Soluble endothelial cell selective adhesion molecule and cardiovascular outcomes in patients with stable coronary disease: A report from the Heart and Soul Study
Introduction
Endothelial cell-selective adhesion molecule (ESAM) is a recently discovered member of the immunoglobulin superfamily of cellular adhesion molecules (CAM) that is highly expressed in vascular and glomerular endothelial cells [1], [2] as well as in platelets [3]. Studies in vitro have suggested that ESAM facilitates monocyte and neutrophil migration to sites of endovascular injury by regulating endothelial tight junctions, endothelial permeability and angiogenesis [1], [4], [5]. As leukocyte diapedesis is a key step in the formation of atherosclerotic plaques [5], [6], these functions of ESAM suggest that it might play a pivotal role in the genesis of atherosclerosis [5], [7].
Murine models of atherosclerosis have provided support for this hypothesis. In apolipoprotein E deficient mice, genetic inactivation of ESAM resulted in markedly smaller atherosclerotic lesions, accompanied by a reduction in arterial macrophages and in the density of vasa vasorum [5]. A recent cross-sectional, observational study of healthy middle-aged subjects from the Dallas Heart Study demonstrated that higher soluble ESAM (sESAM) levels were associated with more atherosclerosis measured by its surrogates – greater aortic wall thickness, higher coronary artery calcium scores, and reduced aortic compliance [7]. A longitudinal study demonstrated that sESAM was associated with increased risk of kidney function decline [8]. However, no study to date has correlated sESAM levels with cardiovascular outcomes. As endothelial function has also been implicated in heart failure [9], [10], we sought to investigate associations of sESAM with cardiovascular outcomes including myocardial infarction, heart failure, and mortality in a well-characterized cohort of subjects with stable ischemic heart disease. We hypothesized that higher levels of sESAM would be independently associated with increased rates of cardiovascular events.
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Participants
We evaluated subjects from The Heart and Soul Study, a prospective cohort study designed to investigate the effects of psychosocial factors on health outcomes in patients with stable ischemic heart disease (IHD). Methods have been previously described [11]. In brief, patients were eligible if they had at least 1 of the following: history of myocardial infarction, angiographic evidence of ≥50% stenosis in ≥1 coronary vessels, evidence of exercise-induced ischemia by treadmill ECG or stress
Baseline characteristics
Among 981 participants enrolled in this study the median follow-up period was 8.9 years (IQR 3.76 years). There were 293 composite events constituting the primary outcome (116 myocardial infarctions, 359 deaths and 164 hospitalizations for heart failure). The mean level of sESAM was 57.5 ± 18.0 ng/mL. When separated into quartiles by sESAM levels, there were significant differences between groups in age, race, gender, smoking status, LDL-cholesterol and glycosylated hemoglobin (Table 1).
Discussion
In this study, we examined associations between levels of sESAM and cardiovascular outcomes in patients with stable ischemic heart disease in order to study possible biological mechanisms in a clinical population. Higher levels of sESAM were associated with increased rates of the composite primary endpoint (myocardial infarctions, heart failure hospitalizations, and death) as well as with its individual components, independent of demographic and clinical factors. The observed relationship
Sources of funding
This work was supported by Meyeon Park's NIH/NIDDK K23 DK099238. The Heart and Soul Study was funded by the Department of Veteran Affairs (Epidemiology Merit Review Program), Washington, DC; grant R01 HL-079235 from the National Heart, Lung, and Blood Institute, Bethesda, MD; the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), Princeton, NJ; the American Federation for Aging Research (Paul Beeson Faculty Scholars in Aging Research Program), New York, NY; and the
Disclosures
All authors report no conflicts of interest.
Acknowledgments
The authors would like to thank the participants in the Heart and Soul study and their families.
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