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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| No intervention | Other | No intervention |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
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Inclusion Criteria:
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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.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Caroline Nguyen, MD | Contact | +41316325000 | caroline.chong-nguyen@insel.ch |
| Name | Affiliation | Role |
|---|---|---|
| Caroline Nguyen, MD | Insel Gruppe AG | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33334254 | Background | 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. | |
| 30897381 | Background |
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| ID | Term |
|---|---|
| D001024 | Aortic Valve Stenosis |
| ID | Term |
|---|---|
| D000082862 | Aortic Valve Disease |
| D006349 | Heart Valve Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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Stool, blood sample, aortic valve
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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. |
| 29902437 | 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. |
| 32201373 | 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. |
| 30846099 | 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. |
| 36318918 | 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. |
| D014694 |
| Ventricular Outflow Obstruction |