Atherosclerosis
Invited commentary
Inflammation and calcification: The chicken or the hen?
*
Paolo Raggi
Mazankowski Alberta Heart Institute, Division of Cardiology and Department of Medicine, University of Alberta, Edmonton, AB, Canada
a r t i c l e i n f o
importance of inflammation in the process of progressive sclerosis
Article history:
Received 15 October 2014
Accepted 17 October 2014
Available online 18 October 2014
of the aortic valve.
Atherosclerosis and aortic valve calcification share the same risk
factors [5] and these may induce inflammation. However, in the
current study inflammation was associated with future calcification
independent of all risk factors except for age [1]; hence one won-
ders if risk factors and inflammation are at all correlated in aortic
valve disease. Of interest, inflammation showed a close association
with future valvular calcification but not pre-existing calcification
In the current issue of the journal, Abdelbaky et al. [1] present a
very interesting study addressing the association of aortic valve
inflammation and calcification. To ascertain whether aortic valve
inflammation precedes subsequent valvular calcification they uti-
lized sequential PET/CT scans performed for cancer surveillance in
patients with stable oncological disorders. Computed tomography
provided information regarding the presence and extent of calci-
[1]. This could suggest that long standing calcification becomes
inert and/or that new stimuli may ignite a strong inflammatory
response. Is it possible that calcification itself may promote
inflammation, so is inflammation the chicken or the hen? Although
limited, there is some experimental and human evidence that this
might be the case. Calcification of the aortic valve is associated with
disruption of the basal membrane, infiltration of inflammatory cells
and lipids deposition [6,7]. Nadra et al. [8] showed that human
macrophages exposed in culture to calcium-phosphate crystals
internalize the crystals in vacuoles and release inflammatory cy-
fication (structural information), while PET provided functional/
activity information. 18Fluoro -deoxyglucose (FDG) is used exten-
sively in oncological PET imaging and has been shown to be
selectively taken up by inflammatory cells, accumulating in nascent
atherosclerotic plaques and the aortic valve [2,3]. In the current
study Abdelbaky et al. [1] showed that FDG uptake in the aortic
valve was higher among patients who showed subsequent pro-
gression of calcification, especially in patients with no detectable
calcification at baseline. Several traditional risk factors for athero-
sclerosis were associated with inflammation and calcification of the
aortic valve at the time of the first scan including age, diabetes
mellitus, dyslipidemia and hypertension. However, on multivari-
able analyses only age and a quantitative measure of FDG uptake
tokines (TNF-
a, IL-1
b and IL-8) via a protein-kinase-C dependent
pathway. TNF-
a
is capable of inducing osteoblastic differentiation
of vascular smooth muscle cells therefore initiating calcification of
the interstitium [9]. Furthermore, recent evidence suggests that
macrophages are capable of releasing matrix vesicles that are rich
in annexin V and alkaline phosphatase, with high calcifying po-
tential [10]. These results suggest that calcium may promote
inflammation which in turn will enhance further calcification. In a
randomized trial of patients affected by end-stage renal disease the
compound Sevelamer arrested the progression of valvular calcifi-
cation, while calcium-based phosphate binders allowed further
progression [11]. Sevelamer is a non-absorbable polymer used as a
gut phosphate binder and has lipid-lowering as well as mild anti-
inflammatory activities [12]. This trial provided partial support to
the hypothesis that calcium and inflammation may be part of a
(
maximum standardized uptake value (SUVmax)) were associated
with inception or progression of valve calcification [1]. In a prior
publication the same authors made a very similar observation in
aortas, where inflammation preceded subsequent calcification [4].
Is inflammation therefore a condition sine-qua-non for future
calcification of the aortic valve? Certainly there were patients who
demonstrated tracer uptake at baseline who did not calcify during a
median follow up of 2 years, hence it does not appear that
inflammation is a necessary and sufficient condition for future
calcification. Nonetheless, numerous pieces of evidence point to the
“vicious cycle”.
What other risk factors could potentially ignite inflammation
and calcification of the aortic valve? As oxidized lipids are found in
calcifying aortic valves, it has been suggested that they could pro-
mote osteoblastic differentiation of valvular fibroblasts and mac-
rophages via activation of the LDL receptor protein-5 (LRP5)/Wnt
and Runx2/Cbfa-1 pathways, eventually inducing calcification [13].
Unfortunately, several trials of statin therapy to reduce serum LDL
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Mazankowski Alberta Heart Institute, University of Alberta School of Medicine,
0
Wu, Fei
