EDITORIAL

Lipoprotein-associated phospholipase
A
2
, a marker of vascular inammation
and systemic vulnerability
Thomas Mu nzel
*
and Tommaso Gori
II Medizinische Klinik fur Kardiologie/Angiologie, Langenbeckstrasse 1, D-55131 Mainz, Germany
This editorial refers to Expression of lipoprotein-
associated phospholipase A
2
in carotid artery plaques pre-
dicts long-term cardiac outcome, by J. Herrmann et al.
doi:10.1093/eurheartj/ehp309
As interventional cardiologists, we are sometimes prone to believe
that plaque quantity, more than plaque biology, is a determinant of
patients prognosis. This concept is unfortunately challenged in
daily practice, as accelerated progression of atherosclerosis,
rupture of a plaque that was not critical at angiography, and/or
dynamic phenomena such as spasm contribute to determine the
patients prognosis. That the extent and severity of coronary
artery disease at angiography is a strong prognostic index for the
risk of subsequent (cardio)vascular events is not under discussion.
However, our understanding of plaque progression and instability
remains far from complete. In line with this concept, Lavi et al.
recently reported that the presence of an abnormal coronary reac-
tivity to an endothelium-dependent stimulus identies areas occu-
pied by plaques with a larger necrotic core, i.e. at higher risk for
rupture.
1
In addition, a number of studies and anecdotal evidence
have shown that endothelial dysfunction and/or oxidative stress,
systemic or local, may predict disease progression/instability and
overall patient prognosis.
2
Although it needs to be acknowledged
that the best therapeutic strategy for plaques that are histologically
vulnerable but cause no severe stenosis at angiography remains
unexplored, the search for new markers and techniques that
help in detecting vulnerable plaques and vulnerable patients
should be considered a priority of modern cardiology.
An effort in this direction is presented by Herrmann et al.
3
who
describe the important role of lipoprotein-associated phospho-
lipase A
2
(Lp-PLA
2
) levels and activity, as measured at the level
of carotid plaques, in predicting future cardiovascular events.
This concept provides further support for the idea that athero-
sclerosis is a systemic disease, and that plaque activation in a
given vascular district is associated with a global increased
cardio- or cerebrovascular risk.
PLA
2
s belong to a superfamily that contains 15 separate groups
and a number of subgroups characterized on the basis of sequence,
molecular weight, disulde bonds, requirement for Ca
2
, and
other molecular and functional features.
4
Five major categories
of PLA
2
s are usually described: these include the secreted small
molecular weight sPLA
2
, the larger cytosolic Ca
2
-dependent
cPLA
2
, the Ca
2
-independent iPLA
2
, the platelet-activating factor
acetylhydrolases, and the lysosomal PLA
2
. In general, PLA
2
s hydro-
lyse the fatty acid from the sn-2 position of membrane phospholi-
pids. The two compounds that result from this reaction are a
polyunsaturated fatty acid that functions as substrate for a
number of enzymes to form various eicosanoids and eicosanoid-
related mediators and a lysophospholipid which can also have
important roles in biological processes. Lysophospholipids such
as lysophosphatidylcholine may also serve as markers of local
LPA
2
activity, although, as Herrmann et al. acknowledge,
3
one
needs to keep in mind that the production of these mediators is
not exclusive to these enzymes. Thus, products of PLA
2
activity
may mediate a variety of biological events, and crucial roles
during signalling and metabolic processes such as host defence,
inammation, and innate immunity have been described for most
of the members of this superfamily.
Platelet-activating factor acetylhydrolases are composed of two
PLA
2
groups, and are mostly produced by macrophages and acti-
vated inammatory cells.
5
One member of this group is the
Lp-PLA
2
, a 45 kDa, Ca
2
-independent secreted enzyme that cata-
lyses a number of reactions of biological importance and that,
notably, is able to bind to both HDL and LDL cholesterol mol-
ecules through as yet incompletely understood mechanisms.
4,5
The physiological role of Lp-PLA
2
and its potential role in deter-
mining cardiovascular pathology is also far from being completely
understood (Figure 1), and there are lines of evidence suggesting
both an anti-inammatory and a proinammatory function of this
enzyme. In human plasma, the majority of the Lp-PLA
2
activity is
present as a complex with LDL and lipoprotein(a). In particular,
Lp-PLA
2
appears to be particularly represented in small dense
* Corresponding author. Tel: 49 6131 17 7250, Fax: 49 6131 17 6615, Email: tmuenzel@uni-mainz.de
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
European Heart Journal
doi:10.1093/eurheartj/ehp311
European Heart Journal Advance Access published August 30, 2009

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LDL particles, which are believed to be more proatherogenic and
to promote Lp-PLA
2
activity. Bound to these lipoproteins, accord-
ingly to the hypothesis recently proposed by Stafforini et al.,
5
Lp-PLA
2
hydrolyses potentially dangerous oxidized phospholipids,
reducing their ability to promote monocyte chemotaxis and
adhesion, and it decreases the bioavailability of the prothrombotic
platelet-activating factor. Thus, in a physiological state, Lp-PLA
2
might actually have a protective, anti-inammatory and antiplatelet
function, as demonstrated by evidence in animal in vivo studies in
which overexpression of human plasma PLA
2
retarded the pro-
gression of conditions associated with cardiovascular disease,
including atherosclerosis and post-ischaemic injury.
6,7
Similarly,
genetic deciency of PLA
2
s has been associated with increased
incidence and severity of cardiovascular conditions in certain (pre-
valently Asian) populations.
8,9
In contrast, other lines of evidence
suggest that Lp-PLA
2
might also have a proatherogenic role, as
the bioproducts of the Lp-PA
2
-mediated hydrolysis of oxidized
phospholipids are also proinammatory moieties, such as lysopho-
sphatidylcholine and oxidized fatty acids, which might have an
important role in inammation. In particular, lysophosphatidylcho-
line has been shown to be involved in inammatory cytokine pro-
duction, in the induction of the expression of adhesion molecules
and cytokines, it has a chemoattractant property for macrophages,
and it induces vascular smooth muscle migration.
10
Interestingly,
the PLA
2
-mediated release of these compounds might be involved
in a deleterious feed-forward mechanism whereby recruitment of
macrophages, T-cell lymphocytes, and mastocytes in activated
plaques may lead to further Lp-PLA
2
production and activity.
This hypothesis of a proatherogenic role for Lp-PLA
2
appears to
be supported by evidence from immunohistochemical studies
suggesting preferential upregulation of Lp-PLA
2
within the necrotic
core and in macrophages surrounding vulnerable and ruptured
plaques as compared with stable ones.
11
Finally, another possibility
has been proposed for the role of PLA
2
in atherogenesis: in the
presence of excessive levels of superoxide anion and nitric
oxide, the formation of peroxynitrite, a potent mediator involved
in endothelial dysfunction and atherogenesis, might lead to oxi-
dative inhibition of the Lp-PLA
2
. This peroxynitrite-induced inhi-
bition, concomitant with lipid oxidation, would cause the
accumulation of oxidized phospholipid species that can form phos-
pholipidprotein adducts whose high immunogenic and proinam-
matory potential further contributes to determine atherogenesis.
5
Substantiating the involvement of PLA
2
in atherogenesis, increased
mass and/or activity of Lp-PLA
2
have been associated (with some
negative ndings) with various cardiovascular endpoints in healthy
subjects and patients with acute coronary syndromes, and a con-
sistently positive association between Lp-PLA
2
and cardiovascular
risk has been reported in patients with stable coronary artery
Figure 1 The controversial role of Lp-PLA
2
. The enzyme hydrolyses a number of mediators potentially involved in atherogenesis, such as
oxidized low-density lipoproteins (oxLDL) and platelet-activating factor (PAF), thus reducing their negative impact. At the same time, products
of Lp-PLA
2
-mediated degradation of these molecules may also have proinammatory, proliferative, and ultimately proatherogenic roles.
Notably, Lp-PLA
2
is itself hyperexpressed in the setting of inammation, and it is inhibited by peroxynitrite (ONOO

). What causes this equili-

brium to tip from a benecial role for Lp-PLA
2
to a proatherogenic role of the enzyme remains unknown.
Editorial Page 2 of 3

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diseases.
5,12,13
Collectively, these data suggest that Lp-PLA
2
might
be a reliable biomarker of cardiovascular risk in various popu-
lations and that it might help in guiding the intensity of preventive
therapy.
Since Lp-PLA
2
may be both a specic marker and a causal
mediator of plaque progression and instability, a more exciting per-
spective is to test the possibility of using it as a therapeutic target.
The development of the specic oral Lp-PLA
2
inhibitors, the aze-
tidinones, has opened up this possibility: therapy with the Lp-PLA
2
inhibitor darapladib has been associated, in animal models and
patients with cardiovascular disease, with a reduction (or
reduced progression) of atherosclerosis and of some morphologi-
cal markers of plaque instability,
14,15
although no effect was shown
on plaque deformability and other parameters of plaque instability.
Thus, until further studies are performed, it needs to be acknowl-
edged that our understanding of the role of Lp-PLA
2
in atherogen-
esis, inammation, and oxidative stress remains incomplete, and
that most of the knowledge to date is founded on evidence of
association more than causation. The study by Herrmann et al.
3
adds further important information, and it emphasizes the fact
that we should consider atherosclerosis as a systemic disease in
which oxidative stress and inammatory mechanisms play a
central role.
In conclusion, Lp-PLA
2
is potentially a marker of vascular inam-
mation, a risk factor, a prognostic biomarker, and ultimately a
target of therapy. In the perspective of further development, at
least three questions are of crucial importance: the rst is
whether Lp-PLA
2
-related parameters can be used as biomarkers
of inammatory activity, with the advantage over C-reactive
protein of possessing some specicity for cardiovascular disease
and/or risk. It is well known that major known risk factors
account for only about half of the variability in cardiovascular
risk, and the quest for more accurate and more sophisticated
risk scores is ongoing. To this end, it will be important to under-
stand how much the addition of Lp-PLA
2
-related parameters
potentiates the prognostic information that derives from conven-
tional (more accessible) risk factors. Also, it will have to be claried
whether the additional information provided by Lp-PLA
2
measures
can be applied in individual patients, and whether Lp-PLA
2
-based
therapeutic strategies improve cardiovascular outcomes.
The second point is what to do to develop Lp-PLA
2
as a thera-
peutic target. Lp-PLA
2
levels are indirectly modied by
lipid-lowering therapies, but therapies based on specic targeting
of Lp-PLA
2
will have to be tested in terms of hard outcomes. In
particular, the true role of Lp-PLA
2
in atherogenesisas a
mediator, a defence mechanism, or a bystanderwill need to be
investigated, and it will need to be claried whether inhibition of
Lp-PLA
2
might lead to paradoxical accumulation of proinamma-
tory or prothrombotic moieties.
Finally, the data from the paper of Herrmann et al., along with
those previously published by the same group,
16
suggest that the
abundance of Lp-PLA
2
at the level of specic plaques might be a
potent prognostic marker in our ongoing quest for the vulnerable
plaque or the vulnerable patient. Newer technologies such as
virtual histology, intravascular ultrasound palpography and thermo-
graphy, optical coherence tomography, and especially non-invasive
techniques would denitely benet from a molecular imaging bio-
marker that allows the study of plaque composition and character-
istics in a safe and reliable way. In this perspective, invasive or
non-invasive technologies that allow identication of biological
markers of instability in single plaques are eagerly awaited.
Conict of interest: none declared.
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Editorial Page 3 of 3

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