Cardiovascular Journal of Africa: Vol 26 No 3 (May/June 2015)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 3, May/June 2015 AFRICA 107
Heart transplantation has improved over the last 30 years and
has gradually become of increasing importance in the treatment
of end-stage heart failure. Survival after transplantation has
been extended with the use of immunosuppressive agents.
Opportunistic infections, rejection and coronary vasculopathy
in the cardiac allograft have led to the development of new
immunosuppressive agents.7
Cyclosporine and tacrolimus have similar efficacy in protection
against acute rejection in heart transplantation. However, they
have similar nephrotoxicity and cardiovascular adverse events
as well. Cardiac allograft coronary vasculopathy (CAV) is the
best predictor of mortality five years after transplantation
and accounts for 31% of deaths. Keogh found that neither
cyclosporine nor tacralimus prevented the development of CAV,
however, MMF did prevent CAV.8
With the use of immunosuppressive agents since the early
1980s, a dramatic improvement has been observed in the
survival of patients who underwent solid organ transplantation.
Understanding the immune mechanism causing rejection has
led to the development of novel immunosuppressive agents,
which are more immune specific and less toxic, and have better
pharmacokinetic and higher rejection-preventing efficacy.
MMF is an organosynthetic agent. Randomised, non-blind
studies have demonstrated thatMMF prevented acute rejection in
patients who underwent kidney, heart and liver transplantation,
and it could be used in the treatment of refractory rejection.
Different from tacrolimus and cyclosporine, MMF does not
cause neurotoxicity or nephrotoxicity. Compared with other
agents, MMF inhibits B lymphocyte proliferation and reduces
smooth muscle cell proliferation, and consequently may play a
key role in the treatment of chronic rejection. Studies on the use
of MMF in preventing acute rejection in patients who undergo
heart transplantation are ongoing.9
A study presented by Roche Pharmaceutical Company at
the subcommittee meeting of the Antiviral Drug Advisory
Committee (ADAC) comprised 650 heart transplantations, in
which the combination of MMF, cyclosporine and steroids
was used in 289 cases. The study found that MMF was safe
and effective for the prevention of rejection in patients who
underwent heart transplantation.10 As a result, the US Food
and Drug Administration (FDA) has approved the extension of
indications for MMF use for the prevention of organ rejection in
patients undergoing heart transplantation.
Multiple drug therapy based on cyclosporine, steroids
and azathioprine has improved the outcomes of solid organ
transplantation. However, acute rejection episodes are not less
common and influence short- and long-term prognosis after
heart transplantation. The benefits of these agents are limited
by their side effects, such as bone marrow suppression and renal
dysfunction. Mathieu et al.11 retrospectively evaluated clinical
and laboratory analyses obtained from 31 consecutive patients
who underwent heart transplantation between 1996 and 1998 in
the Montreal Heart Institute. It was found that the rejection-free
period was significantly longer in the MMF group, the infection-
free period was similar, and there was no difference between the
groups in terms of infectious agents.
Initial studies recommended MMF because it reduces T and
B lymphocyte proliferation and may decrease the frequency
of acute rejection after renal transplantation. A randomised,
double-blind, multi-centre, placebo-controlled study compared
the reliability and efficacy of MMF. Result showed MMF
was well-tolerated and significantly reduced the incidence of
rejection in the six-month period after transplantation.12
Dipchand et al.13 retrospectively investigated patients who
had undergone paediatric heart transplantation in the Hospital
for Sick Children in Toronto, Canada. Of the 21 paediatric cases
who received MMF, 12 were boys and nine were girls. Indication
for transplantation was complex congenital heart disease in 14,
cardiomyopathy in six and acute viral myocarditis in one case.
The results of MMF were found to be encouraging for recipients
of paediatric heart transplantation.
Rose et al .14 conducted a double-blind study comprising 86
patients from three centres. The control group consisted of
650 patients from 28 centres. The patients randomly received
cyclosporine (CYC) and steroids in addition to MMF or
azathioprine (AZA). The levels of anti-HLA antibodies and
anti-vimentin antibodies of the patients were measured using
enzyme-linked immunoassay. The basis of the study was that
vimentin is the major protein of anti-endothelial antibodies
and the production of anti-vimentin antibodies long term is
an independent risk factor for post-transplant coronary artery
disease. Mean annual anti-vimentin antibody titres were found
to be significantly higher in the AZA than the MMF group.
Pharmacodynamics plays an important role in monitoring
immunosuppression therapy. Previous studies have demonstrated
significant correlation between pharmacodynamics, dose, and
graft histology. A study investigated inhibition of lymphocyte
proliferation and inhibition of expression of clusters of
differentiation (CD) 134, CD71, CD11a and CD25 via flow
cytometry. CYC was evaluated in vivo in rats, alone or in
combination with MMF. Inhibition of lymphocyte function was
assessed after 24 hours and found to be higher in all markers in
the combination therapy compared to CYC therapy. 15
Marcus et al.16 conducted a study to investigate the effects
of CYC, FK 506 and MMF on leukocyte infiltration in grafts
(over CD4, CD8, CD11a, CD18) after cardiac transplantation
in rats. Transplantation was performed in 340 rats, which were
divided into four groups: CYC, MMF, FK 506, and the control
group not receiving immunosuppressive agent. It was observed
that CYC and FK 506 decreased graft leukocyte infiltration
(presence of CD4, CD8, CD11a and CD18 in the perivascular
space and intra- and epicardial arteries) compared to the control
group. It was determined that MMF reduced infiltration more
significantly and acted earlier compared to the other two
calcineurin inhibitors.
Weigel et al.17 conducted a study including 36 patients who
underwent orthotopic heart transplantation. The patients were
divided into two groups, AZA and MMF. Within the groups,
there was no difference between the recipients in terms of age,
gender, indication for transplantation, donor age, and donor
ischaemic period. The control group (n = 15) received CYC,
AZA and prednisolone. The study group ( n = 21) received MMF
instead of AZA three months after transplantation. Activation
markers CD25, CD38, CD69 and human leukocyte antigen
(HLA-DR) (found in B lymphocytes), T cells and natural killer
(NK) cells were measured by flow cytometry.
A significant difference was observed in the reduction of B
lymphocyte counts in the MMF group versus the AZA group.
In addition, the percentage of CD38 B lymphocytes, activated T
lymphocytes (CD4/CD25, CD8/CD38), HLA-DR and NK cells