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Frequency and Determinants of “Black Holes” in Sirolimus-Eluting Stent Restenosis
August 2006
In-stent restenosis is the result of neointimal hyperplasia that, by intravascular ultrasound (IVUS) imaging, typically has a homogeneous, echoreflective appearance. Histological and immunohistochemical analyses of “typical” in-stent neointimal hyperplasia tissue have shown spindle-shaped mesenchymal cells (a-actin-positive smooth muscle cells) with very little collagen and elastin.1–3 Clinically, brachytherapy has reduced recurrent in-stent restenosis,4–6 and sirolimus-eluting stent (SES) implantation has reduced first-time in-stent restenosis.7–9 However, both brachytherapy and SES implantation have been associated with reports of unusual long-term IVUS findings, including late stent malapposition, edge restenosis and black holes (echolucent neointimal tissue called “black holes” [BH] by some investigators).10–14 Analysis of retrieved atherectomy specimens from these BH has shown acellular and necrotic tissue lacking connective tissue elements, scattered in an extracellular matrix containing proteoglycan.15 We report the frequency, predictors and IVUS patterns of BH after SES implantation in a “real-world” population.
Materials and Methods
Patients. From our clinical and core IVUS databases, we identified 102 consecutive cases of SES restenosis (33 intrastent and 69 edge restenosis). We obtained prespecified clinical and laboratory data from patient charts. All patients included in this analysis presented clinically with angina and/or stress-induced ischemia that motivated angiographic follow up after SES implantation. The institutional review board approved this study. Written informed consent was obtained from all patients.
IVUS imaging and analysis. IVUS studies were performed using a motorized transducer pullback system (0.5 mm/second) and a ClearView Ultra scanner (Boston Scientific Corp., Natick, Massachusetts) consisting of a rotating 40 MHz Atlantis SR transducer with a 2.6 Fr imaging sheath. Prior to imaging, 100–200 µg of intracoronary nitroglycerin were administered. The ultrasound catheter was advanced > 10 mm beyond the stent, and a imaging run was performed to a point 10 mm proximal to the stent. IVUS images were recorded on half-inch, high-resolution s-VHS videotape for off-line quantitative analysis.
The images were digitized to perform quantitative and qualitative analysis according to the criteria of the American College of Cardiology’s Clinical Expert Consensus Document on IVUS.16 The proximal and distal reference segment elastic external membrane and lumen cross-sectional area were measured at the most normal-looking cross sectional area within 10 mm proximal and distal to the stent, but before any side branch, and reported as a mean of both values. A coronary segment beginning at the distal SES edge and extending to the proximal SES edge was analyzed. A computer-based contour detection program was used for automated three-dimensional reconstruction of the stented segment (Echoplaque, Indec Systems, Inc., Mountain View, California). Cross-sectional area measurements every 0.5 mm included lumen, stent and external elastic membrane cross-sectional area. Calculations included total vessel volume, stent volume, lumen volume, plaque and media volume and neointimal hyperplasia volume. Percentage of obstruction was calculated as neointimal hyperplasia volume divided by stent volume. Additionally, we measured the IVUS-detectable neointimal hyperplasia free length of the stent. Finally, the number of visualized stent struts was counted at the minimum lumen site and at four remote sites 5.0 mm and 10.0 mm proximal and distal to the minimum lumen site (the 5.0 mm and 10.0 mm slices were combined for this analysis).
Intrastent restenosis was defined by the presence of neointimal hyperplasia (percentage of neointimal hyperplasia > 50%) associated with a lumen cross-sectional area 2. When compared to adjacent (and more typical) neointimal hyperplasia, a BH (or “black wall”) was identified by the agreement of two experienced observers as a dark, very echolucent homogeneous region of restenotic tissue which produced no attenuation of the ultrasound signal (Figure 1). Other varieties of intravascular echolucent images, such as thrombus, contained contrast, lipid-rich necrotic core or other image artifacts (e.g., ring down) had to be ruled out as a differential diagnosis. Also, little change in acoustic impedance can result in changes in echo-reflectance and produce an image suggestive of a “dark” zone which does not correspond to a true “black hole”. In order to prevent misinterpretation, we only included in the current study those cases where the IVUS analysts were able to clearly observe the presence of a leading edge, well delimited, around the nonreflective homogeneous tissue, located intraluminal and juxtaposed to the stent struts (the real “black hole” by IVUS definition). The percentage of neointimal hyperplasia area occupied by the BH at its maximum site (Figure 2), the ratio between neointimal hyperplasia and “black hole” volumes, and the ratio between neointimal hyperplasia and BH lengths were calculated.
Statistics. Statistical analysis was performed with the Statistical Package for Social Sciences for IBM-PC (SPSS Inc., Version 11.0). Categorical data are presented as frequencies, and continuous data are presented as mean ± 1 standard deviation (SD). For comparisons of categorical variables, the Fisher’s exact test was used. Continuous variables were compared by one-way analysis of variance. All statistical tests are two-sided.
Results
There were 8 cases of BH among the 102 consecutive cases of SES restenosis. All in-stent restenosis lesions containing a BH were intrastent. Since the mechanisms causing in-stent and edge restenosis are different (predominant neointimal hyperplasia proliferation associated with stent underexpansion as the cause of intrastent restenosis versus edge trauma and failure to cover the entire lesion as the cause of edge restenosis), we opted to include only the in-stent restenosis patients in the statistical analysis. Stable angina pectoris was the most frequent clinical presentation (50% BH patients versus 52% non-BH patients; p = 0.8).
Table 1 shows a comparison of baseline demographics between the 8 patients with BH versus the 25 patients with intrastent restenosis without BH. SES failure occurred earlier among BH patients compared to non-BH patients (89.9 ± 34.3 days versus 161.3 ± 78.9 days; p = 0.001). Fifty percent of BH occurred in saphenous vein graft lesions, while the entire group of non-BH cases were in native arteries (p = 0.0017). Only 2 cases of BH were noticed after Cypher™ stent (Cordis Corp., Miami, Florida) placement in de novo lesions; the rest occurred after treatment of in-stent restenosis and/or after brachytherapy failures. Compared to non-BH cases, a significant proportion of lesions with BH occurred after SES treatment of bare-metal in-stent restenosis (75% versus 32%; p = 0.035). In all of these cases, the BH tissue was noticed in the segment previously treated with a bare-metal stent and retreated with a SES, confirmed by the presence of more than one layer of stent at the region. Three patients in each group had a previous history of vascular brachytherapy failure (p = 0.1). Two patients with BH in saphenous vein grafts also had bare-metal stent restenosis, 1 of whom was treated with brachytherapy.
Tables 2 and 3 show the IVUS analyses. BH tissue was present over 64 ± 16% of the total neointimal hyperplasia length. At its maximum cross-sectional area, BH tissue represented 35.0 ± 12.6% of the total neointimal hyperplasia cross-sectional area (range 15–55%). When assessed as a volume, BH tissue represented 20 ± 8.5% of the neointimal hyperplasia total volume (range 10–28%). Moreover, when the BH length (number of consecutive millimeters that the BH tissue was observed) was measured, we could observe on average, the presence of this tissue in 3.7 mm (ranging from 0.8 mm to 4.8 mm).
Restenosis was more severe among the BH Cypher stent restenosis population as indicated by greater absolute and relative amounts of neointimal hyperplasia. There were no other significant IVUS differences between BH and non-BH lesions. In both groups the length of the restenotic segments was very short (Discussion
The current study highlights the occurrence of BH or “black walls” in patients with SES restenosis. Black holes had a more aggressive restenosis process (earlier occurrence and greater amounts of neointimal hyperplasia) and were more commonly seen in SES failures after treating bare-metal in-stent restenosis or in failures after SES implantation in saphenous vein graft lesions.
The BH appearance of neointimal hyperplasia tissue is speculated to be a consequence of death and/or mutation of neointimal cells in the early stage of endothelial healing following balloon angioplasty or stent deployment. It is still unclear what triggers this uncommon response. Radiation (historically) and drug-eluting stents (currently) may play an important role. In 2001, Kay et al studied 16 patients treated with cold-end radioactive stents and reported that 6 of 8 restenosis cases had this variation of neointimal hyperplasia, constituting (on average) 50% of the neointimal ingrowth in areas of restenosis.17 In 2003, Kay et al published the results of an analysis of 128 consecutive patients enrolled in different brachytherapy protocols (with low and high activity and cold-end radioactive stents). He compared this population to individuals who underwent percutaneous coronary intervention with (n = 48) and without (n = 22) stent implantation. Twenty-eight cases of BH were identified in this study, all among irradiated patients (incidence of 22%). Notably, no BH case was noticed among patients treated with low-dose radiation. In his study, 60% of all BH cases occurred at the edges of the irradiated stent.18
Pivotal studies of Farb have demonstrated that a compacting neointima containing smooth muscle cells in a proteoglycan/ collagen extracellular matrix covering stent struts can be identified as soon as 30 days after bare-metal stent placement.19 Although arterial healing leads to restenosis when neointimal growth is excessive, we should expect to find an endothelialized smooth muscle cell-rich neointima that seals the thrombogenic components in the underlying artery (metallic stent, lipid core, fibrin) from the lumen, thereby providing protection against late stent thrombosis. While both vascular brachytherapy and DES limit neointimal formation, they may also impair endothelialization, contributing to persistent fibrin deposition and leading to continuous platelet recruitment, positive arterial remodeling producing stent malapposition and unhealed arterial dissections. Also as a result of their usage, they can lead to the formation of a hypocelluar or even acellular tissue near the stent strut (most of the time this is basically necrotic tissue with no connective element).20,21
In 2006, Costa et al reported the results of the multicenter study SECURE (Sirolimus-Eluting Bx Velocity balloon expandable stent in a Compassionate Use REgistry), which enrolled a total of 213 patients with a previous history of bare-metal stent restenosis and vascular brachytherapy failure who were then treated with SES implantation. Among 61 lesions (51 patients) that completed 8-month IVUS follow up, there were 12 cases of BH (incidence of 20%).22 In our population the overall incidence of BH after SES failure was 8%. This is significantly lower than the incidence described after brachytherapy failure in the past, and also SES-treatment of brachytherapy failure in the SECURE multicenter study. Unlike after brachytherapy, post-SES black holes occurred within the body of the stent, not at its edges. In the drug-eluting stent era, the more predictable drug distribution within the lengths of the stent could explain the occurrence of this phenomenon intrastent rather than at the stent edges.
BH lesions were associated with a more aggressive neointimal response. Recently, stent underexpansion and stent strut maldistribution were implicated as causes of SES failure.23–25 In the current study, BH and non-BH patients had similar minimum stent cross-sectional area and number of stent struts at the minimum lumen site. This supports underlying biology as causative of this phenomenon, not factors responsible for SES failure.
Clinical relevance. The presence of BH tissue might have its real incidence underestimated, especially after treatment of the complex subset of patients (previous restenotic lesions, previous irradiated patients, CAD in SVG, etc.), and its occurrence may impact the severity of NIH formation leading to an early clinical restenosis with more IVUS-detected NIH tissue. However, its presence does not seem to impact the incidence of stent thrombosis and patient morbidity and mortality. The perfect understanding of the clinical impact of this phenomenon will rely on the more frequent report of its occurrence in the literature.
Study limitations. Baseline IVUS data were not available for most of the patients. Therefore, the presence of BH at the baseline procedure cannot be ruled out. The final IVUS post-treatment did not reveal the presence of that tissue The number or patients in both groups was small, particularly the BH population. The small numbers reflect the effectiveness of SES in reducing in-stent restenosis and the uncommon finding of the BH phenomenon. Serial IVUS was not performed in this study, so we could not assess the changes in the characteristics of in-stent neointimal tissue over time.
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