Multiple Ulcerations in Plaque Behind Stent Struts Resulting in Late Stent Malapposition After Gamma Brachytherapy for In-Stent

Intracoronary stents reduce restenosis compared with conventional balloon angioplasty.1,2 However, in-stent restenosis remains an important clinical problem.3,4 Recently, randomized trials have demonstrated that intracoronary vascular brachytherapy (VBT) reduces recurrence after the treatment of in-stent restenosis.5–7 On the other hand, undesired effects of VBT such as late thrombosis and edge effect are also reported.6–8 Late stent malapposition is one of undesired effects of VBT. This case report describes multiple late stent malappositions after gamma VBT. Case Report. A 57-year-old male with previous stent placement in the mid- and distal right coronary artery (RCA) was admitted due to exertional angina in November 2000. Coronary angiogram revealed a total occlusion at the previously stented segment in the mid-RCA (Figure 1A). There were no significant stenosis in the left anterior descending artery and the left circumflex artery. After written informed consent had been obtained, the patient was enrolled in a randomized trial to compare two doses of gamma VBT (14 Gy vs. 17 Gy) for the treatment of in-stent restenosis (SCRIPPS IV). The occlusion was successfully crossed with a Choice PT guidewire (Boston Scientific, Maple Grove, Minnesota) and dilated with a 3.0 mm Ranger balloon catheter (Boston Scientific) inflated at 12 ATM. After successful dilation, a noncentered, 3.7 French CHECKMATE radiation catheter (Cordis, Miami Lakes, Florida) was inserted and a ribbon with 22 radioactive 192Ir seeds (Best Industries, Springfield, Virginia) was delivered and positioned to cover the treated site (Figure 1B). The precise prescribed radiation dose was unknown (either 14 or 17 Gy to a 2 mm radial distance), because this blinded study is still ongoing. The final angiogram demonstrated a good result (Figure 1C). Intravascular ultrasound (IVUS) was not used in the procedure. After the procedure, the patient was given oral aspirin (325 mg/day) and clopidogrel (75 mg/day) for 6 months. In May 2001, the patient underwent angiography because of recurrent angina. It demonstrated the recurrence of in-stent restenosis of 70% severity in the mid-RCA with luminal irregularity (Figure 1D). A 0.014´´ Balance Middle Weight guidewire (Guidant, Temecula, California) was placed across the lesion into the distal RCA. IVUS imaging was performed in the mid-RCA using a 40-MHz Atlantis IVUS catheter (Boston Scientific). IVUS image revealed a significant stenosis (minimal lumen cross-sectional area [3.8 mm2]). It also revealed multiple ulcerations in plaque behind stent struts, resulting in multiple stent malapposition (Figure 2A, B). Balloon angioplasty using a 3.0-mm Quantum balloon catheter (Boston Scientific) inflated at 18 atm was performed. The final angiogram demonstrated a good result without the luminal irregularity (Figure 1E). The final IVUS imaging showed a good lumen without stent malapposition (Figure 2C). Discussion.? Randomized trials have demonstrated the efficacy of VBT in the treatment of in-stent restenosis.5–7 On the other hand, undesired effects of VBT such as edge effect and late thrombosis have also reported.6–8 Late stent malapposition is an undesired effect, although it is not frequently observed. Kozuma et al. demonstrated late stent malapposition after 32P beta VBT following stenting in a de novo lesion.9 It also showed an enlargement of external elastic membrane volume and plaque volume, and no significant change in stent volume at follow-up. Thus the main mechanism of late stent malapposition after VBT following stenting in the de novo lesion might be vessel enlargement. Morino et al. reported late stent malapposition after VBT for in-stent restenosis as well as de novo lesions, although the majority of cases were seen after stenting in de novo lesions.10 It was also reported that late stent malapposition was observed for all radiation sources (32P, 90Sr/Y, and 192Ir).10 The relationship between late stent malapposition and long-term clinical outcome is unknown. Exposed non-endothelialized stent struts may be associated with a thromboembolic event. There are 3 potential mechanisms of late malapposition after implantation of tubular slotted stents: 1) malapposition that is not recognized at the time of implantation and only detected at follow-up; 2) an increase in external elastic membrane that either occurs in the absence of an increase in plaque or that is greater than the increase in plaque; and 3) a decrease in plaque with or without any change in external elastic membrane.11 In the present case, IVUS was not performed at the time of VBT. Thus possibility of the presence of stent malapposition at that time of VBT cannot be excluded completely. However, the previously stented segment was totally occluded and balloon inflations were performed for in-stent restenosis; the presence of stent malappositions before VBT might be less possible. Late stent malapposition in the absence of brachytherapy has been reported.11,12 Those reports concluded that the mechanism of late stent malapposition was an increase in external elastic membrane that was greater than the increase in plaque plus media, i.e., positive remodeling. On the other hand, in the present case, multiple ulcerations in plaque, i.e., a decrease in plaque, behind stent struts was the mechanism of stent malapposition. Radiation therapy has been used for not only malignant diseases, but also benign, but problematic hyperplastic conditions including keloids,13 heterotopic bone formation,14 and recurrent pterygium.15 In vitro studies have shown that radiation can inhibit serum-stimulated growth of arterial smooth muscle cells and fibroblasts, and decrease collagen synthesis by fibroblasts.16 However, radiotherapy is originally designed to kill relatively fast growing cells.17 Thus, chromosomal damage, resulting in mitotic cell death and apoptosis in smooth muscle cells, fibroblasts, and endothelial cells may occur after VBT.18 In this case, it is conceivable that cell death and apoptosis after VBT resulted in multiple ulcerations in plaque behind stent struts. Condado et al. performed the first clinical feasibility trial on gamma VBT in 22 lesions of 21 patients.19 The prescribed dose was 20–25 Gy at a distance of 1.5 mm from the center of the source. However, based on the luminal diameters determined by the core laboratory, the actual calculated doses ranged between 19 and 55 Gy at the luminal surface. The 3-year follow-up angiogram demonstrated 4 aneurysms. Coronary aneurysms at follow-up were explained by higher prescribed dose. In the present case, prescribed dose (14 or 17 Gy) for VBT has not been unveiled, because the study is still ongoing. The relationship between prescribed dose and biological response varies with the individual probably because of differences in general medical characteristics of the patient, details of the coronary artery disease, and baro-trauma due to coronary intervention.20 Thus we cannot assume whether this patient was included into either 14 or 17 Gy group. Previous gamma VBT studies used a fixed dose prescription (e.g., 15 Gy at 2 mm from the center of the source)7 or a calculated and variable dose prescription (minimum of 8 Gy as long as the maximum dose is limited to 30 Gy) using IVUS.5,6 IVUS-based dosimetry may be useful to avoid insufficient and excessive radiation exposure. This case showed multiple ulcer formation in plaque behind stent struts, resulting in late stent malappositions, after gamma VBT for in-stent restenosis. This presentation also demonstrates the advantage of IVUS imaging to diagnose the underlying mechanism of luminal irregularity of the coronary artery.

1. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331:496–501. 2. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331:489–495. 3. Eltchaninoff H, Koning R, Tron C, et al. Balloon angioplasty for the treatment of coronary in-stent restenosis: Immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998;32:980–984. 4. Bauters C, Banos JL, Van Belle E, et al. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998;97:318–321. 5. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697–1703. 6. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250–256. 7. Waksman R, White RL, Chan RC, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 8. Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026–1030. 9. Kozuma K, Costa MA, Sabate M, et al. Late stent malapposition occurring after intracoronary beta-irradiation detected by intravascular ultrasound. J Invas Cardiol 1999;10:651–655. 10. Morino Y, Bonneau HN, Fitzgerald PJ. Vascular brachytherapy: What have we learned from intravascular ultrasound? J Invas Cardiol 2001;13:409–416. 11. Shah VM, Mintz GS, Apple S, et al. Background incidence of late malapposition after bare-metal stent implantation. Circulation 2002;106:1753–1755. 12. Mintz GS, Weissman NJ, Pappas C, Waksman R. Positive remodeling, regression of in-stent neointimal hyperplasia, and late stent malapposition in the absence of brachytherapy. Circulation 2000;102:E111. 13. Doornbos JF, Stoffel TJ, Hass AC, et al. The role of kilovoltage irradiation in the treatment of keloids. Int J Rad Oncol Biol Phys 1990;18:833–839. 14. Lo TC, Healy WL, Covall DJ, et al. Heterotopic bone formation after hip surgery: Prevention with single-dose postoperative hip irradiation. Radiology 1988;168:851–854. 15. Paryani SB, Scott WP, Wells JWJ, et al. Management of pterygium with surgery and radiation therapy. The North Florida Pterygium Study Group. Int J Rad Oncol Biol Phys 1994;28:101–103. 16. Fischer-Dzoga K, Dimitrievich GS, Griem ML. Radiosensitivity of vascular tissue. II. Differential radiosensitivity of aortic cells in vitro. Rad Res 1984;99:536–546. 17. Prasad KN. Radiation response of human tumors. In: Prasad KN (ed). Handbook of Radiobiology. Boca Raton, Florida: CRC Press, 1995: pp. 305–515. 18. Hall EJ, Miller RC, Brenner DJ. The basic radiobiology of intravascular irradiation. In: Waksman R (ed). Vascular Brachytherapy. Armonk, New York: Futura Publishing Co., Inc., 1999: pp. 63–72. 19. Condado JA, Waksman R, Gurdiel O, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997;96:727–732. 20. Maehara A, Patel NS, Harrison LB, et al. Dose heterogeneity may not affect the neointimal proliferation after gamma radiation for in-stent restenosis: A volumetric intravascular ultrasound dosimetric study. J Am Coll Cardiol 2002;39:1937–1942.