Bioresorbable scaffolds: should we stay simple or go complex?
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ABSTRACT:
SUBMITTER: Ortega-Paz L
PROVIDER: S-EPMC5440260 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Bioresorbable scaffolds: should we stay simple or go complex?
Ortega-Paz Luis L Brugaletta Salvatore S Garcia-Garcia Hector M HM Sabaté Manel M
Cardiovascular diagnosis and therapy 20170601 3
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Project description:Percutaneous coronary intervention (PCI) has undergone major advances including the evolution in stent technology, from bare metal stents (BMS), to their drug eluting counterparts, to the development of bioresorbable scaffolds (BRS). The primary notion of BRS was to facilitate complete vascular healing and restore normal endothelial function following the resorption of stent scaffold while providing equivalent mechanical properties of a metallic drug eluting stents (DES) in the earlier stages. BRS provide attractive physiologic advancements over the existing DES and have shown promising results in initial clinical studies albeit with small sample sizes. Their use has been primarily restricted to patients recruited in clinical trials with limited real-world applicability. Thus, data from larger randomised control trials is awaited. The major objective of this article is to review the evidence on BRS and identify their clinical applicability in current interventional practice.
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Project description:UnlabelledInnovations in drug-eluting stents (DES) have substantially reduced rates of in-segment restenosis and early stent thrombosis, improving clinical outcomes following percutaneous coronary interventions (PCI). However a fixed metallic implant in a vessel wall with restored patency and residual disease remains a precipitating factor for sustained local inflammation, in-stent neo-atherosclerosis and impaired vasomotor function increasing the risk for late complications attributed to late or very late stent thrombosis and late target lesion revascularization (TLR) (late catch-up). The quest for optimal coronary stenting continues by further innovations in stent design and by using biocompatible materials other than cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding, local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics have been recently developed. These devices have been utilized in selected clinical applications so far providing preliminary evidence of safety showing comparable performance with current generation drug-eluting stents (DES). Herein we provide a comprehensive overview of the current status of these technologies, we elaborate on the potential benefits of transient coronary scaffolds over permanent stents in the context of vascular reparation therapy, and we further focus on the evolving challenges these devices have to overcome to compete with current generation DES.Condensed abstract: The quest for optimizing percutaneous coronary interventions continues by iterative innovations in device materials beyond cobalt chromium, platinum chromium or stainless steel for engineering coronary implants. Bioresorbable scaffolds made of biodegradable polymers or biocorrodible metals with properties of transient vessel scaffolding; local drug-elution and future restoration of vessel anatomy, physiology and local hemodynamics were recently developed. These devices have been utilized in selected clinical applications providing preliminary evidence of safety showing comparable intermediate term clinical outcomes with current generation drug-eluting stents.
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Project description:Percutaneous coronary intervention, which is safe, effective, and timely, has become an important treatment for coronary artery diseases and has been widely used in clinical practice. However, there are still some problems that urgently need to be solved. Permanent vessel caging through metallic implants not only prevents the process of positive vessel remodeling and the restoration of vascular physiology but also makes the future revascularization of target vessels more difficult. Bioresorbable scaffolds (BRSs) have been developed as a potential solution to avoid the above adverse reactions caused by permanent metallic devices. BRSs provide temporary support to the vessel wall in the short term and then gradually degrade over time to restore the natural state of coronary arteries. Nonetheless, long-term follow-up of large-scale trials has drawn considerable attention to the safety of BRSs, and the significantly increased risk of late scaffold thrombosis (ScT) limits its clinical application. In this review, we summarize the current status and clinical experiences of BRSs to understand the application prospects and limitations of these devices. In addition, we focus on ScT after implantation, as it is currently the primary drawback of BRS. We also analyze the causes of ScT and discuss improvements required to overcome this serious drawback and to move the field forward.
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Project description:This review focuses on the clinical and biological features of the bioresorbable scaffolds in interventional cardiology highlighting scientific achievements and challenges of the transient scaffolding with Absorb BVS. Special attention is granted to the vascular biology pathways which, involved in the resorption of scaffold, artery remodeling and mechanisms of Glagovian atheroregression setting the stage for subsequent clinical applications. Twenty five years ago Glagov described the phenomenon of limited external elastic membrane enlargement in response to an increase in plaque burden. We believe this threshold becomes the target for development of strategies that reverse atherosclerosis, and particularly transient scaffolding has a potential to be a tool to ultimately conquer atherosclerosis.
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Project description:Numerous advances and innovative therapies have been introduced in interventional cardiology over the recent years, since the first introduction of balloon angioplasty, but bioresorbable scaffold is certainly one of the most exciting and attracting one. Despite the fact that the metallic drug-eluting stents have significantly diminished the re-stenosis ratio, they have considerable limitations including the hypersensitivity reaction to the polymer that can cause local inflammation, the risk of neo-atherosclerotic lesion formation which can lead to late stent failure as well as the fact that they may preclude surgical revascularization and distort vessel physiology. Bioresorbable scaffolds overcome these limitations as they have the ability to dissolve after providing temporary scaffolding which safeguards vessel patency. In this article we review the recent developments in the field and provide an overview of the devices and the evidence that support their efficacy in the treatment of CAD. Currently 3 devices are CE marked and in clinical use. Additional 24 companies are developing these kind of coronary devices. Most frequently used material is PLLA followed by magnesium.
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Project description:Coronary bioresorbable vascular scaffolds are a new appealing therapeutic option in interventional cardiology. The most used and studied is currently the Absorb BVS™. Its backbone is made of poly-L-lactide and coated by a thin layer of poly-D,L-lactide, it releases everolimus and is fully degraded to H2O and CO2 in 2-3 years. Absorb BVS™ seems to offer several theoretical advantages over metallic stent, as it gives temporary mechanical support to vessel wall without permanently caging it. Therefore, long-term endothelial function and structure are not affected. A possible future surgical revascularization is not compromised. Natural vasomotion in response to external stimuli is also recovered. Several observational and randomized trials have been published about BVS clinical outcomes. The main aim of this review is to carry out a systematic analysis about Absorb BVS™ studies, evaluating also the technical improvements of the Absorb GT1 BVS™.
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Project description:A Type II VapB14 Antitoxin regulates biofilm dispersal in the archaeal thermoacidophile Sulfolobus acidocaldarius, not only through traditional Toxin neutralization but also through noncanonical transcriptional regulation. Type II VapC Toxins are ribonucleases that are neutralized by their proteinaceous cognate Type II VapB Antitoxin. VapB Antitoxins have a flexible tail at their C-terminus that covers the Toxin’s active site neutralizing its activity. VapB Antitoxins also have a DNA binding domain at their N-terminus that allows them to not only auto-repress their own promoters but also distal targets. VapB14 Antitoxin gene deletion in S. acidocaldarius stunted biofilm and planktonic growth and increased motility structures (archaella). Conversely, planktonic cells were devoid of archaella in the ΔvapC14 cognate Toxin mutant. VapB14 is highly conserved at both the nucleotide and amino acid levels across the Sulfolobales, extremely unusual for Type II Antitoxins that are typically acquired through horizontal gene transfer. Furthermore, homologs of VapB14 are found across the Crenarchaeota, in some Euryarchaeota, and even bacteria. S. acidocaldarius vapB14 and its homolog in the thermoacidophile Metallosphaera sedula (Msed_0871) were both up-regulated in biofilm cells, supporting the role of the Antitoxin in biofilm regulation. The findings here suggest that a stand-alone VapB-type Antitoxin was the product of selective evolutionary pressure to influence biofilm formation in these archaea, a vital microbial community behavior.
2023-03-27 | GSE226483 | GEO
Project description:Arrestins make up a small family of proteins with four mammalian members that play key roles in the regulation of multiple G protein-coupled receptor-dependent and -independent signaling pathways. Although arrestins were reported to serve as scaffolds for MAP kinase cascades, promoting the activation of JNK3, ERK1/2, and p38, the molecular mechanisms involved were not elucidated, and even the direct binding of arrestins with MAP kinases was never demonstrated. Here, using purified proteins, we show that both nonvisual arrestins directly bind JNK3α2 and its upstream activator MKK4, and that the affinity of arrestin-3 for these kinases is higher than that of arrestin-2. Reconstitution of the MKK4-JNK3α2 signaling module from pure proteins in the presence of different arrestin-3 concentrations showed that arrestin-3 acts as a "true" scaffold, facilitating JNK3α2 phosphorylation by bringing the two kinases together. Both the level of JNK3α2 phosphorylation by MKK4 and JNK3α2 activity toward its substrate ATF2 increase at low and then decrease at high arrestin-3 levels, yielding a bell-shaped concentration dependence expected with true scaffolds that do not activate the upstream kinase or its substrate. Thus, direct binding of both kinases and true scaffolding is the molecular mechanism of action of arrestin-3 on the MKK4-JNK3α2 signaling module.
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Project description:Background: The performance of an everolimus-eluting bioresorbable scaffold (BRS) was inferior to an everolimus-eluting metallic drug-eluting stent (DES) with permanent polymer, mainly due the mechanical features of BRS technology. The performance of BRS as compared to metallic DES with bioresorbable polymers remains unstudied. Methods: This prospective, randomized, multicenter, clinical trial enrolled patients who underwent coronary stenting for de novo coronary lesions. Patients were randomly assigned to bioresorbable polymer everolimus-eluting stents (BP-EES) or everolimus-eluting BRS. The primary endpoint was percentage diameter stenosis (in-device) at 6- to 8-month angiographic surveillance. The main secondary endpoint was the device-oriented composite endpoint (DOCE) of cardiac death/target vessel-myocardial infarction/target lesion revascularization assessed after 12 months and 5 years. Results: The trial was prematurely terminated after the enrollment of 117 of 230 patients (BP-EES, n = 60; BRS, n = 57) due to safety issues associated with BRS technology. The primary endpoint of in-device diameter stenosis at angiographic surveillance was 12.5 ± 7.7% with BP-EES versus 19.3 ± 16.5% with BRS (p = 0.01). The DOCE occurred in 5.0% in the BP-EES group versus 12.3% of patients in the BRS group (hazard ratio [HR] 2.48, 95% confidence interval [CI] 0.64-9.58, p = 0.19) after 12 months and in 11.7% in the BP-EES group versus 26.4% of patients in the BRS group (HR 2.38, 95% CI 0.97-5.84, p = 0.06) after 5 years. Conclusions: BP-EES showed superior mid-term angiographic performance compared with BRS. Clinical event rates did not differ significantly between the groups up to 5 years of follow-up. These results should be interpreted with caution in view of the premature discontinuation of the study.
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