Five-year histological evaluation of paclitaxel-eluting stent for an infrapopliteal lesion: a case report

Abstract

Background

The long-term vascular response to paclitaxel-eluting stents (PESs) in infrapopliteal (IP) lesions remains histologically uncharacterized.

Case summary

A 78-year-old woman with chronic limb-threatening ischaemia underwent implantation of two overlapping paclitaxel-eluting stents from the tibioperoneal trunk to the peroneal artery for an ischaemic ulcer. Multimodality follow-up imaging was obtained at both 3 and 5 years, including optical frequency domain imaging (OFDI) and angioscopy performed immediately before amputation. At 3 years, OFDI and angioscopy demonstrated uncovered struts with adherent thrombus. At 5 years, OFDI and angioscopy showed mature neointima over the proximal and distal segments but persistent fibrin-coated, uncovered struts within the 40-mm overlap. Progressive ischaemia culminated in below-the-knee amputation, permitting stent explantation. Histopathology confirmed proteoglycan-rich neointima at the non-overlapped segments and delayed healing with fibrin deposition and uncovered struts confined to the overlap.

Conclusion

The 5-year histological evaluation of the PES revealed paclitaxel-related impaired endothelialization in IP lesions.

Learning points.

• Intravascular imaging demonstrated partial coverage of the stent struts, especially at the overlap segment of the two paclitaxel-eluting stents (PESs).

• Histological evaluation revealed that PESs in infrapopliteal lesions may delay arterial healing with uncovered struts, suggesting a high risk for stent thrombosis at 5 years after stent implantation.

Introduction

Endovascular therapy (EVT) is widely used for chronic limb-threatening ischaemia (CLTI), and device technology has advanced substantially. However, current European Society of Cardiology guidelines still documented percutaneous transluminal angioplasty (PTA) as the standard treatment strategy for infrapopliteal (IP) disease,¹ and outcomes with paclitaxel-coated devices below the knee remain inconsistent.^2–4 Most evidence on the vascular healing to paclitaxel-eluting stents (PESs) from the femoropopliteal (FP) segment, yet plaque morphology differs between FP and IP lesions,⁵ which may yield distinct healing patterns. In this report, we presented the chronic histopathologic findings of PESs explanted 5 years after implantation in an IP artery.

Summary figure

Case presentation

A 78-year-old woman with diabetes, end-stage renal disease requiring haemodialysis, and a history of coronary artery bypass grafting for ischaemic heart disease underwent her first EVT for CLTI with a left toe ulcer (Rutherford class 5, ankle-brachial index 0.43). During the procedure, a PES (6.0 × 80 mm², Eluvia, Boston Scientific, Marlborough, MA, USA) was implanted in the superficial femoral artery (SFA), and two PESs (3.5 × 80 mm², the SAVAL Drug-Eluting Vascular Stent, Boston Scientific, Marlborough, MA, USA) were implanted from the tibioperoneal trunk to the peroneal artery (Figure 1A–1B). In the IP lesions, stenting was selected after PTA resulted in flow-limiting recoil, and immediate, durable luminal gain was deemed necessary to support wound perfusion in CLTI.

Figure 1.

Digital subtraction angiography before and after paclitaxel-eluting stent implantation. (A) Initial angiography. (B) Final angiography immediately after two paclitaxel-eluting stents implantation.

Three years later, the PES in the left SFA occluded suddenly, necessitating additional EVT. At that time, moderate stenosis was observed in the PESs implanted in IP lesions (Figure 2A, not in the occluded SFA segment) with uncovered stent struts and substantial thrombus in optical frequency domain imaging (OFDI, FastView and LUNAWAVE, Terumo Corporation, Tokyo, Japan) and angioscopy (Forwardlooking, OVALIS Co., Ltd, Osaka, Japan) evaluation (Figure 2 B1–2, C1–2, and D1–2). Subsequently, repeated episodes of delayed wound healing due to lower limb ischaemia required multiple endovascular procedures in the anterior tibial and posterior tibial arteries.

Figure 2.

Intravascular imaging at 3-year/5-year follow-up and histological findings at 5 years after paclitaxel-eluting stent implantation. (A) Follow-up angiography at 3 years (carbon dioxide contrast). (B1–D1) Angioscopic images corresponding to panels B–D, shown in (A). (B2–D2) OFDI images corresponding to panels B–D, shown in (A). (E) Follow-up angiography at 5 years. (F1–H1) Angioscopic images corresponding to panels F–H, shown in (E). (F2–H2) OFDI images corresponding to panels F–H, shown in (E). Note: OFDI and angioscopy evaluation at 3 years (panels B–D) demonstrated neointimal coverage at the proximal segment; however, the overlapped and distal segment remained uncovered. At 5 years, OFDI and angioscopy (F–H), proximal and distal segments were well covered with neointima; however, delayed arterial healing with uncovered struts and fibrin deposition was observed at the overlapped area, which was also confirmed with histological findings (F3–H3, haematoxylin and eosin stain; F4–H4, Movat pentachrome stain). See Supplementary material online, Videos S1–SS6. OFDI: optical frequency domain imaging.

Five years after the initial stent implantation (Figure 2E), the PES in the left SFA occluded once again, requiring EVT. OFDI and angioscopy of the PESs in IP arteries demonstrated partial coverage of the stent struts, especially at the overlap segment of the two stents (Figure 2 F1–2, G1–2, and H1–2). The patient underwent a knee amputation due to the extensive necrosis of the lower limb. The explanted PESs in IP arteries were analysed histologically.

The PESs were patent, with in-stent diameter stenosis ranging from 10% to 70%. The proximal and distal segments were covered by thick proteoglycan-rich neointima (Figure 3, panels A1–2, C1–2, black asterisks) with partial neo-calcification in the distal segment (Figure 3, panel C3). In contrast, within the 40-mm stent-overlap zone, multiple struts remained uncovered, most pronounced along the overlapped struts (Figure 3, panel B3) and were surrounded by circumferential fibrin (Figure 3, panel B4), consistent with delayed arterial healing even 5 years after stent implantation (Figure 3 B1–2). These histologic findings correspond to the serial intravascular imaging at 3 and 5 years, which demonstrated persistent delayed coverage confined to the overlap segment.

Figure 3.

Histological findings at 5 years after paclitaxel-eluting stent implantation. (A1,2–C1,2) Histological specimens corresponding to panels F–H, shown in Figure 2, panel E. Black asterisks, white arrows, and black arrows indicate proteoglycan-rich neointima, fibrin deposition, and uncovered struts, respectively. Delayed arterial healing with uncovered struts and fibrin deposition was observed at the overlapped area, which was also confirmed with histological findings. (A1–C1, haematoxylin and eosin stain; A2–C2, Movat pentachrome stain). A3 and A4 were magnified views of the area shown in A2 and demonstrate neointimal proliferation through fissures in a fractured calcified plaque and neointimal dissection, respectively. B3 and B4 were magnified views of the area shown in B2 and depict stent struts with delayed healing and fibrin deposition (B3 shows stent-strut dropout). C3 and C4 were magnified views of the areas shown in C1 and C2; C3 demonstrates neoatherosclerosis with peri-strut calcification, whereas C4 highlights proteoglycan-rich neointima.

Discussion

This report demonstrated the histological evaluation of PESs 5 years after implantation in IP lesions. Persistent uncovered struts, most pronounced within the overlap zone, indicate incomplete arterial healing and a potential substrate for late thrombosis. Insufficient arterial endothelialization has been linked to sustained stent-thrombosis risk in the coronary field,⁶ and may partly explain the higher incidence of thrombectomy or thrombolysis observed in the PES arm of the SAVAL randomized trial.⁴ In our case, delayed arterial healing with persistent uncovered struts was localized to the 40-mm stent-overlap segment, whereas the proximal and distal segments exhibited mature neointimal coverage. This pattern would support a mechanism driven by overlap-related factors, including locally increased paclitaxel load.

A prior optical coherence tomography (OCT) study in the FP segment by Kozuki et al. reported 93.7% coverage at 8 months with the polymer-free Zilver PTX (Cook Medical, Bloomington, IN, USA).⁷ In contrast, our IP case demonstrated delayed healing confined to the 40-mm stent-overlap segment. Device pharmacokinetics may be relevant: Zilver PTX is polymer-free with relatively short paclitaxel release, whereas the platform used in our case employs a polymer reservoir enabling prolonged elution, which could increase local drug exposure in a small IP artery. Emerging coronary evidence indicates that vascular healing after drug-eluting stent implantation is lesion-specific: heavy calcification and acute coronary syndromes are associated with delayed endothelial coverage and persistent fibrin.^8,9 Although systematic pathology after stenting of lower extremity arteries is limited, FP and IP lesions differ in plaque morphology.⁵ In patients on haemodialysis, medial and intimal calcification are accentuated in IP arteries.¹⁰ Taken together, these factors may predispose IP arteries—particularly in haemodialysis patients—to delayed healing than FP arteries and may have amplified the overlap-confined delayed coverage observed in our case. These considerations support individualized antithrombotic management and procedural strategies that minimize long stent overlaps in IP interventions. Segment-specific imaging-histology correlation studies would be warranted.

Regarding other anti-restenotic drugs, limus-based drug-eluting stents that failed to improve outcomes in FP lesions¹¹ have yielded favourable results for IP lesions,¹² and the recent LIFE-BTK trial (drug-eluting resorbable scaffold vs. angioplasty for infrapopliteal artery disease) demonstrated an efficacy comparable to that of an everolimus-eluting bioresorbable scaffold (BRS).¹³ Although current BRS platforms are limited by scaffold length, a report in the coronary field has suggested excellent late healing after complete scaffold resorption.¹⁴ Given the distinct plaque morphology of IP lesions,⁵ device design and drug kinetics that achieve optimal endothelialization may be essential. Because our observations are derived from a single explant, further histological studies are required to clarify long-term healing mechanisms in IP lesions.

Patient’s perspective

The patient and her family expressed understanding of the need for major amputation due to progressive ischaemic necrosis. They consented to the use of explanted material and clinical images for educational and research purposes, hoping the information would help future patients.

Lead author biography

Dr Yosuke Hata, MD currently works as a cardiologist at Kansai Rosai Hospital, Amagasaki, Japan.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Consent: The authors confirm that written consent for submission and publication of this case report, including images and associated text, has been obtained from the patient in line with COPE guidelines.

Conflicts of interest. None declared.

Funding

None declared.

Data availability

The data supporting the findings of this report are available from the corresponding author upon reasonable request. The data underlying this article are available in the article and in its online Supplementary material.

IRB information

This study was approved by the ethics committee of Kansai Rosai Hospital (Reference number: 2402011).