Rejection Monitoring after Heart Transplantation
The early recognition of acute rejection reactions is decisive for the success of heart transplantation. There are different forms of rejection reactions.
Cellular rejection
Cellular rejection is characterized by the presence of increased numbers of inflammatory cells (lymphocytes, white blood cells). Depending on the degree of severity of rejection, these cells are disordered or occur in clusters and are associated with particular tissue reactions. These reactions may include swelling of the heart muscle cells, bleeding or cell death, which may lead to impairment of heart function, missed heartbeat, breathlessness or generally feeling unwell.
Fig. 1. Different grades of cellular rejection. Top left: no cellular rejection. Top right: slight cellular rejection. Below left: mild cellular rejection. Below right: moderate cellular rejection. (Reproduced by kind permission of Prof. R. Meyer, Cardiac Pathology, DHZB)
Antibody-mediated rejection
In the case of antibody-mediated rejection the body’s messenger substances are deposited in the form of proteins in the small and very small vessels of the heart muscle tissue. There they trigger a rejection reaction of the body; the new heart is weakened and the supply of blood to the heart is reduced. It is not possible for the doctor to distinguish between cellular rejection and antibody-mediated rejection on the basis of the patient’s symptoms alone.
Fig. 2. Protein deposits (antibody deposits in red) in the walls of small and very small vessels. (Reproduced by kind permission of Prof. R. Meyer, Cardiac Pathology, DHZB)
Quilty phenomenon
The Quilty phenomenon is named after the patient in whom it was first discovered. It used to be thought that Quilty – the accumulation of inflammatory cells solely in the innermost layer of the heart muscle – was a side effect of immunosuppressive medication. Today we know that Quilty represents an early stage of cellular rejection. Again, it is not possible for the doctor to distinguish between cellular rejection, antibody-mediated rejection and the Quilty phenomenon on the basis of the patient’s symptoms alone.
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Fig. 3. Quilty phenomenon, i.e. an accumulation of inflammatory cells in the innermost layer (the layer closest to the blood) of the heart muscle. (Reproduced by kind permission of Prof. R. Meyer, Cardiac Pathology, DHZB)
The only technique that enables these different forms of rejection to be distinguished is the heart muscle biopsy. It is still the gold standard for identifying rejection reactions and is used in accordance with the guidelines of the professional organizations. Since the biopsy is a low-risk procedure ‑ but not entirely without risk ‑ and since it cannot be used as a permanent (daily) means of rejection monitoring, other techniques have been developed that offer greater comfort to the patient. Among these are the intramyocardial electrogram (IMEG) and ultrasound examination of the heart (echocardiography).
Intramyocardial electrogram
During the first 2 years after heart transplantation an implanted cardiac pacemaker registers the intramyocardial electrogram (registration of approximately 750 ECG cycles per night), the voltage curve (amplitude) of the right and left heart chamber. By means of an aerial coil that the patient positions on the chest before going to sleep, the signals are transmitted to a bedside monitor and automatically stored. In the morning the data are called up by the central rejection monitoring facility and evaluated. If the IMEG amplitude falls or the heart rate increases, a rejection reaction is suspected and the patient is summoned to the hospital for further tests.
Fig. 4. IMEG rejection monitoring.
Echocardiographic wall motion analysis (1)
Measurement of the power of the heart and other parameters by the usual ultrasound heart examination is not sensitive enough to identify early rejection reactions. With the measurement of the velocity of wall motion of the left ventricle during the contraction and relaxation phases of the heart cycle it is different. This wall motion velocity can be measured with the aid of a special ultrasound procedure known as “tissue Doppler.” If a rejection reaction is present, the wall motion velocity falls and both the contraction and relaxation phases are prolonged.
Fig. 5. Fall in systolic maximal wall velocity from 12.3 cm/s to 8.6 cm/s in a patient with acute rejection. (Reproduced by kind permission of Prof. R. Meyer, Cardiac Pathology, DHZB)
Echocardiographic wall motion analysis (2)
It has been established that the heart muscle contracts not only in the cross-section (becoming “thicker”) but also in the longitudinal axis (becoming “shorter”). This motion and its velocity can be visualized using a method known as “strain echocardiography.” In the presence of a rejection reaction the wall motion velocity also falls, with both the shortening and the velocity of shortening becoming less. The advantage of this method compared with tissue Doppler is that the results are more easily reproducible; the disadvantage is that it requires ultramodern, expensive equipment and is very time-consuming.
Neither IMEG nor echocardiography has reached the diagnostic precision of biopsy harvesting in determining a rejection reaction. Therefore it is still necessary to take biopsies when there are clinical signs of rejection, even if the IMEG and echocardiography show normal findings.
Fig. 6. Two-dimensional strain image from an asymptomatic patient before and during an acute rejection reaction . During rejection the increase in wall thickness (radial strain) is greater in all segments and its velocity significantly lower. (Reproduced by kind permission of Prof. R. Meyer, Cardiac Pathology, DHZB)
Why heart catheter examinations are necessary after heart and heart/lung transplantation
After every heart transplantation changes take place in the large and small blood vessels. Narrowing of the blood vessels may occur and this reduces the blood supply to the heart and therefore threatens the proper functioning of the new organ.
Such changes can be recognized early on by regular examinations. Heart catheterization (coronary angiography) and the collection of heart muscle biopsies are both efficient methods of examination.
Today we know that computed tomography (CT) can show narrowing of the blood vessels due to calcification. This search for calcification is possible without using contrast medium; it is easy to apply and without any negative effects for the patient. However, in patients who have undergone heart transplantation this method is practically useless, since the extent of calcification of the coronary arteries does not reflect the degree of severity of the so-called “transplant vasculopathy.” Even CT with contrast medium does not reliably show the degree of severity of changes in the coronary arteries, since in patients with a transplanted heart it is particularly the very smallest blood vessels that are affected, and these cannot be visualized by CT.
Heart catheterization, on the other hand, provides information on narrowing of the blood vessels without calcification. This imaging procedure has been used for many years and carries only a low risk. The evaluation procedures have been improved, and the method provides excellent information on the vessel situation. Further, if narrowing of blood vessels is present, heart catheterization enables it to be established whether the region of the heart concerned is supplied by other vessel networks (collaterals).
In addition, the harvesting of heart muscle biopsies provides information on abnormal changes in the small vessels and very small vessels that cannot be identified by other procedures. Thus, in a single procedure (heart catheterization with heart muscle biopsy) it can be established at an early stage and with a high degree of certainty whether the transplanted organ is endangered.
For these reasons it is necessary for heart catheter examinations involving the collection of heart muscle biopsies to be performed regularly after heart and heart/lung transplantation.
