Cardiac Allograft Remodeling and Effects of Sirolimus (CAR)

University of Nebraska

Status and phase

Terminated

Phase 1

Conditions

Cardiac Hypertrophy

Immunosuppression

Treatments

Drug: M-TOR Immunosuppression

Radiation: Cardiac MRI

Other: Cardiac Allograft Remodeling

Genetic: Genetic Mechanism of M-TOR

Other: Cardiopulmonary Exercise Test (CPET)

Procedure: Cardiac Biopsy C4D stain

Procedure: Coronary angiography with IVUS

Study type

Interventional

Funder types

Other

Identifiers

NCT01889992

0339-12-FB

Details and patient eligibility

About

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.

Full 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.

Enrollment

42 patients

Sex

All

Ages

19 to 70 years old

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

42 participants in 7 patient groups

Cardiac biopsy C4D stain

Active Comparator group

Description:

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.

Treatment:

Procedure: Cardiac Biopsy C4D stain

Genetic Mechanism of M-TOR

Experimental group

Description:

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.

Treatment:

Genetic: Genetic Mechanism of M-TOR

Cardiac MRI

Active Comparator group

Description:

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.

Treatment:

Radiation: Cardiac MRI

Coronary Angiography with IVUS

Active Comparator group

Description:

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.

Treatment:

Procedure: Coronary angiography with IVUS

Cardiopulmonary Exercise Test (CPET)

Active Comparator group

Description:

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.

Treatment:

Other: Cardiopulmonary Exercise Test (CPET)

MTor Immunosuppression

Experimental group

Description:

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.

Treatment:

Procedure: Coronary angiography with IVUS

Other: Cardiac Allograft Remodeling

Radiation: Cardiac MRI

Drug: M-TOR Immunosuppression

Cardiac Allograft Remodeling

Experimental group

Description:

A surgical procedure in wich a diseased heart is replaced with a healthy heart from a deceased person.

Treatment:

Other: Cardiac Allograft Remodeling