Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 160
- 试验地点
- 1
- 主要终点
- FMD
研究概览
简要总结
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.
详细描述
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-derived nitric oxide signaling pathways. One of the major sources of superoxide is NADPH oxidase; our previous work found that activation of NADPH oxidase contributes to vascular oxidation through the formation of highly immunogenic isolevuglandins (IsoLG-protein adducts) in peripheral mononuclear cells (PBMCs), which stimulates antigen presenting cells (APC) and inflammatory mediators. Inflammation and oxidative stress are modulated by the parasympathetic nervous system (PNS). The investigators and others found that AAs have reduced PNS activity compared with whites. Studies in animal models have shown that parasympathetic nervous stimulation with either acetylcholinesterase inhibitors or direct vagus nerve stimulation protect against oxidative stress and inflammation
There is Sub-study (optional) attached to the above main study. It is to evaluate the effect of trans-auricular vagus nerve stimulation (TaVNS) during a period of enhanced vascular oxidative stress. It is an ancillary, mechanistic, proof-of-concept study to determine if acute vagal stimulation with a Transcutaneous Electrical Nerve Stimulation device (TENS) inhibits immune cell activation and improves markers of endothelial cell dysfunction.
The investigators preliminary data in obese AA women found that stimulation of the PNS cholinergic transmission with the acetylcholinesterase inhibitor, galantamine, blocked the production of oxidative stress and inflammatory cytokines induced by lipids.
The overall goal of the current proposal is to determine if prolonged treatment with galantamine improves endothelial dysfunction and vascular oxidative stress in AAs. For this purpose, the investigators will conduct a proof-of-concept, blinded, randomized, placebo-controlled study to test the effect of 3-month treatment with galantamine (16 mg/day) on vascular oxidative stress and impaired vascular reactivity in AAs.
A total of 160 participants enrolled and will be randomized, so that we can complete 88 AAs (44 per treatment arm) in a 1:1 ratio to 8 mg p.o. twice a day (16 mg/day) of galantamine
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •African American women and men
- •Age 18 to 60 years old
排除标准
- •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)
- •Uncontrolled hypertension defined as persistent blood pressure >140/90 despite the use of anti-hypertensive agents.
- •Diabetes Mellitus type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater hemoglobin A1C (HbA1C) 6.5% or above or the use of anti-diabetic medication
- •The use of nitrates.
- •The metabolism of galantamine is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. We will exclude subjects who have impaired hepatic function and/or who are currently using strong inhibitors of CYP3A4 and CYP2D6 (e.g. ketoconazole and paroxetine, respectively).
- •Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control.
- •Post-menopausal women.
- •The use of any other central or peripheral acetylcholinesterase inhibitor (donezepil (Aricept(R)), pyridostigmine (Mestinon(R)), rivastigmine (Exelon(R)), tacrine (Cognex(R)).
- •First, second or third-degree AV block detected during the screening visit with an ECG
- •Seizures or history of seizures.
- •Current smokers defined as those who smoked a cigarette in the last 30 days.
- •History of recurrent syncope.
- •History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack.
- •History of cardiac shunts.
- •Allergy to eggs or soy.
- •Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)
- •Impaired renal function test (eGFR<60 mL/min/1.73m2)
- •Anemia (hematocrit <34%)
- •Ongoing substance abuse.
- •Treatment with any investigational drug in the one month preceding the study
- •Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study
- •Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
研究组 & 干预措施
Placebo
placebo (micro crystalline cellulose)
- 1 pill once daily for 4 weeks, then 2 pills daily for 8 weeks
干预措施: Placebo (Drug)
TENS 7000
Substudy: the effect of trans-auricular vagus nerve stimulation (TaVNS) will be done by FDA-approved TENS 7000 device and during a period of enhanced vascular oxidative stress
干预措施: TENS 7000 (Device)
Galantamine
Galantamine 16mg/day
- titrating: 4mg once a day for 2 weeks, titrate to 8mg once a day for 2 weeks, then 8mg twice a day for 8 more weeks
干预措施: Galantamine (Drug)
结局指标
主要结局
FMD
时间窗: From baseline to 3 months
flow mediated dilation
NADPH activation in PBMC
时间窗: From baseline to 3 months
NADPH activation as measured by subunits p47phox/gp91 phox in PBMC
NADPH activation in PBMC at TaVNS stimulation
时间窗: From baseline to 120 minutes to 240 minutes
NADPH activation as measured by subunits p47phox/gp91 phox in PBMC.pre- and post-device stimulation measurements before( baseline) and after lipids infusion at 2 and 4 hours
次要结局
未报告次要终点
研究者
Cyndya Shibao, MD
Professor of Medicine
Vanderbilt University Medical Center