a surrogate for vagal stimulation, and during acetylcholine (ACh) infusion (10 to 30 μM). During steady‐state pacing, action potential duration was shorter during ACh infusion (43 ± 9 msec) than during IPS (78 ± 7 msec, P < 0.001) or control (129 ± 5 msec, P < 0.001). In contrast, repolarization gradients were larger during IPS (13 ± 3 msec/mm) than during ACh infusion (3 ± 1 msec/mm, P < 0.01) or control (5 ± 1 msec/mm, P < 0.01). Transmural repolarization gradients were relatively small for each intervention tested. During ACh infusion, atrial tachyarrhythmia (AT) was easily initiated with a single premature stimulus and was associated with a focal pattern of activation (84%). AT also was easily initiated by a single premature stimulus during IPS; however, when repolarization gradients were large, patterns of conduction block and incomplete macroreentry were often observed (64%). Importantly, AT initiation during IPS was associated with focal activity (36%) when repolarization gradients were small.

Conclusion: In contrast to ACh infusion, IPS generally increased dispersion of repolarization and was often associated with patterns of conduction block and incomplete macroreentry, similar to that associated with in vivo cervical vagal stimulation. However, IPS also was associated with a focal pattern of initiation that was independent of local repolarization gradients. These results suggest that during vagal stimulation, AT initiation does not always depend on repolarization gradients.