Spatial Relationships of Complex Fractionated Atrial Electrograms and Continuous Electrical Activity to Focal Electrical Sources: Implications for Substrate Ablation in Human Atrial Fibrillation.

OBJECTIVES: This study sought to evaluate the spatial relationships of focal electrical sources (FSs) to complex fractionated atrial electrograms (CFAE) and continuous electrical activity (CEA). BACKGROUND: Fractionated atrial electrograms have been associated with atrial fibrillation (AF) drivers in computational studies and represent ablation targets in the management of persistent AF. METHODS: We included a subset of 66 patients (age: 63 [56, 67] years, 69% persistent AF) with electroanatomic data from the SELECT AF (Selective complex fractionated atrial electrograms targeting for atrial fibrillation) randomized control trial that compared the efficacy of CFAE with CEA ablation in AF patients undergoing pulmonary vein antral ablation. Focal sources were identified based on bipolar electrogram periodicity and QS unipolar electrogram morphology. RESULTS: A total of 77 FSs (median: 1 [1st quartile, 3rd quartile: 1, 2] per patient) were identified most commonly in the pulmonary vein antrum and left atrial appendage. The proportions of FSs inside CFAE and CEA regions were similar (13% vs. 1.3%, respectively; p = 0.13). Focal sources were more likely to be on the border zone of CFAEs than in CEAs (49% vs. 7.8%, respectively; p = 0.012). Following ablation, 53% of patients had ≥1 unablated extrapulmonary vein FS. The median number of unablated FS was higher in patients with AF recurrence post ablation than in patients without (median: 1 [0, 1] vs. 0 [0, 1], respectively; p = 0.026). CONCLUSIONS: One-half of the FSs detected during AF localized to the border of CFAE areas, whereas most of the FSs were found outside CEA areas. CFAE or CEA ablation leaves a number of FS unablated, which is associated with AF recurrence. These findings suggest that many CFAEs may arise from passive wave propagation, remote from FS, which may limit their therapeutic efficacy in AF substrate modification.

Pulmonary Vein Antrum Isolation in Patients With Paroxysmal Atrial Fibrillation: More Than a Decade of Follow-Up.

BACKGROUND: We report the outcome of pulmonary vein (PV) antrum isolation in paroxysmal atrial fibrillation (AF) patients over more than a decade of follow-up. METHODS AND RESULTS: A total of 513 paroxysmal AF patients (age 54±11 years, 73% males) undergoing catheter ablation at our institutions were included in this analysis. PV antrum isolation extended to the posterior wall between PVs plus empirical isolation of the superior vena cava was performed in all. Non-PV triggers were targeted during repeat procedure(s). Follow-up was performed quarterly for the first year and every 6 to 9 months thereafter. The outcome of this study was freedom from recurrent AF/atrial tachycardia. At 12 years, single-procedure arrhythmia-free survival was achieved in 58.7% of patients. Overall, the rate of recurrent arrhythmia (AF/atrial tachycardia) was 21% at 1 year, 11% between 1 and 3 years, 4% between 3 and 6 years, and 5.3% between 6 and 12 years. Repeat procedure was performed in 74% of patients. Reconnection in the PV antrum was found in 31% of patients after a single procedure and in no patients after 2 procedures. Non-PV triggers were found and targeted in all patients presenting with recurrent arrhythmia after ≥2 procedures. At 12 years, after multiple procedures, freedom from recurrent AF/atrial tachycardia was achieved in 87%. CONCLUSIONS: In patients with paroxysmal AF undergoing extended PV antrum isolation, the rate of late recurrence is lower than what previously reported with segmental or less extensive antral isolation. However, over more than a decade of follow-up, nearly 14% of patients developed recurrence because of new non-PV triggers.

The independent role of the aortic root ganglionated plexi in the initiation of atrial fibrillation: An experimental study.

OBJECTIVE: The major atrial ganglionated plexi (GP) can initiate atrial fibrillation alone without any contribution from the extrinsic cardiac nervous system. However, if stimulation of the ventricular GP, especially the aortic root GP, can provoke atrial fibrillation (AF) alone is unknown. Our study was designed to investigate the independent role of aortic root GP activity in the initiation of AF. METHODS: In 10 Langendorff-perfused canine hearts, the atrial effective refractory period, pulmonary vein effective refractory period, and percentage of AF induced were measured at baseline and during aortic root GP stimulation. RESULTS: Stimulation of the aortic root GP shortened the atrial effective refractory period from 128 ± 10 ms at baseline to 103 ± 15 ms (P < .05) and shortened the pulmonary vein effective refractory period from 139 ± 14 ms to 114 ± 15 ms (P < .05). Furthermore, the percentage of AF induced in the 10 isolated hearts increased from 10% at baseline to 90% during aortic root GP stimulation (P < .05). CONCLUSIONS: In Langendorff-perfused canine hearts, stimulation of the aortic root GP provokes AF in the absence of any extrinsic cardiac nerve activity. The aortic root GP is an important element in the intrinsic neuronal loop that can increase the risk of AF in isolated heart models.

Stimulation of the intrinsic cardiac autonomic nervous system results in a gradient of fibrillatory cycle length shortening across the atria during atrial fibrillation in humans.

INTRODUCTION: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high-frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect. METHODS AND RESULTS: During AF in 25 patients, HFS was delivered to presumed GP sites to provoke a bradycardic vagal response and AFCL was continuously monitored from catheters placed in the pulmonary vein (PV), coronary sinus (CS), and high right atrium (HRA). A total of 163 vagal responses were identified from 271 HFS episodes. With a vagal response, the greatest reduction in AFCL was seen in the PV adjacent to the site of HFS (16% reduction, 166 ± 28 to 139 ± 26 ms, P < 0.0001) followed by the PV-atrial junction (9% reduction, 173 ± 21 to 158 ± 20 ms, P < 0.0001), followed by the rest of the atrium (3-7% reduction recorded in HRA and CS). Without a vagal response, AFCL changes were not observed. In 10 patients, atropine was administered in between HFS episodes. Before atropine administration, HFS led to a vagal response and a reduction in PV AFCL (164 ± 28 to 147 ± 26 ms, P < 0.0001). Following atropine, HFS at the same GP sites no longer provoked a vagal response, and the PV AFCL remained unchanged (164 ± 30 to 166 ± 33 ms, P = 0.34). CONCLUSIONS: Activation of the parasympathetic component of the cardiac ANS may cause heterogenous changes in atrial AFCL that might promote PV drivers.

Low-level right vagal stimulation: anticholinergic and antiadrenergic effects.

INTRODUCTION: We sought to extend the use of low-level vagal stimulation by applying it only to the right vagus nerve (LL-RVS) to suppress atrial fibrillation (AF). METHODS: In 10 pentobarbital anesthetized dogs, LL-RVS (20 Hz, 0.1 ms pulse width) was delivered to the right vagal trunk via wire electrodes at voltages 50% below that which slowed the sinus rate (SR) or atrio-ventricular conduction. Electrode catheters were sutured at multiple atrial and pulmonary vein (PV) sites to record electrograms. LL-RVS continued for 3 hours. At the end of each hour, 40 ms of high-frequency stimulation (HFS; 100 Hz, 0.01 ms pulse width) was delivered 2 ms after atrial pacing (during the refractory period) to determine the AF threshold (AF-TH) at each site. Other electrodes were attached to the superior left ganglionated plexi (SLGP) and right stellate ganglion (RSG) so that HFS (20 Hz, 0.1 ms pulse width) to these sites induced SR slowing and acceleration, respectively. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. RESULTS: (1) Three hours of LL-RVS induced a progressive increase in AF-TH at all sites (all P < 0.05). (2) The SR slowing and acceleration response induced by SLGP and RSG stimulation, respectively, was blunted by LL-RVS. (3) The frequency and amplitude of the neural activity recorded from the ARGP were markedly inhibited by LL-RVS. CONCLUSIONS: LL-RVS suppressed AF inducibility and the chronotropic responses to parasympathetic and sympathetic stimulation. Inhibition of neural activity in the GP may be a mechanism underlying these results.

Roles of the left atrial roof and pulmonary veins in the anatomic substrate for persistent atrial fibrillation and ablation in a canine model.

OBJECTIVES: the aim of this study was to establish the electrophysiological consequences of pulmonary vein encircling ablation (PVEA) and linear left atrial roof ablation (LARA) for the atrial fibrillation (AF) substrate in an experimental model. BACKGROUND: sequential application of ablation lesions is often used in the management of AF, almost always incorporating PVEA and LARA. METHODS: Atrial tachypacing (400 beats/min, 5 weeks) was used to create an AF substrate in 13 dogs. PVEA and LARA were applied in randomized order. Regional atrial refractoriness, AF vulnerability, AF duration, and activation during AF were assessed before and after applying ablation lesion sets. RESULTS: PVEA failed to terminate AF or affect AF duration (742 ± 242 s before vs. 627 ± 227 s after PVEA) but decreased AF vulnerability to single extrastimuli from 91 ± 4% to 59 ± 5% (p < 0.001) by increasing effective refractory periods at sites with suppressed AF induction (from 78 ± 4 ms to 102 ± 8 ms, p < 0.01). LARA terminated AF in 67% of dogs (p < 0.05 vs. PVEA) and reduced AF duration (from 934 ± 232 s to 322 ± 183 s, p < 0.01) without affecting AF vulnerability. Baseline AF mapping showed left atrial (LA)-dominant complex reactivations (LA 9.4 ± 0.9 vs. right atrial 1.1 ± 0.3 reactivations/500-ms window, p < 0.001), with the LA roof frequently involved in re-entry circuits (44 ± 9% of LA reactivations). LARA terminated AF by interrupting LA roof reactivation circuits. In 5 of 13 cases, macro-re-entrant tachycardias (usually perimitral) occurred after LARA eliminated persistent AF. CONCLUSIONS: both PVEA and LARA had beneficial but limited actions in this canine model. LARA suppressed AF perpetuation by interrupting LA roof reactivation, without affecting AF vulnerability. PVEA suppressed AF initiation by prolonging regional effective refractory period but failed to affect the AF-perpetuating substrate. These findings indicate the need to systematically study individual stepwise components to refine AF ablation procedures.

Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi.

AIMS: Previous studies showed that autonomic activation by high-frequency electrical stimulation (HFS) during myocardial refractoriness evokes rapid firing from pulmonary vein (PV) and atria, both in vitro and in vivo. This study sought to investigate the autonomic mechanism underlying the rapid firings at various sites by systematic ablation of multiple ganglionated plexi (GP). METHODS AND RESULTS: In 43 mongrel dogs, rapid firing-mediated atrial fibrillation (AF) was induced by local HFS (200 Hz, impulse duration 0.1 ms, train duration 40 ms) to the PVs and atria during myocardial refractoriness. The main GP in the atrial fat pads or the ganglia along the ligament of Marshall (LOM) were then ablated. Ablation of the anterior right GP and inferior right GP significantly increased the AF threshold by HFS at the right atrium and PVs. The AF threshold at left atrium and PVs was significantly increased by ablation of the superior left GP and inferior left GP, and was further increased by ablation of the LOM. Ablation of left- or right-sided GP on the atria had a significant effect on contralateral PVs and atrium. Administration of esmolol (1 mg/kg) or atropine (1 mg) significantly increased AF threshold at all sites. CONCLUSION: HFS applied to local atrial and PV sites initiated rapid firing via activation of the interactive autonomic network in the heart. GP in either left side or right side contributes to the rapid firings and AF originating from ipsolateral and contralateral PVs and atrium. Autonomic denervation suppresses or eliminates those rapid firings.

Early recovery of pulmonary vein conduction after cryoballoon ablation for paroxysmal atrial fibrillation: a prospective study.

AIMS: To assess the incidence of early pulmonary vein (PV) reconnection, characterize the anatomic features of the reconducting veins, and analyse the time course of their recovery in a series of consecutive patients with paroxysmal atrial fibrillation (AF) undergoing ablation with the Arctic Front Cryoballoon. METHODS AND RESULTS: We prospectively enrolled 26 patients (20 males; age 55.4 +/- 4.1) for circumferential PV cryoballoon isolation for highly symptomatic paroxysmal AF. Following isolation of all veins, we analysed PV potentials in each vein after 30 and 60 min with a circular mapping catheter. After successful electrical isolation of all 104 PV's, recurrence was observed only in three veins (2.8%) after 30 min. Two further cryoballoon applications in each of these veins lead to their isolation. These veins were still electrically disconnected at 60 min. No PV reconnection was observed in any of the other 101 veins (97.1%) at 30 and 60 min. CONCLUSION: Cryoballoon ablation of the PV's ostia is a very effective technique to achieve electrical isolation, with a very low rate of early reconnection.

Atrial septopulmonary bundle of the posterior left atrium provides a substrate for atrial fibrillation initiation in a model of vagally mediated pulmonary vein tachycardia of the structurally normal heart.

BACKGROUND: The posterior left atrium (PLA) and pulmonary veins (PVs) have been shown to be critical for atrial fibrillation (AF) initiation. However, the detailed mechanisms of reentry and AF initiation by PV impulses are poorly understood. We hypothesized that PV impulses trigger reentry and AF by undergoing wavebreaks as a result of sink-to-source mismatch at specific PV-PLA transitions along the septopulmonary bundle, where there are changes in thickness and fiber direction. METHODS AND RESULTS: In 7 Langendorff-perfused sheep hearts AF was initiated by a burst of 6 pulses (CL 80 to 150ms) delivered to the left inferior or right superior PV ostium 100 to 150 ms after the sinus impulse in the presence of 0.5 micromol/L acetylcholine. The exposed septal-PLA endocardial area was mapped with high spatio-temporal resolution (DI-4-ANEPPS, 1000-fr/s) during AF initiation. Isochronal maps for each paced beat preceding AF onset were constructed to localize areas of conduction delay and block. Phase movies allowed the determination of the wavebreak sites at the onset of AF. Thereafter, the PLA myocardial wall thickness was quantified by echocardiography, and the fiber direction in the optical field of view was determined after peeling off the endocardium. Finally, isochrone, phase and conduction velocity maps were superimposed on the corresponding anatomic pictures for each of the 28 episodes of AF initiation. The longest delays of the paced PV impulses, as well as the first wavebreak, occurred at those boundaries along the septopulmonary bundle that showed sharp changes in fiber direction and the largest and most abrupt increase in myocardial thickness. CONCLUSION: Waves propagating from the PVs into the PLA originating from a simulated PV tachycardia triggered reentry and vagally mediated AF by breaking at boundaries along the septopulmonary bundle where abrupt changes in thickness and fiber direction resulted in sink-to-source mismatch and low safety for propagation.

Atrial fibrillation ablation: state of the art.

Among several catheter-based strategies for curing atrial fibrillation (AF), 2 approaches have emerged as dominant strategies in current clinical practice: ostial segmental disconnection of all pulmonary veins (PVs) from the adjacent atrial tissue and circumferential PV ablation, first reported by our laboratory in Milan. The cure for AF by circumferential PV ablation has had a dramatic impact on morbidity, quality of life, and even mortality in patients with the most frequent cardiac arrhythmia. The last 10 years of AF ablation are characterized by a better understanding of AF mechanisms as well as by new and evolving concepts associated with innovation in technologies. We recently demonstrated, for the first time, the role of vagal denervation in enhancing long-term benefits from circumferential PV ablation. Unlike other strategies, our strategy was associated with high success rates in both paroxysmal and chronic AF. As a result, our initial approach did not substantially change over time, and now we have long-term results after >3 years of follow-up. Recently, we demonstrated the safety and feasibility of remote magnetic navigation of a soft magnetic-tip catheter within the left atrium, even at challenging sites for both mapping and ablation in patients with AF. Use of a robotic navigation system has begun a new era in interventional cardiac electrophysiology-without risk of major complications, such as cardiac tamponade or atrioesophageal fistula, even in less experienced laboratories.

Validation of a left atrial lesion pattern for intraoperative ablation of atrial fibrillation.

BACKGROUND: Evidence that atrial fibrillation may begin in early stages from triggers or reentry circuits primarily in the left atrium suggests that the entire Maze 3 lesion pattern may be unnecessary. In the present study we describe a new left atrial lesion pattern for intraoperative linear ablation of chronic atrial fibrillation. METHODS: Endocardial radiofrequency ablation was performed on 12 dogs with chronic atrial fibrillation. Lesions to isolate pulmonary veins in pairs, the left atrial appendage, and connecting lesions between these structures were administered in a randomized approach. RESULTS: Twelve dogs were in chronic atrial fibrillation for 31 +/- 21 days before ablation. Atrial fibrillation was successfully ablated and rendered noninducible in all 12 dogs. All treatment failures observed with less than the full lesion pattern became a success when the remaining lesions were given. CONCLUSIONS: Atrial fibrillation ablation using this left atrial lesion pattern is highly successful in this model. This approach may have significant utility as a concomitant procedure for patients with atrial fibrillation undergoing mitral valve procedures.