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6 Vascular Biology ofSmooth Muscle Cells andRestenosis
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for CX3CR1 [10]. It is expressed on VSMCs and it has been found, that when monocytes are incubated with oxidised LDL, they upregulate their expression of CX3CR1.
This then increases monocyte binding to membrane-bound CX3CL1 on VSMC that
serves to anchor the monocytes to the VSMCs [11].
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6.2.4 VSMC Apoptosis
VSMC are believed to play a central role in stabilising the plaque through the development of the cap. VSMC apoptosis is therefore likely to inuence the stability of
the plaque. In early-stage plaques, the level of apoptosis is found to be very low and
starts to increase with increasing plaque size [12]. Plaque rupture occurs mostcommonly at the shoulder regions of the plaque in which there are lower numbers
of VSMCs and higher number of macrophages. This suggests that VSMC apoptosis
is induced by macrophages at the shoulder region sites, triggering plaque rupture. In
support of this, it has been shown that there are increased levels of VSMC apoptosis
in symptomatic plaques when compared with stable plaques [13].
Another complication of VSMC apoptosis in atherosclerosis is that it is associated with increased inammation. Interestingly, this increase in inammation does
not occur for VSMC apoptosis that is associated with vascular ageing or medial
degeneration. The reason underlying this discrepancy is thought to be due to a lack
of efciency in the clearance of apoptotic VSMCs in atherosclerosis as well as a
slower clearance of inammatory cytokines released from dying cells [5]. Dying
apoptotic VSMCs release IL-1β and necrotic VSMCs release IL-1α. In a healthy
vessel, VSMCs are very efcient at clearing apoptotic VSMCs within ~48 h.
However, in the presence of hyperlipidaemia, the phagocytotic capacity of VSMCs
is impaired, thereby delaying phagocytosis and apoptotic cell and cytokine clearance [14].
6.2.5 VSMCs Origins; Role inAtherosclerosis
Lineage tracing studies using genetically modied mice that enable tracking of cells
have revealed that VSMCs arise from a number of different developmental origins.
For example, the VSMCs in the ascending aorta and aortic arch as well as the head
and neck vessels originate from the neural crest. Coronary VSMCs are generated
from the epicardium and the descending aorta VSMCs arise from somatic mesoderm precursors [15]. The importance of this is that these different developmental
origins can have signicant effects on the development of atherosclerosis. For
example, the descending thoracic aorta is relatively resistant to atherosclerosis when
compared to the aortic arch that rapidly develops plaque. The thoracic aorta has a
signicantly higher level of expression of the developmental genes, the Homeobox
genes, and a reciprocal relationship with NF-κB, a transcription factor that drives
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Re-endothelialisation
Neointimal hyperplasia
Thrombosis
Neoatherosclerosis
Adventitial progenitor contributions
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V. Nankivell et al.
inammation and atherosclerosis [16]. This suggests that there is a relationship
between developmental origin and the susceptibility to developing atherosclerosis.
Other data supports this concept. When VSMCs from neutral crest origin are
exposed to TGF-β, they increase their production of collagen. This does not occur,
however, in VSMCs from the mesodermal zone. Furthermore, homocysteine, a protein that is important in cardiovascular disease, will induce the proliferation of
VSMCs from the neural crest but not from the mesoderm origin [17]. There are also
variations in the propensity to develop atherosclerosis, undergo aortic aneurysm
development and develop calcication [18].
VSMCs contribute to plaque development and stability by: (1) forming a stabilising ‘cap’, (2) differentiating in a highly proliferative synthetic VSMC phenotype,
(3) undergoing apoptosis and (4) through VSMC progenitor cell contributions originating from the adventitia.
6.2.6 Restenosis
VSMCs play a major role in the development of restenosis which is the process of
rapid expansion of a neointima after vascular injury, also called neointimal hyperplasia (Fig 6.3). Restenosis is driven predominantly by inammation, as a result of
the vascular injury, and the inammation causes dysregulated VSMC proliferation
and migration. It is a signicant problem following balloon angioplasty and stent
deployment. The mechanisms and processes of restenosis are biologically distinct
from atherosclerosis. Restenosis occurs over shorter time frames (months-years)
compared to the decades that it takes for an atherosclerotic plaque to develop. A
detailed discussion of restenosis will be included later in this Chapter.
SMC recruitment
-
-SMC proliferation/migration
-SMC differentiation
SMC progenitor
CXCL12
TNF-α
EC
SMC
CCL2
PDGF
Stent
Fig. 6.3 Multiple biological mechanisms associated with in-stent restenosis
EPC mobilisation/recruitment
-
EPC
CXCL12
IL-1β
Stent
platelet activation
-
-thrombus formation
Platelet
Stent
neutrophil activation
-
-monocyte/macrophage
recruitment
Monocyte
CCL2
Stent
CCL5
Neutrophil
Macrophage
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6.2.7 Smooth Muscle Cell Phenotype
6.2.7.1 Contractile Versus Synthetic Phenotype
VSMCs are highly plastic in nature which can play a signicant role in their contributions to atherosclerosis and restenosis. In a healthy adult vascular wall, VSMCs
are able to regulate vasoconstriction and dilatation, and are known as the ‘contractile’ phenotype. However, in response to injury, inammation or different growth
factors, the phenotype of these VSMCs can change. During this switch, VMSCs
down-regulate contractile functions and de-differentiate into a ‘synthetic’ VSMC
phenotype that is highly proliferative and can have deleterious effects such as promoting atherosclerosis and restenosis growth. Synthetic VSMCs have diminished
responses to vasodilators and constrictors and thereby exhibit reduced vascular
function [2].
Changes in the cell surface marker expression prole is the most important way
to characterise changes in VSMC phenotype and this correlates with changes in
function. The contractile phenotype expresses markers that are vital to the SMC
contraction machinery and cell anchorage including: SM-α-actin, SM-myosin
heavy chain (MYH11), calponin, SM22α, smoothelin, h-caldesmon and others [19].
As VSMCs start to de-differentiate to the synthetic phenotype they start to lose
these important contractile markers and increase their expression of proteins
involved in cell cycle progression (cyclins, calmodulin) and ECM remodelling
(matrix-metalloproteinases and collagen), and increase their expression of cytokines [19]. There are also signicant changes in morphology. The contractile elongated spindle-shaped phenotype starts to take on a rhomboid-like shape. There is,
however, a broad range of morphological possibilities in between these two classically described VSMC morphologies and also a large number of different combinations of phenotypic marker possibilities [20]. This diversity is caused through
different stimuli or environmental cues, disease milieu and embryonic origin. In
atherosclerosis, one example of the VSMC phenotype switch is their signicant loss
of α-actin, an important marker of the contractile phenotype, with disease development. This has been validated in rigorous studies using transgenic mice that track
SMC origins and fate. For example, it was demonstrated that greater than 80% of
VSMC-derived cells within an established atherosclerotic plaque do not express
alpha actin [
Recent studies have helped to clearly dene the role of phenotypic switching in
atherosclerosis and there is a growing realisation that inhibition of the differentiation to the synthetic VSMC phenotype may suppress the progression of atherosclerosis. For example, mice heterozygous for myocardin (myocardin
the expression of most VSMC contractile genes and therefore promotes the contractile VSMC phenotype, have increased atherosclerosis when crossed with
atherosclerosis- prone apolipoprotein (apo)E
myocardin (i.e. myocardin
phage recruitment to the plaques. Interestingly, these effects were reversed in a gain
of function myocardin mouse [23].
21, 22].
−/+
), that supports
−/−
−/+
) also increased inammatory pathways and macro-
mouse. The loss of a single allele of
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V. Nankivell et al.
The role of Krϋppel-like factor-4 (KLF4) in phenotypic switching has been studied extensively. KLF4 is required in VSMCs for PDGF and IL-1β-induced differentiation [24]. KLF4 is also found to regulate genes that control and inhibit myocardin.
Deletion of KLF4 is able to prevent and delay phenotypic switching in vivo in
VSMCs in a murine vascular injury model [25]. Interestingly, using a VSMCsspecic KLF4 knockout mouse, no change in phenotypic switching was detected
but there was a reduction in plaque size and increased cap thickness [21].
There is accumulating evidence that micro-RNAs (mi-RNAs), short stretches
(20–30 bases long) of non-coding RNA, play a role in phenotypic switching from
a contractile to a synthetic VSMC phenotype. For example, bioinformatics analyses have predicted that miR let-7g modulates the switch. The target genes for let7g were found to be the genes in the PDGF/mitogen-activated protein kinase
kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/KLF4 signalling
pathway, known to regulate phenotypic switching. Increased levels of let-7g were
found to protect against PDGF and MEKK1-induced differentiation from the contractile to the synthetic VSMC phenotype. Furthermore, in vivo studies revealed
that over- expression of let-7g in apoE
−/−
mice decreases atherosclerosis in
the aorta.
6.2.7.2 Trans-differentiation ofVSMCs toMacrophages
It is well-established that circulating monocytes inltrate the developing plaque and
differentiate into macrophages that take-up modied low-density lipoproteins
(LDL). More recently in both in vitro and in vivo studies, it has been discovered that
VSMCs are also able to engulf modied LDL.It has been demonstrated that VSMCs
are able to take up lipid and form foam cells. Upon internalisation of LDL, the
VSMCs start to acquire a more macrophage-like phenotype and lose their SMC
phenotype [26]. For example, lipid-loaded VSMCs will express macrophage markers including CD86, Mac-2 and ABCA1. Concurrently they lose their expression of
α-actin, tropomyosin, MYH11 and calponin. Accompanying this, lipid-loaded
VSMCs express higher levels of inammatory proteins and are considered therefore
to contribute to the expansion of the plaque in a deleterious fashion [27]. It should
be noted that although VSMCs are able to engulf lipid, the overall phagocytic capacity of VSMCs is much lower than that of a professional phagocytic cell like the
macrophage. These ndings were more recently conrmed in vivo. It was found
−/−
that, in apoE
mice, the cells lining the necrotic core of atherosclerotic plaques
were positive for both VSMC and macrophage markers. Bioinformatic analysis also
conrmed that lipid-loaded VSMCs expressed macrophage markers but overall
expressed markers that were closer to the traditional VSMC state [5]. This, however,
has the potential to also be deleterious. In this trans-differentiated state, macrophages not only perform some of the unfavourable functions of macrophages and
express more inammatory cytokines, they also have impaired benecial macrophage functions including phagocytosis and efferocytosis (process by which apoptotic/necrotic cells are removed from the plaque).
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High-density lipoproteins (HDL) play a key role in efuxing cholesterol from
cells. A recent study has demonstrated that incubation with the HDL sub-particle,
HDL3 is able to reverse the trans-differentiation of VSMCs to macrophages following cholesterol-loading. This is likely to be via the ability of HDL to remove the
excess cellular cholesterol. This was conrmed through the use of VSMCs with a
deletion in the cholesterol transporter, ABCA-1, that mediates cholesterol efux
from cells. Interestingly, the ability of HDL to reverse trans-differentiation was
almost completely lost in these ABCA-1 knockout VSMCs. HDL3 was also able to
restore the expression of myocardin and KLF4, key regulators of differentiation, to
baseline levels following cholesterol loading [27].
Mi-RNAs are known to regulate the trans-differentiation, or conversion, of
VSMCs to macrophages. For example, miR-143/145 regulates myocardin and is
down regulated with cholesterol loading. Conversely, if miR-143/145 levels are
maintained it is able to reverse cholesterol-loading-induced phenotypic change [27].
6.2.8 Smooth Muscle Progenitor Cells
There is increasing evidence indicating the presence of smooth muscle progenitor
cells (SMPCs) in the vasculature. In fact, SMPCs have been located in each layer of
the vessel wall including the intima/neointima, the media and the adventitia [15]. It
is highly likely that these tissue resident vascular progenitor cells also make contributions to the development of both atherosclerosis and restenosis. There is also
evidence, although controversial, that bone marrow-derived SMPCs can contribute
to disease development that will be discussed in this section.
The disease milieu surrounding sites of atherosclerosis or restenosis including
inammatory factors, reactive oxygen species (ROS), hyperlipidaemia and hypertension, are all likely to affect the migration, proliferation, mobilisation and differentiation of SMPCs. In hypertension, for example, there is intimal thickening and
expansion of the media of the blood vessels. There is also an increase in the expression of α-actin. This is suggestive of the possibility that progenitor cells may have
contributed to this adaptive response through enhanced migration and proliferation
in the media, stimulated by inammatory cues. In support of this concept, it has been
demonstrated that SMCs in the neointima of vessel allografts originate from a local
source of progenitor cells that were not from a bone marrow-derived source [28].
Furthermore, it has been shown that there is a local vessel source of SMCs that contributes to atherosclerotic plaque development [29]. Other studies have shown that,
after femoral artery injury, more than 50% of the SMCs in the neointima are derived
from adventitial progenitor cells. These ndings were supported further by a mouse
model that enabled specic lineage tracing of the SMC origin and showed denitively that for an injured artery the main source of SMCs are adventitial progenitor
cells. In the apoE
tracking that adventitial cells migrate into the media and the developing neointima
of the plaque and differentiate into SMCs. In summary, local progenitor populations
−/−
model of atherosclerosis it has also been shown using fate-
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from the vasculature, particularly the adventitia, differentiate into SMCs and can
contribute to the development of restenosis and atherosclerosis disease processes.
It has been reported that bone marrow-derived SMPCs make contributions to the
development of atherosclerosis and restenosis. Apoptotic VSMCs at sites of vascular injury have increasedexpression of the chemokine stromal cell-derived factor 1α
(SDF-1α). SDF-1α has a well-established role in promoting the mobilisation, migration and recruitment of bone marrow-derived progenitor cells to sites of injury or
repair. This suggests that apoptotic VSMCs, through their expression of SDF-1α,
may be attempting to recruit bone marrow-derived SMPCs to the injured site.
Studies have reported the existence of SMPCs in mouse models of arterial injury
and neointimal hyperplasia [30]. It is also reported that bone marrow-derived
SMPCs are present in atherosclerotic plaque, albeit very few. Subsequent SMCspecic lineage-tracking studies in transgenic mice have, however, failed to reproduce these studies. The overall current view is that whilst SMPCs can make
signicant contributions to atherosclerosis and restenosis, these cells are from local
tissue sources and not from a bone marrow-derived source.
V. Nankivell et al.
6.3 Restenosis
Restenosis is the re-narrowing of the arterial lumen. It is induced by vascular injury
that causes an inammatory-driven VSMC hyperproliferation and overproduction
of ECM proteins resulting in excessive neointimal hyperplasia.
6.3.1 Causes andMechanisms ofRestenosis
Percutaneous angioplasty with or without stent deployment is the major mode used
to re-open arteries blocked by atherosclerosis. Both cause signicant damage to the
vessel wall which can result in the expansion of the neointima due to the uncontrolled proliferation of medial SMCs. A combination of important factors including
thrombosis, intimal hyperplasia, re-endothelialisation and remodelling contribute
to the development of restenosis. There have, however, been signicant transformative improvements in the design of current generation drug-eluting stents (DES)
that have reduced the rates of stent-related major adverse cardiovascular events
(MACE). These MACE include: stent restenosis, stent thrombosis and end- organ
infarction.
The initial insult caused by the expansion of an angioplasty balloon catheter
(with or without stent deployment) severely damages the endothelial layer and initiates inammatory events. This causes a signicant impact on the endothelial cells
resulting in injury or complete removal of the endothelial cell layer at the site. In
addition, after injury, medial VSMC apoptosis occurs (e.g. balloon injury causes up
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to 70% mortality of SMCs within 30min [31]). This injury initiates a cascade of
pro-inammatory events which stimulate VSMCs to de-differentiate to a more proliferative and synthetic phenotype which promotes increased re-entry into the cell
cycle, thereby increasing proliferation and migration. VSMC proliferation increases
dramatically in the rst few days following injury leading to the rapid expansion of
a neointima which is SMC-rich. After 4–6weeks, re-endothelisation of the injured
site occurs, however, there is evidence to show that these cells are dysfunctional and
have decreased vascular integrity and increased permeability [32]. At 8weeks post
injury, the proliferation of the VSMCs returns to normal levels. There may, however, still be areas that have not undergone sufcient re-endothelialisation in which
low levels of VSMC proliferation continue. Endothelial cells play an important role
in regulating SMC proliferation and migration. In vivo studies have found that areas
of early re-endothelialisation had less neointimal growth after vessel injury than
those areas with low re-endothelialisation [33]. In an attempt to increase endothelialisation and decrease neointimal hyperplasia after stent deployment, stents coated
with VEGF have been tested in rabbits. However, after 28days the stents failed to
increase re-endothelialisation and reduce neointimal hyperplasia. This indicates that
local delivery of VEGF is not a viable strategy [34].
6.3.1.1 Mechanisms ofInammation-Driven Neointimal Hyperplasia
The inammatory response that causes neointimal hyperplasia and restenosis following vascular injury has not been fully elucidated. The degree of inammation
induced by stent deployment or angioplasty has been associated with the extent of
restenosis as well as the prevalence of macrophages in the initial lesion. Leukocytes
can be recruited to the site of vascular injury which is initiated by binding to platelets and cell adhesion molecules (e.g. ICAM-1 and V-CAM-1). Following injury to
the endothelium there is a release of a host of cytokines including TGF-β1, PDGF
and broblast growth factor (FGF) 2, TNF-α, VEGF, macrophage colony stimulating factor (MCSF), IL-4, IL-1α, IL-1β, IL-8 and CCL2. The release of these cytokines induces the subsequent proliferation and migration of medial VSMCs into the
intima, resulting in expansion of a now SMC rich neointima.
There is also a growing body of evidence that inammatory chemokines are
critically important in the promotion of neointimal hyperplasia and vascular
repair processes. In vitro, incubation with a range of chemokines (CCL2, CCL5
and CX3CL1) increases VSMC proliferation [
35–37]. The transcription factor,
NF-κB, the driver of inammatory processes and chemokine expression, has been
implicated in this process [37]. The involvement of chemokines in neointimal
development has been supported in an in vivo study that showed deletion of CCL2
reduced neointimal formation in a murine model of arterial injury [38].
Furthermore, deletion of TNF- α, a cytokine that stimulates inammation and
NF-κB, was found to prevent neointimal hyperplasia in a murine model of carotid
artery injury [39].
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6.3.1.2 Growth Factors
PDGF is one of the key SMC mitogens that stimulates the growth of SMCs during
vessel repair. However, when present at excessively high levels, such as the case
following angioplasty-induced vascular injury, it can strongly stimulate proliferation and cause neointimal hyperplasia [40]. FGF2 also stimulates medial SMC
proliferation and migration to the intima of injured vessels. Interestingly, FGF2
will not stimulate the proliferation of intimal SMCs as the intimal hyperplastic
response is normal in FGF2 knockout mice. FGF2 is, however, also important in
remodelling following angioplasty as FGF2 knockout mice display decreased
SMC contractility [41]. One study has also identied a role for IL-11in neointimal hyperplasia. IL-11 is an anti-inammatory growth factor known to inhibit
NF-κB. In vitro studies have demonstrated that incubation with IL-11 causes
dose-dependent decreases in bFGF- induced VSMC proliferation as well as a
reduction in pro-inammation cytokine expression from VSMCs including IL-8
and IL-6 [42].
6.3.1.3 Extracellular Matrix (ECM)
The pro-inammatory environment that promotes the proliferation and migration of
VSMCs also results in the release of extracellular matrix proteins that contribute to
intimal expansion. ECM contributes to restenosis in the later stages post- angioplasty.
Histological analysis of human samples has revealed that in tissues with advanced
restenosis, there is a lower cell density surrounded by substantial amounts of
ECM.The ECM proteins induced by angioplasty include type I collagen, as well as
the proteoglycans versican, perlecan, biglycan and hyaluronan, without the decorin
that is present in primary plaques [43]. Some forms of ECM can stimulate SMC
proliferation, whilst other types prevent further ECM accumulation and deposition [44].
6.3.1.4 Percutaneous Arterial Interventions That Cause Restenosis
andTheir Evolution
Whilst balloon angioplasty can be successful in restoring arterial luminal patency,
the procedure is not without its limitations. Vessels have a high likelihood of renarrowing due to the elasticity of the lamina, and any damage to the vessel caused
by the balloon is found to trigger restenosis [45]. Many approaches have been trialled in an effort to reduce both vessel recoil and restenosis. These include drug
strategies such as anticoagulants and antiplatelet agents and growth factor inhibitors, in addition to mechanical strategies including rotational cutting devices and
lasers mounted on catheters [46]. Stents, however, have proven to be very successful
in reducing vessel re-narrowing after angioplasty. Due to the sustained mechanical
support provided to the vessel by the stent, it eliminates vascular recoil which occurs
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once the balloon catheter has been removed. Over the past 50years stent design,
metal composition, coating and strut diameter have been extensively modied to
optimise the effectiveness of stents. Two main classes of stent have dominated, the
bare metal stent (BMS) and the drug eluting stent (DES). Whilst BMS are still routinely used, particularly for peripheral arterial disease, it is the DES which are predominantly used for coronary artery disease.
6.3.1.5 Bare Metal Stents (BMS)
Whilst BMS deployment reduces vessel recoil and increases vessel lumen area (particularly when a sub-optimal angioplasty result is obtained), acute stent thrombosis
is a major complication following BMS deployment. Stent thrombosis after BMS
deployment most commonly occurs within the rst month, particularly in coronary
intervention, with the risk decreasing after re-endothelialisation [47].
To prevent acute thrombus formation, patients are prescribed dual antiplatelet
therapies (DAPT) for a period of time and then single antiplatelet therapy to reduce
acute stent thrombosis following intervention. DAPTs combine aspirin with a
P2Y12 inhibitor (e.g. Clopidogrel or Ticlopidine) and have proven to be the most
effective regime to decrease coronary stent thrombosis, reducing incidence to 1%.
The Stent Anticoagulation Restenosis Study (STARS) showed that the incidence of
death, target lesion revascularisation, vessel thrombosis or MI after 30 days was
3.6% for patients treated alone with aspirin, however, this was signicantly reduced
to 0.5% with DAPT (aspirin+ticlopidine) [48].
While DAPTs are necessary to reduce thrombosis risk, they are not without their
limitations. It is estimated that approximately 4–8% of patients require non-cardiac
surgery within the rst year after stent deployment [49]. Patients relying on DAPT
to reduce their thrombotic risk are faced with the dilemma of continuing DAPT and
risking both minor and major bleeding during surgery and post-operatively.
Alternatively, patients can stop one or both antiplatelet agents, which increases their
risk of a thrombotic event and is dependent on the length of time post-intervention.
Despite antiplatelet therapy, BMS still fail as a result of restenosis or thrombosis.
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6.3.2 Strategies toReduce Neointimal Hyperplasia
Initial studies aimed at reducing neointimal hyperplasia following arterial intervention focused on the systemic delivery of anti-proliferative drugs to reduce SMC
proliferation. One study investigated whether the anti-proliferative drug Tranilast
could reduce restenosis rates after BMS deployment. Initial animal studies found
that the agent was effective in reducing restenosis rates in rabbits and pigs [50, 51].
Furthermore, when Tranilast was studied in a small clinical trial, a modest reduction
in restenosis rates were seen. However, once the drug moved into a large randomised
clinical trial (Prevention of REStenosis with Tranilast and its Outcomes-PRESTO)
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there was no signicant difference in restenosis formation between Tranilast and the
placebo group [52]. Similar outcomes have been seen with other systemic antiproliferative drugs trialled to reduce neointimal hyperplasia.
The main reason cited for the failure of larger clinical trials with systemic antiproliferative therapy was the inadequate level of the drug at the angioplasty site. As
a result, local drug delivery using perfusion balloons was explored. This method
also failed due to the poor uptake of drugs at the site of ination due to the minimal
vessel contact time. Efforts then turned to investigate the potential of drug-eluting
stents (i.e. anti-proliferative drugs released from stents) to reduce restenosis.
6.3.2.1 Drug Eluting Stents
Drug eluting stents (DES) were designed to deliver a sustained dose of antiproliferative drugs to the local area and aimed to overcome the issue of restenosis
experienced in BMS.The stents were coated with a polymer such as phosphoryl
choline silicon carbide which allowed an anti-proliferative drug such as Sirolimus
or Paclitaxel to be coated on and slowly released into the surrounding tissue [53].
Early randomised clinical trials showed promising results, with the rstgeneration DES causing a reduction in SMC proliferation and restenosis rates
post- implantation at both 6 and 12months-post deployment, compared to BMS
[54]. Initial clinical testing of this rst DES in 2003 used the CYPHER™ stent
(Johnson and Johnson), which was coated with the drug Sirolimus. This was
closely followed with TAXUS™ (Boston Scientic) which used Paclitaxel. Both
Sirolimus and Paclitaxel work via inhibition of the cell cycle, however, each
drug does this by a different mode of action. Sirolimus works by halting cell
division in the initial phase (G-phase) of the cell cycle. In contrast, Paclitaxel
arrests cells during the mitosis phase when they are about to divide. While
CYPHER and TAXUS DES reduced restenosis rates when compared to BMS, a
new complication of delayed healing and re-endothelialisation at the deployment site arose.
First-generation DES are prone to late (30days–1year) and very late (>1year)
stent thrombosis as a result of delayed healing, likely caused by the anti-
proliferative
agents released at the stent site. DAPT therapies for BMS were initially recommended for the 4–6-week period following stent deployment, but for DES this was
increased to 12-months in an effort to reduce complications associated with late
stent thrombosis [55].
Due to the necessity for a prolonged use of DAPTs, some patients experience
mild to severe side effects from the medications. For example, continued use of
aspirin can cause gastrointestinal upset and tinnitus. However, prolonged used of
DAPT appears to be essential following coronary DES deployment. Clinical studies
have found that stent thrombosis is signicantly elevated following the cessation of
DAPT at 12-months. Furthermore, the incidence of late stent thrombosis continues
to rise at a rate of 0.6% per year in the following 3years post-procedure resulting in
a high mortality rate of 25% [56]. First generation DES therefore exacerbated the
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