CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
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AFRICA
nitric oxide synthase expression and activity, increased uptake of
LDL-C by macrophages, and stimulation of tissue factor produc-
tion by peripheral blood monocytes.
28-32
CRP elevation indicates the systemic nature of progres-
sive atherosclerotic disease, which suggests that patients with
enhanced inflammation are generally at high risk for progression
of atherosclerotic disease and may exhibit multiple vulnerable
lesions. The concept of early identification of vulnerable patients
who are susceptible to cardiovascular adverse events seems
appealing, and measurement of inflammatory biomarkers may
be a potent adjunctive tool for this purpose.
33
Earlier studies such as the OACIS (Osaka Acute Coronary
Insufficiency study) and the Quebec Cardiovascular study have
shown that CRP levels were significantly raised in the study
group, compared to age- and gender-matched controls.
34,35
The
JUPITER trial has firmly established the utility of CRP as a
biomarker to identify populations that will benefit from preven-
tive therapy. Robert Glynn, the statistician associated with the
project, has conservatively estimated that hsCRP screening
followed by high-dose statin therapy over a five-year period can
prevent more than 250 000 heart attacks, strokes, revascularisa-
tion procedures and premature vascular deaths in the USA alone.
CRP has now emerged as a new diagnostic and therapeutic
modality for the management of coronary artery disease and
stroke.
36
Our study echoes the same finding.
CRP plays a major role in regulating lipoprotein metabo-
lism. It promotes uptake of native LDL-C. CRP has also been
shown to significantly reduce cholesterol efflux from THP-1
(human myelogenous leukaemia cell line) and peripheral blood
mononuclear cells to apoA-I or HDL.
37
CRP also decreases the
expression of ATP-binding membrane cassette transporter A1
(ABCA1) and ABCG1.
38
TNF-
α
is a pro-inflammatory cytokine produced primarily
by activated monocytes/macrophages in response to a variety
of stimuli.
39
Recently, TNF-
α
has been implicated in the patho-
genesis as well as the progression of atherosclerotic plaques in a
number of ways.
40
The possible mechanisms postulated include
the enhanced surface expression of ICAM-1, VCAM-1, and E-
and P-selections on endothelial cells.
41
It also leads to increased
chemokine and scavenger receptor expression.
42,43
Hirschl
et al
.
concluded that the extent of changes in serum TNF-
α
concen-
tration is significantly related to estimates of infarct extent,
obtained scintigraphically.
44
In a study involving South Indian patients with CAD (acute
myocardial infarction, unstable and stable angina), Rajappa
et
al
. found that the ratios of pro-/anti-inflammatory cytokines in
all the study groups increased significantly when patients with
unstable angina were compared to other groups.
45
Ridker
et al
.
concluded that inflammation plays a major role in the acute
coronary syndromes and that TNF-
α
gene and protein expression
persisted in the myocytes over time, which suggests a possible
long-term role of this cytokine in vascular remodelling.
39
Wojciech
et al
. conducted a study on the role of inflamma-
tion in promotion of left ventricular (LV) diastolic dysfunction.
The investigators concluded that plasma levels of TNF-alpha
and IL-6 were elevated and there was an association between
immuno-inflammatory activation, reflected by plasma levels of
cytokines, and LV diastolic dysfunction.
46
The findings of our
study further substantiate the evidence in favour of the pro-ather-
ogenic functions of TNF-
α
. We demonstrated the superiority of
the TNF-
α
/IL-10 ratio in risk stratification of CAD patients in
a previous study.
47
Lp(a) is a complex of apolipoprotein (a) and LDL-C.
Apolipoprotein (a) is an atherothrombogenic moiety that can
competitively inhibit plasminogen activity, leading to impaired
fibrinolysis.
48
Lp(a) has also been implicated in enhanced oxida-
tion and foam cell formation. Lp(a) functions as a dual pathogen
that is thrombogenic, one through its LDL-like characteristics
and the other through its plasminogen-like properties.
49,50
It
forms a link between genetics and two major explanations of
the pathogenesis of atherosclerosis: the fibrin-deposition theory
of Rokitansky and the lipid hypothesis of Virchow.
51,52
Recently,
it has been proposed that in settings of enhanced oxidative
stress and elevated Lp(a) levels, a pro-inflammatory milieu
may predominate that contributes to the clinical expression of
CAD.
53,54
Lipoprotein (a) has a prothrombic role in the pathogenesis
of CAD due to its structural homology with plasminogen and
it has been hypothesised that the former interferes with plas-
minogen activation and creates a thrombogenic milieu. It has
a tendency to self-aggregate and hence, a greater capacity to
bind to glycosaminoglycans and other structures in the vascu-
lar wall. Lp(a) binds avidly to endothelial cells, macrophages,
fibroblasts and platelets, as well as to the sub-endothelial matrix;
and promotes proliferation of vascular smooth muscle cells and
chemotaxis of human monocytes. Due to its unique structural
homology with plasminogen, Lp(a) competes with plasminogen
for binding to plasminogen receptors, fibrinogen and fibrin. It
also induces the production of plasminogen activator inhibitor
1 (the main inhibitor of the fibrinolytic system) and inhibits the
secretion of tissue-plasminogen activator by endothelial cells.
55-58
All these effects may be potentiated by concomitant dyslipidae-
mia.
59
Anuurad
et al
. found that the presence of inflammation as
detected by increased levels of CRP and fibrinogen resulted
in increased Lp(a) levels among African-Americans.
60
It was
shown that a combination of high Lp(a) levels with a high level
of either CRP or fibrinogen was associated with an increased risk
for CAD. These results suggest the possibility of an interaction
between Lp(a) and inflammatory markers and, furthermore, that
the presence of inflammation modulates the risk-factor proper-
ties of Lp(a).
60
Quantification of apolipoproteins A and B provides a meas-
ure of the total number of anti-atherogenic and pro-atherogenic
particles in plasma.
61
The Quebec Heart study demonstrated
accelerated CAD in patients with hyperapolipoproteinaemia-B.
62
Our study also showed a significant rise in the atherogenic apoli-
poprotein B levels in AMI patients in the atherosclerosis-prone
North Indian population, compared with control subjects, and
indicates that the measurement of apo-B concentration can more
accurately delineate coronary artery disease than LDL choles-
terol measurement alone.
Yet another finding of our study was the highly significant
positive correlation between TNF-
α
and lipoprotein (a) in the
CAD-prone North Indian patients with acute myocardial infarc-
tion. The positive correlation between these two parameters
throws some light on the complex interaction between inflam-
mation and dyslipidaemia in the pathogenesis of atherosclerosis
and its ultimate clinical manifestation, namely, acute coronary
syndrome that includes myocardial infarction. The apo(a) gene
