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Impact of Iron Deficiency and Its Correction on Mitochondrial Metabolism of the Cardiomyocyte (MitoCardioFer) (MitoCardioFer)

Primary Purpose

Iron-deficiency, Valvular Heart Disease

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
myocardial biopsy
sternal bone marrow biopsy
blood sample
Sponsored by
University Hospital, Angers
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Iron-deficiency focused on measuring ferric carboxymaltose, mitochondrial metabolism, cardiomyocyte

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥ 18 years
  • Patients that must be operated for a valvular heart surgery (aortic or mitral) scheduled in the month which follows the anaesthesia consultation (visit of inclusion)
  • The preoperative iron status is known
  • Patient signed informed consent

Exclusion Criteria:

  • Refusal of the patient to participate
  • Refusal of the surgeon or the anaesthetist who are responsible of patient management
  • Patients with a known iron overload (for example : hemochromatosis)
  • Counter-indication in the realization of a sternal bone marrow biopsy or myocardial biopsy (for example : endocarditis)
  • Adult patients under legal guardianship
  • Pregnancy

Sites / Locations

  • CHU Angers - DEPARTEMENT D'ANESTHESIE REANIMATION

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Control group

Iron deficiency group

Iron treated group

Arm Description

Patients with no iron deficiency prior to inclusion and who did not receive intravenous iron prior to inclusion. Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)

Patients with iron deficiency who did not receive intravenous iron prior to inclusion. Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)

Patients with iron deficiency who received intravenous iron prior to inclusion (greater than or equal to 1 g ferric carboxymaltose). Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)

Outcomes

Primary Outcome Measures

Measure of the maximal activity of the mitochondrial complex I using spectrometry
Measure of the maximal complex I activity using spectrometry on isolated mitochondria from myocardial biopsy.

Secondary Outcome Measures

Measure of the maximal activity of the others mitochondrial complexes using spectrometry (Complexes II, III and IV)
Quantification of the number of mitochondria per cardiomyocyte using Western-Blot
Quantification and analysis of the complex I assemblage using BN-PAGE
Quantification of myoglobin in cardiomyocytes using Western-Blot
Cardiac function using echocardiography in pre-, intra- and post-operative periods

Full Information

First Posted
May 17, 2018
Last Updated
July 28, 2022
Sponsor
University Hospital, Angers
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1. Study Identification

Unique Protocol Identification Number
NCT03541213
Brief Title
Impact of Iron Deficiency and Its Correction on Mitochondrial Metabolism of the Cardiomyocyte (MitoCardioFer)
Acronym
MitoCardioFer
Official Title
Impact de la Carence Martiale et de Son Traitement Sur le métabolisme Mitochondrial du Cardiomyocyte (MitoCardioFer)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
January 23, 2019 (Actual)
Primary Completion Date
September 7, 2020 (Actual)
Study Completion Date
September 7, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Angers

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
Iron is involved in essential functions of the body. It allows the transport of oxygen in the blood, via hemoglobin, at the muscular level, via myoglobin, and it is also involved in cellular metabolism in general, in particular for the production of ATP at the mitochondrial level, within the cytochromes and iron-sulfur proteins of the respiratory chain. Recently, iron deficiency has been identified as an important prognostic factor in heart failure patients. Iron therapy improves symptoms and physical performances of heart failure patients, even in the absence of anemia. As a result, the correction of iron deficiency is now proposed as one of the therapies for heart failure. However, the pathophysiology of the association between cardiac dysfunction and iron deficiency is still poorly understood. The investigators previously developed a mouse model of iron deficiency without anemia, in which the investigators observed impaired physical performances, a decrease of left ventricular ejection fraction, and a decrease in mitochondrial complex I activity. These abnormalities were normalized after iron injection. These animal data suggest that iron deficiency is responsible for left ventricular dysfunction secondary to mitochondrial I complex abnormalities, and that iron therapy corrects them. Iron deficiency is very common in the preoperative period of cardiac surgery, affecting 40 to 50% of patients. During this surgery, it is possible to perform a myocardial biopsy without risk to the patient. The purpose of this study is to verify in patients requiring valvular heart surgery, if iron deficiency is responsible for a decrease in mitochondrial complex I activity and a decrease in cardiac function during the perioperative period, and to verify whether iron treatment improves these abnormalities.
Detailed Description
Iron is involved in essential functions of the body. It allows the transport of oxygen in the blood, via hemoglobin, at the muscular level, via myoglobin, and it is also involved in cellular metabolism in general, in particular for the production of ATP at the mitochondrial level, within the cytochromes and iron-sulfur proteins of the respiratory chain. Iron deficiency has been shown to be responsible for fatigue and muscle weakness, regardless of the presence of an anemia. Recently, iron deficiency has been identified as an important prognostic factor in heart failure patients, with a prevalence increasing with NYHA class level, and association with mortality. Iron therapy improves the symptoms of heart failure patients and the 6-minute walk test, even in the absence of anemia. The correction of iron deficiency is now proposed as one of the therapies for heart failure. However, the pathophysiology of the association between cardiac dysfunction and iron deficiency is still poorly understood. The investigators previously developed a mouse model of iron deficiency without anemia, in which the investigators observed impaired physical performances, a decrease of left ventricular ejection fraction, and a decrease in mitochondrial complex I activity. These abnormalities were normalized after iron injection. These animal data suggest that iron deficiency is responsible for left ventricular dysfunction secondary to mitochondrial I complex abnormalities, and that iron therapy corrects them. Iron deficiency is very common in the preoperative period of cardiac surgery, affecting 40 to 50% of patients. During this surgery, it is possible to perform a myocardial biopsy without risk to the patient. There is therefore an opportunity to further explore the impact of iron deficiency and its treatment on mitochondrial energy metabolism of cardiomyocytes. We hypothesize that the activity of the mitochondrial complex I is decreased in the presence of iron deficiency and that the iron treatment corrects this decrease. The purpose of this study is to verify in patients requiring valvular heart surgery, if iron deficiency is responsible for a decrease in mitochondrial complex I activity and a decrease in cardiac function during the perioperative period, and to verify whether iron treatment improves these abnormalities.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Iron-deficiency, Valvular Heart Disease
Keywords
ferric carboxymaltose, mitochondrial metabolism, cardiomyocyte

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
3 groups will be performed depending on the presence or absence of a pre-operative iron deficiency and whether they had an iron treatment preoperatively (before their inclusion in the study). However, patient management will not be different in the different groups from their inclusion in the study. Therefore we can consider that there is a single interventional group.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control group
Arm Type
Other
Arm Description
Patients with no iron deficiency prior to inclusion and who did not receive intravenous iron prior to inclusion. Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)
Arm Title
Iron deficiency group
Arm Type
Other
Arm Description
Patients with iron deficiency who did not receive intravenous iron prior to inclusion. Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)
Arm Title
Iron treated group
Arm Type
Other
Arm Description
Patients with iron deficiency who received intravenous iron prior to inclusion (greater than or equal to 1 g ferric carboxymaltose). Intervention : myocardial biopsy, sternal bone marrow biopsy and blood sample (as in the other arms)
Intervention Type
Procedure
Intervention Name(s)
myocardial biopsy
Intervention Description
Myocardial biopsy (after opening cardiac cavities under general anesthesia for valvular surgery) for mitochondrial metabolism analyses.
Intervention Type
Procedure
Intervention Name(s)
sternal bone marrow biopsy
Intervention Description
Sternal bone marrow biopsy (after sternal opening under general anesthesia for valvular surgery) for the quantification of iron stores
Intervention Type
Biological
Intervention Name(s)
blood sample
Intervention Description
blood sample (under general anesthesia for valvular surgery, using the arterial catheter already in place) for hepcidin quantification (hormone not dosed in the usual martial assessment)
Primary Outcome Measure Information:
Title
Measure of the maximal activity of the mitochondrial complex I using spectrometry
Description
Measure of the maximal complex I activity using spectrometry on isolated mitochondria from myocardial biopsy.
Time Frame
At the time of the myocardial biopsy
Secondary Outcome Measure Information:
Title
Measure of the maximal activity of the others mitochondrial complexes using spectrometry (Complexes II, III and IV)
Time Frame
At the time of the myocardial biopsy
Title
Quantification of the number of mitochondria per cardiomyocyte using Western-Blot
Time Frame
At the time of the myocardial biopsy
Title
Quantification and analysis of the complex I assemblage using BN-PAGE
Time Frame
At the time of the myocardial biopsy
Title
Quantification of myoglobin in cardiomyocytes using Western-Blot
Time Frame
At the time of the myocardial biopsy
Title
Cardiac function using echocardiography in pre-, intra- and post-operative periods
Time Frame
At the time of the myocardial biopsy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Patients that must be operated for a valvular heart surgery (aortic or mitral) scheduled in the month which follows the anaesthesia consultation (visit of inclusion) The preoperative iron status is known Patient signed informed consent Exclusion Criteria: Refusal of the patient to participate Refusal of the surgeon or the anaesthetist who are responsible of patient management Patients with a known iron overload (for example : hemochromatosis) Counter-indication in the realization of a sternal bone marrow biopsy or myocardial biopsy (for example : endocarditis) Adult patients under legal guardianship Pregnancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
RINEAU Emmanuel, MD
Organizational Affiliation
University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Angers - DEPARTEMENT D'ANESTHESIE REANIMATION
City
Angers
ZIP/Postal Code
49100
Country
France

12. IPD Sharing Statement

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Impact of Iron Deficiency and Its Correction on Mitochondrial Metabolism of the Cardiomyocyte (MitoCardioFer)

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