| COMMENTARIES |
Low Plasma RANTES Levels Are an Independent Predictor of Cardiac Mortality in Patients Referred for Coronary Angiography
Erdal Cavusoglu, M.D., Division of Cardiology, Department of Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1199, Brooklyn, NY 11203-2098, E-mail: ECavusoglu@aol.com
There is growing evidence which implicates inflammation in the initiation, progression, and complications of atherosclerosis [1,2]. Chemotactic chemokines, or chemokines, are a family of small secreted proteins that play a central role in the inflammatory process because of their ability to direct the migration of leukocytes to sites of vascular injury and inflammation, including developing atherosclerosis [3-6]. They are classified into 4 major groups, according to the arrangement of the conserved cysteine (C) residues in the mature proteins [7]. CC chemokines, which have the first 2 conserved cysteine residues adjacent to each other, constitute the largest family of chemokines. They tend to attract mononuclear cells and are found at sites of chronic inflammation [3].
CCL5 or RANTES (regulated on activation, normal T-cell expressed and secreted) is a chemokine that is secreted by many different cell types, such as endothelial cells, smooth muscle cells, activated T cells, macrophages, and platelets [8-11]. RANTES is a potent chemoattractant for T cells, monocytes, natural killer cells, basophils, and eosinophils [8,12,13]. Platelets sequester RANTES protein in their alpha granules and release it during acute stages of inflammation [8,12,14]. After release from activated platelets, it can subsequently be deposited on inflamed or atherosclerotic endothelium and has been shown to mediate transmigration and shear-resistant arrest of monocytes onto activated endothelium [15]. In addition, RANTES is highly expressed within atheroma [9]. For these reasons, RANTES has been implicated in the genesis of atherosclerosis [4,6]. Despite this, however, there are limited and somewhat conflicting data about the significance of plasma RANTES levels in patients with coronary artery disease. On the one hand, RANTES levels in patients with acute coronary syndromes have been demonstrated to be elevated [16,17], whereas levels in stable CAD have been shown to downregulated [18]. Furthermore, it has also been shown that gene polymorphisms that would be expected to result in reduced levels of RANTES were associated with adverse cardiac events in a stable but high-risk population [19]. These somewhat conflicting observations ther
We measured baseline plasma RANTES levels in a cohort of 389 male patients who were undergoing coronary angiography for a variety of indications at a
The finding that low, rather than high, levels of RANTES were associated with adverse outcomes may at first seem counterintuitive. However, we believe that our data are in accord with the published literature in this regard. For example, in a large case-control study investigating the association of several chemokines with the risk of stable coronary heart disease, it was found that serum levels of RANTES were lower in coronary heart disease patients compared with age- and gender-matched controls, even after adjustment for conventional coronary heart disease risk factors such as diabetes mellitus [18]. This was in contrast to other chemokines, such IP-10 and IL-8, whose levels were increased in patients with coronary heart disease. Along the same lines and perhaps more germane to our findings with respect to prognosis, Boger and colleagues studied the prognostic importance of functional polymorphisms of several chemokines and their receptors in a group of stable but high-risk diabetic patients with ESRD requiring dialysis [19]. They found that patients carrying the RANTES -403A and In1.1C alleles had a significantly higher risk for cardiac mortality on multivariate analysis. While these investigators did not specifically measure plasma or serum levels of RANTES in this particular study, it is noteworthy that the polymorphisms associated with a higher risk of cardiac mortality were also the ones which would be expected to be associated with low expression of RANTES [19,23].
Although the precise mechanism whereby low levels of RANTES are associated with CAD and adverse events remains unknown, there are a number of possible explanations based upon the known actions of RANTES and its receptors. One potential mechanism may be related to the potential upregulation of the CCR5 receptor in the setting of low circulating RANTES levels. The CCR5 receptor is well-known to mediate the transmigration of leukocytes on inflamed endothelium, and has been recently identified as the crucial RANTES receptor associated with atherosclerosis [19,24-27]. Indeed, upregulation of CCR5 in patients with polymorphisms which would be expected to lead to low RANTES expression has already been proposed as a mechanism by which low RANTES could be associated with adverse cardiovascular outcomes [19]. Alternatively, the inverse association between RANTES levels and atherosclerosis may be the result of greater RANTES deposition on the vascular endothelium leading, in turn, to greater CCR5 stimulation. It is known that platelet microparticles contain substantial amounts of RANTES which they deposit on activated endothelium or atherosclerotic arteries [28]. Thus, it is conceivable that the pool of circulating RANTES measurable by routine ELISA could be diminished in patients with atherosclerosis who would be expected to have more extensive deposition of RANTES on activated endothelium. Indeed, von Hundelshausen required the use of a modified ELISA (with perfusion with platelets or exposure to their supernatants) to detect the binding of endothelial surface adherent RANTES [15]. It is unlikely that the commercially available ELISA used in our study was capable of detecting non-circulating surface adherent RANTES.
The finding that RANTES levels were predictive of cardiac mortality and MI in the stable non-ACS population but not in the ACS population is also intriguing and may also seem counterintuitive at first. RANTES levels have been shown to be elevated acutely in patients with an acute coronary syndrome [16,17], and as already stated, this is in contrast to the low levels seen in the setting of chronic and stable CAD [18]. Although not reaching formal statistical significance, ACS patients in our study did have numerically higher RANTES levels than their non-ACS counterparts. The elevated levels of RANTES seen in the setting of ACS is believed to result from the acute release of RANTES from activated platelets that are known to be present in patients with unstable angina and acute myocardial infarction [16]. Indeed, activated platelets have been characterized as having a spontaneous and markedly enhanced release of RANTES [29]. We believe that the inability of RANTES levels to predict long-term adverse cardiovascular outcomes in ACS may be related to the acute spike in RANTES levels which occur in this particular setting. Such a release may be akin to the transient elevation of hs-CRP or other acute phase reactants in patients with an acute inflammatory disorder. Thus, just as acute non-specific elevations of hs-CRP may hinder the ability to use hs-CRP levels for cardiac prognostic purposes, it is conceivable that elevations of RANTES levels due to acutely activated platelets in the ACS setting may obscure the predictive value of low RANTES levels in chronic and stable CAD.
In conclusion, we found that low baseline plasma RANTES levels are independently associated with an increased risk of both cardiac death and MI at 2-year follow-up in an unselected population of males r
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