Introduction
The better efficacy of first-generation drug-eluting stents (DES) compared with bare-metal stents (BMS) in the treatment of patients with coronary artery disease in
de novo coronary lesions has been confirmed in many large-scale randomized clinical trials. However, reports of late (30 days to 1 year) and very late (after 1 year) in-stent thrombosis in patients with DES implantation after the discontinuation of antiplatelet therapy have been released [
1]. Subsequent angiographic investigations have revealed that DES struts do not reach complete neointimal coverage, and this incomplete coverage is associated with an increased risk of thrombus [
2]. Recently, a pathology study has suggested that neoatherosclerosis is a frequent finding in DES-covered segments which occur significantly earlier compared with BMS-covered segments, suggesting that neoatherosclerosis could be accelerated after DES implantation, and in rare cases, contribute to very late thrombotic events [
3]. Although newer-generation DES involves fewer cases of early/late stent thrombosis [
4], these events remain a severe complication because of their high morbidity and mortality. Therefore, the DES used in clinical practice in the past is not fully optimized, and the search for new and improved DES never stops. The present review focuses on translational research in the field of novel DES, including drug discovery, creation of preclinical research models, planning and conducting of first-in-man studies, and developing next-generation DES systems.
Discovery of drugs used on DES
To date, the drugs used in DES include mammalian targets of rapamycin inhibitors, calcineurin inhibitors, taxans, hormones, and cytotoxic antibiotics [
5]. Some potential drugs have been tested extensively in animal models (Table 1), including the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor cerivastatin [
6], the antimigratory drug batimastat [
7], the synthetic cyclin-dependent kinase inhibitor flavopiridol [
8], and antioxidants, such as probucol and carvedilol [
9]. Preclinical assessments have revealed a reduction of neointimal formation in stents coated with these compounds. Although animal studies could not predict final clinical success, they can provide valuable insights regarding safety and biocompatibility aspects.
Another group of potential drugs for the DES platform have been found through systemic administration studies, which showed the effects of decreasing in-stent restenosis. For example, cilostazol in addition to dual antiplatelet therapy is associated with a reduction in major adverse cardiac events in patients undergoing stent-based percutaneous coronary intervention [
10]. The Cilotax trial [
11] examined the effect of a dual DES (cilostazol and paclitaxel) compared with the paclitaxel-eluting Taxus
® stent (Boston Scientific, MA, USA) in a small, clinical pilot study. The above-mentioned trial revealed a significant reduction of the primary endpoint (late lumen loss as a marker of restenosis) in favor of the dual DES (
P = 0.005). These results suggest that cilostazol combined with paclitaxel could yield favorable clinical result. The drugs in the DES are the keys to its efficacy. Therefore, the search for drugs or a combination of drugs that potently target the key pathogenesis of in-stent restenosis continues.
The potential advantages of newer drugs over those used in first-generation DES include the following: inhibition of vascular smooth muscle cell proliferation and migration without affecting endothelial regeneration; restoration of anatomical and functional endothelial integrity; reduction of the risk of stent thrombosis; and reduction of inflammation, especially in the presence of a proinflammatory coating component, such as a polymer.
Pre-clinical animal models
During the development of DES, animal experiments using appropriate models play important roles in the regulatory process used to determine their safety and efficacy before human clinical trials. Sometimes, even after devices have been approved for clinical use, further understanding of their mechanisms can be realized through comparative analysis of animal model research findings with those of clinical pathological specimens.
Rabbit iliac arteries and domestic porcine coronary arteries are the two most widely used animal arteries in assessing DES safety and efficacy [
12]. In the porcine coronary stent model, a thick neointima is reliably induced within 28 days, and a confluent monolayer of endothelial progenitor cells over and between the struts of the stent is observed 48 h after stent implantation. Complete healing with neointima is observed 28 days after stent implantation. Several time points should be used for the evaluation of DES performance. The first is within 28 days to observe for neointimal hyperplasia, and there should be at least 1 later time point to examine the long-term effects, which depends on when “healing” and drug release are completed [
13]. Generally, this process takes 3 to 6 months. The rabbit iliac restenosis model has been studied extensively to test restenosis therapies and to understand the cellular and molecular mechanism of restenosis. Balloon angioplasty in the rabbit model causes histopathologic injury comparable with that seen in human angioplasty. However, a limitation is that, foam cells are commonly found in this model, whereas they are rare in human restenotic neointima. The advantages and disadvantages of the two pre-clinical models are listed in Table 2.
First-in-man studies
The first DES first-in-man (FIM) study was conducted in Brazil [
14]. Since then, many novel DES FIM studies have been carried out worldwide. The purpose of this type of studies is to demonstrate the feasibility and acute safety of novel devices. These studies are frequently conducted with a few patients and include a control group treated with a proven DES. One of the shortcomings of this type of studies is that their power is too weak to show the differences in clinical outcomes compared with other devices, so they can only use surrogate endpoints to demonstrate the device efficacy. Imaging modalities are used as surrogate endpoints, which include in-stent late loss measured by quantitative coronary angiography and percent stent obstruction measured by intravascular ultrasound. Recently, new technologies have been incorporated into FIM studies, such as optical coherence tomography (OCT) and coronary vessel reactive tests. OCT has two advantages over other imaging modalities. First, it has a resolution as high as 10 µm, and is able to evaluate the amount of DES strut coverage in the follow-up procedure; thus, it can be a potential marker of DES biocompatibility. Second, this technology allows for a more detailed investigation of the occurrence of abnormal stent morphologies, such as strut incomplete apposition and intraluminal thrombus formation. Vessel reactive tests assess whether the neointimal tissue covering the DES struts and the reference adjacent segment properly respond to pharmacological agents to assess the physiologic endothelium responsiveness. Although these surrogate endpoints can never replace clinical endpoints, they can prevent larger trials using potentially ineffective novel devices.
Promising and novel DES undergoing translational research
Fully resorbable DES
The long-term limitations of metallic DES include permanent intravascular implantation which precludes surgical revascularization, jailing of side branches, and hampering of noninvasive imaging of coronary arteries with multislice computed tomography and magnetic resonance imaging. Bioabsorbable drug-eluting vascular scaffold (BVS; Abbott Vascular, Santa Clara, California) is a new platform that provides transient vessel dilation with drug delivery capability [
15]. The scaffold consists of a backbone of poly-l-lactide coated with poly-d,l-lactide that contains and controls the release of everolimus, an antiproliferative drug (Novartis, Basel, Switzerland). The first generation of BVS shows slightly higher acute recoil than conventional metallic platform stents [
16]. To further enhance support of the vessel wall, the strut design and manufacturing processes of the polymer are modified, leading to BVS revision 1.1. The device has been investigated in the ABSORB Cohort B trial. The modification of the manufacturing process of the polymer and the geometric changes in the polymeric platform have substantially improved the medium-term performance of the fully resorbable DES to become comparable to that of current unresorbable DES.
DES with genetic modifiers
Using new technologies, bio-material in the coating of DES can cause gene modification, such as RNA interference (RNAi) and adenoviral vectors. RNAi is a system within living cells that takes part in controlling which genes are active and how active they are. Two types of small RNA molecules, namely, microRNA (miRNA) and small interfering RNA (siRNA), are central to RNAi. These small RNAs can bind to other specific RNAs (mRNA), thus increasing or decreasing their activity, such as by preventing an mRNA from producing a protein. RNAi has an important role in defending cells against parasitic genes, such as viruses and transposons. RNAi also directs development and gene expression. This therapeutic principle is an attractive approach for local stent-based therapy. San Juan
et al. [
17] demonstrated that cationized pullulan-based hydrogel could be used as a new biocompatible and biodegradable stent coating for local siRNA-induced gene therapy in the arterial wall. Recently, the evolution of new specialized molecular mechanisms and the ability of viruses to deliver recombinant DNA molecules (transgenes) into host cells have led to better DES development. Adenoviral vectors could be delivered from the bare-metal surfaces of stents with synthetic complexes for reversible vector binding. Han
et al. [
18] reported that the cellular repressor of E1A-stimulated genes (CREG), a secreted glycoprotein, is downregulated as a smooth muscle cell from a quiescent, differentiated phenotype to a proliferative, immature phenotype in balloon-injured carotid artery in rabbit models. In the same study, local CREG delivery to the injured artery mediated by adenovirus inhibits smooth muscle cell dedifferentiation and proliferation, thus reducing neointimal formation (Fig. 1). In rat carotid studies, the deployment of steel stents coated with adenoviral vectors demonstrates both site-specific arterial adenoviral vectors-green fluorescent protein expression and adenovirus-luciferase transgene activity, as observed by optical imaging. Rat carotid stent delivery of adenovirus encoding inducible nitric oxide synthase results in significant inhibition of restenosis [
19]. In addition to adenoviral vectors, the lentiviral vector is very productive in terms of transduction because of its ability to infect both replicating and non-replicating cells; it is also a promising gene vector for future DES development. Bonta
et al. [
20] found that recombinant lentivirus encoding the
Nurr1gene can effectively cause
Nurr1 overexpression in smooth muscle cells (SMCs), which results in the inhibition of SMCs proliferation. Adenovirus-based gene therapy for restenosis is experimental and has not been proven in clinical trials.
Individualized DES
In clinical practice, systemic drug therapies targeting a specific lesion are common. The same is true for next-generation DES, some of which target specific lesions or patient subgroups. Once identified, an optimal combination of drugs or therapeutic strategies, such as pharmaco-based, nucleic acid-based, and/or peptide-based therapies, can more likely accomplish these tasks. These stents allow the directional delivery of a drug or a combination of drugs. Thus, targeting specific cell types, such as smooth muscles and endothelial cells, is possible. Stents designed for specific clinical indications, such as diabetic lesions or vulnerable plaques, are being developed. These stents would not only allow local treatment, but concomitantly exhibit paracrine properties by releasing novel compounds, including adenosine receptor agonists, reperfusion injury salvage kinases, erythropoietin, or glucagon-like peptide-1 in downstream tissues, such as the ischemic myocardium.
Conclusions
Similar to randomized controlled clinical trials, translational research provides sustainable solutions for DES problems. Knowledge of translational research methods for interventional cardiologists would enable better assessment of complex issues in evidence-based medicine, would help integrate effective therapies with clinical practice, and would encourage continuous improvement of interventional cardiology.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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