Histopathology of intraoperatively induced linear radiofrequency ablation lesions in patients with chronic atrial fibrillation
Thomas Deneke1,3,*,
Krishna Khargi2,
Klaus-Michael Müller3,
Bernd Lemke1,
Andreas Mügge1,
Axel Laczkovics2,
Anton E. Becker4 and
Peter H. Grewe1,3
1Medical Clinic II (Cardiology and Angiology), BG Kliniken Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
2Clinic for Cardio-Thoracic Surgery, BG Kliniken Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
3Institute of Pathology, BG Kliniken Bergmannsheil, Ruhr-University Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
4Department of Cardiovascular Pathology, Academic Medical Centre, University of Amsterdam, The Netherlands
Received 20 December 2004; revised 21 February 2005; accepted 3 March 2005; online publish-ahead-of-print 26 April 2005.
* Corresponding author. Tel: +49 234 302 6077; fax: +49 234 302 6084. E-mail address: thomas.deneke{at}ruhr-uni-bochum.de
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Abstract
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Aims Radiofrequency (RF) energy has been extensively used in ablation of arrhythmia but so far no analysis of morphological effects in human left atria has been conducted.
Methods and results We studied 59 ablation lesions from seven patients who died 2 to 22 days after open heart surgery plus intraoperative cooled-tip RF ablation to treat permanent atrial fibrillation (AF) (mean 4, 111 years). The ablation area was studied by macroscopy and histological analysis. RF ablation produced clearly delineated coagulation necrosis (up to a depth of 5.5 mm) bordered by an irregular zone of incomplete necrosis and fresh bleeding even 22 days post-operatively. No superficial charring, thrombotic deposition, or perforation was documented. Endocardium and subendocardium displayed oedematic loosening and microfragmentation of connective tissue fibres. Early after ablation (26 days), interfibrillar disseminated bleeding and necrosis without tissue removal response were found. Later after ablation (21, 22 days), mild inflammatory reaction and granulation tissue appeared. Twenty-five per cent of all studied lesions, especially in the thick region in between left pulmonary veins and mitral annulus (left atrial isthmus) (86%), were non-transmural. Nerve fibres with different degrees of thermal injury were detected in the pulmonary vein ostial region.
Conclusion Intraoperative cooled-tip ablation in AF resulted in coagulation necrosis of endocardium, subendocardium, and the atrial myocardial layer to a depth of 5.5 mm bordered by an irregular zone of incomplete thermal damage. Transmurality of the lesions could only be found in 75% of intraoperatively applied lesions.
Key Words: Radiofrequency ablation Atrial fibrillation Pathology Histomorphology
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Introduction
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Invasive ablation therapy delivered in the left atrium to treat atrial fibrillation (AF) has become engaged in everyday practice of cardiac surgeons and interventionists. Conversion rates after anti-AF surgery have been reported to be as high as 95% depending on prior duration of AF and enlargement of left atrial dimensions. The original Cox-maze procedure as a cut and suture technique is time consuming.1,2 Radiofrequency (RF) ablation as an alternative mode to produce linear lesions has been proposed to facilitate and shorten the procedure. Short-term success and long-term success have been reported to be slightly less convincing when compared with the original Cox-maze procedure partly due to different patient selection.1,36
RF energy has been extensively used in catheter ablation of supraventricular and ventricular arrhythmias. RF ablation produces thermal necrosis and therefore electrophysiological conduction block when lesions are transmural. In order to enlarge lesion extent and reduce endocardial carbonization cooled-tip technology has been introduced.711
However, the pathomorphological alterations induced by RF ablation in human atrial tissue have only been documented in a limited number of case reports on patients after catheter ablation of different arrhythmia (AV-nodal reentry tachycardia, typical atrial flutter, and left ventricular tachycardia). The morphology of left atrial linear ablation in patients with diseased, fibrillating atria has not been reported.1219
We studied the hearts of seven patients in whom intraoperative atrial linear cooled-tip endocardial RF ablation was performed, who had died within 22 days after surgery. In these probes, we evaluated the morphological effects of RF ablation on diseased human atria and documented the depth and transmurality of thermal necrosis.
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Methods
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Seven patients (out of a total of 145 patients) died 222 days after open heart surgery plus atrial cooled-tip RF ablation to treat chronic permanent atrial fibrillation. The hearts of these patients were studied post-mortem and provide the basis of this work. Authorization for autopsy was given in all instances.
The hearts were excised leaving at least 3 cm of pulmonary veins to the left atrium. The surrounding tissues, including oesophagus and mediastinum, were studied. In addition, any sign of arterial embolism was documented.
Post-mortem angiography was performed on all hearts and no coronary stenosis in the proximity of any of the linear ablation lines was noted. In one case with myocardial infarction, occlusion of a bypass graft was documented.
Post-operative rhythm
A 12-lead ECG was recorded everyday after surgery. For six post-operative days, telemetry was performed to detect rhythm disturbances. Arrhythmia occurring was evaluated by 12-lead ECG in order to detect atrial macroreentry or AF.
Macroscopy
The atria were opened following the operative way via interatrial groove and right atrial lateral incision. The right and left atrium was then studied macroscopically and endocardial continuity of lesions was examined (Figure 1). Transverse preparations of each of the pulmonary vein (PV) ostia were performed at different circumferential sites (Figure 3). Lesions traversing the atrium were cross-sectioned as shown in Figure 1, histological preparations were performed and the extent of the lesions was examined.

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Figure 1 Macroscopic aspect of right (A) and left atrium (B) with schematic view of ablation lines (C and D) after biatrial (after mitral valve repair) intraoperative ablation (female, 67 years) (ac: sites of histological sample). All lines surrounded by haemorrhaghic zones (1 mm) (line 1: over the interatrial septum (IAS), line 2: cavotricuspid isthmus, line 3: line from right atrial appendage (RAA) to tricuspid valve (TV), line 4: interconnection line between the two PV blocks, line 5: line from left inferior PV (LIPV) to excised left atrial appendage (LAA), line 6: left atrial isthmus line. IAG, interatrial groove used for surgical access to the left atrium; RIPV, right inferior PV; RSPV, right superior PV; LSPV, left superior PV; SVC, superior caval vein; CS, coronary sinus ostium.
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Figure 3 Morphology of PV ostial lesions 2 days after surgery (A). Macroscopy. (BD). Gross histological transverse view of ablation zone (grey arrows) in transition zone between left atrium (left) and PV (right). (E). magnification from D (Goldner staining) (female, 61 years) (single right arrow denotes myocardial bridge onto PV; asterisk denotes sectioned nerve fibres) (af indicate longitudinal slices for histological sampling). (A) View of right pulmonary veins with three ostia and whitish lesions encircling the pulmonary veins, surgical access via interatrial groove. (B) Left inferior PV ostial region. Left atrial myocardial layer extension upon epicardial side of the PV (M=left atrial myocardium). (C) Left superior PV ostial region with haemorrhaghic demarked ablation zone. Fragmented subendocardial tissue and oedema in the ablation zone. (D) Right superior PV ostial region with hypertrophic, fibrotic left atrial myocardial layer. Intimal fibrosis within the first centimetre of the PV and completely transmural lesion at the ostial region. (E) Magnification of D at the end of the myocardial bridge: Intimal tissue (I) with oedema and loosening of subendocardial (S) connective tissue.
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Histology
The slices of atrial tissue were processed as usual to obtain paraffin blocks. Tissue staining was performed using (1) Elastica-van-Gieson (EvG) staining and (2) Goldner staining (Trichrome-Masson staining) to document thermal myocardial damage. Degrees of myocardial damage (nuclear staining, homogeneity of myocytes, striation), haemorrhage, or amount of inflammatory cells were studied. Complete myocardial necrosis was characterized by rounded, homogenous myocytes with loss of nuclear staining. Thermal effects on collagenous fibres were examined. Histological evaluation of lesion transmurality was based on maximum depth of myocardial necrosis in relation to wall thickness (and region of ablation) (complete transmural lesion was defined as myocardial necrosis throughout the atrial wall). Alterations of vessels (arterial, venous, or nervous) in the region of RF lesions were studied.
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Results
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Patient characteristics
Cardiac surgical procedures performed were mitral valve repair in two; mitral valve surgery plus coronary artery bypassing (CABG) in two; CABG alone in one, CABG plus mitral, aortic, and tricuspid valve surgery in one; and mitral, aortic, and tricuspid valve surgery in one. All patients had reduced left ventricular function (mean ejection fraction 36±17%, EUROSCORE 7.8±3.3), and chronic permanent AF was documented in all patients 111 years prior to the procedure (mean 4±3 years). The additional atrial antiarrhythmic operation was restricted to the left atrium in five and performed as a biatrial procedure in two patients using intraoperatively cooled-tip RF ablation. All ablations were performed during cold blood cardioplegia (810°C, 4 : 1 bloodcrystalloid mixture) (antegrade perfusion during bypass and mitral valve procedure, retrograde perfusion during aortic valve procedures). Linear lesions around each of the PV ostia with interconnection lines, two lines from the left inferior PV ostial line to the mitral valve annulus and up to the excision of the left atrial appendage were performed (Figure 1). In two cases, the left atrial appendage was linearly ablated at the transition zone between appendage and left atrium. Applied energy ranged in between 25 and 30 W with continuous open saline irrigation (320 mL/h) over a 4 mm unipolar tip electrode (Medtronic CardioblateTM). Lesions were performed in a step-wise approach (velocity of ablation for 1 cm ranged in between 3 and 8 s) ablating one area until whitish discolouring of the endocardial surface occurred and then moving on.3,4,11 A change of colour was noted in all patients. No popping indicating a temperature too high was recorded in these patients.
Post-operative rhythm follow-up
All seven patients were in sinusrhythm or atrial paced rhythm after completion of the cardiac surgery. In four cases, phases of AF were documented; in two patients, AF was found at day of death. In the five other cases, sinusrhythm was documented on the day of death (Table 1). No regular supraventricular tachycardia was detected during follow-up.
Cause of death
Patients died 222 days after the procedure and clinical cause of death was substantiated during autopsy to be cardio-respiratory insufficiency and pump failure in three, global cardiac insufficiency and myocardial infarction in the region of a stenosed graft in one, sepsis after pneumonia in two, and cardiogenic shock in one patient.
Pathomorphological macroscopy
We studied 59 lesions in seven patients (including eight lesions from the right atrium). No perforation or damage to mediastinal organs was detected. In all cases, the oesophagus did not show any signs of thermal damage or mechanical trauma.
Linear lesions distinguished as whitish, clearly delineated continuous lines (613 mm wide, mean 10 mm). No complications like endocardial ulceration, perforation, or thrombotic formation were visible (Figure 1). Charring as a result of endocardial carbonization was not found on any of the ablation lines. No alterations, luminal narrowing, or deformation of the PV ostia were seen. All ablation lesions were lined by more or less visible haemorrhagic areas (1 mm) (Figure 1).
In cross-sections, ablation lines appeared as clearly demarcated ovoid shaped areas with haemorrhagic bordering zones (Figure 2).

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Figure 2 Morphology of ablation area 21 days post-operatively (A) and left atrial isthmus line (BD) (male, 65 years). (A). Macroscopic cross-section of an ablation line from the right atrium (arrows point at visible extension of necrosis) with clearly delineated lesion (macroscopically 3 mm deep) and haemorrhaghic border. (B). Histologic cross section (EvG staining) of the non-transmural left atrial isthmus line with intramural haematoma (*) and necrotic core up to a depth of 4.5 mm. (C). Magnification of B: Transition zone from complete necrosis (upper part; anuclear myocardial cells, N=necrosis) and partial thermal damage (below; striation of myocardial cells and some nuclei visible=M). (D). Magnification of B: Capillary rich granulation tissue and removal reaction: Dilated capillaries and intramural bleeding.
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Histology
In all histological specimen, ablation areas were clearly visible and delineated. Pattern of thermal tissue damage was comparable in the seven patients, but tissue reactions were different in the five patients dying within 6 days compared with the two patients dying after 21 and 22 days. The left atrium (mean thickness 5.4 mm, range 310 mm) was found to be thinnest in the region of the PVs (13 mm) and in the region of the posterior left atrial wall (25 mm) and thickest within the left atrial isthmus defined as the region in between left inferior PV ostium and mitral valve annulus (7.4 mm mean thickness, 410 mm). The right atrium consisted of thinner layers of myocardium (mean 3.8 mm, 35 mm). Histology taken from mediastinal organs including the oesophagus did not show signs of thermal injury.
Pattern of thermal necrosis
Thermally induced necrosis of myocardial tissue was documented to include alterations of myocardium, endocardial and subendocardial fibrous tissues, capillary vessels, and nerve fibres.
The core of the coagulation necrosis was characterized by rounded, homogenous myofibrillous layers with signs of complete necrosis. Collagenous fibres were fragmented, irregular, and show oedematic swelling. In the outer margins of the necrotic core, different degrees of reduced nuclear staining and loss of longitudinal and cross-sectional striation (indicating altered myocardium) were seen (Figure 2). No endocardial tissue defects were noted. The subendocardial region showed microfragmentation of elastic fibres and oedematic swelling of fibrous structures. Acellular, homogenized, and sometimes swollen subendocardial fibrotic structures displayed loosening and widening of the otherwise tight interconnections (Figure 3).
Early after ablation (within 6 days), zones of diffuse fresh intramural bleeding with interfibrillous erythrocyte infiltrations of the necrotic myocardium were seen. Blood vessels were hyperemic and dilated, some microvessels exhibited thrombotic occlusion. Fifty per cent of nerve fibres in the ablation area of the PV ostia exhibited vacuolization and reduced cellular staining as different degrees of thermal injury (Figures 3 and 4).

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Figure 4 Histology of PV ostial ablation (Goldner staining; (A) gross histology, (B) magnification from A, male 65 years, 4 days post-operatively). (A). Ostial segment of left superior PV with left atrium (LA): Ablation zone with complete necrosis and oedematic loosening of endocardium, subendocardium and thin myocardial layer. Haemorrhaghic pericarditis (P) seen on the epicardial site of LA. Nerve fibres (N) in the transition zone. (B). Magnification from A: Multiple nerve fibres in the subepicardial fatty tissue, some exhibit different degrees of thermal damage (asterisk).
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A granulated tissue rich of dilated capillaries was found in the outer zones penetrating towards the necrotic core of the ablation area 21 and 22 days after ablation. In the outer layers, zones of fresh bleeding from small blood vessels displaying different degrees of wall alterations and thrombosis were found. Only mild inflammatory reaction with removal of necrotic myofibres was detected in the border zones around the necrotic core (Figure 2).
Areas with intramural haematoma interrupting the atrial wall configuration were found independent to the time-point of death (Figure 2).
Transmurality
Transmurality of a lesion was estimated when complete myocardial necrosis was found reaching up into the epicardial layers (Table 2).
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Table 2 Wall thickness and per cent of completely transmural lesions (number of lesions without transmural necrosis/number of lesions) in different regions of the left and right atrium
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PV ostial lesions
In these regions with thin myocardial layers, complete transmurality was found in all but one probe (96%), where a myocardial fibre traversed the ostium insulated by 2 mm thick fatty tissue. Myocardial bridges reaching on the epicardial aspect of the PVs could be detected up to 23 mm upon the venous side (Table 2).
Left atrial and right atrial lesions
Complete myocardial necrosis was found up to a depth of 5.5 mm. An irregular zone of myocardium with reduced nuclear staining and different degrees of loss of transversal striation margined the complete necrosis. In our preparations, incomplete, non-transmural lesions (ranking in between 50 and 80% of myocardial thickness) were found in 25% of all probes [1/28 PV encircling lesions (4%), 0/7 lesions on posterior left atrial wall, 6/7 of left atrial isthmus lesions (86%), 4/8 in the right atrium (50%), 3/7 in the region between left inferior PV and left atrial appendage (43%), and 1/2 around the left atrial appendage (50%)] (Table 2, Figure 2).
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Discussion
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This research presents the first morphological analysis of lesions induced by cooled-tip RF ablation in diseased fibrillating human atrial specimen in a series of patients. Whereas macroscopy revealed superficial completeness and no thrombotic apposition or charring, cross-sections and histology documented various degrees of non-transmurality. Lesions in the thin myocardial layer of the PV ostial region and the posterior left atrial wall almost always exhibited completely transmural coagulation necrosis. Ablation lines inside the atria revealed a complete thermal myocardial necrosis for a maximum depth of 5.5 mm bordered by an irregular zone of different degrees of myocardial alteration and disseminated fresh bleeding even 22 days post-operatively. At least one lesion per patient did not show complete transmurality when applying histological criteria (25% of all studied ablation lesions).
Transmurality
Our findings are in accordance with studies of RF ablation in animal ventricular or atrial myocardium and case reports of patients dying early after ablation.1021 The depth of the lesions depends on technical aspects such as electrode tip dimensions, location of ablation, as well as operator's skill and experience. Cooled-tip RF ablation is reported to reach up to 7 mm into the cardiac tissue comparable to our findings. This has practical implications when considering atrial myocardial layers to be as thick as 10 mm in patients with AF in some areas specifically the left (between left inferior PV and mitral valve annulus) and right atrial isthmus. In these areas, energy delivery needs to be optimized (higher energy output or larger electrode tip) to induce complete transmural lesions.2,6,1021
The high percentage of non-transmural lesions after endocardial linear ablation in the left atrial isthmus is also indicated by reports from the group of Haissaguérre even though the mode of ablation (intraoperative vs. catheter ablation) is completely different. Haissaguérre et al.22,23 documented the need for ablation from the endocardial site and from within the coronary sinus to produce complete conduction block in the region between left inferior PV ostium and mitral valve annulus. In the studied seven patients with prior permanent AF, sinusrhythm was re-established during follow-up even though non-transmural lesions were found in all cases. Even though these findings are only short follow-up data and are not predictive of long-term success, they are in congruence with our long-term patient follow-up and reported high success rates of RF-ablation modified antiarrhythmic surgical procedures (
85% long-term sinus rhythm).35,11,24 The low incidence (14%) of transmurality in the left atrial isthmus in our report and the high clinical success rates suggest that transmural lesions are not always needed to suppress arrhythmia. No electrophysiologic correlation between histologically non-transmural lesions and electrical conduction was made. It still remains unclear how much transmurality in regard to complete tissue necrosis is needed to induce long-term electrical conduction block.12,13,17,18 In our long-term follow-up collective, only a small portion of patients reported with left atrial flutter (usually including the left atrial isthmus) but non-transmural lesions may facilitate flutter around the mitral valve.4,24
From the paper by Caccitolo et al.,2 it has become clear that endocardial RF ablation around the pulmonary veins produced electrophysiological conduction block by producing transmural lesions. This animal study is in accordance with our analysis documenting a percentage of >95% of transmural lesions in the region of the pulmonary veins.
Pattern of thermal injury
RF ablation in diseased atria produced clearly delineated ovoid shaped zones of coagulation necrosis. Distinctive differences in tissue reaction were found in our study early (up to 6 days post-operatively) and later (2122 days) after intraoperative ablation. Limited knowledge on the morphology of RF ablation in humans has been recovered from rare case reports. One report on ablation in AV-nodal reentry (2 days post-interventional)17 and one report on a case of atrial flutter ablation (4 months)13 depict thermal damage on right atrial tissue documenting a necrotic region consisting of myofibre coagulation necrosis. Case reports on thermal ablation of left ventricular myocardium to treat ischaemic ventricular tachycardia in a total of six patients show disseminated regions of bleeding in lesions reaching up to 7 mm deep (after cooled-tip ablation). No report on a homogenous series of patients ablated within diseased left atria with permanent AF exists.1214,1719
The pattern of thermal injury seen in our series of patients is comparable with the reports on morphology of ablation in human hearts and equals atrial injury by RF ablation in animals. Coagulation necrosis is characterized by defragmentation and destruction of myocytic contractile apparatus leading to loss of electrical conductile function.5,7,9,10,1214,1719
In contrast to these reports on transvenous catheter ablation, we detected zones of fresh bleeding sometimes producing confluent intramural haematoma as a universal finding upto 22 days after intraoperative ablation. Intramural haematoma could be traced back to the finding of prolonged thermal damage to smaller blood vessels with vessel wall alterations (leakage) and thrombosis. The coexistence of intramural haemorrhage in ablation areas has been documented in case reports and animal findings without producing severe clinically detectable complications.5,7,911 In addition, no information on damage to nerve fibres has been given in the reports on human or animal catheter ablation which is a new aspect on the morphology of ablation lesions.
In contrast to the reports on ablation of ventricular tachycardia, we did not find any thrombotic deposits on the ablation areas.12,14 Oesophageal injury as indicated previously by either applying intraoperative25 or catheter RF-ablation26 within the left atrium was not detected in our histology study. This may be due to different surgical preparations and access. In our experience, the posterior left atrial wall was lifted away and isolated from the underlying mediastinal organs.27
Anatomy of the PV ostial region in regard to AF surgery
In patients treated with intraoperative RF ablation, sinus rhythm usually occurs spontaneously within 6 months after the procedure. This late conversion may be in part due to electric remodelling of the atrium. As documented in this study, there was a zone of bleeding and incomplete myocardial necrosis around the necrotic core. Over time, the diffuse haemorrhagic zones were degraded by capillary rich granulation tissue replacing the necrotic core from the epicardial side. This may lead to further enlargement of the initial necrotic zone by inducing granulation tissue removal response. Because of the process of tissue repair a lesion may become larger and produce complete transmurality later on.
In addition, the PV ostial regions were rich of nerve fibres indicating a special role in autonomic innervation. Ablation produced thermal injury of nerve fibres and may modulate intact autonomic innervation.4,11,28
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Conclusions
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RF ablation in AF produced coagulation necrosis of endocardium, subendocardium, and atrial myocardial layers up to a depth of 5.5 mm bordered by an irregular zone of incomplete thermal damage. No superficial thrombotic deposition, charring, or endocardial ulceration of atrial tissue was seen. Fresh intramural bleeding and haematoma due to damaged microvessels were found up to 22 days post-operatively. Nerve fibres around the PV ostia exhibited different degrees of thermal damage.
Only 75% of all studied lesions were completely transmural. The thick myocardial layer in the region between left inferior PV and mitral annulus exhibited complete myocardial necrosis in only one of the seven studied samples (14%).
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Limitations
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This pathomorphological analysis was restricted to a highly selective group of patients dying in hospital within the first 3 weeks after intraoperative cooled-tip RF ablation to cure AF and by this included only a limited number of patients and lesions. No patients with longer follow-up have been included, so no long-term effects of these procedures could be studied. Patients included had different underlying heart disease, which may affect the morphology of the atria in AF and the morphological alterations induced by thermal energy.
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