Acute vasculitis after endovascular brachytherapy

Abstract

$\text{Purpose:}$ Angioplasty effectively relieves coronary artery stenosis but is often followed by restenosis. Endovascular radiation (β or γ) at the time of angioplasty prevents restenosis in a large proportion of vessels in swine (short term) and humans (short and long term). Little information is available about the effects of this radiation exposure beyond the wall of the coronary arteries.

$\text{Methods and Materials:}$ Samples were obtained from 76 minipigs in the course of several experiments designed to evaluate endovascular brachytherapy: 76 of 114 coronary arteries and 6 of 12 iliac arteries were exposed to endovascular radiation from ³²P sources (35 Gy at 0.5 mm from the intima). Two-thirds of the vessels had angioplasty or stenting. The vessels were systematically examined either at 28 days or at 6 months after radiation.

$\text{Results:}$ We found an unexpected lesion: acute necrotizing vasculitis in arterioles located ≤2.05 mm from the target artery. It was characterized by fibrinoid necrosis of the wall, often associated with lymphocytic exudates or thrombosis. Based on the review of perpendicular sections of tissue samples, the arterioles had received between 6 and 40 Gy. This arteriolar vasculitis occurred at 28 days in samples from 51% of irradiated coronary arteries and 100% of irradiated iliac arteries. By 6 months, the incidence of acute vasculitis decreased to 24% around the coronary arteries. However, at that time, healing vasculitis was evident, often with luminal narrowing, in 46% of samples. Vasculitis was not seen in any of 44 samples from unirradiated vessels (0%) and had no relation to angioplasty, stenting, or their sequelae. This radiation-associated vasculitis in the swine resembles the localized lymphocytic vasculitis that we have reported in tissues of humans exposed to external radiation. On the other hand, it is quite different from the various types of systemic vasculitis that occur in nonirradiated humans.

$\text{Conclusion:}$ Endoarterial brachytherapy using ³²P results in vascular effects beyond the adventitia of the target vessel. This necrotizing vasculitis is causally related to radiation, but its mechanism is unclear and a dose effect is not evident. Quite possibly, local upregulation of inflammatory cytokines contributes to this radiation-associated vasculitis, which only involved some of the arterioles in each sample. It is likely that radiation-associated vasculitis also occurs around human coronary arteries and may result in foci of ischemia. To our knowledge, this lesion has not been previously recognized, either in experimental models or in human specimens examined after angioplasty/brachytherapy.

Introduction

Percutaneous transluminal coronary artery balloon angioplasty (PTCA) is a rapid and effective method to relieve myocardial ischemia caused by coronary atherosclerosis. However successful initially, PTCA (with or without stent deployment) is followed by restenosis of the treated arteries in a high proportion of cases (30–40%) 1, 2, 3.

Various strategies have been devised to prevent or treat the restenosis, including pharmacologic interventions (e.g., inhibitors of glycoprotein IIb/IIIa) (4), several models of stents placed at the time of PTCA, including some coated with sirolimus, an inhibitor of cell division (5), and so forth. One approach that has been the subject of extensive experimental studies and multiple clinical trials within the past decade is endovascular irradiation at the time of PTCA. This strategy is based on the observation that the restenosis results from the proliferation of stromal cells in the intima (constriction by neointimal growth), as well as cellular proliferation in the adventitia causing fibrosis and leading to constriction “by remodeling.” It is assumed that such cellular proliferation can be inhibited by ionizing radiation. The arteries have been exposed to either γ emitters (e.g., ¹⁹²Ir) or β emitters (e.g., ³²P) placed in catheters, and the doses have been determined by the activity of the isotope and the dwell time.

The experimental studies have shown that radiation does significantly lower the restenosis rate in swine (short term) and humans (up to several years from the early clinical studies). In one of the several β-radiation multicenter trials (Proliferation Reduction with Vascular Energy Trial), 105 patients were enrolled; the overall restenosis rate at 12 months was 22% in the radiation group and 50% in the controls (2). Recently, the stent restenosis rate was reduced in a controlled trial of 252 patients using γ radiation: 21% stenosis of the stented segment in irradiated vs. 50.5% in controls at 6 months (3). Late thrombosis has been detected in some studies. It occurred in 5.3% of the irradiated patients and only in 0.8% of the controls of the above mentioned gamma trial (3), although it was thought that it was related to the placement of new stents and the discontinuation of antiplatelet therapy. Thrombosis has also occurred in some swine by 3–6 months (6). Otherwise, most swine have not shown long-term adverse results; however, only a small number of animals have been observed for >30 days. As of December 2001, the Food and Drug Administration had licensed the use of various devices utilizing β (³²P, ⁹⁰Sr) or γ (¹⁹²Ir) emitters for endovascular therapy.

Little information is available about the effects of endovascular radiation on structures adjacent to the targeted coronary artery, perhaps because it has been assumed that the limited range of exposure should not affect such structures. We found one unexpected injury in small vessels near the irradiated coronary arteries of swine.