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Heart Transplant
Keywords
Summary
heart transplant, immunosuppression,
Of many medical crises in cardiology, heart transplant seems
pediatric, rejection.
to prevail despite various complications. It is obvious that
heart transplant is not a cure nor complications cease to occur. Over
two decades, several advances have been resulted in median
survival for infants undergoing heart transplantation and less
progress in improved outcomes. Unfortunately, a donor’s heart does
wilt as the immune system is likely to reject. The immune system is
thus complicated as it enables the body to fight against foreign
bodies either disease microbes or transplanted organisms that’s not
genetically identical. Thereof, the transplanted heart is substituted
as a bacteria or virus which becomes rejected. In site, many pediatric
patients are prone to such rejection, increasing mortality and
morbidity to an irrational count after cardiac transplant. Based on
studies on these rejections, each rejection does vary one another as
they might be avoided during and after heart transplant.
Background
Heart transplant has grown to be a therapeutic strategy for patients with heart failure and
respectively offers improved quality life and survival. Many various techniques have been used
to ensure safety and survival of pediatric patients, however in the case of rejection, death rate has
enormously been reviewed. This process whereby recipient’s immune system attacks the
transplanted organ is quite harmful as substances like antigens coats organ surface, therefore,
Rejection in pediatric after heart transplant
immune system respond by attacking the transplanted organ as it detects it to be foreign (virus or
bacteria).37
Although diagnosis has been procured, endomyocardial biopsy seems to be a standard
method to monitor rejection, and due to long-term outcomes after a heart transplant, many other
models have been considered by most researchers to improve rejection after a heart transplant in
pediatric patients. These are immunosuppressive, surgical techniques, transplant selection, and
postoperative care.39
Hence, with respect to plausible rejections in pediatric patients after a heart transplant,
outcomes, limitation, diagnosis, future perspectives, treatments, and other variations will rational
clinical and literature studies to better improve and minimize the rate of mortality and morbidity
in rejection.
Types of Rejection
Acute cellular rejection is the most common rejection which appears at any time and
generally develops within the first 3-6months after transplantation. Analysis of studies shows
that a T cell with a major role in pathogenesis is likely to respond to donor HLA antigens. Mild
symptoms such as fatigue or shortness of breath are often noticed in patients.1 In as much as this
persist, induction and maintenance therapies must be applied to prevent acute cellular rejection in
pediatric heart transplant. Prophylactic immunosuppression must be used at the time of
transplantation to minimize any early rejection. And maintenance therapy may be started at the
time of transplant without the induction therapy.1, 2 Based on recent reports, acute cellular
rejection does occur in patients within the first 6months who substantially were rejected early
after transplantation, are likely to reduce in immunosuppression, exposed to inter-current
Rejection in pediatric after heart transplant
infection, or noncompliance with medication.1 On the other hand, hyperacute rejection
demonstrates a significant effect in pediatric heart transplant patients. As this rejection occurs
graft tissues are protected with the use of a triple-drug immunosuppression regimen. These drugs
calcineurin inhibitor, an antiproliferative agent, and corticosteroid are used to prevent allograft
rejection by suppressing the immune system at multiple different levels.3 However, induction
therapy are strategized with anti-T cell antibodies whereby additional rejection prophylaxis
immediately follow. And these antibodies enhance immunosuppression as T-cell pool or
blocking interleukin-2 receptors are depleted of activated T cells.3 Furthermore, chronic
rejection dated to be a multi-factor is associated with antibodies as well as lymphocytes.
Currently, diagnose for this rejection is a heart biopsy. This can occur over the years. And with
the body constant immune response against foreign organs, the transplanted heart rapidly
develops thus, hardening of the arteries.1 Although biopsies begin two weeks after
transplantation, it becomes less frequent over time and uncertain intense immunosuppression
would improve or get worse prescribed medications are required.1
Clinical Manifestation
Few months after rejection, pediatric patients are more likely to have symptoms that the
body rejects the donor’s heart. Corresponding studies have shown acute rejection in patients after
heart transplant are likely to feel tired, shortness of breath, irregular heartbeat, low blood
pressure, reduced urine, loss of appetite.4 Aside this, other rejections doesn’t often have any
symptoms though a heart attack is critical. The impediment of the immune system also results in
cancer risk, which exposes patients to tumors and non-Hodgkin's lymphoma, among others; as an
immunosuppressant decrease to fight infections, patients are evident to such risk, and abnormal
circulation of blood can cause a sudden cardiac death.6
Rejection in pediatric after heart transplant
Diagnosis of Rejection
In spite of the various diagnoses of rejections, rejection has affected pediatric patients as
mortality and morbidity increases exponentially after a heart transplant. Even the most effective
are limited. Endomyocardial biopsy [EMB] a clinical tool in diagnosing acute cellular rejection,
is used to lessen the extent abnormal systolic in patients after cardiac transplant has been refined
and perfected. Although this technique might be efficient, it is invasive with a risk. In this
controversy, studies indicate that patients are dependent on variables to survive based on his or
her clinical state, expertise in operation, and cardio-pathologist. This safely lowers morbidity in
pediatric heart transplant recipients.6 Chronic rejection also is known as cardiac allograft
vasculopathy [CAV] has been affected by nonimmune donor and recipient factors which include
hyperlipidemia, cytomegalovirus infection, and baseline coronary artery disease. Diagnose like
immunosuppressive therapies initiated by researchers are able to reduce the development of
cardiac allograft vasculopathy in the long term.10 Immunosuppressant contains microbial
substances in which protein properties such as polyclonal and monoclonal are identified to be
antibodies. These antibodies respond to the immune system by depleting circulated T cells,
modulation of cell surface receptor molecules, induction of anergy, and apoptosis of activated T
cells posing a higher risk for patients to develop an infection and malignancy after
transplantation.9
Hyperacute rejection due to the presence of preformed recipient antibodies which is
directed against human leukocyte antigen (HLA) class I molecules is constitutively expressed on
the donor vascular endothelium. This can be induced by inflammation and trauma, and also nonHLA endothelial antigens may lead to hyperacute rejection.9
The table below summarize the diagnosis of each rejection after heart transplant:-
Rejection in pediatric after heart transplant
Table 2. Diagnosis of Rejections
Rejection
Acute Cellular
Diagnosis
Endomyocardial biopsy
Chronic
Immunosuppressive
therapies
Hyperacute
Inflammation and trauma
associated with graft
procurement and
preservation
Limitations
small number of
patients with
significant ACR
diffuse nature of
the disease
preformed
antibodies
Traditional Method
As rejection after heart transplant prose a threat in pediatric patients as the immune
system dictates the heart as a virus, thus, releasing white blood cells to destroy it. Many studies
indicate endomyocardial to be a traditional model of rejection. A clinical tool designed for posttransplant myocardial is widely used for both acute and chronic rejection. This tomographic
technique is held with extreme care to ensure adequate tip visualization. Granting utmost safety,
EMB is inclined to risk of procedural complications and long-term sequelae when constantly
performed (tricuspid regurgitation).11 Therefore, EMB is recommended to be performed in
young patients (strong myocarditis), and recognized to be 1% less in acute complications than
flexible biotopes. Notwithstanding, endomyocardial biopsies is associated with internal injuries
such as artery injury, arrhythmia, perforation of the heart, infection, scarring and even death.12
Hence, EMB is usually used on heart transplant recipients with immediate check-up in
rejection.11, 12 However, with more advanced imaging techniques in diagnosing fewer heart
disorder, is likely to replace EMB, and cellular function of a patient might also be replaced with
gene expression profiling.
Rejection in pediatric after heart transplant
Modern Method
Through surgical procedures, decreased hearts have been operated and replaced with
healthy ones. When a patient is exposed to rejection, the circulatory system which provides
enough oxygen and nutrients throughout the body is disrupted. Thereof, the immune system
prompts to attack any foreign antigens. With this, modern immunosuppression drugs mediated to
deactivate the immune system have helped minimize the rate of mortality and morbidity in
rejection after heart transplant. Few of these are:As white blood cells tend to regulate and trigger immune responses, the Ciclosporin is
thus used to reduce the activity of the patients’ immune system. The de-activity of the T and Blymphocytes from producing substances such as lymphokines; attracting and activating other
immune cells and stimulating the production of antibodies efficiently prevents re-occurring
immune responses respectively.13 In depth to eliminate death during cardiac transplantation,
another chemical immunosuppression drug called Tacrolimus is used to prevent rejection after
pediatric heart transplant. This immunosuppressant is made to prevent an enzyme “calcineurin”
which pose a threat to the T-cells. During transplantation, steroids are being regulated by
surgeons and so side effects are limited for a long period of time.13, 14
A chemical immunosuppression (Mycophenolate acid) also prevents an enzyme inosine
monophosphate dehydrogenase and multiplies B- and T-cell; and this is used to maintain
immunosuppression and chronic rejection. Due to the presence of guanosine salvage pathways in
other cells, the mycophenolate acid blocks lymphocyte as it increases, thereby, blocking DNA
synthesis.13 In as much as rejection is at risk in pediatric heart transplant, immunosuppression is
efficient in induction therapy. In this modern method, immunosuppression doses is used to
lower maintenance level, and improve the use of a biological agent such as a monoclonal or
Rejection in pediatric after heart transplant
polyclonal antibody, at brisk after surgery.13,1 5 As a result, from many studies, it has been proven
that patients on an intense immunosuppressive treatment are at risk of developing lymphomas
and other cancers, increase of potassium in the bloodstream, and immune system becomes
vulnerable to infections.14
Pharmacology of Immunosuppressant Drugs
Evaluating these mechanisms, the lymphocyte depletion is able to recover in the presence
of foreign antigen, which favors unresponsive antigens during the recovery period. Hence,
depletion strategies are likely to be associated with morbidity, thereof, immune system is made
unstable as abnormal functional capacity is plausible due to incomplete recovery with intense
immunodeficiency.18, 20, 23 As recent studies exhibit T-cells do not reject transplanted, the
structure of lymphoid organs becomes acute to the immune system, thus, the lymphoid tissue is
damaged.
Regardless, antigens are prone to lymphoid tissues in which the immune response is
activated, and this activated lymphocytes rationally trigger the graft site and as well rejection is
affected. Although little is known about the effects of most ISDs of traffic of antigen-presenting
cells and lymphocytes, it is detrimental to rejection as impounding traffic of lymphocytes are
actions to many developments among these immunosuppressive agents.18, 19, 20, 23
Also, altering the function of lymphocytes might be the main mechanism of action. As
stated from literature, the sites of action of ISDs on lymphocyte function include blocking CD3
and its role for example, in signal transduction (anti-CD3); blocking calcineurin [tacrolimus
(TAC) and cyclosporine (CsA)]; altering cytokine transcription [glucocorticosteroids (GC)] and
so on.18, 23
Rejection in pediatric after heart transplant
Based on previous statements, immunosuppression aims to deactivate all immune
response, therefore, rejection is prevented. Due to the end-stage heart failure, development of
drug regime is reserved to limit immune response. Thus, a concise diagram shows the
mechanism of these immunosuppressive agents below.19, 20
Figure 1. Mechanism of Action of Immunosuppressive Drugs
Ab = antibody; APC = antigen-presenting cell; CD = complementarity determining region; IL-2
= interleukin-2; IL-2R = interleukin-2 receptor; MHC = major histocompatibility complex; MMF
= mycophenolate mofetil; mRNA = messenger ribonucleic acid; NFAT = nuclear factor of
activated T cells; TCR = T-cell receptor; TOR = target of rapamycin
Nature Clinical Practice Cardiovascular Medicine17
Over board by complexity, immunosuppression drugs have become an effective strategy
to prevent these rejections. In a general disclose, these drugs have been evaluated to influence
Rejection in pediatric after heart transplant
many appropriate scenarios in therapy induction. With a brief overview, the efficacy of these
immunosuppressant aids in reducing the risks of rejection, toxicity, and prospective trials made
to enhance heart transplant in pediatric patients. Though confounding factors are stated in several
manuscripts, the introduction of improved immunosuppressant agents is widely used in rejection,
and listed below.18
Table 3. Summary on the most commonly used drugs, their targets, selectivity, and main
side effects18
Method
Target
Major side effects
Selectivity
Steroids
Lymphocytes/RES
Osteoporosis,
+
diabetes, psychosis,
infection, obesity
Azathioprine
Lymphocytes
Marrow suppression,
++
hepatopathy
Polyclonal
T lymphocytes
Infection,
++
malignancies
antithymocyte
globulin
Monoclonal CD3
antibodies
CD3+ T lymphocytes
Infection,
malignancies
+++
Rejection in pediatric after heart transplant
Mycophenolate
De novo purine
Gastrointestinal
++++
Nephropathy
++++
Nephropathy
++++
None
++++
synthesis in
lymphocytes
Cyclosporine
IL2 inhibition in T
lymphocytes
Tacrolimus
IL2 inhibition in T
lymphocytes
Daclizumab
IL2 receptor
antibodies
Further Research
Ongoing research in rejection has led researchers to find better tools to reduce mortality
and morbidity in pediatric patients after heart transplant. This disorder that attacks and destroys
the immune system of a patient when a new organ is being replaced (harmful virus or bacteria),
does detect and small pieces of transplanted heart are cut, and endomyocardical biopsy is used to
examine dead cells.24, 25, 26
Current studies does show a new test used to diagnose rejection in pediatric patients.
Researchers at Stanford University discovered that dying cells are able to release small pieces of
DNA within rejected heart.24 This so called “Cell-Free” derived DNA (cfdDNA) can be detected
through blood samples. This new technique is used to determine whether or not a heart
transplanted will be rejected. Thus, through sequencing and quantification of cfdDNA,
Rejection in pediatric after heart transplant
researchers are able to examine its effectiveness and monitor as well patients who receives the
heart transplant. In this procedure, blood samples were collected from patients and their heart
donors, and their cell-free circulating DNA was also sequenced. This included single nucleotide
polymorphisms (SNPs); common single nucleotide (A, T, C or G) which varies in the DNA of a
person to another. 24, 25
After researchers had measured changes over time in the sequence and abundance of
immunoglobulin heavy chains in the patients, the measurements of the immune repertoire
provide an accurate and sensible way to manage immunosuppression. Thereof, parts of antibody
related to activate B cells were inversely related to the level of tacrolimus in the patients’ blood.
And this antibody was able to detect immune activation through small pieces of the donated
heart or by looking for donor-derived DNA in the recipients’ blood.24, 25, 27, 28
Although with a larger conceptions, this study does confirm the sequencing of the
immune system to predict rejection, and immunosuppressive therapy is personalized through
repertoire sequencing without incurring risk, discomfort, and expense of an invasive biopsy.24
Future Perspective
Base on literature studies, advances in immunosuppressive therapy have been remarkable
in minimizing steroids and calcineurin inhibitors. And with noninvasive rejection monitoring, it
is said that post-transplant in patients will be increased, thus, incidence of atherosclerotic and
other disorder is reduced. Likewise, in future management of rejection, it needs certain decision
makings, communications training, support, quality of life measures are required in order to
provide both medical and device treatments for pediatric patients. Through education and
Rejection in pediatric after heart transplant
aggressive management, a decrease in the number of recipients and an increase in donors will
help eliminate further risk of rejection in pediatric patients after heart transplant.29, 30
Conclusion
Overall, we must consent to the fact that transplanted heart is a living tissue that grows
normally within pediatric patients. And so, with the use of steroid-free immunosuppressive
regimen, patients’ growth will be in a normal range. Hence, patients who experience early
rejection are at higher risk and with several risk factors, such as frequency of rejection screening,
strategies, intensity of immunosuppression, educating patients and family about early signs of
rejection are ultimately beneficial. Though gaining more concrete insight on individuals’ genetic
and environmental risk factors, these rejections and advance immunosuppression on variables
will further a better understanding in the future as immune systems are tolerant. Thus, mortality
and morbidity are reduced under pediatric heart transplantation.
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