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Cardiac Mitochondrial Function After Heart Transplantation (ENERGY-HTX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04105803
Recruitment Status : Enrolling by invitation
First Posted : September 26, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:

Studies have shown that cardiac function is affected immediately after heart transplantation (HTx), but seems to recover to some extent over the first year. This immediate effect is associated with lack of oxygen in the tissue and reperfusion injury causing cellular energy depletion, mitochondrial failure and cellular damage. This condition may progress into full blown primary graft failure (PGF), characterized as deterioration of the transplanted heart, which is seen in 3-30 % of HTx patients. In addition to PGF, chronic rejection owing to cardiac allograft vasculopathy (CAV) may develop.

PGF and CAV remain the major heart related mortality causes, and additional assessment and treatments are therefore needed.

Acute cellular rejection (ACR) is diagnosed based on endomyocardial biopsies (EMB), which are routinely performed to ensure prober immunosuppression in HTx patients. ACR occur in approximately 25% of HTx patients, and is associated with PGF and CAV. However, mitochondrial function and integrity may prove to be a more sensitive marker of allograft rejection than endomyocardial biopsies. Therefore, assessment of mitochondrial function may allow for earlier detection of allograft rejection and dysfunction. This may be of particular importance as emerging treatments are targeting both energy substrate supply for adenosine-triphosphate generation produced by the mitochondria and mitochondrial function in the failing heart.

Despite the association between graft rejection and mitochondrial function, it remains unsettled whether mitochondrial function associate with PGF, ACR and CAV. Such findings may be of prognostic importance and even elucidate new treatment targets. Hence, we evaluate the mitochondrial status in HTx patients through four studies designed to assess different aspects of the interplay between cardiac function and mitochondrial integrity and function.

Hypotheses:

Study 1: Primary graft pump function is correlated to mitochondrial function in the first myocardial biopsy taken from the donor heart during the operation.

Study 2: Cardiac mitochondrial function improves over the first 3 months after a heart transplantation.

Study 3: Heart transplant patients with moderate to severe coronary graft vasculopathy has impaired mitochondrial function.

Study 4: Myocardial external energy efficiency by positron-emission tomography can be used as a marker of mitochondrial function and chronic rejection in HTx patients.


Condition or disease
Cardiac Allograft Vasculopathy Acute Cellular Graft Rejection Primary Graft Failure Mitochondrial Function

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Study Type : Observational
Estimated Enrollment : 64 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Cardiac Mitochondrial Function After Heart Transplantation
Actual Study Start Date : April 25, 2019
Estimated Primary Completion Date : March 1, 2024
Estimated Study Completion Date : March 1, 2024

Resource links provided by the National Library of Medicine


Group/Cohort
De novo HTx

Procedure: Two perprocedural biopsies under transplantation is performed from the left ventricular septum.

Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit).

Procedure: is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients.

Diagnostic test: Echocardiography and coronary angiography is part of the scheduled standard HTx follow-up visits.

Longterm HTx

Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit).

Procedure: Coronary Angiography is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients.

Diagnostic test: Echocardiography is part of the scheduled standard HTx follow-up visits. No additional examinations will be performed. We will use the standard recordings to calculate the desired parameters.

PET-scan de novo HTx

Radiation: Two PET-scans with 11C-acetate tracer will be performed.

Procedure: Two perprocedural biopsies under transplantation is performed from the left ventricular septum.

Procedure: Endomyocardial biopsies from the right ventricular septum, taken at scheduled standard HTx follow-up visits at our department (protocol is to take 4-5 biopsies, two additional biopsies will be taken at this visit).

Procedure: Coronary Angiography is part of the scheduled standard HTx follow-up visits. This recording will be used for CAV evaluation. In addition to the protocol procedure, we will evaluate the hemodynamic status in the patients.

Diagnostic test: Echocardiography is part of the scheduled standard HTx follow-up visits. No additional examinations will be performed. We will use the standard recordings to calculate the desired parameters.




Primary Outcome Measures :
  1. Study 1+3: Differences in Mitochondrial oxidative capacity [ Time Frame: unpaired comparison differences between groups through study completion, an average of 2 years) ]
    Mitochondrial respiratory capacity evaluated with high resolution respirometry,

  2. Study 2: Changes in mitochondrial oxidative capacity [ Time Frame: unpaired comparison differences between groups (through study completion, an average of 2 years) ]
    Changes in mitochondrial respiratory capacity evaluated with high resolution respirometry,

  3. Study 4: Changes in myocardial external energy efficiency [ Time Frame: Changes from baseline (following HTX) to 6-month post-HTX (paired data) ]

    Changes Myocardial external energy efficiency evaluated by PET-scans with 11C-acetate tracer.

    Calculated by the ratio of myocardial external work (EW) and oxidative metabolism (MVO2).



Secondary Outcome Measures :
  1. Biochemistry [ Time Frame: Through study completion, an average of 2 years. ]
    TNT, proBNP, IL-1, IL-6, TNFalpha, sST2

  2. Cardiac function [ Time Frame: Through study completion, an average of 2 years. ]
    Left ventricular function (GLS) assessed by echocardiography

  3. Invasive hemodynamics [ Time Frame: Through study completion, an average of 2 years. ]
    Pulmonary (mPAP) and wedge pressures (mPCWP) assessed by right heart catheterization

  4. Cellular function [ Time Frame: Through study completion, an average of 2 years. ]

    Rejection state in cardiac tissue (assessed on the international scale for tissue rejection by pathologist):

    Grade 0R - No rejection. Grade 1R, mild - Interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage.

    Grade 2R, moderate - Two or more foci of infiltrate with associated myocyte damage.

    Grade 3R, severe Diffuse infiltrate with multifocal myocyte damage ± edema, ± hemorrhage ± vasculitis.


  5. Mitochondrial structure [ Time Frame: Through study completion, an average of 2 years. ]
    Assessed by electron microscopy (mitochondrial density and matrix folding)


Biospecimen Retention:   Samples With DNA
Blood samples and endomyocardial biopsies.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
HTx patients Patients older than 18 years old can be included in this study provided that they give written consent. Pregnant women will not be included in study 4 because of a risk of genetic modifications based on the radiation from the PET-scans.
Criteria

Inclusion Criteria:

  • Informed consent from participants

Exclusion Criteria:

  • Under 18 years of age
  • Endomyocardial biopsy not feasible assessed by surgeon
  • Pregnancy (Study 4 only)
  • Myocardial infarction, or hospitalization within 1 month due to any cardiac cause (Study 4 only)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04105803


Locations
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Denmark
Aarhus University Hospital Department of Cardiology
Aarhus, Denmark, 8200 Aarhus
Sponsors and Collaborators
University of Aarhus
Novo Nordisk A/S
Investigators
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Principal Investigator: Hans Eiskjær, Prof. Aarhus University Hospital

Publications:

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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT04105803    
Other Study ID Numbers: 1-10-72-367-18
First Posted: September 26, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Vascular Diseases
Cardiovascular Diseases