Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans
Vanderbilt University Medical Center
Summary
Specific Aim 1: To test the hypothesis that prolonged (3-month) treatment with galantamine inhibits NADPH IsoLG-protein adducts formation and improves markers of endothelial cell (EC) dysfunction in AAs. Aim 1a: The investigators will determine if galantamine inhibits NADPH IsoLG-protein adducts formation, superoxide production, and immune cell activation compared to placebo. For this purpose, the investigators will study peripheral blood mononuclear cell (PBMC), a critical source of systemic oxidative stress, collected from study participants. Aim 1b: The investigators will determine if galantamine reduces intracellular Iso-LGs, ICAM-1, and 3-nitrotyrosine, a marker of vascular oxidative stress, in ECs harvested from study participants. Specific Aim 2: To determine if prolonged (3-month) treatment with galantamine improves endothelial dysfunction as measured by vascular reactivity in AAs. The investigators will measure vascular reactivity in response to ischemia in two vascular beds: (a) in conduit arteries (brachial artery) using brachial artery diameter flow-mediated dilation (FMD), and (b) in the microvasculature (MBV) using contrast-enhanced ultrasonography in skeletal muscle. Sub-study (optional) Will study the effect of trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress This proposal will study a novel mechanism that could alter the oxidative and immunogenic responses that contributes to endothelial dysfunction in AAs and will offer a potential pathway for the development of more effective therapies aimed at decreasing the progression of endothelial dysfunction to cardiovascular disease in this population.
Description
Endothelial dysfunction, a pro-thrombotic, inflammatory condition that causes impaired vascular reactivity is an early reversible step in the development of atherosclerosis and cardiovascular disease (CVD). Multiple studies consistently shown that African Americans (AAs) have impaired endothelial function compared to whites. African Americans also experience disproportionately higher CV morbidity and 20% higher mortality than whites or Hispanics. Endothelial dysfunction is caused by the overproduction of reactive oxygen species (ROS), particularly superoxide which interferes with endothelial-d…
Eligibility
- Age range
- 18–60 years
- Sex
- All
- Healthy volunteers
- Yes
Inclusion Criteria: 1. African American women and men 2. Age 18 to 60 years old 3. BMI \>28 Exclusion Criteria: 1. Individuals with a history of physician diagnosed myocardial infarction, angina, heart failure, stroke, or transient ischemic attack, or who had undergone an invasive procedure for CVD (coronary artery bypass graft, angioplasty, valve replacement, pacemaker placement or other vascular surgeries) 2. Uncontrolled hypertension defined as persistent blood pressure \>140/90 despite the use of anti-hypertensive agents. 3. Diabetes Mellitus type 1 or type 2, as defined by a fasting pl…
Interventions
- DrugGalantamine
4mg daily titrating up to 8mg twice a day
- DrugPlacebo
1 pill a day for 4 weeks, 2 pills a day for 8 weeks
- DeviceTENS 7000
The FDA-approved TENS 7000 device will be used for Trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress. This device will be supplemented with ear clip electrodes. The site of the stimulation for such electrodes are the tragus or concha. The device will have built in safety controls to minimize additional risks to the subjects (as per FDA guidance on stimulators). We will use typical stimulation conditions (30 Hz, 300 µs) and amplitude dependent on perception threshold.
Location
- Chaney JohnsonNashville, Tennessee