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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Aortic Aneurysm and Dissection
• Intervention / Treatment: Other: Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Angers, France
    • Olivier FOUQUET

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aneurysm group; Patients operated for aneurysm of the ascending aorta according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).	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 parts1 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 anaesthesiaOne tube of whole blood stored at -80°C for metabolomic analysis.One tube of blood stored at -80°C for plasma cytokines
Active Comparator: Type A aortic dissection group; Patients operated for type A aortic dissection according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).	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 parts1 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 anaesthesiaOne tube of whole blood stored at -80°C for metabolomic analysis.One tube of blood stored at -80°C for plasma cytokines
Sham Comparator: Control group; Patients without aortic aneurysm or aortic dissection operated for aortic valve replacement (AVR) and/or coronary artery bypass with a saphenous vein graft for proximal aortic anastomosis to collect the aortic sample. For patients operated for AVR, an aortic sample will be collected before closing the aorta.	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 parts1 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 anaesthesiaOne tube of whole blood stored at -80°C for metabolomic analysis.One tube of blood stored at -80°C for plasma cytokines

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Level of tissue expression of the genes and coding for the proteins Fis1	Level expression of Fis1 by RT-qPCR	1 month
Level of tissue expression of the genes and coding for the proteins Drp1	Level expression of Drp1 by RT-qPCR	1 month
Level of tissue expression of the genes and coding for the proteins Nfr1	Level expression of Nfr1 by RT-qPCR	1 month
Level of tissue expression of the genes and coding for the proteins Tfam	Level expression of Tfam by RT-qPCR	1 month
Level of tissue expression of the genes and coding for the proteins PGC1⍺	Level expression of PGC1⍺ by RT-qPCR	1 month
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Protein of remodelling and constitution of extracellular matrix: Metalloprotease MMp2	Level expression of Metalloprotease MMp2 by western blot	1 month
Proteins of remodelling and constitution of extracellular matrix: Timp 1/2	Level expression of Timp 1/2 by western blot	1 month
Proteins of remodelling and constitution of extracellular matrix: Collagene I/III	Level expression of Collagene I/III by western blot	1 month.
Protein of remodelling and constitution of extracellular matrix: Elastine	Level expression of Elastine by western blot	1 month
Proteins of survival cell: Bcl2/Bax	Level expression of Bcl2/Bax by western blot	1 month
Proteins of survival cell: Cytochrome C	Level expression of Cytochrome C by western blot	1 month
Proteins of oxydative stress: NADPH	Level expression of NADPH by western blot	1 month
Proteins of oxydative stress: OxyD	Level expression of OxyD by western blot	1 month
Proteins of oxydative stress: Sod 1/2	Level expression of Sod 1/2 by western blot	1 month
Proteins of Smooth Muscle Cell reactivity: Myh11	Level expression of Myh11 by western blot	1 month
Proteins of Smooth Muscle Cell reactivity: Acta 2	Level expression of Acta 2 by western blot	1 month
Proteins of Smooth Muscle Cell reactivity: MLC20	Level expression of MLC20 by western blot	1 month
Proteins of Smooth Muscle Cell reactivity: Rock1	Level expression of Rock1 by western blot	1 month
Proteins of Smooth Muscle Cell reactivity: Rhoa	Level expression of Rhoa by western blot	1 month
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Collaborators: Fondation de l'Avenir

Publications and helpful links

General Publications

• 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.
• 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 protein OPA1 in hypertension. FASEB J. 2021 Jul;35(7):e21678. doi: 10.1096/fj.202000238RRR.
• 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.2007.08.009. Epub 2007 Aug 9.
• 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.
• 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 adaptation to pressure overload. Cardiovasc Res. 2012 Jun 1;94(3):408-17. doi: 10.1093/cvr/cvs117. Epub 2012 Mar 8.
• 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 Injuries in Opa1+/- Mouse Model. PLoS One. 2016 Oct 10;11(10):e0164066. doi: 10.1371/journal.pone.0164066. eCollection 2016.

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2022
• Primary Completion (Actual): October 23, 2023
• Study Completion (Estimated): October 23, 2024

Study Registration Dates

• First Submitted: June 3, 2022
• First Submitted That Met QC Criteria: June 25, 2022
• First Posted (Actual): June 28, 2022

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: June 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: oxydative stress; extracellular matrix; cell survival; mitochondrial fusion; metabolomic profiling of aortic aneurym; metabolomic profilng of aortic dissection
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm
• Other Study ID Numbers: 2022-A00719-34

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The data will be collected in a coded manner: first letter of the surname, first letter of the patient's first name, serial number of inclusion in the center by the physicians investigating the study in the electronic observation notebook managed by the DRCI of University Hospital of Angers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No