Resveratrol in Metabolic Syndrome: Effect on Platelet Hyper-reactivity and HDL Lipid Peroxidation

Study Overview
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Brief Summary
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Metabolic syndrome is a group of risk factors that increase a patient's likelihood for heart attack, stroke and diabetes. Our research is aimed at understanding whether a drug, resveratrol, commonly found in grapes and red wine, would have any benefit in reducing risk factors in patients that have metabolic syndrome. Despite the use of aspirin and cholesterol reducing medications, patients with metabolic syndrome still often have sticky platelets and dysfunctional lipid profile. This is likely due to inflammation and high oxidative state. In animal studies, this drug has reduced platelet stickiness and reduced oxidative stress. However, the effects of this drug have not been researched in patients with metabolic syndrome. We are interested in studying whether the benefits of resveratrol described in animal models can be translated to patients with metabolic syndrome who display high markers of oxidative stress. We plan to give a short intervention of drug to patients and then determine if the drug successfully: Decreases the stickiness of platelets. This is important because sticky platelets are more likely to form clot and contribute to plaque formation. Reduce the circulating dysfunctional HDL. HDL and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the blood vessel wall, coagulation, and platelet aggregation. Dysfunctional HDL, as occurs in metabolic syndrome patients, cannot properly protect against atherosclerosis.

Detailed Description
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Patients with metabolic syndrome are at increased risk of thrombotic complications, including myocardial infarction and cardiovascular death. A meta-analysis of the studies assessing cardiovascular risk in metabolic syndrome found a pooled relative risk for incident cardiovascular events and death of 1.78. This propensity for thrombotic vascular events is in the context of an increasing prevalence of metabolic syndrome, which in the 2003-2006 NHANES Survey was found in 34% of the US population over the age of 20. Two important contributors to the development of myocardial infarction and stroke are lipid rich atheromatous plaques and concomitant platelet aggregation in response to the fissuring of these plaques. A growing body of evidence implicates oxidative modification of lipoprotein lipids and apolipoproteins in the genesis of plaques. Platelet hyperactivity and the variable response to antiplatelet therapy are features of the metabolic syndrome. Oxidative modifications of LDL enhance activation of platelets, which themselves are oxidatively stressed. Myeloperoxidase (MPO) initiates lipid peroxidation leading to dysfunctional HDL production. Therefore, the hypotheses for the proposed investigations will address the effects of resveratrol on platelet hyperactivity and HDL protein modifications in patients with metabolic syndrome. Resveratrol, as predicted from its structure, is an electron rich molecule that can reduce free radicals. It has distinctive actions, however, that differ from compounds that are conventionally referred to as anti-oxidants. It has particular potency as an inhibitor of radical formation by a number of peroxidases that likely participate in the pathophysiology of metabolic syndrome. These include MPO, the peroxidase site of prostaglandin H synthase-1 (PGHS-1; cyclooxygenase-1(COX-1)) and cytochrome c. We will test the hypothesis that: resveratrol reduces platelet activation in patients with metabolic syndrome. and that resveratrol reduces the oxidative modification of HDL proteins in patients with metabolic syndrome.

Official Title
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Resveratrol in Metabolic Syndrome: Effect on Platelet Hyper-reactivity and HDL Lipid Peroxidation

Conditions
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Metabolic Syndrome

Intervention / Treatment
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* Dietary Supplement: Resveratrol
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metabolic Syndrome Exclusion Criteria: Evidence of coronary artery disease Indication for use of aspirin for secondary prevention of thrombotic events Use of non-steroidal anti-inflammatory drugs or anti-platelet agents Pregnancy Patients with history of bleeding or gastrointestinal ulcers Patients with major illnesses such as ongoing malignancies, infections, cirrhosis

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo capsule given three times daily X 3 weeks | Dietary Supplement: Placebo<br>* 1000mg tid placebo<br>* Other names: tid dosing;|
| Experimental: Resveratrol<br>Resveratrol 1 gram three times daily X 3 weeks | Dietary Supplement: Resveratrol<br>* 1000mg tid<br>* Other names: tid dosing;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in parameters of platelet activation | Measure platelet-monocyte aggregates by flow cytometry | baseline, 3 weeks after intervention | 
| Change in parameter for platelet oxidative stress | Measure malondialdehyde adducts of platelet proteins | Baseline, 3 weeks after intervention | 
| Change in parameter for platelet oxidation levels | Measure superoxide production by platelets | Baseline, 3 week after intervention | 
| Serum Thromboxane measurments | Measure thromboxane to assess inflammation | Baseline, 3 weeks after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxidative modifications of HDL | Measure change in malondialdehyde adducts in HDL proteins | baseline, three weeks after intervention | 
| Change in plasma oxidative stress | Measure change in plasma isoprostanes | baselines, three weeks after intervention |