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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 12 NUMBER 1 • JULY 2015
9
The greater the number of cardiovascular risk factors that
apply to a woman, the higher her hs-CRP level.
13
Elevated CRP
levels have been associated with the presence of the metabolic
syndrome, diabetes and chronic heart failure. Furthermore, recent
studies show that a high CRP value is correlated with an increased
incidence and prevalence of auto-immune diseases in women, such
as rheumatoid arthritis and lupus erythematosus.
3-6
The Women’s Health study demonstrated that the addition of
hs-CRP to the Framingham score improved the predictive accuracy
of cardiovascular risk, especially in women with a 5–20% risk in 10
years.
14
Evidence from the Women’s Ischemia Syndrome Evaluation,
a prospective study, reported that high levels of amyloid serum
A, IL-6, sICAM1 and CRP had the highest predictive accuracy in
27 347 postmenopausal women apparently without cardiovascular
disease.
15
The guidelines do not however recommend routine
evaluation of this inflammatory biomarker, CRP.
2,11
Fibrinogen
High levels of fibrinogen are associated with an increased risk
of cardiovascular disease in both men and women, but there
are still substantial gender-specific differences.
6,13
On one hand,
plasma fibrinogen levels increase with menopause, but also
during the use of oral contraceptives and pregnancy.
16,17
On the
other hand, hormone replacement therapy lowers serum levels
of fibrinogen.
16
The latest European guidelines on cardiovascular disease
prevention in clinical practice recommend the determination of
fibrinogen levels as part of a refined risk assessment in patients
with an unusual or moderate CVD risk profile (class IIB, level B).
11
Interleukin-6 (IL-6)
IL-6 stimulates hepatic release of CRP and fibrinogen, both acute-
phase reactants involved in the process of atherosclerosis and
atherothrombosis. Unfortunately, there are contradictory data
regarding the role of IL-6 in the development of coronary heart
disease in women.
10,17
Atherosclerosis
reported from the British Women’s Heart and
Health study that the level of this cytokine was not directly associated
with the risk of coronary heart disease.
18
Interestingly, the Women’s
Health Initiative showed a direct correlation between high levels of
IL-6 and ischaemic heart disease.
10
Undoubtedly, cardiovascular risk
was not assessed only by measuring the IL-6 plasma levels, but also
by determining other cardiovascular risk factors.
10
Matrix metalloproteinase-9 (MMP-9)
MMP-9, along with CRP, IL-6 and increased levels of leukocytes may
provide accuracy in the prediction of developing coronary heart
disease in women.
10,17,19
E-selectin
Various studies impugn the relationship between E-selectin
and cardiovascular risk.
17,19
On the other hand, there is evidence
to support the predictive value of E-selectin for cardiovascular
events.
17,19,20
Haemostasis markers
There are sufficient data concerning the association of D-dimer,
coagulation factor VII, von Willebrand factor and fibrinogen levels
with the risk of coronary heart disease in women (after statistical
adjustments for traditional risk factors).
21
Studies demonstrated the
presence of high levels of coagulation factor VII in women suffering
from angina or other cardiovascular diseases.
22-25
However, the most
eloquent reports support the use of D-dimer in estimating prognosis
of cardiovascular death and other events in women.
26
Plasminogen activator inhibitor-1 (PAI-1)
Recent studies identified lower PAI-1 levels in premenopausal than
postmenopausal women.
16,17
The concentration of PAI-1 was lower
in women taking hormone replacement therapy, compared with
non-users.
6,16
Gene-specific differences and changes in PAI-1 values
during the postmenopausal years may be related to PAI-1 gene
polymorphism. The 4G/5G mutation was found more frequently
among postmenopausal women with coronary heart disease than
in premenopausal women.
16
Lipoprotein (a) [Lp(a)]
As is well known, elevated levels of Lp(a) increase the risk of
ischaemic heart disease in both men and women. Investigators
demonstrated a clear association between Lp(a), LDL cholesterol,
hypertension, hyperhomocysteinaemia and hyperfibrinogenaemia
in men. Also in women an increase in Lp(a) levels with age has
been reported.
6
Notably, Lp(a) is an emerging cardiovascular risk factor in both
pre- and postmenopausal women as it contributes to the formation
of atherosclerosis. Sometimes high levels of Lp(a) are correlated
with high CRP levels.
27
High Lp(a) values together with abnormal blood lipid levels are
risk factors for cardiovascular disease in women, even in those
under 60 years.
16
New research on women offers strong evidence
that heart attack risk increased as Lp(a) levels rose.
28
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
Recent data confirm the involvement of Lp-PLA2 in the development
of atherosclerosis by modifying the affinity of LDL particles for
extracellular matrix proteins.
30-32
Moreover, Lp-PLA2 favours lipid
accumulation in arterial walls, lipid peroxidation, and hydrolysis of
lysophospholipids and free fatty acids.
33,34
Lp-PLA2 may be identified
as an independent risk factor for rupture of atheroma plaque and
thrombo-embolic events.
12
The latest European guidelines on cardiovascular disease
prevention in clinical practice recommend the determination of
Lp-PLA2 values as part of a refined risk assessment in patients
at high risk of a recurrent acute atherothrombotic event (class
IIB, level B).
11
The 2010 ACCF/AHA Guideline for the Assessment
of Cardiovascular Risk in Asymptomatic Adults reported that
calculation of Lp-PLA2 levels may be reasonable for cardiovascular
risk assessment in intermediate-risk asymptomatic adults (class IIb
level B).
35
The recent Nurses’ Health study showed that levels of Lp-PLA2
were significantly associated with the incidence of ischaemic heart
disease in women.
36
According to some research results, women
have higher levels of secretory phospholipase A2 (sPLA2) than men.
It was reported that elevated sPLA2 levels were correlated with high
CRP levels.
27,37
Homocysteine
In general, women present with lower homocysteine values
than men, but elevation occurs during the menopausal years.
16,38