Defining Strategies for Improving Endothelial and Fibrinolytic Dysfunction in Obesity

Obesity is an increasingly important risk factor for cardiovascular disease in men and women
and is associated with the premature development of atherosclerosis, and increased risk of
stroke. A classical perspective of cardiovascular risk does not adequately explain all of
the cardiovascular events associated with obesity. Elevated plasma levels of plasminogen
activator inhibitor type I (PAI-1) are one of the biochemical hallmarks for obesity and
likely contribute the increased risk of atherothrombotic events in patients with obesity.
The central hypothesis of this proposal is that the increased risk of atherothrombotic
events in patients with obesity. The central hypothesis of this proposal is that vascular
PAI-1 excess promotes the development of intravascular thrombosis. We will test the
hypothesis that secreted factors from adipocytes have autocrine, paracrine and endocrine
effects that have a deleterious effect on the fibrinolytic system, either by enhancing PAI-1
production or impairing endothelial t-PA release. From a public health perspective, there is
no greater threat to America's cardiovascular health than the epidemic of obesity. It is
anticipated that this study will provide new insights nto the molecular mechanisms that
contribute to the development of fibrinolytic dysfunction and cardiovascular disease in
obesity.

Inclusion Criteria:

- Male or females between the ages of 18 to 65 years of age.

- Documented diagnosis for the metabolic syndrome:

- Subjects with hypertension (SP>130mmHg)

- Subjects with central obesity (females waist >35"; males waist >40")

- Subjects with dyslipidemia (HDL <40mg/dl, triglycerides > 150 mg/dl)

- Subjects who are insulin resistance (fasting glucose >100mg/dl)

Exclusion Criteria:

- Subjects who smoke

- Women who are pregnant (confirmed by urine beta-HCG).

- Women who are breast feeding

- Subjects with documentation of the following health risk:

- Subjects with serum creatinine >2.0 mg/dl (males), >1.8 mg/dl (females)

- Subjects whose creatinine clearance < 50 mls/min

- Subjects with serum potassium >5.5mEql

- Subjects with Type 2 diabetes with microalbuminuria (spot urine
protein/creatinine ration >0.2)

- Subjects who are currently taking the following medications:

- Warfarin