Effect of Propionic Acid Supplementation on Endothelial Function

NCT05135702 | Not Yet Recruiting

• 1 other identifier: PRO39540
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief Summary

Coronary Artery Disease (CAD) remains a leading cause of morbidity and mortality worldwide despite improved mitigation of traditional risk factors. Large association studies have linked the gut microbiome alterations with inflammation, CAD, and traditional CAD risk factors. Subsequent studies have shown concomitant improvements in gut dysbiosis, inflammation, and cardiometabolic diseases using probiotics and other gut-modulating therapies. To date, many studies have shown a correlative relationship between intestinal bacteria composition and the presence of CAD, or severity of heart attacks, but few have begun to elucidate potential metabolic and immunologic mechanisms. The investigator's recently supplemented Lactobacillus plantarum 299v in men with stable CAD, which improved systemic inflammation and brachial artery flow-mediated dilation (BA-FMD) - a measure of endothelial function and a predictive CAD precursor. Improvement in BA-FMD positively correlated with increased serum propionic acid (PA) concentrations. PA is a gut microbiome-derived short chain fatty acid (SCFA) with known human vascular receptors and implicated in endothelial function, innate immunity, and glucose homeostasis. Whether PA is mediating improvement in endothelial dysfunction or inflammation in the investigator's prior experiment remains unknown. The investigator's objective is to determine whether endothelial cell function is improved by dietary supplementation of sodium propionate in patients with established coronary artery disease. Furthermore, the investigators wish to elucidate to what extent inflammation is reduced by this therapy, by both measuring serum inflammatory markers and by seeing if plasma from treated patients induces anti-inflammatory transcriptomic responses from cultured endothelial cells and peripheral blood mononuclear cells, both of which are involved in atherosclerosis. Specific Aim 1 will determine the impact of dietary PA supplementation on endothelial function and traditional CAD risk factors in patients with CAD. The investigators will utilize ultrasound to assess the percent change in BA-FMD before and after dietary PA supplementation. The extent of endothelium-dependency of these responses will be tested by measuring BA-FMD following nitroglycerin administration. The investigators will also measure markers representative of traditional CAD risk factors, such as lipid levels and HgbA1C. Specific Aim 2 will determine anti-inflammatory changes in vivo and in transcriptomic signatures of cultured EC and PBMCs induced by dietary PA. The investigators will measure changes to systemic serum inflammatory markers involved in atherosclerotic processes using a targeted metabolomics approach, using plasma from the investigator's cohort before and after PA supplementation. Plasma samples will be used to incubate aforementioned cells to compare transcriptomic signatures of cells subjected to pre-supplementation plasma versus post-supplementation plasma. The investigators will use Ingenuity Pathway Analysis to determine changes to inflammatory pathways and i.i.com to determine whether more anti-inflammatory signatures were induced. Specific Aim 3 will determine the impact of PA supplementation on gut microbiome taxonomy and diversity. As an optional additional clinical study activity, the investigators will collect stool samples before and after dietary PA supplementation, subject samples to multiplex 16S RNA sequencing, and calculate the Shannon Diversity Index. This will help us determine changes in individual gut microbiome constituents and diversity of the entire population.

Conditions

Cardiovascular Diseases; Endothelial Dysfunction

Outcome Measures

Primary Outcomes (1)

• Change in baseline flow mediated dilation (FMD) at 4 weeks

  This is a measurement of endothelial function in the brachial artery

  baseline and week 4

Study Arms (2)

Sodium Propionate First

EXPERIMENTAL

Subjects in this arm will consume 500mg sodium propionate powder twice daily for four weeks, mixed into their food/drink. This is followed by four weeks of placebo twice daily.

Dietary Supplement: Sodium Propionate; Dietary Supplement: Placebo

Placebo First

PLACEBO COMPARATOR

Subjects in this arm will consume a placebo twice daily for four weeks, mixed into their food/drink. This is followed by four weeks of 500mg sodium propionate powder, twice daily.

Dietary Supplement: Sodium Propionate; Dietary Supplement: Placebo

Interventions

Sodium Propionate DIETARY_SUPPLEMENT

a 500 mg powder dietary supplement that can be mixed into food or drinks. It will be taken twice daily for four weeks.

Placebo First; Sodium Propionate First

Placebo DIETARY_SUPPLEMENT

a color, size, calorie, and consistency-matched powder dietary supplement that can be mixed into food or drinks. It will be taken twice daily for four weeks.

Placebo First; Sodium Propionate First

Eligibility Criteria

• Age: 40 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• History of known coronary artery disease as defined by having one or more of the following:
• history of myocardial infarction
• angiogram demonstrative \>=50% stenosis in at least 1 major epicardial coronary artery
• a previous stress test that showed evidence of ischemia (that has not been revealed to be a false positive test by angiography)
• CT coronary study showing EITHER a coronary artery calcium (CAC) score of \>400, OR a description of "significant stenosis" of one or more epicardial arteries.

You may not qualify if:

• Unstable angina or myocardial infarction by history, ECG, and/or enzymatic criteria within 1 month of enrollment.
• LV dysfunction as defined by an LV ejection fraction documented as \< 45% within 1 year of enrollment by an echocardiogram, MRI, or nuclear imaging.
• Uncontrolled hypertension with a blood pressure greater than 170/100 mmHg at the screening visit.
• Known history of chronic renal insufficiency, liver dysfunction, or cancer besides non-melanoma skin carcinomas or localized prostate cancer requiring systemic treatment within five years of enrollment.
• Known history of cognitive impairment or inability to follow study procedures.
• Patient with GI tract illness such as short gut syndrome, inflammatory bowel disease, or an ileostomy.
• Patient with an implanted defibrillator or permanent pacemaker on which the potential participant is known to rely upon for greater than 50% of ventricular depolarizations.
• Patients who received probiotics, prebiotics, or short chain fatty acid supplements (e.g. propionate, butyrate, acetate-containing supplements) within the past 4 weeks.
• Patients who received antibiotics in the last 12 weeks.
• Patients with dosing changes of vasoactive medications and HMG-CoA reductase inhibitors in the 6 weeks prior to enrollment.
• Pregnancy
• Those who are daily drinkers or use illicit drugs.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

sodium propionate

Central Study Contacts

Michael E Widlansky, MD, MPH

CONTACT

4149556759; mwidlans@mcw.edu

Benjamin C Hofeld, MD

CONTACT

4149556759; bhofeld@mcw.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: November 15, 2021
• First Posted: November 26, 2021
• Study Start (Estimated): July 1, 2027
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: September 25, 2025

Record last verified: 2025-09