Detection Of Cardiac Allograft Rejection Research Articles

Noninvasive diagnosis of cardiac allograft rejection in an orthotopic canine model

A decline in the R wave voltage obtained from surface electrocardiograms once correlated with cardiac allograft rejection. With cyclosporine therapy, however, these electrocardiographic findings became inconsistent, occurring only during severe rejection episodes. Despite cyclosporine use, intramyocardial unipolar peak-to-peak amplitudes obtained from plunge electrodes are reported to be highly sensitive and specific for diagnosing rejection. These reports are based on heterotopic grafts, which atrophy over time, making long-term voltage changes during rejection difficult to interpret. The purpose of this study was to use analysis of unipolar peak-to-peak amplitudes as a prospective monitoring tool for diagnosing orthotopic cardiac allograft rejection. Ten adult mongrel dogs underwent orthotopic heart transplantation with the attachment of four intramyocardial leads. The unipolar peak-to-peak amplitudes were measured daily and compared with endomyocardial biopsy results. We found that intramyocardial unipolar peak-to-peak amplitude analysis had a sensitivity and a specificity of 100% for diagnosing rejection. We also found that as the number of myocardial leads increased, the sensitivity of detecting rejection also increased. We conclude that unipolar peak-to-peak amplitude analysis is an accurate noninvasive means for early detection of cardiac allograft rejection in an orthotopic model. Its success should allow less frequent, more selective use of endomyocardial biopsy.

Non-invasive detection of cardiac allograft rejection by multivariate analysis of computer generated M-mode data in pediatric patients

Non-invasive detection of cardiac allograft rejection by multivariate analysis of computer generated M-mode data in pediatric patients

Noninvasive diagnosis of cardiac allograft rejection: the effect of procainamide.

The surface electrocardiogram (ECG) has been used as a noninvasive technique for the diagnosis of cardiac allograft rejection. Alteration in conduction, R-wave amplitude, and rhythm have been associated with rejection. These ECG findings are modulated by the myocyte sodium channel, but are inconsistent and occur only during severe rejection episodes. The purpose of this study was to (1) characterize changes in cardiac electrophysiology during allograft rejection using the highly sensitive intramyocardial electrocardiogram and (2) determine whether pharmacological sodium channel blockade with procainamide enhances subtle ECG changes. Nine mongrel dogs underwent heterotopic heart transplantation in which four intramyocardial leads (one anteriorly and posteriorly on each ventricle) were attached. Leads exited to a subcutaneously placed ECG block which was transcutaneously accessed posttransplant to record direct intramyocardial electrocardiograms. Six animals were treated with procainamide, while three were not and served as controls. Daily measurements included the QRS, QT, and QTc intervals and the R-wave amplitude. Endomyocardial biopsies were performed weekly and also when significant decline in ECG amplitude occurred. Detailed ECG interval analysis failed to establish any correlation between conduction and rejection, even in the procainamide-treated group. Intramyocardial amplitude analysis, however, had a sensitivity of 100% and a specificity of 86% for the diagnosis of rejection. The results indicate that intramyocardial ECG interval analysis is not predictive of rejection even when prolonging conduction with procainamide. Amplitude analysis, however, remains an accurate noninvasive means for the early detection of cardiac allograft rejection and should allow more selective use of endomyocardial biopsy.

Scintigraphic detection of early cardiac rejection by iodine 123-labeled monoclonal antibody directed against monomorphic determinant of major histocompatibility complex class II antigens

Although it has been shown that early cardiac rejection can be visualized by radioimmunoscintigraphy targeting major histocompatibility complex class II antigen, the use of antibodies that bind to a polymorphic determinant of class II antigen has certain disadvantages for clinical application. This investigation was designed to examine the feasibility of scintigraphic detection of cardiac allograft rejection by using a monoclonal antibody that reacts with a monomorphic determinant of rat IA antigens. Twenty PVG rats (RT1 c) and five DA rats (RT1 a) underwent heterotopic transplantation with DA hearts. Two of the 20 allografted rats were treated with FK506 (2 mg/kg/day). Seventeen rats were injected intravenously with 80 μCi of iodine 123-labeled monoclonal antibody reactive with a monomorphic determinant of rat major histocompatibility complex class II antigens (Ox6) 16 hours before scintigraphy, and images were compared with those obtained by injection of 123I-labeled monoclonal antibody against a polymorphic determinant of class II antigens (F17-23-6, anti-RT1 a) (n = 8). Background activity was higher in rats injected with Ox6 than in rats injected with F17-23-6. Uptake of labeled Ox6 in the grafts reflected the severity of rejection as determined by histopathologic criteria. Rejecting allografts with lymphocyte infiltration but without myocyte necrosis could be identified by the scintigraphy with use of labeled Ox6. The ratios of radioactivity in the graft to radioactivity in the blood (percent injected dose per gram of tissue) in rats with grade IA and IB rejection (0.56 ± 0.12, n = 4, p < 0.001) and in rats with grade IIIA and IIIB rejection (0.60 ± 0.09, n = 4, p < 0.001) were significantly greater than in rats with nonrejecting grafts (0.24 ± 0.08, n = 9). In conclusion, radioimmune scintigraphy with use of 123I-labeled monoclonal antibody directed against a monomorphic determinant of major histocompatibility complex class II antigen appears to be a sensitive and noninvasive method for detecting cardiac allograft rejection.

Noninvasive detection of cardiac allograft rejection by prospective telemetric monitoring

A method for cardiac allograft surveillance that is less invasive than endomyocardial biopsy is needed. A fall in the unipolar peak-to-peak amplitude recorded from cardiac allografts has been shown to detect rejection when retrospectively compared with endomyocardial biopsy. This study was performed to assess the sensitivity and specificity of prospective telemetric unipolar peak-to-peak amplitude surveillance in detecting rejection of heterotopic canine cardiac allografts occurring through triple drug immunosuppression. Native heart and graft amplitudes were telemetrically acquired on a daily basis. A fall in normalized unipolar peak-to-peak graft amplitude to less than 85% was used as an indication for biopsy. A quantitative rejection score was calculated for each endomyocardial biopsy (rejection score greater than 0.66 = histologic rejection). Rejection was documented in all animals. Thirty-six biopsies were performed (10 control biopsies and 26 amplitude-directed biopsies); 25 of the 36 demonstrated rejection. Sensitivity and specificity were 88% and 91%, respectively. A linear correlation between unipolar peak-to-peak amplitude and rejection severity was seen (R = 0.87, p less than 0.001). The first true positive amplitude was associated with mild-to-moderate rejection (rejection score = 1.63 +/- 0.45). Unipolar peak-to-peak amplitude recorded from native hearts remained stable during allograft rejection. It is concluded that prospective, telemetric cardiac allograft surveillance can accurately detect rejection occurring through ongoing immunosuppression.

Evidence of allograft related transplantation antigen binding cells for detection of cardiac allograft rejection—Preliminary report

In 8 heart transplant recipients in follow-up checks we have evaluated the binding of transplantation antigen loaded methacrylate-carrier to peripheral mononuclear cells (rosette technique). All patients were treated with a triple-drug regimen for immunosuppression, consisting of steroids, azathioprine and cyclosporine A. The increase of the number of these antigen binding cells over a limit value of 30 RFC/103 MNC is a reliable sign of a beginning immune reaction against the graft. The evidence is given by comparing the results with these of situation in endomyocardial biopsies (EMB). The test is predictive 3 to 6 days before infiltrating cells are visible in biopsies and donor independent (use of antigen mixture from cadaver spleens).

Noninvasive detection of cardiac allograft rejection by analysis of the unipolar peak-to-peak amplitude of intramyocardial electrograms

The use of standard electrocardiographic monitoring to detect cardiac allograft rejection has become unreliable since the advent of cyclosporine immunosuppression. Unipolar peak-to-peak amplitude analysis has been shown to be a quantitative measure of ischemic myocardial injury. This study was performed to determine if unipolar peak-to-peak amplitude analysis could accurately detect cardiac allograft rejection as determined by blinded endomyocardial biopsies. Ten adult mongrel dogs underwent heterotopic (n = 7) or orthotopic (n = 3) cardiac transplantation with placement of sutureless screw-in electrodes (Medtronic, Inc, Minneapolis, MN) on the anterior and posterior aspect of each ventricle. Postoperatively, animals were immunosuppressed for seven to ten days with cyclosporine and prednisone and then allowed to reject the transplant. Digitally processed intramyocardial electrograms were obtained daily. Endomyocardial biopsy was performed 1 week postoperatively and then at three to five day intervals for histological correlation. A unipolar peak-to-peak amplitude decline of 15% or greater occurred one to three days before the biopsy detection in 10 of 10 episodes of rejection. There were no false negatives and one false positive (although a small focal lymphocytic infiltrate was present). Thus, noninvasive unipolar peak-to-peak amplitude analysis was 100% sensitive and 90% specific in predicting and detecting cardiac allograft rejection.

Sensitivity of scintigraphy with 111In-lymphocytes for detection of cardiac allograft rejection

We recently demonstrated the feasibility of noninvasive detection of cardiac allograft rejection after administration of indium-111-labeled lymphocytes. To determine the sensitivity and specificity of the technique, as well as its value for delineating the severity of rejection, we studied 16 dogs with heterotopic thoracic cardiac allografts. Five animals were evaluated while exposed to immunosuppressive agents. Animals were scanned sequentially after administration of 100–400 μCi of indium-111-labeled autologous lymphocytes. Myocardial lymphocyte infiltration was expressed as the indium excess (IE), defined as the ratio of indium activity of the transplant or native heart compared with that in blood. Scintigraphic results were compared with characteristics of simultaneously obtained endomyocardial biopsies. Among 17 biopsy documented episodes of rejection, 16 were detected scintigraphically. Among 18 biopsies with no evidence of rejection, scintigraphy was uniformly negative. Thus, the sensitivity and specificity of scintigraphy were 94 and 100%, respectively. Biopsies graded as showing no rejection were associated with an IE of 0.3 ± 0.5 (±SD); those graded as mild, 2.8 ± 1.7; those as moderate, 10.7 ± 7.2; and those graded as indicative of severe rejection, 14.2 ± 4.5. Thus, scintigraphy with indium-111-labeled lymphocytes sensitively and specifically detects cardiac allograft rejection and delineates the intensity of the rejection process. It should be useful clinically for assessing potential allograft rejection noninvasively.

The detection of cardiac allograft rejection by alterations in proton NMR relaxation times.

The ability of proton NMR relaxation times to detect cardiac allograft rejection was studied in an inbred rat heterotopic cardiac transplantation model. Hearts from 25 Lewis X Brown Norway F1 hybrid rats were anastomosed to the abdominal aorta and vena cava of Lewis recipients; 25 Lewis donor hearts served as isograft controls. Groups of five allografts and five isografts were harvested daily between two and six days post-transplant. The relaxation times T1 and T2 of the transplanted hearts were determined in vitro with a 10 MHz spectrometer. T1 and T2 values in allografts did not differ significantly from those in isografts at days 2 and 3 post-transplant. However, at days 4, 5, and 6 T1 and T2 of the allografts were significantly prolonged. This finding correlated with an elevation in tissue water content and the onset of rejection as determined histologically. An additional 21 allografts, treated with cyclosporine, were studied in the same way from four to more than 100 days post-transplant. T1 and T2 values of these treated allografts did not change significantly during the observation period and were similar to the relaxation values obtained in the isografts at days 2 to 6. These data suggest that serial measurements of myocardial T1 and T2 may be useful in detecting acute cardiac allograft rejection and monitoring the effect of antirejection treatment.