bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Free Radicals in the Pathogenesis of Amiodarone Toxicity
Authors: VERECKEI ANDRAS , BLAZOVICS ANNA , GYORGY ISTVAN , FEHER ERZSEBET , TOTH MIKLOS , SZENASK GABOR , ZSINKA AGNES , FOLDIAK GABOR , FEHER JANOS
Published: May 2007

Free Radicals and Amiodarone Toxicity. Introduction: In vitro and in vivo studies were performed to elucidate the pathogenesis of amiodarone toxicity.

Methods and Results: Rats were treated with amiodarone alone (500 mg/kg body weight per day) or together with antioxidants (silibinin or MTDQ‐DA: 50 mg/kg body weight per day) or with either antioxidanl alone. They received amiodarone for 30 days and antioxidant for 33 days (3 days pretreatment) In vitro, amiodarone induced a dose‐dependent chemiluminescence signal, which was inhibited by the two dihydroquinolin‐type antioxidants (MTDQ‐DA, CH 402). Chemiluminometric results from liver homogenate demonstrated that simultaneous treatment with silibinin partially prevented the liver homogenate superoxide anion radical scavenger capacity decreasing effect of amtodarone. Amiodarone treatment caused a significant increase of NADPH and Fe3+ induced lipid peroxidalion in the liver microsomal fraction, which antioxidants (silibinin, MTDQ‐DA) were unable to prevent. Light microscopy of the lung tissue in amiodarone‐treated rats showed accumulation of foamy macrophages with thickening of the interalveolar septa, pneumonitis, and variable interstitial tibrosis. Antioxidant treatment did not prevent these changes. Electron micrographs of lung from amiodarone‐treated ruts showed lysosomal phospholipoidosis, intralysosomal electron dense deposits, and increased lysosome number and size. In contrast to rats treated with amiodarone alone, those treated with both amiodarone and silibinin had significantly fewer lysosomes (P < 0.01); the lysosome size, shape, and internal characteristics remained he same. Simultaneous treatment with silibinin and amiodarone decreased lysosomal phospholipoidosis compared to amiodarone treatment alone. Simultaneous treatment with MTDQ‐DA and amiodarone did not show any beneficial effect. Pulse radiolysis and cobalt 60‐gamma (60Co‐γ) radiolysis studies showed that the main free radical product in a reducing environment was a very reactive aryl radical formed after the partial deiodination of the amiodarone molecule. The radioseasitizing effect of amiodarone was also verified in rat liver microsomal preparations using in vivo amiodarone with or without MTDQ‐DA pretreatment and 60Co‐γ irradiation with or without the in vitro addition of antioxidants (CH 402, MTDQ‐DA). In vivo, the MTDQ‐DA treatment also had a radiosensitizing effect; however, the in vitro addition of both antioxidants resulted in a radio‐protective effect. The aryl radical also may emerge in vivo during the metabolism of amiodarone.

Conclusion: These observations suggest that amiodarone in vitro and in vivo generates free radicals that may play a role in the pathogenesis of amiodarone toxicity beside other well‐established mechanisms, and antioxidants may have a partial protective effect against amiodarone toxicity.
Assessment of Beat‐by‐Beat Control of Heart Rate by the Autonomic Nervous System: Molecular Biology Techniques Are Necessary, But Not Sufficient
Authors: LEVY MATTHEW N. , YANG TIANEN , WALLICK DON W.
Published: May 2007

Neural Control of Heart Rate. Vagus nerve activity can change heart rate substantially within one cardiac cycle, and the chronotropic effects decay almost completely within one cardiac cycle after cessation of vagal activity. The ability of the vagus nerves to regulate heart rate beat by beat can be explained in large part by the speed at which the neural signal is transduced to a cardiac response and by the rapidity of the processes that restore the basal heart rate when vagal activity ceases. Currently, the question of whether the cardiac tells can transduce the sympathetic neural signals rapidly enough to implement beatwise regulation is controversial. Emphasis on the speed of the processes that initiate the responses may, however, be misplaced. Instead, the processes that terminate the responses to autonomic neural activity (especially those processes that remove the released neurotransmitters) are probably the main determinants of the ability of the vagal and sympathetic systems to affect beatwise control. The norepinephrine (NE) released from the sympathetic nerve endings is removed from the cardiac tissues much more slowly than is the acetylcholine that is released from the vagal terminals. As a consequence of the potential deleterious effects associated with the slow removal of NE, the cardiac neural control system has evolved such that the sympathetic nerves ordinarily release NE at a slow rate. Hence, changes in sympathetic neural activity can alter cardiac behavior only slightly from beat to beat. Hence, beatwise control of cardiac function would be negligible, regardless of how swiftly the sympathetic nerve impulse is transduced t o a change in cardiac‐performance.
Recent Insights Pertaining to Sarcolemmal Phospholipid Alterations Underlying Arrhythmogenesis in the Ischemic Heart
Authors: Ph.d. JANE McHOWAT. , YAMADA KATHRYN A. , WU JIANYI , YAN GAN‐XIN , CORR PETER B.
Published: May 2007

Sarcolemmal Phospholipid Alterations and Arrhythmogenesis. Myocardial ischemia in vivo is associated with dramatic electrophysiologic alterations that occur within minutes of cessation of coronary flow and are rapidly reversible with reperfusion. This suggests that subtle and reversible biochemical alterations within or near the sarcolemma may contribute to the electrophysiologic derangements. Our studies have concentrated on two amphipathic metabolites, long‐chain acylcarnitines and lysophosphatidylcholine (LPC). which have been shown to increase rapidly in ischemic tissue in vivo and to elicit electrophysiologic derangements in normoxic tissue in vitro. Incorporation of these amphiphiles into the sarcolemma at concentrations of 1 to 2 mole %, elicits profound electrophysiologic derangements analogous to those observed in ischemic myocardium in vivo. The pathophysiological effects of the accumulation of these amphiphites are thought to be mediated by alterations in the biophysical properties of the Sarcolemmal membrane, although there is a possibility of a direct effect upon ion channels. Inhibition of carnitine acyltransferase I (CAT‐I) in the ischemic cat heart was found to prevent the increase in long‐chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmias including ventricular tachycardia and fibrillation. This review focuses on the electrophysiologic derangements that are observed during early ischemia and presents data supporting the concept that accumulation of these amphiphiles within the sarcolemma contributes to these changes. The potential contribution of these amphiphiles to the increases in extracellular potassium and intracellular calcium are examined. Finally, recent data pertaining to the accumulation of long‐chain acylcarnitines on cell‐to‐cell uncoupling are presented. In addition to the events reviewed here, there are many other alterations that occur during early myocardial ischemia, but the results from multiple studies over the past two decades indicate that the accumulation of these amphiphiles contributes importantly to arrhythmogenesis and that development of specific inhibitors of CAT‐I or phospholipase A may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.
Morphology of the Cardiac Conduction System in Patientswith Electrophysiologically Proven Dual Atrioventricular Nodal Pathways
Authors: YEN HO SIEW , McCOMB JANET M. , SCOTT CHRISTOPHER D. , ANDERSON ROBERT H.
Published: May 2007

Conduction System in Dual AV Nodal Pathways. Introduction: Although the electrophysiologic criteria for dual atrioventricular nodal pathways are well established, the anatomical substrate is still unclear.

Methods and Results: We examined the hearts from 10 patients who had been studied electrophysiologically prior to cardiac transplantation. All 10 patients were male, aged 22 to 60years. Nine of the 10 patients had dual atrioventricular nodal pathways according to acceptedcriteria. Histologic studies of the atrioventricular conduction system showed normal structureof the atrioventricular node in all 10 hearts, with minor variations within the node in 3 cases, within the penetrating bundle in 3 cases, and within the nonbranching bundle in 3 cases. Theatrial approaches to the atrioventricular node were generally scanty in 6 hearts. The solitarycase that was shown electrophysiologically to lack dual pathways had no obvious difference inthe structure of the nodal area other than sparsity of transitional cells. We were unable tolocate any extranodal atrial tracts as described by other investigators.

Conclusion: The anatomical substrate for conduction over dual pathways may he too subtleto be detected by gross morphologic studies. Since dual pathways were unmasked in allpatients but one during electrophysiologic studies, it may be that the potential for these pathways is ubiquitous.
“Paradoxical” AH Shortening Caused By Proximal Coronary Sinus Stimulation During Orthodromic Reciprocating Tachycardia
Authors: SUZUKI FUMIO , HARADA TOMO‐O , KAWARA TOKUHIRO , TANAKA KAZUSHI , HIRAO KENZO , HIEJIMA KAZUMASA , LEHMANN MICHAEL H.
Published: May 2007

AH Shortening During ORT. Introduction: During extrastimulation or entrainment of orthodromic atrioventricular (AV) reciprocating tachycardia (ORT), the atriuni‐His (AH) interval as measured at the His‐bundle recording site is expected to lengthen due to extrastimu‐Lation‐dependent or pacing rate‐dependent slowing of AV nodal conduction by impulses that penetrate the tachycardia circuit. We report 6 patients in whom the AH interval “paradoxically” shortened during ORT in response to extrastimulation and rapid pacing from the proximal coronary sinus.

Methods and Results: Accessory pathway location was right anterior (1 patient), right anteroseptal (1 patient), and left anterior (4 patients). Cycle length of ORT was stahle (variation ≤ 5 msec) and ranged from 325 to 410 msec. During ORT, extrastimulation and rapid pacing were performed from the proximal coronary sinus and the right atrium. Extrastimulation from the proximal coronary sinus late in diastole caused significant shortening of AH interval in all patients hy a mean of 18 ± 3 msec (range 15 to 20 msec). AH shortening was demonstrated without a change of either the timing or morphologic appearance of the low septal right atrium at the H is‐bundle recording site. This phenomenon was not ohserved during right atrial extrastimulation. Rapid pacing from the proximal coronary sinus at cycle lengths of 305 to 390 msec (i.e., 15 to 20 msec shorter than the cycle length of each ORT) again demonstrated shortening of AH interval in all patients by a mean of 15 ± 3 msec (range 10 to 20 msec). By contrast, rapid pacing from the right atrium demonstrated classical AH prolongation at any paced cycle length.

Conclusion: AH shortening without a change of either the timing or morphologic appearance of the low septal right atrium at the His‐handle recording site confirms the existence of a distinct posterior atrial input to the AV node. In this setting low septal right atrial activation is not requisite for AV nodal conduction. Whether activation of the low septal right atrium is essential for. or contributes to, AV nodal conduction of atrial impulses from locations other than the proximal coronary sinus needs to he determined.
Spontaneous Activity in Transgenic Mouse Heart:
Authors: KLINE RICHARD P. , SOROTA STEVE , DRESDNER KARL P. , STEINHELPER MARK E. , LANSON NICHOLAS A. , WIT ANDREW L. , CLAYCOMB WILLIAM C. , FIELD LOREN J.
Published: May 2007

Spontaneous Activity in Transgenic Mouse Heart and AT‐1 Myocytes. Introduction: We have generated transgenic animals that heritably develop atrial tumors composed of difTerentiated proliferating cardiomyocytes. Experiments were initiated to characterize (he electrical properties of these cells.

Methods and Results: We show that the primary atrial tumors are composed of discrete foci that exhibit spontaneous automatic activity. A direct correlation was observed between tumor size and firing rate of these foci. In addition to the primary atrial tumors, we examined the propertie.s of cultured cardiomyocytes isolated from a transplantable transgenic tumor lineage (designated AT‐1 cells). Cultured AT‐1 cells arc al.so spontaneously automatic. The action potential eontiguration from these preparations is similar to that observed in nontransgenic atrial cardiomyocytes, albeit somewbat more depolarized and of longer duration. As would be expected for cardiomyocytes of atrial origin, the transgenic cardiornyocyte preparations hyperpolarize during muscarinic stimulation due to increased K+ conductance mediated by a pertussis toxin sensitive G‐protein. Assessment of pbarmacologic blockage of the “if” pacemaker current suggests that the automaticity of both transgenic cardiomyocyte preparations may be of novel origin. In this context, the cultured AT‐1 cells sbowed spontaneous bebavior that was clearly of cellular origin; this activity was manifest as transient bursts of electrical activity followed by periods of electrical quiescence. this bursting pattern is unusual for normal adult cardiomyocytes, but has been observed in several other cell types. In the primary tumors, automatic behavior may arise from a similar cellular origin or alternatively from a microreentrant phenomena.

Conclusion: Primary tumors and AT‐1 cells sbow essential atrial Electrophysiology with important novel features.
Effect of Rate on Changes in Conduction Velocity and Extracellular Potassium Concentration During Acute Ischemia in the In Situ Pig Heart
Authors: HARPER JAMES R. , JOHNSON TIMOTHY A. , ENGLE CONNIE L. , MARTIN DAVID G. , ELEET WILLIAM , GETTES LEONARD S.
Published: May 2007

Rate Effects on Conduction and [K+]e During Ischemia. Introduction: The purpose nf our study was to determine if the slowing oflongitudinal intraventricular conduction in the in situ porcine heart during acute regional no‐flow ischemia was rate dependent. Further, we investigated whether any rate dependence could he correlated to a rate‐dependent component of the ischemiainduced rise in extracellular potassium concentration. [K+]e.

Methods and Results: We studied in situ hearts in nine anesthetized open chest pigs in which acute no‐flow ischemia was induced by occlusion of the left anterior descending coronary artery. To determine the effects of steady‐state rate on the slowing of conduction and rise in [K+]e during ischemia, we varied the rate of stimulation during sequential occlusions from 90 to 150 beats/min. Longitudinal conduction velocity was determined by unipolar electrodes embedded in a plaque that was sutured to the epicardial surface in the center of the ischemic zone. Myocardial [K+]e was determined simultaneously by potassium‐sensitive electrodes placed at or within 1 to 2 mm of the epicardium in close proximity to the activation recording electrodes. Conduction vehxity decreased more rapidly at the more rapid rates of stimulation although the reduction in conduction velocity occurring prior to the onset of conduction block was similar at both rates. The potassium change was not rate dependent and rose at the same rate regardless of the rate of stimulation.

Conclusion: Our study demonstrates that the steady‐state rate‐dependent component of the slowing of intraventricular conduction induced by acute ischemia in the in situ porcine heart occurs in the absence of a rate‐dependent component in the rise of [K+]e. Between rates of 90 and 150 beats/min, the rate dependence of the conduction slowing may be attributed to one or more potassium‐independent factors such as the rate‐dependent changes in resting membrane potential, in V̇max of the action potential upstroke, and in cell‐to‐cell uncoupling, which have hcen observed in other models of acute ischemia.
Generation of Reentry in Anisotropic Myocardium
Authors: PANFILOV ALEXANDER V. , KEENER JAMES P.
Published: May 2007

Reentry in Anisotropic Myocardium. Introduction: We investigated numerically the effects of the rotation of finer axis orientation through the myocardial wall on wave propagation.

Methods and Results: We show that because of this rotation and inherent discrete properties of myocardium, a premature stimulus can create unidirectional conduction block leading to reentry.

Conclusion: The dynamics of the subsequent reentrant patterns are complicated by the presence of rotational anisotropy, as the center of reentry drifts, and the reentry terminates in finite time when it collides with the domain boundary.
Sequential Bilateral Bundle Branch Block During Dofetilide, A New Class III Antiarrhythmic Agent, In a Patient with Atrial Fibrillation
Authors: CRIJNS HARRY J.G.M. , KINGMA J. HERRE , GOSSELINK A.T. MARCEL , DALRYMPLE H.W. , De LANGEN CEES D.J. , LIE KI
Published: May 2007

Sequential Bilateral BBB During Dofetilide. Introduction: I in mechanism of wide QRS complex tachycardias during dofetilide infusion was studied in a patient with atrial fibrillation.

Methods and Results: Endocardial recording from the intraventricular conduction system showed that dofetilide caused “classic” aberrant conduction (Ashman phenomenon, typical QKS morphology) at high prematurity ratios (preceding interval = 1.78 X coupling interval 290), thus mimicking ventricular ectopy. In addition, there was frequent sequential bilateral bundle branch block, caused by a significant difference in preceding bundle‐to‐bundle intervals (mean difference ± 1 SD: 74 ± 26 msec).

Conclusion: The present findings may prove helpful in the clinical assessment of wide QKS complex rhythms after dofetilide and possibly other “pure” Class III antiarrhythmics.
Site of Accessory Pathway Block After Radiofrequency Catheter Ablation in Patients with the Wolff‐Parkinson‐White Syndrome
Authors: CALKINS HUGH , MANN CHING , KALBFLEISCH STEVEN , LANGBERG JONATHAN J. , MORADY FRED
Published: May 2007

Site of Accessory Pathway Block. Introduction: Recent studies have demonstrated that the most common site of accessory pathway conduction block following the introduction of a premature atrial stimulus during atrial pacing is between the accessory pathway potential and the ventricular electrogram. consistent with block at the ventricular insertion of the accessory pathway. However, no prior study has evaluated the site of conduction block during radiofrequency catheter ablation procedures. Therefore, the objective of this study was to determine the site of conduction block after catheter ablation of accessory pathways by analyzing and comparing the local electrograms recorded before and after radiofrequency energy delivery at successful ablation sites.

Methods and Results: The electrograms evaluated in this study were obtained from 85 consecutive patients who underwent successful radiofrequency catheter ablation of a manifest accessory pathway. The 50 left free‐wall accessory pathways were ablated using a ventricular approach and the 35 right free‐wall or posteroseptal accessory pathways were ablated using an atrial approach. The characteristics of local electrograms recorded immediately before and immediately after successful ablation of the accessory pathway were determined in each patient. The site of accessory pathway block was determined by comparing the amplitude, timing, and morphology of the local eleclrograms at successful sites of radiofrequency catheter ablation before and after delivery of radiofrequency energy. A putative accessory pathway potential was present at the successful target site in 74 of the 85 patients (87%). Conduction block occurred between the atrial electrogram and the accessory pathway potential in 66 patients (78%) and between the accessory pathway potential and the ventricular electrogram in eight patients (9%). The site of block could not be determined in 11 patients (13%) in whom an accessory pathway potential was absent. Conduction block occurred most frequently between the atrial electrogram and the accessory pathway potential regardless of accessory pathway location. No electrogram parameter or accessory pathway characteristic was predictive of the site of conduction block.

Conclusion: The results of this study demonstrate that conduction block occurs most frequently between the local atrial electrogram and the accessory pathway potential during radiofrequency catheter ablation of accessory pathways. This is true regardless of whether the accessory pathway is ablated from the atrial or ventricular aspect of the mitral or tricuspid annulus.
Alpha1‐Adrenergic Blockade and Sudden Cardiac Death
Authors: VANOLI EMILIO , HULL STEPHEN S. , FOREMAN ROBERT D. , FERRARI ANTONIO , SCHWARTZ PETER J.
Published: May 2007

Alpha1‐Adrenergic Blockade and Sudden Cardiac Death. Introduction: The primary goal of the present study was to test whether selective pharmacologic blockade of alpha1 receptors, and specifically of the subtype alpha1a could prevent ventricular fibrillation (VF) during acute myocardial ischemia.

Background: The development of new autonomic interventions is of clinical interest in view of the failure of traditional; antiarrhythmic drugs to prevent sudden death. Experimental evidence indicates that alpha, receptors, and in particular the subtype alpha1a may he involved in the genesis of malignant arrhythmias during acute myocardial ischemia and reperfusion. Despite this evidence, questions have been raised about the actual antifibrillatorv efficacy of alpha‐adrenergic blockade in the acutely ischemic myocardium. The effects of prazosin and of abanoquil (UK 52,046), a highly selective alpha1a receptor blocker, were tested and compared with propranolol in a conscious animal preparation for sudden death.

Methods and Results: Ten dogs with a 1‐month‐old anterior wall myocardial infarction were studied. These dogs had all developed, in control conditions, VF during a 2‐minute occlusion of the circumflex coronary artery while exercising (n=9) or lying on the table (n=1). Afterwards, the dogs underwent additional tests with the following intravenously administered drugs: abanoquil (n=10; 1μg/kg. prazosin (n=9; 0.1 mg/kg), and propranolol (n=10; 1 mg/kg). Internal control analysis was used. All dogs tested had recurrence of VF with both alpha‐adrenergic blockers. Propranolol significantly reduced heart rate during ischemia and prevented VF in 5 of 10 dogs tested (P < 0.05). When heart rate was kept constant by atrial pacing (n = 3), 2 of the 3 animals remained protected by propranolol. Just prior to onset of VF, heart rate was not significantly different in the control and in the abanoquil tests (237 ± 45 and 253 ± 34 beats/min, respectively), whereas it was higher (P < 0.05) with prazosin (288 ± 40 beats/min).

Conclusions: Alpha, and alpha1a receptor blockers do not prevent VF secondary to acute myocardial ischemia in the presence of elevated sympathetic activity and heart rate. In the same setting, beta‐adrenergic blockade prevents the reflex heart rate increase due to ischemia and provides a significant protection.
Fatigue Phenomenon in Accessory Pathways
Authors: LI HUAGUI G. , KLEIN GEORGE J. , YEE RAYMOND , THAKUR RANJAN K.
Published: May 2007

Fatigue Phenomenon in APs. Fatigue phenomenon is transient failure of conduction following a period of repetitive excitation. Fatigue in iiccessory pathways is uncommon, and its electrophysiologic characteristics and clinical implications are unknown. Among the 215 patients who underwent electrophysiology studies from July 1992 to December 1993, 4 (2%) were found to exhibit fatigue over accessory pathways. The accessory pathway was posteroseptal in three patients and right free wall in one patient. The mean anterograde effective refractory period of the accessory pathway was 295 ± 26 msec (range 270 to 330, basic drive cycle length 600 msec). Three patients had neither retrograde accessory pathway conduction nor inducible tachycardia even with infusion of isoprotereno). The fatigue phenomenon was observed after both atrial and ventricular stimulation in three patients and only after ventricular stimulation in one patient. Fatigue was dependent on duration more than rate of stimulation. We conclude that pathways exhibiting fatigue have a low margin of safety for conduction and are unlikely to be clinically problematic.
The Role of the Membrane Potential of Endothelial and Smooth Muscle Cells in the Regulation of Coronary Blood Flow
Authors: DAUT JüRGEN , STANDEN NICHOLAS B. , NELSON MARK T.
Published: May 2007

Membrane Potential of Coronary Endothelial and Smooth Muscle Cells. In the mammalian heart the supply of oxygen and energy‐rich substrates through the coronary arterioles is continuously adapted to the variations of cardiac work. The coronary resistance arteries and the surrounding myocardium form a functional unit with multiple interactions between coronary endothelial cells, smooth muscle cells, perivascular nerves, and cardiac muscle cells. We describe the mechanisms underlying the electrical and chemical communication between the different cell types, the ionic channels contributing to the resting potential of endothelial and smooth muscle cells, and the mechanisms responsible for modulation of the resting potential. The main conclusion of our analysis is that the membrane potential of coronary endothelial and smooth muscle cells is one of the major determinants of coronary blood flow, and that modulation of the membrane potential provides a way to dilate or constrict coronary resistance arteries. It is proposed that the membrane potential of the myo‐endothelial regulatory unit, i.e., of the endothelial cells and the underlying smooth muscle cells in the terminal arterioles, may function as an integrator of the numerous local and global vasodilator and constrictor signals that provide for the adaptation of coronary blood flow to the metabolic demands of the heart.
Initiating Reentry:
Authors: SPACH MADISON S. , JOSEPHSON MARK E.
Published: May 2007

Cellular Coupling as a Basis for Arrhythmias. Until recently only two types of media have been considered to provide the nonuniformities necessary to initiate cardiac reentry: (1) continuous isotropic media with intrinsic repolarization inhomogeneities; and (2) continuous isotropic media free of inhomogeneities in which repolarization nonuniformities are introduced transiently. The purpose of this article is to establish cellular coupling as a basis for arrhythmias by placing a new type of inhomogeneity, nonuniform anisotropy due to sparse side‐to‐side coupling between cells, in an overall perspective with the other nonuniformities that lead to reentry. Review of experimental and theoretical models of reentry leads to the following picture: with slowed conduction, reentrant circuits diminish in size and the nonuniformities necessary for reentry are provided by nonuniform anisotropy. Repolarization nonuniformities create functionally different pathways for reentrant circuits of relatively large size (> 30–50 mm2). Nonuniform anisotropic cellular coupling, which is associated with underlying microfibrosis, makes it possible for reentry to occur in small areas (< 10–15 mm2). A general property found in nonuniform anisotropic bundles is the presence of functionally different pathways in the absence of intrinsic repolarization inhomogeneities‐one of fast longitudinal conduction with a longer refractory period, and another of “very slow” transverse conduction with a shorter refractory period. Since it is not known if nonuniform anisotropy exists in the AV node, the best known structure with small reentrant circuits, we performed microscopic extracellular measurements in the AV node of the rabbit. The transitional Zone of the AV node was found to have markedly nonuniform anisotropic conduction properties. The analysis provides the view that functionally different pathways of small reentrant circuits, including those of the AV node, need to be reevaluated in terms of the role of nonuniform anisotropic cellular coupling.
Changes in Autonomic Tone Following Thrombolytic Therapy for Acute Myocardial Infarction:
Authors: ZABEL MARKUS , KLINGENHEBEN THOMAS , HOHNLOSER STEFAN H.
Published: May 2007

Heart Rate Variability in Acute MI. Introduction: Little data are available on changes in autonomic tone during the first 24 hours of acute infarction in patients undergoing thromholytic therapy. Particularly, the association of changes in autonomic tone to reperfusion of the infarctrelated artery has not been evaluated in man. Heart rate variability (HRV) is a noninvasive tool to assess cardiac autonomic tone, which carries prognostic information in postinfarction patients.

Methods and Results: To assess changes in autonomic tone with ungiographically assessed success of thrombolysis in patients with acute infarction, the proportion of adjacent RR intervals different by greater than 50 msec (pNN50) was analyzed from 24‐hour Holler monitoring initiated before the start of thrombolytic therapy in 103 consecutive patients. Mean heart rate (HR) and pNN50 were available in 95 of 103 patients and were separately analyzed for the first hour after initiation of thrombolysis (reperfusion phase) and the first 24 hours. As assessed by coronary angiography 90 minutes after start of thrombolysis, 74 patients (78%) had successful coronary artery reperfusion. HR averaged 72 ± 13/min for the first hour in all 95 patients and 74 ± 13/min for the first 24 hours. The respective values for pNN50 were 11±2%± 11±7% for the first hour and 9±7%± 9±2% for the first 24 hours. Patients with inferior myocardial infarction (MI) had a lower mean HR of 72 ± 12/min versus 76 ± 13/min (P = 0±11) and a higher pNN50 (11±2%± 9±8% versus 7±6%± 8±3%, P = 0±01) compared to patients with anterior MI. The mean HR correlated weakly with pNN50 (r = ‐0±33, P < 0±01). For patients with coronary artery patency after 90 minutes, mean HR was 70 ± 12/min for the first hour compared to 80 ± 13/min for patients without (P = 0±003). For the first 24 hours, these values were 72 ± 12/min compared to 80 ± 14/min (P = 0±02). For the first hour, pNN50 averaged 12±6%± 12±4% for patients with successful reperfusion compared to 6±6%± 7±3% for patients without (P = 0±024). For the first 24 hours, these values were 9±2%± 8±5% compared to 11±5%± 11±3% (P = NS). Patients with inhospital ventricular fibrillation (n = 8) had a higher mean HR throughout the first 24 hours (88 ±16/min vs 73 ± 12/min, P = 0±008) compared to patients with an uneventful course. Additionally, there was a trend toward a lower HRV in patients with ventricular fibrillation.

Conclusion: Thrombolysis‐induced reperfusion of the infarct‐related artery results in a higher vagal tone during the early hours of MI as compared to failed reperfusion. This finding is independent from intfarct location and associated with a trend toward a lower incidence of ventricular fibrillation during the acute phase of infarction.
Alpha1‐Adrenergic Receptor Modulation of Repolarization in Canine Purkinje Fibers
Authors: HO LEE JAE , ROSEN MICHAEL R.
Published: May 2007

Alpha‐Agonists and Repolarization. Introduction: Alpha‐adrenergic receptor stimulation increases contractility and prolongs repolarization. These effects are modulated by α1‐adrenergic receptor‐mediated inhibition of transsarcolemmal potassium currents.

Methods and Results: We used standard microelectrode techniques to study the actions of 4‐aminopyridine (4‐AP), which blocks the transient outward current, Ito, and WAY‐123,398, which blocks the delayed rectifier, Ik, on canine Purkinje fiber action potential prolongation induced by phenylephrine. At a basic cycle length of 1 second, phenylephrine (0.1 to 10 μ) dose‐dependently prolonged action potential duration at 90% repolarization (APD90) from 331 ± 10 msec to 400 ± 12 msec (P < 0.05) at phenylephrine, 10 μ. Phenylephrine did not change phase 1 or plateau height. 4‐AP (0.1 mM) decreased phase 1 magnitude, shifted plateau height to more positive potentials (from 0.1 ± 1.8 mV to 14.3 ± 1.1 mV [P < 0.05]), and shortened APD90 from 318 ± 9 msec to 294 ± 8 msec (P < 0.05). 4‐AP did not block phenylephrine effects on APD90, which increased, at 10 μ phenylephrine, from 294 ± 8 msec to 342 ± 6 msec (P < 0.05). In contrast, WAY‐123,398 (0.1 μ) prolonged APD90 from 360 ± 6 msec to 452 ± 6 msec (P < 0.05), and had no effect on plateau height. In the presence of WAY‐123,398, phenylephrine no longer increased APD9o.

Conclusion: (1) Agents that block Ito shorten APD in Purkinje fibers; and (2) the α‐agonist mediated increase of APD in canine Purkinje fibers can be explained by inhibition of Ik.
Properties of the Fluorescent Sodium Indicator “SBFI” in Rat and Rabbit Cardiac Myocytes
Authors: LEVl ALLAN J. , LEE CHIN O. , BROOKSBY PAUL
Published: May 2007

SBFI in Cardiac Myocytes. Introduction: Although some properties of the fluorescent sodium indicator “SBFT” are known, there is no accepted method by which the SBFI signal might be calibrated for intracellular Na (Nai) in cardiac cells. The first aim of this study was to characterize the loading and compartmentalization of this indicator in single cardiac myocytes. The second aim was, from experimental observation, to develop a rational calibration method for SBFI. The third aim was to use this Na indicator to study the dependence of tonic contraction on Nai in voltage‐clamped ventricular myocytes.

Methods and Results: SBFI was incorporated into myocytes by incubating with the acetoxymethyl ester (10 μM) for 2 hours. This led to an intracellular concentration of SBFI free acid of 122 ± 17 μM. We considered a number of issues with respect to compartmentalization of indicator and, under our conditions, we found the majority (71%) of indicator was situated in the cytoplasm. Therefore, SBFI indicates mainly changes of cytoplasmic Na. Calibration of the indicator for Na, was performed by equilibrating internal and external Na. We investigated the conditions required for optimum transmembrane Na equilibration and found it necessary to use a calibration solution free of both Ca and magnesium (Mg). The Na ionophores gramicidin D and monensin were both required, and it was also necessary to inhibit the Na/K pump for optimum Na equilibration. Using these conditions, the Nai concentration in quiescent rat ventricular myocytes was 10.9 ± 0.74 mM (mean ± SEM, n = 40; equivalent to an Na activity of 8.3 mM). The concentration of Nai was significantly lower in quiescent rabbit myocytes: 3.8 ± 0.23 mM (n = 24; equivalent to an Na activity of 2.9 mM). In voltage‐clamped rabbit myocytes, inhibition of the Na/K pump caused a rise of Vi: there were also marked effects on the tonic shortening elicited by ramp depolarizations. As Nai rose, the magnitude of tonic shortening increased and its voltage dependence also changed.

Conclusion: These results confirm the suitability of SBFI for measuring Na, in cardiac cells. Provided that steps are taken to optimize transmembrane Na equilibration, the indicator can be calibrated for Nai. The different Nai of rat and rabbit myocytes has implications for the function of sarcolemmal Na/Ca exchange in each cell type. An Nai of 10.9 mM in rat myocytes gives a calculated reversal potential for the exchange of‐35 mV. In comparison, an Na; of 3.8 mM in rabbit myocytes leads to a reversal potential for the exchange +45 mV. Therefore, relatively small changes of Nai can shift the reversal potential of the exchange to values that are substantially more positive or negative than zero. The behavior of voltage‐dependent tonic contraction in rabbit myocytcs was consistent with the Na/Ca exchange reversal potential being more positive than zero in these cells.
Radiofrequency Catheter Ablation of Idiopathic Left Ventricular Tachycardia:
Authors: KOTTKAMP HANS , CHEN XU , HINDRICKS GERHARD , WILLEMS STEPHAN , BORGGREFE MARTIN , BREITHARDT GÜNTER
Published: May 2007

Idiopathic Left Ventricular Tachycardia. Introduction: Idiopathic left ventricular tachycardia with a QRS pattern of right bundle branch block and left‐axis deviation constitutes a rare but electrophysiologically distinct arrhythmia entity. The underlying mechanism of this tachycardia, however, is still a matter of controversy. This report describes findings in a 42‐year‐old man who underwent successful radiofrequency catheter ablation of idiopathic left ventricular tachycardia.

Methods and Results: On electrophysiologic study, the tachycardia was reproducibly induced and terminated with double ventricular extrastimuli. Intravenous verapamil terminated the tachycardia whereas adenosine did not. Detailed left ventricular catheter mapping during sinus rhythm revealed a fragmented delayed potential at the mid‐apical region of the inferior site near the posterior fascicle of the left bundle branch. At the same site, continuous electrical activity throughout the entire cardiac cycle was recorded during ventricular tachycardia. Repeated spontaneous termination of this continuous electrical activity in late diastole was followed immediately by termination of the tachycardia. Single application of radiofrequency current for 20 seconds at this site completely abolished inducibility of the tachycardia. After catheter ablation, at the identical site of preablation recording of the fractionated potential during sinus rhythm, no fragmented delayed activity could be recorded. There was no complication from the ablation procedure.

Conclusion: The preablation recordings of fragmented delayed potentials during sinus rhythm and continuous diastolic electrical activity during tachycardia, together with ablation characteristics and previously reported electrophysiologic properties of this arrhythmia, may further support microreentry as the underlying mechanism in idiopathic left ventricular tachycardia.
Role of L‐Type Calcium Channel Window Current in Generating Current‐Induced Early Afterdepolarizations
Authors: MING ZHEN , NORDIN CHARLES , ARONSON RONALD S.
Published: May 2007

Ionic Mechanism of EADs. Introduction: Early afterdepolarizations (EADs) can give rise to triggered activity and thereby produce cardiac arrhythmias. We used the whole‐cell patch clamp technique to examine the relationship between L‐type Ca2+ channel window current and the generation of EADs in single ventricular myocytes isolated from guinea pig hearts.

Methods and Results: With a high concentration of EGTA in the internal solution and Na+‐containing physiologic external solution, EADs were induced in unclamped cells by injecting intracellular depolarizing current pulses. During voltage clamp protocols designed to simulate action potentials interrupted by EADs, we recorded an inward shift in total current up to 0.7 pA/pF over 400 msec at test steps in the range of the take‐off potential for EADs. Cd2t (0.2 mM) blocked most of the inward shift of current during the test steps and abolished EADs. When the same voltage clamp protocol was used following perfusion with an Na+‐free, K+‐free external solution, the Cd2+‐sensitive inward currents recorded during the test steps were similar to those obtained in physiologic external solution. The overlapping range of potentials for partial activation of the d and f variables of L‐type Ca2+ current (“window” region) measured in Na+‐free, K+‐free external solution was virtually the same as the voltage range of the Cd2+–sensitive inward currents.

Conclusion: Our experiments suggest that: (1) EADs can arise under conditions of high EGTA buffering of intraccllular [Ca2+]; and (2) under these conditions, L‐type Ca2+ channel window current plays a major role in the initiation of EADs.
Cardiac T‐Type Calcium Current:
Authors: VASSORT GUY , ALVAREZ JULIO
Published: May 2007

Modulation of T‐Type Calcium Channels. A low threshold, voltage‐gated calcium current is reported in most cardiac tissues but rarely in ventricular cells. This article reports some recently described characteristics and discusses their possible pathophysiologic implications. It also reviews the alterations induced in this current by a variety of chemical agents including several neuromediators in cardiac and other tissues.
The Long‐Term Outcome of Visually Directed Subendocardial Resection in Patients Without Inducible or Mappable Ventricular Tachycardia at the Time of Surgery
Authors: NATH SUNIL , HAINES DAVID E. , KRON IRVING L. , DiMARCO JOHN P.
Published: May 2007

Visually Directed Subendocardial Resection. introduction: in prior studies, 20% to 40% of patients undergoing subendocardial reaction (SER) for ventricular tachycardia (VT) could not he mapped intraoperatively because the VT was either noninducible or nonmappable following the ventriculotomy. The optimal surgical approach to such patients is not known.

Methods and Results: In this study, we retrospectively compared the long‐term survival and functional outcome of 29 patients with VT and prior myocardial infarction who were either noninducible or nonmappable intraoperatively and underwent a visually directed extended SER These results were then compared to 85 patients who had inducible VT intraoperatively and underwent a map‐guided sequential SER. The two patient groups had different clinical characteristics. The visually directed cohort was more likely to he male, experienced fewer VT episodes before surgery, and underwent fewer antiarrhythmic drug trials prior to reaction. In addition, the visually directed group had slower VT induced at a preoperative electrophysiologic study and was less likely to present to the operating room in stock or incessant VT than the map‐guided group. The postoperative VT clinical recurrence or inducibility rate was 14% in both the visually directed and map‐guided groups. The long‐term actuarial survival at 1, 3, and 5 years was 93%, 86%, and 75%, respectively, in the visually directed group, compared to 77%, 58%, and 58%, respectively, in the map‐guided group (P = 0.06). There were no documented nonfatal recurrences of VT in either group. At 24 months following surgery, 77% of patients who had a visually directed SER were in New York Heart Association Functional Class I or II, compared to 46% of patients who underwent a map‐guided SER (P < 0.05).

Conclusion: In patients with VT and prior myocardial infarction, the inability to induce or map the VT in the operating room does not preclude a favorable long‐term outcome if a visually directed extended SER technique is used.
Intracoronary Ethanol Ablation in Swine:
Authors: HAINES DAVID E. , WHAYNE JAMES G. , DiMARCO JOHN P.
Published: May 2007

Intracoronary Ethanol Ablation. Introduction: Intracoronary ethanol ablation has been successfully used as arrhythmia therapy, hut the dose response of ventricular function and arrhythmogenesis to varying ethanol concentrations is undefined.

Methods and Results: Twenty‐six anesthetized pigs weighing 50 ± 11 kg underwent left and right heart catheterization. Ablation solutions composed of normal saline with ethanol in concentrations of 0%, 10%, 25%, 50%, 75%, and 100% were mixed with metrizamide, a nonionic contrast agent (3.75 g per 20 mL), then infused into branch or distal coronary arteries in each of the left anterior descending and left circumflex coronary artery distributions. Hemodynamic measurements, and coronary and left ventricular angiography were performed before and after ablation. Programmed electrical stimulation was performed preablation and at a chronic‐study at 4 to 6 days. Excised hearts were examined pathologically. Fifty‐two lesions were created in 26 animals, and 24 animals survived to the follow‐up study. Minimal hemodynamic alterations were observed in response to ablation. As the ethanol concentration of the ablation solution was increased, the prevalence of spontaneous nonsustained and sustained ventricular tachyarrhythmias increased (P = 0.0002), the ablation vessels were more persistently occluded (P = 0.028), and the postablation global left ventricular ejection fraction showed greater impairment (P = 0.002). Identifiable myocardial lesions were identified in all study groups, including those receiving the 0% ethanol infusion. Lesion size increased significantly with increasing ethanol concentration (P = 0.0004) but there was significant variance within groups. In response to programmed electrical stimulation, ventricular fibrillation was a nonspecific finding before and after ablation. In contrast, monomorphic ventricular tachycardia was induced only at postablation testing, and four of five of these animals underwent infusions with ethanol concentration of ≥ 50% ethanol.

Conclusion: Concentrations of ≥ 50% ethanol are most effective in creating large ventricular lesions in intracoronary ethanol ablation, but are associated with more impairment of left ventricular function, and have a greater likelihood of acute and early chronic arrhythmia aggravation.
Pathophysiology of Gap Junctions in Heart Disease
Authors: SEVERS NICHOLAS J.
Published: May 2007

Cardiac Gap Junctions. Electrical coupling between cardiac muscle cells is mediated by specialized sites of plasma membrane interaction termed gap junctions. These junctions consist of clusters of membrane channels that directly link the cytoplasmic compartments of neighboring cells. Each gap‐junctional channel consists of two connexons, one from each of the interacting plasma membranes, extending across the narrow extracellular gap. Connexons are constructed from connexins. a multigene family of conserved proteins. Different connexins confer specific electrophysiologic characteristics on the assembled channel protein. The major connexin of the mammalian heart is connexin43, although other types of connexins are also expressed, notably connexin40 in myocytes of the atrioventricular conduction system. Confocal laser scanning microscopy of anti–connexin43 immunolabeled samples reveals two major abnormalities in myocardial gap junctions in ischemic heart disease: loss of the usual ordered distribution of gap junctions at border zones adjacent to infarct scars, and reduction in the quantity of connexin43 gap junctions in myocardium distant from the infarct. These and other changes reported in myocardial gap‐junctional communication pathways following infarction may result in heterogeneous anisotropic conduction and reduced conduction velocity, (hereby forming a proarrhythmic substrate. Current evidence suggests that reduction in conuexin43 content is a general pathogenetic feature of cardiac disease, and that changes in the expression levels of other connexin types may contribute to altered electrophysiologic function in the diseased heart.