Targeting ER Stress in Vascular Dysfunction

NCT ID: NCT04001647

Last Updated: 2025-04-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-01
• Study Completion Date: 2022-08-16

Brief Summary

Aging and obesity are both risk factors for cardiovascular disease (CVD). One process that links both of these conditions to CVD is vascular dysfunction. Data from animal studies indicate that endoplasmic reticulum (ER) stress may play an important role in the development of endothelial dysfunction in aging and obesity. Therefore, the goal of this study is to investigate the relative contributions of aging and obesity on vascular dysfunction and ER stress. Additionally, this study will determine if taking an oral supplement for 8 weeks will improve vascular dysfunction and ER stress. Results from this study have the potential to identify a safe treatment option for improving vascular function in aging and obese populations.

Detailed Description

Aging is the primary risk factor for cardiovascular disease (CVD). One critical process that links aging to CVD is the development of vascular dysfunction, characterized by endothelial dysfunction and arterial stiffness. Both endothelial dysfunction and arterial stiffness predict cardiovascular events in older individuals. Aging often coincides with obesity, another independent risk factor for CVD. Although vascular function is well characterized in both aging and obesity, it's unclear how these two conditions interact to modulate vascular function, and whether the combination of aging and obesity has additive or compounding effects on endothelial dysfunction and arterial stiffness.

Currently, it is unknown whether vascular dysfunction is driven by the same underlying cellular mechanisms in aging and obesity. Accumulating data in experimental animals suggest that ER stress may be an important factor in aging- and obesity-related vascular dysfunction. Additionally, middle-aged and older obese adults with endothelial dysfunction display evidence of ER stress within biopsied endothelial cells. In light of these data, the overall goal of this proposal is to test the hypothesis that ER stress is associated with human vascular dysfunction in the settings of aging and obesity, and to determine the efficacy of the chemical chaperone tauroursodeoxycholic acid (TUDCA), an established inhibitor of ER stress, to reduce endothelial cell ER stress and improve vascular function in these at-risk individuals. Results from this study have the potential to identify a novel, safe, and clinically relevant intervention strategy for the treatment of vascular dysfunction in an aging population at high-risk for the development of CVD.

Conditions

Vasodilation; Arterial Stiffness

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

TUDCA

Young and older healthy weight and obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive 1750 mg/day of the dietary supplement tauroursodeoxycholic acid (TUDCA) for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.

Group Type: EXPERIMENTAL

Acetylcholine

Intervention Type: DRUG

Endothelium-dependent vasodilation will be determined via graded intra-arterial infusions of acetylcholine (ACh). Doses of 1, 4, 8, and 16 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Sodium Nitroprusside

Intervention Type: DRUG

Endothelium-independent vasodilation will be determined via graded intra-arterial infusions of sodium nitroprusside (SNP). Doses of 0.25, 0.5, 1, and 2 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Ascorbic Acid

Intervention Type: DRUG

The influence of oxidative stress on arterial stiffness and vasodilation will be assessed by using intravenous ascorbic acid (AA). A single supra-physiological dose of 0.06 g/kg fat-free mass (FFM) will be infused over 20 min followed by a drip infusion of 0.02 g/kg FFM administered over 60 min.

Placebo

Older obese participants will visit the lab for assessment of vascular function prior to the intervention. Aortic stiffness will be evaluated non-invasively using carotid-femoral pulse-wave velocity. A physician will place a catheter in the brachial artery for endothelial cell biopsies and local vasodilator infusions. A venous catheter will also be placed for the systemic ascorbic acid infusion. Aortic stiffness measures and vascular responses to vasodilator infusions will be performed before and after the ascorbic acid infusion. Following the completion of the vascular assessments, participants will receive oral capsules containing a placebo treatment for 8 weeks. Participants will return to the lab after the 8 week intervention and the vascular assessments described above will be repeated.

Group Type: PLACEBO_COMPARATOR

Acetylcholine

Intervention Type: DRUG

Endothelium-dependent vasodilation will be determined via graded intra-arterial infusions of acetylcholine (ACh). Doses of 1, 4, 8, and 16 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Sodium Nitroprusside

Intervention Type: DRUG

Endothelium-independent vasodilation will be determined via graded intra-arterial infusions of sodium nitroprusside (SNP). Doses of 0.25, 0.5, 1, and 2 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Ascorbic Acid

Intervention Type: DRUG

The influence of oxidative stress on arterial stiffness and vasodilation will be assessed by using intravenous ascorbic acid (AA). A single supra-physiological dose of 0.06 g/kg fat-free mass (FFM) will be infused over 20 min followed by a drip infusion of 0.02 g/kg FFM administered over 60 min.

Interventions

Acetylcholine

Endothelium-dependent vasodilation will be determined via graded intra-arterial infusions of acetylcholine (ACh). Doses of 1, 4, 8, and 16 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Intervention Type: DRUG

Sodium Nitroprusside

Endothelium-independent vasodilation will be determined via graded intra-arterial infusions of sodium nitroprusside (SNP). Doses of 0.25, 0.5, 1, and 2 μg/100ml forearm volume/min will be infused in the brachial artery for 3 minutes each.

Intervention Type: DRUG

Ascorbic Acid

The influence of oxidative stress on arterial stiffness and vasodilation will be assessed by using intravenous ascorbic acid (AA). A single supra-physiological dose of 0.06 g/kg fat-free mass (FFM) will be infused over 20 min followed by a drip infusion of 0.02 g/kg FFM administered over 60 min.

Intervention Type: DRUG

Other Intervention Names

ACh; SNP; AA; Vitamin C

Eligibility Criteria

Inclusion Criteria

• Young, healthy weight adults (age: 18-35; BMI 18.5-24.9 kg/m2)
• Young, obese adults (age: 18-35; BMI 30- 39.9 kg/m2)
• Older, healthy weight adults (age: 60-80; 18.5-24.9 kg/m2)
• Older, obese adults (age: 60-80; 30-39.9 kg/m2)

Exclusion Criteria

• blood pressure >140/90 mmHg
• triglycerides >500 mg/dL or LDL cholesterol >190 mg/dL
• current smoking or history of smoking in the last 12 months
• diagnosed chronic disease including cancer, cardiovascular, diabetes, kidney, liver, and pancreatic disease
• weight change >3 kg in the past 3 months or actively trying to lose weight
• >12 alcoholic drinks/week
• hormone replacement therapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Colorado State University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frank Dinenno, PhD

Role: PRINCIPAL_INVESTIGATOR

Colorado State University

Locations

Colorado State University

Fort Collins, Colorado, United States

Countries

United States

Other Identifiers

TUDCA and Vascular Health

Identifier Type: -

Identifier Source: org_study_id