Page 218 - Read Online

Page 2 of 14 Jagpal et al. Vessel Plus 2018;2:24 I http://dx.doi.org/10.20517/2574-1209.2018.27

INTRODUCTION
Over the past 50 years, heart transplantation has evolved to become an acceptable treatment for end-stage
heart failure. Immunosuppression has been pivotal to the success of this procedure. Many drugs have been
involved in post-transplant immunosuppressive regimens. However, current guidelines recommend the use
of calcineurin inhibitors, tacrolimus and ciclosporin. Due to the potency of these drugs, patients are prone
to a variety of side effects including diabetes. Preventing post-transplant diabetes mellitus (PTDM) is an
important element of successful immunosuppression in cardiac transplantation, as uncontrolled diabetes
is associated with cardiovascular morbidity and mortality. This can be detrimental to heart transplant
recipients as they are already at risk of cardiac allograft vasculopathy (CAV).

The aim of this paper is to retrospectively analyse the possibility of developing diabetes mellitus in heart
transplant patients who have been treated with either a ciclosporin or tacrolimus-based regimen. This will
be done by focusing on fasting glucose and HbA1c levels in 52 patients up to a year after transplantation.

History of heart transplantation
[1]
In 1967, Barnard performed the first successful human-to-human heart transplant in Cape Town, South
Africa. The techniques used during this operation were created by Dr. Norman Shumway several years
[1]
earlier and are still used in modern times . Although a breakthrough in science at the time, the patient
[1]
died of Pseudomonas pneumonia on the 18th day postoperatively . This highlighted concerns surrounding
immunosuppressive regimen, an issue which would remain prevalent for subsequent years.
[1]
A year on from Barnard ’s success, more than 100 cardiac transplants were performed at transplant centres
around the world. But due to the high risk of complications, the procedure soon declined with only 9 taking
[2]
place in 1971. During this time, one-year survival was 30% . A key advancement in rejection monitoring
[4]
[3]
was the introduction of endomyocardial biopsy and the classification of histological rejection . This
allowed clinicians to combine clinical and histological findings to make the diagnosis of rejection more
accurate. Worldwide interest in heart transplantation was revived in the 1980s after an immunological
milestone, the introduction of ciclosporin A.

[5]
Between April 2016 and March 2017, 197 heart transplants were performed in the UK with one-year
[6]
survival over 80% . This is a testament to the progress made since the 1970’s. Nevertheless, there are still
serious challenges facing the field, limiting the success of heart transplantation. Such barriers include
CAV, a type of chronic rejection that results in hardened arteries. This can compromise long term survival
of the cardiac allograft and ultimately lead to cardiac arrest. Another major barrier is created by chronic
[7]
immunosuppression, which can result in drug induced complications including diabetes mellitus .

Overview of rejection immunology
Complex mechanisms of immunity pose a significant barrier to successful transplantation. In cardiac
transplantation, the response to alloantigens is mediated by host T-cells. Peptide antigens are presented
[8]
to T-cell receptors in the context of major histocompatibility complex, by antigen-presenting cells . This
binding leads to an increase in cytoplasmic calcium ions, which in turn activates the protein phosphatase,
[9]
calcineurin. When activated, calcineurin dephosphorylates nuclear factor of activated T-cells (NFAT) .
Following this, NFAT triggers the upregulation IL-2 expression, leading to T-cell stimulation.

The adaptive response is efficiently suppressed by conventional drugs. But, when unsuccessful, alloimmune
response can lead to destruction of the allograft (rejection). Rejection is categorised into three major types:
hyperacute, acute and chronic. Due to effective screening (HLA and ABO blood-group cross-matching)
[10]
on transplant recipients, hyperacute rejection is rare . Although acute and chronic rejection are more
common, the mechanisms involved are incompletely understood. There is, however, a variety of immune-
[11]
system components involved, including the T-cell response mentioned above .