Cardiac Allograft Remodeling and Effects of Sirolimus (CAR)

August 26, 2023 updated by: University of Nebraska

Cardiac Allograft Remodeling and Effects of Sirolimus on Its Progression

Cardiac allograft remodeling causes poor quality of life, allograft failure and increased mortality after heart transplantation. Risk factors for cardiac allograft remodeling and its progression are poorly defined and there is a need for effective interventions.This is a multi-factorial phenomenon, associated with various immunological and non-immunological factors. Animal studies suggest M-TOR inhibition attenuates cardiac allograft remodeling secondary to down-regulation of M-TOR downstream targets and increased autophagy. There is a paucity of data regarding effect of Sirolimus, a M-TOR inhibitor, on human heart remodeling.

This aim of the proposal to identify the prevalence of cardiac allograft remodeling on current immunosuppressive strategies and determine risk factors for its development. It will also identify molecular pathways associated with cardiac allograft remodeling and determine the impact of Sirolimus on these pathways.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Heart transplantation has become a well-established treatment option for patients with end-stage heart disease and currently has a one-year survival rate of 90%, a five-year survival rate of 70%, and 10-year survival rate of 50%. The introduction of anti-rejection treatment thirty years ago with drugs known as calcineurin inhibitors have resulted in a significant improvement in the survival of heart transplant recipients. However, most of this improvement occurs during the first year after transplantation. Beyond the first year, the mortality rate of heart transplant recipients has not changed, which indicates that the causes of late complications have not been affected in the last three decades by improvements in post-transplant care. It becomes apparent that in order to improve the late outcomes, the focus in heart transplant research needs to be shifted to the prevention and the treatment of late complications.

Cardiac allograft remodeling (CAR), or changes in heart's geometric pattern, is one of the common complications after heart transplantation and often inflicts poor quality of life, heart failure, and decreased survival. The risk factors and mechanism for the development and progression of CAR are poorly defined, and there is no effective treatment for this condition. In the proposed study, we will identify the prevalence, risk factors, and effect of CAR on physical capacity, cardiac vascular disease, and patient survival after a heart transplant. For assessment of heart geometry, we will use cardiac magnetic resonance imaging (CMRI), a techniques used to visualize the internal structures of the body in detail. CMRI is considered as being a "gold standard" for evaluating the heart's structure and function. We will also evaluate the molecular and genetic markers associated with development and progression of CAR after heart transplantation.

The drug Sirolimus, a new anti-rejection agent, can be used in place of calcineurin inhibitors after heart transplantation. Recent experimental and animal studies indicate that Sirolimus can attenuate the changes in the heart's geometry after a transplant (i.e., CAR) and improve heart function. We will assess the effect of Sirolimus on CAR in humans and will evaluate molecular and genetic markers associated with this effect.

It is our goal to provide an important insight into the nature of CAR after heart transplantation and its response to new anti-rejection drug Sirolimus. This information will have a significant impact on the treatment of heart transplant recipients and thus improve quality of life and prolong survival after heart transplantation.

Study Type

Interventional

Enrollment (Actual)

42

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
    • Nebraska
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska 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

19 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • All adult cardiac transplant recipients undergoing heart transplantation at UNMC/TNMC.

Exclusion Criteria:

  • Adult cardiac transplant recipients with acute rejection (ISHLT R> grade 2) or acute infection.

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Cardiac biopsy C4D stain
A procedure that removes a very small sample of your heart muscle so that it can be evaluated in the lab. This procedure may be done to determine the cause of cardiac myopathy (a weakened heart muscle) or to check for rejection after a heart transplant.
Procedure: Cardiac Biopsy C4D stain
A long, thin tube called a biopsy catheter is inserted through a vein in your neck or grion and guided through your blood vessels to your heart.
Other Names:
  • heart biopsy
Experimental: Genetic Mechanism of M-TOR

To identify the molecular and genetic mechanisms associated with development of early post-transplant CAR, and to evaluate the impact of mTOR-inhibitor Sirolimus on this process.

Sirolimus dosage is based on blood levels.
Genetic: Genetic Mechanism of M-TOR
To identify the molecular and genetic mechanisms associated with development of early post-transplant CAR, and to evaluate the impact of mTOR-inhibitor Sirolimus on this process.
Active Comparator: Cardiac MRI
Cardiac Magnetic Resonance Imaging (MRI) produces no side effects from the magnetic fields and radio waves and doesn't carry a risk of cancer or birth defects. Serious reactions to the special contrast dyes used for MRI are very rare. The MRI examination poses almost no risk to the average patient when appropriate safety guidelines are followed, however side effects are possible and include headache, nausea, dizziness, change in taste and allergic reaction. Such reactions usually are mild and easily controlled by medication.
Radiation: Cardiac MRI
1 month post HTx, year 1 and year 2 annual post HTx eval. CMRIs completed using 1.5-Tesla Whole Body MRI system. Scout images will determine short & long-axis views of the heart. ECG-gated cine MR of 3 long axis and a contiguous short axis orientation will be obtained. T1-weighted delayed enhancement images will be obtained 10 minutes after injection of a gadolinium-based contrast agent. Measurements from each slice will be summed using the method of disks. Myocardial mass will be estimated by multiplying the myocardial wall volume at end diastole by the specific gravity of muscle (1.05gm/ml) and LV hypertrophy will be defined as LV mass indexed to height in meters 2.7 >/=35.8 g/m 2.7) (18). Delayed Gadolinium enhancement will be defined as any enhancement pattern greater than 0%.
Active Comparator: Coronary Angiography with IVUS

Coronary angiography is a test that uses dye and special x rays to show the insides of your coronary arteries. The coronary arteries supply oxygen-rich blood to your heart.

Intravascular ultrasound is a test that uses sound waves to see inside blood vessels. This article discusses intravascular ultrasound to see inside the coronary arteries, the blood vessels that supply the heart.
Procedure: Coronary angiography with IVUS

Coronary angiography is a test that uses dye and special x rays to show the insides of your coronary arteries. The coronary arteries supply oxygen-rich blood to your heart.

Intravascular ultrasound is a test that uses sound waves to see inside blood vessels. This article discusses intravascular ultrasound to see inside the coronary arteries, the blood vessels that supply the heart.
Active Comparator: Cardiopulmonary Exercise Test (CPET)
Is a highly sensitive, non-invasive stress test. It is considered a stress test because the exercise stresses your body's systems by making them work faster and harder. A disease or condition that affects the heart, lungs or muscles will limit how much faster and harder these systems can work. A CPET assesses how well the heart, lungs, and muscles are working individually, and how these systems are working in unison. Your heart and lungs work together to deliver oxygen to your muscles, where it is used to make energy, and to remove carbon dioxide from your body.
Other: Cardiopulmonary Exercise Test (CPET)
The Cardiopulmonary Exercise Test is a highly sensitive, non-invasive stress test. It is considered a stress test because the exercise stresses your body's systems by making them work faster and harder. A disease or condition that affects the heart, lungs or muscles will limit how much faster and harder these systems can work. A CPET assesses how well the heart, lungs, and muscles are working individually, and how these systems are working in unison. Your heart and lungs work together to deliver oxygen to your muscles, where it is used to make energy, and to remove carbon dioxide from your body.
Other Names:
  • Stress test
Experimental: MTor Immunosuppression

Sirolimus

Sirolimus dosage is based on blood levels.

To assess the potential of mTOR immunosuppressant Sirolimus in attenuation of CAR in HTx recipients and therefore, improve pre-existing cardiac allograft function, vasculopathy, and exercise capacity.
Radiation: Cardiac MRI
1 month post HTx, year 1 and year 2 annual post HTx eval. CMRIs completed using 1.5-Tesla Whole Body MRI system. Scout images will determine short & long-axis views of the heart. ECG-gated cine MR of 3 long axis and a contiguous short axis orientation will be obtained. T1-weighted delayed enhancement images will be obtained 10 minutes after injection of a gadolinium-based contrast agent. Measurements from each slice will be summed using the method of disks. Myocardial mass will be estimated by multiplying the myocardial wall volume at end diastole by the specific gravity of muscle (1.05gm/ml) and LV hypertrophy will be defined as LV mass indexed to height in meters 2.7 >/=35.8 g/m 2.7) (18). Delayed Gadolinium enhancement will be defined as any enhancement pattern greater than 0%.
Procedure: Coronary angiography with IVUS

Coronary angiography is a test that uses dye and special x rays to show the insides of your coronary arteries. The coronary arteries supply oxygen-rich blood to your heart.

Intravascular ultrasound is a test that uses sound waves to see inside blood vessels. This article discusses intravascular ultrasound to see inside the coronary arteries, the blood vessels that supply the heart.

Other: Cardiac Allograft Remodeling
A surgical procedure in which a diseased heart is replaced with a healthy heart from a deceased person.
Other Names:
  • heart hypertrophy
Drug: M-TOR Immunosuppression

Sirolimus (INN/USAN), also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B-cells by inhibiting their response to interleukin-2 (IL-2).

Sirolimus dosage based on blood levels.

Other Names:
  • Sirolimus
Experimental: Cardiac Allograft Remodeling
A surgical procedure in wich a diseased heart is replaced with a healthy heart from a deceased person.
Other: Cardiac Allograft Remodeling
A surgical procedure in which a diseased heart is replaced with a healthy heart from a deceased person.
Other Names:
  • heart hypertrophy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment in left ventricular hypertrophy
Time Frame: One year
The primary end point will be the change from baseline in LV mass indexed to height in meters 2.7 and LV concentricity as assessed by MRI during 12 months of the treatment.
One year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assess outcomes
Time Frame: One year
The secondary end points will be changes from baseline in LV function.
One year
Access outcomes
Time Frame: One year
Exercise performance (peak VO2, equivalent for carbon dioxide (VE/VCO2)and coronary vessel intimal thickening.
One year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety end points
Time Frame: Three years
Safety end points will be SRL side effects and prevalence of acute cellular cardiac rejection (ISHLT ≥ 2R) and AMR.
Three years

Collaborators and Investigators

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

Sponsor

University of Nebraska

Investigators

  • Principal Investigator: Brian Lowes, MD, University of Nebraska

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 (Actual)

April 24, 2013

Primary Completion (Actual)

September 27, 2018

Study Completion (Actual)

September 27, 2018

Study Registration Dates

First Submitted

June 19, 2013

First Submitted That Met QC Criteria

June 26, 2013

First Posted (Estimated)

July 1, 2013

Study Record Updates

Last Update Posted (Actual)

August 30, 2023

Last Update Submitted That Met QC Criteria

August 26, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0339-12-FB

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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