Case Report. A 76-year-old man visited our hospital because of worsening chest oppression on exercise. His coronary risk factors were hypertension, diabetes mellitus (diet alone), and a past history of smoking. He had undergone balloon angioplasty of his proximal and distal left circumflex coronary arteries (LCX) 16 and 14 years prior, respectively. He also underwent coronary artery stenting with a 3.0 x 24 mm AVE GFX (Medtronic, Minneapolis, Minnesota) for mid-left anterior descending coronary artery (LAD) stenosis 11 years earlier. A follow-up coronary angiography at the same hospital 14 months after stent deployment showed 50% stenosis at the stented segment without in-stent restenosis. The current study was performed 10 years from the last angiogram. Left ventriculography showed normal systolic function and coronary angiography revealed significant in-stent restenosis of 90% stenosis in the mid-LAD and 75% stenosis in the proximal right coronary artery. In the LCX, there was 75% stenosis.
We decided to perform percutaneous coronary intervention for a mid-LAD lesion that we believe was responsible for the effort angina pectoris (Figure 1). We used both intravascular ultrasound (IVUS) with a 2.7 French (Fr) IVUS catheter (Atlantis Pro 2; Boston, Scientific, Natick, Massachusetts) and optical coherence tomography (OCT) at baseline, after predilatation, after aspiration, and after stenting with a 0.016-inch OCT catheter (Image Wire, Light Lab Imaging, Westford, Massachusetts) and a 3 Fr occlusion balloon catheter (Helios, Goodman, Nagoya, Japan). PCI was performed using a transradial 6 Fr system.
Before predilatation, IVUS showed diffuse fibrous plaque from the middle segment of the stent to the distal segment of the stent. OCT showed homogeneous high intensity in the distal segment (Figure 2A) and high intensity accompanied by attenuation in the proximal segment (Figure 2B). IVUS findings corresponding to the OCT images did not show a clear difference between the two images. Thin-cap fibroatheroma was also detected at the proximal segment to the severest narrowing (Figure 3A). Furthermore, low signals were found surrounding some stent struts (Figure 3B). There was a tubular structure (diameter = 100 µm) expanding from the peri-stent to the intima, suggesting neovascularization observed 3 mm distal to the proximal edge (Figure 4). These findings could not be obtained by IVUS images corresponding to each OCT image. Stent expansion was sufficient. After balloon dilatation with a 3.0 x 10 mm noncompliant balloon (Hiryu™; Terumo, Tokyo, Japan) at 16 atmospheres, the stenosis decreased and the plaque was prolapsed distally to the stent (Figure 1). The prolapsed material was observed by IVUS and OCT (Figures 5A and 5B). IVUS could not discriminate the floating material itself; however, it was clearly identified by OCT. The distal half of the material had a high-intensity homogenous signal and the proximal half showed superficial high intensity with deep low signals, suggesting that they were composed of different components (Figures 5A and 5B). At the same time, plaque in the stent segment decreased and the resultant tissues showed heterogenous plaque containing high signals with partial low signals by OCT; however, they had high homogeneity by IVUS (Figure 5C). Angiography revealed there was no distal embolism other than the prolapsed material.
We successfully retrieved the entire body of the material using an aspiration catheter (Eliminate™). Macroscopically, the retrieved tissue was whitish-yellow and microscopically it was composed of two layers (Figures 6A–6E). The superficial part of the tissue consisted of mainly hypocellular tissue with hyaline degeneration and adjacent fibrous cellular tissues were detected in the deeper layer. Special staining and immunohistochemical analysis by CD 68 staining and anti-smooth muscle cell (SMC) alpha-actin staining revealed the fibrous cellular tissues contained macrophages and polymorphic SMC at the background of proteoglycans detected by Alcian blue staining (Figures 6 and 7). Macrophages existed predominantly in the border between two layers. We deployed a 2.5 x 20 mm Taxus Liberte™ (Boston Scientific) to cover the resultant plaque from the mid-portion of the stent to 8 mm distal to the distal stent edge at 12 atmospheres and post-dilated with a 3.0 x 10 mm Hiryu™ noncompliant balloon. The angiographic (Figure 1), IVUS and OCT (Figure 8) results were excellent.
Discussion. In this case, we could confirm that newly developed atherosclerosis existed next to the healed intimal hyperplasia even 11 years after bare-metal stent (BMS) implantation. Furthermore, to the best of our knowledge, this is the first case report in which the OCT findings were evaluated histologically and immunohistochemically in an extended late-phase in-stent restenosis after BMS implantation.
Although drug-eluting stents have decreased restenosis rates dramatically, a major drawback is that late and very late stent thromboses have become problematic. Thus, BMS have re-entered the spotlight, because it is generally believed that once a stented lesion has healed and becomes coated with a scar-like layer of hypocellular fibrous tissue, the lesion becomes stable and no recurrent stenosis occurs. However, information about the long-term efficacy of BMS is sparse.
In spite of the efficacy and stability of coronary BMS in the early and medium-term phases, the long-term safety of implanted stents remains controversial. Choussal et al1 described the clinical stability of the stented target site at 8–10 years after coronary stenting. In contrast, Kimura et al2 reported that 7–11 years of angiographic follow-up demonstrated late luminal renarrowing beyond 4 years, which did not necessarily require target lesion PCI. They also reported that the long-term luminal response after coronary stenting was triphasic: an early restenotic phase (until 6 months); an intermediate-term regression phase (from 6 months to 3 years); and a late re-narrowing phase (beyond 4 years).
A previous study3 and our case clearly demonstrated that new atheroscleroric progression is observed facing the healed neointimal layer inside the implanted stents. In our case, pathologically the retrieved tissue appeared to be double-layered, suggesting that accumulation of the tissue might have occurred in 2 stages. In actual fact, the restenosis occurred with a time lag of over 10 years after the last angiography at another hospital that showed moderate intimal hyperplasia with 50% stenosis. The detection of macrophages by CD 68 staining and pleomorphic SMC by anti-SMC alpha-actin staining might suggest that activation of the intimal hyperplasia may have restarted or continued once the intimal hyperplasia had remained stabilized for over 10 years following BMS implantation.
The pathological mechanism of new atherosclerotic plaque formation in an extended long-period follow-up is not known. Takano et al4 speculated that expanded intraintimal neovasularization may play a key role in atheroscrelotic progression and surrounding tissue instability, as well as intraplaque neovascularization of nonstent segments. Our pathological findings revealed sparse neovascularization because material was retrieved from the superficial layer only. However, OCT detected a microvessel expanding from near the stent struts to the intima in the stent. The trigger for the development of microvessels into plaque still needs to be elucidated, although persistent chronic inflammation may somehow be involved. Inoue et al6 reported that autopsied samples after implantation of Palmaz-Schatz coronary stents (19 patients autopsied after noncardiac death 2–7 years post-stenting) demonstrated that stainless-steel stents evoked a remarkable foreign-body inflammatory reaction to the metal. They concluded that peristrut chronic inflammatory cells might accelerate new indolent atherosclerotic changes and plaque vulnerability. Although we were unable to obtain material from the peri-stent area, there were low signals surrounding some stent struts, potentially indicating the presence of inflammation even 11 years after BMS deployment.
Autopsy studies have suggested that coronary thrombosis may occur in the absence of cardiac symptoms, resulting in progression of atherosclerosis.7 Burke et al8 supported the hypothesis of plaque rupture as a mechanism of increased luminal narrowing. They reported a low but significantly increased rate of cell proliferation in the SMC-rich regions of healed rupture sites, providing evidence of further plaque expansion. The matrix within the healed fibrous cap consists of a proteoglycan-rich mass or a collagen-rich scar, depending on the healing phase. The pathological findings in this case seem to be similar to those reported in this study. Regarding the pathological mechanism of in-stent restenosis after 11 years, we speculate that persistent peri-strut chronic inflammation6 might have yielded neovascularization accelerating new indolent atherosclerotic change5 and consequent plaque vulnerability, which may have caused plaque ruptures or plaque erosions. Following this, as a healing process, a proteoglycan-rich mass associated with SMC narrowed the lumen, as was the case in the non-stented vessels.
In this case, we were able to correlate angiographic extended late phase in-stent restenosis with in vivo OCT, IVUS and ex vivo histopathology stains. OCT may be a better tool than IVUS for evaluating the detailed characteristics of in-stent restenosis. The different pathological components of prolapsed plaque were reflected in the OCT images.
- Choussat R, Klersy C, Black AJR, et al. Long-term (8 years) outcome after Palmaz-Schatz stent implantation. Am J Cardiol 2001;88:10–16.
- Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary artery stents. N Engl J Med 1996;334:561–566.
- Hasegawa K, Tamai H, Kyo E, et al. Histopathological findings of new in-stent lesions developed beyond five years. Cathet Cardiovasc Diagn 2006;68:554–558.
- Takano M, Yamamoto M, Inami S, et al. Appearance of lipid-laden intima and neovascularization after implantation of bare-metal stents. J Am Coll Cardiol 2010;55:26–32.
- Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:2316–2325.
- Inoue K, Abe K, Ando K, et al. Pathological analyses of long-term intracoronary Palmaz-Schatz stenting: Is its efficacy permanent? Cardiovasc Pathol 2004;13:109–115.
- Mann J, Davies MJ. Mechanism of progression in native coronary artery disease: Role of healed plaque disruption. Heart 1999;82:265–268.
- Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: Evidence that subclinical rupture has a role in plaque progression. Circulation 2001;103:934–940.