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Ann Thorac Surg 1998;66:1343-1349
© 1998 The Society of Thoracic Surgeons

Original articles: cardiovascular

Daily noninvasive rejection monitoring improves long-term survival in pediatric heart transplantation

Roland Hetzer, MD, PhDa, Evgueni V. Potapov, MDa, Johannes Müller, MDa, Matthias Loebe, MDa, Manfred Hummel, MD, PhDa, Yuguo Weng, MDa, Henning Warnecke, MD, PhDa, Peter E. Lange, MD, PhDb

a Department of Cardiac, Thoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
b Department of Pediatric Cardiology and Congenital Heart Diseases, Deutsches Herzzentrum Berlin, Berlin, Germany

Address reprint requests to Dr Hetzer, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
e-mail: (hetzer{at}dhzb.de)

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Acute rejection episodes and transplant vasculopathy (TVP) account for most of the late deaths after heart transplantation in both adults and children. Accumulating evidence indicates that fatal acute rejection and TVP are related to unrecognized and untreated early and ongoing acute rejection. Day-by-day surveillance of the heart and prompt treatment of any rejection may yield improved long-term survival.

Methods. In almost all patients having transplantation at our institution (978 patients since 1986), the intramyocardial electrogram (IMEG) was recorded routinely every day through a telemetry pacemaker and transmitted to our center by telephone modem. Earlier studies showed a substantial voltage drop in the IMEG QRS complex is highly indicative of acute rejection, including humoral rejection. In this study, we reviewed the data from 69 pediatric patients up to 16 years old for the incidence of acute rejection, TVP, and long-term outcome. Diagnostic endomyocardial biopsies were performed in only 10 patients, and recent coronary angiograms from 29 children were reviewed.

Results. In 50 children discharged after heart transplantation, IMEG surveillance data for a mean of 2.9 years indicated 72 acute rejection episodes. During follow-up of 1 month to 10.5 years (mean follow-up, 4.4 years), 2 patients died late of causes unrelated to either rejection or TVP. Another patient died of rejection during unrecognized underimmunosuppression nearly 8 years after transplantation and nearly 3 years after discontinuing IMEG recordings. Two patients without IMEG recording died of acute rejection or late TVP. In 1 patient, moderate TVP was seen on an angiogram after 4 years (incidence, 2.0%; 5-year incidence, 5.6%).

Conclusions. Daily recording of the IMEG can reliably detect early stages of acute rejection episodes, and immediate rejection treatment seems to keep the incidence of TVP low. The IMEG appears better than all the other rejection monitoring protocols currently in use.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Heart transplantation in children has become well established after the success of this treatment in adult patients during the 1980s. The most recent surveys of the International Registry for Heart and Lung Transplantation, including 40,738 heart transplantations between 1982 and February 1997 [1], indicate that 3,446 children have undergone transplantation during this period; the number ranges between 332 and 393 per year [2].

Whereas the operative technique in pediatric patients follows the one used in adults, with some modifications in patients with congenital defects, a few specific pediatric aspects have been identified [3, 4]. Acute rejection episodes and transplant vasculopathy (TVP) account for most of the late deaths [2], and accumulating evidence suggests that the occurrence of TVP may well be related to the incidence and the level of acute or ongoing rejection [5, 6]. That TVP limits graft survival and therefore, at least theoretically, necessitates one or more repeat transplantations for the patient to reach adult age has raised unresolved ethical questions and may create serious problems for organ relocation in the future [7]. Thus, the high priority must be placed on understanding TVP and preventing occurrence. In our opinion, this can be accomplished by early recognition of every acute rejection episode, both cellular and humoral, and consequent rejection suppression. Here we discuss our method of rejection monitoring and immunosuppression in children and present our results.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Between 1986 and December 1997, 72 orthotopic heart transplantations were performed in 69 children between the ages of 8 days and 16 years (mean age, 8.4 years). Seven children were less than 1 year old. There were 47 boys and 22 girls with various congenital heart defects (n = 11), cardiomyopathy (n = 55), and acute myocarditis (n = 3) (Table 1).


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  		Table 1. Diagnoses in 69 Pediatric Patients Undergoing Heart Transplantation Between 1986 and 1997

 
In 15 patients, heart transplantation was preceded by mechanical circulatory support for 3 to 98 days. A left ventricular assist device was used in 4; a biventricular assist device, in 9; and an extracorporeal membrane oxygenator, in 2. Ischemic time ranged from 47 minutes to 5 hours (mean time, 183 minutes). Donor organ preservation followed the method we apply for adult transplantation [8]. In patients with myocardial disease, orthotopic transplantation was performed as in adults according to the method of Shumway and Cooley [8, 9]. In patients with congenital heart defects, anatomic modifications were made. For example, in patients with hypoplastic left heart syndrome, deep hypothermia and circulatory arrest were used according to the method of Bailey and associates [10], or an atrial septum was created by modifying the atrial incisions on the donor heart.

Immunosuppression
The immunosuppression regimen was based on a triple-drug combination of cyclosporin A, azathioprine, and steroids with induction cytolytic therapy with antithymocyte globulin. Cyclosporin A was given immediately before transplantation at a dose of 4 mg/kg of body weight orally in older children or 1 mg/kg intravenously in children younger than 8 years. Azathioprine, 5 mg/kg of body weight was administered preoperatively, and during the operation, methylprednisolone, 15 mg/kg, was given before and immediately after cross-clamp release. After transplantation, the dose of cyclosporin A was aimed at trough levels higher than 300 ng/mL, that of azathioprine was guided by the white blood cell count (4,000 to 6,000/µL), and steroids were tapered to 0.15 mg/kg of body weight within the first 60 days.

On the first postoperative day, patients received one dose of rabbit antithymocyte globulin (Merieux, 2.5 mg/kg, or Biotest, 1.5 mg/kg of body weight). The rabbit antithymocyte globulin was repeated on the second postoperative day if the cyclosporin A trough level was lower than 100 ng/mL. When rejection was suspected, it was treated by pulsed steroid administration of methylprednisolone, 10 mg/kg of body weight twice a day, for 3 to 4 days. If signs of rejection did not resolve, antithymocyte globulin was added at the same rate as for induction therapy, or finally, a murine monoclonal antibody (OKT3) was given until rejection signs disappeared. In the later course after heart transplantation, pulsed steroid treatment was adequate, in general, to cope with acute rejection.

In the early period after transplantation, the children were examined every week for 8 weeks, then every 2 weeks, and then every 3 weeks up to 6 months postoperatively. After that, they were seen at variable intervals depending on the postoperative course. Between these visits, blood levels of cyclosporin A, red cell, white cell, and platelet counts, and kidney function were monitored every week, and immunosuppression was adapted individually.

In the early postoperative period, weekly control of urine Legionella antigen was performed. In addition, application of cytomegalovirus (CMV) replication virus in peripheral mononuclear cells was monitored in CMV-positive recipients and in CMV-negative recipients of a CMV-positive donor heart by determining CMV early antigen in peripheral mononuclear cells.

For prophylaxis of herpes simplex infection, acyclovir (10 mg/kg of body weight) was administered for up to 6 months after transplantation. For prophylaxis of Pneumocystis carinii infection and toxoplasmosis, a combination of sulfamethoxazole and trimethoprim was given at a dose of 5 mg/kg for up to 12 months.

Rejection monitoring
The primary tool for rejection monitoring in our practice has been the observation of the electrical potentials in the transplanted heart, in both the right and left ventricles by the intramyocardial electrogram (IMEG). This has been used in 978 patients, or the majority of our patients who have had heart or heart-lung transplantation at our institution since 1986. The IMEG system allows day-by-day surveillance of the heart and records changes consistent with acute rejection, both cellular and humoral, in a highly reliable fashion, as previous studies [11–14] have convincingly documented.

IMEG
All 69 children except 1 received an IMEG system, mainly at the time of transplantation. Patients who had been on mechanical support had implantation of the IMEG system once all skin incisions had healed. In 1 child, the system was explanted later because of pocket infection.

The IMEG method is based on the day-to-day changes in the maximal QRS complex amplitude. The IMEG is recorded in a unipolar fashion by two epicardial leads (Medtronic CapSure EPI 4965-35) on the right and left ventricles. The leads are implanted during the transplant procedure, and a commercially available pacemaker (St. Jude Medical–Pacesetter Paragon II) is placed in the left upper abdominal quadrant below the superficial fascia. This particular pacemaker model was chosen to facilitate a relatively broad-band transmission of low-frequency signals. The IMEG voltage is recorded by means of a receiver coil taped to the skin above the pacemaker, and the signals are transferred to a bedside receiver (Figs 1, 2).



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  		Fig 1. Telemetric pacemaker, receiver coil plus skin electrode, and bedside receiver (current model).

 


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  		Fig 2. Five-year-old child demonstrating recording method for intramyocardial electrogram through a bedside receiver (earlier model).

 
Because the amplitude of the QRS complex is influenced by the circadian rhythm and the adrenergic status of the patient, the IMEG recordings are made at night between 1 and 6 AM when the patient is asleep. During this time, the IMEG data are transmitted telemetrically to the bedside receiver in up to 40 stacks, one stack every 8 minutes. Each stack contains the IMEG data for 16 seconds. All QRS complexes are detected by software and measured precisely. The average of all measured QRS complex values result in a voltage value, the IMEG value for that particular day. The data from the bedside receiver are transmitted to our in-hospital computer facilities by telephone modem. As the recordings are made during the night, the data transfer usually is performed every morning. The in-hospital computer delivers a printout daily (Fig 3). If there is a negative deviation in the IMEG amplitude of more than 8% versus the physiologic variability that lasts for more than 3 consecutive days, this is considered highly indicative of rejection, and the patient is called to the hospital for further studies [13].



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  		Fig 3. Original intramyocardial electrogram (IMEG) printout over 34 days. The heavy solid line represents the course of the average IMEG voltage as recorded every night, and the two thin lines mark the upper and lower levels of IMEG voltage variations. The asterisk marks a sudden drop in voltage from the previously stable level. Two days later, pulsed steroid rejection treatment was initiated and effected a return of voltage to the previous level after 6 days (triangle). The heart rate (dotted line) showed only minor rate increases during the rejection process. (HTx = heart transplantation.)

 
In addition to IMEG monitoring, echocardiography, with particular emphasis on diastolic ventricular properties [15], is used as diagnostic tool at our institution. It is also performed by local pediatricians, who transmit their data to us. Endomyocardial biopsies were performed in only 10 children when the IMEG and echocardiographic data or were doubtful at the time of routine catheter studies. In 29 children, electively planned repeat left and right heart catheterization studies including coronary angiography were done 3 months to 8 years after transplantation (mean time, 3.5 years). The most recent angiographic findings were reexamined.

Statistical analysis
Nonparametric ordinal variables were evaluated using the Mann-Whitney U test, and a p value of less than 0.05 was considered significant. Survival data were analyzed with the standard Kaplan-Meier actuarial techniques for estimation for survival probabilities. All statistical analysis were performed using SPSS for Windows, release 6.0 (SPSS, Inc, 1989–1993).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Seventeen of the 69 children died within the first 3 months after heart transplantation. The causes of death were early graft failure in 13, transmitted sepsis in 1, multiorgan failure in 2, and brain death in 1. Among these 17 patients were a high number of infants (5/7), patients who had received mechanical support (4/15), and patients who had complex congenital heart defects, many of whom had had one or several previous operations (8/11). Fifty-two children were discharged home.

The actuarial survival rate for the entire group was 74% at 1 year and 68% at 5 years (Fig 4). Among the 50 discharged patients under continual IMEG recording, the 1-year survival rate was 100% and the 5-year rate, 94.3% (Fig 5).



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  		Fig 4. Actuarial survival for all patients indicates a 1-year survival rate of 74% and a 5-year survival rate of 68.2%. For comparison, the recent international registry survival curve [2] is added. (ISHLT = International Society of Heart and Lung Transplantation.)

 


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  		Fig 5. Actuarial survival for 50 children discharged from hospital who were in intramyocardial electrogram group. Survival at 1 year was 100% and at 5 years, 94.3%.

 
Rejection episodes
In the IMEG group of 50 patients, 72 acute rejection episodes were recorded and treated. These episodes were observed in 35 patients; 15 children were free from any rejection-typical IMEG changes. Thus, the incidence of rejection was 1.44 episodes per patient or 0.03 per IMEG month (Fig 6).



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  		Fig 6. Distribution of acute rejection episodes as observed by intramyocardial electrogram (IMEG) in all patients with IMEG recording. The rate of rejection is high early after transplantation and rapidly drops to occasional episodes. The horizontal lines indicate duration of adherence to IMEG protocol after transplantation. Some patients have been on this protocol for 5 years or longer.

 
There were five late deaths, two of which involved the patients without IMEG recordings. One had had transplantation in 1986 when IMEG devices were not yet implanted in all patients. This patient, a 15-year-old adolescent, had had an uneventful course except for some rejection episodes early after transplantation. During the next 3 years, he underwent a total of 46 endomyocardial biopsies, and the specimens demonstrated several episodes of mild (1A) rejection. Then two (1B) rejection episodes were seen, occurring within 1 month. The patient died of suddenly aggravated heart failure 4 weeks later. Postmortem examination revealed extensive, diffuse TVP. Earlier repeated coronary angiograms had indicated some diffuse wall irregularities.

The other patient without IMEG recordings who died late was a 5-year-old boy with dilated cardiomyopathy. He had received an IMEG system at the time of heart transplantation, but a pacemaker pocket infection, developed and the telemetry pacemaker was removed. He was discharged home 4 weeks after heart transplantation and was readmitted 1 week later with frank cardiac failure caused by massive rejection, which remained refractory to all our methods of immunosuppression.

Three late deaths occurred in patients who had continual IMEG recording during the initial years after transplantation. One underwent transplantation for endomyocardial fibrosis when he was 1 year old. After an uneventful course and 3 years of IMEG recording, the patient was readmitted for respiratory failure caused by previously unrecognized viral pneumonia. He died of pneumonia and sepsis. Another patient with endomyocardial fibrosis had transplantation at the age of 2 years 5 months. She had a good postoperative recovery and died 2 years 4 months later in a distant hospital of an intracerebral hemorrhage.

The third patient was 8 years 2 months old at the time of transplantation. He received a second heart 2 days later because of graft failure. He made a slow recovery but later had an entirely normal and uneventful course with 4 years of IMEG recording. At 7 years 8 months after transplantation, he discontinued the cyclosporin A regimen for several weeks without the knowledge of the local pediatrician. He was readmitted with advanced heart failure and signs of severe humoral rejection. He was placed on a respirator, given intravenous catecholamines, and received high-dose immunosuppression with steroids, antithymocyte globulin and OKT3 for 4 days. Although heart function was restored, the patient died of intractable sepsis.

Echocardiographic follow-up
The most recent data obtained by routine echocardiography indicated that global ventricular function is well preserved in all survivors but 1. The exception is an adolescent who underwent heart transplantation 6 years ago. The left ventricular ejection fraction was temporarily reduced to 30% because of inconsistent adherence to the immunosuppression regimen. This patient also has major changes in TVP on the coronary angiogram.

Coronary angiography
The most recent coronary angiograms from 29 patients, invariably with IMEG monitoring, were reviewed. The findings were normal up to 8 years after transplantation in all patients except the 1 patient just mentioned with marked TVP first seen 4 years after transplantation.


   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Our follow-up data on 50 children discharged from the hospital after heart transplantation under continual daily monitoring of the electrical potentials (IMEG) of the transplanted hearts suggest the benefits of this method. No major acute rejection episodes have been missed, and the rate of clinically and angiographically detectable TVP in these patients during a mean follow-up of 4.4 years and a maximum follow-up of more than 10 years has remained low. In only 1 child was TVP documented by angiography. This corresponds to a highly satisfactory survival rate of 94.3% after 7 years.

It is well documented that in children, as in adults, the incidence of acute rejection episodes rapidly decreases with time after transplantation, thus making such episodes rare beyond 2 years [5, 6, 16]. On the basis of this experience, we recommend that the IMEG tracings be made every night for at least 1 years after transplantation. By this time, however, many patients have come to rely on their monitoring habit as a form of security, which makes them choose to continue the practice. The mean monitoring time in children is now 2.9 years, and some continue with the recordings for more than 5 years. Even many years after transplantation, there is a slight, but well-known risk of acute rejection. We assume that the patient who sustained a severe and fatal rejection almost 8 years after transplantation because of insufficient immunosuppression might have survived had he still been on IMEG surveillance. The average per patient rate of 1.44 acute rejections diagnosed by the IMEG is in strong agreement with the range of 1.4 to 1.8 per patient reported by other pediatric transplant groups [5, 6, 17, 18].

Although in adults, most transplant teams continue to use routine endomyocardial biopsies for rejection detection, most pediatric teams have established less invasive protocols and rely primarily on repeat echocardiography [4, 19]. Both methods, biopsy and echocardiography, however, include the disadvantages of substantial intervals between examinations, reliance on an expert investigator, and considerable traveling for the patient and the family. With respect to echocardiography, these problems can be aggravated by interobserver variability [20]. Standard biopsy specimens can miss rejection because of sampling error, and conventional staining may underestimate humoral rejection [21].

Our experience with the IMEG system in more than 900 patients, both adults and children, with a sampled monitoring time of more than 2,500 years, has demonstrated several advantages over the other two methods. Rejection episodes are reliably recognized at an early stage, thus allowing prompt treatment to block further development to more severe stages. Because advanced stages of rejection were not seen, the amount of additional immunosuppression necessary to terminate rejection was moderate. The most striking finding was that there were no deaths from acute rejection provided the patient adhered strictly to short-interval, preferably daily, IMEG recording and the transmission of recorded data was faultless.

Anecdotal proof of the value of our method is the case of an 11-year 10-month–old girl who came to us from Bratislava in then Communist Czechoslovakia, for a transplantation procedure in 1989. With the intervention of the authorities, the IMEG computer made a phone call daily across the "iron curtain" for 1 years, thus securely monitoring the child’s heart, which is still working perfectly.

The reasons for IMEG amplitude changes in the course of rejection episodes are not fully understood. Experimental measurements of the membrane potentials in myocardial cells during rejection show a prolongation of the action potential duration (APD 75) and a delayed slew rate of the activated action potential [14]. This membrane dysfunction may be caused by immunologic processes that mediate an increase in nitric oxide and other free radicals with a deleterious effect on membrane proteins [22].

The high sensitivity and the only moderately high specificity imply that there is a certain percentage of false-positive assessments from the IMEG recordings. For instance, we observed that systemic infections by CMV or herpes virus can lead to a drop in IMEG voltage. Extreme variations in serum electrolytes such as in renal insufficiency can influence the IMEG voltage. In addition, the amplitude can be altered by pericardial fluid because of the unipolar nature of the recordings. This condition can be excluded by echocardiographic examination or infection monitoring.

At an earlier stage in our IMEG use, comparative studies were undertaken to evaluate the reliability of the IMEG [11–13]. Taking biopsy findings as a reference, we [12] found the IMEG had a 100% sensitivity and a 97% specificity in detecting acute rejection. When IMEG and echocardiographic findings were combined, it became apparent that these noninvasive methods were superior to biopsy. This again may be explained by the inherent deficiencies of biopsy-based rejection surveillance, ie, sampling error and overlooking humoral rejection. There is a small risk of sensor pocket infection and need of device removal, which in our series accounted for one fatal rejection in the pediatric group.

Transplant vasculopathy is the most dangerous late disease in transplanted grafts with a reported incidence in both adults and children as high as 30% to 50% at 5 years. The debate continues about the relevance of methods to diagnose TVP, which has a 5-year incidence of 8% to 43% in the pediatric population [4, 6, 18, 23]. Of the 50 children with continual IMEG surveillance in this series, only 1 patient has documented TVP, an incidence of 1.5%. This gives rise to a calculated incidence at 5 years of 5.6%. However, these data are based on evaluations of angiographic studies from only 29 patients. On the other hand, the well-preserved ventricular function demonstrated at echocardiography in all patients suggests that the coronary system is not altered to the point of graft dysfunction.

The most important observation in this context to date is that there has been no death related to TVP in the IMEG group. The evidence is growing that TVP may well be subsequent to the amount of acute rejection activity resulting from underimmunosuppression in the early period after transplantation. Several investigators [5, 6] have blamed smouldering low-grade untreated rejection for later vasculopathy. This leads us to believe that the rather low incidence of TVP in our IMEG patients may well be explained by the early detection and the prompt treatment of every rejection episode. The only patient in our entire pediatric heart transplant experience who died of TVP underwent transplantation before the routine use of the IMEG and was followed by conventional repeat endomyocardial biopsies, which, in fact, showed some grade 1A rejection that was not treated.

In conclusion, we strongly believe that short-interval, preferably daily, monitoring of acute rejection activities during the first few years after heart transplantation does enhance long-term survival. The IMEG system seems to provide a comfortable and reliable tool for achieving this goal. With use of this method, acute rejection episodes can be treated when developing, and this seems to keep the incidence of TVP. Only prospective, randomized trials can prove the superiority of one technique of rejection monitoring over others. After comparing the data from our admittedly small patient group with data in the literature, we still prefer our approach and will continue to rely on the IMEG in pediatric patients. An advanced monitoring device developed by our group that records not only electrogram voltage but also myocardial impedance and regional wall motion, is currently in clinical trials and is expected to further expand the observation pattern of the transplanted grafts in a telemetric fashion.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Hosenpud J., Bennet L., Keck B., Fiol B., Novick R. Registry of the International Society for Heart and Lung Transplantation: fourteenth official report—1997. J Heart Lung Transplant 1997;16:691-712.[Medline]
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  8. Pasic M., Loebe M., Hummel M., et al. Heart transplantation: a single-center experience. Ann Thorac Surg 1996;62:1685-1690.[Abstract/Free Full Text]
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  10. Bailey L.L., Assaad A.N., Trimm R.F., et al. Orthotopic transplantation during early infancy as therapy for incurable congenital heart disease. Ann Surg 1988;208:279-286.[Medline]
  11. Warnecke H., Tietze U., Hetzer R. Noninvasive monitoring of cardiac allograft rejection by intramyocardial electrogram recordings. Circulation 1986;74(Suppl 3):72.[Abstract/Free Full Text]
  12. Warnecke H., Müller J., Cohnert T., et al. Clinical heart transplantation without routine endomyocardial biopsy. J Heart Lung Transplant 1992;11:1093-1102.[Medline]
  13. Müller J., Warnecke H., Spiegelsberger S., Hummel M., Cohnert T., Hetzer R. Reliable noninvasive rejection diagnosis after heart transplantation in childhood. Heart Lung Transplant 1993;12:189-198.[Medline]
  14. Grauhan O., Müller J., Knosalla C., et al. Das intramyokardiale Elektrodiagramm (IMEG) in der Diagnostik der humoral vermittelten Abstoßung nach Herztransplantation. Z Kardiol 1996;85:745-752.[Medline]
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  19. Boucek M., Mathis C., Boucek R., et al. Prospective evaluation of echocardiography for primary rejection surveillance after infant heart transplantation: comparison with endomyocardial biopsy. J Heart Lung Transplant 1994;13:63-73.
  20. Santos-Ocampo S., Sekarski T., Saffitz J., et al. Echocardiographic characteristics of biopsy-proven cellular rejection in infant heart recipients. J Heart Lung Transplant 1996;15:25-34.[Medline]
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