Elsevier

Atherosclerosis

Volume 243, Issue 2, December 2015, Pages 546-552
Atherosclerosis

Soluble endothelial cell selective adhesion molecule and cardiovascular outcomes in patients with stable coronary disease: A report from the Heart and Soul Study

https://doi.org/10.1016/j.atherosclerosis.2015.10.092Get rights and content

Highlights

  • Endothelial cell-selective adhesion molecule (ESAM) is postulated to play a role in atherogenesis.

  • We found that in the Heart and Soul Study, soluble ESAM levels associate with myocardial infarction, heart failure, and death after adjustment for demographic and clinical risk factors.

  • These associations are completely attenuated after adjustment for kidney function.

  • sESAM may be a marker for cardiovascular risk among individuals with chronic kidney disease.

Abstract

Background and Aims

Endothelial cell-selective adhesion molecule (ESAM) is selectively expressed on vascular endothelium and is postulated to play a role in atherogenesis. We investigated the association of serum soluble ESAM (sESAM) levels with subsequent cardiovascular outcomes in patients with stable ischemic heart disease.

Methods

We measured sESAM levels in 981 patients with stable coronary disease enrolled between September 2000 and December 2002 in a prospective cohort study. Poisson regression models were used to define the relationship between baseline sESAM levels and cardiovascular outcomes, including myocardial infarction, heart failure hospitalization, and mortality.

Results

There were 293 occurrences of the composite endpoint over a median follow-up of 8.9 years. After adjusting for demographic and clinical risk factors, participants in the highest sESAM quartile (compared to the lower three sESAM quartiles) had a higher rate of the composite endpoint (incident rate ratio (IRR) 1.52 (95% CI 1.16–1.99) as well as of its individual components: myocardial infarction (IRR 1.64 (1.06–2.55)), heart failure hospitalizations (IRR 1.96 (1.32–2.81)), and death (IRR 1.5 (1.2–1.89)). These associations were no longer significant after adjustment for estimated glomerular filtration rate.

Conclusions

sESAM levels associate with myocardial infarction, heart failure, and death after adjustment for demographic and clinical risk factors, but not after adjustment for kidney function. sESAM may be involved in the pathogenesis of concurrent kidney and cardiovascular disease.

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.

Section snippets

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.

References (27)

  • T. Hara et al.

    Endothelial cell-selective adhesion molecule regulates albuminuria in diabetic nephropathy

    Microvasc. Res.

    (2009)
  • F. Wegmann et al.

    ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability

    J. Exp. Med.

    (2006)
  • G. Lippi et al.

    Arterial thrombus formation in cardiovascular disease

    Nat. Rev. Cardiol.

    (2011)
  • Cited by (9)

    • Food and plant bioactives for reducing cardiometabolic disease: How does the evidence stack up?

      2017, Trends in Food Science and Technology
      Citation Excerpt :

      No significant differences were detected in the levels of alanine transaminase (ALT), aspartate transaminase (AST), and creatinine between the two groups, indicating that the BBR should not have negative effects on kidney and liver (Meng et al., 2012). The observed effect of BBR on adhesion molecules is of particular interest considering the recent results of the Heart and Soul study, showing that the serum level of these adhesion molecules is a significant predictor of CV outcomes in patients with stable coronary artery disease (Park et al., 2015). Some clinical trials have also tested BBR in combination with other nutraceuticals including RYR (as previously mentioned) and silymarin to investigate if the association with RYR could achieve a greater reduction of cholesterolaemia.

    • Soluble endothelial cell-selective adhesion molecule and incident cardiovascular events in a multiethnic population

      2017, American Heart Journal
      Citation Excerpt :

      Further studies in older cohorts may help clarify the relationship between sESAM, coronary atherosclerosis burden, and CVD. A recent report in patients with baseline stable coronary disease revealed similar findings that sESAM levels were associated with incident cardiovascular end points, including MI, heart failure, and death.29 In contrast to our study, however, adjustment for renal function as measured by eGFR attenuated this association.

    • Plasma palmitoylethanolamide (PEA) as a potential biomarker for impaired coronary function

      2017, International Journal of Cardiology
      Citation Excerpt :

      On the other hand, PEA levels failed to be associated with other circulating biomarkers of endothelial dysfunction/activation, such as soluble ICAM-1 and VCAM-1. Although controversial, circulating levels of adhesion molecules were previously described as generally related with endothelial injury and CV risk [17–19]. However, the modification of these parameters were more related to a “non-specific” endothelial dysfunction in different arterial districts instead of being selective for certain key organs, such as the heart, the brain, and the kidney.

    View all citing articles on Scopus
    View full text