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a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, New York
b Division of Cardiology, Mount Sinai School of Medicine, New York, New York
Accepted for publication April 23, 2008.
* Address correspondence to Dr Filsoufi, Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, 1190 Fifth Ave, Box 1028, New York, NY 10029 (Email: farzan.filsoufi{at}mountsinai.org).
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Abstract |
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Methods: Twelve domestic pigs underwent beating-heart epicardial PV isolation using cryothermy (n = 6) or radiofrequency (n = 6) energy. Follow-up was 30 days for 3 animals of each group and 90 days for the others. Lesions were assessed by epicardial pacing, cardiac magnetic resonance imaging (MRI), and histologic analysis.
Results: Immediate and long-term electrical isolation of PVs was achieved with both energy sources. Histologic analysis showed transmural lesions in all animals at 30 and 90 days. Cardiac MRI showed no evidence of PV stenosis or thrombus formation. Mean left atrial ejection fraction was 0.36 ± 0.01, 0.36 ± 0.02, and 0.36 ± 0.01 at baseline and at 30 and 90 days, respectively (p = 0.360 and 0.230, respectively) and not significantly different with cryothermy or radiofrequency ablations.
Conclusions: Beating-heart PV isolation using epicardial cryothermy or radiofrequency ablation produces transmural lesions with complete electrical conduction block, with low or no risk of endocardial thrombosis or PV stenosis. This approach may be useful for PVI in selected patients with AF caused by PV triggers.
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Introduction |
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As a consequence, efforts have been directed towards the development of less invasive and safer ablation techniques. Since Haïssaguerre and colleagues [4] have shown that in most instances AF originates from the left atrial pulmonary vein (PV) junction, several simplifications of the classic Cox-Maze procedure have been used [5]. It has been suggested that PV isolation alone can be an effective treatment modality in a large proportion of patients, particularly those with paroxysmal AF [6].
Surgically, PV isolation can be performed endocardially or epicardially. The epicardial approach has the advantage because it can be performed on a beating heart. Various energy sources have been used, most commonly cryothermy and radiofrequency, to create lines of conduction block. However, one concern regarding epicardial approaches to PV isolation has been the creation of electrically effective transmural lesions [7]. In addition, potential complications such as thrombogenicity and PV stenosis associated with this procedure have not been systematically investigated.
The purpose of this animal study was to determine comparative efficacy and safety of epicardial beating-heart PV isolation using cryothermy or radiofrequency energy. Conduction block was assessed by pacing. The depth of the epicardial lesion and endocardial damage was assessed by histologic analysis. Magnetic resonance imaging (MRI) was performed at 30 and 90 days to evaluate for immediate and long-term complications of thrombosis and pulmonary vein stenosis.
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Material and Methods |
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The study used 12 adult Yorkshire domestic pigs (Animal Biotech Industries, Allentown, NJ), 4 to 5 months old and weighing 30 to 40 kg. Six animals underwent epicardial PV isolation using cryothermy as the energy source, and in the other 6, radiofrequency energy was used. Three animals of each group were followed up for 30 days, and the remaining 3 animals had a follow-up of 90 days. Efficacy of lesions was assessed by epicardial pacing to determine electric conduction block. After ablation, cardiac MRIs were performed to look for thrombosis and PV stenosis, and evaluate left atrial function. Histologic analysis was performed on specimens to evaluate the extent of transmural fibrosis.
Intraoperative Management and Operative Technique
Anesthesia was induced with an intramuscular injection of ketamine (15 mg/kg) and xylazine (2 mg/kg). After pharyngotracheal intubation, isoflurane (1.5% to 2%) was administered to maintain anesthesia. Lidocaine (100 mg) was given by means of a bolus infusion and was used as a cardioprotectant before sternotomy as well as before dissection of the PVs. Norepinephrine was administered at a variable dosage to maintain adequate arterial mean pressures. Animals were not anticoagulated with heparin during the procedure.
Standard surgical instrumentation and sterile precautions were used in all animals. A left femoral artery catheter was placed for pressure monitoring. Continuous electrocardiographic monitoring was performed. The heart was exposed through a median sternotomy. All subsequent procedures were performed on the beating heart, without the use of cardiopulmonary bypass.
The pericardium was opened and retraction sutures were placed. The left- and right-sided PVs were carefully dissected and encircled with heavy Mersilene suture (Ethicon, Somerville, NJ). Pacing thresholds for each PV were determined as described below. Ablation probes were then placed and PV isolation performed from the left atrium. Anatomic localizations of lesions were right and left atrial cuffs adjacent to the ostia of the PVs.
Pulmonary Vein Isolation Using Cryothermy
For cryothermy ablation, an argon-based Cryoclamp probe (CryoCath Technology, Montreal, Quebec, Canada) was mounted in a clamp device (Fig 1A). The device used in this study includes a thermostat that displays real-time tissue temperatures. Following the current guidelines of the manufacturer, clamp lesions in our study consisted of 45 seconds at a mean temperature of –145°C for each side. After the ablation procedure, the ablation site was irrigated with saline, and the clamp was released when the thermostat indicated a temperature exceeding 4°C.
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Lesion Assessment by Epicardial Pacing
The lesions created during the PV isolation were assessed by epicardial pacing. Epicardial pacing was performed from the PV to determine left atrial capture before and after the procedure and at follow-up using a single-chamber temporary pacemaker (Model 5348, Medtronic Inc, Minneapolis, MN) and pairs of reusable epicardial pacing electrodes. Bipolar pacing was performed at each PV distal to the ablation site at a rate 25% above the heart rate of the individual animal. Preprocedural pacing was performed to record baseline pacing thresholds. Postprocedural and follow-up pacing were done to control for completeness of conduction block. Completeness of conduction block was defined as the inability to capture the atrium at a pacing threshold exceeding 20 mA.
Postoperative Management
After the procedure, all animals were transferred to a recovery room and monitored for 48 hours. For the remainder of the study, the animals were under surveillance in the institutional animal facility. All animals received analgetic treatment with buprenorphine (0.03 mg/kg, intramuscular), Banamine (2 mg/kg, intramuscular; Schering-Plough, Kenilworth, NJ), and fentanyl patch (50 mg/h) for at least 72 hours. Antibiotic prophylaxis consisted of intramuscular cephazolin (25 mg/kg) for 10 days. No anticoagulant or antiplatelet treatment was used preoperatively, intraoperatively, or postoperatively in this model.
Magnet Resonance Imaging
Cardiac MRIs were performed before the procedure and at 30 or 90 days later. All animals were sedated with a single dose of ketamine (15 mg/kg) and xylazine (2 mg/kg). The animals were placed supine in a clinical 1.5-T MRI scanner (Magneton Sonata, Siemens Medical Solutions, Erlangen, Germany) and fitted with a phased-array cardiac surface coil for image reception. The imaging protocol consisted of multiple anatomic and functional cine images and velocity-encoded images. All images were synchronized to the cardiac rhythm with a 5-lead electrocardiogram. MRIs were captured in transverse, coronal, and sagittal planes to assess the PVs. Cross-sectional images were used to determine the diameter of each vessel. Left atrial function was assessed by the determination of ejection fraction.
Terminal Procedure and Histologic Analysis
After the second MRI, animals were transferred to the operating room. Anesthesia was administered with 2% isoflurane. The sternum was reentered through the primary incision. The left- and right-sided PVs were redissected, and follow-up epicardial pacing was performed. Animals were then euthanatized by the intracardial administration of an overdose of sodium pentobarbital.
The hearts were harvested en bloc. The main trunks of the left- and right-sided PVs were retained. The left atrium was opened, the PV ostia were identified, and the specimen was inspected grossly for any evidence of intraatrial thrombus formation, PV stenosis, or endothelial disruption. The hearts were immersed in 10% formalin for 24 hours.
The circular clamp lesions were carefully excised from the heart and cut open to create a longitudinal specimen. The specimens were then cut into 3- to 5-mm cross-sections and placed on the embedding cartridge. The tissue sections were stained in hematoxylin and eosin and trichrome and microscopically examined to assess transmurality of the lesions and the effect of the energy sources on integrity of the endothelium.
Statistical Analysis
Results are described as mean and standard deviation. Comparison of preoperative and postoperative variables was performed using the Student t test. A value of p < 0.05 was considered statistically significant.
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Results |
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Pulmonary Vein Isolation Using Cryothermy
All left and right PV lesions were made with a single application of the cryothermy ablation clamp. The average temperatures during the procedure measured at 30 and 45 seconds were –139.8° ± 1.4°C and –145.5° ± 2.3°C for the left PV lesions and –142.5° ± 1.4°C and –148.2° ± 2.1°C for the right PV lesions respectively, (p = 0.230 and 0.170 at 30 and 45 seconds, respectively).
Pulmonary Vein Isolation Using Radiofrequency
The average ablation time was 8.5 ± 1.6 seconds for the left PVs and 9.0 ± 2.6 seconds for the right PVs (p = 0.560). The average temperature achieved was 52.3° ± 1.5°C.
Immediate postprocedural pacing demonstrated complete conduction block, with no atrial capture with PV pacing at 20 mA for all lesion sets (radiofrequency and cryothermy) in all animals.
Follow-up Data at 30 and 90 Days
Assessment of lesions by epicardial pacing
At the 30-day follow-up, pacing was performed in 4 animals and showed complete conduction block across all lesions (cryothermy, n = 2; radiofrequency, n = 2). In 2 animals follow-up pacing at 30 days was not possible because of severe hemorrhage from the right ventricular lesions due to dense adhesions and cardiac arrest before complete dissection of the PVs (1 animal from each group). At the 90-day followup, complete conduction block was shown in 5 animals (radiofrequency, n = 3; cryothermy, n = 2). Pacing at 90 days was not performed in 1 animal due to intractable ventricular fibrillation before complete dissection of the PVs.
Cardiac MRI
Follow-up MRI at 30 days did not show any evidence of PV stenosis independent from the cryothermy or radiofrequency energy source (Fig 3). PV diameters were not different when the 2 were groups were compared (Table 1). However, an overall increase of the PV diameters was noted compared with the baseline values. This was probably related to the growth of the animals throughout the study period, as reflected by the weight gain (Table 1). Assessment of left atrial function showed normal function in both cryothermy and radiofrequency groups, with no impairment of left atrial ejection fraction compared with the baseline measurement. There was no evidence for mitral or tricuspid valve regurgitation. MRI did not reveal thrombosis in the areas of ablation after cryothermy or radiofrequency PV isolation. At late follow-up (90 days), MRI showed no evidence of PV stenosis. The PV diameters increased compared with the baseline and the 30-day levels but were not different between the two groups (Table 1). Left atrial function also remained unchanged at 90 days after the procedure.
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Comment |
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Surgical treatment of AF has become an important adjunctive procedure in patients undergoing cardiac procedures. Excellent results have been achieved with the traditional Cox-Maze III procedure, which has been the gold standard for surgical treatment of AF [8]. However, this procedure is relatively complex, technically challenging, and requires cardiopulmonary bypass support with prolonged cardiac ischemic time. Haïssaguerre and colleagues [4] showed that most ectopic foci that trigger AF are located in PVs. Several simplified approaches to the surgical ablation of AF by PV isolation have been introduced [9].
Initially, surgical PV isolation was performed endocardially using radiofrequency [9, 10] or cryothermy probes [11]. These approaches still require cardiopulmonary bypass support and cardiac arrest and are therefore predominantly performed in the setting of mitral valve procedures. The development of epicardial clamp devices used for electrical isolation of the PVs from the left atrium has several advantages. It can be performed in a very short period of time without opening the left atrium and without cardiopulmonary bypass and cardioplegic arrest in patients undergoing off-pump coronary artery revascularization.
Epicardial ablation devices such as bipolar radiofrequency and argon-based cryothermy devices are currently available. Despite their application in clinical practice, only a few studies have investigated the creation of stable transmural lesions and long-term persistence of conduction block at the level of the PVs. Potential side effects such as endocardial disruption and the risk of thrombus formation as well as PV stenosis are not well characterized.
Transmurality
Obtaining transmural lesions is important to ensure conduction block and therefore long-term efficacy of PV ablation procedures. Concerns have been raised regarding the transmurality of lesions in beating-heart epicardial ablation procedures because of the thickness of the atrial structures, the presence of epicardial fat, and "heat-sink effects" from endocardial circulating blood (blood cooling effect in radiofrequency procedures; blood warming effect in cryothermy ablation) [12].
In an ovine model of epicardial and endocardial radiofrequency ablation using a probe device, Thomas and colleagues [7] showed that lesion transmurality depends on atrial wall thickness and epicardial fat content. The authors were unable to create transmural epicardial lesions when the target tissue measured more than 4 mm. In the presence of epicardial fat, effective lesions were only detected in 43%, whereas complete lesions were detected in all sections in which no epicardial fat was present. In addition, the authors observed that epicardial lesions were less effective compared with endocardial lesions and postulated that a cooling effect of endocardial blood flow during epicardial ablation might have reduced the depth of lesions [7].
Efficacy of epicardial cryothermy for PV isolation has not been investigated. It has been hypothesized that, analogous to the heat-sink effect, the warming effect of endocardial blood flow will make successful epicardial beating-heart ablation with cryothermy probe devices less effective [3, 12]. However, with the development of epicardial ablation clamps, complete occlusion of blood flow during the energy delivery process can be achieved and the heat-sink effect might have been abolished.
In the present study with the use of a long-term porcine model, we demonstrated that both radiofrequency and cryothermy clamp devices effectively isolate the PV origins from the left atrium. During radiofrequency ablation, energy was applied for an average of 8.7 seconds, leading to a tissue temperature of 52°C, whereas cryothermy was applied for 45 seconds at a mean temperature of –146°C. Immediate and long-term complete conduction block was achieved in all animals. Histologic analysis confirmed transmural lesions with both energy sources.
In a short-term porcine model, Gaynor and colleagues [13] have also reported the creation of transmural lesions using a bipolar radiofrequency clamp device. In a canine model using an epicardial cryothermy clamp at a mean temperature of –58°C for 20 seconds, Milla and colleagues [14] achieved transmural PV lesions in 93%. In their study, however, the clamp was applied for a shorter time period at a higher temperature. We used a significantly lower temperature (–146°C) for 45 seconds, and transmural lesions were achieved in all animals with no adverse effects. Previous studies, however, are limited by lack of additional histologic and pacing information beyond 30 days. Data from the present study also demonstrate no progression or regression of transmural fibrosis 90 days after ablation. Thus both, cryothermy and radiofrequency clamp devices are effective in obtaining permanent transmural lesions and can be reliably used for long-term PV isolation.
Thrombogenicity
The creation of endocardial lesions can lead to endocardial disruption and subsequent thrombus formation in patients undergoing both percutaneous catheter-based [15, 16] or surgical ablation procedures, particularly with unipolar radiofrequency devices [10]. The overall clinical incidence of thromboembolic events after percutaneous radiofrequency ablation procedures has been estimated at 0.6%, with an increased risk of 1.8% to 2% for left-sided procedures [15]. Endocardial hyperthermic tissue necrosis caused by radiofrequency ablation may lead to the disruption of the endocardial layer, leading to platelet adhesion, activation, aggregation, fibrin generation, and subsequently thrombus formation. Endocardial cryothermy lesions have been associated with less thrombogenicity, probably due to preservation of the atrial endocardial integrity [17]. In a canine model of percutaneous endocardial ablation comparing cryothermy and radiofrequency, Khairy and colleagues [17] showed in histologic analysis that unipolar radiofrequency led to intralesional hemorrhage, whereas cryothermy created well-circumscribed discrete lesions. In their study, radiofrequency was associated with a more than fivefold increased risk of thrombus formation with larger thrombus volumes compared with cryothermy. In our series using an epicardial approach, we did not observe any thrombus formation, and our histologic analysis showed integrity of the endocardial layer independent of the energy source at the 30- or 90-day follow-up.
As seen in the present study, in a porcine model of epicardial radiofrequency PV isolation, Melby and colleagues [13] did not observe thrombus formation 30 days after the procedure. The absence of thrombus formation during epicardial PV isolation using clamp devices could be because the lesion proceeds from the epicardial to the endocardial layer with minimal endocardial disruption.
The present study provides additional important histologic information such as extent of the lesion and timing of the healing process with both energy sources. Khairy and colleagues [17] compared the effects on the target tissue after the percutaneous endocardial application of cryothermy and radiofrequency in a short-term animal model. Replacement by fibrous tissue was more confined with radiofrequency lesions compared with cryothermy, and they suggested that use of radiofrequency energy might be associated with a slower postablation healing. In the present study, however, no histologic difference in the degree and extent of the healing process and fibrosis was seen at 30 and 90 days. Thus "controlled" application of the jaws of the clamp around the PVs leads to a well-circumscribed tissue injury with subsequent fibrotic replacement.
Pulmonary Vein Stenosis
Stenosis of the PV is a known complication after percutaneous endocardial PV isolation and occurs in 1% to 10% of patients [18–20]. Echocardiography evaluation 48 hours after radiofrequency PV isolation showed an increase in peak Doppler flow in 33% of patients in at least one PV, suggesting some degree of early PV stenosis [19]. It has been shown that PV stenosis may develop beyond the early postprocedural phase [20, 21]. Arentz and colleagues [20] reported a rate of 28% patients with PV stenosis up to 2 years after the endocardial ablation procedure. Similar concerns have been raised after epicardial PV isolation. An animal study using MRI did not show any evidence of PV stenosis 30 days after epicardial PV isolation [14]. In the present study, PV diameter remained unchanged and was correlated with the weight of the animals at the 30- and 90-day follow-up. Thus, it is likely that epicardial isolation of PV using cryothermy or radiofrequency is not associated with stenosis.
Finally, PV isolation did not affect left atrial function at the 30- or 90-day follow-up as has been previously shown with even more extensive left atrial ablation procedure [14].
Strengths and Limitations
This animal study provides histologic and MRI data with respect to transmural lesions, thrombus formation, and PV stenosis after epicardial PV ablation comparing two energy sources. This animal model has certain limitations, however, and the findings cannot be directly applied to the clinical situation. There are significant differences between human anatomy and that of the porcine model. Humans have larger pulmonary PVs and more epicardial fat, making epicardial ablation potentially more difficult. Although findings of this study might be applicable to patients with paroxysmal AF with PV triggers, they might not be applicable to patients with longstanding persistent AF, particularly in patients with rheumatic heart disease and mitral valve regurgitation, who often present with thickened atria. It is further likely that PV stenosis might develop beyond 90 days after ablation.
Conclusion
Pulmonary vein isolation using cryothermy or bipolar radiofrequency clamps is a reliable, safe, and simple procedure. The beating heart PV isolation procedure can be performed in a very short period of time. Durable transmural lesions with complete electrical conduction block at the level of PV can be created with both energy sources. The creation of fibrotic scar lines does not lead to endocardial disruption, thrombus formation, or PV stenosis up to 3 months after the procedure, regardless of the energy source. Left atrial function is not affected. If this procedure is associated with a high success rate in clinical practice, the development of minimal invasive approaches might extent the indication of this procedure to the surgical treatment of patients with lone AF in whom catheter ablation has failed.
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