Involvement of the Gut Microbiota in Calcified Aortic Stenosis

Aortic Stenosis Clinical Trial

— Gut-CAS  

Official title:

Involvement of the Gut Microbiota and Its Metabolites in the Pathophysiology of Calcified Aortic Stenosis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06021535
• Other study ID #: BASEC Nr (2023-01173)
• Status: Not yet recruiting
• Start date: January 1, 2024
• Est. completion date: December 31, 2028

Study information

• Verified date: August 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: Caroline Nguyen, MD
• Phone: +41316325000
• Email: caroline.chong-nguyen[@]insel.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Calcific aortic stenosis (CAS) is a disease characterized by progressive calcification of the aortic valve, obstructing the passage of blood from the left ventricle into the general circulation. It is the most frequent cause of valve disease in the elderly. To date, no means of preventing the disease has been discovered, and the only treatment available is valve replacement during cardiac surgery, or percutaneous implantation of a valve prosthesis when the narrowing becomes severe and causes symptoms.

The intestinal flora or microbiota, the reservoir of all the microorganisms in the gut, is implicated in numerous diseases, particularly of the intestine. But to date, no study has established a link between CAS and microbiota. The intestinal microbiota acts through molecules produced by itself or the host and passing into the bloodstream. In the pathophysiology of CAS, the valve leaflets are breached and do not heal. These molecules can enter and have beneficial or deleterious effects, in particular promoting calcification of aortic valve cells.

Concrete objectives:

Improve understanding of calcific aortic stenosis in humans Study the composition of intestinal flora in patients with aortic stenosis and compare it with healthy subjects Study the molecules in the intestinal flora likely to be involved in the development of aortic stenosis in humans.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: December 31, 2028
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Group of patients with CAS:

• Calcified aortic stenosis diagnosed on a cardiac ultrasound or CT not older than 3 months

• Severe aortic stenosis: surgical indication based on symptoms and ultrasound data (high gradient aortic stenosis : Vmax> 4m/s, mean gradient > 40mmHg, area < 1cm², low flow low-gradient CAS: left ventricular ejection fraction (LVEF) < 40%, Vmax< 4m/s, mean gradient < 40mmHg, area < 1cm², paradoxical low-gradient CAS: LVEF > 55%, Vmax< 4m/s, mean gradient < 40mmHg, area < 1cm²)

• Moderate CAS: 3m/s <Vmax< 4m/s, 20mmHg < mean gradient < 40mmHg

• Mild CAS: 2,6m/s < Vmax < 2.9m/s, mean gradient < 20mmHg

• Aortic sclerosis: calcified remodeling of the aortic valve visible on ultrasound or CT.

Control group - free of CAS:

• No calcified aortic stenosis verified on a cardiac ultrasound or CT not older than 3 months

Exclusion Criteria:

• Treatment interfering with the composition of the intestinal microbiota: local or systemic corticosteroids within the last 3 months, antibiotics within the last 3 months, antiretrovirals, bile acid chelators (questran and colesevelam), HIV-targeted antiretroviral therapies, selective serotonin reuptake inhibitor-type antidepressants

• Clinical criteria: history of cholecystectomy, documented chronic liver disease in the patient, failure to fast on the day of the blood test, inflammatory bowel disease

• Patients requiring emergency intervention (myocardial infarction, acute aortic or mitral insufficiency, cardiogenic shock).

• AS of rheumatic origin, infective endocarditis.

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Valve Stenosis
• Constriction, Pathologic
• Gastrointestinal Microbiome
• Metabolomics

Intervention

Other:
• No intervention
No intervention

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern

References & Publications (6)

Agus A, Planchais J, Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018 Jun 13;23(6):716-724. doi: 10.1016/j.chom.2018.05.003. — View Citation

Kocyigit D, Tokgozoglu L, Gurses KM, Stahlman M, Boren J, Soyal MFT, Canpinar H, Guc D, Saglam Ayhan A, Hazirolan T, Ozer N. Association of dietary and gut microbiota-related metabolites with calcific aortic stenosis. Acta Cardiol. 2021 Jul;76(5):544-552. doi: 10.1080/00015385.2020.1853968. Epub 2020 Dec 18. — View Citation

Liu Z, Li J, Liu H, Tang Y, Zhan Q, Lai W, Ao L, Meng X, Ren H, Xu D, Zeng Q. The intestinal microbiota associated with cardiac valve calcification differs from that of coronary artery disease. Atherosclerosis. 2019 May;284:121-128. doi: 10.1016/j.atherosclerosis.2018.11.038. Epub 2018 Dec 4. — View Citation

Morvan M, Arangalage D, Franck G, Perez F, Cattan-Levy L, Codogno I, Jacob-Lenet MP, Deschildre C, Choqueux C, Even G, Michel JB, Back M, Messika-Zeitoun D, Nicoletti A, Caligiuri G, Laschet J. Relationship of Iron Deposition to Calcium Deposition in Human Aortic Valve Leaflets. J Am Coll Cardiol. 2019 Mar 12;73(9):1043-1054. doi: 10.1016/j.jacc.2018.12.042. — View Citation

Shan Y, Pellikka PA. Aortic stenosis in women. Heart. 2020 Jul;106(13):970-976. doi: 10.1136/heartjnl-2019-315407. Epub 2020 Mar 22. — View Citation

Yilmaz B, Fuhrer T, Morgenthaler D, Krupka N, Wang D, Spari D, Candinas D, Misselwitz B, Beldi G, Sauer U, Macpherson AJ. Plasticity of the adult human small intestinal stoma microbiota. Cell Host Microbe. 2022 Dec 14;30(12):1773-1787.e6. doi: 10.1016/j.chom.2022.10.002. Epub 2022 Oct 31. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Richness of the gut microbiota	The primary endpoint is the evaluation (16S ribosomal ribonucleic acid (rRNA) sequencing) of the species richness using alpha diversity parameters such as the Shannon and Simpson index and diversity between samples using beta diversity with Bray-Curtis dissimilarity approach. The investigators will then identify the bacteria with taxonomy analysis and statistical differences will be done using MaAsLin (Microbiome Multivariable Association with Linear Models) for patients with and without CAS.	The sample will be collected at the time of inclusion (with a margin of two additional days depending on the patient's ability to pass stools). The analysis will be performed at the end of the sample collection (an average of 2 years)
Secondary	Comparison of the levels of the tryptophane metabolites of the gut microbiota in the blood, feces and the aortic valve between patients with and without CAS	The metabolites being studied include tryptophan metabolites (kynurenine pathway, serotonin pathway).	The full analysis will be performed at the end of the sample collection. One intermediate analysis is scheduled when half of the samples are collected (one year and two years)
Secondary	Comparison of the levels of the short chain fatty acids (SCFA) metabolites of the gut microbiota in the blood, feces and the aortic valve between patients with and without CAS	The metabolites being studied include SCFA (acetate, propionate and butyrate).	The full analysis will be performed at the end of the sample collection. One intermediate analysis is scheduled when half of the samples are collected (one year and two years)
Secondary	Comparison of the levels of the trimethylamine N oxide (TMAO) metabolites of the gut microbiota in the blood, feces and the aortic valve between patients with and without CAS	TMAO is derived from trimethylamine (TMA), itself generated by the action of the gut microbiota on dietary choline and phosphatidylcholine contained in red meat, eggs, dairy products and saltwater fish. TMAO and its derivatives (L Carnitine) are measured in blood, stool and valves.	The full analysis will be performed at the end of the sample collection. One intermediate analysis is scheduled when half of the samples are collected (one year and two years)
Secondary	Comparison of the levels of the bile acids metabolites of the gut microbiota in the blood, feces and the aortic valve between patients with and without CAS	The metabolites being studied include 4 bile acids and their derivatives (Cholic, Chenodeoxycholic, Deoxycholic and Lithocholic acid)	The full analysis will be performed at the end of the sample collection. One intermediate analysis is scheduled when half of the samples are collected (one year and two years)
Secondary	Diversity of bacteria families in men and women	Primary endpoint: The primary endpoint is the evaluation (16S rRNA sequencing) of the species richness using alpha diversity parameters such as the Shannon and Simpson index and diversity between samples using beta diversity with Bray-Curtis dissimilarity approach.	The sample will be collected at the time of inclusion (with a margin of two additional days depending on the patient's ability to pass stools). The analysis will be performed at the end of the sample collection (an average of 2 years)
Secondary	Prevalence of bacterial families or species in the microbiota of patients with CAS over the course of time and disease progression.	Primary endpoint: The primary endpoint is the evaluation (16S rRNA sequencing) of the species richness using alpha diversity parameters such as the Shannon and Simpson index and diversity between samples using beta diversity with Bray-Curtis dissimilarity approach.	The sample will be collected at the time of inclusion (with a margin of two additional days depending on the patient's ability to pass stools). The analysis will be performed at the end of each year of follow up (an average of 2 years)
Secondary	Prevalence of bacterial families or species in the microbiota of men versus women with CAS over the course of time and disease progression.	Primary endpoint: The primary endpoint is the evaluation (16S rRNA sequencing) of the species richness using alpha diversity parameters such as the Shannon and Simpson index and diversity between samples using beta diversity with Bray-Curtis dissimilarity approach.	The sample will be collected at the time of inclusion (with a margin of two additional days depending on the patient's ability to pass stools). The analysis will be performed at the end of each year of follow up (an average of 2 years)