Cardiac Allograft Remodeling and Effects of Sirolimus

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.

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.