Semester

Summer

Date of Graduation

2011

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Community Practice

Committee Chair

Anoop Shankar.

Abstract

In recent years several mechanistic animal studies have proposed new insights, including the role of endothelial dysfunction, in the pathogenesis of common cardiometabolic disorders such as diabetes mellitus, hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). However, few studies in humans have followed up these emerging leads from animal models. Because traditional risk factors have been shown not to completely explain all the observed risk of cardiometabolic outcomes in the general population, there is a need to examine novel mechanisms such as endothelial dysfunction in population-based studies, so as to identify new ways of preventing and/or treating these diseases. In this context, we examined the novel hypothesis that higher serum levels of markers of endothelial dysfunction, including soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1), are positively associated with the risk of developing diabetes mellitus, hypertension, CKD and cardiovascular mortality in four separate studies. We measured sVCAM-1 and sICAM-1 levels from stored serum in a random sample (n=1793) of baseline participants from the Beaver Dam Eye Study, a population-based, longitudinal cohort study of n=4926 subjects (55% women), aged .43 years from Beaver Dam, Wisconsin. The main outcomes of interest were 15 year incidence of diabetes mellitus, hypertension, CKD and CVD mortality occurring between the baseline examination at 1988-90 to the end of mortality follow-up at Dec 31, 2002. During the stated follow-up period, 156 subjects developed diabetes mellitus, 257 subjects developed hypertension, 269 subjects developed CKD and 212 subjects died of cardiovascular causes. We found that serum levels of sVCAM-1 and SICAM-1 are positively related to diabetes mellitus in men only (hazards ratio [HR] (95% confidence interval [CI])=2.29 [1.18-4.44] for sVCAM-1 in men), and with hypertension (HR=2.14 [1.42-3.23] for sVCAM-1) and CVD mortality (HR=1.79 [1.17-2.76] for sICAM-1) in both men and women. In contrast, markers of endothelial dysfunction were not found to be related to CKD. In conclusion, we have shown that serum markers of endothelial dysfunction are associated with higher risk of developing diabetes mellitus, hypertension and CVD mortality, but not with CKD.

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