CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 6, July 2012
AFRICA
333
possible predictors of plaque instability. This holistic view of
plaque instability was the cardinal point of our study.
Our study revealed that serum leptin levels were significantly
higher in the patient group than in the controls. Hyperleptinaemia
has been implicated in the aetiopathogenesis of atherosclerosis in
a number of studies.
17-20
The various underlying mechanisms
responsible for its pro-atherogenecity are being revealed with
a multitude of
in vitro
and
in vivo
studies. These include
influences on cytokine signalling mechanisms,
21
stimulation
of pro-inflammatory cytokine production,
22
stimulation of
smooth muscle cell proliferation,
23
up regulation of phagocytotic
mechanisms,
17
platelet aggregation and thrombosis,
24,25
and the
promotion of endothelial dysfunction.
26
Serum leptin is also responsible for the stimulation of
mitochondrial superoxide production
27
and calcification of
smooth muscle cells.
21
It has been observed that leptin levels
correlate with insulin resistance, obesity and cardiovascular risk
factors.
In fact, it has been hypothesised that the disturbances
in adipocytokine balance and signalling pathways in obesity
eventually culminate in atherosclerotic disease.
23,28
Our findings are in accordance with studies carried out by
many researchers. Serum leptin levels could predict adverse
cardiovascular events, even after adjustment for the traditional
risk factors, in the WOSCOPS trial.
18
Cincone
et al.
reported
a positive correlation between serum leptin levels and intima–
media thickness in healthy individuals.
29
Karaduman
et al
.
evaluated the levels of hs-CRP and leptin in atherosclerotic
plaques and found leptin levels to be significantly higher in
diabetics than non-diabetics.
17
Iribarren
et al
. reported a positive correlation between
serum leptin levels and coronary artery calcium scores in
healthy women.
30
Reilly
et al.
concluded from their study that
plasma leptin levels may represent a marker for adiposity,
insulin resistance and vascular dysfunction, leading eventually
to atherosclerosis.
31
However, the Quebec Heart study as well as
a study carried out by van den Beld did not find any correlation
between leptin levels and cardiovascular events.
32
C-reactive protein level has been established as a determinant
of the inflammatory process in atherosclerosis. In fact, hs-CRP
levels have been correlated with disease initiation, progression
and prognosis.
33
CRP carries out a multipronged attack on the
endothelium with pro-inflammatory, stimulatory and pro-oxidant
actions leading to endothelial dysfunction and other events that
predispose to atherosclerosis. The mechanisms are explained in
our previous article.
34
The present study also highlights the significance of hs-CRP
levels in determining CAD. The ability of statins to decrease
CRP levels has garnered interest in the recent years. The
PROVE IT TIMI 22 (PRavastatin Or atorVastatin Evaluation
and Infection Therapy
–
Thrombolysis In Myocardial Infarction
22) study highlighted that the CRP levels after statin therapy
were as efficient in predicting CAD as LDL levels.
35
The recent
JUPITER study also highlighted the pro-atherosclerotic role of
CRP and its response to statin therapy.
36
Pravastatin therapy led to maximal benefit in patients with
highest CRP values regardless of their LDL concentrations,
according to the Cholesterol And Recurrent Events (CARE)
trial.
37
Similar findings were reported by the AFCAPS/
TexCAPS24 and Physicians Health study.
38,39
Our study also
highlights the importance of hs-CRP in the prediction of unstable
plaques. However, caution is warranted in the interpretation of
the utility of hs-CRP due to its non-specificity. Being an acute-
phase reactant, its significance must be analysed by excluding all
other causes of its elevation.
Anand
et al
. concluded from their study that CRP was
independently associated with CAD in Asian Indians after
adjustment for Framingham risk factors and anthropometric
measurements.
40
The INTERHEART study demonstrated
that increased apolipoprotein B/apolipoprotein AI, smoking,
abdominal obesity, psychosocial stress, diabetes mellitus and
hypertension accounted for 90% of the CAD risk in Asian
Indians.
413
PAPP-A is an emergent biomarker signifying plaque instability.
The role of PAPP-A as a biomarker for unstable atherosclerotic
plaques was initially suggested by Bayes-Genis
et al
., who
measured PAPP-A levels in the cells and the extracellular matrix
of unstable plaques in eight patients who had sudden death due
to cardiac causes.
13
PAPP-A is a member of the metzincin metalloproteinase
superfamily and is also produced by non-placental tissue such
as fibroblasts, vascular endothelial cells and vascular smooth
muscle cells. The circulating form of the protein comprises a
heterotetrameric complex formed of two subunits of 200 and
250 kDa, bound by eosinophil major basic protein.
42
PAPP-A
is secreted by activated macrophages that take part in the
atherosclerotic process.
Studies have revealed that PAPP-A contributes to plaque
instability by promoting degradation of the extracellular matrix
of the fibrous cap.
43
PAPP-A acts as an insulin-like growth factor
(IGF) binding protein 4 protease. PAPP-A degrades IGF-binding
protein 4 protease and thus increases the availability of free
IGF-I.
44
IGF-I induces macrophage activation, chemotaxis,
LDL cholesterol uptake by macrophages, and the release of
pro-inflammatory cytokines by these cells.
45,46
IGF-I is also
implicated in the proliferation and migration of smooth muscle
cells and the consequent vascular response to injury.
45,47
These
events lead to the initiation of plaque destabilisation.
We observed significantly higher levels of PAPP-A in the
patients compared to the control group. It also emerged as a
good indicator of plaque vulnerability, just behind hs-CRP, with
an area under curve of 0.732. Our findings corroborate the
results of previous studies that have been carried out.
48,49
Lund
et al
. concluded that PAPP-A was a good predictor of both
ischaemic cardiac events and the need for revascularisation in
patients with ACS.
50
Cosin-Sales
et al
. concluded from their
study on patients with ACS that those with complex coronary
lesions had significantly higher PAPP-A levels than patients who
were free of such lesions.
13
Heeschen
et al.
evaluated PAPP-A
levels in 547 patients with angiographically proven ACS. They
found that elevated PAPP-A levels indicated an increased risk
TABLE 4. MULTIVARIATE REGRESSIONANALYSIS OF THE
VARIOUS PARAMETERS IN THE STUDY
Fasting plasma glucose
0.194 Triglycerides
0.010
Fasting insulin
0.026 Cholesterol
0.051
Leptin
0.000 Ldl
0.041
Ck-mb
0.383 Hdl
0.241
Papp-a
0.001 Ldl/hdl
0.202
Crp
0.396 Cholesterol/hdl
0.230
Lipoprotein (a)
0.111
