Identification of Non Invasive Biomarkers of Immune Endothelial Injury and Repair Associated With Cardiac Allograft Vasculopathy

Heart transplantation is the best option for patients with end-stage heart failure. Cardiac allograft vasculopathy (CAV) is the leading cause of death following cardiac transplantation and is not managed by current therapies. Its pathogenesis traduces in an accelerated form of coronary artery disease (CAD) with similarities to atherosclerosis but also particular features of endothelial dysfunction associated to the alloimmune conflict and humoral responses toward the graft. Intravascular ultrasound (IVUS) is the validated invasive method for late CAV diagnosis, but occurs lesions are established. Identification of reliable non-invasive early endothelial injury biomarkers that reflect mechanisms of cardiac damage thus remain a major challenge to optimize therapeutic management of post transplant morbidity. Endothelial dysfunction is a central feature of both CAV and CAD and results from a desquilibrium in the balance of endothelial lesion and repair that is partly controlled by recipient immune system. Through their expression of receptors sensing antibodies (FcR CD16) and endothelial stress-induced signals (CX3CR1 fractalkine receptor and NKG2D MICA receptors), Natural Killer (NK) cells represent effector cells with unique potential to generate both humoral and innate immune injury of graft endothelium.

Study Overview

• Status: Unknown
• Conditions: Cardiac Allograft Vasculopathy
• Intervention / Treatment: Biological: blood samples

• Study Type: Interventional
• Enrollment (Anticipated): 170
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Marseille, France
    • Assistance Publique Hopitaux de Marseille

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject > 18 years at the time of the inclusion,
• Subject having benefited from a heart transplant more than 11 months ago in the service of cardiac surgery concerned whatever is the treatment to immunosuppresseur current
• Subject benefiting from a coronarography within the framework of their surveillance comment-Clerk's Office beyond 12 months
• Subject having given their consent

• Affiliated to the Social Security

  * HTC with Cardiac allograft vasculopathy:

• Subject with coronaropathies diagnosed by the coronarography

  * TC without Cardiac allograft vasculopathy:

• Subject without coronaropathies diagnosed by the coronarography

  * untransplanted

• Untreated Subject by immunosuppresseurs
• Subject without antécédaent of transfusion
• Subject without history of transplantations
• Subject with coronaropathies diagnosed by a coronarography

Exclusion Criteria:

• Presenting a contraindication to the coronarography
• Subject refusing to practise the examination of coronarography
• Subject reaches(affects) of a cancer other one than cutaneous
• Subject achieves of hepatic Incapacity (ALAT and\or ASAT > 3N)

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: HTC with Cardiac allograft vasculopathy; HTC:heart transplanted recipients	Biological: blood samples
Other: HTR without Cardiac allograft vasculopathy	Biological: blood samples
Other: untransplanted	Biological: blood samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of endothelial lesion-repair biomarkers	through phenotypic and quantitative analysis of circulating endothelial progenitors subsets and (repair potential)	24 MONTHS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of anti endothelial NK innate immune responses parameters	Anti endothelial, anti HLA anti MIC antibody detection in recipient' serum by luminex and flow cytometry; Evaluation of soluble Fractalkine and MIC levels in serum through ELISA; Analysis of CX3CR1 and CD16 polymorphism and phenotypic NK cell surface expression; Assay of serum induced and natural NK cell cytotoxicity against coronary and endothelial cell targets	24 MONTTHS

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille

Publications and helpful links

General Publications

• Paul P, Picard C, Sampol E, Lyonnet L, Di Cristofaro J, Paul-Delvaux L, Lano G, Nicolino-Brunet C, Ravis E, Collart F, Dignat-George F, Dussol B, Sabatier F, Mouly-Bandini A. Genetic and Functional Profiling of CD16-Dependent Natural Killer Activation Identifies Patients at Higher Risk of Cardiac Allograft Vasculopathy. Circulation. 2018 Mar 6;137(10):1049-1059. doi: 10.1161/CIRCULATIONAHA.117.030435. Epub 2017 Nov 2.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): May 1, 2014
• Study Completion (Anticipated): November 1, 2014

Study Registration Dates

• First Submitted: February 14, 2011
• First Submitted That Met QC Criteria: April 2, 2012
• First Posted (Estimate): April 3, 2012

Study Record Updates

• Last Update Posted (Estimate): August 29, 2014
• Last Update Submitted That Met QC Criteria: August 28, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: identify early non invasive markers that index the endothelial lesion/ regeneration potential in association with CAV in heart transplanted recipients (HTR)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases
• Other Study ID Numbers: 2010-A01145-34; 2010 18 (Other Identifier: AP HM)