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

Active, not recruiting

• Conditions: Transplant Failure; Heart Transplant Rejection; Antibody-mediated Rejection
• Interventions: Diagnostic Test: Echocardiogram; Diagnostic Test: Cardiac magnetic resonance; Diagnostic Test: Coronary angiography; Diagnostic Test: Endomyocardial biopsy

• Registration Number: NCT05184426
• Lead Sponsor: Juan Francisco Delgado Jimenez

Brief Summary

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

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.

Study Timeline

• Study Start: 2021-04-01
• Study First Submitted: 2021-07-19
• Study First Submitted QC: 2021-12-21
• Study First Posted: 2022-01-11
• Status Verified: 2022-06
• Last Update Submitted: 2022-06-14
• Last Update Posted: 2022-06-21
• Primary Completion: 2024-09-30
• Study Completion: 2029-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. 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.

2. 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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Exposed: Positive anti-HLA antibodies	Cardiac magnetic resonance	Heart transplant patients who have developed antiHLA antibodies after transplant
Exposed: Positive anti-HLA antibodies	Endomyocardial biopsy	Heart transplant patients who have developed antiHLA antibodies after transplant
Exposed: Positive anti-HLA antibodies	Echocardiogram	Heart transplant patients who have developed antiHLA antibodies after transplant
Exposed: Positive anti-HLA antibodies	Coronary angiography	Heart transplant patients who have developed antiHLA antibodies after transplant
Non-exposed: Negative anti-HLA antibodies	Echocardiogram	Heart transplant patients without antiHLA antibodies with similar transplant date to its correspondent case.
Non-exposed: Negative anti-HLA antibodies	Cardiac magnetic resonance	Heart transplant patients without antiHLA antibodies with similar transplant date to its correspondent case.
Non-exposed: Negative anti-HLA antibodies	Coronary angiography	Heart transplant patients without antiHLA antibodies with similar transplant date to its correspondent case.
Non-exposed: Negative anti-HLA antibodies	Endomyocardial biopsy	Heart transplant patients without antiHLA antibodies with similar transplant date to its correspondent case.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Hospital Universitario Puerta de Hierro Majadahonda; 🇪🇸 Majadahonda, Madrid, Spain

Hospital General Universitario Gregorio Marañon; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain