MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta

Aortic Aneurysm and Dissection Clinical Trial

— MITAORTA  

Official title:

MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05434481
• Other study ID #: 2022-A00719-34
• Status: Active, not recruiting
• Phase: N/A
• Start date: September 7, 2022
• Est. completion date: October 23, 2024

Study information

• Verified date: June 2024
• Source: University Hospital, Angers
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main objective is to compare the mitochondrial dynamic between patients operated for aneurysm of ascending aorta or type A aortic dissection (AAD) or control group

Description:

In an aortic aneurysm process, the alteration of the extracellular matrix (ECM) as well as the apoptosis of the smooth muscle cells are due to inflammatory phenomena and oxydative stress, involving mitochondria which has a key place within cells.

Mitochondrial fusion and fission constitute mitochondrial dynamic and are involved in the mechanisms described above.

The alteration of mitochondrial dynamics has been demonstrated in many pathologies, in particular neurological, cancer and cardiovascular disease and generally occurs in favor of fission.

In a mouse model (FASEB J, 2021, Robert P ), the role of mitochondrial fusion has been demostrated as a protective factor against hypertension in resistance arteries and a deletion of OPA1 (optic Atrophy 1) fusion protein may lead to aneurysm until aortic dissection. The results of this experimental study suggest a role of the alteration of mitochondrial dynamic in the development of aneurysm and aortic dissection.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: October 23, 2024
• Est. primary completion date: October 23, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Aneurysm aortic group: patients treated for an aneurysm of the ascending thoracic aorta with surgical indication according to the ESC guidelines (2014).

• Aortic dissection group: patients treated for type A acute aortic dissection or intramural hematoma of the ascending thoracic aorta in emergency.

• Control group: patients operated for aortic valve replacement (little aortic sample before closing aortotomy) or coronary artery bypass grafting which the use of a saphenous graft and the performance of a proximal anastomosis on the ascending aorta is planned

Exclusion Criteria:

• Patients under 18 years old

• Other acute aortic syndromes (penetrating ulcers, iatrogenic or traumatic dissections)

• Patients treated for aortic valve replacement in the context of infective endocarditis

• Patients treated for emergency aortic valve replacement or coronary bypass surgery**

• Pregnant, parturient and breastfeeding women

• Patients protected by an administrative or judicial measure (curatorship, guardianship)

• Patients receiving psychiatric care under duress

• Adults subject to a legal protection measure.

• Patients whose the samples planned for the study could not be taken;

• Patients in the control group whose tissue sampling will not be performed.

Related Conditions & MeSH terms

• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm and Dissection

Intervention

Other:
• Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases
For each patient: a segment of aorta will be sampled and cutted into 4 parts 1 fragment placed in a Falcon tube containing DMEM (Dulbecco's Modified Eagle Medium, Thermo Fisher®), temporarily stored at + 4°C, for primary culture of smooth muscle cells will allow analysis of the mitochondrial network. 1 fragment placed in a Falcon tube containing Allprotect Tissue Reagent (QIAGEN®), stored at -80°C for gene (RT-PCR) and protein (Western Blot) analysis. 2 fragments each placed in dry cryotube stored at - 80°C will be used for metabolomic analysis. For each patient, 2 arterial blood samples will be collected before general anaesthesia One tube of whole blood stored at -80°C for metabolomic analysis. One tube of blood stored at -80°C for plasma cytokines

Locations

Country	Name	City	State
France	Olivier FOUQUET	Angers

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Angers	Fondation de l'Avenir

Country where clinical trial is conducted

France, 

References & Publications (6)

Archer SL. Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N Engl J Med. 2013 Dec 5;369(23):2236-51. doi: 10.1056/NEJMra1215233. No abstract available. — View Citation

Le Page S, Niro M, Fauconnier J, Cellier L, Tamareille S, Gharib A, Chevrollier A, Loufrani L, Grenier C, Kamel R, Sarzi E, Lacampagne A, Ovize M, Henrion D, Reynier P, Lenaers G, Mirebeau-Prunier D, Prunier F. Increase in Cardiac Ischemia-Reperfusion Inj — View Citation

Piquereau J, Caffin F, Novotova M, Prola A, Garnier A, Mateo P, Fortin D, Huynh le H, Nicolas V, Alavi MV, Brenner C, Ventura-Clapier R, Veksler V, Joubert F. Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptat — View Citation

Robert P, Nguyen PMC, Richard A, Grenier C, Chevrollier A, Munier M, Grimaud L, Proux C, Champin T, Lelievre E, Sarzi E, Vessieres E, Henni S, Prunier D, Reynier P, Lenaers G, Fassot C, Henrion D, Loufrani L. Protective role of the mitochondrial fusion pr — View Citation

Toda M, Yamamoto K, Shimizu N, Obi S, Kumagaya S, Igarashi T, Kamiya A, Ando J. Differential gene responses in endothelial cells exposed to a combination of shear stress and cyclic stretch. J Biotechnol. 2008 Jan 20;133(2):239-44. doi: 10.1016/j.jbiotec.2 — View Citation

Trabado S, Al-Salameh A, Croixmarie V, Masson P, Corruble E, Feve B, Colle R, Ripoll L, Walther B, Boursier-Neyret C, Werner E, Becquemont L, Chanson P. The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age. PLoS One. 2017 Mar 9;12(3):e0173615. doi: 10.1371/journal.pone.0173615. eCollection 2017. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Level of tissue expression of the genes and coding for the proteins (Optic Atrophy 1) OPA1	Level expression of, (Optic Atrophy 1) OPA1 by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins MFN1 (Mitofusin 1)	Level expression of MFN1 (Mitofusin 1) by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins MFN2 (Mitofusin 2)	Level expression of MFN2 (Mitofusin 2) by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins Fis1	Level expression of Fis1 by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins Drp1	Level expression of Drp1 by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins Nfr1	Level expression of Nfr1 by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins Tfam	Level expression of Tfam by RT-qPCR	1 month
Primary	Level of tissue expression of the genes and coding for the proteins PGC1?	Level expression of PGC1? by RT-qPCR	1 month
Primary	Analysis of mitochondrial network	To analyze the mitochondrial network, vascular smooth muscle cells will be extracted from the wall of aorta samples and seeded in Petri dish. When 80% confluence is obtained, cells will be incubated with a green fluorescent marker (Mitotacker Green Probes) and 3D fluorescence microscopy will be used. Analysis of mitochondrial network will be done after characterization of mitochondrial shapes and distribution in the different aorta samples.	1 month
Secondary	Protein of remodelling and constitution of extracellular matrix: Metalloprotease MMp2	Level expression of Metalloprotease MMp2 by western blot	1 month
Secondary	Proteins of remodelling and constitution of extracellular matrix: Timp 1/2	Level expression of Timp 1/2 by western blot	1 month
Secondary	Proteins of remodelling and constitution of extracellular matrix: Collagene I/III	Level expression of Collagene I/III by western blot	1 month.
Secondary	Protein of remodelling and constitution of extracellular matrix: Elastine	Level expression of Elastine by western blot	1 month
Secondary	Proteins of survival cell: Bcl2/Bax	Level expression of Bcl2/Bax by western blot	1 month
Secondary	Proteins of survival cell: Cytochrome C	Level expression of Cytochrome C by western blot	1 month
Secondary	Proteins of oxydative stress: NADPH	Level expression of NADPH by western blot	1 month
Secondary	Proteins of oxydative stress: OxyD	Level expression of OxyD by western blot	1 month
Secondary	Proteins of oxydative stress: Sod 1/2	Level expression of Sod 1/2 by western blot	1 month
Secondary	Proteins of Smooth Muscle Cell reactivity: Myh11	Level expression of Myh11 by western blot	1 month
Secondary	Proteins of Smooth Muscle Cell reactivity: Acta 2	Level expression of Acta 2 by western blot	1 month
Secondary	Proteins of Smooth Muscle Cell reactivity: MLC20	Level expression of MLC20 by western blot	1 month
Secondary	Proteins of Smooth Muscle Cell reactivity: Rock1	Level expression of Rock1 by western blot	1 month
Secondary	Proteins of Smooth Muscle Cell reactivity: Rhoa	Level expression of Rhoa by western blot	1 month
Secondary	Analysis of Plasma Metabolomes	154 metabolites will be measured in plasma samples. Plasma data blocks will be submitted to multiblock orthogonal component analysis (MOCA) after normalizing concentrations of plasma samples by their weights.	2 years
Secondary	Analysis of Aorta Metabolomes	136 metabolites will be measured in plasma samples. Plasma data blocks will be submitted to multiblock orthogonal component analysis (MOCA) after normalizing concentrations of aorta samples by their weights.	2 years