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

Primary Purpose

Aortic Aneurysm and Dissection

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases
Sponsored by
University Hospital, Angers
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Aortic Aneurysm and Dissection focused on measuring extracellular matrix, cell survival, oxydative stress, mitochondrial fusion, metabolomic profiling of aortic aneurym, metabolomic profilng of aortic dissection

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Olivier FOUQUETRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Sham Comparator

Arm Label

Aneurysm group

Type A aortic dissection group

Control group

Arm Description

Patients operated for aneurysm of the ascending aorta according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).

Patients operated for type A aortic dissection according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).

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.

Outcomes

Primary Outcome Measures

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
Level of tissue expression of the genes and coding for the proteins MFN1 (Mitofusin 1)
Level expression of MFN1 (Mitofusin 1) by RT-qPCR
Level of tissue expression of the genes and coding for the proteins MFN2 (Mitofusin 2)
Level expression of MFN2 (Mitofusin 2) by RT-qPCR
Level of tissue expression of the genes and coding for the proteins Fis1
Level expression of Fis1 by RT-qPCR
Level of tissue expression of the genes and coding for the proteins Drp1
Level expression of Drp1 by RT-qPCR
Level of tissue expression of the genes and coding for the proteins Nfr1
Level expression of Nfr1 by RT-qPCR
Level of tissue expression of the genes and coding for the proteins Tfam
Level expression of Tfam by RT-qPCR
Level of tissue expression of the genes and coding for the proteins PGC1⍺
Level expression of PGC1⍺ by RT-qPCR
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.

Secondary Outcome Measures

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

Full Information

First Posted
June 3, 2022
Last Updated
February 9, 2023
Sponsor
University Hospital, Angers
Collaborators
Fondation de l'Avenir
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1. Study Identification

Unique Protocol Identification Number
NCT05434481
Brief Title
MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta
Acronym
MITAORTA
Official Title
MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 7, 2022 (Actual)
Primary Completion Date
September 6, 2025 (Anticipated)
Study Completion Date
September 6, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Angers
Collaborators
Fondation de l'Avenir

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aortic Aneurysm and Dissection
Keywords
extracellular matrix, cell survival, oxydative stress, mitochondrial fusion, metabolomic profiling of aortic aneurym, metabolomic profilng of aortic dissection

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Aneurysm and Dissection of Ascending Thoracic Aorta
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Aneurysm group
Arm Type
Active Comparator
Arm Description
Patients operated for aneurysm of the ascending aorta according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).
Arm Title
Type A aortic dissection group
Arm Type
Active Comparator
Arm Description
Patients operated for type A aortic dissection according the guidelines on the diagnosis and treatment of aortic diseases (European Society of Cardiology - 2014).
Arm Title
Control group
Arm Type
Sham Comparator
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases
Intervention Description
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
Primary Outcome Measure Information:
Title
Level of tissue expression of the genes and coding for the proteins (Optic Atrophy 1) OPA1
Description
Level expression of, (Optic Atrophy 1) OPA1 by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins MFN1 (Mitofusin 1)
Description
Level expression of MFN1 (Mitofusin 1) by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins MFN2 (Mitofusin 2)
Description
Level expression of MFN2 (Mitofusin 2) by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins Fis1
Description
Level expression of Fis1 by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins Drp1
Description
Level expression of Drp1 by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins Nfr1
Description
Level expression of Nfr1 by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins Tfam
Description
Level expression of Tfam by RT-qPCR
Time Frame
1 month
Title
Level of tissue expression of the genes and coding for the proteins PGC1⍺
Description
Level expression of PGC1⍺ by RT-qPCR
Time Frame
1 month
Title
Analysis of mitochondrial network
Description
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.
Time Frame
1 month
Secondary Outcome Measure Information:
Title
Protein of remodelling and constitution of extracellular matrix: Metalloprotease MMp2
Description
Level expression of Metalloprotease MMp2 by western blot
Time Frame
1 month
Title
Proteins of remodelling and constitution of extracellular matrix: Timp 1/2
Description
Level expression of Timp 1/2 by western blot
Time Frame
1 month
Title
Proteins of remodelling and constitution of extracellular matrix: Collagene I/III
Description
Level expression of Collagene I/III by western blot
Time Frame
1 month.
Title
Protein of remodelling and constitution of extracellular matrix: Elastine
Description
Level expression of Elastine by western blot
Time Frame
1 month
Title
Proteins of survival cell: Bcl2/Bax
Description
Level expression of Bcl2/Bax by western blot
Time Frame
1 month
Title
Proteins of survival cell: Cytochrome C
Description
Level expression of Cytochrome C by western blot
Time Frame
1 month
Title
Proteins of oxydative stress: NADPH
Description
Level expression of NADPH by western blot
Time Frame
1 month
Title
Proteins of oxydative stress: OxyD
Description
Level expression of OxyD by western blot
Time Frame
1 month
Title
Proteins of oxydative stress: Sod 1/2
Description
Level expression of Sod 1/2 by western blot
Time Frame
1 month
Title
Proteins of Smooth Muscle Cell reactivity: Myh11
Description
Level expression of Myh11 by western blot
Time Frame
1 month
Title
Proteins of Smooth Muscle Cell reactivity: Acta 2
Description
Level expression of Acta 2 by western blot
Time Frame
1 month
Title
Proteins of Smooth Muscle Cell reactivity: MLC20
Description
Level expression of MLC20 by western blot
Time Frame
1 month
Title
Proteins of Smooth Muscle Cell reactivity: Rock1
Description
Level expression of Rock1 by western blot
Time Frame
1 month
Title
Proteins of Smooth Muscle Cell reactivity: Rhoa
Description
Level expression of Rhoa by western blot
Time Frame
1 month
Title
Analysis of Plasma Metabolomes
Description
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.
Time Frame
2 years
Title
Analysis of Aorta Metabolomes
Description
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.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Olivier FOUQUET, Dr
Phone
0241357896
Email
olfouquet@chu-angers.fr
Facility Information:
Facility Name
Olivier FOUQUET
City
Angers
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Olivier FOUQUET, Dr
Phone
241357896
Ext
+33
Email
olfouquet@chu-angers.fr

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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
Citations:
PubMed Identifier
28278231
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.
Results Reference
background
PubMed Identifier
34133045
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 protein OPA1 in hypertension. FASEB J. 2021 Jul;35(7):e21678. doi: 10.1096/fj.202000238RRR.
Results Reference
result
PubMed Identifier
17850909
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.2007.08.009. Epub 2007 Aug 9.
Results Reference
result
PubMed Identifier
24304053
Citation
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.
Results Reference
result
PubMed Identifier
22406748
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 adaptation to pressure overload. Cardiovasc Res. 2012 Jun 1;94(3):408-17. doi: 10.1093/cvr/cvs117. Epub 2012 Mar 8.
Results Reference
result
PubMed Identifier
27723783
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 Injuries in Opa1+/- Mouse Model. PLoS One. 2016 Oct 10;11(10):e0164066. doi: 10.1371/journal.pone.0164066. eCollection 2016.
Results Reference
result

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

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