Elsevier

Atherosclerosis

Volume 200, Issue 1, September 2008, Pages 221-227
Atherosclerosis

Prospective association of vascular endothelial growth factor-A (VEGF-A) with coronary heart disease mortality in Southeastern New England

https://doi.org/10.1016/j.atherosclerosis.2007.12.027Get rights and content

Abstract

Background

Autopsy data suggest that plaque neovascularization may be associated with coronary heart disease (CHD) death. Since vascular endothelial growth factor-A (VEGF-A) is upregulated in angiogenesis and therefore neovascularization, we hypothesized that individuals with elevated levels of VEGF-A at baseline would be a greater risk of dying of CHD compared to those with lower levels over time.

Methods

We measured VEGF-A levels in 46 CHD death cases and a 14% random sample of 2321 community participants who were free of self-reported CHD at baseline. Traditional CHD risk factors such as age, gender, family history of CHD, cigarette smoking, hypertension, total cholesterol/HDL ratio, diabetes mellitus, were also evaluated at baseline. Mortality follow-up was determined through linkage of baseline data with the National Death Index.

Results

During a median of 13 years of follow-up, 46 subjects died of coronary heart disease. Mean VEGF-A levels were significantly higher in the CHD death cases than among the random population sample (400 pg/ml vs. 303 pg/ml, p = 0.0004). In proportional hazards models adjusting for traditional risk factors, the hazard ratios (95%CI) for CHD death associated with increasing tertiles of VEGF-A were 1.0 (referent), 2.12 (0.74, 6.10), and 3.85 (1.37, 10.78), respectively (Ptest for trend = 0.008).

Conclusion

In this population-based prospective, case-cohort study, baseline levels of VEGF-A showed a significant independent association with the risk of CHD death.

Introduction

Recent advances in our understanding of atherosclerosis have raised the possibility that increased expression of vascular endothelial growth factor-A (VEGF-A) may result in an increased risk of coronary heart disease (CHD) death [1], [2], [3], [4], [5]. Vascular endothelial growth factor-A (also called VEGF-A or simply VEGF) was first reported in 1971 as the primary regulator of angiogenesis and vascular permeability [1]. In adults, VEGF-A is expressed in virtually all vascularized tissues, including large blood vessels and the myocardium [6]. Low physiological levels of VEGF-A levels appear to be needed to maintain vascular homeostasis, but VEGF-A appears to be upregulated in active angiogenesis processes such as in ischemic skeletal muscle [7], [8]. Because of its profound effect on blood vessel remodeling, randomized clinical trials using VEGF to promote therapeutic angiogenesis in patients with myocardial and peripheral ischemia have been performed but with negative or equivocal results [6].

Partly on this basis, it has been suggested that excess VEGF-A may contribute to neovascularization of atherosclerotic lesions and thus possibly increase plaque instability. In this regard, post-mortem studies have found a significant correlation between the density of new vessels as a measure of the extent of neovascularization in the intima and the incidence of luminal stenosis, the extent of chronic inflammatory infiltrates, the formation of granulation tissue and the degree of atheromatous changes [11]. Similarly, patients with symptomatic atherosclerosis appear to have a denser network of vasa vasorum and high intimal macrophage content [12].

Despite these suggestive data, data linking VEGF-A to coronary heart disease death has not been evaluated in any prospective epidemiologic studies to our knowledge. Based upon these previous findings, we hypothesized that middle-aged adults with elevated levels of VEGF-A at baseline will have a greater risk of coronary heart disease death over time compared than those with lower levels of VEGF-A at baseline.

Section snippets

Methods

We conducted a prospective nested case-cohort study within a community-based sample of 2321 adults from southeastern New England. All participants completed household interviews between 1990 and 1993. Death record information was obtained through 2004 to identify cases.

All study participants were enrolled in the Pawtucket Heart Health Program (PHHP) risk factor assessment activities [13], [14], [15]. The PHHP was a community demonstration project conducted between 1981 and 1990 to evaluate

Results

Baseline characteristics of the total cohort, the comparator sub-cohort, and of the CHD case group are presented in Table 1. No clinically relevant differences were observed between the sub-cohort and the total cohort derived from the community samples in the variables measured. As might be expected, CHD death cases were more likely to be: male, older, present cigarette smokers, more physically inactive, diabetic, hypertensive, and dyslipidemic than the sub-cohort.

Overall, baseline plasma

Discussion

In this prospective study performed in a population-based setting, baseline levels of VEGF-A were linearly associated with increased CHD mortality, even after adjustment for traditional cardiovascular risk factors. These epidemiologic data thus provide support for the concept raised in prior pathologic studies and in intervention trials that excess levels of VEGF-A may be associated with an increased risk of CHD death. The role of VEGF-A in atherogenesis remains controversial. VEGF is an

Acknowledgments

We would like to thank posthumously Richard Carleton, MD (deceased), principal investigator for the Pawtucket Heart Health Program for having the foresight to save the frozen sera from the PHHP project, Lisa Billington for her help with typing this manuscript, and Gary Bradwin from Boston Children's Hospital Clinical and Epidemiologic Laboratory for his help in analyzing the serologic samples for VEGF-A and hs-CRP.
Funding sources: Brown University Salomon Award, NHLBI R03, Donald W Reynolds

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