Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada.

This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94-3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92-7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer's disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.

Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation.

Epithelial ovarian carcinoma is characterized by high frequency of recurrence (70% of patients) and carboplatin resistance acquisition. Carcinoma-associated mesenchymal stem cells (CA-MSC) have been shown to induce ovarian cancer chemoresistance through trogocytosis. Here we examined CA-MSC properties to protect ovarian cancer cells from carboplatin-induced apoptosis. Apoptosis was determined by Propidium Iodide and Annexin-V-FITC labelling and poly-ADP-ribose polymerase cleavage analysis. We showed a significant increase of inhibitory concentration 50 and a 30% decrease of carboplatin-induced apoptosis in ovarian cancer cells incubated in the presence of CA-MSC-conditioned medium (CM). A molecular analysis of apoptosis signalling pathway in response to carboplatin revealed that the presence of CA-MSC CM induced a 30% decrease of effector caspases-3 and -7 activation and proteolysis activity. CA-MSC secretions promoted Akt and X-linked inhibitor of apoptosis protein (XIAP; caspase inhibitor from inhibitor of apoptosis protein (IAP) family) phosphorylation. XIAP depletion by siRNA strategy permitted to restore apoptosis in ovarian cancer cells stimulated by CA-MSC CM. The factors secreted by CA-MSC are able to confer chemoresistance to carboplatin in ovarian cancer cells through the inhibition of effector caspases activation and apoptosis blockade. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and the phosphorylation of its downstream target XIAP underlined the implication of this signalling pathway in ovarian cancer chemoresistance. This study reveals the potentialities of targeting XIAP in ovarian cancer therapy.

Dynamics of revolution time variability in cycling pattern: voluntary intent can alter the long-range autocorrelations.

Long-range dependency has been found in most rhythmic motor signals. The origin of this property is unknown and largely debated. There is a controversy on the influence of voluntary control induced by requiring a pre-determined pace such as asking subjects to step to a metronome. We studied the cycle duration variability of 15 men pedaling on an ergometer at free pace and at an imposed pace (60 rpm). Revolution time was determined based on accelerometer signals (sample frequency 512 Hz). Revolution time variability was assessed by coefficient of variation (CV). The presence of long-range autocorrelations was based on scaling properties of the series variability (Hurst exponent) and the shape of the power spectral density (α exponent). Mean revolution time was significantly lower at freely chosen cadence, while values of CV were similar between both sessions. Long-range autocorrelations were highlighted in all series of cycling patterns. However, Hurst and α exponents were significantly lower at imposed cadence. This study demonstrates the presence of long-range autocorrelations during cycling and that voluntary intent can modulate the interdependency between consecutive cycles. Therefore, cycling may constitute a powerful paradigm to investigate the influence of central control mechanisms on the long-range interdependency characterizing rhythmic motor tasks.

Patient assessment for cardiac resynchronization therapy: Past, present and future of imaging techniques.

It has been proposed that dyssynchrony assessment before cardiac resynchronization therapy (CRT) implantation could help predict response to CRT. It is known that up to 40% of patients who receive a CRT device for established indications do not respond to CRT. Great expectations came from the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study, which would finally identify the ultimate echocardiographic dyssynchrony criteria to help select responders. The recently published PROSPECT trial failed to identify an ideal parameter of dyssynchrony. Patient selection for CRT should involve a multimodal approach, and new promising tools are being investigated in that view. The present review integrated new data coming from the exciting field of imaging with currently available evidence to generate a stepwise approach to patient selection.

Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo.

Irradiated cells induce chromosomal instability in unirradiated bystander cells in vitro. Although bystander effects are thought to be linked to radiation-induced secondary cancers, almost no studies have evaluated bystander effects in vivo. Furthermore, it has been proposed that epigenetic changes mediate bystander effects, but few studies have evaluated epigenetic factors in bystander tissues in vivo. Here, we describe studies in which mice were unilaterally exposed to X-irradiation and the levels of DNA damage, DNA methylation and protein expression were evaluated in irradiated and bystander cutaneous tissue. The data show that X-ray exposure to one side of the animal body induces DNA strand breaks and causes an increase in the levels of Rad51 in unexposed bystander tissue. In terms of epigenetic changes, unilateral radiation suppresses global methylation in directly irradiated tissue, but not in bystander tissue at given time-points studied. Intriguingly, however, we observed a significant reduction in the levels of the de novo DNA methyltransferases DNMT3a and 3b and a concurrent increase in the levels of the maintenance DNA methyltransferase DNMT1 in bystander tissues. Furthermore, the levels of two methyl-binding proteins known to be involved in transcriptional silencing, MeCP2 and MBD2, were also increased in bystander tissue. Together, these results show that irradiation induces DNA damage in bystander tissue more than a centimeter away from directly irradiated tissues, and suggests that epigenetic transcriptional regulation may be involved in the etiology of radiation-induced bystander effects.

Amiodarone reduces procedures and costs related to atrial fibrillation in a controlled clinical trial.

BACKGROUND: Atrial fibrillation is the most common sustained cardiac arrhythmia, and engenders significant health care costs. The impact of various treatment options for atrial fibrillation on hospital costs has not been evaluated in a randomized trial. METHODS: We analysed 1-year follow-up data on 392 patients randomized to low dose amiodarone (200 mg. day(-1)) or alternative first-line therapy (sotalol or propafenone) in a multicentre trial (Canadian Trial of Atrial Fibrillation, CTAF). RESULTS: Patients in the amiodarone group had fewer electrical cardioversions (65 vs 109 for patients in the sotalol/propafenone group, P<0.0001), and pacemaker insertions (4 vs 11, P=0.07). The average amiodarone patient spent fewer days in hospital (0.47 vs 0.97, P=0.01), and incurred lower costs ($532 vs $898, P=0.03), for admissions where atrial fibrillation was the admitting diagnosis. Average total hospital costs per patient for all admissions, as well as average combined hospital and physician costs per patient, showed wide variations within the treatment arms and were not significantly different between groups. CONCLUSION: For patients in whom antiarrhythmic drug therapy is indicated, low dose amiodarone significantly reduces atrial fibrillation-related costs by reducing the number of atrial fibrillation-related procedures.

Catheter cryoablation of the atrioventricular node in patients with atrial fibrillation: a novel technology for ablation of cardiac arrhythmias.

INTRODUCTION: Recent animal studies demonstrated the feasibility and safety of applying percutaneous catheter cryoablation technology for ablation of arrhythmogenic sites. The studies also showed that reversible "ice mapping" can be performed before creating permanent lesions. We investigated the feasibility and safety of applying this new technology in man. METHODS AND RESULTS: Cryoablation of the AV node (AVN) using a 9-French quadripolar catheter with a 4-mm electrode tip was attempted in 12 patients (mean age 67.8 +/- 11.4 years) with refractory atrial fibrillation. Whereas technical issues prevented adequate tissue contact in two patients, complete AVN block was obtained in the remaining 10 patients after 4.8 +/- 1.9 cryoapplications lasting 5.5 +/- 0.2 minutes resulting in temperatures of -58.1 degrees +/- 5.4 degrees C. In all patients with sinus rhythm at the time of the procedure, cryomapping at warmer temperatures induced reversible AVN block and allowed confirmation of a successful site before definitive ablation. Intracardiac echocardiography was performed in three patients and allowed visualization of the cryocatheter-endocardial contact and cryolesion formation. No major procedural complications were reported. After 6 months of follow-up, 8 of 10 initially successful patients remained in complete block; 1 had partial recovery of AVN conduction manifested by atrial fibrillation with a slow ventricular response, and 1 fully recovered AVN conduction. CONCLUSION: (1) Catheter cryoablation of the AVN can be performed safely in man. (2) Reversible cryomapping is feasible and may offer an advantage over radiofrequency ablation. (3) Cryocatheter-endocardial contact and cryolesion growth can be monitored with intracardiac echocardiography.

Spontaneous episodes of atrial fibrillation after implantation of the Metrix Atrioverter: observations on treated and nontreated episodes. Metrix Investigators.

OBJECTIVES: We sought to evaluate the number and duration of device-treated and self-terminating, nontreated episodes of atrial fibrillation (AF) after implantation of the Metrix Atrioverter. BACKGROUND: A recent study has shown that the Atrioverter can rapidly restore sinus rhythm in patients with AF; however, the effect of the device on the clinical course of the arrhythmia in these patients is unknown. METHODS: The Atrioverter was implanted in 51 patients with symptomatic, recurrent, drug-refractory AF. The device was programmed to periodically monitor the cardiac rhythm. Defibrillation of AF episodes was performed under physician observation. RESULTS: During a mean follow-up of 260 +/- 144 days, 1,161 episodes of AF were observed during valid monitoring periods in 45 of 51 patients. Forty-one patients experienced 231 episodes for which they sought defibrillation therapy. The average duration of the treated episodes during valid monitoring periods (190 of 231 episodes in 39 of 41 patients) was significantly longer than that of the nontreated episodes (38 +/- 44 vs. 10 +/- 8 h; p < 0.05). The time between episodes requiring Atrioverter therapy increased, and the risk of having an episode requiring treatment decreased. No changes were observed in the number and duration of the short-lasting, nontreated episodes as time since implantation of the device increased. CONCLUSIONS: In patients with symptomatic, recurrent, drug-refractory AF, the frequency of long-lasting episodes, which were treated under observation with repeated defibrillation using the Atrioverter, decreased. The number and duration of short-lasting, nontreated episodes did not change during the 20-month study period. The effect of ambulatory use of the device on the recurrence of short-lasting episodes needs to be evaluated.

Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators.

BACKGROUND: The restoration and maintenance of sinus rhythm is a desirable goal in patients with atrial fibrillation, because the prevention of recurrences can improve cardiac function and relieve symptoms. Uncontrolled studies have suggested that amiodarone in low doses may be more effective and safer than other agents in preventing recurrence, but this agent has not been tested in a large, randomized trial. METHODS: We undertook a prospective, multicenter trial to test the hypothesis that low doses of amiodarone would be more efficacious in preventing recurrent atrial fibrillation than therapy with sotalol or propafenone. We randomly assigned patients who had had at least one episode of atrial fibrillation within the previous six months to amiodarone or to sotalol or propafenone, given in an open-label fashion. The patients in the group assigned to sotalol or propafenone underwent a second randomization to determine whether they would receive sotalol or propafenone first; if the first drug was unsuccessful the second agent was prescribed. Loading doses of the drugs were administered and electrical cardioversion was performed (if necessary) within 21 days after randomization for all patients in both groups. The follow-up period began 21 days after randomization. The primary end point was the length of time to a first recurrence of atrial fibrillation. RESULTS: Of the 403 patients in the study, 201 were assigned to amiodarone and 202 to either sotalol (101 patients) or propafenone (101 patients). After a mean of 16 months of follow-up, 71 of the patients who were assigned to amiodarone (35 percent) and 127 of those who were assigned to sotalol or propafenone (63 percent) had a recurrence of atrial fibrillation (P<0.001). Adverse events requiring the discontinuation of drug therapy occurred in 18 percent of the patients receiving amiodarone, as compared with 11 percent of those treated with sotalol or propafenone (P=0.06). CONCLUSIONS: Amiodarone is more effective than sotalol or propafenone for the prevention of recurrences of atrial fibrillation.

Cryothermal ablation of the slow pathway for the elimination of atrioventricular nodal reentrant tachycardia.

BACKGROUND: We report the first successful slow pathway ablation using a novel catheter-based cryothermal technology for the elimination of atrioventricular nodal reentrant tachycardia (AVNRT). METHODS AND RESULTS: Eighteen patients with typical AVNRT underwent cryoablation. Reversible loss of slow pathway (SP) conduction during cryothermy (ice mapping) was demonstrated in 11 of 12 patients. Because of time constraints, only 2 sites were ice mapped in 1 patient. Seventeen of 18 patients had successful cryoablation of the SP. One patient had successful ice mapping of the SP, but inability to cool beyond -38 degrees C prevented successful cryoablation. A single radiofrequency lesion at this site eliminated SP conduction. No patient has had recurrent AVNRT over 4.9+/-1.7 months of follow-up. During cryoablation, accelerated junctional tachycardia was not seen and was therefore not available to guide lesion delivery. Adherence of the catheter tip during cryothermy (cryoadherence) allowed atrial pacing to test for SP conduction. Cryoablation in the anterior septum produced inadvertent transient PR prolongation consistent with loss of fast pathway conduction in 1 patient and transient (6.5 seconds) 2:1 AV block in another. On rewarming, the PR interval returned to normal, and the AV nodal effective refractory period was unchanged in both. Accelerated junctional tachycardia was seen on rewarming in both but not during cryothermy. CONCLUSIONS: Cryothermal ablation of the SP was achieved in patients with this novel technique. Successful ice mapping of both the SP and fast pathway was demonstrated. The ability to test the functionality of specific ablation sites before production of a permanent lesion may eliminate inadvertent AV block.

Transvenous catheter ice mapping and cryoablation of the atrioventricular node in dogs.

While radiofrequency catheter ablation is very effective, it does not allow for prediction of success prior to full delivery of the energy. We investigated the use of cryoablation using a new catheter on the AV node to determine (1) if a successful site might be identified prior to the ablation itself, and (2) the parameters of cryoablation of the AV node using a new cryocatheter. In eight dogs, the cryoablation catheter was advanced to the AV node to produce transient high degree AV block by lowering the temperature to a minimum of -40 degrees C (ice mapping). Transient high degree AV node block was obtained in seven of eight animals at a mean temperature of -39.9 +/- 11.6 degrees C. No significant pathological modification was found in all animals but one and, in all cases, electrophysiological parameters of the AV node measured before, 20 minutes, 60 minutes, and up to 56 days after cryoapplication were not significantly different. In the 12 other dogs, after ice mapping, cryoablation of the AV node was attempted with a single freeze-thaw cycle in 6 dogs (group I) and a double freeze-thaw cycle in the other 6 dogs (group II). Chronic complete AV block was obtained in only one animal in group I compared to all animals in group II. Ablation of the AV node is effective with a double freeze-thaw cycle using a percutaneous catheter cryoablation system. Ice mapping of the area allows for identification of the targeted site.

The T-type Ca(2+) channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs.

BACKGROUND: Ca(2+) overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca(2+) channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca(2+) channel blocker mibefradil on tachycardia-induced atrial remodeling. METHODS AND RESULTS: Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76+/-5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7+/-2.4%), AF duration (414+/-232 seconds), and AF inducibility by single extrastimuli (41+/-10% of sites) compared with 10 unpaced control dogs (ERP 114+/-3 ms, ERP heterogeneity 13.8+/-0.9%, AF duration 7+/-3 seconds, AF inducibility 1.9+/-1.0% of sites). The changes caused by atrial tachycardia were strongly attenuated in mibefradil dogs, with ERPs averaging 102+/-7 ms, ERP heterogeneity 18.8+/-1.4%, AF duration 3+/-1 seconds, and AF inducibility 9.6+/-4.0% of sites. Among mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute mibefradil administration did not alter ERP or AF. CONCLUSIONS: Mibefradil, a drug with strong T-type Ca(2+) channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.

Reentrant pathway during ventricular echoes is confined to the atrioventricular node : high-resolution mapping and dissection of the triangle of koch in isolated, perfused canine hearts.

Background-During ventricular echoes, reentrant excitation is supposed to involve 2 functionally distinct pathways in the atrioventricular (AV) nodal area. The exact pathway of reentrant excitation is unknown. The objectives of this study were to analyze electrical activity in the AV nodal area after ventricular stimulation and during ventricular echoes and to assess the role of perinodal atrial tissue in AV nodal reentry. Methods and Results-In 16 isolated, blood-perfused canine hearts, multiterminal electrodes were used to map electrical activity in Koch's triangle after ventricular stimulation and during ventricular echoes. The subendocardial cell layers were chemically destroyed in 3 hearts. Incisions in the posterior approach to the compact node were made in 6 hearts. The apex of the triangle of Koch was surgically dissociated from the perinodal atrial tissue in 5 hearts. Retrograde atrial activation occurred via 2 distinct endocardial exit sites. Ventricular echoes could be induced in all hearts irrespective of the atrial activation pattern. Simultaneous retrograde activation of both exit sites often preceded reciprocation. Ventricular echoes were demonstrable after chemical destruction of the endocardium and after surgical dissociation of the perinodal atrial tissue from the AV node. Conclusions-Our data show that the reentrant pathway during ventricular echoes is confined to the AV node. The tissue that connects the node to the endocardial exit sites has to be excluded from the reentrant circuit responsible for single echoes.

Double component action potentials in the posterior approach to the atrioventricular node: do they reflect activation delay in the slow pathway?

OBJECTIVES: The aim of the study was to elucidate the mechanism of double component action potentials in the posterior approach to the atrioventricular (AV) junctional area. BACKGROUND: Double component action potentials are often associated with activation delay and therefore might be a marker of the location of the so-called slow pathway. METHODS: The AV junction was scanned for double component action potentials in Langendorff perfused pig and dog hearts, using conventional microelectrode recordings. Characteristics of these action potentials were investigated during basic and premature stimulation and cooling of the anterior approach to the node. RESULTS: During basic stimulation, double component action potentials were recorded in 19 out of 20 hearts. In 74% of these cases, the second component occurred before the His deflection. During premature stimulation this percentage was 50%, while delay between the two components always increased. In 80% of the cases, the amplitude of the two components became <20 mV during progressive shortening of the coupling interval. The first component was generated by activation in superficial layers, the second one by activation in deeper layers. Cooling of the anterior region revealed that the second component was caused by activation arriving from the anterior region. CONCLUSIONS: Double component action potentials in the posterior approach to the AV node are generated by the asynchronous arrival of wave fronts in different, weakly coupled layers or by the summation of asynchronously arriving wave fronts. They are not always associated with activation delay in the slow pathway.

Optimal management with Class I and Class III antiarrhythmic drugs should be done in the outpatient setting: protagonist.

It has been suggested that patients be admitted for the initiation of Class I and Class III antiarrhythmic drugs to avoid serious proarrhythmic consequences. The most clinically significant proarrhythmic response to Class IC agents is likely due to an interaction with acute ischemia, and hospitalization for initiation of drug therapy has little predictive or preventive value. Amiodarone has a low risk of proarrhythmia, and any proarrhythmic reactions are generally delayed. Class IA and Class III antiarrhythmic drugs cause acquired long QT syndrome arrhythmias, which can occur soon after initiation of therapy; however, only about half of the arrhythmic events occur within 3 days of initiation of therapy. It could be argued that all patients should be hospitalized to begin Class IA or Class III drugs; however, this approach has a low yield and is extremely expensive. An alternative is to use Class IA and Class III drugs for patients at low risk of torsades de pointes (e.g., males without heart failure, ventricular tachyarrhythmias, or active coronary disease), in whom hospitalization for drug initiation is not warranted. Higher risk patients are probably better treated with other agents, such as Class IC drugs or amiodarone for women without organic heart disease and amiodarone for patients with heart failure, a history of ventricular tachycardia, or active coronary disease. When a Class IA or Class III drug is required for patient with an increased risk of torsades de pointes, hospital admission for drug initiation may be indicated.

Feasibility of cardiac cryoablation using a transvenous steerable electrode catheter.

We investigated the feasibility of using cryogenic technology in an electrode catheter for percutaneous ablation of cardiac tissue. Despite its high success rate, radiofrequency catheter ablation has important limitations especially with regards to the treatment of ventricular arrhythmias associated with a chronic scar. Arrhythmia surgery experience has shown that freezing with a hand held probe can permanently ablate the arrhythmogenic substrate of ventricular tachycardia associated with an old scar. Moreover, cryosurgery also allows for reversible "ice mapping," in which the area likely responsible for the arrhythmia can be evaluated by suppressing its electrophysiologic properties prior to the creation of an irreversible state. A new steerable cryoablation catheter using Halocarbon 502 as a refrigerant was utilized in six dogs. Serial cryoapplications were performed in the right and left ventricles. In two dogs, we attempted reversible ice mapping of the AV node. Pathological evaluation of the lesions was done acutely in all the animals. Forty-two cryoapplications were delivered at a mean temperature of -45 +/- 9.8 degrees C. No lesion was found at pathological evaluation for 16 cryoapplications which did not achieve a temperature of less (colder) than -30 degrees C. The remaining applications resulted in 26 lesions which were hemorrhagic and sharply demarcated from normal myocardium. Histological evaluation revealed contraction band necrosis. Reversible ice mapping of the AV node was successfully achieved in two animals. Cryoablation is feasible using an electrode catheter with multiple electrodes. This technology has the potential to allow for reversible ice mapping to confirm a successful ablation target before definitive ablation.

Is there a future for antiarrhythmic drug therapy?

Drug therapy has traditionally been the mainstay of treatment for both ventricular and supraventricular arrhythmias. However, increasing knowledge about the potentially significant adverse effects of these medications, together with the emergence of new, nonpharmacological approaches to the treatment of arrhythmias, has led some to question the future of antiarrhythmic drug therapy. Antiarrhythmic drugs are quite effective in terminating a variety of arrhythmias, including atrioventricular (AV) node re-entrant and AV tachycardias (particularly calcium antagonists and adenosine), atrial flutter (class III agents) and atrial fibrillation (class IA and IC drugs. The chronic use of antiarrhythmic drugs has been increasingly limited by a fear of adverse effects (especially proarrhythmia) and the availability of highly effective nonpharmacological alternatives (particularly ablation for re-entrant tachycardias involving the AV node and bypass tracts and cardiovertor/defibrillators for malignant ventricular arrhythmias. Atrial fibrillation (AF) continues to be a therapeutic challenge for which there is no safe and curative nonpharmacological therapy. Antiarrhythmic drugs of classes IA, IC and III show efficacy in preventing recurrence of AF but there are concerns about possible pro-arrhythmic complications. In the future, antiarrhythmic agents will continue to be used acutely to terminate a broad range of sustained arrhythmias. Chronic use is likely to depend on the development of safer and/or more effective compounds, as well as on improved ways of predicting which patients are likely to develop pro-arrhythmic reactions. The development of molecular electrophysiology will allow for the identification of agents with selected ion channel blocking profiles which may prove efficacious with a lower risk of complications. Finally, an improved understanding of arrhythmia substrates may permit the identification of therapy that prevents arrhythmias by acting on the underlying substrate, rather than simply trying to modify the electrical end product.

Origin of heat-induced accelerated junctional rhythm.

INTRODUCTION: The application of high-frequency current to the AV junctional area results in a temperature rise in the myocardium and may cause accelerated junctional rhythm (AJR). The aim of the study was to characterize heat-induced AJR in an in vitro animal model. METHODS AND RESULTS: Studies were performed in isolated perfused pig and rabbit hearts. Using a small heating probe, we could induce AJR from a discrete area located in the middle of the triangle of Koch, which was smaller than the area from which RF energy application could elicit AJR. Histology showed that the heat-sensitive area was located over, or close to, the compact AV node. It did not correspond with the areas where double potentials were found or with the site(s) of earliest atrial activation during VA conduction. Microelectrode recordings revealed that AJR arose in nodal-type cells. Heat increased the slope of the phase 4 depolarization and shortened the action potential duration. Two types of AJR were observed: the first one was regular and the second one showed irregularity in the intervals. Interaction of multiple foci and the presence of conduction block between the foci and the His bundle caused the irregularity of the His-His intervals during the second type of AJR. CONCLUSION: AJR observed during heat and RF application in the AV nodal area results from the effect of heat on AV nodal cells with underlying pacemaker activity. The heat-sensitive area is located over, or very close to, the compact AV node.

Anisotropic conduction in the triangle of Koch of mammalian hearts: electrophysiologic and anatomic correlations.

OBJECTIVES: The purpose of this study was to characterize anisotropy in the triangle of Koch by relating electrophysiology with anatomy. BACKGROUND: Atrioventricular (AV) node fast and slow pathway characteristics have been suggested to be due to nonuniform anisotropy in the triangle of Koch. METHODS: During atrial pacing, we determined the electrical activity within the triangle of Koch by multichannel mapping in 11 isolated hearts from pigs and dogs. Orientation of fibers was determined in nine hearts. RESULTS: Fibers were parallel to the tricuspid valve annulus (TVA) in the posterior part of the triangle of Koch. In the midjunctional area, the direction of the fibers changed to an orientation perpendicular to the TVA. During stimulation from posterior and anterior sites, activation proceeded parallel to the TVA at a high conduction velocity (0.5 to 0.6 m/s). During stimulation from sites near the coronary sinus, a narrow zone of slow conduction occurred in the posterior part of the triangle of Koch where activation proceeded perpendicular to the fiber orientation. Above and below this zone, conduction was fast and parallel to the annulus. After premature stimulation, conduction delay in the triangle of Koch increased by 4 to 21 ms; in contrast, the AH interval increased by 80 to 210 ms. CONCLUSIONS: Data support the concept of anisotropic conduction in the triangle of Koch. Activation maps correlated well with the arrangement of superficial atrial fibers. Comparison of conduction delay in the triangle of Koch and AH delay after premature stimulation disproves that anisotropy in the superficial layers plays an important role in slow AV conduction.

Electrical activity in Koch's triangle.

The authors have conducted several experimental studies of the cellular electrophysiology of the atrioventricular (AV) node employing the Langendorff-blood perfused heart of both dogs and pigs. Two types of experiments are described: experiments showing that cells with electrophysiological characteristics of typical nodal cells can be found outside Koch's triangle; and mapping experiments during the induction of ventricular echo beats in an attempt to delineate the reentrant circuit thought to underlie AV nodal reentry.