Endothelial Injury and Development of Coronary Intimal Thickening After Heart Transplantation

September 1, 2017 updated by: Catalin Toma, MD, Gladwin, Mark, MD

Coronary allograft vasculopathy (CAV) is the leading cause of late graft failure and second leading cause of late mortality after heart transplantation. CAV has been associated with a variety of traditional risk factors for atherosclerosis; however, immune mediated injury from development of de-novo donor-specific antibodies after transplantation also likely plays an important role. Similar to the progression of traditional atherosclerosis, it is likely that endothelial dysfunction is the precursor to the development of intimal thickening and CAV.

The investigators hypothesize that coronary allograft vasculopathy after heart transplantation as defined by progressive neointimal hyperplasia is preceded by endothelial dysfunction, which in turn is at least partly mediated by donor specific antibodies.

The investigators are proposing a prospective study in humans to test the above hypothesis and further mechanistically understand how CAV progresses. In this study the investigators will test for coronary endothelial function by infusing acetylcholine into the coronary artery and measure intimal hyperplasia by optical coherence tomography (OCT) and compare findings in patients with and without donor specific antibodies.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • University of Pittsburgh Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Subjects who are 1 year post heart transplantation
  • Subjects will include both male and females
  • Be at least 18 years of age

Exclusion Criteria:

  • Known coronary artery disease after transplantation
  • Evidence of strong or moderate antibodies already present at the time of the transplant
  • Severe renal dysfunction defined as creatinine clearance of <30 or on hemodialysis.
  • 3 or more episodes of acute cellular rejection
  • Females who are pregnant
  • Patients requiring endomyocardial biopsy at the time of catheterization
  • Patients unable to tolerate heparin or systemic anticoagulation
  • History of multi-organ transplant
  • Patients unable to give consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single arm
All subjects will undergo a Brachial Artery Flow Medicated Dilation prior to heart catheterization. After routine heart catheterization, images of their coronary artery will be recorded by Optical Coherence Tomography (OCT) during infusion of Acetylcholine.
Device: Optical Coherence Tomography
OCT imaging of the LAD coronary artery
Other Names:
  • OCT
Drug: Acetylcholine
Infusion in the coronary artery to study endothelial function
Other Names:
  • Miochol
  • Miochol-e
Procedure: Brachial Artery Flow Mediated Dilation
Assess peripheral brachial artery endothelial function

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary endpoint will be a comparison of intimal thickness in the coronary artery by Optical Coherence Tomography with presence or absence of donor specific antibodies.
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Assessment of epicardial coronary endothelial function by measuring change in vessel size in response to acetylcholine and how this compares to peripheral endothelial function.
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years
Prospectively determine the association of HLA and non-HLA donor specific antibodies that activate complement with endothelial dysfunction and intimal thickening.
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years
Gene expression of white blood cells by microRNA and how this relates to endothelial function and intimal thickness.
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years
Plaque characterization in coronary artery by OCT
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years
Natural progression of coronary allograft vasculopathy over first 2 years after transplantation
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years
Comparison of endothelial function in the coronary artery with presence or absence of donor specific antibodies.
Time Frame: baseline (year 1 post transplant) and annually for 2 years
baseline (year 1 post transplant) and annually for 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gladwin, Mark, MD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

September 1, 2014

Study Completion (Actual)

May 1, 2017

Study Registration Dates

First Submitted

May 2, 2013

First Submitted That Met QC Criteria

May 6, 2013

First Posted (Estimate)

May 7, 2013

Study Record Updates

Last Update Posted (Actual)

September 6, 2017

Last Update Submitted That Met QC Criteria

September 1, 2017

Last Verified

September 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO12060201
  • American Heart Association (Other Grant/Funding Number: 14CRP19880025)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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