Tissue Characterization of In-Stent Neointima Using Optical Coherence Tomography in the Late Phase After Bare-Metal Stent Implantation　– An Ex Vivo Validation Study –

Abstract

Background: We performed an ex vivo study to investigate optical coherence tomography (OCT) imaging for differentiating several types of neointimal tissue during the later phases after bare-metal stent (BMS) implantation as compared with histologic results.

Methods and Results: OCT imaging was performed in 6 autopsy hearts for 10 BMS with implant duration >4 years. OCT qualitative neointimal tissue characterization was based on tissue structure and classified as homogeneous pattern, heterogeneous pattern with visible struts, or heterogeneous pattern with invisible struts. Corresponding histological analyses of each 2-mm cross-section of the entire BMS were performed. Of 81 cross-sections, histological analysis revealed that the homogeneous pattern of neointima on OCT (n=39) contained smooth muscle cells with collagen, indicating high neointimal maturity. The heterogeneous patterns with visible struts (n=35) contained different tissues, including a proteoglycan-rich myxomatous matrix or dense calcified plate deposition. The heterogeneous patterns with invisible struts (n=7) included neointimal lipid/necrotic core formation, accumulation of foam cells, or microcalcification scattering. Of the 66 cross-sections containing large microvessels within the neointima on histology, only 6 (9%) were visualized by OCT.

Conclusions: The present study confirmed the potential use of OCT in differentiating several types of neointima after BMS implantation. The image interpretation of OCT, based on visualization of stent struts, enables identification of several types of neointimal tissues, including in-stent fibroatheroma formation, more accurately. (Circ J 2015; 79: 2224–2230)

Although drug-eluting stents (DES) are now commonly used for patients with stable angina, bare-metal stents (BMS) are still widely used for thrombotic lesions in acute myocardial infarction because of their ability to seal and shield the vulnerable plaque with the development of mature intima. The vascular response after the implantation of BMS is characterized by neointimal tissue proliferation during the first 6 months, followed by a regression phase of up to 4 years.¹ However, very late stent thrombosis has recently been reported to occur after 4 years.² Pathologic studies have suggested that late complications following BMS implantation are related to inappropriate vessel healing and the development of in-stent fibroatheroma, with macrophage infiltration and necrotic core formation inside the stent.³ Therefore, in vivo detection of in-stent fibroatheroma formation would be beneficial in the prevention of very late stent thrombosis after BMS implantation.

Intracoronary optical coherence tomography (OCT) can characterize different in-stent tissue morphologies with lipid or calcium deposition, which has been confirmed by histological studies.⁴ Recent OCT studies have reported the identification of morphological features of the neointimal tissue in the late phase (>4 years) after BMS implantation; however, there remains a large discrepancy in the prevalence of lipid neointima between the OCT images and histological studies.^3,5,6

To interpret OCT images accurately, visualization of the stent strut is critical. Our previous ex vivo histological validation revealed that in-stent fibroatheroma was visualized as a low-signal-intensity region with diffuse borders and stent struts were invisible behind neoatherosclerosis.⁷ Therefore, in the present study, we investigated the validity of OCT images in differentiating several types of neointimal tissue in the late phase after BMS implantation compared with histological results and aimed to improve diagnostic accuracy using stent strut-based image interpretation.

Methods

Study Specimens

We examined 10 BMS with implant duration ≥4 years (mean: 86±18, range: 48–108 months) taken from 6 cadavers (5 males, 1 female). The causes of death were: sepsis/infection (n=2), blue toe syndrome (n=1), pneumonia (n=1), endocarditis (n=1), and congestive heart failure (n=1). No definite stent thrombosis was documented in these subjects. All stented coronary arteries were dissected at autopsy within 6 h of death. The harvested coronary arteries were immediately stored in phosphate-buffered saline. The time between death and OCT examination did not exceed 12 h. The experimental and ex vivo study protocols were approved by the Institutional Review Board of Hyogo College of Medicine, and written informed consent was given by the patients’ relatives in all cases.

OCT Imaging Protocol

At autopsy, within 6 h after death, the coronary specimens were resected with the surrounding fatty tissue for ex vivo OCT imaging in 0.9% saline at 37℃. The surrounding fatty tissue was carefully removed from each coronary specimen and the side branches were tied off to preserve a perfusion pressure of 60–80 mmHg. A time-domain OCT system was used, enabling the position of the interrogating beam on the specimen to be monitored by a visible light beam in real time. An over-the-wire type occlusion balloon catheter (Helios; LightLab Imaging, Westford, MA, USA) was advanced over a 0.016-inch imaging wire (Image Wire; LightLab Imaging) proximal to the stented segment. The occlusion balloon was then inflated to 0.6 atm (60,795 Pa), and 0.9% saline was infused from the distal tip of the occlusion balloon at 0.5 ml/s to clear the imaging field. An imaging run was performed from the distal to the proximal segments of the stent using an automated transducer pullback at 1.0 mm/s. All images were acquired at 15.6 frames/s. After OCT examination, multiple 6-0 prolene sutures with a tapered surgical needle were carefully inserted into the stented segment as a reference point for co-registration between the OCT and histological images.

OCT Image Analysis

Cross-sectional areas at each level of the OCT images were measured in the co-registered images using proprietary software (LightLab Imaging) by 2 independent observers blinded to the histological diagnosis. Qualitative neointimal tissue characterization was based on tissue structure and backscatter using validated criteria for plaque characterization.⁸ This analysis was accomplished only for cross-sections >30% of the neointimal area. A homogeneous pattern was defined as neointimal tissue with uniform optical properties and without focal variation in the backscattering pattern. Heterogeneous patterns were defined as those with focally changing optical properties and variation in the backscattering patterns. The heterogeneous patterns were divided into 2 groups according to the visualization of the stent strut behind the low backscattered neointima (heterogeneous pattern with visible strut and heterogeneous pattern with invisible strut) (Figure 1). Neointimal calcium depositions were identified as signal-poor regions with sharply delineated borders.⁴ A large microvessel within the neointima was considered to be present if there were at least 3 contiguous cross-sectional OCT images with non-signal tubule-luminal structures and without detection of a connection to the vessel lumen.⁹

Figure 1.

Classification of neointimal tissue by optical coherence tomography imaging. Qualitative neointimal tissue characterization was based on tissue structure and backscatter using validated criteria for plaque characterization. (A) Homogeneous pattern defined as a neointimal tissue with uniform optical properties. (B) Heterogeneous pattern with visible strut defined as neointimal tissue with focally changing optical properties and visible stent struts behind the low-signal-intensity region. (C) Heterogeneous pattern with invisible strut had the same neointimal tissue properties as in B, but the stent struts behind the low-signal-intensity region were invisible.

Histological Study

After the OCT examinations, the stented segments were fixed in 10% neutral buffered formalin for 48 h, then embedded in methyl methacrylate. Histological cross-sections were sliced 5-μm thick, adjusted at the suture position inserted by OCT, and guided at 2-mm intervals, using a diamond wafering blade. A total of 106 histological cross-sections were obtained from the autopsy specimens. Of those, 25 histological sections were excluded because of cutting artifacts (n=9), co-registration difficulty (n=9), and a small amount of neointima (n=7). Each slice was stained with hematoxylin and eosin, Masson’s trichrome, and elastica van Gieson. The histological classifications were based on the evaluation of a single pathologist (H.H.), who was blinded to the imaging results.

Statistical Analysis

Student t-test was performed to compare continuous variables and the Mann-Whitney U test was used for skewed distributions. The categorical variables are expressed as both number and percentage and compared using the χ² test or Fisher’s exact test.

Results

A total of 81 cross-sections were analyzed by OCT and histology. A summary of the profile of each specimen is shown in Table 1.

Table 1. Patient and Stent Characteristics in Ex Vivo Validation Study of OCT Imaging of Neointima After BMS Implantation

Case no.	Age/sex	Cause of death	Vessel	Stent*	Stent size (mm)	Duration of stenting (months)
1	76/M	Blue toe	RCA	S670	3.0×24	108
			LCX	Multilink	3.0×15	108
2	80/F	Pneumonia	RCA	Tsunami	4.0×10	80
			RCA	Express	3.5×32	86
			RCA	Express	3.0×28	86
3	76/M	Sepsis	RCA	Driver	4.0×18	60
			LCX	Tsunami	2.5×15	96
4	56/M	Sepsis	RCA	Vision	3.5×15	96
5	40/M	Heart failure	RCA	Driver	3.5×24	48
6	74/M	Endocarditis	RCA	Express	3.5×32	80

*S670 (Medtronic, Minneapolis, MN, USA); MultiLink (Abbott Vascular, Santa Clara, CA, USA); Tsunami (Terumo Corp, Tokyo, Japan); Express (Boston Scientific, Natick, MA, USA); Driver (Medtronic); Vision (Abbott Vascular). BMS, bare-metal stent; OCT, optical coherence tomography; LCX, left circumflex coronary artery; RCA, right coronary artery.

Histological Analysis

Histological analysis showed that all stent struts were covered by neointima. In the majority of cases (n=39, 48%), neointimal tissue contained smooth muscle cells and extracellular matrix containing proteoglycans and collagen fibers, similar to the tissue typically seen less than 1 year after BMS application. However, in the remaining 42 tissue samples (52%), the histology of the neointimal tissue contained other components, including foam cell accumulation (n=5, 6%), neointimal lipid/necrotic core formation (n=3, 4%), and a proteoglycan-rich myxomatous matrix (n=20, 25%). Calcium deposition within the neointima was identified in 14 sections (17%): 12 dense calcified plates and 2 microcalcifications. Large microvessels within the neointima were identified in 66 cross-sections (81%) and were often positioned around the stent struts within the proteoglycan-rich myxomatous layer.

OCT Analysis

In accordance with the histological findings, OCT images also showed that all stent strut surfaces were covered by neointima. Among the 81 cross-sections, the overall prevalence of homogeneous pattern, heterogeneous pattern with visible strut, and heterogeneous pattern with invisible strut on OCT images was 39 (48%), 35 (43%), and 7 (9%), respectively. Microvessels within the neointima were identified in 6 cross-sections (7%) on OCT: 1 cross-section of a homogeneous pattern neointima and 5 cross-sections of a heterogeneous pattern neointima with visible strut.

Histological Neointimal Features Characterized by OCT

The detailed descriptions of the histological features of each type of neointima characterized by OCT are summarized in Table 2 and Figure 2. Histological analysis revealed that the homogeneous pattern of neointima on OCT (n=39) was entirely comprised of smooth muscle cells with an extracellular matrix containing collagens and proteoglycans, indicating high neointimal maturity. The histological findings of the neointima categorized as heterogeneous pattern with visible strut included many different tissues: (1) proteoglycan-rich myxomatous matrix in the deeper layer (n=20); (2) dense calcified plate deposition within the neointima (n=12); (3) accumulation of foam cells on the luminal surface (n=2); or (4) microcalcification scattered on the luminal surface (n=1). Likewise, the histological findings of neointima categorized as a heterogeneous pattern with invisible strut comprised the following tissue types: (1) fibroatheroma (neointimal lipid/necrotic core formation) (n=3); (2) accumulation of foam cells on the luminal surface (n=3); or (3) scattered microcalcification on the luminal surface (n=1). Of the 66 cross-sections that contained large microvessels within the neointima on histology, only 6 (9%) were visualized by OCT. Microvessels that were identified by OCT were histologically located in the collagen-rich intima (n=1) and proteoglycan-rich myxomatous matrix (n=5) (Figure 3).

Table 2. OCT Tissue Characterization and Histological Results in Ex Vivo Study of Neointima After BMS Implantation

	Homogeneous pattern (n=39)	Heterogeneous pattern with visible strut (n=35)	Heterogeneous pattern with invisible strut (n=7)	P value
Atherogenic change
Foam cell	0	2 (6)	3 (43)	<0.001
Atheroma/necrotic core	0	0	3 (43)	<0.001
Dense calcified plate deposition	0	12 (34)	0	<0.001
Other findings
Microcalcification	0	1 (3)	1 (14)	0.1
Proteoglycan-rich myxomatous matrix	0	20 (57)	0	<0.001
Microvessels	24 (62)	35 (100)	7 (100)	<0.001

Data are presented as n (%). BMS, bare-metal stent; OCT, optical coherence tomography.

Figure 2.

Optical coherence tomography (OCT) properties of in-stent tissue and corresponding histological images. (A) OCT images indicating high intensity surface (arrows) and diffuse border following shadows with weakly visible strut. (B) Corresponding histological image from the same section of the lesion in A (Masson trichrome, scale bar=1,000 μm). (C) Histological image of the same cross-section in B shows foam cell accumulation (arrowheads) on the luminal surface (Masson trichrome, scale bar=200 μm). (D) OCT images indicating a high intensity surface and diffuse border following shadows (arrows) with invisible strut. (E) Corresponding histological image from the same section of the lesion in D (H&E, scale bar=500 μm). (F) Histological image of the same cross-section of the lesion in E shows large necrotic core (*) covered by a thin fibrous cap (H&E, scale bar=100 μm). (G) OCT image showing low intensity area with a sharply delineated border and visible strut (arrows). (H) Corresponding histological image from the same section of the lesion in G (H&E, scale bar=500 μm). (I) Histological image of the same cross-section of the lesion in H shows dense calcium deposits within the neointima (*) (H&E, scale bar=100 μm). (J) OCT image showing low intensity area with an overlying signal-rich band (arrows) and a weakly visible strut. (K) Corresponding histological image from the same section of the lesion in J (H&E, scale bar=1,000 μm). (L) Histological image of the same cross-section of the lesion in K shows large amounts of microcalcification (arrowheads) at the surface of fibrous intima (H&E, scale bar=200 μm). (M) OCT image showing low intensity area with diffuse border (arrows) and a clearly visible strut. (N) Corresponding histological image from the same section of the lesion in M (H&E, scale bar=1,000 μm). (O) Histological image of the same cross-section of the lesion in N shows proteoglycan-rich myxomatous matrix (*) in the deeper layer (H&E, scale bar=100 μm). Stent struts indicated by arrows in (C,E,I,K,O).

Figure 3.

Optical coherence tomography (OCT) properties of peri-strut microvessels and corresponding histological images. (A) OCT image indicating neointimal tissue with focally changing optical properties in the deeper layer and visible stent struts behind the low-signal-intensity region. (B) Corresponding histological image from the same section of the lesion in A (H&E, scale bar=1,000 μm). (C) Magnified image of the inset in A reveals non-signaling tubule-luminal structures around the stent struts (arrows). (D) Histological image of the same cross-section of the lesion in B shows microvessels within the proteoglycan-rich myxomatous matrix layer (arrows) (H&E, scale bar=200 μm).

Discussion

The main findings of the present study were as follows: (1) the qualitative histological and OCT findings of neointimal tissue characterization in the late phase after BMS implantation were heterogeneous; (2) in-stent fibroatheroma formation was observed, although rarely, in the late phase; (3) invisible stent struts behind the low-signal-intensity region on OCT can be used to identify in-stent fibroatheroma formation; and (4) only 9% of large microvessels within the neointima were identified by OCT.

The initial reaction to the mechanical damage induced by stent implantation is platelet activation and thrombus formation accompanied by an inflammatory reaction. This is followed by activation of cytokines, leading to the proliferation and migration of smooth muscle cells within the media. These cellular responses lead to intimal thickening by smooth muscle cells and the surrounding extracellular matrix with or without progression to restenosis.^10,11 Therefore, in the early phase after BMS implantation (<6 months), the neointima is usually composed of smooth muscle cells in a proteoglycan and collagen-rich matrix. Maturation of the fibrotic scar, characterized by the reduction of proteoglycans and redifferentiation and disappearance of smooth muscle cells, leading to regression of the neointimal volume, is usually observed from 6 months to 4 years after stent implantation.¹² This vascular response has been confirmed by clinical angiographic studies, showing that the minimum lumen diameter on coronary angiography increased from 6 months to 4 years after coronary stenting.¹³

However, beyond 4 years, late luminal narrowing has been observed.¹³ Studies have revealed a metallic sensitivity reaction in patients treated for tibial fractures with stainless steel plates, several months after implantation.¹⁴ In the coronary arteries, a chronic inflammatory reaction, characterized by infiltration of macrophages and T lymphocytes, can be found in the late phase.¹⁵ Furthermore, foreign-body giant cells persist around the stent struts for the lifetime of the implant.¹⁶ This heavy cellular infiltration around the stent struts may induce neointimal atherosclerotic changes. In a recent report,¹⁷ 14 BMS thrombotic lesions were examined histopathologically using tissue obtained by directional coronary atherectomy; atherosclerotic lesion progression was found to occur inside the implanted stent. Therefore, identifying in-stent fibroatheroma formation in vivo is clinically important to prevent very late stent thrombosis after BMS implantation, which is a potentially life-threatening event.

Recent advances in intravascular OCT systems have made it possible to characterize and differentiate the various types of neointimal tissues. Gonzalo et al identified various OCT patterns of restenosed tissue after BMS implantation,¹⁸ and Takano et al suggested that neointima with a lipid component, neointimal disruption, and thrombus, as detected by OCT, were found more frequently in the late phase (≥5 years) than in the early phase (<6 months).⁶ Nagoshi et al showed the difference between BMS and DES based on the morphological OCT patterns of the neointimal tissue.¹⁹ In the present study, homogeneous signal-rich neointima with low attenuation was present in neointimal tissue composed of smooth muscle cells in a proteoglycan and a collagen-rich matrix. Because OCT measures the intensity of light returning from a tissue, collagen fiber-rich neointima, which has a higher heterogeneity in the optical index of refraction, exhibits stronger optical scattering and therefore a stronger OCT signal. In contrast, tissue made up of lipids, such as the necrotic core, appear as low intensity areas with diffuse borders because of the presence of a strong scattering layer at the surface of these tissues with extensive underlying signal attenuation. Our previous ex vivo histological validation study of atherosclerotic plaques in native coronary arteries also revealed that the necrotic core is visualized as a low-signal-intensity region with diffuse borders.²⁰ Similarly, the fibrin-rich extracellular matrix and proteoglycan-rich myxomatous matrix appear as low-signal-intensity regions on OCT. Because the dimensions of these extracellular matrixes are significantly smaller than the wavelength of the near-infrared light, there is little reflected light returning from these tissues. As a result, OCT images of these tissues show weaker optical scattering and therefore a lower OCT signal intensity. The difference between these 2 low-signal-intensity regions is whether the OCT light signal exists in the low-signal-intensity regions. If the OCT light signal exists in low-signal-intensity regions, such as the fibrin-rich extracellular matrix and proteoglycan-rich myxomatous matrix, the stent struts behind are visible. Conversely, the stent struts behind the low-signal-intensity region are invisible when the OCT light signal does not exist in a low-signal-intensity region such as in-stent fibroatheroma formation. Thus, OCT is a promising imaging modality for differentiating in-stent neointimal morphologies in vivo.

Our study found that the heterogeneous pattern with invisible strut on OCT included not only in-stent fibroatheroma formation but also macrophage foam cell accumulation on histology. Several reports have shown that macrophages present as a high reflectivity surface with strong background attenuation on OCT.^21–23 Thus macrophage foam cell images are generally considered difficult to distinguish from thin-cap fibroatheroma because of the presence of a strong scattering layer on the luminal surface. In our study, 3 of 5 cross-sections that included foam cells showed heterogeneous pattern with invisible strut; the remaining 2 cases (2/5) showed a weakly visible strut. Whether the stent struts behind a low-signal-intensity region are visible or invisible may depend on the amount of foam cells on the luminal surface. However, to confirm this hypothesis, further investigations are needed with larger samples.

Scattered microcalcification was visualized as a low-signal-intensity tissue with diffusely delineated borders. OCT light signal attenuation due to multiple scattering may be the reason why microcalcification on OCT was visualized as similar to in-stent fibroatheroma formation images on OCT. Whether the stent struts behind a low-signal-intensity region are visible or invisible may depend on the amount of microcalcification scattering on the luminal surface. Therefore, careful interpretation is required to diagnose in-stent fibroatheroma formation on OCT; longitudinal imaging in the absence of calcific plaque proximal and distal to the lesion may be helpful.

In this study, there was a distinct discrepancy between the incidence of microvessels on histology and OCT, particularly in the heterogeneous patterns. Vorpahl et al demonstrated that small black holes in atheromatous plaques observed on OCT correlated well with the pathohistological evidence of intraplaque neoangiogenesis in autopsy cases.²⁴ Although the precise reason for this discrepancy is unknown, it may relate to differences in target specimens. Another potential reason is that microvessels and extracellular matrix have similar light-scattering properties under OCT. Neovascularization that is adjacent to stent struts is a common finding in the late phase after BMS implantation.^25,26

Study Limitations

First, the number of samples was limited; therefore, further studies are required to confirm the significance and application of our findings in a larger cohort. Second, coronary arteries were derived after autopsy from the hearts of patients following non-cardiovascular deaths. Third, the OCT images of the coronary arteries were taken from cadavers in the absence of cardiac motion; cardiac motion artifacts may influence the images taken in vivo. Fourth, frequency domain OCT is generally used in the clinical setting instead of time-domain OCT that we used in this study. Although the wavelength of light is same in the 2 systems, the type of system may affect to the image of OCT. Fifth, formalin perfusion-fixation with pressure of the coronary specimens was not performed, which might affect visualization of microvessels on histology.

Finally, a lack of immunochemical staining might affect the histological diagnosis.

Conclusions

The results of the present study confirmed the potential use of OCT in differentiating several types of neointima after BMS implantation. OCT image interpretation based on visualization of stent struts allows the identification of several types of neointimal tissues, including in-stent fibroatheroma formation, more accurately.

Acknowledgments

The authors thank the staff in the Department of Surgical Pathology at Hyogo College of Medicine for their excellent assistance with this study.

Disclosures

No grants to authors or institutions concerning this study.

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