Introduction
Inflammation is a physiological reaction that can become a pathological
effect, associated with several diseases and characterized by the
release of mediators, including metabolites of the arachidonic acid
cascade. Cysteinyl leukotrienes (cysteinyl-LTs), namely
LTC4, LTD4, and LTE4,
are potent pro-inflammatory lipid mediators long known to play an
important role in asthma1, that have also been
implicated in other inflammatory conditions, such as allergic rhinitis
(AR), atopic dermatitis, and urticarial2.
Additionally, their involvement has been hypothesized in several
cardiovascular diseases (CVDs), such as acute myocardial infarction
(MI), ischemic stroke (IS), atherosclerosis, aortic aneurysms and
intimal hyperplasia3-6. Increased intracoronary
production of cysteinyl-LTs was detected in patients undergoing coronary
angioplasty7 and by systemic urinary
LTE4 excretion in acute MI and ischemic heart disease
patients8-10. Several proteins in the 5-lipoxygenase
pathway, including both CysLT receptors, were found in the arterial wall
of patients at different stages of
atherosclerosis11-14. Finally, besides the increase in
cysteinyl-LTs concentration in CVDs, a number of genetic studies also
support a link between cysteinyl-LTs, their receptors and
CVD15-18.
In the 1990s, after the discovery that cysteinyl-LTs were implicated in
asthma, a number of LT modifiers, i.e. 5-lipoxygenase pathway
inhibitors, but particularly CysLT1 receptor antagonists
(LTRAs), were developed and are now widely used to treat asthma and
other allergic conditions19. However, CVDs,
particularly atherosclerosis, have a crucial inflammatory
component20,21, and given the role of cysteinyl-LTs in
modulating vascular tone and inflammation22-24, LTRAs
have been proposed as potential therapeutics for such
diseases6,25. The potent and selective
CysLT1 receptor antagonist montelukast was first
approved by the Food and Drug Administration to be used in different
stages of asthma both in adults and children and later on also for the
treatment of seasonal and perennial AR19. In addition,
in preclinical animal models, montelukast has been shown to
significantly reduce the formation of atherosclerotic plaques and
intimal hyperplasia, and to reduce the level of reactive oxygen species
production and apoptosis, demonstrating beneficial effects on
endothelial cells functions and myocardial remodeling
(see26 and6 for recent reviews).
Furthermore, montelukast has been demonstrated to inhibit oxidized
low-density lipoprotein-induced monocyte adhesion to endothelial cells,
suggesting a protective role in the early stages of
atherosclerosis27. Montelukast also protects against
aorta dilatation and reduces aortic rupture and aneurism development in
three independent animal models of abdominal aortic
aneurysm28.
Therefore, considerable data exists in CVD for a role of LTRAs in
general, and of montelukast in particular, in controlling and reducing
CV risk25,29. Indeed, asthmatic patients receiving
montelukast have lower levels of CV disease-associated inflammatory
biomarkers and lipid levels30, while a recent
nationwide cohort study on incident or recurrent ischemic events
provided a first indication for a role of montelukast for secondary
prevention of CVDs31. In order to explore a potential
complementary approach to other agents for CVD prevention, we performed
an observational retrospective study including eight hundred asthmatic
patients exposed or non-exposed to montelukast to assess the efficacy of
montelukast in prevention of a major CV event such as MI o