Effect of Plasma Ceramides on Peripheral Vascular Function

The goal of this clinical trial is to determine the effect of elevated plasma ceramides on peripheral vascular function. Subjects will consume a high fat meal consisting of long chain fatty acids (to increase plasma ceramides) or medium chain fatty acids (control). Subjects' vascular function will be assessed with laser Doppler flowmetry to measure their artery function and with the CytoCam device to assess their peripheral microvascular endothelial function.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Vascular Disease; Endothelial Dysfunction; Lipid Disorder
• Intervention / Treatment: Other: High Saturated Fat

Detailed Description

Following decades of decline in mortality, death due to heart disease is increasing, and remains the #1 cause of death in the United States. Although acute ischemic events are typically due to obstructive plaque within the coronary conduit arteries, strong evidence suggests that dysfunction within the coronary microvasculature is a more powerful predictor of major adverse cardiac events (MACE) than severity of atherosclerosis. The coronary microvasculature likely also contributes to other forms of cardiovascular disease including heart failure with preserved ejection fraction (HFpEF). While assessment of the coronary microvasculature is highly invasive and expensive, interrogation of the peripheral microvasculature offers a more feasible approach. Recent studies have concluded that peripheral microvascular dysfunction mirrors the functional status of the coronary microvasculature. Further, impaired peripheral microvascular function is associated with increased risk of MACE in patients with stable coronary artery disease (CAD), suggesting that the microvasculature plays a critical role in the pathogenesis of heart disease.

Elevated plasma ceramides are also associated with risk of MACE in otherwise healthy individuals as well as in heart failure both with and without reduced ejection fraction (HFrEF and HFpEF, respectively). Recently it was shown that ceramide levels are increased in patients with early CAD. Exposure to exogenous ceramide causes microvascular endothelial dysfunction in arterioles from healthy individuals.

However the effect of ceramide on human in vivo peripheral microvascular function represents a critical knowledge gap that needs to be addressed. This study will observe how blood vessels respond to acetylcholine and nitroglycerin before and after increased plasma ceramide. Acetylcholine induce endothelial-dependent dilation whereas nitroglycerin is an endothelial-independent dilator. Therefore although both are vasodilators they elicit dilation very differently. The nitroglycerin is used to ensure the subject can dilate even despite endothelial dysfunction. Lack of a response to acetylcholine suggests that the subject may have endothelial dysfunction, which is a precursor to cardiovascular disease. Increased plasma ceramide may evoke peripheral in vivo microvascular dysfunction that mirrors that of the coronary microvasculature thus providing a less invasive means to assess future cardiovascular risk.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julie K. Freed, MD, PhD; Phone Number: 414-955-7487; Email: jfreed@mcw.edu
• Study Contact Backup: Name: Shona Hang, MSPH; Phone Number: 414-955-2348; Email: shang@mcw.edu

Study Locations

• United States
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert Hospital
      • Contact: Shona; Phone Number: 414-955-2348; Email: shang@mcw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Health adults aged 18-40 years
2. English-speaking only
3. Not pregnant

Exclusion Criteria:

1. Healthy individuals under 18 years or over 40 years of age
2. Non-English speaking
3. Pregnant individuals
4. Heart rate <60 or >100
5. Systolic blood pressure <100 or >160
6. Subjects with visible open sores or wounds in mouth
7. Lactose intolerant or allergy to dairy products
8. Diabetes Mellitus
9. Coronary Artery Disease
10. High blood pressure
11. High cholesterol
12. Heart failure
13. Current tobacco use
14. Chemotherapy within the last 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Medium Chain Fatty Acid High Fat Meal; This arm will assess the effect of increased plasma ceramide on peripheral microvascular function after consuming a medium chain fatty acid high fat meal.	Other: High Saturated Fat; High saturated fat meal
Experimental: Long Chain Fatty Acid High Fat Meal; This arm will assess the effect of increased plasma ceramide on peripheral microvascular function after consuming a long chain fatty acid high fat meal.	Other: High Saturated Fat; High saturated fat meal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Cardiovascular Conductance	Use laser Doppler flowmetry to measure blood flow	6 hours
Endothelial-Dependent Total Vessel Density	Use a microscope (CytoCam) to look at blood vessels	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reactive Hyperemia	Measure the volume of flow following cuff release	Year 2
Endothelial-Dependent Total Vessel Density	Use incident dark field technology to assess endothelial dependent increases in total vessel density	Year 2

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Anticipated): December 31, 2026
• Study Completion (Anticipated): December 31, 2027

Study Registration Dates

• First Submitted: October 4, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 4, 2021

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Endothelium; Ceramide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vascular Diseases; Peripheral Arterial Disease; Peripheral Vascular Diseases; Lipid Metabolism Disorders
• Other Study ID Numbers: 00041566

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No