62 / 74
CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
324
AFRICA
demonstrated significantly elevated IL-6 levels, along with higher
levels of D-dimer, homocysteine, CRP and soluble vascular
cellular adhesion molecule-1 (sVCAM-1) in PAD subjects,
which were also related to adverse calf muscle characteristics.
45
This suggests higher levels of inflammation may correlate
with functional impairment and functional decline in PAD
patients. The association between IL-6 and PAD was stronger
in African-American women than in non-Hispanic whites,
42
proving that in addition to gender differences, there are also
ethnic dissimilarities.
Tumour necrosis factor-alpha (TNF-
α
)
TNF-
α
pro-inflammatory effects range from mediating cellular
activation and proliferation to inducing acute-phase responses
and destructive cellular outcomes such as apoptosis or cellular
necrosis.
46
TNF-
α
is therefore a pro-angiogenic cytokine.
In one study performed on 91 healthy volunteers, serum
TNF-
α
concentrations were inversely correlated with age, but
only in men; in females, no distinct age-related changes were
observed.
47
Circulating TNF-
α
was increased in PAD patients
(both men and women) in several studies,
47-49
with additional
increases noticed after treadmill stress testing.
48
Gender
differences were not assessed
48,49
or were not significant.
50
Cellular adhesion molecules
Cellular adhesion molecules (CAMs) are integral membrane
proteins that mediate cell-to-cell binding. Some of them, such as
the selectins and integrins, are involved in leukocyte extravasation
and the inflammatory response.
51
A rise in sICAM and sVCAM-1 levels was associated with
the progression of PAD in some studies.
52,53
In both male and
female subjects included in the Edinburgh Artery Study, high
initial circulating levels of ICAM were correlated with a decrease
in the ABI at one-year follow up.
22
Recent research has shown
that elevated levels of ICAM-1 were associated with a slower
walking pace and a shorter stride length [along with the rise
in high-sensitivity CRP (hs-CRP) and reactive oxygen species
(ROS) levels], which may suggest that chronic inflammation
and oxidative stress can influence walking pace and distance in
elderly PAD patients.
23
McDermott
et al.
demonstrated that high levels of hs-CRP,
IL-6, VCAM-1, ICAM-1 and homocysteine were associated with
difficulties in completing the six-minute walk test (SMWT) by
patients with PAD.
54
In another research published by Gardner
et al.
, African-American women with PAD had higher levels of
serum ICAM-1 and leptin than their male counterparts.
3
The
same study found that Caucasian women had higher levels of
VCAM-1 than men.
3
Cellular adhesion molecules were also assessed as markers of
arterial disease in children. In one paediatric study, ICAM-1 was
positively related to CIMT in obese, hypertensive adolescents,
55
while another study performed in healthy young children found
that higher plasma levels of the chemokine CCL5, also known
as RANTES (regulated on activation, normal T cell expressed
and secreted) were positively correlated with arterial stiffness, but
not with CIMT.
56
In the same article, monocyte chemo-attractant
protein 1 (MCP-1), VCAM and ICAM did not correlate with
any of the studied vascular characteristics, namely CIMT,
common carotid distensibility or Young’s elastic modulus.
56
These conflicting results suggest more research is needed for
a better understanding of the role of adhesion molecules in
vascular ageing and remodelling.
Markers of oxidative stress
Oxidative stress, a disturbance in the pro-oxidant–antioxidant
balance in favour of the former, plays a major role in the
development of atherosclerosis
57
and PAD.
58
Numerous studies
have shown a rise in ROS,
59,60
alongside a decrease in serum nitric
oxide (NO) levels in individuals with PAD.
61
NO (a vasoprotective
factor) decrease is partly explained by NO removal secondary to
oxidation by excess ROS.
57
In comparison with controls, PAD subjects (both males
and females) had increased urinary isoprostanes (a marker of
oxidative stress) and NOX2 (one isoform of NADPH oxidase,
a major producer of ROS) activation, contributing to reduced
flow-mediated dilatation observed in these patients; these effects
were reversed by administration of an antioxidant.
62
High serum levels of myeloperoxidase, an enzyme involved
in inflammation and oxidation,
63
were associated with PAD;
the association was stronger in African-Americans compared
to non-Hispanic whites, and it was independent of gender.
64
Another study indicated a predictive value for major adverse
cardiovascular events, such as myocardial infarction, stroke or
death in males or smokers with PAD.
65
In the same way, elevated
levels of galectin-3, a lectin involved in inflammation, oxidative
stress and angiogenesis, were significantly associated with an
increased risk of cardiovascular mortality in PAD subjects.
66
It seems that endothelial oxidative stress is more important
for the development of symptomatic PAD in African-American
women, so the effect is gender and race specific. Gardner
et al.
found that African-American females with symptomatic PAD
had significantly higher levels of both inflammatory and oxidative
stress biomarkers compared to their male counterparts.
3
In the
same study, women also had a poorer peripheral circulation
than men, especially concerning the smaller distal vessels, with a
markedly reduced exercise capacity and daily activity compared
to men.
3
Other markers
Serum beta-2 microglobulin (
β
2M), one of the major
histocompatibility complex class I molecules, is a risk factor for
increased CIMT
67
and a predictor of total mortality in older
adults.
68
Kals
et al.
had shown that levels of
β
2Mwere significantly
higher in patients with PAD and correlated with aortic pulse-wave
velocity, a measure of arterial stiffness.
69
In a nested case–control
study performed in two cohorts,
β
2M was identified as a risk
factor for developing PAD, but only in the male cohort.
70
Other markers such as leptin and apolipoprotein CIII were
found to be higher in women than in men diagnosed with PAD.
3
In a case–control study, adiponectin was significantly lower in
women developing PAD compared to healthy controls.
71
Similar
to adult data, paediatric observational studies had shown
an inverse correlation between plasma adiponectin levels and
CIMT,
72
establishing it as a marker of vascular ageing.
Circulating levels of the N-terminal prohormone of brain
natriuretic peptide (NT-proBNP), a marker of haemodynamic