MuLtimodality EvaluatiOn of aNtibody mEdiated Damage in Heart Transplantation (LEONE-HT)

Study Overview
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Brief Summary
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Cross-sectional evaluation of antibody mediated injury in heart transplantation patients through a multimodal approach: electron microscopy, optic microscopy, immunohistochemistry techniques, transthoracic echocardiography, cardiac magnetic resonance, pressure guide wire, intravascular ultrasound

Detailed Description
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Heart transplant survival has barely improved in the last decades and unsatisfactory for a large proportion of heart transplant recipients. The development of leukocyte antigen antibodies (anti-HLA) in the post-transplant patient is associated to the main causes of graft dysfunction. The mechanisms of this damage are unclear and there's no effective treatment. The investigators aim is to identify early markers of graft injury through a complete morphological and functional evaluation with histological analysis, immunological assays, advanced imaging techniques and invasive evaluation of coronary vasculature in patients with anti-HLA compared to matching controls. The investigators propose a cross-sectional study within a large heart transplant cohort. This is a multicentric observational multimodal study. The investigators aim is to establish early characteristics of antibody mediated damage and set the bases for future studies looking for new treatment targets.

Official Title
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MuLtimodality EvaluatiOn of aNtibody mEdiated Damage in Heart Transplantation (LEONE-HT)

Conditions
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Transplant Failure, Heart Transplant Rejection, Antibody-mediated Rejection

Intervention / Treatment
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* Diagnostic Test: Echocardiogram
* Diagnostic Test: Cardiac magnetic resonance
* Diagnostic Test: Coronary angiography
* Diagnostic Test: Endomyocardial biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Exposed: Heart transplant recipients De novo antiHLA detection (after heart transplant): Mean fluorescence intensity (MFI)) > 2000 for donor-specific antibodies Standard fluorescence intensity (SFI) > 150 000 for non-donor specific antibodies Detailed immunological history: Determination of anti-HLA antibodies before heart transplant. Serial determination of anti-HLA antibodies during heart transplantation follow-up Known HLA typing of the donor. Non-exposed: Heart transplant procedure contemporary to the index case with negative anti-HLA antibodies. Exclusion Criteria: Recipient of a second HT Multiple organ transplantation Unknown immunological history Recipients sensitized with anti-HLA antibodies against donor's HLA before the transplant CMR contrast will not be administered in patients with glomerular filtration rate < 30 ml/kg/1.73m2 Patients with implanted cardiac devices or any other magnetic resonance non-compatible metallic prosthetic material will not undergo CMR.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Exposed: Positive anti-HLA antibodies<br>Heart transplant patients who have developed antiHLA antibodies after transplant | Diagnostic Test: Echocardiogram<br>* Ultrasound study to assess cardiac anatomy and function<br>Diagnostic Test: Cardiac magnetic resonance<br>* MR to assess cardiac anatomy, function and tissue damage<br>Diagnostic Test: Coronary angiography<br>* Cathteterization to assess coronary anatomy. Intravascular ultrasound to obtained a detailed assessment of vessels anatomy. Guidewire pressure to assess microcirculation<br>Diagnostic Test: Endomyocardial biopsy<br>* Optic microscopy, immunofluorescence, transmission electron microscopy<br>|
| Non-exposed: Negative anti-HLA antibodies<br>Heart transplant patients without antiHLA antibodies with similar transplant date to its correspondent case. | Diagnostic Test: Echocardiogram<br>* Ultrasound study to assess cardiac anatomy and function<br>Diagnostic Test: Cardiac magnetic resonance<br>* MR to assess cardiac anatomy, function and tissue damage<br>Diagnostic Test: Coronary angiography<br>* Cathteterization to assess coronary anatomy. Intravascular ultrasound to obtained a detailed assessment of vessels anatomy. Guidewire pressure to assess microcirculation<br>Diagnostic Test: Endomyocardial biopsy<br>* Optic microscopy, immunofluorescence, transmission electron microscopy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histology findings with transmission electron microscopy (TEM) | Detailed description of the antibodies-mediated graft injury depending on exposition-time through a detailed evaluation | 14 days | 
| Histology findings with optic microscopy (OM) | Detailed description of the antibodies-mediated graft injury depending on exposition-time through a detailed evaluation | 14 days | 
| Histology findings with immunohistochemistry (IHQ) techniques. | Detailed description of the antibodies-mediated graft injury depending on exposition-time through a detailed evaluation | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular function (pressure guidewire) | Index of microcirculatory resistance | 14 days | 
| Microvascular function (pressure guidewire 2) | Coronary flow reserve | 14 days | 
| Microvascular function (cardiac magnetic resonance) | Quantitative perfusion evaluation | 14 days | 
| Increased water content (intracellular edema) | T2 recovery times mapping (cardiac magnetic resonance) to detect intracellular edema (endothelial vacuolization) as an early sign of microvascular damage | 14 days | 
| Myocardial fibrosis (cardiac magnetic resonance) | T1 recovery time mapping to identify remodeling and fibrosis secondary to microvascular damage | 14 days | 
| Myocardial fibrosis (cardiac magnetic resonance 2) | Extracellular volumen quantification to identify remodeling and fibrosis secondary to microvascular damage | 14 days | 
| Myocardial fibrosis (echocardiography) | Global longitudinal strain to identify remodeling and fibrosis secondary to microvascular damage | 14 days | 
| Serum markers of fibrosis | FGF - 23, PICP, PIIINP, galectin-3, soluble-ST2 as serum/plasmatic markers of fibrosis and remodeling | 14 days | 
| Coronary allograft vasculopathy (CAV) | Fractional flow reserve (coronary physiology) as early marker of CAV | 14 days | 
| Coronary allograft vasculopathy (CAV 2) | Intimal thickness (intravascular ultrasound) as early marker of CAV | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart transplant, Anti-HLA antibodies, Magnetic Resonance, Echocardiogram, Transmission electron microscope