Involvement of the Gut Microbiota in Calcified Aortic Stenosis

NCT06021535 | Not Yet Recruiting

• 1 other identifier: BASEC Nr (2023-01173)
• Study Type: observational
• Target: 100
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Aortic Stenosis; Gastrointestinal Microbiome; Metabolomics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• 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 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)

• 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 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)

• 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

  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)

• 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 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)

• Diversity of bacteria families in men and women

  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)

Study Arms (2)

Calcified Aortic Stenosis

Patients with calcified aortic valve or aortic stenosis will be enrolled Stool, blood samples and aortic valve of operated patients will be retrieved to evaluate the composition of the gut microbiota and its metabolites A follow up is planned for patients with no intervention on the aortic valve to assess the evolution of the aortic stenosis and the change in the gut microbiota.

Other: No intervention

Control

Patients without calcified aortic valve will be enrolled Stool and blood samples will be retrieved to evaluate the composition of the gut microbiota and its metabolites No follow up is scheduled.

Other: No intervention

Interventions

No intervention OTHER

No intervention

Calcified Aortic Stenosis; Control

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

In this study the investigators aim at enrolling patients with calcified aortic stenosis as well as a control group (patients without calcified aortic stenosis) and aim for an even distribution between female and male participants.

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Related Publications (6)

• 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.

  PMID: 33334254 BACKGROUND

• 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.

  PMID: 30897381 BACKGROUND

• 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.

  PMID: 29902437 BACKGROUND

• 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.

  PMID: 32201373 BACKGROUND

• 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.

  PMID: 30846099 BACKGROUND

• 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.

  PMID: 36318918 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Stool, blood sample, aortic valve

MeSH Terms

Conditions

Aortic Valve Stenosis

Condition Hierarchy (Ancestors)

Aortic Valve Disease; Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases; Ventricular Outflow Obstruction

Study Officials

• Caroline Nguyen, MD

  Insel Gruppe AG

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caroline Nguyen, MD

CONTACT

+41316325000; caroline.chong-nguyen@insel.ch

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2023
• First Posted: September 1, 2023
• Study Start: January 1, 2024
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2028
• Last Updated: September 1, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share