Mohamad C.N. Sinno, MD, and Hakan Oral, MD
A 56-year-old woman presented for evaluation and management of recurrent paroxysmal palpitations over several years who remained symptomatic despite atrioventricular nodal blockade. Physical examination and laboratory studies were all normal. A transthoracic echocardiogram showed a normal left ventricular function with mild enlargement of the left atrium (LA diameter = 43 mm). Ambulatory monitoring revealed that the palpitations correlated with atrial fibrillation. Addition of class IC antiarrhythmic medication to her drug regimen was initially effective in suppressing her palpitations. Over the past few months, she noticed increased palpitations despite full adherence to medications. The patient was referred to for consideration of catheter ablation.
Atrial fibrillation (AF) affects 1% to 2% of the general population and is the most prevalent cardiac arrhythmia. The incidence of AF increases with age and structural heart disease.1 AF is often symptomatic and impairs quality of life. Affected patients are at 1.5- to 1.9-fold increased risk for mortality as reported in the Framingham study.2 AF is a leading cause of stroke both due to loss of atrial systole and associated prothrombotic state often observed in patients with AF. AF with uncontrolled ventricular response is also responsible for tachycardia-mediated cardiomyopathy or acute systolic and diastolic heart failure exacerbations. In the AFFIRM trial, except for anticoagulation which is known to reduce stroke risk, there was no difference in mortality among patients randomized to a rate or rhythm control strategy.3 However, it has been suggested that potential beneficial effects of sinus rhythm maintenance may have been negated by the proarrhythmic effects of antiarrhythmic drugs, which were exclusively used for rhythm control and were effective in maintaining sinus rhythm in only 30% of the patients in the AFFIRM trial. A subsequent post hoc analysis of the AFFIRM trial demonstrated a survival benefit in patients who remained in sinus rhythm. Catheter ablation of AF has been demonstrated to have a superior efficacy over antiarrhythmic drug therapy in patients with AF and has been associated with an improvement in quality of life, left atrial size, and left ventricular ejection fraction. Whether maintenance of sinus rhythm with catheter ablation is also associated with an improvement in survival remains to be determined in large and prospective randomized studies. However, early observations from single center case registries suggest a positive association.
PATHOGENESIS OF PAROXYSMAL ATRIAL FIBRILLATION
Initiators of atrial fibrillation are harbored inside the pulmonary veins (PVs) in >90% of the cases, and repetitive high frequency discharges from these PVs often trigger AF5 (Figure 35-1). Ectopy can arise from different sites within the same PV or from different PVs in the same patient. Besides being triggers, PVs are also responsible for perpetuation of AF. Intermittent PV tachycardias have been demonstrated to play a critical role in initiation and perpetuation of AF.6 In a prior study, isolation of PVs in patients with paroxysmal AF was associated with a progressive increase in AF cycle length and subsequent termination of AF in 75% of patients, rendered AF noninducible in 57%, and prevented recurrence in 74%.7
FIGURE 35-1 Pulmonary vein (PV ) ectopy initiating atrial fibrillation (AF). Surface leads V1, II, and III, recording from inferior left (LI) PV, coronary sinus (CS), and ablation catheter (ABL). A premature beat (arrow) arising from the LIPV, earliest LA 10-1, precedes atrial activity on the surface ECG (arrow on surface ECG), conducts to the left atrium (LA) and initiates AF.
ELECTROPHYSIOLOGICAL PROPERTIES OF PULMONARY VEINS
Experimental evidence from isolated, blood-perfused dog hearts support triggered activity, reentry, and automaticity as the mechanisms of arrhythmogenesis in PVs.8 Nonhomogenous muscle fiber orientation at the ostia of PVs correlates with zones of delayed conduction and fractionated signals facilitating reentry within the PVs. These electrophysiological properties of PVs were confirmed with optical mapping in atrial preparations of dog hearts demonstrating delayed conduction, heterogeneous depolarization, conduction block, and reentry in 60% of preparations. Besides, sustained focal discharges localized near the PV ostia were also demonstrated with isoproterenol infusion.9
In clinical studies, the effective refractory period (ERP) of the four PVs was shorter than the LA ERP in patients with AF. In the same study, the opposite was true for patients without AF. Decremental conduction between the PV and LA and the slow conduction within the PVs was also noted to be more prevalent in patients with AF suggesting a pivotal role for reentry within PV musculature in AF perpetuation.10 Furthermore, pace-termination and entrainment of PV-induced arrhythmias provide indirect evidence supportive of reentry as a mechanism for AF.
There is also evidence that automaticity and triggered activity may play a role in the genesis of AF. Discrete ectopic discharges and adenosine sensitive focal tachycardias have been demonstrated using high-density mapping within PVs, and there was no evidence of reentry in some reports. Besides, early reports in animal models have identified pacemaker regions in the distal parts of the muscular sleeves within the pulmonary vein where it joins the smooth muscle. Those PV sites were referred to as subsidiary pacemakers in the 1980s and are capable of developing oscillatory after-potentials, large enough to reach threshold and cause extrasystoles.11 Digitalis treated atrial preparations were shown to develop oscillatory after-potentials and act as ectopic foci.
PULMONARY VEIN ANATOMY
Embryologically, the PVs arise from the posterior LA without distinct boundaries separating the ostium, antrum, and LA (Figure 35-2). Nonuniform sleeves of myocardium extending from the LA into PVs constitute the arrhythmogenic substrate for paroxysmal AF. These myocardial sleeves are more developed in the upper than the lower PVs, extend between 2 and 25 mm distally into the vein, and are thickest at the LA-PV junction. Sleeves tend to be thicker in the “carina” region separating the inferior from the superior veins with fibrous tissue filling gaps between those sleeves at the LA-PV junction and within the PVs. Sleeves most commonly wrap around the LA-PV junction in a circumferential manner, but some are oriented in a longitudinal or oblique fashion. Therefore, the anisotropic arrangement of these muscle fibers may provide a substrate for reentry.
FIGURE 35-2A Magnetic resonance imaging reconstruction of the atrial and pulmonary vein anatomy. (A) Three-dimensional reconstruction of the left atrium and pulmonary veins, view from a posterior perspective. Note the left common ostium (LCPV) of the left pulmonary veins and the separate ostia of the right inferior pulmonary vein (RIPV) and right superior pulmonary vein (RSPV).
FIGURE 35-2B Computed tomography reconstruction of the atrial and pulmonary vein (PV) anatomy. Intra-atrial reconstructed views of the posterior LA. Note the “saddles” between adjacent PVs. The complex, funnel-shaped approaches to the veins are apparent. In this case, there is a common ostium for the left-sided veins (LCPV). Also demonstrated is the narrow ridge that separates the left PVs from the left atrial appendage (LAA). Abbreviations: R, ridge between LAA and PVs; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein.
CATHETER ABLATION OF ATRIAL FIBRILLATION
According to current guidelines, catheter ablation for symptomatic AF is considered a second-line treatment after failure of antiarrhythmic medications. Expert consensus acknowledges the pivotal role of PVs in AF and recommends complete electrical isolation of PVs.12 Electrical isolation requires demonstration of entrance block into the vein. PV isolation is often sufficient in patients with paroxysmal AF. However, in patients with persistent AF who may have electroanatomical remodeling, modification of the atrial substrate beyond PVs may often be necessary.13
Initial efforts targeted arrhythmogenic foci within the PVs by focal applications of radiofrequency energy often within the PV or one of its branches.5 However, this approach was associated with a high recurrence rate both from the same PV and also other PVs and with a high incidence of PV stenosis.14 Since the electrical connection between the PVs and the left atrium occur via insulated, discrete myocardial fibers, referred to as PV fascicles, complete isolation of PVs by segmental ostial ablation followed.5,15 Subsequently, left atrial circumferential ablation or wide area circumferential ablation (Figure 35-3) that included most if not all of the antrum was shown to be superior to isolation of PVs at the ostial level.15
FIGURE 35-3 Three-dimensional reconstruction of the left atrium using the Biosense CARTO 3 mapping system. (A) Anteroposterior (AP) view of the left atrium (LA) and pulmonary veins (PVs) with circumferential ablation (red dots) around the antrum. (B) Posteroanterior (PA) view with a rightward tilt of the left atrium (LA) and pulmonary veins (PVs) with circumferential ablation (red dots) around the antra of individual PVs. Abbreviations: LAA, left atrial appendage; LI, left inferior pulmonary vein; LS, left superior pulmonary vein; RI, right inferior pulmonary vein; RS, right superior pulmonary vein.
The PV antrum that includes most of the posterior left atrium shares similar histoembryological origin to the tubular portion of the PV and appears to have a similar arrhythmogenic potential as the PVs. As a matter of fact a majority of the non-PV foci that initiate AF arise from the posterior left atrium and PV antrum. Later ablation strategies evolved as antral PV isolation that aims to isolate the PVs by antral ablation specifically targeting antral potentials (that have similar characteristics to the PV potentials such as high frequency activation) and by confirming complete isolation of PVs.12 The mechanisms of superior efficacy of antral PV isolation may include: (1) elimination of PV arrhythmogenicity; (2) elimination of drivers of AF such as rotors that often have anchor points in the antrum of PVs; (3) elimination of non-PV triggers that may originate within the PV antrum; (4) debulking of the left atrium; and (5) ablation of ganglionated plexi that often are located on the epicardial aspect of the PV antrum.
Access to the left atrium is established by transseptal puncture under fluoroscopic guidance with or without intracardiac echocardiography (ICE) (Figure 35-4). Once LA access is achieved, anticoagulation with unfractionated heparin is recommended with a target-activated clotting time between 300 and 350 seconds. Continuing anticoagulant therapy with warfarin or dabigatran throughout the ablation procedure has been associated with a lower incidence of thromboembolic complications without an increase in bleeding or pericardial tamponade.16,17
FIGURE 35-4 (A) Utilization of phased-array intracardiac echocardiography for visualizing the thin portion of the interatrial septum. (B) Tenting of the fossa ovalis by the dilator and BRK needle assembly. Note that the assembly is pointing toward the left atrial midcavity.
A circular mapping catheter along with the ablation catheter are advanced across the transseptal access site for mapping and ablation. Catheter navigation and ablation guidance inside the LA could be facilitated with fluoroscopy, ICE, and three-dimensional mapping systems. Electrical isolation of the pulmonary veins is typically performed at antral locations (Figure 35-5). It has been suggested to use a rowing circular catheter to precisely map the antral potentials in some studies. However, this often can be achieved with a typical ablation catheter. Mapping around the circumference of the vein allows recording of PV potentials that are often merged with LA signals. The PV potentials are sharp, high frequency signals that are <50 ms in duration and follow the left atrial electrograms during normal sinus rhythm. Pacing from within the coronary sinus advances the left atrial electrograms while delaying conduction into the left-sided PVs separating the two signals (Figure 35-6).
FIGURE 35-5 Antral PV isolation. Shown are left lateral (A) and posteroanterior (B) projections of a 3-dimensional electroanatomic depiction of the left atrium (LA). Red tags indicate ablation sites. Abbreviations: LI, left inferior; LS, left superior; PV, pulmonary vein; RI, right inferior; RS, right superior. Reproduced with permission from Oral H, Chugh A, Yoshida K, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol. 2009;53(9):782-789. Copyright Elsevier.
FIGURE 35-6 CS pacing at a drive cycle length of 600 ms and a single extrastimulus delivered at 300 ms after circumferential ablation around the left inferior pulmonary vein. The pulmonary vein potential on the circular mapping catheter during CS pacing at 600 ms is fused with the left atrial far field potential (arrow). There is decremental conduction into the pulmonary vein with the delivery of a single extrastimulus at 300 ms showing the earliest site of PV activation on LA 4-5 (arrow head). Targeted ablation at the antrum close to LA 4-5 electrically isolated this vein.
Visualization of the course of the esophagus along the posterior wall of the left atrium is helpful to avoid inadvertent applications of radiofrequency energy in the immediate proximity of the esophagus. Strategies to minimize the risk of esophageal injury include visual assessment of esophagus position relative to intended ablation targets, avoidance of ablation near the esophagus, titration of RF energy, and duration and monitoring of intraluminal esophageal temperatures. However, the safest approach to avoid esophageal injury remains to be determined.
Real-time visualization of the esophagus could be achieved by fluoroscopic imaging of the esophageal lumen containing barium or another radio-opaque marker, or with real time intracardiac ultrasound from the right or left atrium.
Avoidance of ablation anterior to the esophagus is achieved by modifying the lesion sets either closer to the PVs or away from the antrum. A potential pitfall of creating a wider lesion set is the difficulty in achieving persistent and complete electrical isolation of the pulmonary veins.
RF energy titration is often used to minimize the risk of esophageal injury during catheter ablation of critical targets close to the esophagus. Observational studies reveal that esophageal heating can happen during RF applications along the posterior LA wall. Rapid heat transfer in the order of 0.05 to 0.1 degrees per second to the esophagus may predict potential thermal injury instances.18 Besides, there is evidence that the esophagus cools slowly, and closely coupled RF applications at the same site can result in a greater degree of mural esophageal heating.18 However, there are limited data on the safety thresholds for the maximum power, temperature, and duration during applications of energy. A commonly used approach is to limit the power to 15 to 20 watts and to not deliver energy for more than 10 to 15 seconds a time. However, it remains unclear whether this approach offers sufficient safety. Cryoablation can also lead to esophageal injury; therefore, caution should also be exercised with this modality.
After entrance block is confirmed within the PV (Figure 35-7), isoproterenol and/or adenosine can be administered to assess residual arrhythmogenic foci and dormant PV conduction19 (Figure 35-8). Additional ablation after PV isolation targeting reconnected PV fascicles or sustained atrial ectopy after administration of adenosine or isoproterenol has been shown to predict improved clinical outcomes.19
FIGURE 35-7 Ablation at the right superior pulmonary vein antrum results in electrical isolation of this PV from the left atrium (entrance block). Arrows highlight the sharp and narrow pulmonary vein potentials. Abbreviations: LA, circular mapping catheter; ABL, ablation; CS, coronary sinus.
FIGURE 35-8 Dormant electrical activity within the right superior pulmonary vein. There are atrial far-field signals recorded on the circular mapping catheter (LA) positioned antrally (asterix). With administration of 12 mg of adenosine, AV nodal block occurs with evidence of pulmonary vein activity (arrows). Abbreviations: ABL, ablation; CS, coronary sinus.
Based on the results of world-wide registry, the overall complication rate for AF ablation procedures is estimated as 6%, may including a 0.2% risk of procedural death, 1.2% risk of tamponade, 1% for cerebrovascular accident, and <2% for PV stenosis. Atrioesophageal fistula is one of the most feared complications of catheter ablation and is often fatal. The incidence is about 0.01%. Vascular access related complications can also occur. Phrenic nerve injury may occur in 0.1% of patients using conventional RF catheters and up to 7% during cryoballoon ablation.
PATIENT MANAGEMENT AND FOLLOW-UP
Patients referred to for catheter ablation are started on oral anticoagulation prior to the procedure. Uninterrupted anticoagulation using warfarin at a target INR 2-3 in the periprocedural period has been demonstrated to be associated with a lower risk of thromboembolic events without an increase in hemorrhagic complications compared to interrupted anticoagulation and bridging with low molecular weight heparin.16 LMWH has been shown to increase vascular access site complications. In a recent study, dabigatran was also found to be safe and as effective as uninterrupted warfarin, when discontinued 24 hours prior to the procedure and resumed 4 hours after vascular hemostasis is achieved. Similarly, rivaroxaban, with the dose held on the day of the procedure, appears to be equally safe and effective when compared with uninterrupted coumadin.20 Data is still lacking behind apixaban use in patients presenting for left atrial ablation procedures. The utility of newer anticoagulants, including apixaban, and optimal dosing regimens need to be confirmed in large-scale prospective studies.
Early recurrences of AF within the first 2 to 3 months can be transient most likely due to an inflammatory response to ablation. Although early recurrence of AF carries an independent risk of treatment failure, its occurrence should not prompt immediate reablation attempts, as 20% to 57% of patients may not have any further arrhythmias during long-term follow-up. Since the mechanism of AF postablation may be different from that of the patient’s clinical arrhythmia and may resolve completely upon resolution of the inflammatory process, some operators choose to treat all patients with suppressive antiarrhythmic agents for the first 1 to 3 months following ablation (blanking period). Repeat ablation procedures should be delayed for at least 3 months following the initial procedure if the patient’s symptoms can be controlled with medical therapy.
The HRS Consensus Statement suggests that follow-up should begin within 3 months after the ablation procedure and continue at 6-month intervals for at least 2 years.
Pulmonary vein arrhythmogenicity plays an important role in initiation and perpetuation of AF. Antral pulmonary vein isolation remains as a key step in targeting AF and is often sufficient to eliminate paroxysmal AF. PV antrum is often as arrhythmogenic as the tubular portion of the PVs and should be included as an ablation target. Whether accurate identification and elimination of drivers of AF beyond the PVs and their antrum will improve the outcomes of antral PV isolation or even eliminate the need for it, remains to be determined in future studies.
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