Cardiac Allograft Vasculopathy Clinical Trial
— ENERGY-HTXOfficial title:
Cardiac Mitochondrial Function After Heart Transplantation
Verified date | July 2020 |
Source | University of Aarhus |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Observational |
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.
Status | Enrolling by invitation |
Enrollment | 64 |
Est. completion date | March 1, 2024 |
Est. primary completion date | March 1, 2024 |
Accepts healthy volunteers | |
Gender | All |
Age group | 18 Years and older |
Eligibility |
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) |
Country | Name | City | State |
---|---|---|---|
Denmark | Aarhus University Hospital Department of Cardiology | Aarhus |
Lead Sponsor | Collaborator |
---|---|
University of Aarhus | Novo Nordisk A/S |
Denmark,
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* Note: There are 14 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Study 1+3: Differences in Mitochondrial oxidative capacity | Mitochondrial respiratory capacity evaluated with high resolution respirometry, | unpaired comparison differences between groups through study completion, an average of 2 years) | |
Primary | Study 2: Changes in mitochondrial oxidative capacity | Changes in mitochondrial respiratory capacity evaluated with high resolution respirometry, | unpaired comparison differences between groups (through study completion, an average of 2 years) | |
Primary | Study 4: Changes in myocardial external energy efficiency | 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). |
Changes from baseline (following HTX) to 6-month post-HTX (paired data) | |
Secondary | Biochemistry | TNT, proBNP, IL-1, IL-6, TNFalpha, sST2 | Through study completion, an average of 2 years. | |
Secondary | Cardiac function | Left ventricular function (GLS) assessed by echocardiography | Through study completion, an average of 2 years. | |
Secondary | Invasive hemodynamics | Pulmonary (mPAP) and wedge pressures (mPCWP) assessed by right heart catheterization | Through study completion, an average of 2 years. | |
Secondary | Cellular function | 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. |
Through study completion, an average of 2 years. | |
Secondary | Mitochondrial structure | Assessed by electron microscopy (mitochondrial density and matrix folding) | Through study completion, an average of 2 years. |
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