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