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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
AFRICA
325
stress, were significantly higher in male patients with PAD,
73
but lower than in patients (men and women) with poorly
compressible arteries (the latter being defined as having an
ABI
>
1.4 or an ankle blood pressure
>
255 mmHg).
74
Higher
NT-proBNP levels were associated with lower functional capacity
in individuals with PAD. In this study by Fan and collaborators,
female gender was another independent predictor of lower
functional capacity.
75
It was also noted that elevated NT-proBNP
levels were linearly related to the risk of complications in PAD
subjects, including overall cardiovascular mortality, independent
of gender.
76
We may speculate that this might be caused by
associated heart failure due to concomitant coronary artery
disease in these patients, but we cannot completely rule out PAD
from the pathophysiological chain.
The soluble receptor for advanced glycation end-products
(sRAGE) was found to be lower in patients with coronary
artery disease compared to healthy controls.
77
Individuals with
associated PAD (82% were males) had even lower levels of
sRAGE.
77
sRAGE has protective effects against the harmful
interaction of advanced glycation end-products (AGEs) with
RAGE.
78
This interaction increases the production of ROS and
arterial stiffness,
79
leading to accelerated atherosclerosis and an
increased risk of developing symptomatic PAD.
The transforming growth factor-beta (TGF-
β
) is another
cytokine with pro-fibrotic and pro-inflammatory effects.
80,81
Studies showed discordant results regarding TGF-
β
plasma
levels in PAD patients; decreased,
53
increased,
80
or no significant
differences
82
versus controls. Gender variations were not reported
53
or not statistically significant.
80,82
These data could be explained
by the mixed effects of TGF-
β
, both as a pro-inflammatory and
fibrotic cytokine on the one hand, and as a major orchestrator
of vascular repair on the other.
Vascular endothelial growth factors (VEGFs) are essential
signalling proteins and key regulators of angiogenesis.
83
In
a study in which women and African-Americans were well
represented, VEGF-A serum levels were decreased in PAD
patients compared to controls.
50
The lower levels of VEGF-A in
patients with PAD and claudication suggest that they had lower
levels of neo-angiogenesis.
50
Paradoxically, serum VEGF-A levels
were increased in several studies on PAD patients.
83-86
Recent studies demonstrated that there are splice variants of
VEGF-A: VEGF-A165a, with pro-angiogenic activity, which
was decreased in patients with clinically manifested PAD, and
VGFA-A165b, with anti-angiogenic properties, which were
increased.
83
This might explain the discrepancies found in studies
in which total VEGF-A was measured.
CD163 is a scavenger receptor for the tumour necrosis
factor-like weak inducer of apoptosis (TWEAK).
87
TWEAK, a
member of the tumour necrosis factor superfamily of structurally
related cytokines, determines an increase in pro-inflammatory
cytokine secretion, which is associated with the development
of atherosclerosis.
88
In one study, performed on white males,
the ratio between plasma levels of CD163 and TWEAK was
increased in patients with more severe PAD.
89
The results were
confirmed in another study performed on both males and
females, which did not reveal any gender differences.
90
Plasma thrombospondin-1 (TSP-1) level, an adhesive
glycoprotein that mediates cell-to-cell and cell-to-matrix
interactions, was increased in a study that included only white
male patients with PAD.
91
Another study, in which 31% of the
subjects were females and 62% African-Americans, revealed
no significant differences in TSP-1 levels.
92
TSP-1 is a potent
inhibitor of angiogenesis by enhancing endothelial colony-
forming cell (ECFC) adhesion,
91
and elevated levels may restrict
capillary growth in PAD patients,
93
leading to deficient collateral
circulation and worsening of PAD symptoms.
Matrix metalloproteinases (MMPs) are a family of
endopeptidases that contribute extensively to tissue remodelling
by degrading extracellular matrix components.
94
PAD is a
manifestation of systemic atherosclerosis and MMPs have
been involved in all stages of plaque development.
94
It seems
that MMP-9 plays a major role in the process of new blood
vessel formation, its deficit compromising ischaemia-induced
neovascularisation by decreasing the mobilisation and migration
of circulating endothelial progenitor cells (EPC), but also by
affecting vasculogenesis.
95
Other results indicate that MMP-10
activity may contribute to plaque rupture and its associated
complications.
94
Recent case–control studies showed an association between
PAD and elevated circulating levels of MMP-2,
53,96
MMP-8,
97
MMP-9,
53,96,98
and MMP-10.
96
In some studies, levels of MMPs
(MMP-9
96
and MMP-10
94
) were positively correlated with the
severity of PAD. These cited works included both males and
females, but gender differences were not assessed.
Gardner’s study demonstrated that Caucasian women had
higher levels of MMP-9, along with higher VCAM-1 and lower
hepatocyte growth factor (HGF) levels than Caucasian men.
African-American women with clinically manifested PAD also
had evidence of increased endothelial oxidative stress compared
to their male counterparts.
3
These findings point towards women
being a more vulnerable group of PAD subjects, exibiting a more
pronounced pro-inflamatory profile of circulating biomarkers
than men, and thus requiring stricter lifestyle intervention and
medical management.
Novel biomarkers and conventional risk factors
Smoking was for decades considered to be the main risk factor
for developing clinically manifested PAD, and recent data
confirm its leading pathogenic role along with diabetes mellitus.
12
Cigarette smoking increases oxidative stress at the level of the
vascular endothelium and promotes vascular inflammation.
99
In
PAD patients, fibrinogen levels are higher as the disease is more
extensive, but in female subjects there was a more pronounced
increase with smoking status.
19
Research by Rom
et al.
conducted on a cohort of heavy
smokers showed a positive association between CRP levels and
smoking history after adjustment for possible confounders.
100
Among over 1 800 participants in the Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial (PLCO), current smokers
had an array of significantly increased inflammatory markers
compared to former or non-smokers, ranging from acute-phase
proteins (CRP), to chemokines (C-C motif ligands), interleukins
and soluble receptors such as soluble vascular endothelial growth
factor receptor 3 (sVEGFR-3).
101
However, these values seemed to
normalise in time after smoking cessation, approximating those
of never smokers after some years. No gender-specific differences
were reported in any of these studies. This proves that smoking
effects on vascular inflammation are reversible with cessation,
and that its consequences are equally harmful in both genders.