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NCT Number: NCT06021535

Involvement of the Gut Microbiota in Calcified Aortic Stenosis

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.

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Key information

Conditions

Aortic Stenosis Aortic Valve Disease Aortic Valve Stenosis Cardiovascular Diseases Gastrointestinal Microbiome Heart Diseases Heart Valve Diseases Metabolomics Ventricular Outflow Obstruction

Age range

18 year–90 year

Sex eligibility

All sexes

Study type

Observational

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

No intervention

Other

No intervention

Primary outcomes

  1. Richness of the gut microbiota

    Time frame: 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)

    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.

Secondary outcomes

  1. 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

    Time frame: 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)

    The metabolites being studied include tryptophan metabolites (kynurenine pathway, serotonin pathway).

  2. 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

    Time frame: 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)

    The metabolites being studied include SCFA (acetate, propionate and butyrate).

  3. 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

    Time frame: 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)

    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.

  4. 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

    Time frame: 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)

    The metabolites being studied include 4 bile acids and their derivatives (Cholic, Chenodeoxycholic, Deoxycholic and Lithocholic acid)

  5. Diversity of bacteria families in men and women

    Time frame: 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)

    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.

  6. Prevalence of bacterial families or species in the microbiota of patients with CAS over the course of time and disease progression.

    Time frame: 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)

    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.

  7. Prevalence of bacterial families or species in the microbiota of men versus women with CAS over the course of time and disease progression.

    Time frame: 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)

    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.

Study contacts

Contact information is provided by the study sponsor or research team.

Caroline Nguyen, MD

CONTACT

[email protected]

+41316325000

Sponsors and collaborators

Lead sponsor

Insel Gruppe AG, University Hospital Bern

Other

Registry information

Official study title

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

Acronym: Gut-CAS

Important dates

Study start
2024
Primary completion
2025
Study completion
2028
First posted
Sep 1, 2023
Registry last updated
Sep 1, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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