use of epicardial electrocardiogram for detecting cardiac allograft rejection☆

Use of Epicardial Electrocardiograms for Detecting Cardiac Allograft Rejection Eric D. Irwin, MD, Richard W. Bianco, BS, Rose Clack, BS, John Grehan, BA, David P. Slovut, MD, Raouf Nakhleh, MD, R. Morton Bolman 111, MD, and Sara J. Shumway, MD Division of Cardiovascular and Thoracic Surgery and Department of Laboratory Medicine and Pathology, University of Minnesota Hospitals, Minneapolis, Minnesota

Since the advent of cyclosporin A surface electrocardiograms have been unreliable for diagnosing cardiac allograft rejection. Although several noninvasive methods have been proposed, none have been sufficiently accurate to be considered for clinical use. We have studied the use of the QRS complex amplitude, the unipolar peak-to-peak amplitude, recorded from intramyocardial electrodes for detecting rejection. Ten adult mongrel dogs underwent placement of intramyocardial electrodes on each ventricle. After stabilization of signals the hearts were transplanted heterotopically into unmatched recipients receiving cyclosporin A, azathioprine and methylprednisolone. Endomyocardial biopsies were performed

he diagnosis of rejection in patients who have under- T gone cardiac transplantation continues to be a problem without an ideal solution. To date rejection can be diagnosed only by the use of serial percutaneous transvenous endomyocardial biopsies (EMBs). There are, however, a number of problems with the use of EMBs for the diagnosis of rejection.

First, inadequate tissue is obtained for proper assess- ment in up to 6% of biopsies [l], and even with apparently adequate tissue EMBs are reported to have a 15% false-negative rate [2]. Second, obtaining a biopsy specimen is an invasive procedure that is associated with a small but not insignificant risk of complication [3-51. Third, biopsies are expensive and can be performed only in-specialized centers. Fourth, the time required for tissue processing results in an 8- to 24-hour delay in obtaining the diagnosis. Finally, biopsies cannot be performed frequently enough to assure that rejection will be diagnosed in its earliest stages when damage to the transplanted heart is only minimal. Thus a widely available, noninvasive method for detecting the onset and reversal of cardiac allograft rejection is needed. This will allow patients to be followed up more closely, and at a lower risk to the patient as well as at a lower cost.

Several noninvasive techniques have been used in the

Presented at the Twenty-eighth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Feb %5, 1992.

Address reprint requests to Dr Shumway, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, UHMC Box 207, Minneapolis, MN 55455.

after stabilization of unipolar peak-to-peak amplitude, twice weekly thereafter, and when unipolar peak-to- peak amplitude fell significantly. This detected 13 of 14 episodes of rejection. There was one false-positive and one false-negative result. The false-negative study became positive the following day. Thus, analysis of unipolar peak-to-peak amplitude detected all episodes of rejection in a clinically relevant time frame and was able to detect mild forms of rejection and multiple episodes of rejection in the same heart even in the presence of therapeutic levels of cyclosporin A.

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past for detecting allograft rejection. They have, however, generally reported results that lacked sufficient accuracy for determining clinical therapy in cardiac transplant recipients. During the initial decade of cardiac transplantation the results of several studies suggested that changes in the amplitude of the QRS complex measured from standard 12-lead electrocardiograms could be used to detect severe rejection [6, 71. With the advent of cyclosporin A (CSA) this is no longer true [8, 91.

Analysis of R-wave voltage, the peak-to-peak amplitude of unipolar electrograms (UPPA), obtained from intramyocardial plunge electrodes has been shown to be an accurate, sensitive, and quantitative predictor of local irreversible myocardial ischemic injury [lo]. In this study the UPPA decrease correlated closely with the local histo- logical changes that subsequently developed. With ini- tially encouraging results in ischemic preparations other investigators applied this method to the diagnosis of rejection in patients after cardiac transplantation. Wahlers and colleagues [ll] studied 13 patients who underwent orthotopic cardiac transplantation with simultaneous im- plantation of a telemetric pacemaker. Voltages were measured from electrodes placed on the right atrium and ventricle. They found that signals recorded via standard telemetry units failed to provide adequate accuracy for determining therapy in patients.

Rosenbloom and colleagues [ 121 circumvented some of these problems by recording intramyocardial electrograms directly from epicardial pacing electrodes. Elec- trodes were placed on the anterior and posterior aspect of

0 1992 by The Society of Thoracic Surgeons 0003-4975/92/$5.00

670 IRWIN ET AL ECG DETECTION OF REJECTION

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each ventricle. By avoiding the use of telemetry they were able to demonstrate significantly better results, with a 100% sensitivity and a 91% specificity. Thus UPPA recorded directly from four ventricular epicardial pacing electrodes detected rejection in cardiac allografts with sufficient accuracy to be considered for clinical application. There were, however, three questions that remained unanswered by this study: (1) would the use of CSA adversely affect the accuracy of this method as it had with standard 12-lead electrocardiograms, (2) could this method be used for detecting repetitive episodes of rejection in the same heart, and (3) could mild forms of rejection be detected using this technique? The following study was designed to answer these questions as well as to further test the use of UPPA for diagnosing rejection.

Material and Methods All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" as published by the National Institutes of Health (NIH publication No. 85-23, revised 1985).

Abdominal Heterotopic Transplantation Our first four studies used heterotopic transplantation in the abdomen. The heart from an unmatched donor dog was procured after preservation with potassium crystal- loid cardioplegia and topical hypothermia with iced saline solution. After explantation of the heart the superior vena cava, inferior vena cava, and pulmonary veins were ligated. The donor aorta and pulmonary artery were then prepared.

The recipient animal was anesthetized with sodium pentothal and placed on a ventilator for maintenance anesthesia with halothane and oxygen. A laparotomy was then performed, and the infrarenal inferior vena cava and aorta were isolated. Anastomoses of the donor pulmonary artery to the recipient inferior vena cava and the donor aorta to recipient aorta were fashioned using continuous monofilament suture. The heart was then deaired by removal of the pulmonary artery clamp and venting of the aorta. After this, arterial blood flow was restored and the heart defibrillated. A biopsy cannula was then placed through the free wall of the right ventricle, and screw-in epicardial pacing electrodes (Medtronic, Inc, Minneapo- lis, MN) were affixed to the anterior and posterior aspect of each ventricle. The electrodes were then connected to a block that allowed direct percutaneous electrical connec- tions to be made. The electrode block and biopsy cannula were then placed in subcutaneous pockets, and the abdomen was closed in layers.

Thoracic Heterotopic Transplantation Eight adult mongrel dogs received thoracic heterotopic cardiac transplants as previously described [13]. The heart from an unmatched donor was procured as described for abdominal transplantation. After explantation of the heart an atrial septa1 defect was created and the mitral valve rendered incompetent. This provided optimal decompres- sion of the left ventricle. The pulmonary valve was also

rendered incompetent. This reduces the tendency for the right ventricular volume to decrease with time, as is seen in the unloaded heart, and facilitates performance of EMB. The superior and inferior venae cavae were then ligated and the pulmonary veins oversewn. The donor aorta and pulmonary artery were then prepared for anas- tomosis.

The recipient animal was anesthetized with sodium pentothal, placed on a ventilator, and maintained under general anesthesia using halothane and oxygen. Through a left thoracotomy, the recipient superior vena cava and left innominate artery were mobilized. End-to-side anas- tomosis of the donor pulmonary artery to the recipient superior vena cava was performed with continuous monofilament suture. Similarly, the donor aorta was anastomosed to the recipient left innominate artery. Upon completion of the anastomoses venous clamps were re- moved and the heart deaired. After this, arterial blood flow was restored and the heart defibrillated. A biopsy cannula was then affixed to the free wall of the right ventricle. This model provides a heart that is perfused and contracting in a nonworking setting with electrical activ- ity.

The chest incision of the recipient was then closed in layers, and the biopsy cannula and electrode block were placed in separate subcutaneous pockets. The animal was then allowed to awaken and was taken to the postoperative care facility.

Electrodes Sutureless intramyocardial screw-in electrodes (Medtronic, Inc) were placed on the anterior and posterior aspects of each ventricle of the donor animal. These were brought through the chest wall to a subcutaneous pocket, where they were affixed to a block that allowed direct electrical connection to be made with the epicardial pacing electrodes. The posterior surface of the block contained a standard indifferent electrode.

Immunosuppression Protocol Each recipient animal received CSA (18 mg * kg-' * day-') and azathioprine (3 mg - kg-' * day-') starting 2 days before transplantation and continuing postoperatively. On the day of transplantation methylprednisolone (1 g as an intravenous bolus) was given preoperatively . This dose was continued through postoperative day 3. On postoperative day 4 this was decreased to 500 mg intravenously and then 125 mg intravenously on postoperative day 5. After this, the animals received methylprednisolone (1 mg * kg-' - day-'). After stabilization of voltages recorded from the endomyocardial electrodes, an EMB was performed. After tissue verification of viable nonre- jecting myocardium the methylprednisolone was tapered. If after 3 days there was no evidence of rejection, administration of azathioprine and methylprednisolone was discontinued and CSA administration was maintained at therapeutic levels. If after 5 additional days there was no evidence of rejection CSA doses were reduced by one half. After 3 to 5 days if there was no evidence of rejection the administration of CSA was discontinued until biopsy

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confirmation of rejection was obtained. After biopsy confirmation of rejection immunosuppression identical to that used in the immediate postoperative period was resumed.

Unipolar Peak-to-Peak Amplitude Data Acquisition Starting on postoperative day 1 intramyocardial electrograms were recorded daily. The initial data acquisition system consisted of a variable-gain signal amplifier with filter settings of 1,000 Hz high-pass and 0.05 Hz low-pass. Data were then recorded using an analog-to-digital con- verter (Dataque Instruments, Akron, OH) installed in a personal computer. At present we use a four-channel electrocardiogram isolation unit and amplifier, with the same filter settings, coupled to the analog-to-digital con- verter for data acquisition.

Unipolar Peak-to-Peak Amplitude Analysis Data for each lead were obtained by averaging the QRS amplitudes of 10 beats. Daily average voltage for each electrode was compared with the maximum average voltage obtained in the three previous determinations (reference voltage). The averaged voltage for a given day was divided by the reference voltage for that electrode and expressed as a percent. This process was repeated with each average daily voltage compared with the previous days’ average daily voltage. The ratios for the four leads were averaged to determine the total percent retained UPPA. A total UPPA decline of greater than 15% for the four-lead average, compared with the reference value for the previous 3 days, or a decline of greater than 9% over 1 day was considered indicative of rejection necessitating EMB for tissue confirmation.

Endomyocardial Biopsy Endomyocardial biopsy specimens were obtained after stabilization of recorded voltages, usually occurring between postoperative days 5 and 8, twice weekly thereafter, and when criteria for UPPA reduction were present. Biopsies were performed using standard cardiac biopsy forceps (Cordis) or rigid bronchoscopy biopsy forceps. To perform an EMB animals were lightly anesthetized with sodium pentothal and the subcutaneous pocket contain- ing the biopsy cannula was opened using sterile technique. The forceps were then advanced through the cannula and multiple specimens obtained. At the completion of the study the animals were sacrificed. The transplanted hearts were then explanted for gross and micro- scopic examination.

Histologic Grading All biopsy specimens were evaluated by a cardiac pathol- ogist who was unaware of the UPPA findings or physio- logical state of the heart. Cardiac samples were graded histologically according to the criteria of Billingham and colleagues [14]. All specimens obtained at postmortem examination were examined and graded in a similar manner.

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Fig I . Example of electrocardiograms recorded from intramyocardial electrodes: a representative four-lead electrocardiogram recorded using the electrocardiogram isolation unit with low-pass and high-pass filter settings of 0.05 Hz and 1,000 Hz , respectively.

Results An example of a daily tracing recorded from the four epicardial leads is shown in Figure 1. We have found a large number of biphasic QRS complexes in our data; as a result, we use the difference in voltage between the most negative and the most positive deflections of the QRS complex to determine the amplitude of the QRS complex for UPPA calculations. Unipolar peak-to-peak amplitude calculations were carried out as described in the Material and Methods section. Figure 2 shows the time course of UPPA changes, expressed as a percentage of the reference value from the previous 3 days. This is plotted against days after transplantation. This figure demonstrates changes in UPPA that detected three biopsy-proven episodes of rejection in the same animal. These occurred in the presence of therapeutic CSA levels throughout the course of the study.

Thirteen of 14 biopsy-confirmed episodes of rejection were detected using a 15% reduction in UPPA compared with the greatest reference voltage of the previous 3 days or a 9% decrease from the previous day. No evidence of rejection was seen in eight of nine biopsy specimens obtained when UPPA criteria for rejection were absent. There was one episode of rejection that was not detected by strict UPPA criteria; this represented the only false- negative result in our study. There was one false-positive UPPA study in our experiment. This represents a sensitivity of 93% and a specificity of 88% for the diagnosis of rejection in this canine model of cardiac allograft trans-


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Postoperative Day

Fig 2. Changes in percent retained unipolar peak-to-peak amplitude (UPPA) that detected three episodes of biopsy-proven rejection in the same transplant recipient.

plantation. It should be noted, however, that the UPPA for the one false-negative study became positive the following day and a repeat biopsy demonstrated rejection. Thus UPPA detected all episodes of rejection in a clinically relevant time frame. The sensitivity for detecting episodes of rejection in a clinically relevant time frame was 100%. We believe that including this data point is justified because clinically EMBs are performed at intervals of 1 to 2 weeks or more.

Additionally, in this study there were four episodes of mild rejection and three episodes of moderate rejection. All of these rejection episodes were correctly diagnosed by analysis of UPPA recorded from intramyocardial electrodes.

To help explain the difference between this analysis and that of other authors we analyzed our data using alternative lead combinations. We reanalyzed the electrocardiographic data from the last six transplants and calculated UPPA for two- and three-lead combinations. Table 1

Table 1. Sensitivity of Lead Configurations Using Fewer Than Four Electrodes

Electrode Configuration Sensitivity

LVA + LVP RVA -t RVP LVA + RVA LVP -t RVP LVA -t LVP + RVA LVA + LVP + RVP LVA -t LVP + RVA + RVP

47% 35% 41 % 47% 53% 53 % 100%"

a In a clinically relevant time frame; see text for discussion.

LVA = anterior aspect of the left ventricle; the left ventricle; = posterior aspect of the right ventricle.

LVP = posterior aspect of RVP RVA = anterior aspect of the right ventricle;

shows the sensitivity of two- and three-lead combinations for diagnosing rejection for the last six transplants. As can be seen, no lead combination with less than four leads approached the diagnostic accuracy obtained by using all four leads for analysis.

Twelve of the 14 episodes of rejection in this study occurred while therapeutic doses (9 mg/kg twice per day) were being administered. In 7 of these cases therapeutic levels of CSA (>150 pg/L) were present. Cyclosporin A levels were subtherapeutic in the remaining 7 cases, less than 100 pg/L in 4 and 100 to 149 pg/L in the remaining 3 episodes of rejection.

Comment These data demonstrate that the analysis of UPPA measured from intramyocardial electrograms is capable of detecting rejection with sufficient accuracy to be considered for clinical application. This method remains valid even in the presence of therapeutic levels of CSA and can be used to detect repeated episodes of rejection within the same heart. This is important as it may reduce the number of endomyocardial biopsies needed for diagnosing rejection.

The use of percutaneous transvenous EMB was orig- inally described by Sakakibara and Konno in 1962 [15] and subsequently adapted for monitoring rejection in cardiac transplant recipients by Caves and colleagues in 1973 [16]. This method, however, suffers from several limitations. First, obtaining a biopsy specimen is an invasive procedure that is associated with a small but not insignificant risk of complication. This is demonstrated in one recent series, at a major transplant center, where the incidence of complications associated with EMB was reported to be between 0.3% and 1.3% [3]. These complications included local infection, pneumothorax, and rupture of the right ventricle with hemorrhage [3]. Furthermore, with EMB inadequate tissue is obtained in up to 6% of biopsies [l]. Even with apparently adequate tissue, EMB is reported to have a 15% false-negative rate [2]. This is believed to occur because of the more patchy infiltrates seen in the rejecting myocardium of patients treated with CSA-based immu- notherapy. Thus the use of EMB fails to provide the ideal level of accuracy. A second problem with the use of biopsies is the expense. This is particularly important as EMBs are currently used primarily for screening purposes. Thus a noninvasive, less expensive, method is needed to reduce the number of biopsy specimens obtained for surveillance purposes alone. This will allow closer follow-up for the patients at a lower risk and with lower health care costs. A third problem with EMBs is that they can be performed only in specialized centers. This results in substantial expense for the patient and can cause a delay in the diagnosis if patients must be trans- ferred to special centers. Additional delays in diagnosis result from the time required for tissue processing once the biopsy specimen is obtained. This results in an additional delay of 8 to 24 hours before pathology results are available and the diagnosis of rejection is confirmed or excluded. The analysis of UPPA is straightforward and

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IRWIN ET AL 673 ECG DETECTION OF REJECTION

can be performed with minimal delay. A final problem with EMB is seen in the late posttransplant period when biopsies cannot be performed frequently enough to en- sure that rejection will be diagnosed in its earliest stages. Thus a widely available, noninvasive method for detecting the onset and reversal of cardiac allograft rejection is needed. Even though the need for EMB may not be eliminated by such a method, a reduction in the number of biopsies is desirable. Our results suggest that analysis of UPPA from four epicardial electrodes can fill this need as it allows closer follow-up for patients at a lower risk with lower health care costs.

The exact cellular processes responsible for the electrocardiographic changes seen during allograft rejection are not clearly understood. Cellular changes seen during acute allograft rejection in patients treated with azathioprine and methylprednisolone consist of diffuse edema, leukocyte infiltration, and myocardial necrosis. These changes are thought to be responsible for alterations in the cardiac action potential, which result in the voltage decline seen in standard electrocardiograms during episodes of acute rejection. With the addition of cyclosporine to immunosuppressive regimens rejection is changed to a process characterized by patchy areas of focal rejection with minimal edema. This has resulted in the loss of consistent changes in surface electrocardiograms associated with the rejection process. Thus standard surface electrocardiograms are no longer sufficiently accurate to be considered clinically applicable [8, 91.

Other conditions are known to reduce the accuracy of standard 12-lead electrocardiograms and the more sophis- ticated forms of analysis of electrocardiograms recorded from electrodes placed on the skin surface. These include the presence of pericardial or pleural effusions, edema, sepsis, pneumothorax, or pulmonary consolidation. In their series Keren and associates [17] found that postoperative changes in the mediastinum prevented signal- averaged electrocardiograms from diagnosing rejection in the early posttransplantation period. Analysis of UPPA from intramyocardial electrodes offers the advantage of assessing the heart independent of these changes and provides important advantages for diagnosing rejection in cardiac transplant recipients. During the early posttransplantation period Keren and colleagues [17] also found that signal averaging of surface electrocardiograms could not reliably diagnose mild forms of rejection. In this study we were able to detect even mild forms of rejection.

In the current study we found that electrograms recorded from intramyocardial electrodes were more accurate in diagnosing rejection than other authors have reported [ll, 181. We believe that this can be accounted for by differences in instrumentation. Wahlers and associates [ l l ] have evaluated the use of electrodes placed on the epicardial surfaces of the right atrium and right ventricle in patients undergoing orthotopic cardiac transplantation. Monitoring voltages from these electrodes via a telemetric pacemaker they were unable to correlate histologic grades of rejection with corresponding changes in voltages recorded from the electrodes. Warnecke and associates, using similar instrumentation, reported an

87.9% sensitivity for detecting rejection in human allografts. We believe that our ability to detect all episodes of rejection is the result of using four electrodes. As the rejection process is occasionally patchy, four electrodes may detect an episode that would have been missed by a single electrode. This is shown in Table 1, where combinations of two or three leads demonstrated sensitivities of 53% or less.

Avitall and colleagues [ 181 examined the electrophysiologic changes occurring during acute rejection of heterotopic cardiac allografts using a canine model in which no immunosuppression was given. They also 'failed to find correlations between changes in the UPPA and either mild or moderate rejection. There are, however, several differences between the current study and the work of Avitall and colleagues. First, when immunosuppression is not used, stabilization of the tissue-electrode interface does not occur. Without such a period of stabilization it is very difficult to differentiate the effects of rejection from the short-term tissue-electrode interactions. Our work as well as that of others [12, 141 has shown that a period of 5 days is needed to allow stabilization. In our current protocol we implant the electrodes at least 7 to 10 days before transplantation to allow stabilization. In the clinical setting, where the donor and recipient have the same blood type, rejection during the first 7 days is unusual and thus an adequate time period for stabilization is present. Furthermore, a biopsy specimen obtained 7 to 10 days after transplantation would be very desirable, so as to provide a baseline for further comparison. Thus a period of nearly 2 weeks would be available for stabilization of tissue-electrode interactions. This period could be modi- fied further if long-term studies demonstrated this to be necessary. Finally, the present study, as did the work of Rosenbloom and colleagues [12] compares daily UPPA values with data recorded over the preceding 3 days. This tends to neutralize the more long-term effects of electrode-tissue interactions seen over weeks or months. Studies of longer duration are needed to determine the optimal interval for data acquisition in the chronic setting.

An additional use of this technology could be the early detection of allograft atherosclerosis. As previously reported [lo], ischemia may produce abrupt and substantial declines in the UPPA. Exercise-induced regional ischemia could readily be identified by the local intramyocardial electrode in the ischemic region.

Finally, with the application of this technology, one should be able to increase the intervals between biopsies. If the average UPPA remains unchanged, biopsy would be safely postponed until it was indicated clinically. If a decrease in UPPA was noted and rejection clinically suspected, a biopsy would be performed for verification. As UPPA decline occurs early in the time course of acute allograft rejection, this information may lead to earlier detection of episodes of rejection. This would allow treat- ment to be instituted more expeditiously and limit damage to the graft.

In conclusion, UPPA analysis using four intramyocardial screw-in electrodes provides a noninvasive, highly sensitive, and specific indicator of cardiac allograft rejec-


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tion. Its application may substantially reduce the number of EMBs needed and allow for closer follow-up at less risk to the patient and at lower cost to the health care system.

We acknowledge financial support provided by Medtronic Inc, who provided partial funding for this work by a Synergy Tech- nology Transfer Award (Medtronic Inc, Minneapolis, MN).

References 1. Cooper DKC, Fraser RC, Rose AG, et al. Technique, compli-

cations and clinical value of endomyocardial biopsy in patients with heterotopic heart transplants. Thorax 1982;37 727-31.

2. Sibley RK, Olivari MT, Ring WS, Bolman RM. Endomyocar- dial biopsy in cardiac allograft recipient: a review of 570 biopsies. Ann Surg 1986;203:177-87.

3. Anastasiou-Nana MI, OConnell JB, Nanas JN, et al. Relative efficiency and risk of endomyocardial biopsy: comparison in heart transplant and nontransplant patients. Cathet Cardio- vas Diagn 1988;18:7-11.

4. Parrillo JE, Aretz HT, Palacios I, et al. The results of transvenous endomyocardial biopsy can frequently be used to diagnose myocardial diseases in patients with idiopathic heart failure. Endomyocardial biopsies in 100 consecutive patients revealed a substantial incidence of myocarditis. Circulation 1984;69:93-101.

5. Nippoldt TB, Edwards WD, Holmes DR, et al. Right ventricular endomyocardial biopsy. Clinicopathologic correlates in 100 consecutive patients. Mayo Clin Proc 1982;57:407-18.

6. Hess ML, Hastillo A, Wolfgang TC, et al. The noninvasive diagnosis of acute and chronic cardiac allograft rejection. J Heart Transplant 1981;1:31-8.

7. Oyer PE, Stinson EB, Bieber CT, et al. Diagnosis and treat- ment of acute cardiac allograft rejection. Transplant Proc 1979;11:29&303.

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Haberl R, Weber M, Reichenspurner H, et al. Frequency analysis of the surface electrocardiogram for recognition of acute rejection after orthotopic cardiac transplantation in man. Circulation 1987;76:101-8. Cooper DKC, Charles RG, Rose AG, et al. Does the electrocardiogram detect early acute heart rejection? J Heart Trans- plant 1985;4:546-8. Lofland GK, German LD, Ross M, et al. The local unipolar depolarization complex: a quantitative electrophysiologic in- dex of irreversible myocardial ischemic injury. Surg Forum

Wahlers T, Haverich A, Schafers HJ, et al. Changes of the intramyocardial electrogram afier orthotopic heart transplantation. J Heart Transplant 1986;5:45&4. Rosenbloom M, Laschinger JC, Saffitz JE, et al. Noninvasive detection of cardiac allograft rejection by analysis of the unipolar peak-to-peak amplitnde of intramyocardial electrograms. Ann Thorac Surg 1989;47407-11. Jamieson SW, Burton NA, Reitz BA, et al. A new method for heterotopic cardiac transplantation in the dog. J Surg Res 1982;32:15&3. Billingham ME, Cary NRB, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. J Heart Transplant 1990;9:587-93. Sakakibara S, Konno S. Endomyocardial biopsy. Jpn Heart J 1962;3:53743. Caves PK, Stinson EB, Graham AF, et al. Percutaneous transvenous endomyocardial biopsy. JAMA 1973;225:28%91. Keren A, Gillis AMM, Freedman RA, et al. Heart transplant rejection monitored by signal-averaged electrocardiography in patients receiving cyclosporin. Circulation 1984;7O(Suppl 1):124-9. Avitall B, Payne DD, Connolly RJ, et al. Heterotopic heart transplantation: electrophysiologic changes during acute rejection. J Heart Transplant 1988;7176-82.

1984;35:269-71.

DISCUSSION

DR T. BRUCE FERGUSON (St. Louis, MO): I would like to endorse the concept of this type of monitoring of cardiac transplantation, but I have several questions for the group from Minneapolis. We have recently completed a number of studies looking at this same type of technology, some of which were published in Circulation several months ago and additional data that were presented at the meeting of the Western Thoracic Surgical Association last year. The difference between our studies and your study have to do with the analysis and recording of the intramyocardial electrograms.

We have found that if the data are obtained in a way that allows pure recording of the UPPA, the mathematical summation of the different epicardial electrograms is really not necessary. We demonstrated in our article published in Circulation that there are two-, three-, and four-electrode combinations that can be used, but if the algorithms used to determine the amplitude of the peak to peak potential are done in a way we would consider to be proper, you can get the same information recording absolute amplitude values from as few as two electrograms. These results have been confirmed by the group at the Berlin Heart Center as well, both experimentally and clinically.

So my first question is, do you have an explanation for this discrepancy and for the low sensitivity and specificity associated with your individual amplitude recordings from the individual electrodes? Second, are you attempting to address this problem

in any future studies, as obviously this is a technique that is applicable to pacemaker telemetry technology, which cannot be done if you need four electrograms to be able to perform the analysis? And finally, have you attempted any of these types of studies in your transplant patient population at the University of Minnesota?

DR IRWIN Thank you very much for your comments. We have also looked at alternative ways of calculating UPPA. Specifically, we have summed the voltage of the four leads and compared this with the summed voltages of the 3 previous days. Using this we have found that there is no change in accuracy for detecting rejection, a finding similar to what you have discussed.

As to the optimal number of leads, our data suggest that the use of four leads adds significantly to the sensitivity of the method, particularly for detecting milder forms of rejection. In the literature many of the episodes of rejection that were detected using fewer leads were more advanced than those that we were able to detect using four leads. I am unaware of any other factors that could account for this disparity.

DR AXEL HAVERICH (Hannover, Germany): At our institution we have been very interested in this electrocardiogram for noninvasively detecting cardiac allograft rejection, and we started implanting telemetric pacemaker systems in these pa-

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IRWINETAL 675 ECG DETECTION OF REJECTION

tients in 1983. After a study period of about 2 years, we were so disappointed clinically that we stopped using this methodology for detecting allograft rejection.

Now, after more than 5 years of follow-up, we took 20 long-term survivors after cardiac transplantation and revitalized this study. Looking at telemetric electrocardiographic amplitudes, both for the atrial and the ventricular part, we saw a tremendous shift in the R waves in these patients over the years. In some, the R waves had increased by more than 200%; in some they were down by 100 to 120%. Therefore, I think one of the major issues of noninvasive cardiac allograft surveillance, namely, the late detection, will be impossible by using this system.

DR IRWIN: In this study we have no data evaluating changes in baseline voltages occurring over periods of 3 to 5 years. In our protocol we compare the daily voltage with the peak voltage of the 3 previous days to account for variation in the baseline. Clearly, the optimal interval between electrocardiograms that will allow one to account for variation in baseline, without reducing the sensitivity of the method, needs to be addressed in clinical studies.

DR PETER W. BARRETT (New Haven, CT): I have two quick questions. First, somehow I do not quite consider this noninvasive in that everybody does not like to leave hardware in a transplant patient. Do you know or are you womed about an increased incidence of infection? Second, you mentioned that it is detecting earlier rejection, but we all often do not treat earlier rejection. Have you had any work with biopsy results that correlate with myocyte necrosis?

DR IRWIN In this study we were able to detect a wide range of severities of rejection, including some early grades that would not necessarily be treated. In our data approximately one half of the episodes were associated with more severe myocyte necrosis. These cases correlated with more profound changes in voltages. The magnitude of change in voltage that would be treated would need to be addressed in more detail in clinical trials.

As to the issue of leaving hardware in the patient, we are also concerned about the associated risk of infection. We are anx- iously awaiting the development of telemetric pacemakers that have sufficient accuracy to resolve, within a few percent, differences in voltages. Then this technology can be applied clinically using telemetry rather than requiring percutaneous access.

Notice From The Society of Thoracic Surgeons

The Twenty-ninth Annual Meeting of The Society of Thoracic Surgeons will be held at the San Antonio Con- vention Facility in San Antonio, Texas, January 25-27, 1993. There is no registration fee for the meeting for members of The Society. The registration fee is also waived for speakers, residents, and fellows. A $250.00 guest registration fee will apply to all other nonmember physicians.

The Twenty-sixth Postgraduate Course is scheduled for Sunday, January 24, 1993. The registration fee is $65.00 for all attendees. The Postgraduate Program will include minisymposia dealing with Thoracoscopy, Current Pul- monary Surgical Problems, Decisions in Cardiac Surgery, and Transplantation. A C.C.C.E.T.S. Basic Science Lec- ture and a special luncheon presentation by Floyd Loop on a subject of general interest will also be included.

In addition to the Postgraduate Program, this year’s Annual Meeting will include a scientific poster session, breakfast seminars, the annual movie night, a wide range

of surgical exhibits, and a complete schedule of scientific presentations drawn from the largest volume of abstracts ever submitted for presentation to The Society.

An advance program information booklet will be mailed to all members of The Society this fall. It will include a detailed schedule of events as well as registration and housing forms and other pertinent information regarding the Annual Meeting. Nonmembers wishing to receive the advance program booklet should write to the Secretary of The Society, Richard P. Anderson, MD.

Richard P. Anderson, M D Secretary The Society of Thoracic Surgeons 401 N Michigan Avenue Chicago, IL 60611 (312) 644-6610 FAX (312) 527-6635

use of epicardial electrocardiogram for detecting cardiac allograft rejection☆

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