An Overview of Heart Transplantation
The first human heart transplant was performed by Dr. Christian Bernard in South Africa in 1967. Since that fateful day, heart transplantation has progressed from a medical curiosity to an accepted therapy for end-stage heart failure.
In the early years, survival beyond year one was only 20 percent, due mainly to a then-primitive understanding of the complexities of the immune system that leads to rejection. There were only a handful of medicines available to prevent rejection and no easy way to diagnose it. With the development of current heart biopsy techniques to monitor rejection, and the addition of a variety of agents to suppress and treat rejection, survival rates grew to the current estimates of greater than 90 percent in the first year.
Improved donor-heart management, with special preservation solutions and the increased reliability of transportation, has enabled a more extensive allocation system of available organs. Preservation, in addition to excellent survival results, stimulated the growth of heart transplantation with the number of transplants increasing nationwide from fewer than 50 per year in the 1970s to the current annual figure of about 2,000.
Although remarkable progress has been achieved in heart transplantation in the past two decades, significant discomfort still exists following the procedure. This is due to the consequences and the side effects of the drugs used to prevent rejection. Early transplant-related problems include rejection and infection. Chronic problems such as high blood pressure, kidney malfunction, diabetes, obesity, and bone weakening are frequently observed. One of the major long-term problems relates to a form of chronic rejection in which the arteries of the new heart become blocked in an untreatable fashion, necessitating a repeat of the whole transplant process with a new heart.
Despite all the side effects related to transplant, transplanted patients' quality of life is frequently dramatically improved. Exercise performance is greatly enhanced and most patients return to a normal life routine.
Newer therapies are currently being developed that focus on treating both the acute and, more important, the chronic rejection that occurs after transplant. However, strategies to teach the body to accept a foreign organ, a concept known as tolerance, remain the true holy grail of transplantation.
Supply versus demand
The sustained improvement in survival following heart transplantation has led to an increase in the number of potential transplant candidates. Current estimates indicate that between 14,000 and 15,000 people per year could benefit from heart transplantation. The continued expansion of heart transplantation is currently limited by the availability of donor hearts, which has remained stagnant at approximately 2,000 per year. Public awareness campaigns have minimally increased the donor pool.
Improved medical therapy for heart failure has helped to defer transplantation in large numbers of patients. Despite these efforts, the transplant candidate wait-list continues to lengthen. Alternatives to transplant are actively being pursued, with mechanical assist devices and other biological donors, such as animal organs, under development.
Who is a Heart Transplant Candidate?
Cardiac transplantation involves the surgical replacement of a badly diseased heart with a healthy heart from a human donor who has sustained brain death. A heart transplant is performed when congestive heart failure cannot be treated by any other medical or surgical means. It is reserved for those individuals with a decreased quality of life or those at high risk of dying from their heart disease within one or two years.
Most patients who undergo a transplant have one of two problems. The first is irreversible damage to the heart muscle caused by coronary artery disease, commonly called hardening of the arteries, and multiple heart attacks. The other problem is cardiomyopathy, or heart muscle disease, which may be caused by bacterial or viral infection, high blood pressure, or hereditary factors.
In both conditions, the heart cannot contract as it should because of damage to the muscle cells. Therefore, the person cannot function normally due to the heart's inability to pump enough oxygen to all of the body's tissues. Occasionally, heart transplants are performed on people with other forms of heart disease. These might include the defects of the valves of the heart, congenital heart defects (abnormalities of the heart from birth), or rare conditions like heart tumors.
The Heart Transplant Evaluation Process
Heart transplantation is a treatment rather than a cure and has its own inherent risks and benefits. This being so, not every potential patient with heart failure would benefit from a transplant. The purpose of the evaluation process is to select those patients who would benefit the most with the least risk.
A battery of tests exist, which include blood and skin tests, x-rays, ultrasound evaluation of the heart, abdomen, neck and leg arteries, an exercise stress test, and cardiac catheterization. Each of these tests helps to grade the severity of the heart disease and to exclude other potentially problematic conditions, such as cancer, which would interfere with the success of the heart transplant.
Conditions that prevent transplantation
Sometimes, during the evaluation process a condition is discovered that would make transplantation too difficult or dangerous. This could be an active infection in the body, high blood pressure in the lungs, or severe thickening of the arteries. Or if a potential candidate has a condition that makes it dangerous to take the medications required after transplant, they would also be excluded.
Psychiatric evaluation
In addition to the medical evaluation, a psychiatric evaluation is performed that provides insight into how the patient will function emotionally and if he or she would be able to cope with the stress of the transplantation experience. If transplantation is recommended, the psychiatrist can help the patient and family deal with the stress of chronic illness, the difficulties of the long waiting period, the operation itself, recuperation, and the long-term follow-up regimen.
Physical condition evaluation
Because exercise is vital to successful recuperation after transplant, physical therapy evaluation is also very important. The therapist assesses the patient's current physical condition and the limitations caused by the illness. This assessment is done to ensure participation in a routine exercise program following the operation. Due to the profound weakening effects on the muscles of the steroid regimen required after transplant, all patients are encouraged to exercise regularly in the time leading up to surgery as well. The physical therapist recommends a tailored exercise program for before and after surgery, and teaches energy-conserving techniques to use while waiting for the new heart.
Social support and financial/insurance evaluation
Finally, the social worker will meet with eligible patients and their family members to learn about available social support network, coping strategies, money and insurance status. They will also appraise the patient's feelings about their illness and the possibility of having a heart transplant.
The evaluation process is not only for the team to gather information about the patient. It's also for the patient and his or her family to learn about the specific transplant program, meet the team members, and learn about what it means to be a transplant recipient.
The Heart Transplant List
Once they have been accepted as a potential heart transplant recipient, the patient is placed on the nationwide heart transplant list. This list is managed by an independent organization named UNOS (United Network of Organ Sharing), which matches the donor heart to the appropriate recipient. UNOS also ensures fair allocation amongst all transplant centers of the limited number of hearts based on how long they've been on the list; it's a first-listed, first-served basis. Patients are categorized by blood group and size, as these are the only two variables that are important for matching in heart transplantation. Depending on blood type and severity of illness, the waiting time is between one month and greater than two years.
The Heart Transplant Operation
Even though the waiting period can be a long one, most patients say that they are never fully prepared when the telephone rings, signaling that a new heart is available. Time is critical once a suitable heart is identified. While the patient is being prepared for surgery, another group of surgeons has traveled, usually by jet aircraft or ambulance, to the donor hospital where they examine the health of the new heart, extract it, and carefully pack it in a special cold preservation fluid for transport.
The heart transplant operation involves making an incision through the breastbone—the sternum—and the bone is divided to expose and allow access to the old heart. The recipient is then connected to a heart-lung machine that will circulate and oxygenate the blood while the old heart is removed and the new heart is implanted and functioning. The operation is carefully synchronized to the progress being made by the team of surgeons harvesting the donor heart. There is continuous communication between the harvest team and the transplant surgical team to carefully time the donor heart's arrival because it can only survive a maximum of six hours outside the body.
When the timing is right, the surgeon will open the heart sac that surrounds the diseased heart and disconnect it from the great arteries and veins. Left in place is the small portion of the old heart required to make the necessary connections to the veins returning from the lungs. The new heart is carefully fitted and sewn to the remaining portions of the great vessels and lung veins. This method is called the orthotopicprocedure and is the most common surgical method used today to implant donor hearts. After the new heart begins to function, the patient is removed from the heart-lung machine, the breast bone is closed and the patient is transferred to the intensive care unit to begin the recuperation process.
Post-transplant procedures
Immediately after the transplant surgery is completed, the new heart is supported with intravenous medications for about one to two days until it recovers from the shock of the transplant. Patients can immediately feel the difference a healthy heart makes. Because the immune system gets activated the minute the new heart begins beating, medications to prevent rejection are administered even in the hours before the transplant and immediately afterwards. A typical stay in the intensive care unit is one to three days and the total hospital length of stay is an average of ten to fourteen days.
Medications That Prevent Rejection
Every person has a genetic blueprint that is specific to the individual, much like a fingerprint, and is displayed on every cell of the body. A normal immune system is composed of two major cell types: the T cell and the B cell. Together, these cells constantly survey the blood stream for anything that does not display the individual's genetic blueprint. When they encounter a foreign cell, whether it be human, bacterial, or viral, the T cell elaborates a protein called interleukin-2, which circulates in the blood stream and acts as a messenger to recruit and activate other T and B cells to fight and destroy the foreign substance. This defense mechanism is clearly important to rid our body of harmful bacteria and viruses, but is also why the body rejects the new heart.
Since the T cell is the first step in the rejection process, it is targeted by most strategies that suppress the immune system. The first category of drugs includes Prednisone. It works by preventing the T cell from recognizing the foreign cell. Cyclosporine or Tacrolimus are two drugs that comprise the second category of rejection medicines. They work by impairing the T cell's ability to make the messenger protein interleukin-2 that is required to recruit the cellular army to destroy the heart.
The third category of drugs works by preventing the army cells from getting activated and multiplying if the messenger signal managed to get to them. The drugs in this category are known as Azathioprine, Mycophenolate Mofetil, and Sirolimus. By using the three agents together, lower doses of each can be used, which thus limits the side effects of each individual agent. In concert, these three categories of drugs comprise the mainstay of the medicines used to prevent rejection in heart transplantation.
The greatest risk of rejection is within the first three to six months after transplant and therefore, the highest doses of the drugs are used during this period. After that, the doses are reduced to the lowest levels possible. Some degree of immunosuppression will always be required and if the drugs are completely discontinued, the patient will die of heart failure due to rejection.
The field of transplant immunology is rapidly evolving as the nuances of the immune system are elucidated. Newer drugs that are currently being developed and tested offer more selective immunosuppression and have a less hazardous side-effect profile. More important, the new concept known as tolerance entails retraining the immune system to accept the new heart as self rather than foreign. This is the focus of the next era of organ transplantation. It will allow acceptance of the new heart without placing the transplant recipient at increased infection risk due to reduced immune system.
What is Rejection and How is it Diagnosed?
Acute and chronic are the two types of rejection that occur. Acute rejection involves an infiltration of the new heart with immune cells that destroy its muscle fibers and eventually lead to its pumping failure. Unfortunately, there are no specific signs or symptoms of rejection until it is severe, and subsequently, patients develop heart failure. Because of this, a technique of heart biopsy was developed, which allows a survey of random pieces of heart muscle to see if they are indeed infiltrated by immune cells signifying rejection. This alerts the physician to increase, change, or add anti-rejection medicines to abort the rejection before heart damage occurs.
The current technique of biopsy is a simple 20-minute outpatient procedure. Under local anesthetic, a small plastic tube is placed in the vein in the neck that leads directly into the heart. Once in place, a wire with an end-resembling tweezers is inserted into the heart through the plastic tube and a small piece of heart tissue is removed under x-ray guidance and is analyzed for the presence of rejecting immune cells. Because the new heart has no nerves, this procedure is painless with the exception of the anesthetic part required for the tiny skin incision.
Chronic rejection occurs when the immune cells invade the arteries of the new heart, rather than the muscle. This infiltration gradually causes a blockage throughout the length of the artery and blood can no longer flow through the arteries to supply the pumping heart muscle. With insufficient blood flow to support its function, the heart muscle begins to die and, again, the patient experiences heart failure.
The best way to diagnose this kind of rejection is by coronary catheterization. In this procedure, dye that can be seen by x-ray is injected into the arteries of the new heart by a plastic tube placed through the femoral artery in the leg that leads to the main blood vessel in the body, the aorta. Similar to heart biopsy, this procedure is an outpatient procedure and is relatively painless.
There are no currently available medications to specifically prevent or reverse this rejection process once it occurs. When it is severe, the only treatment is to repeat the transplant with a new heart. Unlike acute rejection, which occurs most frequently within the first few months of transplant and then disappears, chronic rejection takes years to develop and continues to progress. Therefore, although most heart biopsies are performed repeatedly early after transplant, and then only as indicated by rejection suspicion, surveillance for chronic rejection is performed annually.
Summary
Heart transplantation is an effective therapy for patients suffering from end-stage heart failure and enables most to return to a normal level of functioning. Although impacting favorably on quality and quantity of life in carefully selected patients, transplantation is limited by chronic rejection and the side effects of the medications required to prevent rejection.
Unfortunately, demand greatly exceeds supply with regard to donor heart availability. Therefore, other methods of medically and surgically treating heart failure are being devised and tested. On the medical frontier is the promise, currently in its infancy, of gene therapy and being able to clone and grow a new heart or inject new heart muscle cells to replace damaged ones.
Finally, our understanding of the immune system is improving every day. Applying this new knowledge, medications are currently being used and developed that specifically target the T cells that have been activated against the new heart, rendering the rest of the immune system intact. This prevents the risk of infection and also many of the other undesired side effects. When these strategies are perfected, rejection might be avoided completely. Then hearts not only from human, but also animal donors, may be successfully used (much like the current use of animal heart valves) and the organ shortage will be overcome.
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