Coronary artery perforation (CAP) is a rare but life-threatening complication of percutaneous coronary intervention (PCI) [1]. Covered stents are considered an effective bailout strategy for CAP [2, 3]. Currently, the most widely used covered stent, GRAFTMASTER stent (Abbott Vascular), is designed in a “sandwich” fashion. A Polytetrafluoroethylene (PTFE) membrane is placed between two layers of 316L stainless steel stents [4]. However, such design has led to a large profile and the flexibility and trackability of the device are compromised. Reports have suggested that the device failure rate was 14.6% in complex lesions, such as calcified and torturous lesions [5]. Moreover, at 3-year follow-up, the incidence of target vessel revascularization (TVR) and definite stent thrombosis post this double-layer cover stents implantation was 26% [6] and 3.5% [7], respectively. To reduce the adverse events and improve the deliverability, newer generation of covered stents, such as BeGraft (Bentley InnoMed GmbH, Hechingen, Germany) and PK Papyrus (Biotronik, Lake Oswego, OR, USA) stents, have adopted the design to a single layer metal stent [8]. In comparison to the GRAFTMASTER, the BeGraft and PK Papyrus were associated with higher device success rates [9]; however, both stents did not lower the incidence of in-stent restenosis (ISR) and TVR [10], as compared with the GRAFTMASTER.

The underlying mechanism of ISR after covered stent implantation has remained elusive. A putative reason is that PTFE, as a foreign body, can stimulate intimal proliferation [11, 12, 13]. To resolve this issue, some covered stents [6] use the pericardium, a collagen-rich biological tissue, to replace the PTFE membrane. Disappointingly, the pericardium-covered stent was not associated with a lower incidence of ISR than that of the PTFE or polyurethane stent [6]. Previous studies [12, 14] showed that the combination of a PTFE-covered stent and an underlying long sirolimus-eluting stent implantation is associated with better angiographic follow-up results, as evidenced by a reduction in the incidence of ISR. Such data indicate that antiproliferative drugs could decrease covered-membrane induced intimal proliferation. Therefore, we designed a covered stent system consisting of a single layer of drug-eluting stent and a layer of PTFE membrane wrapped at the outer layer of the stent. In this study, we aimed to evaluate the safety and efficacy of this drug-eluting covered stent in a porcine coronary perforation model.

In the present study, we investigated the safety and efficacy of a novel covered stent in a swine coronary perforation model. The findings from the present study are summarized as follows: (1) A controllable and safe CAP model was developed using guidewire assisted by micro-catheter. (2) The novel drug-eluting covered stent had a high success rate in sealing the coronary perforation without any incidence of cardiac tamponade. (3) The novel drug-eluting covered stent demonstrated a relatively sustained antiproliferative effect up to 6 months post implantation.

Coronary artery perforation (CAP), especially Ellis type III CAP, is a life-threatening complication of PCI, and is associated with a high incidence of cardiac tamponade (42.9%) [19], however, the technique of creating an animal model of CAP has not been previously addressed. To evaluate the efficacy of covered stents, we developed a CAP animal model. Our model has two salient features. First, the perforation was controllable. We used a micro-catheter to control the position and size of the perforation. Second, the model was relatively secured. A protective soft tip guidewire allowed an immediate deployment of the covered stent, thereby avoiding cardiac tamponade and percutaneous pericardial drainage. In this study, all Ellis type III perforations were successfully established using guidewire guided by micro-catheter without inducing any cardiac tamponade required treatment. We believe this coronary perforation model is promising for a variety of applications such as vascular injury, cardiac tamponade, and device evaluation in cases with coronary perforation.

Covered stents are considered an effective bailout strategy for Ellis types III coronary perforation which cannot be salvaged with a prolonged balloon inflation [5]. Covered stents with a “sandwich-like” structure have a device failure rate in the range of 16.7% [20] to 23.8% [21] in complex lesions. Compared to the GRAFTMASTER stent, the new generation PK Papyrus stent is associated with a shorter delivery time (8 vs. 15 min, p = 0.001), and a higher procedural success rate (86% vs. 69%, p = 0.216) [9]. Similar to the BeGraft and PK Papyrus stents, the covered stent established in the present study adopted the design of a single layer metal stent with a single layer of PTFE membrane, and has a small crimped profile that ranged between 1.1 and 1.3 mm. In our study, the device success rate was 100% without any incidence of cardiac tamponade and cardiac arrest.

In-stent restenosis (ISR) is a major concern of covered stents that needs to be resolved. Current data suggest that the rate of ISR in PTFE covered stent-treated patients range between 29.2% [20] and 54.6% [22]. Although the deliverability of the newer generation covered stents has greatly improved due to the adoption of a single layer design of metal stent, the incidence of ISR remains high. Kufner et al. reported outcomes from 61 coronary perforation patients treated with the BeGraft covered stent. During a follow-up of 192.8 $\pm$ 144.2 days, the incidence of binary angiographic restenosis was 26.9% in overall patients and 45.5% in patients with very complex lesions [23].

The underlying mechanism of ISR post PTFE covered stent implantation is considered to be associated with the following reasons [11, 12, 13, 21]: (1) delayed endothelialization, (2) thrombus formation, (3) intimal proliferation stimulated by PTFE, and (4) stent malapposition or vascular injury such as dissection. To avoid such causes of ISR, intensive antiplatelet treatment, OCT or IVUS guided stent implantation and specific histocompatible materials could be used. To improve the biocompatibility, the asneugraft® Dx stent used pericardium, a collagen-rich biological tissue, to replace the PTFE membrane. Unfortunately, the pericardium covered stent demonstrated a higher occurrence of ISR than the PTFE covered stent [6].

Papafaklis et al. [14] and Hou et al. [12] reported that the combination of PTFE-covered stents and an underlying long sirolimus-eluting stent implantation offered better angiographic follow-up results, as evidenced by a decrease in the stent-edge or stent-segment binary restenosis. Therefore, we hypothesized that antiproliferative drugs could decrease neointimal proliferation induced by the PTFE. In the present study, we used a stent platform with PLGA biodegradable polymer. The dosage of sirolimus on the covered stent was 225 $\mu$g, which may decrease the restenosis. Furthermore, OCT was introduced to optimize the stent implantation and avoid any vascular dissection, a major risk factor of ISR [24]. At 1-month angiographic follow-up, the LLL was significantly lower with our novel drug-eluting covered stent than with the non-drug eluting stents. At the 6-month follow-up, in comparison to the control covered stent, the drug-eluting covered stent still demonstrated a lower LLL. Histological analysis showed that, in comparison to the control stent, the drug-eluting covered stent significantly decreased the mean plaque area. The drug-eluting covered stent demonstrated a relatively sustained antiproliferative effect up to 6 months post implantation. Notably, the MLD reduced gradually after post PCI in both groups (Table 1). Although restenosis is a progressive phenomenon that begins in the early hours after the barotrauma determined by PCI [25], and even after DES implantation, the rate of restenosis is still around 10% [26]. Nevertheless, our results could provide a new conceptual design of covered stent to treat neointimal proliferation induced by the covered membrane. However, these results were obtained in a porcine model, and as such, the safety and efficacy of this drug-eluting covered stent needed to be further investigated in human subjects. The in-stent thrombosis is a safety concern associated with covered stent implantation. In the present study, OCT was introduced to avoid stent malapposition or under expansion, a risk factor for thrombosis. At 1-month follow-up, no in-stent thrombosis was observed, and all stent segments demonstrated complete endothelialization in swine examined with OCT.

Covert stent was mainly used for the treatment of CAP, but also could be used for other indications such as coronary artery aneurysms (CAA), pseudoaneurysms, arterial-venous fistula, etc. [27, 28, 29]. Previous studies showed that CAA was the second most frequent indication for covered stents, but with a relatively high rate of stent thrombosis [2, 27]. Using intravascular imaging or a computed tomography scan to achieve accurate landing zone assessment and stent sizing during CAA with covered stents is recommended [27]. Post-dilatation and procedural guidance with intravascular imaging may lead to optimal apposition and expansion of the stent, which could improve the long-term outcomes. Besides CAP and CAA, covert stent also could be used to treat pseudoaneurysm, arterial-venous fistula, saphenous vein graft, etc. [27, 28, 29, 30]. Information regarding covered stents in these off-label use was heterogeneous and limited to small sample size studies, highlighting the unmet need for large-scale trials in these settings.

In the present study, the swine coronary perforation mode which was developed using guidewire assisted by micro-catheter seemed to be a controllable and safe CAP model. In this CAP model, implantation of a novel drug-eluting covered stent was proven to be safe and effective with a high device success rate and without any incidence of stent thrombosis or delayed endothelialization. Moreover, the novel drug-eluting covered stent demonstrated a relatively sustained antiproliferative effect up to 6 months post implantation. Our findings need to be confirmed in future studies with a larger sample size and long-term follow-up.

LT had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. YL, JZ, XW and RW contributed to the data collection, analysis and interpretation, and the writing of the manuscript. CG, FM, WY, RW and LT contributed substantially to study design, the data analysis and interpretation, and the critical revision of the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

The animal study was approved by the Ethics Committee of Xijing Hospital, Fourth Military Medical University (Xi’an, China) (No. IACUC-20150511).

We thank our research staff at the Heart Center of XijingHospital, and the nurses and technologists at the cardiac catheterization laboratories of the Heart Center of Xijing Hospital. We thank Yinyi (Liaoning) Biotech Co., Ltd (Dalian, China) for providing technical support on the design and production of the novel covered stent in our study. Thanks to all the peer reviewers for their opinions and suggestions.

This work was financially supported by the National Key R&D Program of China (Grant No. 2018YFA0107400), Program for National Science Funds of China (Grants No. 82070853, 81730011, 81970721 and 81927805), Program for Changjiang Scholars and Innovative Research Team in University (Grant No. PCSIRT-14R08).

Yinyi (Liaoning) Biotech Co., Ltd (Dalian, China) kindly assisted us on the design and production of the novel covered stent. We declare that Yinyi (Liaoning) Biotech Co., Ltd had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. The authors declare no conflicts of interest.