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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
AFRICA
323
In this review, we summarise the present knowledge regarding
the involvement of novel markers of atherosclerosis in the
development of PAD in women.
Inflammatory markers
Although not a novel marker, fibrinogen, an important acute-
phase protein, is responsible for increasing blood viscosity, with
secondary prothrombotic effects.
6
Regardless of the presence
of PAD symptoms, various studies have demonstrated the
presence of elevated fibrinogen levels in subjects with marked
peripheral atherosclerosis.
17,18
The association between high levels
of fibrinogen and PAD is stronger in men than in women, while
for the latter it seems to be positively correlated with smoking.
19
The Multi-Ethnic Study of Atherosclerosis (MESA), which
included individuals without a known history of cardiovascular
disease, demonstrated that women of all ethnic groups had
higher median levels of C-reactive protein (CRP) than men.
20
Numerous clinical trials have shown that there is a robust and
independent association between CRP and the presence of PAD,
regardless of gender.
17,21-23
In a recent study, Gardner
et al.
found a direct relationship
between CRP levels and the progression of PAD,
23
while
Pradhan’s study demonstrated a strong association between
CRP, soluble intracellular adhesion molecule-1 (sICAM-1),
high-density lipoprotein cholesterol (HDL-C) levels, triglyceride/
HDL-C ratio and symptomatic PAD in women.
22
Female subjects
with high levels of CRP enrolled in the Women’s Health Study
had a significantly greater risk of developing PAD over time.
17
CRP is also a marker associated with an increased risk
of developing PAD-related complications, as shown by the
European Prospective Investigation into Cancer and Nutrition
(EPIC): Norfolk cohort.
24
High serum levels of CRP before
endovascular therapy in haemodialysis-requiring PAD
patients were independently associated with increased risk of
re-intervention, amputation and even overall mortality.
25
Similar to data obtained in adults, CRP is probably the
most studied inflammatory biomarker in children. Jarvisalo
et
al.
found that healthy young children with higher CRP levels
had higher carotid intima–media thickness (CIMT) and lower
brachial artery flow-mediated dilatation.
26
The Pathobiological
Determinants of Atherosclerosis in Youth Study (PDAY), which
included subjects aged 15 to 34 years, demonstrated a direct
relationship between CRP levels and abdominal aorta or right
coronary artery atherosclerotic lesions.
27
As in older adults, CRP
levels were higher in young women.
27
Other studies, such as the Cardiovascular Risk in Young
Finns study,
28
and Giannini and colleagues’ work,
29
did not find
an association between childhood CRP levels and adult CIMT.
These findings are in line with current knowledge that high levels
of inflammatory markers are independent predictors of adverse
cardiovascular outcomes, and this seems to be true irrespective
of gender or age.
Homocysteine
Thirty per cent of young patients with PAD have increased
blood levels of homocysteine compared to 1% in the general
population, as it may be a stronger risk factor for PAD than
for coronary artery disease.
8
In the MESA study, homocysteine
along with high levels of interleukin-6, fibrinogen and D-dimers,
were significantly correlated with the presence of PAD, even
after adjustment for traditional cardiovascular risk factors.
5
A meta-analysis published in 2009, comprising 14 studies,
found that homocysteine levels were elevated in PAD patients
compared to healthy controls.
30
Even among the PAD group,
blood levels increased with age, being higher in elderly subjects.
31
Along with other traditional atherosclerosis risk factors such
as smoking, diabetes, arterial hypertension and dyslipidaemia,
homocysteine is thought to be an important predisposing factor
for the development of PAD in women.
32
Several older studies
showed an association between high homocysteine levels and
PAD in women.
33-35
On the other hand, more recent studies give different results.
Elevated levels of homocysteine had been found only in male
subjects with PAD in a Japanese-Brazilian population.
36
Pradhan
et al.
found no correlation between homocysteine levels and
the presence of PAD in female subjects.
22
Using data from
two large cohort studies (72 348 female participants from
the Nurses’ Health Study and 44 504 males from the Health
Professionals Follow-Up Study), of whom only subjects with
clinically manifested PAD were selected, Bertoia
et al.
showed
that homocysteine levels were positively associated with the risk
of developing PAD only in men, not in women.
37
In children, elevated plasma homocysteine levels correlated
significantly with increased CIMT and decreased flow-mediated
dilatation, but only in young girls,
38
as opposed to findings of
recent adult studies. Another study enrolling adolescents with
multiple risk factors for atherosclerosis proved that individuals
with CIMT in the upper quartile had significantly higher mean
plasma homocysteine levels than those of subjects in the lower
quartile. Unfortunately, gender differences were not analysed.
39
Lipoprotein (a)
In the Invecchiare in Chianti (inCHIANTI) study, performed
on a cohort from Tuscany, Italy, there was a strong correlation
between high levels of lipoprotein (a) and lower-limb PAD in
both men and women over 60 years of age.
40
In the MESA study,
which included 4 618 participants, significantly elevated levels of
lipoprotein (a) were detected only in Hispanic Americans (men
and women) with PAD.
41
High circulating levels of lipoprotein (a), along with other
inflammatory markers, were also associated with a reduced
ankle–brachial index (ABI) and the presence of clinically
significant PAD in an African-American cohort,
42
confirming
this is an establised risk factor for atherosclerosis, regardless
of vascular teritory involved, ethnicity or gender. Its inherent
procoagulant effects via its apolipoprotein (a) component, which
can inhibit fibrinolysis, makes it an independent marker of acute
vascular thrombotic complications.
43
Interleukin-6 (IL-6)
IL-6 is the main interleukin that exerts procoagulant effects.
It is also involved in the inflammatory process by stimulating
macrophages and contributing greatly to arterial smooth
muscle cell proliferation, thus promoting atherosclerotic plaque
formation.
44
Two large studies, the Edinburgh Artery Study
22
and the Walking and Leg Circulation (WALCS) II cohort
44