Adenosine restores atrio-venous conduction after apparently successful ostial isolation of the pulmonary veins

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1 European Heart Journal (2004) 25, Clinical research Adenosine restores atrio-venous conduction after apparently successful ostial isolation of the pulmonary veins Massimo Tritto a, *, Roberto De Ponti b, Jorge A. Salerno-Uriarte b, Giammario Spadacini a, Raffaella Marazzi b, Paolo Moretti a, Marcelo Lanzotti b a Cardiology Department Mater Domini, via Gerenzano, 2, Castellanza, VA, Italy b Cardiovascular Sciences Department, Ospedale di Circolo and Fondazione Macchi, Varese, University of Insubria, Varese, Italy Received 3 May 2004; revised 6 August 2004; accepted 26 August 2004 Available online 11 November 2004 KEYWORDS Adenosine; Catheter ablation; Atrial fibrillation; Pulmonary vein; Mapping Aims Pulmonary vein (PV) isolation is a curative treatment for patients with atrial fibrillation. The aim of this study was to evaluate prospectively the effects of adenosine administration on the PV activity and atrio-venous conduction after PV isolation. Methods and results Twenty-nine patients (21 m; age: 55 ± 8 years) were submitted to ostial PV isolation guided by basket catheter recordings. After successful isolation, the effects of a 12 mg intravenous bolus of adenosine were tested in 62 PVs. In 22/62 PVs (35%), left atrium (LA)-to-PV conduction was transiently (16.6 ± 7.1 s, range: s) or permanently (3 PVs) restored in response to adenosine administration. The prevalence of this phenomenon was 39% in left superior PVs, 43% in right superior PVs, and 22% in left inferior PVs (p = 0.365). It occurred more frequently in the presence of dissociated PV activity (11/15 PVs, 73% vs. 11/47 PVs, 23%; p = 0.002), whereas it was not influenced by the median duration of the radiofrequency current (RFC) delivery for each PV [19 (IQR: 12 26) min vs. 16 (IQR: 11 24) min: p = 0.636]. A lengthening or shortening of the LA-PV conduction time was observed at LA-PV conduction appearance and disappearance in 36% and 55% of the cases, respectively. Further RFC applications (median: 5.5 min, IQR: 4 11 min) at the residual conduction breakthrough(s) indicated by the basket catheter recordings definitively eliminated adenosineinduced recovery of LA-PV conduction in all cases. Finally, when present, intrinsic PV discharge was invariably depressed by adenosine administration. Conclusions Adenosine may transiently or permanently re-establish LA-PV conduction after apparently successful PV isolation. This phenomenon is abolished by additional RFC delivery. However, its possible influence on the clinical results of PV ablation must be evaluated by properly designed, randomized studies. c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: ; fax: address: m.tritto@libero.it (M. Tritto) X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi: /j.ehj

2 2156 M. Tritto et al. Introduction The pulmonary vein (PV) musculature represents the major source of ectopies initiating atrial fibrillation (AF). 1 Electrical isolation of the PVs from the left atrium (LA) by means of segmental lesions deployed at the PV ostium conduction breakthroughs can be achieved with transcatheter techniques. 2 4 The goal of the procedure is to completely eliminate or dissociate the distal PV activity; however, the lesion is often unstable and LA-PV conduction relapses are frequently observed (both acutely and chronically). 4,5 The effects of pharmacologic-agents on PV activity and atrio-venous conduction (AVC) have not been adequately studied. Arentz and co-workers 6 demonstrated for the first time that adenosine may induce transient coupling of the left superior PV activity with that of the LA after successful PV isolation. However, the prevalence and significance of this phenomenon, as well as the potential implications for the ablation procedures, are still unknown. The aim of this study was to prospectively investigate the electrophysiological effects of adenosine on the residual PV musculature and AVC after successful isolation of different PVs. Methods Patients characteristics The study population consisted of 29 consecutive patients (21 men; mean age: 55.3 ± 7.6 years) with drug-refractory (P2 anti-arrhythmics including amiodarone in 24/29 patients) paroxysmal (21 patients) or persistent (8 patients) AF who underwent PV electrical isolation. Arrhythmia was documented 5 years [median; interquartile ranges (IQR): 3 8 years] before referral, and the patients had a median of 50 (IQR: ) AF episodes per year. Thirteen patients had arterial hypertension, three had coronary artery disease, and 13 had no structural heart disease. The maximal LA transverse diameter at 2D-echocardiography was 43.3 ± 4.2 mm. Electrophysiological study and PV isolation The procedure was performed in the unsedated state, after all anti-arrhythmics were discontinued for P5 half-lives. The Institutional Ethics Committee approved the protocol and a written informed consent was obtained from all patients. Oral anticoagulants were administered to all patients for at least 2 months before the procedure, and were replaced by subcutaneous heparin starting 48 h before cardiac catheterization. A transoesophageal echocardiogram was performed in all cases to exclude LA thrombi. A quadripolar catheter was inserted through a left antecubital vein and placed within the distal coronary sinus. A double LA catheterization was obtained by means of transseptal punctures (23 patients), or through a patent foramen ovale, and, thereafter, intravenous heparin was continuously administered to maintain an activated clotting time between 250 and 300 s. Selective angiograms of all PVs were performed to define the number and locations of PV ostia. An 8F, 64-pole, basket catheter (BKC 31 mm diameter; Constellation 8031, Boston Scientific, San Jose, CA, USA), inserted into the PV through a fixed-curve (55 or 120 ), 8.5F guiding catheter (Convoy, Boston Scientific, San Jose, CA, USA), was used for PV activation mapping. The BKC electrodes were combined to obtain three cross-sectional series (distal, mid, proximal; 6 mm distance between cross-sections) of eight circumferential, overlapping (1 2, 2 3, 3 4, etc.), bipoles. The proximal series of the recording electrodes was closer to the angiographically defined PV ostium. A 7F, 4-mm tip, deflectable catheter (Stinger, BARD Electrophysiology, Billerica, MA, USA), inserted into the LA through an 8F long-sheath (Preface, Biosense Webster, Diamond Bar, CA, USA), was used for further mapping and ablation. Surface ECG leads and bipolar intracardiac electrograms (bandpass filter setting: Hz) were digitally recorded on a electrophysiology workstation (Mennen PC-EMS, Maastricht, Limburg, The Netherlands). PV isolation was performed delivering pointby-point radiofrequency current (RFC) pulses (45 60 s duration) under temperature control (max temperature: C, max power: W) at the atrial aspect of the PV ostium where the earliest PV activation was recorded by the BKC proximal recording cross-section. RFC delivery was prolonged up to 240 s at sites where a change in the AVC breakthrough occurred and/or PV isolation was obtained. Initial endpoints of the procedure were the complete disappearance of all PV potentials distally to the lesion (entrance block) and the dissociation of the PV activity (spontaneous or pacing-induced) from that of the LA (exit block). Adenosine administration protocol After a 10 min waiting period following each PV isolation, a 12 mg rapid bolus of adenosine was given through a peripheral intravenous line. Thereafter, the surface ECG and intracardiac recordings were continuously monitored for a 2 min period to assess the drug effect on LA-PV conduction and PV spontaneous activity. In order to validate the reproducibility of the adenosine effects, its administration was repeated, in the first 15 PVs, two or three times both in sinus rhythm and during distal coronary sinus pacing (in eight left sided PVs). In cases of AVC reappearance, the following parameters were evaluated: (1) the site of earliest PV activation on the BKC; (2) the modality of LA-PV electrogram coupling and dissociation; (3) the duration of the phenomenon. To evaluate the possible influences of inter-pv electrical conduction 7 in particular PV activation patterns observed during the study protocol, adenosine was administered after isolation of both left PVs in the last 10 patients, having the BKC in one vein and the ablation catheter in the other. Finally, changes in the discharging rate of the intrinsic PV rhythm (if present), and the appearance of spontaneous PV depolarizations (in absence of a spontaneous PV activity) were also assessed. If adenosine induced AVC recovery, the effect of further RFC pulses delivered at the residual conduction breakthrough(s) shown by the BKC recordings was tested. Statistical analysis Values are expressed as mean ± 1SD for normally distributed continuous variables, median and IQR (25th and 75th percentiles) for skewed distributions (assessed by means of Kolmogorov Smirnov one-sample test), and counts and percentages for categorical variables. Continuous variables were compared by the Student s t test or Mann Whitney U test as appropriate. Categorical variables were compared by v 2 or Fisher s exact test. A two-sided p value less than 0.05 was considered statistically significant.

3 Adenosine restores atrio-venous conduction after ostial isolation of the pulmonary veins 2157 Results PV isolation PV isolation was achieved in 74 PVs (all targeted PVs) with a median duration of RFC applications of 16 (IQR: 11 25) min per PV, delivered at a median of 3 (IQR: 3 4) quadrants of the PV ostial perimeter. Twenty-eight left superior, 26 right superior, and 20 left inferior PVs were ablated; the right inferior PV was not targeted in this series of patients because of the lack of evidence of its involvement in arrhythmogenicity (demonstration of spontaneous PV ectopies and/or AF initiation from the vein), the low rate of AF initiation from that vein reported in previous publications, 1 and the inability to map it consistently with the present BKC technologies. Moreover, in four patients with multiple AF initiations from a single PV (three left superior PVs and one right superior PV) only the culprit PV was isolated. Finally, five left inferior PVs were not considered for ablation because of their small diameter and no evidence of spontaneous arrhythmogenicity. After isolation, 15 PVs showed a intrinsic rhythm (persisting >10 min) with a cycle length duration of ± ms (range ms). Spontaneous recovery of LA-PV conduction was observed in three PVs before adenosine administration and in 1 PV not submitted to the adenosine-test. Response to adenosine administration The effects of adenosine were tested in 62 PVs: 23 left superior, 21 right superior, and 18 left inferior PVs. Adenosine was not administered after 12 PV isolations because of patient intolerance to the drug side-effects during previous evaluations, or to prolonged procedure duration. Overall, AVC was re-established by adenosine in 22 PVs (35%), transiently in 19 cases (mean duration of conduction: 16.6 ± 7.1 s; range s) and permanently in three cases (Fig. 1). Transient reappearance of LA-PV conduction was completely reproducible in all cases in which adenosine was repeatedly injected both during sinus rhythm or coronary sinus pacing. AVC usually relapsed at the beginning of the adenosineinduced bradycardia phase and terminated during the subsequent period of sinus rhythm acceleration (mean sinus rhythm cycle length at LA-PV conduction recovery and cessation: ± 607 and 776 ± 201 ms, respectively), but it was also observed during coronary sinus pacing (Fig. 2). The prevalence of LA-PV conduction recovery in the tested PVs was 39% (9 PVs), 43% (9 PVs), and 22% (4 PVs) for left superior, right superior, and left inferior PVs, respectively (p = 0.365). This phenomenon occurred more frequently in PVs showing an intrinsic discharge as compared to those that were electrically silent (11/15 PVs, 73% vs. 11/47 PVs, 23%; p = 0.002). However, the median duration of RFC applications was similar in PVs with (19 min, IQR: 12 26) or without (16 min, IQR: 11 24) adenosine-induced AVC recovery (p = 0.636). Patterns of activation during adenosine-induced LA-PV conduction recurrence The LA-PV conduction time was fixed in 14 cases (64%), while it gradually shortened in the others (Fig. 1). Similarly, LA-PV activity dissociation occurred abruptly in 10 cases (45%), while it was preceded by a gradual prolongation of the LA-PV conduction time in the others (Fig. 3). During adenosine-induced AVC, the site of the earliest PV activation was recorded from the proximal electrodes of the BKC (close to the lesion) in nine cases (41%), and from the mid or distal electrodes in the others (Fig. 3). Interestingly, in six cases (28%), the proximal electrodes of the BKC apparently showed only a single electrogram due to the far-field LA activation without any detectable PV potential. When this conduction pattern was observed in the left PVs, simultaneous mapping of superior and inferior PVs showed a different timing of LA-PV conduction resumption and disappearance in the two veins in two cases (Fig. 3), or AVC reappearance only in one of the two PVs in the other two cases. Finally, in all cases AVC recovery occurred at a previously ablated PV quadrant. Effect of additional RFC delivery Additional RFC pulses with a median duration of 5.5 (IQR: 4 11) min definitely abolished adenosine-induced AVC in all cases. During repeated adenosine injections, in 14 PVs AVC recovered a median of 2 (IQR: 1 3; range 1 7) times before the permanent effect was achieved. RFC was applied at a single location in 18 PVs (80%), or at different PV quadrants in the others because of the presence of multiple conduction breakthroughs. RFC was initially delivered at the PV ostium in correspondence of the quadrant showing the earliest PV activation (irrespective of the proximal or distal location). However, in 10/13 cases (73%) showing an AVC breakthrough distally to the PV ostium, RFC applications at the site of the earliest PV activation on the mid or distal BKC recordings (61 cm from the PV ostium) were required to eliminate LA-PV conduction recovery. Effects of adenosine on PV activity Intrinsic PV activity was invariably depressed by adenosine (marked prolongation in the PV rhythm cycle length or suppression of spontaneous discharge) either before AVC was re-established or when this phenomenon did not occur (Fig. 4). Conversely, PV ectopies occasionally due to transient unidirectional PV-LA conduction, or inducing sustained AF were observed during adenosineinduced LA-PV conduction period in five cases (Fig. 5).

4 2158 M. Tritto et al. Fig. 1 In both panels, from top to bottom, surface ECG lead V1 is displayed together with the recordings of the distal coronary sinus (CSd) and of three series of eight circumferential bipoles (1 2, 2 3, etc.) obtained from different cross-sections of the basket catheter (distal: BTD, mid: BTM, proximal: BTP) placed in the right superior PV. The tracings were recorded after PV isolation was achieved, 23 s after adenosine injection. (a) In the first beat of the sequence only small amplitude, far-field, atrial electrograms (open circle) were recorded within the PV from the basket electrodes. Starting withthe next sinus beat, sharp, high amplitude PV electrograms reappear due to adenosine-induced AVC recovery (arrows). The earliest PV activation is recorded from the BTM 8-1 electrodes (located at the roof of the PV), slightly distally to the ostial lesion. Note also the 10 ms shortening of LA-PV conduction time in the last two beats of the sequence. (b) After a 12.3 s period, an abrupt disappearance of PV potentials indicating LA-PV conduction termination is observed (asterisk).

5 Adenosine restores atrio-venous conduction after ostial isolation of the pulmonary veins 2159 Fig. 2 On each panel, surface ECG lead 2 is displayed together with bipolar recordings obtained from the mid left superior PV (BTM 4 5) during distal coronary sinus pacing after ostial PV isolation. Following adenosine administration, AVC abruptly resumes (arrows) and terminates (asterisk) after a 15 s conduction period. St: stimulus artifact. Clinical outcome After the initial ablation procedure, 20 patients (69%) remained free of AF recurrences as assessed by repeated clinical evaluations and Holter monitorings performed at a time distance of 1, 2 and then every 3 months. In the other nine patients, AF relapses were not correlated with the prevalence of adenosine-induced AVC recovery (5/16 patients, 31% vs. 4/13 patients, 31%; p = 1.0). Six patients underwent a second ablation procedure (after 2.8 ± 0.7 months) during which 13 previously ablated PVs were remapped. Overall, 10 of these veins (77%) showed a spontaneous recovery of LA-PV conduction which was not predicted by the results of the adenosine-test performed during the previous procedure (6/8 PVs, 75% vs. 4/5 PVs, 80% with positive or negative adenosine test, respectively; p = 1.0). Finally, at a 6.3 ± 2.4 month follow-up, 23 patients (79%) had no evidence of AF recurrence and, among them, three patients were on anti-arrhythmic drugs due to frequent, symptomatic atrial ectopies. Complications No significant complications occurred during the procedure or in the follow-up period. Most patients experienced transient discomfort with flushing and dyspnoea during adenosine injection. No PV stenoses were caused by the initial (to obtain PV isolation) or the additional (to abolish AVC recovery) RFC applications as demonstrated by PV angiograms performed during either the initial or the second ablation procedures. Discussion Major findings This study demonstrates that adenosine administration may re-establish LA-PV conduction, after apparently successful PV isolation, in a relatively large proportion of PVs (35% in the present series). Conversely to what was previously reported in a preliminary report, 6 this phenomenon may occur in all PVs and is significantly predicted by the presence of an intrinsic PV discharge. Although more frequently transient, adenosine-induced AVC may also reappear permanently suggesting that this phenomenon could be the herald of a future instability of the lesion. This finding might be of importance since recent reports demonstrated that LA-PV conduction recurrences are extremely frequent after successful PV isolation, 5 and they probably account for the largest number of AF relapses during the follow-up. High-resolution PV mapping allows a reliable identification of the residual conduction area(s) on a three-dimensional scale. Moreover, this study demonstrates for the first time that adenosine-induced AVC recovery can be consistently abolished by additional RFC delivery to obtain a stable PV isolation. Also, this finding has potential implications as it permits the planning of a randomized study aimed at testing whether an ablation strategy, guided by the results of the adenosine-test, could translate into a better clinical outcome in terms of AF recurrences. Mechanism of adenosine-induced LA-PV conduction recurrence and effect on PV activity The mechanism underlying this phenomenon is unclear. At the atrial level, also including the muscular sleeves covering the PVs, 8,9 adenosine causes cell hyperpolarization and reduction of both action potential duration and refractoriness. 10 Since functional LA-PV conduction block can be achieved even in the presence of stunned PV fascicles surviving at the borders or on the epicardial surface of the PV ostial lesion, due to partial cell membrane depolarization and refractoriness prolongation produced by the thermal injury, 11 adenosine may render these fibres transiently (or even permanently by accelerating an already ongoing conduction recovery process) excitable and, thus, AVC may be re-established. This hypothesis could also be indirectly supported by the observation that adenosine-induced AVC recovery occurs more frequently after isolation of PVs covered by thicker and broader mus-

6 2160 M. Tritto et al. Fig. 3 Simultaneous mapping of the left superior PV through a basket catheter and the left inferior PV with the ablation catheter (LIV) placed slightly distally to the ostial lesion. The basket recordings are arranged as in Fig. 1. After adenosine administration, AVC simultaneously recovers in both PVs (panel (a) arrows). Note that the earliest PV activation is recorded from the distal basket electrodes (BTD 5 6) located at the antero-superior aspect of the vein perimeter, while only low-amplitude PV potentials can be detected at the ostial site. After 13 s (panel (b)), AVC abruptly disappears only in the left inferior PV (asterisk), followed by a dissociated discharge from the same vein (arrowhead). After another 13 s (panel (c)), AVC also terminates in the left superior PV (asterisk), preceded by a prolongation in LA-PV conduction time. See text for further discussion.

7 Adenosine restores atrio-venous conduction after ostial isolation of the pulmonary veins 2161 Fig. 4 One minute continuous recording of surface ECG lead 2 and bipolar electrograms obtained from the distal right superior PV (BTD 6-7) is shown. A dissociated PV rhythm (asterisks) with a 3.6 s cycle length is present after ostial PV electrical isolation. Following adenosine administration, AVC is not re-established but a 12 s pause occurs in the PV discharge (fourth panel). Afterwards, intrinsic PV rhythm resumes at the initial cycle length duration and slightly accelerates (2.4 s cycle length) during the compensatory sinus tachycardia phase (last panel). cular sleeves, like the superior PV branches 8,9 and those PVs exhibiting an intrinsic discharge, 12 and that it can be abolished by further RFC applications. This possible explanation is indeed widely speculative and requires further confirmations. Alternatively, this phenomenon might have been indirectly promoted by adenosine-induced sinus cycle length prolongation in the presence of a rate-dependent LA-PV conduction block, even if it may also reproducibly occur during overdrive atrial pacing. The pharmacokinetic properties of adenosine 10 well account for the mean duration of LA-PV conduction observed in the present study. In agreement with experimental data, 13 dissociated PV discharge was consistently depressed or transiently abolished by adenosine administration as a consequence of cell hyperpolarization. 10 Nonetheless, in some cases, PV arrhythmogenicity was observed during adenosine administration including isolated PV ectopies (occasionally related to transient unidirectional PV-LA conduction), and AF initiations possibly facilitated by the drug effects on the atrial action potential duration. 10 Notably, PV arrhythmias only occurred during AVC recurrence periods. Patterns of activation during adenosine-induced LA-PV conduction recurrence Coupling and uncoupling of LA and PV activations in response to adenosine administration frequently exhibited a varying conduction time. This finding is in agreement with the decremental conduction properties of the atrio-venous junction, 14 but it might also reflect different degrees of adenosine effects (e.g., hyperpolarization) during the initial or the terminal phase of the drug action. Interestingly, in a large proportion of cases (59%), the earliest endocardial PV activation during adenosineinduced AVC was recorded from the mid or distal electrodes of the BKC and not from the ostial area (proximal electrodes). In addition, in some cases no apparent PV electrograms could be recorded from the proximal electrodes. These findings highlight the need of combined longitudinal and circumferential mapping in order to detect the phenomenon and to correctly identify the residual conduction breakthrough. Consistently with anatomical data demonstrating multi-layer and vortex fibre arrangement at LA-PV junction, 8,9 this distinctive activation pattern might be due to epicardial fibres having an endocardial insertion distally to the PV ostium. Alternatively, it might be explained by an electrotonically mediated, early activation of the distal PV musculature (as the PV ostium is less excitable because of RFC

8 2162 M. Tritto et al. Fig. 5 AF initiation following adenosine-induced AVC recurrence. Recordings are arranged as in Fig. 1. The basket catheter and the ablation catheter (LSV) are placed within the right superior and left superior PVs, respectively. AVC recurs in both PVs (arrows) and is followed by sustained atrial fibrillation initiation. The tracing magnification with a faster paper sweep (long arrows) demonstrates that atrial fibrillation initiation is due to rapid discharges from the proximal right superior PV (arrows).

9 Adenosine restores atrio-venous conduction after ostial isolation of the pulmonary veins 2163 injury) which, subsequently, reflects back toward the PV ostium. 15 Finally, the behaviour of AVC recovery and disappearance during simultaneous mapping of both left superior and inferior PVs rule out the involvement of inter-pv connections in the genesis of this activation pattern. 7 When a distal early PV activation was found, adenosine-induced AVC recovery was often abolished only after RFC delivery within the vein, but reasonably this goal could also be obtained through high-power RFC applications at the PV ostium. Implications for catheter ablation procedures Our ablation strategy was aimed at minimizing the number of ablation procedures in subjects with electrophysiological features suggesting a possible higher risk of AF recurrences. The clinical outcome of our small study population, which is slightly better compared to that reported after a single ablation procedure in other series of patients treated with similar ablation techniques and with equivalent follow-up durations, 2 4 indirectly supports our approach. On the other hand, the absence of correlation between AF relapses and the results of the adenosine-test is not surprising since the same ablation strategy was applied in all patients, and this finding might also be of importance as additional ablation could have prevented more AF recurrences. Nonetheless, further randomized studies with adequate design and follow-up are needed to address these important questions. Limitations Although we have occasionally observed AF initiation during adenosine-induced AVC recovery, it is not known if these PVs might also be responsible for clinical AF episodes. The abolition of adenosine-induced AVC recovery could be questionable since it is time-consuming and, most importantly, it might expose the patient to increased risks (PV stenoses, embolisms, etc.). However, the reliable identification of the residual conduction breakthrough by three-dimensional PV mapping and the use of low-energy RFC delivery may significantly reduce the risk of complications of this modified ablation strategy. Finally, the use of an irrigated-tip RFC ablation which produces deeper lesions could affect the prevalence of adenosine-induced AVC recovery, but the finding of acute recurrence might, also with this approach, be an important tool to predict long-term AVC recurrence and AF relapses. Conclusions Adenosine may transiently or permanently re-establish LA-PV conduction after apparently successful PV isolation. 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Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation. Circulation 2003;108: Arentz T, Shah D, Jais P et al. Adenosine induces pulmonary vein activity after successful ostial pulmonary vein isolation: evidence for a new pathway. Pacing Clin Electrophysiol 2002;25(Part II):566.. [Abstract]. 7. Tritto M, De Ponti R, Zardini M et al. Electrical connection between pulmonary veins in humans. Circulation 2001;104:e Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins: an anatomic study of human hearts. Circulation 1966;34: Ho SY, Cabrera JA, Tran VH et al. Architecture of the pulmonary veins: relevance to radiofrequency ablation. Heart 2001;86: Freilich A, Tepper D. Adenosine and its cardiovascular effects. Am Heart J 1992;123: Nath S, Haines DE. Pathophysiology of lesion formation by radiofrequency catheter ablation. 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