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COMMENTARIES
POSTED IN OCTOBER 2009
The Association of Leukotriene Signaling with Matrix Metalloproteinase (MMP)
Activity in Atherosclerotic Plaque Vulnerability and In-stent Restenosis
Authors: Magnus Bäck and Daniel Ketelhuth
The inflammatory activity and extracellular
matrix (ECM) composition of an atherosclerotic lesion may
represent a better evaluation of plaque vulnerability than
radiographic and echographic determinations of coronary
or carotid artery lumen occlusions. For example, pro-inflammatory
signaling induced by leukotrienes, and the ECM-degrading
enzyme family of matrix metalloproteinases (MMPs) have
individually been associated with atherosclerotic plaque
instability [1,2]. In addition, recent findings indicate
that these two pathways are intimately linked, with implications
not only for inflammation-induced plaque rupture, but also
in abdominal aortic aneurysms (AAA) [3] and the response
to percutaneous interventions of stenotic or occluded vessels
[4].
The synthesis of leukotrienes takes
place locally within the atherosclerotic lesion through
the 5-lipoxygenase pathway
of arachidonic acid metabolism [5]. Inhibition of the leukotriene
pathway induces beneficial effects in animal models of
atherosclerosis [6] and intimal hyperplasia [7]. Genetic
association studies have in addition shown that certain
polymorphisms within the genes encoding the enzymes involved
in leukotriene biosynthesis correlate not only with subclinical
atherosclerosis but also with an increased risk of myocardial
infarction and stroke [8], suggesting a link between the
leukotriene pathway and plaque rupture.
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Patients after Kawasaki Disease and Premature Atherosclerosis: A Surge of Accumulating
Evidence
Authors: Nobutaka Noto, MD., Ph.D., FACC,
Tomoo Okada, M.D., Ph.D, and Hideo Mugishima, M.D., Ph.D.
Kawasaki disease (KD) is a systemic vasculitis
of unknown etiology in infants and children. First described
in Japan in 1967, KD has been described worldwide among
children of all races and ethnicities. More than 4,000
hospitalizations associated with KD were reported in 2000
in the United State [1]. In Japan, a national survey of
KD has been performed every 2 years since 1970. The most
recent nineteenth survey covered 2005 and 2006 and showed
that there were 10,041 and 10,434 new cases of KD in those
years, respectively. As of 2006, there have been 225,682
patients since 1970 [2]. Therefore, patients diagnosed
with KD in the sixties and seventies have already reached
adulthood. The increased incidence of young adults with
a history of KD during childhood has been accompanied by
a new problem of an association between post-KD lesions
and atherosclerosis.
Clinical and subclinical inflammation of
coronary and systemic arteries after KD may form the substrate
for long-term functional and structural abnormalities and
increase the risk of premature atherosclerosis. In fact,
some studies have demonstrated that alterations in the
lipid profile and generalized endothelial dysfunction persist
for a long time after the clinical resolution of KD [3,4].
There is accumulating evidence that flow-mediated dilatation
(FMD) of the brachial artery induced by reactive hyperemia,
a noninvasive marker of endothelial function, is abnormal
in post-KD patients with or without coronary artery lesions
(CAL) [5,6]. Furthermore, some studies have shown that
adverse cardiovascular profiles, characterized by proatherogenic
alteration of lipid profiles [7], increased intima-media
thickness (IMT) of the carotid artery [8,9], and arterial
stiffness [10,11], occur in patients after KD with CAL.
KD patients with CAL have been shown to have ongoing systemic
inflammation years after disease onset, as evidenced by
high-sensitivity C-reactive protein (hs-CRP) levels that
are significantly higher than those seen in normal age-matched
children or in patients with KD without CAL. Inflammatory
mediators, such as hs-CRP, may themselves promote atherosclerosis
[12]. In contrast, a recent study indicated that KD patients
have some abnormalities that are risk factors for atherosclerosis,
but there is no long-term systemic arterial endothelial
dysfunction regardless of the degree of coronary artery
involvement [13,14]. With respect to the noninvasive methods
of investigating endothelial dysfunction and vascular structural
changes suggestive of atherosclerosis after KD, data are
conflicting.
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