Ignite Creation Date:
2024-05-06 @ 4:54 PM
Last Modification Date:
2024-10-26 @ 2:18 PM
Study NCT ID:
NCT05135702
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-08-21
First Post:
2021-11-15
Brief Title:
Effect of Propionic Acid Supplementation on Endothelial Function
Sponsor:
Medical College of Wisconsin
Organization:
Medical College of Wisconsin
Study Overview
Official Title:
Effect of Propionic Acid Supplementation on Endothelial Function in Patients With Coronary Artery Disease
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 investigators 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 investigators prior experiment remains unknown The investigators 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 investigators 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 iicom 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
The investigators 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 investigators prior experiment remains unknown The investigators 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 investigators 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 iicom 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
Detailed Description:
Endothelial dysfunction ED is a pathological state of vessel function characterized by increased expression of pro-vasoconstrictive mediators and increased thrombotic risk ED is associated with the development of atherosclerosis including coronary artery disease CAD and with increased risk of cardiovascular events Therefore there is an ongoing research effort to restore endothelial function in order to reduce the risk of cardiovascular morbidity associated with endothelial dysfunction
The gut microbiome has been well correlated with the presence of CAD and alterations to the gut microbiome have been mechanistically linked to the severity of myocardial infarction Animal experiments showed that alteration of gut bacteria with supplementation of Lactobacillus plantarum 299v Lp299v and vancomycin is associated with reduced leptin levels size of myocardial infarction and improved post -ischemic cardiac function In humans dietary supplementation with Lp299v was associated with significant reductions in LDL-cholesterol fibrinogen and leptin concentrations in smokersThe investigatorsrecently showed in men with stable CAD that six weeks supplementation with Lp299v improved endothelial function as assessed by brachial artery flow-mediated dilation BA-FMD a widely accepted noninvasive modality of assessing vascular endothelial function This intervention concurrently reduced serum inflammatory markers IL-8 IL-12 and leptin and post-probiotic plasma drove an anti-inflammatory transcriptomic response in cultured peripheral blood mononuclear cells Interestingly these beneficial changes were not accompanied by changes in gut microbiome constituents Instead the increase seen in BA-FMD was positively correlated with an increase in serum propionic acid one of the short-chain fatty acids a set of molecules produced by gut microbes and freely absorbed into human circulation Propionic acid is known to improve endothelial function reduce systemic inflammation and improve glucose homeostasis in several models These experiments suggested that Lp299vs beneficial effects were mediated by changes to the existing gut microbiomes metabolism as opposed to changes to microbial constituents The investigators identified propionic acid as a potential mediator of these beneficial outcomes
In this study the investigators objective is to assess if there is any impact of sodium propionate dietary supplementation on vascular endothelial function and on the levels of circulating inflammatory markers related to endothelial dysfunction In addition the investigators also will study if the impact on endothelial function is associated with either anti-inflammatory changes in relevant vascular cell types eg endothelial cells peripheral blood mononuclear cells or on the constituents of the gut microbiome itself
Endothelial function is easily measurable by non-invasive means Endothelial dysfunction measured non-invasively independently predicts future cardiovascular risk in patients both with and without clinically apparent cardiovascular disease Conduit vessel endothelial function in humans is commonly quantified by measurement of BA-FMD which represents the endothelium-dependent relaxation of a conduit artery-typically the brachial artery - due to an increased blood flow BA-FMD correlates with impaired endothelium-dependent relaxation in the coronary arteries and is a commonly recognized barometer of cardiovascular risk BA-FMD is an ideal surrogate marker of cardiovascular risk to monitor the acute impact of Lp299v supplementation on vascular endothelial function
The gut microbiome has been well correlated with the presence of CAD and alterations to the gut microbiome have been mechanistically linked to the severity of myocardial infarction Animal experiments showed that alteration of gut bacteria with supplementation of Lactobacillus plantarum 299v Lp299v and vancomycin is associated with reduced leptin levels size of myocardial infarction and improved post -ischemic cardiac function In humans dietary supplementation with Lp299v was associated with significant reductions in LDL-cholesterol fibrinogen and leptin concentrations in smokersThe investigatorsrecently showed in men with stable CAD that six weeks supplementation with Lp299v improved endothelial function as assessed by brachial artery flow-mediated dilation BA-FMD a widely accepted noninvasive modality of assessing vascular endothelial function This intervention concurrently reduced serum inflammatory markers IL-8 IL-12 and leptin and post-probiotic plasma drove an anti-inflammatory transcriptomic response in cultured peripheral blood mononuclear cells Interestingly these beneficial changes were not accompanied by changes in gut microbiome constituents Instead the increase seen in BA-FMD was positively correlated with an increase in serum propionic acid one of the short-chain fatty acids a set of molecules produced by gut microbes and freely absorbed into human circulation Propionic acid is known to improve endothelial function reduce systemic inflammation and improve glucose homeostasis in several models These experiments suggested that Lp299vs beneficial effects were mediated by changes to the existing gut microbiomes metabolism as opposed to changes to microbial constituents The investigators identified propionic acid as a potential mediator of these beneficial outcomes
In this study the investigators objective is to assess if there is any impact of sodium propionate dietary supplementation on vascular endothelial function and on the levels of circulating inflammatory markers related to endothelial dysfunction In addition the investigators also will study if the impact on endothelial function is associated with either anti-inflammatory changes in relevant vascular cell types eg endothelial cells peripheral blood mononuclear cells or on the constituents of the gut microbiome itself
Endothelial function is easily measurable by non-invasive means Endothelial dysfunction measured non-invasively independently predicts future cardiovascular risk in patients both with and without clinically apparent cardiovascular disease Conduit vessel endothelial function in humans is commonly quantified by measurement of BA-FMD which represents the endothelium-dependent relaxation of a conduit artery-typically the brachial artery - due to an increased blood flow BA-FMD correlates with impaired endothelium-dependent relaxation in the coronary arteries and is a commonly recognized barometer of cardiovascular risk BA-FMD is an ideal surrogate marker of cardiovascular risk to monitor the acute impact of Lp299v supplementation on vascular endothelial function
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None