Feasibility study on stereotactic radiotherapy for total pulmonary vein isolation in a canine model.

We tested the feasibility of pulmonary vein (PV) and left atrial (LA) posterior wall isolation using non-invasive stereotactic ablative body radiotherapy (SABR) and investigated pathological changes in irradiated lesions in a canine model. Seven male Mongrel dogs received single-fraction 33 Gy SABR. We designed the en-bloc circular target of total PVs and LA posterior wall to avoid the esophagus. The circular box lesion included the LA roof and ridge, low posterior wall, and posterior interatrial septum. At 6 weeks or 4 months post-SABR, electrical isolation of the SABR lesion was confirmed using LA posterior wall pacing, and histopathological review was performed. Electrical isolation of all PVs and the LA posterior wall was achieved in three of five dogs in the 4-month group. There was one target failure and one sudden death at 15 weeks. Although two dogs in the 6-week group failed to achieve electrical lesion isolation, the irradiated atrial myocardium showed diffuse hemorrhage with inflammatory cell infiltration. In successfully isolated 4-month model dogs, we observed transmural fibrotic scarring with extensive fibrosis on irradiated atrial tissue. The findings suggest that this novel circular box-design radiotherapy technique using SABR could be applied to humans after further studies are conducted to confirm safety.

Safety and efficacy of stereotactic radioablation targeting pulmonary vein tissues in an experimental model.

BACKGROUND: Stereotactic radioablation (SR), a commonly used therapy to treat malignant tumors, has been used to treat refractory ventricular tachycardia, but the feasibility of treating atrial fibrillation with SR is unknown. OBJECTIVE: We evaluated the safety and efficacy of SR targeting pulmonary vein (PV) antral tissues as a potential therapy for atrial fibrillation. METHODS: Seventeen adult canines and 2 adult swine underwent surgical fiducial marker placement, 3-dimensional anatomic rendering computed tomography angiogram of the left atrium, and creation of a treatment plan targeting the right superior PVs. Four treatment doses (15, 20, 25, and 35 Gy) were administered to 4 cohorts. Subjects were monitored for 3-6 months, followed by electrophysiological testing, gross pathological examination, and histopathology in 2 subjects. RESULTS: All subjects received SR treatment without complication. Electrophysiology study and gross pathological analysis demonstrated treatment effect in all treated PVs at 35 Gy and 25 Gy (n = 11 of 11 [100%]), with a partial effect at 20 Gy (n = 4 of 5 [80%]; 1 did not undergo repeat electrophysiology study) and 15 Gy (n = 1 of 2 [50%]). No evidence of collateral injury was found in tissues directly adjacent to the treated PVs. In 2 subjects, detailed histopathology demonstrated evidence of circumferential, transmural scar at the PV ablation sites, with sparing of the surrounding structures. CONCLUSIONS: SR is safe and effective for creating precise circumferential scar and electrical isolation of the right superior PV in an experimental model, with dose dependence between delivered radioablative energy and observed electrical effects.

Pulmonary veins stenosis relief after an inappropriate radiofrequency catheter ablation of atrial fibrillation in a young non-competitive athlete.

One of the major complications of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) is pulmonary vein stenosis (PVS). The natural history of PVS, especially when it involves more than one vein, leads to severe and irreversible pulmonary hypertension with end-stage right heart failure that can require, in extreme cases, even heart-lung transplantation. We report the case of a young patient who underwent RFCA for a single lasting episode of AF and developed PVS years later. He was treated with ballon venoplasty followed by stent implantation in left pulmonary vein because of PVS relief. This reported case emphasizes the need of an adequate indication for RFCA for AF, considering the benefit-risk ratio especially in young patients with normal cardiac function.

Remote Magnetic versus Manual Navigation for Radiofrequency Ablation of Paroxysmal Atrial Fibrillation: Long-Term, Controlled Data in a Large Cohort.

Purpose. We aimed to study long-term outcome after pulmonary vein isolation (PVI) guided by remote magnetic navigation (RMN) and provided comparative data to outcome after manual navigation (MAN). Methods. Three hundred thirty-six patients with symptomatic paroxysmal AF underwent PVI by irrigated point-by-point radiofrequency (RF) ablation (RMN, n = 114 versus MAN, n = 222). Patients were followed up with symptom guided rhythm monitoring for a period up to 43 months. The end point of the study was freedom from repeat ablation after a single procedure and without antiarrhythmic drug treatment (ADT). Results. At the end of follow-up (median 26.3 months), freedom from repeat ablation was comparable between RMN and MAN (70.9% versus 69.5%, p = 0.61). At repeat, mean number of reconnected veins was 2.4 ± 1.2 in RMN versus 2.6 ± 1.0 in MAN (p = 0.08). The majority of repeat procedures occurred during the first year (82.1% in RMN versus 78.5% in MAN; p = 0.74). Conclusion. On the long term (up to 3 years) and in a large cohort of patients with paroxysmal AF, RMN-guided PVI is as effective as MAN guided PVI. In both strategies the majority of repeat procedures occurred during the first year after index procedure.

Dose-escalation study for cardiac radiosurgery in a porcine model.

PURPOSE: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. METHODS AND MATERIALS: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm(3)). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. RESULTS: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. CONCLUSIONS: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

Histopathological effects and evolution of transvenous ß-radiation applications in right and left atria: an animal study.

AIMS: ß-radiation is a novel potential energy source for the creation of myocardial lesions. While the feasibility of delivering ß-radiation via a deflectable transvenous catheter has been described, dose effects and the time course of histopathological changes have not been previously assessed. The purpose of this study was to characterize pathological aspects of cardiac lesions induced by ß-radiation in an animal model at various stages of evolution and in response to different dose exposures. METHODS AND RESULTS: Nine dogs and one pig were studied. The cavotricuspid isthmus, antrum of pulmonary veins (PVs), and mitral isthmus were irradiated (25, 50, 75, or 100 Gy) with strontium-yttrium-90, delivered via a deflectable catheter (cavotricuspid isthmus and mitral isthmus) or a double-loop catheter (antrum of PVs). Eighteen lesions were created. Animals were sacrificed at 2 weeks, 1 month, 3 months, or 6 months. Lesions were processed for morphometric histopathological analyses. Over the first month, lesions were characterized by inflammation, haemorrhage, and myocyte necrosis. Thereafter, fibrotic replacement was predominant. Transmurality of lesions was observed in 50% of cases, with no dose-response effect (P = 0.976). Surface fibrin thrombus was present in 50% of cases and was essentially limited to lesions assessed within the first month. No neighbouring injury or pulmonary venous stenosis was observed. CONCLUSIONS: Atrial lesions created by ß-radiation are characterized by an inflammatory phase with surface fibrin thrombosis during the first month and replacement fibrosis thereafter. No appreciable dose-response effect was noted within the 25-100 Gy range tested.

Vascular injury after whole thoracic x-ray irradiation in the rat.

PURPOSE: To study vascular injury after whole thoracic irradiation with single sublethal doses of X-rays in the rat and to develop markers that might predict the severity of injury. METHODS AND MATERIALS: Rats that received 5- or 10-Gy thorax-only irradiation and age-matched controls were studied at 3 days, 2 weeks, and 1, 2, 5, and 12 months. Several pulmonary vascular parameters were evaluated, including hemodynamics, vessel density, total lung angiotensin-converting enzyme activity, and right ventricular hypertrophy. RESULTS: By 1 month, the rats in the 10-Gy group had pulmonary vascular dropout, right ventricular hypertrophy, increased pulmonary vascular resistance, increased dry lung weights, and decreases in total lung angiotensin-converting enzyme activity, as well as pulmonary artery distensibility. In contrast, irradiation with 5 Gy resulted in only a modest increase in right ventricular weight and a reduction in lung angiotensin-converting enzyme activity. CONCLUSION: In a previous investigation using the same model, we observed that recovery from radiation-induced attenuation of pulmonary vascular reactivity occurred. In the present study, we report that deterioration results in several vascular parameters for

Pathological effects of pulmonary vein beta-radiation in a swine model.

INTRODUCTION: Atrial fibrillation (AF) may be triggered by ectopic beats originating in sleeves of atrial myocardium entering the pulmonary veins (PVs). PV isolation by means of circumferential ostial or atrial radiofrequency ablation is an effective but also a difficult and long procedure, requiring extensive applications that can have serious potential complications. Our objective was to examine pathological effects of PV beta-radiation, particularly the ability to destroy PV myocardial sleeves without inducing PV stenosis and other unwanted effects, in order to establish its potential feasibility for the treatment of AF. METHODS AND RESULTS: Ten minipigs were studied. A phosphorus-32 source wire centered within a 2.5-mm diameter balloon catheter (Galileo III Intravascular Radiotherapy System, Guidant, Santa Clara, CA, USA) was used to deliver beta-radiation to the superior wall of the right PV trunk. Pathological analysis was performed either immediately after ablation (2 pigs) or 81 +/- 27 days later (8 pigs). Acute effects of PV beta-radiation consisted of endothelial denudation covered by white thrombus, elastic lamina disruption, and PV sleeve necrosis. Late effects consisted of mild focal neointimal hyperplasia that reduced the PV luminal area by only 1.3 +/- 1.8%, elastic lamina thickening, and PV sleeve fibrosis. Four of these 8 PVs were completely re-endothelized. Lesions were transmural in 6 of 10 radiated PVs and segmental, involving 28 +/- 7% of the right PV perimeter. CONCLUSION: Intravascular beta-radiation can induce transmural necrosis and fibrosis of PV myocardial sleeves without PV stenosis and other unwanted effects, which supports a potential usefulness of this energy source in the treatment of AF.

Pathological effects of extensive radiofrequency energy applications in the pulmonary veins in dogs.

INTRODUCTION: The long-term complications of catheter ablation within the pulmonary veins are unknown. The development of pulmonary vein stenosis has recently been described after catheter ablation to treat either chronic or paroxysmal atrial fibrillation. The purpose of this study was to examine the pathological and hemodynamic effects of radiofrequency (RF) energy application within the pulmonary veins. METHODS AND RESULTS: Right heart and transseptal catheterization were performed in 9 anesthetized mongrel dogs. The pulmonary vein ostia were cannulated and pulmonary venous pressure was measured before RF energy application in up to 4 separate pulmonary veins. Animals were euthanized at intervals of 2 to 4 weeks (n=3), 6 to 8 weeks (n=3), or 10 to 14 weeks (n=3) after ablation. Repeat catheterization before euthanasia demonstrated statistically significant differences in pulmonary capillary wedge pressure, cardiac output, pulmonary vascular resistance, and systemic vascular resistance (P<0.05) compared with the baseline. Luminal narrowing was observed in 22 of 33 pulmonary veins to which RF energy was applied. Of these, 7 were totally occluded, 7 had severe stenosis, and 8 were only minimally narrowed. Histological examination revealed intimal proliferation with organizing thrombus, necrotic myocardium in various stages of collagen replacement, endovascular contraction, and a proliferation of elastic lamina. CONCLUSIONS: Applications of RF current within the pulmonary veins may result in pulmonary vein narrowing or complete occlusion. These observations should be considered in treatment of arrhythmias originating within the pulmonary veins.

Vascular changes in irradiated lungs: a morphometric study.

The lungs from eight patients who had received thoracic irradiation for the treatment of malignant disease have been studied and a morphometric analysis of the vascular changes present has been made. We found a marked difference between the changes we observed in the pulmonary vessels and those described in systemic vessels after exposure to irradiation. In the former the changes are more pronounced in the venous circulation, and in the latter they are described as being almost confined to the arteries. This difference is a reflection of the difference in oxygen saturation of the blood in the two types of vessels. We suggest that this difference can be explained by the possible role of super-oxide free radicals in the generation of these effects.

The pulmonary vascular pathology of experimental radiation pneumonitis.

Dogs exposed by inhalation to an aerosol of fused aluminosilicate particles containing the radionuclide yttrium 90 developed radiation pneumonitis. The aerosol had a mean aerodynamic diameter of 0.8 to 1.2 mu with a sigma(g) of 1.6 to 1.9. The 36 dogs included in this report received initial lung burdens of 590 to 5200 muCi (90)Y/kg body weight and died at 7.5 to 237 days after exposure with total cumulative radiation doses to lung of 9300 to 70,000 rads. Vascular lesions in the lungs were marked. Early changes included edema of vessel walls with leukocytic infiltration, dilation of perivascular lymphatic channels, and occasional periarterial lymphangiectasia. Splitting and reduplication of the elastica were occasionally visible. The most striking inflammatory vascular changes were vasculitis and fibrinoid necrosis, which involved bronchial and pulmonary vessels at some-what different times. Such lesions were often segmental and included fibrinoid necrosis and a variable leukocytic infiltrate in and around the actively involved lesions. Vasculitis was most commonly seen in small muscular arterioles, but veins and venules also occasionally exhibited similar inflammatory lesions. Progressive vascular inflammation led to extensive intimal proliferative lesions and fibromuscular hypertrophy with eventual fibrous accumulation around blood vessels, obliterative intimal and medial thickening, and luminal narrowing. Such changes eventually formed the morphologic basis for increased pulmonary vascular resistance and the development of cardiac dilation and hypertrophy reflecting pulmonary hypertension.