Brief Communication

Histopathologic Validation of Optical Coherence Tomography Findings of Non-Apposed Side-Branch Struts in Porcine Arteries

Ae-Young Her, MD, Jung-Sun Kim, MD, Yong Hoon Kim, MD, Dong-Ho Shin, MD Byoung-Keuk Kim, MD, Young-Guk Ko, MD, Donghoon Choi, MD, Yangsoo Jang, MD, Myeong-Ki Hong, MD

Ae-Young Her, MD, Jung-Sun Kim, MD, Yong Hoon Kim, MD, Dong-Ho Shin, MD Byoung-Keuk Kim, MD, Young-Guk Ko, MD, Donghoon Choi, MD, Yangsoo Jang, MD, Myeong-Ki Hong, MD

Abstract: Background. The presence of uncovered struts overlying side branch is considered to be a potential risk of stent thrombosis. The accuracy in detection of neointimal strut coverage at branch point by optical coherence tomography (OCT) has not been validated in comparison with histology. Methods. A total of 5 stents (3 drug-eluting stents and 2 bare-metal stents) were implanted in the bifurcation segment of normal coronary arteries in 4 domestic swine (weight, 25-40 kg). The animals underwent follow-up OCT at 30 days after stent implantation and were then sacrificed for histologic evaluation. The neointimal coverage of the non-apposed struts over the side branch was assessed by light microscopy. Every millimeter of the stent was specified by the OCT frame rate, and comparisons between OCT and pathologic findings were performed through precise histological-OCT frame matching. Results. OCT images at the side branch corresponded well with histological cross-sections. The tissues covering struts as assessed by OCT contained smooth muscle cells with proteoglycan-collagen matrix, but platelets are attached above the neointima in one of them on histologic examination, suggesting that most of the struts were well healed, with normal neointimal coverage.  Conclusion. This study demonstrated the accuracy of OCT for the detection of neointimal coverage of non-apposed struts over the side branch.

J INVASIVE CARDIOL 2013;25(7):364-366

Key words: cardiac imaging, restenosis, stenting

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Previous autopsy studies found that incomplete neointimal coverage and fibrin deposition after stent implantation are more frequently observed in struts lying across the side-branch ostium in bifurcation lesions (termed ‘nonapposed side-branch struts’), and these struts are offered as potential triggers for late and very late stent thrombosis after drug-eluting stent implantation.1,2 Jailing of the side branch with stent struts is sometimes inevitable in daily practice; however, there is no definite evidence that shows an association between stent-jailed side branch and higher thrombotic risk in clinical studies.3 Recent studies by optical coherence tomography (OCT) reported the existence of tissue coverage, probably neointimal tissue, over the non-apposed side-branch struts.4,5 However, these OCT observations need to be interpreted with caution, because the presence of tissue coverage assessed by OCT does not imply the presence of neointima rich in smooth muscle cells (SMCs) and proteoglycan-collagen matrix. Therefore, we sought to investgate the accuracy of OCT in detection of strut coverage over the non-apposed side-branch stent in porcine coronary arteries.  

A total of 5 stents (3 zotarolimus-eluting stents (3.0 x 12 mm Endeavor Sprint; Medtronic) and 2 bare-metal stents (3.0 x 12 mm; Medtronic) were implanted in the bifurcation segments (2 mm diameter) of normal major epicardial coronary arteries in 4 domestic swine (25-40 kg) that underwent follow-up OCT study at 30 days after stent implantation. All animals were premedicated with 100 mg of aspirin and 300 mg of clopidogrel at least 12 hours before the procedure and received 100 mg of aspirin and 75 mg of clopidogrel daily after stent implantation. 

The OCT examination was performed using a conventional OCT system (Model M2 Cardiology Imaging System; Light Lab Imaging, Inc), and every subsequent millimeter was specified by the OCT frame rate, allowing for precise histological-OCT frame matching. A side-branch strut in the OCT images was defined as the portion that was disconnected from the adjacent vessel wall directly at the ostial site of the side-branch vessel. 

The stented arterial segments were then carefully dissected. Individual slides at the predetermined sites were cut on a rotary microtome, mounted, and stained with hematoxylin and eosin stains. The histological images were compared to their corresponding OCT stented segments until the best and closest visual match was found. 

Figure 1 shows that each OCT image corresponded well with the histological cross-sectional image. The serial OCT images showed neointimal proliferation around these non-apposed side-branch struts, extending from the vessel wall to the strut, despite no direct connection between stent struts and vessel wall of the coronary artery. On histologic assessment, neointima covering the side-branch struts predominantly consisted of SMCs with proteoglycan-collagen matrix close to the luminal surface. One of them (Figure 1D) demonstrated that stent struts were covered by SMC-rich neointima, but platelets were attached above the neointima, which corresponded to a site in the neointimal area with an irregular surface in the OCT image (Figure 1D2).

Previous pathologic studies have reported the association of late stent thrombosis with delayed neointimal healing that represented incomplete or absent neointimal coverage following drug-eluting stent implantation.1,6  It has also been suggested that underlying morphology of the artery has influence on vessel healing. For example, strut penetration into necrotic core of ruptured plaque causes delayed healing in patients presenting with acute myocardial infarction (AMI).7 Besides AMI, when the stent struts are placed across the side-branch vessels, it might intrinsically represent a typical example of the lack of neointimal coverage. Some OCT studies have reported the presence of tissues covering non-apposed struts over the side-branch, which is suggestive of the presence of probable neointima.4-5,8 However, the histopathologic validation data regarding OCT findings on the non-apposed side-branch struts are lacking. 

In this study, we observed that most of the tissues covering struts over the side branch in OCT images corresponded to normal neointima rich in SMCs and proteoglycan-collagen matrix in histologic sections. Stent implantation induces a substantial local inflammatory reaction in the injured vessel wall that is followed by the proliferation of vascular components, such as SMCs and extracellular matrix, leading to neointimal thickening.9 However, a recent study demonstrated that after vascular injury such as stenting, smooth muscle progenitor cells are also mobilized from bone marrow, triggered by the inflammatory response.10 These progenitors migrate to the site of vascular damage and differentiate into SMCs. Then, these cells proliferate and finally cause neointimal formation.10 The present study findings may be an appropriate example to support the hypothesis from those studies, because we observed normal neointima covering struts at the side branch even with no intact neighboring segments. 

One randomized trial compared clinical benefits between the simple stent crossover strategy (a non-apposed side-branch generating technique) versus systematic final kissing-balloon angioplasty (a non-apposed side-branch reducing technique) for the treatment of bifurcation lesions, but failed to prove any clinical advantage of systematic final kissing-balloon angioplasty over the simple stent crossover strategy,11 indicating that the mere presence of non-apposed metal struts over the side branch is not necessarily associated with adverse clinical events. Thus, the result of this study raises the hypothesis that healed struts with neointimal coverage do not increase the risk of thrombosis, while unhealed struts might do so. The current study revealed that OCT can accurately detect neointimal coverage of non-apposed struts over the side branch, suggesting the utility of OCT for the maintenance of patients treated with the simple stent crossover strategy without final kissing balloon. 

Study limitations. This study has some limitations. First, OCT-based strut coverage corresponded to histological neointima rich in SMCs and proteoglycan-collagen matrix in a normal porcine coronary artery model, but its agreement in human atherosclerotic vessels is still unknown. Second, the presence of strut coverage does not thoroughly imply the presence of neointima with a functionally intact endothelium. Finally, the sample size of animals is small. 

Conclusion 

OCT-evaluated strut coverage over the side-branch stent corresponded to SMCs with proteoglycan-collagen matrix, which could be suggestive findings of the presence of “true” neointima.  

References

  1. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435-2441.
  2. Farb A, Burke A, Kolodgie F, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation. 2003;108(14):1701-1706. 
  3. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation. 2006;114(18):1955-1961.
  4. Her AY, Lee BK, Shim JM, et al. Neointimal coverage on drug-eluting stent struts crossing side-branch vessels using optical coherence tomography. Am J Cardiol. 2010;105(11):1565-1569.
  5. Gutierrez-Chico JL, Regar E, Nuesch E, et al. Delayed coverage in malapposed and side-branch struts with respect to well-apposed struts in drug-eluting stents: in vivo assessment with optical coherence tomography. Circulation. 2011;124(5):612-623.
  6. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193-202.
  7. Nakazawa G, Finn AV, Joner M, et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation. 2008;118(11):1138-1145.
  8. Gutierrez-Chico JL, Gijsen F, Regar E, et al. Differences in neointimal thickness between the adluminal and the abluminal sides of malapposed and side-branch struts in a polylactide bioresorbable scaffold: evidence in vivo about the abluminal healing process. JACC Cardiovasc Interv. 2012;5(4):428-435.
  9. Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol. 2002;22(11):1769-1776.
  10. Inoue T, Sata M, Hikichi Y, et al. Mobilization of CD-34 positive bone marrow-derived after coronary stent implantation: impact on restenosis. Circulation. 2007;115(5):553-561.
  11. Niemela M, Kervinen K, Erglis A, et al. Randomized comparison of final kissing balloon dilatation versus no final kissing balloon dilatation in patients with coronary bifurcation lesions treated with main vessel stenting: the Nordic-Baltic Bifurcation Study III. Circulation. 2011;123(1):79-86.

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*Joint first authors. 

From the 1Department of Internal Medicine, College of Medicine, Kangwon National University, Chuncheon, Korea, 2Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea, and 3Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

Funding: This study was supported by the Cardiovascular Research Center, Seoul, Korea.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 18, 2013, provisional acceptance given February 13, 2013, final version accepted February 28, 2013.

Address for correspondence: Myeong-Ki Hong, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea. Email: mkhong61@yuhs.ac 

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