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6 Vascular Biology ofSmooth Muscle Cells andRestenosis

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vascular biological biocompatibility issues of intervention and highlighted the need for improved stent technologies and designs.

Second generation DES have subsequently been developed that signicantly overcome many of the issues exhibited by rst-generation DES.Second-generation coronary DES incorporate more biocompatible polymers. They are also thinner with more exible cobalt-chromium or platinum struts and release newer antiproliferative drugs. In the second-generation stents two limus analogs (Zotarolimus and Everolimus) have replaced paclitaxel, which have a wider toxic-therapeutic ratio. Combined, these changes have markedly lowered, although not completely eliminated, the rates of late-thrombosis. Whether event-free survival can be further improved by more enhancements in stent design is uncertain. Bioresorbable stents are the latest stent technology in which drugs are eluted from bioresorbable polymer- free systems. They are designed to gradually disappear over the course of a year, a time at which vessel remodelling should be complete. They therefore offer theoretical advantages over DES but are yet to show improved clinical outcomes and are thus far disappointing. Contemporary second-generation DES are therefore the leading stent and clinical outcomes following their deployment are generally very good, but have plateaued and have largely remained unchanged over the past decade. The principal remaining causes of failure include early and late inammatory and hypersensitivity reactions to the drugs or stent polymers, mechanical problems such as strut fracture and longitudinal deformation, very late issues with a permanent metallic implant such as vessel straightening, loss of cyclic strain, vasomotion and adaptive vascular remodelling, and, in particular, neoatherosclerosis.

6.3.2.2 Drug-Coated Balloons

Drug-coated balloons (DCBs) are a newly developed device in which the antiproliferative drugs found in DES are coated onto the surface of the balloon. The drugs are delivered to the site of stenosis following balloon ination which causes contact with the vessel wall. DCBs display a number of advantages over DES.For example, the balloons allow for uniform delivery of the drugs. In DES, by contrast, it has been shown that different gradients of drug concentration by non-uniform strut distribution can trigger neointimal overgrowth in sirolimus-eluting stents. DCBs also avoid the issues related to the presence of a metallic stent and do not require a polymer carrier. They are therefore less likely to induce unfavourable responses and allow for complete restoration of the vessel to its original state with a functional endothelium. Finally, DCBs allow for more exibility in future treatment options.

Paclitaxel is primarily used for coating DCBs. The reason for this is that paclitaxel is highly lipophilic and allows for passive absorption through cell membranes which improves treatment uptake and effect. More recently carrier excipients for DCBs have been developed that greatly facilitate drug transfer during the short period of contact between the inated balloon and the vessel wall. The excipient prevents crystallisation of the drug on the balloon surface which hinders drug

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transfer and absorption. The excipent also, therefore importantly, prevents the loss of drugs into the blood stream. A variety of exipients have been developed including iopromide, urea and shellac that display a diversity of responses, indicating that improvements in this technology still need to be made.

Clinical studies have shown early promise for the treatment of both coronary and lower extremity vascular disease. A number of recent studies report their use, in particular, for the femoropopliteal artery. DCBs show good efcacy when the atherosclerotic lesions are medium length and minimally calcied. Other indications that are being investigated include niche lesion subsets such as small vessels and bifurcations in which stents are not a viable alternative. Another interesting use is for the treatment of in-stent restenosis or for a restenotic site that previously received balloon angioplasty. Whilst DCBs are still in their infancy and procedural improvements (e.g. ination pressure, duration) still need to be made, they do show excellent promise as the next revolution in PCI.

6.3.2.3 Emerging Role ofmiRNAs inRestenosis

The discovery of microRNAs (or miRNAs) has revealed a further layer to the regulation of restenosis, amongst an already large number of regulators. MiRNAs are short RNA molecules that repress gene expression by binding to the 3′UTR of mRNA (region of mRNA that immediately follows the translation termination codon) transcripts to either degrade the transcript or prevent translation completely or partially. MiRNAs have been investigated for their potential to either be a therapeutic target or a biomarker of disease. Recent evidence has revealed that miRNAs play roles in several aspects of the vascular response to injury and a vast number of miRNAs have been reported to inuence VMSC proliferation, migration and apoptosis (reviewed in Gareri etal [57]). One of the more highly reported miRNAs is miR-21 which is highly expressed in both VSMCs and ECs and increases further following vascular injury [58]. This suggests that it plays a role in restenosis. In support of this, if VSMCs are serum starved to slow their proliferation, miR-21 levels decrease. Furthermore, inhibition of miR-21 increases VSMC apoptosis and reduces cell growth in vitro and after vascular injury in vivo. Intravenous infusion of an anti-miR-21 to reduce miR-21, caused dose-dependent suppression of luminal closure, without affecting re-endothelialisation [

58]. Systemic delivery of miR-21

causes, however, a number of other unwanted side effects including increased serum creatine concentrations. Further studies with a local delivery approach in which the anti-miR-21 was coated onto the stents was found to effectively reduce restenosis without causing any unwanted side effects. Further experimentation revealed that PTEN (phosphatase and tensin homolog deleted on chromosome 10), an antiproliferative protein, was a direct target of miR-21, which may explain the mechanism for its action on VSMCs [58]. Another study also reported that circulating levels of miR-21 were a predictor of restenosis after interventional therapy in patients with lower extremity arterial occlusive disease [59]. Furthermore, miR-21 levels are signicantly correlated with age, diabetes and hypertension.

6 Vascular Biology ofSmooth Muscle Cells andRestenosis

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MiR-146a is another miRNA of interest as it targets the pro-proliferative transcription factor KLF4. KLF4, in turn, binds to the promoter region on miR-146, thereby forming a feedback loop in which they regulate each other [60]. Other restenosis- related mechanisms of miRNAs have also been revealed. MiR-612 and miR-125a-5p, for example, act on PDGF that promotes the phenotypic switch and increases VSMC proliferation [61, 62]. Studies have found that overexpression of both miR-612 and miR-125a-5p inhibits VSMC proliferation and migration.

Therapeutic approaches using infusions of inhibitors (anti-miRNAs) or mimics that overexpress miRNAs have been utilised in animal models of vascular injury and restenosis. In a rabbit model of carotid balloon angioplasty, infusion of miR- 140-3p to increase its circulating levels, was found to reduce restenosis. Similarly, infusions of miR-126 and miR-495 are found to reduce restenosis in rodent models [63, 64].

A number of circulating miRNAs have been found to have predictive value for in-stent restenosis. miR-195, miR-320a and miR-572 have all been associated with in-stent restenosis for patients with PAD [65, 66]. Furthermore, miR-93-5p has been found to be predictive of coronary in-stent restenosis [67].

The number of miRNAs reported to regulate and predict restenosis continues to increase. Future stent technologies may indeed incorporate miRNA release in an effort to further reduce the complications of DES-related restenosis.

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6.4 Neoatherosclerosis

Neoatherosclerosis is an important contributing factor to the late stent-related cardiovascular events after deployment of DES. It may be the major nal common denominator in late stent failure and is not decreasing in prevalence as stent technology improves. Indeed, autopsy series have shown no difference between the rstand second-generation DES in the prevalence of coronary neoatherosclerosis [68]. Neoatherosclerosis is time-dependent, with its prevalence increasing the longer the stent is in place. The histopathology of neoatherosclerosis is similar to native atherosclerosis, containing macrophage/foam cells, cholesterol clefts, areas of calcication and necrotic cores. Neoatherosclerosis occurs within much shorter time frames than native atherosclerosis and develops at 6 months–5 years post-stent deployment, rather than over a lifetime. Neoatherosclerosis accelerates late expansion of the neointima as a key cause of stent failure. The neointimal plaques can also become unstable, with ruptured thin-capped neointimal plaques acting as the primary cause of very late stent thrombosis [69]. Although the mechanisms of neoatherosclerosis are not entirely elucidated, the higher occurrence of neoatherosclerosis in DES may be the result of drug resistance, a reaction to the DES polymers or DES-induced delayed re-endothelialisation.

It has been widely hypothesised that the formation of neoatherosclerosis is closely related to the progression of native arterial atherosclerosis [70]. During stent deployment .the vascular wall undergoes expansion by stent struts, which

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causes endothelial denudation, signicant medial injury, plaque compression and rupture of the internal elastic lamina. These events trigger an inammatory response that initiates the development of neoatherosclerosis. The original plaque that is compressed by the stent is also a source of growth factors and chemokines that further promote neoatherosclerosis. In support of this theory, in a serial intravascular ultrasound study, smaller atherosclerotic plaques behind the stent correlated with the extent of neointimal formation. A better understanding of biological processes that drive the early and late inammatory reactions to stenting may therefore aid in further reducing the risk of in-stent restenosis and neoatherosclerosis.

6.5 Conclusions

VSMCs have a fascinating array of functions and phenotypes that are inuenced by their surrounding stimuli and origin. They play an important role in regulating the constriction and dilatation of vessels and participate in the development of vascular inammatory pathologies such as restenosis and atherosclerosis(Fig. 6.3). The reliance upon angioplasty and stents to treat atherosclerotic stenosis and occlusions in the last two decades has signicantly increased, which has led to a rise in complications such as restenosis, stent thrombosis and neoatherosclerosis. The continuing development of new ways to prevent in-stent restenosis is therefore critically important. With the recent increase in knowledge regarding the involvement of miRNAs in the regulation of restenosis, it raises the possibility for miRNAs to be incorporated into future stent technologies. A continued understanding of the multiple roles of VSMCs and their regulation in atherosclerosis and restenosis will be important for the road ahead.

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https://doi.org/10.1161/CIRCRESAHA.115.308237.

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