CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 9, October 2012
508
AFRICA
albeit with high rates of re-intervention. Even so, limited data
exist and further investigations are required before definitive
recommendations for the endovascular treatment of tibial vessel
disease can be formulated.
Neo-intimal hyperplasia and the incidence of
restenosis
Within six months of a successful angioplasty, restenosis occurs
in up to 55% of patients. Restenosis following angioplasty
and stenting is largely due to neo-intimal hyperplasia (NIH)
–
the thickening of the tunica intima of a blood vessel as a
physiological healing response to a reconstructive procedure
or endarterectomy. It is currently understood that NIH involves
the proliferation and migration of medial smooth muscle cells
(
SMCs) into a region as it becomes stenotic.
20
Although therapeutic interventions and continued stent design
and coating have been applied, restenosis, even after drug-eluting
stent implantation, remains a significant clinical problem.
21,22
Also, therapeutic interventions seem to have preceded the
understanding of the biology of the process of restenosis.
Moreover, the regulation of NIH is largely not understood and, as
a result, advancements in therapeutic interventions are restricted.
The incidence of restenosis a year after coronary angioplasty
and bare-metal stenting is approximately 30%,
23
whereas
restenosis a year after carotid artery stenting has been reported
as approximately 18%.
24
A meta-analysis of the incidence of
restenosis three years after bare-metal stenting for peripheral
artery disease, specifically femoro-popliteal disease, was 61%.
25
In another study that investigated the efficacy of sub-intimal
stent implantation for long, multi-segmental lower limb occlusive
lesions, 37% restenosis after approximately one year was
reported,
26
whereas a 17% incidence at two years of re-occlusions
and restenosis was reported by a prospective study for sub-intimal
angioplasty of the femoro-popliteal or tibial arteries.
27
While limb salvage, ulcer healing and re-intervention rates are
relatively low after below-the-knee endovascular intervention,
restenosis rates remain extremely high.
7
This highlights the
importance of understanding the regulation of NIH.
Therapeutic management of CLI
In CLI patients who are not amenable to surgical intervention
for revascularisation, treatment options are very limited.
Even though the optimal treatment has yet to be identified,
therapeutic angiogenesis is increasingly being used in the
non-operative management of CLI. This new strategy includes
the administration of growth factors, transcription factors
and progenitor cells to induce angiogenesis. Surprisingly, the
cytokines used in therapeutic angiogenesis, such as VEGF and
FGF, are the also the factors thought to influence NIH following
revascularisation.
Similarly, and discussed below, the profile of progenitor
cell differentiation in the acute phase post stenting has been
suggested as a predictor of restenosis following endovascular
intervention. Having said that, clinical trials of cytokine-based
therapy in patients not amenable to surgery have produced
mixed results, while those using autologous cell transplantation
have been much more promising.
28
Specifically, the safety and
efficacy of autologous endothelial progenitor cell therapy has
been established from small cohort studies and results from
larger trials currently underway will further consolidate this
evidence.
29,30
The following sections describe the necessity of investigating
the role of cytological and biochemical factors in vessel wall
injury and other cardiovascular co-morbidities in an attempt at
attenuating NIH following future revascularisation procedures.
From this published evidence, it is clear that new strategies
in preventing NIH are imperative. Furthermore, a better
understanding of the regulation of NIH could facilitate future
therapeutic targets.
Cytological factors and neo-intimal
hyperplasia
At the site of stent-induced vascular cell injury, an abundance
of cytokines and growth factors are released, and circulating
mononuclear cells are mobilised to the site of injury. The
local abundance of cytokines and growth factors provides an
appropriate environment for cell growth, cell differentiation and
cell proliferation.
Vascular progenitor cells (VPCs)
Circulating mononuclear cells have been implicated in the
process of in-stent NIH and VPCs form part of this population
of cells.
31
VPCs differentiate into either endothelial or smooth
muscle lineage, depending on the local environment they find
themselves in. Only in the last decade have studies suggested
the involvement of VPCs in the development of NIH,
32-34
and in
2007,
Inoue
et al
.
showed a relationship between NIH and the
mobilisation of VPCs into the circulation at the acute phase after
vascular stent-induced injury.
35
Moreover, inhibition of NIH by
the drug sirolimus is mediated through its potent inhibitory effect
on circulating VPCs.
36
Very recently, Wang
et al.
(2011)
showed a strong correlation
between the VPC differentiation profile and the severity of
post-stent NIH following coronary stenting.
20
This suggests
that VPC differentiation may potentially be a future tool in
identifying patients at risk of restenosis after coronary stenting.
However, this relationship has not been investigated in any other
areas of stent-induced vascular injury. Future studies should
investigate the relationship, if any, between the acute-phase
VPC differentiation profile and extent of NIH following either
femoro-popliteal or tibial artery stenting.
Biochemical factors and neo-intimal
hyperplasia
As mentioned above, an abundance of biochemical factors such
as cytokines and growth factors are released at the site of stent-
induced vascular cell injury. These factors are important in the
regulation of angiogenesis. However, data on their involvement
in regulating NIH following lower limb revascularisation are
either limited or non-existent.
Cellular adhesion molecules (CAMs)
CAMs, glycoproteins present on cell surfaces, bind with other
cells or the extracellular matrix. The firm adhesion of leukocytes
and lymphocytes to endothelial cells are, however, mainly
mediated by immunoglobulin CAMs, such as intercellular
