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

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:

1. Decreases the stickiness of platelets. This is important because sticky platelets are more likely to form clot and contribute to plaque formation.
2. 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.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Resveratrol

Detailed Description

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:

1. resveratrol reduces platelet activation in patients with metabolic syndrome. and
2. that resveratrol reduces the oxidative modification of HDL proteins in patients with metabolic syndrome.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Houston, Texas, United States, 77004
      • Baylor University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo capsule given three times daily X 3 weeks	Dietary supplement: Placebo; 1000mg tid placebo; Other Names: tid dosing
Experimental: Resveratrol; Resveratrol 1 gram three times daily X 3 weeks	Dietary supplement: Resveratrol; 1000mg tid; Other Names: tid dosing

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: John A Oates, MD, Vanderbilt University

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): February 7, 2019
• Study Completion (Actual): April 7, 2019

Study Registration Dates

• First Submitted: August 14, 2014
• First Submitted That Met QC Criteria: August 15, 2014
• First Posted (Estimate): August 19, 2014

Study Record Updates

• Last Update Posted (Actual): April 19, 2019
• Last Update Submitted That Met QC Criteria: April 17, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Insulin Resistance; Hyperinsulinism; Syndrome; Metabolic Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Resveratrol
• Other Study ID Numbers: 130996

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No