The Role of the Atrial Neural Network In Atrial Fibrillation: The Metastatic Progression Hypothesis.

With the advent of catheter ablation of atrial fibrillation (AF) there has been acceleration in our understanding of the mechanisms underlying the etiology of this common clinical arrhythmia. In this regard, the role of the intrinsic cardiac autonomic nervous system in the initiation and maintenance of AF began to receive attention in numerous experimental and clinical investigations. Up to now, the focus has been on the large ganglionated plexi (GP) which are located in the posterior left atrium mainly at the pulmonary vein-atrial junctions. As long term outcomes have been reported and single procedures have indicated diminished success rates particularly for persistent/long standing persistent AF, emphasis has begun to shift away from the pulmonary vein isolation (PVI) alone as well as GP ablation with or without PVI. An understanding of the atrial substrate represented by the extensions of the intrinsic cardiac autonomic system constituting the atrial neural network is beginning to evolve. In this review, the contribution of the intrinsic cardiac autonomic nervous system to the etiology of AF is addressed, particularly in regard to the greater prevalence of AF in the elderly. In addition, we emphasize the involvement of the atrial neural network in the "metastatic" progression of paroxysmal to persistent and long standing persistent forms of AF.

Focal atrial fibrillation: experimental evidence for a pathophysiologic role of the autonomic nervous system.

INTRODUCTION: Focal paroxysmal atrial fibrillation (AF) was shown recently to originate in the pulmonary veins (PVs) and superior vena cava (SVC). In the present study, we describe an animal model in which local high-frequency electrical stimulation produces focal atrial activation and AF/AT (atrial tachycardia) with electrogram characteristics consistent with clinical reports. METHODS AND RESULTS: In 21 mongrel dogs, local high-frequency electrical stimulation was performed by delivering trains of electrical stimuli (200 Hz, impulse duration 0.1 msec) to the PVs/SVC during atrial refractoriness. Atrial premature depolarizations (APDs), AT, and AF occurred with increasing high-frequency electrical stimulation voltage. APD/AT/AF originated adjacent to the site of high-frequency electrical stimulation and were inducible in 12 of 12 dogs in the SVC and in 8 of 9 dogs in the left superior PV (left inferior PV: 7/8, right superior PV: 6/8; right inferior PV: 4/8). In the PVs, APDs occurred at 13+/-8 V and AT/AF at 15+/-9 V (P < 0.01; n = 25). In the SVC, APDs were elicited at 19+/-6 V and AT/AF at 26+/-6 V (P < 0.01; n = 12). High-frequency electrical stimulation led to local refractory period shortening in the PVs. The response to high-frequency electrical stimulation was blunted or prevented after beta-receptor blockade and abolished by atropine. In vitro, high-frequency electrical stimulation induced a heterogeneous response, with shortening of the action potential in some cells (from 89+/-35 msec to 60+/-22 msec; P < 0.001; n = 7) but lengthening of the action potential and development of early afterdepolar-izations that triggered APD/AT in other cells. Action potential shortening was abolished by atropine. CONCLUSION: High-frequency electrical stimulation evokes rapid ectopic beats from the PV/SVC, which show variable degrees of conduction block to the atria and induce AF, resembling findings in patients with focal idiopathic paroxysmal AF. The occurrence of the arrhythmia in this animal model was likely due to alterations in local autonomic tone by high-frequency electrical stimulation. Further research is needed to prove absolutely that the observed effects of high-frequency electrical stimulation were caused by autonomic nerve stimulation.

Functional anatomy of AV conduction: changing concepts in the ablation era.

Transitional cell populations (TCs) are located adjacent to the compact AV node in the rabbit. TCs located superior to the compact AV node and inferior to the interatrial septum (midpathway) have the longest Wenckebach cycle length (WBCL) (208 +/- 12 ms), but fail to determine AV WB when the posterior and/or anterior inputs remain intact. When all 3 TC populations remain intact, AV WB is determined at a shorter CL (195 +/- 15 ms) by TCs of the posterior input. With transection of the posterior TC input into the compact AV node, AV conduction is maintained at a longer AV WBCL consistent with WB within TCs located superior and anterior to the compact AV node. AV conduction remains intact in most hearts after transection of posterior and anterior TC populations from the compact AV node, with AV WB determined by TC input from the midpathway at a prolonged CL (214 +/- 10 ms) consistent with the pretransection midpathway WBCL. In a separate set of experiments, surgical separation of the 3 TC inputs from each other was performed while maintaining connection of the 3 individual TC inputs to the compact AV node remained intact. Stimulation of the proximal input from any 2 of the 3 TC inputs summated to produce a longer AV WBCL than observed from either AV nodal input alone. Data provided by the ablation of AV nodal inputs show the existence of 3 anatomically and functionally distinct populations of TCs providing independent and summated atrial input into the compact AV node.

Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation.

BACKGROUND: Vagal stimulation shortens the atrial effective refractory period (AERP) and maintains atrial fibrillation (AF). This study investigated whether the parasympathetic pathways that innervate the atria can be identified and ablated by use of transvenous catheter stimulation and radiofrequency current catheter ablation (RFCA) techniques. METHODS AND RESULTS: In 11 dogs, AERPs were determined at 7 atrial sites during bilateral cervical vagal nerve stimulation (VNS) and electrical stimulation of the third fat pad (20 Hz) in the right pulmonary artery (RPA). VNS shortened the AERP at all sites (from 123+/-4 to 39+/-4 ms, P<0.001) and increased the covariance of AERP (COV-AERP) (from 9+/-3% to 27+/-13%, P<0.001). RPA stimulation shortened the AERP at all sites from 123+/-4 to 66+/-13 ms (P<0.001) and increased the COV-AERP from 9+/-3% to 30+/-12% (P<0.001). In 7 dogs, transvascular RFCA of the parasympathetic pathways along the RPA was performed, and in 3 dogs, additional RFCA of parasympathetic fibers along the inferior (n=2) or superior (n=1) vena cava was performed. RFCA blunted the AERP shortening at all sites during VNS (114+/-4 ms after RFCA), abolished the increase of COV-AERP during VNS (12+/-7% after RFCA), and led to an increase of the baseline AERP (123+/-4 ms before versus 127+/-3 ms after RFCA, P=0.002). Before RFCA, AF could be induced and maintained as long as VNS was continued, whereas after RFCA, AF was no longer inducible during VNS. CONCLUSIONS: -Transvascular atrial parasympathetic nerve system modification by RFCA abolishes vagally mediated AF. This antifibrillatory procedure may provide a foundation for investigating the usefulness of neural ablation in chronic animal models of AF and eventually in patients with AF and high vagal tone.

[Treatment of tachycardic atrial fibrillation by catheter-assisted electrical stimulation of the cardiac parasympathetic nervous system]. / Die Behandlung des tachykarden Vorhofflimmerns durch kathetergestützte elektrische Stimulation des kardialen parasympathischen Nervensystems.

UNLABELLED: Treatment of tachycardic atrial fibrillation (AF) is difficult in patients with congestive heart failure because many drugs which exert negative dromotropic effects (beta-blockers, calcium channel antagonists) may depress ventricular contractility and/or decrease arterial blood pressure. We have identified 2 intravascular sites in the superior (SVC) and inferior vena cava (IVC) where parasympathetic nerves, which innervate the atrioventricular node, can be stimulated electrically. In 8 dogs, a 7-F catheter with an expandable electrode basket at its tip was non-fluoroscopically positioned in the SVC and in the proximal IVC (time for positioning: 3-5 minutes). High-frequency electrical parasympathetic stimulation (PS) with 20 Hz at an impulse duration of 0.1 ms was performed during pacing induced AF. RESULTS: With increasing stimulus strength, a graded ventricular rate slowing was observed during PS in the SVC and IVC (P < 0.01, ANOVA). The negative dromotropic effect started instantaneously after onset of PS and ceased immediately after termination of PS. During ventricular pacing at a constant rate, no decrease of the arterial blood pressure was observed during PS. PS in the IVC yielded significantly lower stimulation thresholds than in the SVC. CONCLUSIONS: Transvenous parasympathetic stimulation for ventricular rate control during AF can easily be achieved in the SVC and IVC in dogs. This procedure may provide a foundation for investigating the usefulness of PS in humans. If the results translate to patients, PS may be very beneficial in the treatment of AF in patients with congestive heart failure.

The acute and subchronic toxicity of BRB-I-28, a novel class Ib antiarrhythmic agent, in CD-1 mice.

The acute and subchronic toxic effects of BRB-I-28 (7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane HCl), a novel class Ib antiarrhythmic agent, were investigated in male and female mice. The estimated oral LD(50) for BRB-I-28 was 128 mg/kg (male mice) and 131 mg/kg (female mice). In subchronic oral studies, four groups of mice (15/sex/group/dose) were fed daily with diets containing BRB-I-28 for 90 consecutive days. The equivalent daily doses were approximately 0, 16, 32, 76 (male) and 0, 18, 37, 89 mg/kg (female). All mice survived. Food consumption per day was decreased, but water consumption per day was increased (in a non-dose-dependent manner). However, both mean body weight and mean body weight gain were not significantly changed as were true for hematological and clinical chemistry profiles, except for serum Na(+) concentration (male) and serum K(+) concentration in male and female mice (high dose levels). Hepatocellular necrosis occurred in male and female mice (in a dose-dependent fashion). Renal cortical vacuoles and myocardial necrosis with low numbers of lymphocytic infiltrations were present in female mice (middle and high doses). Lesions in the liver, kidney and heart were mild with (very small) changes in serum biochemical values. These data suggest that BRB-I-28 has limited toxic potential, and coupled with low proarrhythmic and other desirable cardiovascular effects, makes BRB-I-28 worthy of further development.

Transvenous parasympathetic nerve stimulation in the inferior vena cava and atrioventricular conduction.

INTRODUCTION: In previous reports, we demonstrated a technique for parasympathetic nerve stimulation (PNS) within the superior vena cava, pulmonary artery, and coronary sinus to control rapid ventricular rates during atrial fibrillation (AF). In this report, we describe another vascular site, the inferior vena cava (IVC), at which negative dromotropic effects during AF could consistently be obtained. Moreover, stimulation at this site also induced dual AV nodal electrophysiology. METHODS AND RESULTS: PNS was performed in ten dogs using rectangular stimuli (0.1 msec/20 Hz) delivered through a catheter with an expandable electrode basket at its tip. Within 3 minutes and without using fluoroscopy, the catheter was positioned at an effective PNS site in the IVC at the junction of the right atrium. AF was induced and maintained by rapid atrial pacing. During stepwise increase of the PNS voltage from 2 to 34 V, a graded response of ventricular rate slowing during AF was observed (266 +/- 79 msec without PNS vs 1,539 +/- 2,460 msec with PNS at 34 V; P = 0.005 by analysis of variance), which was abolished by atropine and blunted by hexamethonium. In three animals, PNS was performed during sinus rhythm. Dual AV nodal electrophysiology was present in 1 of 3 dogs in control, whereas with PNS, dual AV nodal electrophysiology was observed in all three dogs. PNS did not significantly change sinus rate or arterial blood pressure during ventricular pacing. CONCLUSION: Stable and consistent transvenous electrical stimulation of parasympathetic nerves innervating the AV node can be achieved in the IVC, a transvenous site that is rapidly and readily accessible. The proposed catheter approach for PNS can be used to control ventricular rate during AF in this animal model.

Endovascular neural stimulation via a novel basket electrode catheter: comparison of electrode configurations.

We previously showed that parasympathetic stimulation by a basket electrode catheter (BEC) positioned in the superior vena cava (SVC) can slow sinus rate (SR) or ventricular response (VR) during atrial fibrillation (AF). In 11 dogs, anesthetized with Na-pentobarbital, standard ECG leads II and aVR, blood pressure and right atrial electrograms were continuously monitored. Two different BEC configurations (B1, B2) were tested in the SVC. B1 consisted of five metal splines, each 3 cm in length. Stimulation was applied between adjacent splines. B2 consisted of 2 electrodes at opposite ends of each of 5 splines and a larger electrode at the middle of each spline. Stimulation was delivered between the two end electrodes and the middle electrode on the same arm. Stimulation consisted of square wave stimuli, each 0.1 msec duration, frequency 20 Hz at voltages from 1-40 V. Six dogs were studied with B1 and five were studied with the B2 configuration. The average voltage required to produce a 50% decrease in heart rate was 22+/- 12 V when stimulating between adjacent splines (B1) compared to 10+/- 5 V when stimulating along a single spline (B2), a 55% decrease (p

Preliminary acute and subchronic toxicity studies of GLG-V-13, a novel class III antiarrhythmic agent, in mice.

The acute and subchronic toxic effects of GLG-V-13 (3-[4-(1H-imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nona ne dihydroperchlorate, CAS 155029-33-7), a novel class III with some class Ib antiarrhythmic activity, were investigated in mice. The estimated LD50 for GLG-V-13 given orally were 419 mg/kg for male mice and 383 mg/kg for female mice, respectively. The acute toxic signs appeared to be of the central nervous system in origin. Four groups of mice (15 per sex, group and dose) were fed daily with diets containing GLG-V-13 for 90 consecutive days. The equivalent daily doses were 0, 22, 50 and 121 mg/kg/day and 0, 27, 60 and 136 mg/kg/day for male and female mice, respectively. All of the mice survived. Food consumption was decreased. However, mean body weight and body weight gain were not significantly changed. Gross pathological changes, especially in the lungs and liver, were found in the middle and high dose groups. Consistent increased mean corpuscular hemoglobin concentration and decreased mean corpuscular hemoglobin were observed in all dose groups. Hepatocellular necrosis was found in both male and female mice treated with the drug and was dose-dependent. Marked vacuolation of the X zone in the adrenal gland with mild to moderate deposition of ceroid pigments (brown degeneration) was observed in female mice. Lesions in the kidneys and adrenal glands may be a possible reason for changes in serum sodium and potassium ions concentrations leading to an increase in water intake. A significant reduction in cholesterol in the high dose group may be a favorable pharmacological effect of GLG-V-13. The data from the 90-day subchronic toxicity studies indicate that GLG-V-13 appears to have limited systemic toxicity potential.

Is there longitudinal dissociation in the undamaged his bundle? In vitro studies in the normal canine heart.

We investigated the concept of longitudinal dissociation in the His-Purkinje system in vitro. Hearts were excised from the eleven anesthetized dogs and a septal preparation containing the exposed His bundle and the entire right bundle branch and left bundle branch were displayed in a two-dimensional arrangement pinned to the bottom of a superfusion chamber. Tyrodes solution, gassed with 95% O2 and 5% CO2, at 37 degrees C was continuously passed over the preparation. Pacing was performed over a wide range of heart rates (30 to 180/min) from the proximal His bundle and by moving bipolar electrodes we monitored activation at various sites along the right and left bundle branch. The earliest site of muscle activation (27+/-2 msec) on the left septum was a relatively large area in the midposterior septal region; whereas, on the right septum the earliest site of activation (27+/-3 msec) was a relatively small zone at the base of the anterior papillary muscle, (p, N.S). The larger area of early activation on the left compared to the right is consonant with a left to right septal vector accounting for the Q wave in the standard bipolar leads in the normal heart and the loss of Q waves in left bundle branch block. We conclude that His-Purkinje and ventricular muscle activation is remarkably synchronous on both sides of the heart and accounts for optimal contractile function during His bundle or biventricular pacing compared to standard site ventricular pacing, particularly in patients with left ventricular dysfunction.

Effect of GLG-V-13, a class III antiarrhythmic agent, on potassium currents in rabbit ventricular myocytes.

The effects of a new Class III antiarrhythmic drug, GLG-V-13, on the 4-aminopyridine sensitive transient outward current, on the inward rectifier potassium current, on the ATP sensitive potassium current and on the rapid and slow components of the delayed rectifier potassium current were studied in single rabbit ventricular myocytes using the whole-cell voltage-clamp technique. GLG-V-13 blocked the rapid component of the delayed rectifier potassium current in a dose-dependent manner, with an estimated EC50 value of 0.36 microM. At high concentration, the slow component of the delayed rectifier potassium current was also depressed by the drug (40% effect at 10 microM concentration). The transient outward current, the inward rectifier potassium current and the ATP sensitive potassium current were not influenced by GLG-V-13, even at 10 microM concentration. Thus, GLG-V-13 blocks predominantly the rapid component of the delayed rectifier potassium current which may play a significant role in the prolongation of repolarization by the drug in ventricular tissue.

Ventricular rate control during atrial fibrillation by cardiac parasympathetic nerve stimulation: a transvenous approach.

OBJECTIVES: To identify intravascular sites for continuous, stable parasympathetic stimulation (PS) in order to control the ventricular rate during atrial fibrillation (AF). BACKGROUND: Ventricular rate control during AF in patients with congestive heart failure is a significant clinical problem because many drugs that slow the ventricular rate may depress ventricular function and cause hypotension. Parasympathetic stimulation can exert negative dromotropic effects without significantly affecting the ventricles. METHODS: In 22 dogs, PS was performed using rectangular stimuli (0.05 ms duration, 20 Hz) delivered through a catheter with an expandable electrode-basket at its end. The catheter was positioned either in the superior vena cava (SVC, n = 6), coronary sinus (CS, n = 10) or right pulmonary artery (RPA, n = 6). The basket was then expanded to obtain long-term catheter stability. Atrial fibrillation was induced and maintained by rapid atrial pacing. RESULTS: Nonfluoroscopic (SVC) and fluoroscopic (CS/RPA) identification of effective intravascular PS sites was achieved within 3 to 10 min. The ventricular rate slowing effect during AF started and ceased immediately after on-offset of PS, respectively, and could be maintained over 20 h. In the SVC, at least a 50% increase of ventricular rate (R-R) intervals occurred at 22 +/- 11 V (331 +/- 139 ms to 653 +/- 286 ms, p < 0.001), in the CS at 16 +/- 10 V (312 +/- 102 ms vs. 561 +/- 172 ms, p < 0.001) and in the RPA at 18 +/- 7 V (307 +/- 62 ms to 681 +/- 151 ms, p < 0.001). Parasympathetic stimulation did not change ventricular refractory periods. CONCLUSIONS: Intravascular PS results in a significant ventricular rate slowing during AF in dogs. This may be beneficial in patients with AF and rapid ventricular response since many drugs that decrease atrioventricular conduction have negative inotropic effects which could worsen concomitant congestive heart failure.

Transvenous parasympathetic cardiac nerve stimulation: an approach for stable sinus rate control.

INTRODUCTION: Epicardial electrical stimulation of parasympathetic nerves innervating the sinus node has been shown to decrease sinus rate. We investigated whether intravascular parasympathetic cardiac nerve stimulation (IPS) can be achieved over a relatively long-term period to slow the supraventricular rate. METHODS AND RESULTS: Fifteen dogs were investigated. IPS was performed with rectangular stimuli (0.05-msec duration, 20 Hz) using a catheter with an expandable electrode basket. The catheter was positioned in the superior vena cava (SVC; n = 9) or right pulmonary artery (RPA; n = 6). The basket then was expanded to hold the catheter in place. Nonfluoroscopic identification of effective IPS sites was achieved within 5 minutes in the SVC. Increasing IPS voltage resulted in a graded response of supraventricular rate slowing. A 50% prolongation of the baseline atrial cycle length was achieved with 28 V in the SVC (1,056 +/- 355 msec vs 489 +/- 154 msec; P < 0.001) and 25 V in the RPA (1,181 +/- 306 msec vs 518 +/- 138 msec; P < 0.01). The rate slowing started immediately after IPS onset, terminated abruptly after IPS cessation, and could be maintained over 10 hours. A rate slowing effect also was observed when the sinus rate was increased by isoproterenol (SVC: 304 +/- 8 msec/RPA: 341 +/- 9 msec with isoproterenol vs SVC: 635 +/- 12 msec with isoproterenol + IPS at 39 V/ RPA: 584 +/- 16 msec with isoproterenol + IPS at 38 V; n = 6). CONCLUSION: IPS results in a significant supraventricular rate slowing that is stable over a relatively long period and may be applied to slow undesirable sinus tachycardia in acute ischemic syndromes or to counteract undesirable chronotropic effects of catecholamines during treatment of cardiogenic or septic shock and acute congestive heart failure.

Longitudinal dissociation within the posterior AV nodal input of the rabbit: a substrate for AV nodal reentry.

BACKGROUND: Longitudinal dissociation of an anatomic pathway into 2 electrophysiologically distinct pathways has been hypothesized as a basis for localized AV nodal reentry and supraventricular arrhythmias. METHODS AND RESULTS: Extracellular bipolar and intracellular microelectrodes were used to record activation in the superfused rabbit AV junction. A subset of rabbit hearts (n=19 of 72) demonstrated dissociation of the posterior AV nodal input into >/=2 functional pathways. Antegrade AH conduction was maintained by a pathway just inferior to the tendon of Todaro. Rate-dependent conduction block was observed in a second pathway just superior to the tricuspid annulus, allowing retrograde activation of the distal portion of the inferior posterior AV nodal input and leading to the formation of apparent "dead-end" pathways. The superior (antegrade) and inferior (retrograde) pathways were separated by a band of well-polarized but poorly excitable transitional cells. Additional decreases in the atrial cycle length progressively increased the AH interval, further delaying retrograde activation of the inferior pathway, and progressively moved the site of conduction block in the inferior pathway proximally, thus extending the length of the retrograde conduction pathway and allowing circus movement within the transitional cells of the posterior AV nodal connection. CONCLUSIONS: Longitudinal dissociation within the posterior AV nodal input can give rise to localized reentry and AV nodal reentrant tachycardia.

Phase 1B ventricular arrhythmia in the dog: localized reentry within the mid-myocardium.

Intramural and epicardial composite electrograms, signal-averaged orthogonal bipolar electrograms across the ischemic zone, and closely-spaced bipolar electrograms from subendocardium, mid-myocardium, and subepicardium were utilized to determine if phase 1B reentry resulted from localized reentry within ischemic mid-myocardium. During the first 10 minutes following coronary ligation, activation delays were largest in ischemic subepicardium, with continuous electrical activity in ischemic epicardium linking a ventricular extrasystole to the preceding beat. During the 15-30 minute period, activation delay observed in ischemic mid-myocardium exceeded activation delay on the epicardial surface. Ventricular extrasystoles were associated with mid-myocardial delays > 130 msec. With short-coupled extrasystoles (< 300 msec), electrical activity in ischemic mid-myocardium linked an extrasystole with the preceding beat. Although single extrasystoles with coupling intervals > 300 msec were also associated with mid-myocardial delays > 130 msec, most extrasystoles (68%) demonstrated an isoelectric gap > 20 msec. The data demonstrate an association between delayed activation within ischemic mid-myocardium and phase 1B arrhythmia resulting from (1) localized reentry in ischemic mid-myocardium and (2) a delay-dependent "non-reentrant" mechanism.

Electrical conduction between the right atrium and the left atrium via the musculature of the coronary sinus.

BACKGROUND: The purpose of this study was to determine whether the coronary sinus (CS) musculature has electrical connections to the right atrium (RA) and left atrium (LA) and forms an RA-LA connection. METHODS AND RESULTS: Six excised dog hearts were perfused in a Langendorff preparation. A 20-electrode catheter (2-4-2-mm spacing center to center) was placed along the CS. Excision of the pulmonary veins provided access to the LA, and a second 20-electrode catheter was placed along the LA endocardium opposite the CS catheter. An incision opened the CS longitudinally, and microelectrodes were inserted into the CS musculature and adjacent LA myocardium. Continuous CS musculature was visible along a 35+/-9-mm length of the CS beginning at the ostium. During lateral LA pacing, CS electrodes recorded double potentials, a rounded, low-frequency potential followed by a sharp potential. The rounded initial potential propagated in the lateral-to-septal direction and represented "far-field" LA activation (timing coincided with adjacent LA potentials and with action potentials recorded from microelectrodes in adjacent LA cells). The sharp potential represented CS activation (timing coincided with action potentials recorded from CS musculature). A distal LA-CS connection (earliest sharp potential in the CS during lateral LA pacing) was located 26+/-7 mm from the ostium. During RA pacing posterior to the CS ostium, CS electrodes recorded septal-to-lateral activation of the high-frequency potential, with slightly later activation of the rounded potential (LA activation). Incisions surrounding the CS ostium isolating the ostium from the RA had no effect on the CS musculature and LA potentials during RA pacing within the isolated segment containing the CS ostium. RA pacing outside the isolated segment delayed activation of the CS musculature until after LA activation, confirming that the RA-CS connection was located in the region of the CS ostium as well as confirming the presence of the LA-CS connection. CONCLUSIONS: In canine hearts, the CS musculature is electrically connected to the RA and the LA and forms an RA-LA connection.

Evidence for multiple atrio-AV nodal inputs in the normal dog heart.

INTRODUCTION: Complete AV block after combined fast pathway (FP) and slow pathway (SP) ablation is uncommon. The purpose of this study was to interrupt activation of these and additional inputs by placing a radiofrequency lesion across the interatrial septum between the FP and SP ablation sites. METHODS AND RESULTS: In eight anesthetized open chest dogs, FP ablation induced significant A-H prolongation (deltaA-H: 51 +/- 14 msec; P < 0.001) and a shift of earliest retrograde atrial activation from the anterior septum to the region of the coronary sinus (CS) os. Subsequently, ablation of the interatrial septum across the fossa ovalis was successful in 5 of 8 dogs, changing the sequence of atrial activation (A) so that A at the His-bundle electrogram, which initially preceded A at the CS os (18 +/- 4 msec vs 46 +/- 7 msec, P < 0.01), now followed CS os A (81 +/- 31 msec vs 59 +/- 20 msec, P < 0.05). Additional ablation of the SP caused a type II Mobitz AV block or complete AV block in 5 of 8 dogs. The four dogs with complete AV block showed a stable, high junctional escape rhythm at a rate of 64 +/- 16 beats/min. Pacing between the ablation lesions and the AV node in one dog showed 1:1 AV conduction and Wenckebach-type AV block indicating preserved AV nodal function. Histology showed necrotic changes in the FP and SP transitional cell zones and in the atrial tissue of the interatrial septum. However, the compact AV node, His bundle, and adjacent atria and transitional cells were undamaged. CONCLUSION: There are additional AV nodal inputs in the interatrial septum in addition to the anterior FP and posterior SP inputs. Ablation of all of these may be required, if the aim is production of complete AV block proximal to the AV node with a high junctional escape rhythm.

Critical atrial site for ablation of pacing-induced atrial fibrillation in the normal dog heart.

INTRODUCTION: Radiofrequency catheter ablation (RFA) has been used recently to treat atrial fibrillation (AF). The purpose of this study was to investigate a new approach to preventing AF by RFA. METHODS AND RESULTS: In open chest, anesthetized dogs, AF (lasting > 30 sec) was induced after burst stimulation, and electrophysiologic parameters were recorded before and after RFA. In group 1 (9 dogs) we performed selective and combined slow and fast pathway RFA, whereas in group 2 (11 dogs) RFA was applied as a linear lesion at the mid-atrial septum between the inferior vena cava and the fossa ovalis. After ablation, the Wenckebach cycle length was significantly prolonged only in group 1 (194 +/- 23 vs 282 +/- 35 msec, P = 0.002), whereas the interval between the stimulus (S) artifact applied at the high right atrium to the His bundle (H) (SH interval) prolonged to the same extent in both groups (162 +/- 14 vs 146 +/- 45 msec, P = NS); group 1 due to an A-H prolongation whereas in group 2 it was due to an intra-atrial conduction delay. In group 1 AF still remained inducible, although with a longer mean R-R interval (215 +/- 16 vs 433 +/- 88 msec, P < 0.05). No instance of complete AV block developed. In group 2, sustained AF was noninducible in 10 dogs and its duration was markedly shorter in the remaining one (8 sec). Gross anatomy and histology did not reveal any damage inside of Koch's triangle, and particularly to the compact AV node. CONCLUSION: These findings suggest that RFA at the mid-atrial septum prevents AF in the normal dog heart. This approach might also be successful in those clinical settings in which the atrial septum plays a critical role in the maintenance of sustained AF.

Electrophysiology of the atrio-AV nodal inputs and exits in the normal dog heart: radiofrequency ablation using an epicardial approach.

INTRODUCTION: We studied the effects of selective and combined ablation of the fast (FP) and slow pathway (SP) on AV and VA conduction in the normal dog heart using a novel epicardial ablation technique. METHODS AND RESULTS: For FP ablation, radiofrequency current (RFC) was applied to a catheter tip that was held epicardially against the base of the right atrial wall. SP ablation was performed epicardially at the crux the heart. Twenty-three dogs were assigned to two ablation protocols: FP/SP ablation group (n = 17) and SP/FP ablation group (n = 6). In 12 of 17 dogs, FP ablation prolonged the PR interval (97 +/- 10 to 149 +/- 22 msec, P < 0.005) with no significant change in anterograde Wenckebach cycle length (WBCL). Subsequent SP ablation performed in 8 dogs further prolonged the PR interval and the anterograde WBCL (117 +/- 22 to 193 +/- 27, P < 0.005). Complete AV block was seen in 1 of 8 dogs, whereas complete or high-grade VA block was seen in 6 of 8 dogs. In the SP/FP ablation group, SP ablation significantly increased WBCL with no PR changes. Combined SP/FP ablation in 6 dogs prolonged the PR interval significantly, but no instance of complete AV block was seen. VA block was found in 50% of these cases. Histologic studies revealed that RFC ablation affected the anterior and posterior atrium adjacent to the undamaged AV node and His bundle. CONCLUSION: Using an epicardial approach, combined ablation of the FP and SP AV nodal inputs can be achieved with an unexpectedly low incidence of complete AV block, although retrograde VA conduction was significantly compromised.

Facilitation of epinephrine-induced afterdepolarizations by class III antiarrhythmic drugs.

The electrophysiologic actions of epinephrine (10(-9) M, 10(-8) M, and 10(-7) M) were evaluated in canine Purkinje fibers pretreated with the class III antiarrhythmic drugs clofilium (10(-7) M) or d,l-sotalol (10(-6) M). Clofilium and d,l-sotalol prolonged action potential duration at 50% and 90% of repolarization without provoking early afterdepolarization (EAD) or delayed afterdepolarization (DAD). Subsequent administration of epinephrine provoked both bradycardia-dependent EADs and tachycardia-dependent DADs in clofilium-treated Purkinje fibers, with predominantly EADs observed in d,l-sotalol-treated Purkinje fibers. A temporary increase in Ca0(+2) from 1.35 mM to 5 mM suppressed both EADs and DADs. The data demonstrate facilitation of epinephrine-induced EADs and DADs by class III antiarrhythmic drugs. The acute suppression of both EADs and DADs observed following an acute increase in Ca0(+2) suggests inward Na(+)-Ca0(+2) exchange current as a basis for both EADs and DADs observed in the presence of class III antiarrhythmic drugs and epinephrine.