the lipid - lowering drugs have an outstanding track record of lowering cholesterol and improving outcomes .
clinical trials such as miracle ( 2001 ) , reversal ( 2004 ) , normalize ( 2004 ) , prove it ( 2004 ) , establish ( 2004 ) , asteroid ( 2006 ) , jupiter ( 2008 ) , japan - acs ( 2009 ) , saturn ( 2011 ) , zeus ( 2014 ) , and ibis-4 ( 2015 ) have demonstrated that lowering ldl levels through intensive statin therapy can slow progression , or even partially reduce the total atheroma volume ( tav ) up to a 13.14 mm in ibis-4 trial or a 6.3% per cent atheroma volume ( pav ) in japan acs trial ( vs up to 8.2 mm tav and 12.5% pav in zeus trial with a combination of ezetimibe and atorvastatin ) [ 1 - 3 ] . of note ,
these findings also suggest that necrotic core and mineral deposits may resist risk factor modification or systemic drug therapy .
moreover , these trials documented   reduction of fibrous tissue and certain amount of intramural lipids with very slight effect on necrotic core accelerating calcium deposition in the coronary lesions whereas the fact that numerous studies of cholesterol lowering have failed to document a mortality benefit , and , so , the benefits of statins may have been overstated . current percutaneous coronary intervention ( pci ) using drug - eluting stents ( des ) is associated with a small , though sizeable risk of delayed healing , late stent thrombosis , abnormal vasomotion   and neoatherosclerosis   ( fig .
new devices such as bioresorbable scaffolds ( brs ) have been tested in more than 100,000 humans in the past six years ( absorb bvs 
bioresorbable vascular scaffold , abbott vascular , santa clara , ca ) [ 5 , 8 ] .
these devices scaffold the diseased coronary artery and elute an anti - proliferative drug that counteracts constrictive remodeling , and excessive neointimal hyperplasia [ 7 , 10 ] . until now
, the brs platform has been used in both real - world and complex lesions due to the nature of patient selection in these clinical trials [ 8 , 11 - 13 ] .
brs may represent a new era in cardiovascular medicine , since interventions will address not only the obstructive component of atherosclerotic disease , but also the biologic and functional properties of the vessel .
brs may thus be viewed as platforms upon which bioactive compounds are added to act as the disease - modifying agents .
new generations of devices may help us to fulfill our ultimate goal of atheroregression below the glagov threshold by reversing atherogenesis , slowing the ageing process and triggering repair of diseased arteries .
glagov s observation   in 1987 suggests that vascular remodeling maintains the artery lumen dimensions   as long as the plaque burden threshold of 40% is not trespassed ; a stage where the growth of the plaque can no longer be accommodated by external elastic membrane ( eem ) enlargement ( see fig .
this process or a window of the eem enlargement ( between a 20% and 55% pav )   in accommodating the plaque and maintaining the lumen dimensions is referred to as the glagov phenomenon , which is a cornerstone issue in the modern - day atheroprotective strategies .
moreover , it was documented in prospect trial   that pb>70% is an independent predictor of non - culprit major adverse cardiac events ( mace ) .
therefore , plaque reduction below the glagov threshold would imply some kind of atherosclerosis reversal setting back a lesion .
the biocompatibility of poly - l - lactic acid ( plla ) was controversial [ 17 , 18 ] . among the first polymeric devices to be studied was the plla bioabsorbable stent designed and tested by stack et al .
, reported to hold up to 1,000 mmhg crush pressure and maintain its radial strength for 1 month .
this stent was almost completely degraded by 9 months with minimal thrombosis , moderate neointimal growth and a limited inflammatory response in porcine coronary arteries .
tamai , an interventional cardiologist who passed away in 2009 , invented the first - in - man fully biodegradable stent ( igaki - tamai stent ) made of plla . at that time ,
the pioneering experimental studies using a non - biodegradable polyethylene - terephthalate braided mesh stents in porcine animal models were published by the group of prof .
patrick serruys ( erasmus mc , rotterdam , the netherlands ) in 1992 [ 12 , 18 , 19 ] . to date , absorb bvs is the first device which has shown phenomena such as late lumen enlargement ( without pathological remodeling ) and wall thinning with reduction of plaque burden .
reversing atherosclerosis following transient scaffolding of a dilated stenotic lesion now provides the opportunity to further explore the general understanding of device therapy and local drug delivery in vascular biology .   in general , preclinical studies of brs eluting mtor ( mammalian target of rapamycin ) inhibitor everolimus in the porcine coronary model
have shown that polymeric struts completely disappeared and remnants were fully incorporated into the vessel wall within 4 years ( fig .
4 ) , becoming indiscernible by histology , oct and vh - ivus [ 2 , 5 , 8 , 18 , 20 , 21 ] . moreover , a circumferential evaluation of the healing process by oct after brs implantation showed a minimal amount of neointima forming a neocap of 170 m , which potentially contributes to plaque stability . as in the porcine model , late lumen enlargement , and plaque - media reduction with wall thinning
were also observed in humans using ivus ( a 12.7% pav reduction in absorb a trial between 6 and 24 months , and a 7.9% plaque area decline in absorb b trial between 24 and 36 months ) .
however we must mind the fact that existing today intravascular approaches to assess vascular contours remain not properly optimized , and can be one of the misguiding options which not allow us to ultimately judge the patterns of the artery remodeling after deployment of the transient interventions with absorb bvs .
in contrast to brs , a non - resorbable metal cage as used in the current generation of des fixes the vessel boundaries , interferes with mechanotransduction , disturbs shear stress , and induces chronic irritation of the underlying tissue with a severe immune - inflammatory response , progressive neoatherosclerosis   and expansive remodeling [ 15 , 16 ] . the first two publications on absorb bvs eluting everolimus and then results of absorb a and b trials in patients have reported three seminal observations ( see table 1 ) made respectively at 6-month and 24-month follow - up : a ) complete resorption documented indirectly by optical coherence tomography ( oct ) , intravascular ultrasound ( ivus ) grey scale and ivus radiofrequency backscattering ; b ) physiologically or pharmacologically induced restoration of vasomotion in the scaffolded area ; c ) late luminal enlargement with plaque / media regression documented by ivus and oct between 6 and 24 months [ 1 , 8 , 11 , 12 , 18 - 20 ] . however ,
analysis of the first - generation absorb bvs revealed unwanted late scaffold recoil which was fully remediated by a second - generation design and process that showed an unchanged scaffold area at 6 months follow - up .
further evaluation at 12 and 24 months follow - up as well as analysis by oct and ivus confirmed the persistence of an unchanged scaffold area without substantial loss in lumen area , while vasomotion became detectable .
these observations brought the evidences of the ongoing yielding process   and mechanical integrity of the scaffold to the vessel [ 2 , 5 , 7 , 18 ] .
a 3-year follow - up of this second generation is currently under way to refine these observations and to confirm whether the first signs of late lumen enlargement are detectable .
the absorb ii trial   had a 2:1 single - masked design matching absorb bvs with everolimus - eluting metallic stent , and a small sample population of 501 patients , with sophisticated co - primary endpoints of nitrate - induced vasomotion and changes in minimum lumen diameter ( in - stent late loss ) at 3 years .
the similar post implantation acute recoil ( 0.19 mm for both , p=0.85 ) , and lower acute lumen gain were documented for brs by both angiography ( 1.15 mm vs 1.46 mm , p<0.0001 ) and ivus ( 2.85 mm vs 3.60 mm , p<0.0001 ) .
the 1-year composite device orientated endpoint was similar between brs and metallic stent groups ( 16 patients [ 5% ] vs 5 patients [ 3% ] , p=0.35 ) .
three patients in the brs group had definite or probable scaold thrombosis ( one definite acute , one definite sub - acute , and one probable late ) , compared with no patients in the metallic stent group which is consistent with the previous studies [ 25 , 26 ] . the absorb iii trial confirmed non - inferiority of absorb bvs if compare with xience v stent . in this large , multicenter , randomized trial , 2008 patients with stable or unstable angina were randomly assigned in a 2:1 ratio to receive an everolimus - eluting bioresorbable vascular ( absorb ) scaffold ( 1322 patients ) or an everolimus - eluting cobalt  chromium ( xience ) stent ( 686 patients ) .
target - lesion failure at 1 year occurred in 7.8% of patients in the absorb group and in 6.1% of patients in the xience group ( difference , 1.7 percentage points ; 95% confidence interval , 0.5 to 3.9 ; p=0.007 for noninferiority and p=0.16 for superiority ) .
device thrombosis within 1 year occurred in 1.5% of patients in the absorb group and in 0.7% of patients in the xience group ( p=0.13 ) .
so , for today , the extensive experience ( see table 1 ) demonstrates such advantages of brs as reduction of late events ( absorb extend , 2014 ) , restored vessel function ( absorb cohort b trial , 2014 ) , reduced revascularization rates ( absorb ii , 2014 ) , plaque regression ( two multi - imaging modality studies of absorb a and b trials documented a biphasic change of the total plaque area ) , and lumen gain ( absorb cohort b trial , 2011 , 2013 ) [ 3 , 28 ] . definitely , brs performs well in stemi patients covering the lesions if compare with des , but thrombosis raises concerns .
meanwhile , brs are generally more challenging to implant in comparison with metallic stents ( especially in complex lesions ) , and careful patient and lesion selection is crucial to ensure the good results with this technology .
moreover , clinical experience with these devices remains rather limited ( amid growing evidence of late clinical events attributed to late restenosis , late or very late stent thrombosis and in - stent neoatherosclerosis ) , and further comparative efficacy data are required before we can be sure of the place of these devices in the routine clinical practice .
thus , absorb bvs in combination with other state - of - the - art approaches could pave the way for a new era of atheroregression and vascular reparative therapy .
mtor is a key mediator of proliferation , growth , survival , motility , autophagy , protein synthesis , inflammation and metabolism .
mtor is a part of two distinct multiprotein complexes , of which only mtor complex 1 ( mtorc1 ) is sensitive to cyclic macrolides , whereas mtor complex 2 ( mtorc2 ) is not .
preclinical systemic application of mtor inhibitors decreases atherosclerotic plaque formation in both apolipoprotein e knockout ( apoe ) and low - density lipoprotein - receptor knockout ( ldl - r ) mice .
systemic mtor inhibitors also increase plasma triglycerides and ldl cholesterol levels which may be mediated , at least in part by decreased levels of hepatic ldl - r and increased pcsk9 .
chronic rapamycin treatment prolongs life span in c. elegans , drosophila and mice [ 30 , 31 ] . at the molecular level
the following questions on mtorc1 inhibition remain unanswered : what are the effects of mtor inhibitors on vascular healing , foam cell formation , autophagy , cholesterol metabolism and reverse cholesterol transport as well as their effects on vascular ageing .   the previous bench and bedside findings support the concept that brs could set the stage for  physiological reversal of atherosclerosis ( 60 articles , 2006 - 2012 , collected in the absorb publication compendium , erasmus university medical center library , rotterdam , the netherlands ) [ 8 , 12 ] .
new treatment such as systemic mtorc1-inhibitor administration , advanced statins ( such as rosuvastatin ) [ 1 , 2 ] , lp - pla2 inhibitor darapladib , apoa - i milano , pcsk9 , other drug agents , and tailored physical exercises may improve clinical results after brs implantation .
2 ) is mediated by late wall thinning with putative atheroregression , and late lumen enlargement with unmodified or even expanded eem , resulting in a dilated 
it has been hypothesized that the reversal of atherosclerosis is a result of reorganization of the extracellular matrix ( ecm ) by non - fibrillar collagen , elastin and entire connective tissue , with mobilization and reduction of the necrotic core , in conjunction with a change in macrophage ( whereas existence of 6 subtypes : m1 , m(hb ) , mhem , m2 , mox , m4 ) , local immunity ( including response of adventitia and adventitial tertiary lymphoid organs ) , myofibroblast ( mf ) , vascular smooth muscle cell ( vsmc ) phenotypes and pools with the certain role of micro - rnas in atherosclerotic plaque formation and rupture , through regulation of inflammation , microcalcification , angiogenesis and apoptosis , and interaction with biomechanical factors .
it is unknown whether this  plaque and media regression on ivus [ 20 , 32 ] is a true atherosclerotic regression , with change in vessel wall composition and plaque morphology or a pseudo - regression due to resorption of the polymeric struts , remodeling of the provisional matrix left behind , or shrinking of new tissue [ 33 , 34 ] .
true atherosclerotic regression will be only confirmed and understood when the unresolved mechanistic questions are answered in vitro and in vivo , assuming that mtor inhibitors durably affect central pathways in progression of atherosclerosis [ 12 , 29 ] , particularly halting vascular smooth muscle proliferation and migration .
the restoration of vasomotion   and the recapping of lesions   in patients with absorb bvs implantation open a new page in the history of the intravascular treatment already dubbed  vascular reparative therapy by some investigators [ 6 , 11 , 18 ] .
brs may potentially stimulate specific molecular pathways promoting vascular remodeling , innate [ 9 , 36 ] and adaptive immunity , and trigger mechanisms including re - endothelialization , cellular reorganization , and resorption of calcium by osteoclast - like cells .
the rebuilding of the vessel wall via de- and transdifferentiation of the resident and other stem or progenitor cells is regulated by shear stress or mechanical tension and growth factors such as tgf , extra domain a fibronectin ( ed - a fn ) and other cytokines [ 38 , 39 ] .
thus , brs hypothetically triggers the physiological recovery of the vessel wall after the intervention , optimizing the biologic response to its implantation and enhancing atheroprotective mechanisms in the target lesion .  
the mobilization and subsequent reduction of the necrotic core is a cornerstone target for brs , halting macrophage - dependent pathways with impact on prolonged endoplasmic reticulum stress , phenotype and activity as well as primary and secondary necrosis .
the activity of the adventitia   as a niche for stem and progenitor cells , source of myofibroblasts , and a gate for inflammatory cells including b and t cells [ 41 , 42 ] is a pivotal element of the vessel wall homeostasis , which might be also affected by brs .
furthermore , the turnover of endothelium and optimal re - endothelialization with engraftment of circulating progenitors [ 42 , 43 ] as well as neovascularization [ 10 , 33 , 44 ] and switch over vsmc or myofibroblasts [ 33 , 34 ] are other factors determining the restoration of the vessel wall and optimal artery remodeling after absorb bvs implantation .  
brs is also able to potentially modulate biologic effects of shear stress and mechano - transduction with a slow adaptive response of the vessel wall to the mechanical degradation of the brs , facilitating restoration of cyclic strain by affecting the arterial stiffness as well as rearrangement of collagen / elastin density and the connective tissue frame .
the degradation of fibrillar and accumulation of non - fibrillar  hyaline - like   collagen maintains the balance of the fiber density between different sublayers , thereby probably changing the mechanics of the artery and ensuring the  conservation or 
this degradation , accompanied by continuous slow increase of production of elastic constituents with turnover of collagen , provokes overcompensated extension of the vessel wall .
the cellular mechanisms of the above - mentioned arterial remodeling remain unclear due to the limited interpretation of some histology studies [ 5 , 6 , 8 ] .
the russell - movat pentachrome staining does not allow distinction between the synthetizing phenotype of vsmc and mf .
both types of cells synthesize smooth muscle alpha - actin and vimentin as well as collagen and proteoglycans , and have their distinction mostly in the transcriptional mechanism of protein expression . the only difference between these cell types is expression of myosin ( lacking in mf ) and desmin ( absent in vsmc ) .  
5 ) such as vsmc , mf and macrophage subsets ( along the m1 - m2 spectrum ) may play a major role in the overcompensated remodeling and formation of the so called oct ( optical coherence tomography)-documented phenomenon of  golden tubes ( novel optically - bright homogenous internal layer ) observed after absorb bvs implantation with fibro - elastic reconstruction [ 45 - 50 ] .
the polylactate of brs is highly biocompatible and promotes normal metabolism with degradation up to products of the krebs cycle .
metabolic turnover of lactate could be a key factor in the mitochondria- and ros - mediated response to the exhaustion of energy and cell respiration .
this approach is of significant value in designing new therapeutic strategies for alleviation of mitochondrial dysfunction and bioenergetics failure observed in atherosclerosis . during the first 1 - 3 months after implantation local or systemic
( long - term ) mtorc1 inhibition using everolimus could modify parameters such as endothelial function ( reduce enos expression at high shear stress ) ; apoptosis / autophagy ( stimulate innate immunity ) ; matrix generation ( inhibit collagen synthesis ) ; vsmc proliferation and migration ; cholesterol efflux ( due to increased abca1 ) ; cholesterol uptake ( suppression of scavenger receptors sr - a , sr - bii , cd68 , cd36 , lox-1 ) [ 52 , 53 ] ; monocyte chemotaxis ( decrease in mcp-1 and sdf-1 ) [ 52 , 53 ] , promoting a favorable immune and repair response with reduction of the necrotic core and atheroregression .
taken together , brs and mtorc1 inhibition may tip the balance in favor of scaffolding - mediated atheroprotection , and provide means to induce regression of atheroma below the glagov threshold .
this potential for atheroregression and vascular reparative therapy by brs is also apparent in the development and application of bioactive nano - structured constructs for tissue regeneration and engineering .
brs as a scaffold is able to act as a temporary template , guiding cell organization , growth and differentiation and providing structuring stability and a 3d environment where cells can produce new tissue .
current experience with the brs implantation provides evidence of this effect [ 5 , 6 ] .
dislocated struts and organized thrombus mediated by implantation of brs in the lumen may cause rebuilding of the artery wall and formation of new tissue   with benign clinical prognosis .
6 ) should confer excellent mechanical properties , timely release of appropriate drugs and defined duration of resorption .
the currently available brs platform ( absorb bvs , abbott vascular , santa clara , ca ) is a balloon expandable open - cell design device consisting of a polymer backbone of poly - l - lactide ( plla ) coated with a thin layer of 1:1 mixture of an amorphous matrix of poly - d , l - lactide ( pdlla ) , and 1.0 g / mm of the antiproliferative drug everolimus . a novel optimal brs platform could have a hybrid - cell design ( open cells in the middle and closed cells at the edges ) with thinner struts ( 40 - 80 m ) and stronger mechanical properties ( radial strength at least 900 - 990 mmhg ) with extra benefits such as slow drug releasing system for :   mtor and mptp ( mitochondrial permeability transition pore ) inhibitors which suppress cytochrome c and apoptosis as well as provide anti - proliferative effects via the peripheral benzodiazepine receptor , or other drugs , for example , regulators of immune - inflammatory response such as new generations of limus in stable formulation  micro - crystalline or in a lipid envelope ; a preservation of the endothelial function is potentially possible with microrna either , which is able to inhibit proliferative vsmc , thus preventing restenosis , while selectively promoting re - endothelialization and preserving endothelial function .
lipid metabolism modulators , for instance , rosuvastatin , lipoprotein - associated phospholipase a2 inhibitor , new substances such as pcsk9 inhibitors , apoa1-milano , monoclonal antibodies against oxldl ; reparative therapy of vasomotion and artery remodeling ; agents against spontaneous and necrotic - core - mediated calcification such as calcitriol and paricalcitol ; components of ecm , including components ( powders ) of adipose tissue , or recombinant with minimal concentration of platelet - reactive substances ; anti - platelet drugs with minimal local toxicity , atheroprotective and reparative potential .
the abluminal nanocoating ( thickness no more than 100 - 150 nm ) with bioresorbable polymer or nano - pores , and incorporation of nanoparticles , which are able to carry any drug could be helpful for the management of the vessel wall immediately after implantation and prevention of enhanced atherogenesis , atherothrombosis or detrimental and perverted biological feedback to the intervention .
local ( drug - carrying nanoparticles within the backbone ) or systemic administration ( for example , low - dose chronic prescription of everolimus up to 2 mg each 2 days , or pulse therapy by 7.5 mg x 3 days , 5 mg x 2 days ) [ 55 , 56 ] of mtor inhibitor enhances optimal re - endothelialization and the local cellular milieu s response and also provides general atheroprotective effects . applying a drug - coated balloon   for pre - dilatation might be another solution for the local anti - proliferative therapy .
calcium - phosphate [ 17 , 56 ] or magnesium bioresorbable nanoparticles in the backbone and sophisticated management of the polymer structure (  raw and rubber resin , shape memory technologies , solid freeform fabrication with micro - filamentation ) with alterations of carbon bonds are able to substantially alter mechanical properties of the scaffold ( such as conformability , recoil , eccentricity or asymmetry ) and allow reduction of strut thickness .
moreover , the pdlla - luminal layer can be coated with antibodies to capture progenitor cells selectively , such as against cd73 , cd105 ( cells with pro - mesenchymal phenotype ) or cd34 ( bone marrow - derived cells ) and cd133 ( endothelial cells ) .
cell - capturing approaches involve different progenitor cell types with unpredictable local inflammatory and immune response and require sophisticated selection of capture antibodies .   the concept of the multifunctional bioresorbable electronic stent/ scaffold presented by the group of dr .
d. son   from south korea seems mostly revolutionary merely because it s comprising all the emerging technologies together including the most advanced achievements of the bioinert nanomaterial with the flexible flow / temperature sensors and memory storage devices , anti - inflammatory and drug - loaded nanoparticles .
transient scaffolding using brs is foreseen as a potential platform upon which bioactive compounds will be added to act as disease - modifying agents .
the very recent results obtaining with brs suggest that in the near future we might be able to treat coronary atherosclerotic plaques , prevents neoatherosclerosis , and partially restores the structure and function of the vessel wall .
furthermore , it is essential that brs management attempts to promote partial anatomical and functional recovery of coronary artery and leads to some kind of repair with extracellular matrix - related 
conservation of the arterial architecture .   in some recent studies on endoluminal long  term
follow up of brs - treated plaque , oct ( optical coherence tomography ) has documented homogeneous layer of tissue , highly reflecting the incident light so that the appearance of the vessel has been dubbed 
 sealing by coronary angioplasty was introduced two decades ago [ 12 , 35 ] .
after intervention , the healing mechanisms with intimal proliferation would provide a new , smooth , and elastic coat that is capable to cap the plaque prone to rupture .
potentially , both late lumen enlargement with lesion recapping and plaque burden reduction after the brs scaffolding underscore the clinical value of the transient scaffolding as a very promising approach for the reversal of atherogenesis below the glagov threshold .
in fact , design of the fully brs pursues three aims : ( 1 ) revascularization with transient support of the lumen : the revascularization with brs implies enough support to attain acute gain comparable to that of bms , prevention of constrictive remodeling , maintenance of the artery dimensions during at least first six months after the intervention , and sufficient inhibition of biologic response by local drug delivery system to avoid restenosis ; ( 2 ) restoration of a physiological response ( shear stress , cyclic strain , vasomotion , immune - inflammatory response and morphology ) of the transiently scaffolded vessel ; and ( 3 ) benign scaffold resorption .
resorption of brs is another major challenge and should correspond to certain conditions such as gradual degradation and elution of bio - products in order to minimize inflammation , while allowing restoration of vessel architecture .  
thus , if all the above parameters are carefully controlled , brs may pave the way for atheroregression , optimal adaptive remodeling , tissue engineering , and partial vascular recovery .
the adoption of transient scaffolding using bioresorbable platforms and the progress of new technologies have created an attractive field for device design in interventional cardiology and an important tool for treatment of atherosclerosis .
this is largely due to the ability to guide artery remodeling , to generate multifunctional nanoagents bearing combinations of targeting , diagnostic , and therapeutic moieties .
these approaches have the potential to achieve the goal of atheroregression below the glagov threshold , thereby targeting restoration of vessel integrity .
 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 . 
TRANSIENT SCAFFOLDING THROUGH THE PRISM OF THE GLAGOV REMODELING  A KEY MECHANISM TO MAINTAIN LUMEN PATENCY
ATHEROPROTECTIVE AND CLINICAL ACHIEVEMENTS OF ABSORB BVS IN CLINICAL TRIALS
OPTIMIZING BRS  TARGETING KEY MOLECULAR AND CELLULAR PATHWAYS
OPTIMIZING BRS  IN SEARCH OF THE IDEAL PLATFORM
TRANSIENT SCAFFOLDING OPENS A NEW ERA OF VASCULAR REPARATIVE THERAPY
CONCLUSION
CONFLICT OF INTEREST