Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans

Endothelial Dysfunction Clinical Trial

Official title:

Enhancing Parasympathetic Activity to Improve Endothelial Dysfunction, Vascular Oxidative Stress in African Americans

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04769206
• Other study ID #: 202376
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 20, 2021
• Est. completion date: December 31, 2028

Study information

• Verified date: April 2024
• Source: Vanderbilt University Medical Center
• Contact: Cyndya Shibao, MD
• Phone: 615-936-4584
• Email: cyndya.shibao[@]vumc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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-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.

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.

Specifically, the investigators will evaluate whether galantamine treatment inhibits the activation of NADPH-IsoLG formation and the subsequent immunogenic responses in PBMCs. Furthermore, the investigators will determine if galantamine decreases markers of oxidative stress and inflammation in harvested endothelial cells (ECs) and improves vascular reactivity in the same study subjects. The planned studies will provide a comprehensive assessment of the mechanism underlying the effect of increased PNS cholinergic transmission on endothelial dysfunction.

If the investigators' hypothesis is correct, and galantamine improves endothelial dysfunction in AAs, a population with a high risk for CVD, they will discover a novel mechanism that could alter the oxidative and immunogenic responses in this population and will offer a potential pathway for the development of more effective therapies aimed at decreasing CVD.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: December 31, 2028
• Est. primary completion date: December 1, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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 plasma glucose of 126 mg/dL or greater hemoglobin A1C (HbA1C) 6.5% or above or the use of anti-diabetic medication

4. The use of nitrates.

5. 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).

6. 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.

7. Post-menopausal women.

8. The use of any other central or peripheral acetylcholinesterase inhibitor (donezepil (Aricept(R)), pyridostigmine (Mestinon(R)), rivastigmine (Exelon(R)), tacrine (Cognex(R)).

9. First, second or third-degree AV block detected during the screening visit with an ECG

10. Seizures or history of seizures.

11. Current smokers defined as those who smoked a cigarette in the last 30 days.

12. History of recurrent syncope.

13. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack.

14. History of cardiac shunts.

15. Allergy to eggs or soy.

16. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >3.0 x upper limit of normal range)

17. Impaired renal function test (eGFR<60 mL/min/1.73m2)

18. Anemia (hematocrit <34%)

19. Ongoing substance abuse.

20. Treatment with any investigational drug in the one month preceding the study

21. Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study

22. Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Related Conditions & MeSH terms

• Endothelial Dysfunction

Intervention

Drug:
• Galantamine
4mg daily titrating up to 8mg twice a day
• Placebo
1 pill a day for 4 weeks, 2 pills a day for 8 weeks

Locations

Country	Name	City	State
United States	Chaney Johnson	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	FMD	flow mediated dilation	From baseline to 3 months
Primary	NADPH activation in PBMC	NADPH activation as measured by subunits p47phox/gp91 phox in PBMC	From baseline to 3 months