Differentiation of the Electrophysiological Effects on the Atrial Myocardium Between the Pure Na Channel Blocker, Pilsicainide, and Flecainide

The purpose of this study was to identify the difference between the pure Na channel blocker, pilsicainide and Ic-antiarrhythmic drug, flecainide, on the atrial electrophysiological characteristics. METHODS: The subjects consisted of 24 patients (48 +/- 12 years-old: P-group) in whom pilsicainide was administrated intravenously (1 mg/kg/10 min) and 31 patients (47 +/- 15 years-old: F-group) in whom flecainide was administrated intravenously (2 mg/kg/10 min). The atrial effective refractory period (ERP-A), intra-atrial conduction time (CT), max intra-atrial conduction delay (Max CD), repetitive atrial firing zone (RAFZ), fragmented atrial activity zone (FAZ) and intra-atrial conduction delay zone (CDZ) were measured before and after the drugs. RESULTS: Pilsicainide and flecainide significantly prolonged the ERP-A (211 +/- 27 msec to 246 +/- 39 msec; p < 0.001, 217 +/- 25 msec to 244 +/- 33 msec; p < 0.001, respectively) and CT (121 +/- 33 msec to 149 +/- 43 msec; p < 0.001, 122 +/- 22 msec to 153 +/- 27 msec; p < 0.001, respectively) to the same degree. However, the Max CD was shortened by pilsicainide, but not by flecainide. The RAFZ, FAZ and CDZ decreased in the P-group (21 +/- 25 msec to 4 +/- 10 msec; p < 0.01, 24 +/- 24 msec to 14 +/- 18 msec; p < 0.05, 56 +/- 29 msec to 43 +/- 32 msec, p < 0.05, respectively), but not in the F-group. CONCLUSIONS: The effects of atrial conduction delays may differ between pilsicainide and flecainide. Further examination will be needed to explain this mechanism.     

The pharmacological response of ischemia-related atrial fibrillation in dogs: evidence for substrate-specific efficacy

OBJECTIVE: Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF. METHODS AND RESULTS: Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective. CONCLUSIONS: Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.     

Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation

Aims Atrial fibrillation (AF) shortens the atrial action potential and the atrial refractory period. These changes promote persistence of AF. Pharmacological prolongation of atrial action potential duration (APD) may therefore help to prevent recurrent AF. In addition to prolonging APD, sodium channel blockers may prevent AF by inducing post–repolarization refractoriness (PRR). We studied whether two antiarrhythmic drugs (sotalol, flecainide) prolong APD or induce PRR in the fibrillating human atrium. Methods In 12 patients with persistent AF (11 male, 58 ± 5 yrs, 27 ± 7 months duration of AF), we recorded monophasic action potentials from the right atrial appendage and inferior right atrium at baseline and 15 minutes after intravenous administration of sotalol (1.5 mg/kg) or flecainide (2 mg/kg). APD and effective refractory periods (ERP) were determined. Results Both drugs prolonged APD90 during AF (flecainide from 109 ± 7 ms to 137 ± 10 ms, sotalol from 108 ± 6 ms to 131 ± 8 ms, both p < 0.05 vs. baseline). Sotalol prolonged ERP in parallel to APD (from 119 ± 8 ms to 139 ± 8 ms, p < 0.05). Flecainide induced PRR by prolonging ERP more than APD90 (from 134 ± 9 ms to 197 ± 28 ms, p < 0.05 vs. baseline and vs. sotalol). Conclusions Flecainide and sotalol prolong the atrial action potential during atrial fibrillation in humans. In addition, flecainide induces atrial PRR. These electrophysiological effects may reduce AF recurrences and prevent their persistence.Drs. Kirchhof, Engelen and Breithardt are Members of the Kompetenznetz Vorhofflimmern     

The effects of class IA antiarrhythmic drug on the common type of atrial flutter in combination with pacing therapy

In 11 patients with common type of atrial flutter (common AF), rapid atrial pacing from the high right atrium was performed before and/or after class Ia antiarrhythmic drug administration, confirming transient entrainment by decreasing the pacing cycle length by 10 ms. In 10 patients before the drug administration, common AF was not interrupted although the pacing cycle length was decreased to 200 ms in 5 patients, accelerated atrial flutter or atrial fibrillation was induced in 4 patients, and common AF was converted into sinus rhythm in only 1 patient. After the drug administration common AF was converted into sinus rhythm in 5 out of 6 patients. The class Ia antiarrhythmic drug prolonged the common AF cycle length (255 +/- 12 ms vs. 298 +/- 37 ms, p less than 0.005) and widened the entrainment zone (64 +/- 7 ms vs. 90 +/- 20 ms, p less than 0.05). The widening of the entrainment zone and the prolongation of the common AF cycle length facilitate the successful conversion of common AF at a longer pacing cycle length, which would not precipitate atrial fibrillation or accelerated atrial flutter. The combination therapy of rapid atrial pacing and the class Ia antiarrhythmic drug is thought to be useful in the therapy of common AF.     

Effect of disopyramide on initiation of atrial fibrillation and relation to effective refractory period

Electrophysiologic studies were performed before and after intravenous administration of disopyramide (2 mg/kg) to 40 patients with either documented or suspected atrial fibrillation (AF). In control studies, sustained AF (greater than 1 minute), nonsustained AF (1 to 60 seconds) and no AF were found in 14, 18 and 8 patients, respectively. After disopyramide, the ability to initiate AF was totally lost in 18 patients (group A), while 22 patients (group B) showed sustained AF (11 patients) or nonsustained AF (11 patients). The effective refractory period of the atrium was 232 +/- 41 ms in the control study and 266 +/- 49 ms after disopyramide. Atrial functional refractory periods before and after disopyramide were 282 +/- 43 and 317 +/- 48 ms, respectively. The differences and ratios of the refractory periods after and before disopyramide were higher in group A than in group B (p less than 0.001). The prolongation of atrial refractoriness after disopyramide was important to suppress the initiation of AF in group A. In some group B patients, on the other hand, the initiation of AF was promoted after disopyramide. Disopyramide may alter the atrial electrophysiologic substrate required for AF initiation.     

Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs.

Flecainide is effective against certain supraventricular arrhythmias (atrial fibrillation and atrioventricular [AV] node reentrant tachycardia), but its mechanisms of action are unknown. Previous in vitro work suggests that flecainide attenuates rate-dependent action potential duration shortening, producing tachycardia-dependent prolongation of the refractory period. This study was designed to assess whether similar changes occur in vivo and whether the effects of flecainide on AV node conduction depend on heart rate and on direction of propagation (anterograde vs. retrograde). The effects of flecainide at three clinically relevant concentrations were assessed in open chest, morphine-chloralose-anesthetized dogs. Flecainide increased atrial refractory period in a concentration- and rate-related fashion (e.g., dose 3 increased the atrial effective refractory period by 9 +/- 4% at a cycle length of 1,000 ms but by 36 +/- 5% and 55 +/- 10% at a basic cycle length of 400 and 300 ms, respectively; p less than 0.001 for each). Flecainide attenuated the action potential duration accommodation (measured by monophasic action potentials) to heart rate, causing tachycardia-dependent action potential duration prolongation and accounting for most of the rate-dependent atrial effective refractory period changes. Flecainide increased Wenckebach cycle length, but the concentration-response curve was much steeper in the retrograde (slope 41 +/- 7 ms/mumol.liter-1) than in the anterograde direction (17 +/- 4 ms/mumol.liter-1; p less than 0.01), indicating more potent effects on retrograde conduction. The depressant action of the drug on the AV node was also rate dependent, with an effect on the AH interval at a basic cycle length of 400 ms that averaged 1.8, 1.5 and 2 times that at a basic cycle length of 1,000 ms for doses 1 (p less than 0.05), 2 (p less than 0.01) and 3 (p less than 0.001), respectively. Conclusions: 1) Flecainide suppresses atrial action potential duration accommodation to heart rate changes in vivo, leading to rate-dependent atrial effective refractory period prolongation, which may be important in suppressing atrial fibrillation. 2) The drug has frequency- and direction-dependent effects on AV node conduction, which may lead to selective antiarrhythmic actions during AV node reentry.     

Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation.

Class Ic antiarrhythmic drugs are effective in the treatment of atrial fibrillation, but their mechanism of action is unknown. In previous work, we have found that flecainide causes tachycardia-dependent increases in atrial action potential duration (APD) and effective refractory period (ERP) by reducing APD accommodation to heart rate. The present study was designed to evaluate the efficacy and mechanisms of action of flecainide in an experimental model of sustained atrial fibrillation (AF). AF was produced by a brief burst of atrial pacing in the presence of vagal stimulation and persisted spontaneously until vagal stimulation was stopped. The actions of flecainide at two dose levels were compared with those of isotonic glucose placebo in each dog, with a randomized order of blinded drug administration. Flecainide terminated AF in all 16 dogs, while glucose was effective in none (p less than 0.0001). Flecainide increased atrial ERP and reduced conduction velocity in a tachycardia-dependent manner. Doses of flecainide that converted AF resulted in larger changes in ERP than in conduction velocity, increasing the minimum path-length capable of supporting reentry (wavelength). In addition, flecainide reduced regional heterogeneity in ERP and wavelength, an action opposite that of vagal stimulation. Atrial epicardial mapping with a 112-electrode atrial array was used to study the mechanism of flecainide action on AF. Under control conditions, multiple small zones of reentry coexisted. Flecainide progressively increased the size of reentry circuits, decreased their number, and slowed the frequency of atrial activation until the arrhythmia finally terminated; all changes were compatible with an increase in wavelength. We conclude that flecainide terminates atrial fibrillation in this experimental model by causing tachycardia-dependent increases in atrial ERP, which increase the wavelength at the rapid rates characteristic of AF to the point that the arrhythmia can no longer sustain itself.     

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.     

Electrophysiologic effects of flecainide on guinea pig atrium]

We investigated the effects of flecainide on guinea pig atrial muscle. Using Langendorff's method, the whole heart of a guinea pig was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Then, with right atrial extrastimulus and high frequency pacing method, the following values were measured before and after administration of flecainide (10(-7)-10(-5) M). A) Effective refractory period (ERP); the longest coupling interval which failed to produce right atrial activity at premature stimulus. B) Interatrial conduction time (ACT); After right atrial stimuli by trains at PCL 200 ms for 5 min the interval from the stimulation to the first deflection of the left atrial activity. C) Atrial fibrillation threshold (AFT); the minimal amount of current required to induce atrial fibrillation lasting for more than 30 sec by 50 Hz high frequency stimulation. Flecainide lengthened ERP (> or = 3 x 10(-5) M) and ACT (> or = 10(-7) M). Flecainide (10(-5) M) significantly increased AFT which correlated well with ERP (r = 0.81, p < 0.002) and ACT (r = 0.84, p < 0.002). In conclusion these effects of flecainide on guinea pig atrium might explain in part the clinical effectiveness of the drug on paroxysmal atrial fibrillation.     

Flecainide augments muscle sympathetic nerve activity in humans.

The Cardiac Arrhythmia Suppression Trial has shown that treatment with flecainide is associated with an increased incidence of cardiac death in patients following myocardial infarction. It is believed that there is a complex mechanism involving an interaction between flecainide, sympathetic activation, and acute ischemia that is responsible for the increased risk of sudden death. The purpose of this study was to determine the effects of flecainide on muscle sympathetic nerve activity (MSNA) in humans. We measured MSNA using microneurography and cardiac output using the dye dilution method in 30 healthy individuals. Measurements were made at rest and after the oral administration of flecainide (200mg, n=12) or placebo (n=9), or intravenous administration of propranolol (0.2 mg/kg, n=9). Flecainide significantly increased heart rate and decreased the cardiac index (both p<0.01). Flecainide increased the burst rate from 16.7 +/- 3.5 to 23.3 +/- 4.1 bursts/min and the burst incidence from 26.6 +/- 5.1 to 34.7 +/ -5.6bursts/100 heartbeats (both p<0.01). For all of the hemodynamic parameters except heart rate, the effects of propranolol were similar to those of flecainide. Propranolol also increased the burst rate by 52 +/- 34% and the burst incidence by 106 +/- 39%. These results suggest that flecainide suppresses myocardial contractility and produces reflex-mediated increases in sympathetic nerve firing in humans.     

Electrophysiologic studies in atrial fibrillation. Slow conduction of premature impulses: a possible manifestation of the background for reentry

Extrastimulus-induced intraatrial conduction delays were measured in 12 patients with documented episodes of atrial fibrillation (AF) by recording atrial electrograms at the high right atrium, His bundle region, and coronary sinus. Seventeen patients with and without heart disease, but without atrial arrhythmias served as the control group. During baseline-paced atrial rhythms, a conduction delay zone could be delineated, near the atrial effective refractory period, during which all extrastimuli produced conduction delays. When compared at the same paced cycle lengths (500 to 650 ms), the patients with AF had shorter atrial effective refractory periods (mean +/- standard deviation 206 +/- 24.1 versus 233 +/- 28.2 in control patients, p less than 0.02), wider conduction delay zones (79 +/- 21.7 ms versus 52 +/- 21 in control patients, p less than 0.01), and longer conduction delays both to the His bundle region (64 +/- 18.3 ms versus 35 +/- 21.7 in control patients, p less than 0.005) and the coronary sinus (76 +/- 18.9 ms versus 35 +/- 16.1 in control patients, p less than 0.001). Repetitive atrial responses were recorded in 6 patients with AF and in 9 control subjects. Sinus nodal function abnormalities were detected in 6 of the patients with fibrillation. Patients with AF had a higher tendency than control subjects to develop slow intraatrial conduction, as well as shorter effective refractory periods. Since both features would favor reentry, they may be the electrophysiologic manifestations of the abnormalities making these patients prone to atrial reentrant arrhythmias. Repetitive atrial responses were of no predictive value. Sinus nodal dysfunction was frequently found, but was not essential for the occurrence of AF.     

Flecainide controlled-release for prevention of atrial fibrillation relapse

Flecainide acetate instant release (LI) has been prescribed for years in the prevention of atrial fibrillation (AF) relapse after sinus rate conversion. A new controlled-release (LP) formulation of flecainide was recently introduced. The objectives of this observational study were to evaluate the benefit/risk ratio of LI or LP flecainide treatment for prevention of AF relapse. METHODS: EPIFLEC study was an open, prospective, observational study conducted by 151 cardiologists who had prescribed either flecainide LI (group 1) to 838 patients or flecainide LP (group 2) to 214 patients or flecainide LI before LP (group 3) to 242 patients. In these patients, AF was either paroxystic (35%) or persistant (65%). Concomitant pathologies were observed in 80% of these patients (mean age 68 years) with a high incidence (50%) of hypertension. The mean duration of treatment was 6.9 +/- 6.7 months in group 1 (LI), 6.2 +/- 3.1 months in group 2 (LP) and 12.7 +/- 5.4 months in group 3 (LI-LP). RESULTS: mean daily dosages of flecainide were similar among the 3 groups. Antithrombotic drugs were prescribed in 74% (group 1) to 83% (group 2) of the patients and another antiarrhythmic drug was associated to flecainide among 12 to 21% of the patients. AF relapse was observed in 171 patients in group 1 (LI), 38 patients in group 2 (LP) and 39 patients in group 3 (LI-LP). The incidence of AF relapse was compared in groups 1 and 2 at 10 months of follow-up and AF relapse probability was not significantly different between flecainide LI and LP :26 +/- 2% and 23 +/- 4% respectively (OR = 0.99, CI 95%:0.69-1.4; p = 0.96). A multivariate analysis showed that previous multiples episodes of AF, electrical shock rate conversion and history of flutter and hypertension were independent predictors of AF relapse. Among 11 deaths observed during follow-up, only 2 were cardiovascular. The most frequent non lethal cardiovascular adverse events were arrhythmias or cardiac conduction disorders and were limited to less than 5% of the patients. Only 5 supraventricular transient pro arrhythmias episodes were recorded. CONCLUSION: this pharmaco-epidemiological study in private practice confirms that flecainide is able to prevent AF relapse in 75% of patients at 10 months and that the tolerance of the treatment is acceptable in these patients.     

Transthoracic tissue Doppler imaging of the atria: a novel method to determine the atrial fibrillation cycle length

Background: The atrial fibrillation cycle length (AFCL) is a critical parameter for the perpetuation and termination of AF. In the present study, we evaluated a new method to measure the AFCL based on transthoracic tissue Doppler imaging (TDI) of the right atrium (RA) and left atrium (LA). Methods: Twenty patients with AF (6 acute AF, 14 persistent or permanent AF) were studied. A quadripolar catheter was positioned at RA or LA to measure AFCL (AFCL_EGM, gold standard). Transthoracic echocardiography (apical 4‐chamber view) was used to perform pulsed wave TDI at the free wall of RA or LA. AFCL_TDI was defined as the time interval between two consecutive positive to negative crossings of the baseline of the atrial time velocity curves. AFCL_EGM and AFCL_TDI were measured at baseline and during a 10‐minute infusion of flecainide (1.5 mg/kg). Results: Measurement of AFCL_TDI was feasible in all but one patient. At baseline, AFCL_EGM was 170 ± 22 ms, AFCL_TDI 172 ± 22 ms (difference 2 ± 5 ms). AFCL_TDI correlated significantly with AFCL_EGM (R = 0.91, P < 0.0001). Bland‐Altman analysis showed a bias of ?2 ms with a 95% limit of agreement between ?26 ms and +22 ms. During flecainide, the AFCL_TDI method yielded an AFCL prolongation from 176 ± 23 ms at baseline to 279 ± 68 ms (P < 0.01) after 10 minutes of infusion (57 ± 26%). Conclusions: (1) Tissue Doppler imaging of the atria during transthoracic echocardiography can be used to reliably determine the AFCL during both acute and persistent or permanent AF. (2) Continuous measurement of AFCL with TDI can be used to monitor the effect of antiarrhythmic drugs on atrial rate during AF. (3) This novel method is attractive because of the ease of acquiring the data and its noninvasive character.     

Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs

OBJECTIVE: Atrial fibrillation (AF) induces electrical and ionic remodeling of the atria. We investigated whether AF-induced remodeling alters the electrophysiological and anti-fibrillatory effects of class I (flecainide) and class III (d-sotalol, ibutilide) anti-arrhythmic drugs. METHODS: In 9 goats, the effects of flecainide (6 mg/kg) and d-sotalol (6 mg/kg) on atrial electrophysiology were measured both before and after 48 h of electrically induced AF. During a 1-h infusion period the atrial effective refractory period (AERP) and conduction velocity (CV) were measured both during slow and rapid pacing (interval 400 and 200 ms). In 8 other goats, the rate-dependent effects of ibutilide (0.12 mg/kg) on AERP were determined. RESULTS: The effects of flecainide on atrial conduction and refractoriness were not altered after 48 h of AF. At a dose of 6 mg/kg flecainide reduced the CV200 by 19+/-5% in normal atria and by 21+/-9% after 48 h of AF (p=0.20). The AERP200 was prolonged by 10+/-6% and 8+/-7%, respectively (p=0.40). In contrast, the effect of d-sotalol on atrial refractoriness was markedly diminished. During control d-sotalol prolonged the AERP400 by 17+/-6% compared to only 6+/-5% after 2 days of AF (p<0.01). Also ibutilide lost much of its class III effect on the AERP by electrical remodeling (from 15 to 5%; p<0.05). The loss of class III action was less pronounced at rapid heart rates. CONCLUSIONS: AF-induced atrial electrical remodeling in the goat did not modulate the action of flecainide on atrial conduction and refractoriness. In contrast, the class III effects of d-sotalol and ibutilide on the atria were strongly reduced after 2 days of AF. The prolongation of QT-duration was not affected.     

Monophasic action potentials of the right atrium in patients with paroxysmal atrial fibrillation

To investigate the mechanism of atrial fibrillation (AF), monophasic action potentials (MAPs) from the atrial myocardium were studied in 7 patients with paroxysmal AF (PAF) and in 7 control individuals. The MAPs were recorded using a contact catheter during sinus rhythm and continuous pacing at the high right atrium (HRA) with pacing cycle lengths of 600, 500 and 400 ms. MAPs were obtained from 6 sites in each participant. The MAPD90 was measured from onset to 90% of MAP repolarization. Average, maximal and minimal MAPD90 (avMAPD90, maxMAPD90 and minMAPD90) were obtained from all participants. The dispersion of MAPD90 (dispMAPD90) was defined as the difference between maxMAPD90 and minMAPD90. The width of each atrial potential (WAP) and the wavelength index (WLI=MAPD90/WAP) were determined. Average, maximal and minimal WLI (avWLI, maxWLI and minWLI) were obtained from all participants. The avMAPD90 and maxMAPD90 did not significantly differ between the 2 groups. The minMAPD90 in the PAF group was significantly smaller than that in the control group at HRA pacing with cycle lengths of 500 and 400 ms (210+/-18ms vs 245+/-14 ms, p<0.05; 207+/-23 ms vs 238+/-20 ms, p<0.05; respectively). The dispMAPD90 was significantly longer in the PAF group than in the control group during sinus and HRA pacing. The WAP value did not differ between the 2 groups. The minWLI in the PAF group was significantly smaller than that in the control group at HRA pacing with cycle lengths of 500 and 400 ms (3.3+/-0.5 vs 3.8+/-0.3, p<0.05; 3.2+/-0.4 vs 3.7+/-0.3, p<0.02). A shortened and widened dispersion of atrial refractoriness may play an important role in the genesis of AF. Furthermore, smaller wavelengths may form in the atrium of patients with PAF.     

High‐Resolution Analysis of the Surface P Wave as a Measure of Atrial Electrophysiological Substrate

Background: At present atrial electrophysiology can only be assessed by invasive study. This limits available data in humans concerning atrial electrophysiologic changes in disease and in response to intervention. Indirect evidence suggests that the signal‐averaged P wave (SAPW) may provide noninvasive markers of atrial electrophysiology but no direct evaluations that measure both refractoriness and conduction time have been reported. Methods: We investigated 9 patients attending for diagnostic electrophysiological studies (4 male; mean age 35.7 years). A 20‐pole catheter was positioned in the right atrium; a decapole catheter was placed in the coronary sinus. Atrial effective refractory period (AERP) and conduction times were measured at the lateral and septal right atrium and the left atrium during sinus rhythm (SR) and at pacing cycle lengths of 600, 500, and 400 ms. Simultaneous SAPW recordings were taken during SR and pacing at 600 ms. Intravenous flecainide (2 mg/kg) was given after which the protocol was repeated. Results: Flecainide slowed conduction significantly at all sites (P < 0.05). During baseline measurements, rate adaptation of AERP was observed (P < 0.02 at the septum). Flecainide increased filtered P wave duration (P < 0.05) and reduced P wave energies (P < 0.05). Negative correlation was observed between P wave energies and conduction time with an inverse relationship between high‐frequency energy and left atrial AERP. Conclusions: The SAPW provides a noninvasive marker of atrial electrophysiology.     

Right atrial modification of maze surgery does not affect refractoriness and conduction patterns of human lone atrial fibrillation.

BACKGROUND: Tissue mass and structure are relevant for initiation and persistence of fibrillation. Modification of the right atrium during maze surgery may change the arrhythmogenic substrate of atrial fibrillation (AF). METHODS AND RESULTS: Epicardial mapping was performed in 9 patients undergoing unmodified maze III surgery for lone paroxysmal AF. Simultaneous recording of AF on the right and left atrium was carried out with two spoon-electrodes each harbouring 64 terminals. Activation maps of AF were made to study AF wavelet organization. The recording position on right and left atria was outside the surgical field and remained unchanged before and after surgery. Before surgery, mean right and left fibrillatory intervals were 174+/-23 ms, and 175+/-26 ms, respectively, and did not differ. After completed right atrial surgery, these fibrillary intervals remained unchanged. Mean right and left atrial dispersion of refractoriness (expressed as the coefficient of variation) were 4.2+/-0.8 and 5.2+/-3.8 ms. Only right atrial dispersion of refractoriness increased significantly after right-sided surgery. Prior to surgery, activation patterns of the left atrium were more complex than that of the right atrium. The left activation patterns became less complex afterwards; the right atrial activation patterns did not change. CONCLUSION: The right atrial modification of maze III surgery neither affects atrial refractoriness during human lone AF nor changes AF wavelet organization. Thus, right atrial surgery does not modify the arrhythmogenic substrate of AF. These findings may imply that maze surgery can be restricted to the left atrium.     

Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat

INTRODUCTION: During atrial fibrillation (AF), there is fractionation of extracellular potentials due to head-to-tail interaction and slow conduction of fibrillation waves. We hypothesized that slowing of the rate of AF by infusion of a Class I drug would increase the degree of organization of AF. METHODS AND RESULTS: Seven goats were instrumented with 83 epicardial electrodes on the left atrium, left atrial appendage, Bachmann's bundle, right atrium, and right atrial appendage. AF was induced and maintained by an automatic atrial fibrillator. After AF had persisted for 4 weeks, the Class IC drug cibenzoline was infused at a rate of 0.1 mg/kg/min. AF cycle length (AFCL), the percentage of fractionated potentials, conduction velocity (CV), and direction of propagation of the fibrillation waves were measured during baseline, after AFCL was increased by 20, 40, 60, and 80 ms, and shortly before cardioversion. Infusion of cibenzoline increased the mean of the median AFCLs from 96 +/- 6 ms to 207 +/- 43 ms (P < 0.0001). The temporal variation in AFCL in different parts of the atria was 8% to 20% during control and, with the exception of Bachmann's bundle, was not significantly reduced during cibenzoline infusion. CV decreased from 76 +/- 14 ms to 52 +/- 9 cm/s (P < 0.01). Cibenzoline increased the percentage of single potentials from 81%+/- 4% to 91%+/- 4% (P < 0.01) and decreased the incidence of double potentials from 14%+/- 4% to 7 +/- 5% (P < 0.01) and multiple potentials from 5%+/-% to 1%+/- 2% (P < 0.001). Whereas during control, linking (consecutive waves propagating in the same direction) during seven or more beats occurred in 9%+/- 15% of the cycles, after cibenzoline the degree of linking had increased to 40%+/- 33% (P < 0.05). During the last two beats before cardioversion, there was a sudden prolongation in AFCL from 209 +/- 37 ms to 284 +/- 92 ms (P < 0.01) and a strong reduction in fractionated potentials (from 22%+/- 12% to 6%+/- 5%, P < 0.05). CONCLUSION: The Class IC drug cibenzoline causes a decrease in fractionation of fibrillation electrograms and an increase in the degree of linking during AF. This supports the observation that Class I drugs widen the excitable gap during AF.     

Reversal of electrophysiologic effects of flecainide on the accessory pathway by isoproterenol in the Wolff-Parkinson-White syndrome

To determine the reversibility of the effects of flecainide on accessory pathways, electrophysiologic studies were performed in the drug-free control state, after flecainide loading and with isoproterenol infusion during flecainide treatment in 12 patients with symptomatic preexcitation syndrome. After the baseline drug-free evaluation, oral flecainide was given in dosages of 50 to 200 mg twice daily (mean daily dose 282 +/- 75) for at least 4 days before the repeat electrophysiologic study. Isoproterenol infusion was given in dosages of 1 to 4 micrograms/min to increase the heart rate at rest by 50%. Anterograde block in the accessory pathway was observed in 3 patients with flecainide therapy, whereas in the other patients the anterograde refractory period increased from 243 +/- 20 to 315 +/- 23 ms (p less than 0.05). The shortest preexcited RR interval during atrial fibrillation lengthened from 234 +/- 27 ms before flecainide to 313 +/- 38 ms (p less than 0.05). Retrograde block occurred in 2 patients after flecainide, whereas the retrograde refractory period of the accessory pathway increased from 247 +/- 26 to 337 +/- 45 ms in the other patients. Orthodromic atrioventricular reciprocating tachycardia, inducible in 10 patients before therapy, became noninducible in 3 patients. Its rate was significantly slowed in the other 7 patients (from 346 +/- 50 to 471 +/- 81 ms). In 2 patients the tachycardia was nonsustained during flecainide treatment. Atrial fibrillation, inducible in all patients at baseline, was rendered nonsustained and more difficult to induce in 7 patients with flecainide. When isoproterenol was infused during flecainide treatment, complete anterograde (3 patients) or retrograde block (2 patients) persisted in the accessory pathway.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects and clinical efficacy of flecainide in children with recurrent paroxysmal supraventricular tachycardia

The electrophysiologic effects of intravenous flecainide were evaluated in 16 patients aged 9 +/- 4 years: 15 with recurrent paroxysmal supraventricular tachycardia (SVT) and 1 with overt accessory pathway and history of syncope. Eleven patients had an accessory pathway; it was concealed in 2, overt in 9 and in 10 of these patients an orthodromic atrioventricular reentrant tachycardia was induced. Five patients without accessory pathway had an atrioventricular nodal reentrant tachycardia. After intravenous flecainide (1.5 mg/kg) the effective refractory period of the atrium and ventricle increased significantly; the anterograde and retrograde effective refractory periods of the atrioventricular node did not. Flecainide blocked retrograde conduction in the accessory pathway in 4 patients (effective refractory period 245 +/- 41 ms) and anterograde conduction in 8 of 9 patients (effective refractory period 284 +/- 57 ms). The mean cycle length of orthodromic reciprocating tachycardia and atrioventricular nodal reentrant tachycardia increased significantly. After flecainide tachycardia was noninducible in 6 patients with orthodromic reciprocating tachycardia and in 1 with atrioventricular nodal reentrant tachycardia. It was inducible but nonsustained (less than or equal to 30 seconds) in 1 patient with orthodromic reciprocating tachycardia and in 3 with atrioventricular nodal reentrant tachycardia. Fifteen patients continued oral flecainide treatment for 19 +/- 11 months.(ABSTRACT TRUNCATED AT 250 WORDS)