What is Heart Transplantation Rejection?
Heart transplantation is a medical procedure used to treat patients suffering from very severe heart failure. This operation is only considered for these patients when all other treatments, like medicines or device therapies, have not relieved their symptoms. The International Society for Heart and Lung Transplantation laid out guidelines in 2016 to help identify which patients are potential candidates for a heart transplant.
Thanks to careful patient selection and medical treatments to suppress the immune system after the transplant, the chance of success following a heart transplant has improved. Despite this progress, one of the key challenges of heart transplantation is still the potential for the body to reject the new heart, which is referred to as heart transplantation rejection (HTR).
Rejection of the new heart can occur at any given time – it can happen as soon as during the operation or many years later. When rejection happens and how long it happens after the transplant can be really important in determining the cause and figuring out what’s going on. If HTR happens within the first 24 hours after surgery, it’s called early graft dysfunction. If it happens weeks to years following the procedure, it’s referred to as late graft dysfunction.
What Causes Heart Transplantation Rejection?
The reason for heart transplant rejection (HTR) can depend on when the rejection happens. Rejection can occur early after the transplant, and it can be primary or secondary.
Primary graft dysfunction (PGD) is when the new heart doesn’t function properly from the start because it’s unable to pump blood efficiently. This condition can lead to shock and require additional medical support to maintain the blood circulation, even when there’s no immune response or other identifiable reasons. However, a universally accepted definition for PGD is still not available. Some factors that can contribute towards the development of PGD include:
1. Existing heart disease in the donor’s heart
2. Damage to the heart immediately after transplant
3. Injury to the new heart during the process of organ retrieval, conservation, and implantation.
Secondary graft dysfunction is a form of early rejection that happens due to identifiable reasons, such as:
1. Very fast rejection of the new heart
2. An increased work for the right side of the heart, caused by more blood or pressure
3. Unnoticed high blood pressure in the lungs of the recipient
There’s also a form of rejection that can happen later, called acute allograft rejection, and it can be cellular or antibody-mediated. This type of rejection has a higher risk in younger patients, female donors or recipients, and when there’s a greater mismatch in human leukocyte antigen (HLA, a type of protein on your cells that can cause an immune response).
A condition called cardiac allograft vasculopathy (CAV), a disease of the blood vessels in the new heart, can also result in rejection. It’s more likely when the recipient has high cholesterol, a certain viral infection (cytomegalovirus), insulin resistance, coronary heart disease in the donor’s heart, the recipient being younger, or a history of acute rejection.
Other potential reasons for the failure of the new heart can include a recurrence of heart diseases like amyloidosis, sarcoidosis, giant cell myocarditis, genetic iron overload (hereditary hemochromatosis), and cancers like primary cardiac lymphoma.
Risk Factors and Frequency for Heart Transplantation Rejection
In 2015, the International Society for Heart and Lung Transplantation reported that 5,074 heart transplants were done. People who received heart transplants from 1982 until June 2015 lived on average 10.7 years (for adults) and 16.1 years (for children). The number of adults surviving after a heart transplant is 94.8% after 1 year, 84.1% after 5 years, and 72.3% after 10 years. The number of heart transplant rejections has decreased by using drugs to suppress the immune system. Rejection decreased from 30.5% in 2004-2006 to 24.1% in 2010-2015.
Approximately 20-40% of patients may face a specific problem called primary graft dysfunction (PGD) after a heart transplant. In 2018, a six-year follow-up study found a PGD rate of 31%. However, another study in 2011 reported a lower rate of 23%. Deaths caused by the new heart being rejected (acute allograft rejection) are as high as 11% in the first three years after transplantation. Almost half of patients showing signs of heart rejection seven years after transplantation are showing symptoms of a specific type of rejection caused by antibodies. Coronary artery vasculopathy, a heart condition, can develop over time in heart transplant recipients and is the primary cause of death between the first and third year post-transplantation, making up for 17% of deaths after the third year.
Signs and Symptoms of Heart Transplantation Rejection
When assessing someone who has had a heart transplant, it’s important to get a detailed medical history and do a physical check-up. Part of this process involves looking at the patient’s medication history and whether they’ve been consistently taking their immunosuppressant therapy. A change in the way their heart ventricles are functioning could be a warning sign of possible transplant rejection.
The time frame of when they start experiencing rejection can also provide a hint towards the diagnosis. People often complain about symptoms like:
- Orthopnea (difficulty breathing when lying down)
- Shortness of breath
- Paroxysmal nocturnal dyspnea (waking up from sleep, gasping for breath)
- Sudden fainting (syncope)
- Feeling your heart racing or fluttering (palpitations)
- Nausea or loss of appetite
- Weight gain
- Swelling in the body (edema)
- A type of irregular heart rhythm (atrial flutter)
- Reduced urine output (oliguria)
- Low blood pressure (hypotension)
The physical examination might reveal signs of heart failure as well. These can include higher than normal jugular vein pressure, extra sounds heard when the doctor listens to the heart with a stethoscope, and swelling in the arms and legs.
Testing for Heart Transplantation Rejection
If certain symptoms and signs are present, they could indicate the presence of heart transplant rejection (HTR). It’s usually discovered during routine heart biopsies. These are typically conducted in the initial stages after a heart transplant – weekly for the first month, bi-weekly for the next one and a half months, and then monthly for about three to four months. After that, they are done every three months for the remainder of the first year.
From research, routine heart biopsies after the first year have not proven to be necessarily beneficial. A study recommends event-based biopsies three years post-transplant due to a low rejection rate. The diagnosis is based on certain tissue changes noticed during the biopsy. However, in up to 20% of cases, the biopsy may not show rejection even when it is happening. This calls for additional monitoring measures.
These other methods of monitoring can include checking levels of certain proteins in blood (troponin), doing an ultrasound of the heart (Doppler echocardiography), conducting a specific type of heart MRI (T2 weighted cardiac MRI), and using specific medical imaging tests. One exciting development is the use of “gene expression profiling.” This is a technique where scientists look at your genes’ activity levels. A study found that this method was as good and safe as using a heart biopsy.
Furthermore, heart tissue changes could be accompanied by antibodies (proteins produced by the immune system) directed against certain structures in the heart transplant tissue. In the absence of these antibodies, other non-HLA antibodies should also be examined.
In the first five years after a heart transplant, doctors closely monitor for a condition called Cardiovascular allograft vasculopathy (CAV), where the transplanted heart’s blood vessels become narrow or blocked. This is usually done with an annual check-up involving a procedure to see the blood vessels (coronary angiography). If the patient has severe kidney disease, doctors may instead use a scan that uses sound waves to create images of the heart (dobutamine stress echocardiography). After five years, this stress echocardiography continues annually, and coronary angiography may or may not be done depending on the patient’s overall health condition. If the results still aren’t clear, an Intravascular ultrasound, which uses sound waves to create images inside the blood vessels, should be performed. A safer and equally accurate alternative to coronary angiography is coronary CT angiography.
Treatment Options for Heart Transplantation Rejection
After a heart transplant, the patient usually has to take medicines called immunosuppressants. These work to ‘turn off’ or reduce the activity of the body’s immune system—thus stopping it from attacking the new heart, thinking it’s an invader. Some common medicines included in this therapy are steroids and other drugs like cyclosporine, sirolimus/tacrolimus, and mycophenolate mofetil. Their effectiveness may depend on the patient’s condition and the type of rejection occurring.
If a patient experiences something called Primary Graft Dysfunction (PGD), they may need treatment with high-dose medicines focused on improving heart function. In extreme cases, devices like an intra-aortic balloon pump, extracorporeal membrane oxygenator (ECMO), or another type of temporary heart assist device may be needed.
Acute Cellular Rejection (ACR) is one common type of rejection after heart transplant. It can be treated with steroids and other drugs, either orally or intravenously. The selection among different treatment options often depends on the patient’s general health and how severe the rejection is. Generally, if a patient’s heart function is severely affected by the rejection or if the tissue samples show a high severity of rejection, the treatment approach might be more aggressive.
In some cases, the rejection may not cause the patient to feel sick but can only be detected by tissue samples. These are usually treated with low-dose steroids unless the patient is experiencing severe symptoms.
Antibody-Mediated Rejection (AMR) is another type of rejection that can be severe and associated with worse outcomes. The most common treatment for it includes a combination of steroids with certain antibodies. Apart from these, medical treatments showing some promise include the use of a drug called Rituximab.
Despite the options mentioned above, sometimes rejection is strong and may not respond to the initial treatments. In these cases, doctors have to resort to alternative methods like photopheresis (light therapy), total lymphoid irradiation (a type of radiation therapy), or changes in the immunosuppressive medication regimen.
What else can Heart Transplantation Rejection be?
When a doctor suspects a heart transplant rejection, some conditions that might also exhibit similar symptoms are:
- Primary graft dysfunction
- Secondary graft dysfunction
- Acute allograft rejection
- Cardiac allograft vasculopathy
- Amyloidosis
- Sarcoidosis
- Giant cell myocarditis
- Hereditary hemochromatosis
- Lymphoproliferative disorders such as non-Hodgkin lymphoma
These possibilities would need to be examined for a comprehensive diagnosis to be made.
What to expect with Heart Transplantation Rejection
The odds of surviving for a year after a heart transplant (HTx) are very high, nearly 90%. The average lifespan of patients who have undergone a heart transplant has significantly improved over time. However, patients who need a form of life support known as extracorporeal membrane oxygenation before their heart transplant may not do as well after the procedure.
Rejection of the new heart, where the body’s immune system attacks the transplanted organ, is responsible for about 10% of deaths in the first three years after transplant. There is also a steady increase in the occurrence of a condition known as CAV, which is the thickening of blood vessels in the new heart, after the transplant.
From five years after the transplant, cancer is the most common cause of death amongst heart transplant recipients. Approximately 2-4% of patients end up needing a second heart transplant. However, the results after a second transplant are generally not as good compared to the first heart transplant.
Possible Complications When Diagnosed with Heart Transplantation Rejection
There are several complications that can arise from heart transplant rejection. These include:
- Damage to the tricuspid valve (a valve in the heart), which can be caused by repeated diagnosing procedures such as endomyocardial biopsy.
- Failure of the transplanted heart graft.
- Irregular heart rhythms in the upper chambers of the heart, also known as atrial arrhythmia.
- Development of a type of cancer called lymphoproliferative malignancy.
- A condition called cardiac allograft vasculopathy, which affects the blood vessels of the heart.
- Acute rejection of the transplanted heart graft.
- An increased inclination to catch secondary infections.
- Experiencing serum sickness, a reaction to anti-thymocyte globulin, a medication given during transplantation.
- Acute heart attack, or myocardial infarction.
- The need for another heart transplantation.
- Death.
Preventing Heart Transplantation Rejection
Following a heart transplant, it’s crucial for patients to have regular check-ups and stick to their prescribed medication. Patients need to understand the pros and cons of medication that suppresses the immune system, including the fact that their body might still reject the new heart despite taking these medications. By teaching patients to recognize the early signs and symptoms of rejection, we can help them avoid serious problems.
Patients should also be aware that these immune-suppressing drugs can increase the chances of experiencing irregular heartbeats, known as atrial arrhythmia, and lymphoproliferative disorders, which involve abnormal growth of cells in the immune system. This information is critical for all heart transplant patients.
