β-Radiation for the Creation of Linear Lesions in the Canine Atrium
Background— Creating linear lesions is important for the treatment of arrhythmias such as atrial flutter and fibrillation. Making these lesions with standard radiofrequency catheters can be difficult and may result in charring and thrombosis. The purpose of this study was to evaluate β-radiation as a novel energy source for creating linear myocardial lesions.
Methods and Results— Eight dogs with intact conduction across the cavotricuspid isthmus were studied. The isthmus was irradiated (25 to 50 Gy) with strontium/yttrium-90 delivered via a deflectable 7F catheter (Novoste Corporation). There were no immediate effects, but bidirectional conduction block developed during follow-up studies in 7 of 8 dogs. The dog without conduction block received 25 Gy. After the animals were euthanized, histology revealed transmural, linear areas of fibrosis without any thrombus.
Conclusions— β-Radiation can safely and effectively create linear lesions that are contiguous and nonthrombogenic. This energy source may become an interesting adjunct to radiofrequency for the treatment of atrial flutter and fibrillation.
Received April 5, 2004; revision received June 18, 2004; accepted June 28, 2004.
Creating effective linear myocardial lesions is of increasing importance in the ablative treatment of cardiac arrhythmias. Although the cavotricuspid lesion for typical atrial flutter is the most common example of this, other macroreentrant arrhythmias, such as atypical or left-sided atrial flutter, congenital arrhythmias, and some types of ventricular tachycardia, also need strategically placed linear lesions for a curative ablation. Importantly, recent studies have likewise shown the usefulness of left atrial linear lesions in the treatment of atrial fibrillation.1,2
Standard radiofrequency ablation catheters create linear lesions by the “drag technique,” which can be challenging in such areas as the left atrium, in which the anatomy may force an ablation element away from tissue.3 Such incomplete lesions may be ineffective or may even provide a substrate for subsequent macroreentry.4 Placing long, linear lesions can therefore require multiple radiofrequency applications, rendering the process time consuming. Such prolonged procedure times and multiple linear lesions can lead to charring and thrombus formation.5 This is of particular concern in the left atrium, in which initial attempts at performing a percutaneous maze procedure resulted in pulmonary vein stenosis and pulmonary hypertension.6
Radiation heart disease is well described in patients who have undergone external beam radiation for mediastinal tumors. Although the most common clinical manifestation is pericarditis, myocardial fibrosis is also recognized.7 Such fibrosis can be associated with conduction disturbances ranging from bundle-branch block to complete AV block.8 β-Radiation is now used extensively in coronary arteries to treat in-stent restenosis.9 When strategically deployed, its safety has been documented, and a catheter-based method for delivering this energy source to the heart already exists.
The purpose of the present study was to evaluate whether β-radiation could be used in a canine model to create linear lesions with minimal catheter manipulation and little endothelial damage. In addition to providing proof of concept, we also attempted to determine the dose requirements and time course of β-radiation effects. We chose to target cavotricuspid conduction because this can be easily assessed by use of standard pacing maneuvers.
Eight healthy mongrel dogs were induced with pentothal 25 mg/kg, intubated, and maintained on a respirator with halothane. Through 2 femoral venous punctures, 7F sheaths were introduced. A 20-pole recording catheter (Halo, Cordis Webster) was placed around the tricuspid annulus. Cavotricuspid isthmus conduction was assessed at baseline by stimulation lateral and septal to this isthmus. Stimulation was performed at twice threshold with a deflectable quadripolar catheter (Cordis Webster). The direction of conduction was assessed by observing the atrial activation sequence recorded from a 20-pole catheter. After this assessment, the quadripolar deflectable catheter was replaced with the β-radiation catheter.
β-Radiation Catheter Design
The β-radiation delivery system developed by Novoste is similar to that used in the coronary arteries,10 consisting of a hydraulic delivery system, source train, and catheter. The hydraulic delivery system houses the source train (strontium/yttrium [Sr/Y]-90) and deploys it to the distal catheter. The Beta-Cath Delivery Catheter used was specifically tailored for this experiment and was a 7F, deflectable catheter with 2 radiopaque markers identifying the distal and proximal limits of the radiation source train (40 mm in length). The dose prescribed at a point 2 mm from the center of the source axis was 25 or 50 Gy.
The distal marker of the Beta-Cath ablation catheter was first placed in the right ventricle past the tricuspid valve (TV), with the catheter deflected across the valve to ensure apposition against the isthmus. The radiation source train was advanced into position by use of the hydraulic transfer device, with the distal marker indicating the position of the distal end of the 40-mm source train. A first irradiation was performed in this position. The catheter was then withdrawn until the proximal marker was in the inferior vena cava (IVC) while the same catheter apposition against the isthmus was maintained. With the catheter in this more proximal isthmus position, the radiation source train was once again advanced to the catheter tip, with the proximal marker indicating that the proximal end of the source train was in the IVC. Irradiation in this second position was performed. The train was kept in each position for 8 minutes, resulting in a delivered dose of 50 Gy. In the last 2 animals, 25 Gy was delivered over a period of 4 minutes. The catheter was not displaced during these applications. Because the source train was relatively short, this maneuver was performed to ensure complete irradiation of the cavotricuspid isthmus. After each irradiation, the source train was drawn back into the transfer device. The Beta-Cath ablation catheter was removed, and the quadripolar catheter was reinserted for repeat testing of isthmus conduction.
After ablation, the dogs were housed in a kennel for study at a later date to evaluate the late effects of irradiation. Repeat electrophysiological testing was performed at different times after irradiation. The first 2 animals were restudied 4 weeks after ablation; animals 3 and 4 were restudied at 2 weeks, 4 weeks, and 3 months after ablation; and animals 5 to 8 were restudied at 1, 2, and 4 weeks and 3 months after ablation. All animals were euthanized immediately after the last electrophysiological study. All animals were cared for in accordance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences.
After euthanization, hearts and lungs were resected, then fixed in formaldehyde. After 1 to 2 weeks, the pericardial space was dissected. Gross examination of the cavotricuspid isthmus was performed to observe endocardial surface changes. Cross sections of the isthmus were made from the TV to the IVC and stained with Gomori’s trichrome and hematoxylin-phloxine-saffron stains.
All 8 dogs showed intact bidirectional conduction across the cavotricuspid isthmus during baseline electrophysiological studies (Figure 1, A and B). The pacing maneuvers were repeated immediately after irradiation, and no acute conduction block was demonstrated (Table).
Late Effects of β-Radiation on Conduction
During follow-up electrophysiological studies, 7 of 8 dogs developed complete, bidirectional isthmus block (Figure 1, C and D). When present, this was demonstrated at the first repeat electrophysiological study after β-irradiation. The earliest recorded evidence of block was 1 week after radiation in 3 dogs (Table). Thus, bidirectional conduction block was demonstrated in 2 of 2 dogs that were initially reevaluated 4 weeks after radiation, 2 of 2 dogs that were reevaluated 2 weeks after radiation, and 3 of 4 that had a repeat study at the 1-week point.
Postradiation isthmus block was persistent, as evidenced by an electrophysiological study performed immediately before euthanization (1 to 3 months). The sole dog without isthmus block received 25 Gy of β-radiation and never developed any change in isthmus conduction despite a 3-month follow-up.
Histological Examination of β-Radiation Effects on the Canine Atrium
After euthanization, the lung surfaces and pericardium were examined for lesions, and none were present. On gross examination of the right atria, contiguous, slightly elevated linear lesions extending from the IVC to the TV were noted. These lesions were distinguished only by a paler coloration compared with adjacent tissue, and there was no macroscopic evidence of thrombus or charring. Similar pale discolorations were noted across the TV leaflets.
Microscopic analysis revealed well-circumscribed lesions confined to the isthmus in 7 of 8 hearts. These lesions did not show any endothelial disruption, only thickening (Figure 2). The underlying myocardium showed transmural disruption of cellular architecture, with cells showing evidence of myolysis and vacuolization as seen with both Gomori’s trichrome and hematoxylin-phloxine-saffron staining. Gomori’s trichrome staining highlighted areas of marked fibrosis (green staining). The lesions were well demarcated from adjacent, normal myocardium and formed contiguous lesions from the IVC to the TV. In the 2 dogs euthanized at 1 month, the histological appearance was more exudative and fibrinous, whereas by 3 months, complete fibrotic scar formation had taken place.
In the animal without any electrophysiological evidence of conduction block, no gross or microscopic abnormalities were found in the cavotricuspid isthmus.
This study constitutes the first demonstration that strategically delivered β-radiation can alter conduction properties in the canine myocardium. These animal data showed electrophysiological, gross pathological, and histological evidence of the effects of β-radiation. In all but 1 dog, complete bidirectional isthmus block was demonstrated by use of standard pacing techniques. The actual isthmus lesions were initially difficult to locate on gross pathology. As opposed to radiofrequency lesions, in which endothelial damage and charring can be seen, the only lesion visible on gross pathology was slightly raised, whitish discolorations from the IVC to the TV. This reflects the fact that fibrotic replacement is the chief mechanism of injury with β-radiation, as confirmed by the histological findings. None of these changes were present in the sole dog without conduction block, suggesting that the catheter delivering only 25 Gy was not in close enough proximity to effect these changes or cause tissue damage.
β-Radiation presents certain advantages compared with other energy sources used for ablation. The present study suggests its effectiveness in creating linear lesions with a single application without requiring any catheter displacement. Furthermore, the length of the lesion can be proportional to the length of the radiation source train and therefore is adjustable. Devising catheters to produce this kind of long, contiguous, linear lesion with single radiofrequency applications has been difficult, because contact is crucial to creating a thermal lesion. Because of the previously described mechanism of injury, an ablation catheter using β-radiation does not require direct contact with cardiac tissue to create a lesion. As in the coronary arteries, the distance from the center of the source train to the target tissue is one of the more important determinants of the radiation dose absorbed by said tissue. In this sense, proximity to the target tissue may be more relevant than actual tissue contact, thus distinguishing this from other forms of ablative energy.
The radioactive source train used in the study is identical to the source train used in the commercially available Beta-Cath 5F System. The source train is composed of multiple individual sealed sources containing radioactive 90Sr and its radioactive progeny, 90Y. 90Sr and 90Y both undergo radioactive decay by the emission of a β-particle. The amount of energy transferred from a β-particle to a medium (ie, the absorbed dose) is dependent on the initial incident energy of the β-particle and the density/thickness of the medium. Each source train used in the study was calibrated traceable to the National Institute of Standards and Technology to provide the user with absorbed dose rate to water at 2 mm from the centerline of the source train (as per the Beta-Cath System User’s Manual). Monte Carlo computer models that consider source train construction have shown general agreement with measured data, although some discrepancies may exist for points at a distance of <1 mm, potentially within the catheter.11 By use of a straight-line β-radiation source train with a prescribed dose of 18.4 Gy at a point 2 mm from the center of the source axis, dose distribution at depths of 1, 2, 3, 4, and 5 mm have been measured at 39.9, 18.4, 9.3, 4.7, and 2.2 Gy, respectively.12 At least 1 published study, however, suggests a more marked decrease of 75±28% per millimeter in coronary artery segments.13 Nonetheless, this suggests that high dose rates can be delivered at the catheter surface to accommodate variations in isthmus anatomy, whereas doses absorbed by tissues at a distance remain low.
One of the potential limitations of β-radiation as an energy source, however, is that there can be variations in the dose that is delivered to various segments of the isthmus. The use of a deflecting wire to obtain a curvilinear treatment geometry in the study can potentially cause dose perturbations comparable to those in the coronary brachytherapy literature regarding the effects of curvature, guidewire, and stent-strut shielding dose delivery.14,15 Thus, these studies highlight some of the difficulties encountered in vascular brachytherapy. Dose calculations are often performed in idealized situations and with vessel geometries that may not always accurately reflect the clinical situation. Furthermore, there are known variations in dosage delivery along the length of the source train, with the distal edges of the treated area sometimes receiving a lower delivered dose of β-radiation. Despite these limitations, however, it is important to note that in the present canine experiments, electrophysiologically effective and histologically evident lesions were obtained in all but 1 case.
Unlike radiofrequency, β-radiation creates its lesions by gradual fibrotic replacement of the underlying myocardial cells (Figure 2C). This accounts for the lack of endothelial disruption and thrombus on the ablated surface. This characteristic is also responsible for the primary disadvantage of this form of energy: there are no immediate electrophysiological effects. The earliest documented changes in conduction occurred 1 week after radiation. Use of this energy form then requires precise positioning of the ablation catheter, because lesions cannot be verified acutely.
Thus, β-radiation can affect conduction and appears to be particularly adept at creating contiguous linear lesions. This may prove to be useful in ablating certain difficult arrhythmogenic substrates, such as atypical atrial flutter or atrial fibrillation, particularly in light of the fact that this energy source is nonthrombogenic and does not require direct contact between the radiation catheter and the myocardial tissue. We conclude that β-radiation holds promise as an alternate energy source for ablation and merits further study.
Dr Bonan is the Medical Director of Novoste Corp. Dr Guerra is a consultant for Novoste.
The authors wish to thank Craig Reed for his expert technical assistance during the preparation of this manuscript.
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