Mechanism of Vascular Injury and Repair　― Importance of Lesion Morphology ―

Generational advances in drug-eluting stent (DES) technology have resulted in reduced rates of target lesion revascularization across broad patient and lesion subsets with improved safety with respect to stent thrombosis. However, concerns about incomplete stent healing due to impaired endothelial regeneration (i.e., reendothelialization) have emerged. Even with 2nd-generation DES, the annual rate of target lesion failure of 2–4% is relatively high. Indeed, this failure rate is similar to the rates observed after the implantation of bare metal stents (BMS) or 1st-generation DES.¹ A 2nd-generation DES, the everolimus-eluting stent (EES), is a universally used stent, and its long-term efficacy and safety have been established by ample clinical experience and clinical trials.^2,3 In terms of the repair mechanism from vascular injury after stenting, however, the problem of delayed reendothelialization has been evident also in the EES.⁴ Delayed reendothelialization causes loss of neointimal coverage over the stent struts, which not only represents impaired vessel healing but also leads to neoatherosclerosis, late catch-up (very late restenosis) and rarely, late or very late stent thrombosis.⁵

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Our group has discovered that in the process of repair from stent-induced vascular injury, bone marrow-derived progenitor cells, including both endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), play a pivotal role.^4,6–9 CD34⁺ cells, including both EPCs and SMPCs, mobilize from the bone marrow into the circulation soon after BMS implantation. This was observed especially in patients who experienced later restenosis. However, mobilization was suppressed after implantation of a 1st-generation DES, the sirolimus-eluting stent (SES).^6–8 The 2nd-generation EES also suppresses early mobilization of CD34⁺/CD133⁺/CD45^low cells. This cell fraction includes more EPCs than with the BMS, but fewer compared with the SES.⁴ A 3rd-generation DES, the SYNERGY^® stent (Boston Scientific), shows even lower suppression of CD34⁺/KDR⁺ cells, a cell fraction that includes more EPCs compared with the EES.⁹ Optical coherence tomography (OCT) has demonstrated that the mobilization of progenitor cells is associated with stent healing (i.e., stent coverage).^4,9

In this issue of the Journal, Jimenez-Quevedo et al¹⁰ also investigate early changes in the levels of progenitor cells, CD133⁺/KDR⁺/CD45^low cells, and observed OCT-based stent healing. They also demonstrated that early progenitor cell mobilization was associated with stent coverage. Together, these studies present unique translational research that combines data obtained using cell biological technology, flow cytometric analysis, and advanced diagnostic imaging (OCT), which enables precise evaluation with a minimum resolution of 10 μm.

There have been reports that OCT findings immediately after stent placement are associated with stent failure in the late phase,¹¹ and thus, it is recommended to perform stent optimization using intravascular imaging modalities such as OCT and intravascular ultrasound (IVUS), especially for complex lesions.¹² Factors that determine stent-induced vascular injury include the selection of the stent size relative to vessel size, inflation pressure, and other factors. However, the most important factor may be the lesion morphology prior to stent placement.¹³ Because the properties of the underlying plaque at stent sites potentially have many effects on stent expansion, stent apposition, and the occurrence of dissection,¹¹ the effects of lesion morphology should be considered when assessing vascular injury after stent implantation. The only limitation in the study by Jimenez-Quevedo et al¹⁰ is the lack of morphological assessment of the lesions by OCT prior to stenting. Considering that stent optimization was performed by OCT in all cases, lesion morphology might affect stent-induced vascular injury and the subsequent occurrence of stent failure. Therefore, it is thought that patient factors such as lesion morphology account for a large proportion of the cases of stent failure.

The question is how to improve lesion properties as much as possible prior to stent placement. For that purpose, statins are indispensable, and effects of eicosapentaenoic acid are also expected.^14,15 In future percutaneous coronary intervention procedures, it will be important to emphasize the method of lesion preparation prior to stent placement. Specifically, we should devise ways to minimize vascular damage caused by stent placement by lesion morphology assessment using intravascular imaging modalities, strategy selection for the preparation of calcified plaques, and improving our understanding of the lesion characteristics and accurate measurement of vessel size, lesion diameter and lesion length, which greatly contribute to the prevention of edge dissection and stent under-expansion.

Future translational research that explores the mechanism of the repair process of injured vessels using basic science technologies and evaluates clinical outcomes using state-of-the art medical technologies will make important contributions to the field and will lead to the selection of better stents and improved procedures. We look forward to such research.

Disclosure

S. Toyoda has received honoraria from Bayer Yakuhin, Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd. S. Toyoda received a research grant from Abiomed Japan Inc. T. Inoue is a member of the Editorial Board of Circulation Journal.

References

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