CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 3, May/June 2014
138
AFRICA
activatable fibrinolysis inhibitor, von Willebrand factor,
fibrinogen, haematocrit, leukocyte and platelet counts.
10
These
novel biomarkers of cardiovascular risk are classified into three
categories: inflammatory markers, haemostasis markers, and
other biomarkers.
Inflammatory markers
High-sensitivity C-reactive protein (hs-CRP)
The latest European guidelines on CVD prevention in clinical
practice (2012) recommend the determination of high-sensitivity
CRP levels as part of the refined risk assessment in patients with
an unusual or moderate CVD risk profile (class IIB, level B).
11
Normal values for this inflammatory factor are below 2 mg/dl.
CRP levels in women are higher than in men, especially
during puberty.
2
The JUPITER trial reported that an hs-CRP
value over 2 mg/dl in association with a low-density lipoprotein
(LDL) cholesterol value below 130 mg/dl in women without
cardiovascular pathology increases the risk of cardiovascular
events.
12
Moreover, high levels of CRP in women without
cardiovascular disease are important predictors for the
development of fatal heart attack and stroke.
13
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
