Detection Of Cardiac Allograft Rejection Research Articles

Relationship between donor-derived cell-free DNA and tissue-based rejection-related transcripts in heart transplantation

IntroductionEndomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs which may provide further insight into the pathophysiology of allograft rejection and injury. MethodsThis is a retrospective observational study of 156 endomyocardial biopsy (EMB) evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood prior to EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) were compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated. ResultsMMDx characterized allograft tissue as no rejection (NR) (62.8%), antibody-mediated rejection (ABMR) (26.9%), T-cell-mediated rejection (TCMR) (5.8%), and mixed ABMR/ TCMR (4.5%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (76.3% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters correlated with dd-cfDNA scores, including DSAST, GRIT, HT1, QCMAT and S4. For individual transcripts, tissue ROBO4 was significantly correlated with dd-cfDNA in both non-rejection and rejection as assessed by MMDx. ConclusionCollectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA and expression of ROBO4 (a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of antibody-mediated rejection (AMR), which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection (ACR).

Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

T1 mapping of the right ventricle in heart transplant recipients: how does it correlate with endomyocardial biopsy findings?

Abstract Aim Noninvasive detection of cardiac allograft rejection is highly desirable. We sought to assess how right ventricular (RV) T1 mapping correlates with endomyocardial biopsy findings. Methods All patients underwent right heart catheterization with biopsy and cardiac magnetic resonance (CMR) irrespective of symptoms, as part of the institutional registry protocol dedicated to heart transplant (HTx) recipients. CMR studies were performed using a 1.5 T scanner and analyses by using a commercially available software (CMR42, Circle CVI, Calgary, Canada). Endocardial and epicardial borders were drawn on end-systolic and end-diastolic phases for ventricular function analysis. For T1 measurements, region of interests located at the RV free-wall were drawn manually on midventricular short-axis slices avoiding blood pool and epicardial fat. Extracellular volume (ECV) was calculated as ECV = (1 − hematocrit) × (ΔR1 myocardium/ΔR blood), where R1 = 1/T1. Late gadolinium enhancement (LGE) images were also obtained using a phase-sensitive inversion recovery segmented gradient echo sequence. Hyperenhancement was assessed semi-quantitatively as segmental (2–3 cm) or diffuse (>3 cm). Allograft rejection was determined based on the severity of inflammatory infiltrates and myocyte damage on pathological specimens according to the standardized International Society for Heart and Lung Transplantation (ISHLT) nomenclature. Results In all, 61 paired studies were evaluated. None of the patients had heart failure symptoms. We defined 3 subgroups: Group I; never rejected (n=23), group II; biopsy remarkable for rejection (n=19) and group III; history of past rejection(s) (n=19). RV volumes and ejection fraction (EF) did not differ between the groups. However, rejections were nicely mirrored by T1 time and particularly by ECV. Of note, T1 time and ECV improved but not completely normalized after resolution of rejection. Overall, T1 time (cut off 1060ms) and ECV (cut off 35%) were sensitive (84%, both) and had high negative predictive values (88% and 87%, respectively) but not specific (43% and 52% respectively) for discriminating rejection related subclinical RV damage. Their specificity slightly improved to 52 and 61% respectively, if patients with previous rejection were excluded (Figure 1). LGE did not discriminate rejection. Conclusion RV volumes and EF are insensitive to detect allograft rejection. Native T1 time and ECV of the RV, as a means of extracellular expansion, likely reflect interstitial fibrosis, oedema, and inflammation that are typical for, but not limited to allograft rejection. Hence, these parameters can help to exclude rejection but have limited standalone value for making the nonivasive diagnosis due to their low specificity. These results cannot be extrapolated to the left ventricle. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): University of Baskent

Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection.

Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation. Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n=125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication. Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R. RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection.

Dynamic computed tomography perfusion imaging for detection of cardiac allograft rejection and myocardial ischemia in a heart transplant recipient

Dynamic computed tomography perfusion imaging for detection of cardiac allograft rejection and myocardial ischemia in a heart transplant recipient

Native T1 Mapping in the Diagnosis of Cardiac Allograft Rejection: A Prospective Histologically Validated Study

ObjectivesThis study aimed to determine the role of T1 mapping in identifying cardiac allograft rejection. BackgroundEndomyocardial biopsy (EMBx), the current gold standard to diagnose cardiac allograft rejection, is associated with potentially serious complications. Cardiac magnetic resonance (CMR)–based T1 mapping detects interstitial edema and fibrosis, which are important markers of acute and chronic rejection. Therefore, T1 mapping can potentially diagnose cardiac allograft rejection noninvasively. MethodsPatients underwent CMR within 24 h of EMBx. T1 maps were acquired at 1.5-T. EMBx-determined rejection was graded according to International Society of Heart and Lung Transplant (ISHLT) criteria. ResultsOf 112 biopsies with simultaneous CMR, 60 were classified as group 0 (ISHLT grade 0), 35 as group 1 (ISHLT grade 1R), and 17 as group 2 (2R, 3R, clinically diagnosed rejection, antibody-mediated rejection). Native T1 values in patients with grade 0 biopsies and left ventricular ejection fraction >60% (983 ± 42 ms; 95% confidence interval: 972 to 994 ms) were comparable to values in nontransplant healthy control subjects (974 ± 45 ms; 95% confidence interval: 962 to 987 ms). T1 values were significantly higher in group 2 (1,066 ± 78 ms) versus group 0 (984 ± 42 ms; p = 0.0001) and versus group 1 (1,001 ± 54 ms; p = 0.001). After excluding patients with an estimated glomerular filtration rate <50 ml/min/m2, there was a moderate correlation of log-transformed native T1 with high-sensitivity troponin T (r = 0.54, p < 0.0001) and pro–B-type natriuretic peptide (r = 0.67, p < 0.0001). Using a T1 cutoff value of 1,029 ms, the sensitivity, specificity, and negative predictive value were 93%, 79%, and 99%, respectively. ConclusionsMyocardial tissue characterization with T1 mapping displays excellent negative predictive capacity for the noninvasive detection of cardiac allograft rejection and holds promise to reduce substantially the EMBx requirement in cardiac transplant rejection surveillance.

Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection

Exosomes are cell-derived circulating vesicles that play an important role in cell-cell communication. Exosomes are actively assembled and carry messenger RNAs, microRNAs and proteins. The "gold standard" for cardiac allograft surveillance is endomyocardial biopsy (EMB), an invasive technique with a distinct complication profile. The development of novel, non-invasive methods for the early diagnosis of allograft rejection is warranted. We hypothesized that the exosomal proteome is altered in acute rejection, allowing for a distinction between non-rejection and rejection episodes. Serum samples were collected from heart transplant (HTx) recipients with no rejection, acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of serum exosome was performed using a mass spectrometer (Orbitrap Fusion Tribrid). Principal component analysis (PCA) revealed a clustering of 3 groups: (1) control and heart failure (HF); (2) HTx without rejection; and (3) ACR and AMR. A total of 45 proteins were identified that could distinguish between groups (q < 0.05). Comparison of serum exosomal proteins from control, HF and non-rejection HTx revealed 17 differentially expressed proteins in at least 1 group (q < 0.05). Finally, comparisons of non-rejection HTx, ACR and AMR serum exosomes revealed 15 differentially expressed proteins in at least 1 group (q < 0.05). Of these 15 proteins, 8 proteins are known to play a role in the immune response. Of note, the majority of proteins identified were associated with complement activation, adaptive immunity such as immunoglobulin components and coagulation. Characterizing of circulating exosomal proteome in different cardiac disease states reveals unique protein expression patterns indicative of the respective pathologies. Our data suggest that HTx and allograft rejection alter the circulating exosomal protein content. Exosomal protein analysis could be a novel approach to detect and monitor acute transplant rejection and lead to the development of predictive and prognostic biomarkers.

Genetic and genomic approaches to the detection of heart transplant rejection.

Since Christiaan Barnard performed the first heart transplant in 1967, over 100,000 heart transplants have been performed worldwide. As was true then, rejection remains the major threat to the function and survival of the allograft. The development of the endomyocardial biopsy as a means to monitor for rejection has allowed heart transplantation to thrive as a therapy for patients with end-stage heart disease. The need for a noninvasive method of rejection surveillance led to the development of the first genetic test for allograft rejection, the AlloMap®. In this article, after presenting the pathological and clinical features of cardiac allograft rejection, the authors discuss the development and application of gene-expression testing for the detection of cardiac allograft rejection. We then explore emerging 'omic' approaches that will be the rejection detection methods of the future.

Diagnostic performance of multisequential cardiac magnetic resonance imaging in acute cardiac allograft rejection

We evaluated cardiac magnetic resonance imaging (CMR) as a non-invasive test for cardiac allograft rejection. We performed CMR on 50 heart-transplant recipients. Acute rejection was confirmed in 11 cases by endomyocardial biopsy (EMB) and presumed in 8 cases with a recent fall in left-ventricular ejection fraction (LVEF) not attributable to coronary allograft vasculopathy. Control patients had both normal LVEF and no significant rejection on EMB. Cardiac magnetic resonance imaging evaluated myocardial function, oedema, and early and late post-Gadolinium-DTPA contrast enhancement. Patients with confirmed rejection demonstrated elevated early relative myocardial contrast enhancement (4.1 +/- 0.3 vs. 2.8 +/- 0.2, P < 0.001) and a trend to higher oedema suggested by higher relative myocardial intensity on T(2)-weighted imaging compared to controls (2.1 +/- 0.1 vs. 1.7 +/- 0.1, P = 0.1). With rejection defined as increased early contrast enhancement or myocardial oedema, the sensitivity and specificity of CMR compared with EMB were 100 and 73%, respectively. Eight patients with presumed rejection also had elevated early myocardial contrast enhancement compared with controls, (8.7 +/- 1.9 vs. 2.8 +/- 0.2, P < 0.05), which reduced following increased immunosuppression (8.7 +/- 1.9 vs. 4.6 +/- 1.2, P < 0.05). In these patients LVEF improved following increased immunosuppression (32 +/- 5 vs. 46 +/- 5%, P < 0.05). Cardiac magnetic resonance imaging is a promising modality for non-invasive detection of cardiac allograft rejection.

Ultrasonic backscatter tissue characterization in cardiac diagnosis

Ultrasonic tissue characterization has shown the potential to yield information about structural and functional properties of cardiovascular tissue. The development of real-time two-dimensional integrated backscatter imaging has made feasible clinical investigations of ultrasonic tissue characterization, including detection of stunned myocardium in patients with acute ischemia, recognition of remote infarction, detection of cardiac allograft rejection, and study of diffuse myocardial involvement with systemic diseases such as diabetes mellitus. Technical improvements and scientific advances in the understanding of the interaction between ultrasound and tissue may open an even wider range of clinical applications. Even in its present, relatively preliminary form, tissue characterization appears to have the potential for clinical application. Additional clinical experience will stimulate refinements and increases in the diagnostic power of this promising approach.

396: Molecular diagnostic assay for the non-invasive detection of cardiac allograft rejection: Implication for transplant nursing practice

396: Molecular diagnostic assay for the non-invasive detection of cardiac allograft rejection: Implication for transplant nursing practice

254: Clinical implementation of molecular testing for the non-invasive detection of cardiac allograft rejection

The CARGO study developed and validated a gene expression test in peripheral blood mononuclear cells (PBMC) using real-time polymerase chain reaction (PCR) for 20 genes. The genes were derived from microarray analysis of genes whose expression increased or decreased as a result of rejection (R). The molecular test was compared to biopsy (Bx) and was able to discriminate the absence of R and immune quiescence from immune activation.

Molecular Beacons Illuminate Subcellular Events

Building on decades of technological advances and imaging experience, during which noninvasive imaging of cardiac structure and function, myocardial perfusion and viability, and noncoronary vascular pathology have become intimately entwined in routine clinical practice, advanced imaging techniques are now poised to deliver noninvasive coronary arteriograms and to delineate the coronary artery wall in exquisite detail. At the same time that these highly promising methods for anatomic imaging at the macroscopic level are creating great excitement among physicians, their patients, and the public, a quieter imaging revolution is underway with steady progress in detecting and tracking fundamental biological processes at the cellular and subcellular levels. In the era of genomic research, molecular biology, and stem cell therapies, these methods have great potential to accelerate understanding of basic pathophysiological processes in animals and humans and to develop new tools for early diagnosis and drug development. Cardiovascular molecular imaging is taking hold. See p 1800 Molecular imaging is the science of visually representing, characterizing, and quantifying cellular/subcellular biological processes in intact organisms. These processes include gene expression, protein–protein interaction, signal transduction, cellular metabolism, and both intracellular and intercellular trafficking. Molecular imaging has the potential to quantify these events, to monitor multiple events simultaneously, to localize these events in 3 dimensions, and to monitor these events serially. Thus, biological processes can be identified and studied in time and space, providing “4-dimensional” information. The emergence of molecular imaging has coincided with and has been made possible by the enormous progress in molecular biology, cell biology, and transgenic animal models, as well as the development of imaging probes that are specific, reproducible, and quantifiable.1 Molecular imaging was once the sole domain of nuclear medicine, with tracers developed for both positron emission tomography (PET) and single photon emission computed tomography (SPECT). Examples include antimyosin antibodies for …

Issue Highlights

HomeCirculationVol. 110, No. 25Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published21 Dec 2004https://doi.org/10.1161/circ.110.25.3743Circulation. 2004;110:3743CARDIAC MORTALITY IS HIGHER AROUND CHRISTMAS AND NEW YEAR’S THAN AT ANY OTHER TIME: THE HOLIDAYS AS A RISK FACTOR FOR DEATH, by Phillips et al.It has long been appreciated that cardiovascular mortality increases in the winter months. Speculation on the mechanisms have centered on whether the winter peak was related to climate. In this issue of Circulation, Phillips and colleagues observe that over and above the winter mortality peak, there is an approximately 5% excess in both cardiac and noncardiac deaths on both Christmas and New Year’s days. The investigators examined data from the United States from 1973-2001, representing 53 million deaths, and found that the excess holiday mortality actually has increased over time. The investigators observed that the holiday spike was more notable for outpatient than inpatient deaths, leading the authors to speculate that delays in seeking treatment may contribute to the excess holiday mortality. The authors explore many potential possible explanations of their findings, but clearly further research is needed to uncover the mechanisms definitively. See p 3781.PREDICTORS OF QUALITY-OF-LIFE BENEFIT AFTER PERCUTANEOUS CORONARY INTERVENTION, by Spertus et al.The primary benefit of percutaneous coronary intervention (PCI) is to improve quality of life and reduce symptom burden. Many investigators have identified patient characteristics associated with the risk of complications, but few have sought to determine which patients experience the most quality-of-life benefit. Spertus and colleagues, in a prospective, observational study of 1518 patients undergoing PCI as part of nonacute care, determined the correlates of improved quality of life 1 year after the procedure using the Seattle Angina Questionnaire. This information can assist physicians and their patients in estimating the benefit of PCI in stable patients. See p 3789.DETECTION OF CARDIAC ALLOGRAFT REJECTION AND RESPONSE TO IMMUNOSUPPRESSIVE THERAPY WITH PERIPHERAL BLOOD GENE EXPRESSION, by Horwitz et al.The detection of cardiac transplant rejection is difficult. Endomyocardial biopsy, the “gold standard,” is less than perfect because of its invasive nature and vulnerability to sampling error. Horwitz et al advance the novel concept that gene profiling of leukocytes may provide a noninvasive way to detect and follow cardiac rejection. Their elegant findings constitute proof of this principle by showing that leukocyte gene profiling was able to distinguish patients with from those without rejection, and, further, to follow the course of resolution. If validated in larger trials, this new approach offers an important breakthrough in the management of transplant recipients. See p 3815.Visit www.circ.ahajournals.org:Clinician UpdateClinical Utility of Serial and Continuous ST-Segment Recovery Assessment in Patients With Acute ST-Elevation Myocardial Infarction: Assessing the Dynamics of Epicardial and Myocardial Reperfusion. See p e533.Images in Cardiovascular MedicineScimitar Syndrome With Esophageal Varices: Magnetic Resonance Angiography Detects Anomalous Pulmonary Venous Return. See p e540.Download figureDownload PowerPointCorrespondenceLetter Regarding Article by Li et al,“C-Reactive Protein Upregulates Complement-Inhibitory Factors in Endothelial Cells.” See p e542. Previous Back to top Next FiguresReferencesRelatedDetails December 21, 2004Vol 110, Issue 25 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.110.25.3743 Originally publishedDecember 21, 2004 PDF download Advertisement

Detection of Cardiac Allograft Rejection and Response to Immunosuppressive Therapy With Peripheral Blood Gene Expression

Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.

1089-114 C-reactive protein but not markers of myocardial necrosis may preclude endomyocardial biopsy for the detection of cardiac allograft rejection

1089-114 C-reactive protein but not markers of myocardial necrosis may preclude endomyocardial biopsy for the detection of cardiac allograft rejection

Detection of cardiac allograft rejection by multi-parameter gene expression analysis on circulating mononuclear cells using real-time RT-PCR

Detection of cardiac allograft rejection by multi-parameter gene expression analysis on circulating mononuclear cells using real-time RT-PCR

Value of QT dispersion analysis for noninvasive detection of cardiac allograft rejection

1/2 }, are measures of the spatial irregularity of myocardial electrical conduction. Both have been identified as risk markers in relation to several cardiopathies, and increased QTc dispersion has been related to increased risk of life-threatening ventricular arrhythmias and sudden death.5 and 6 For example, there is growing evidence that QT dispersion and QTc dispersion are correlated with the risk of sudden death among patients with congestive heart failure,7 left ventricle (LV) hypertrophy due to hypertrophic cardiomyopathy,8 ischemic cardiopathy,9 or mitral valve prolapse.10 QT dispersion is also increased in patients with arrhythmogenic right ventricular dysplasia.11 It has been suggested that QT dispersion may be a useful marker or predictor of cardiovascular morbidity and mortality due to complex ventricular arrhythmias in patients with rheumatoid arthritis12 or Duchenne muscular dystrophy13 or of increased risk of cardiac complications in liver transplant candidates.14 The usefulness of QT dispersion analysis in heart transplant patients is still unknown, and few studies have been done in this area. It has been suggested that cardiac allograft vasculopathy results in ventricular repolarization abnormalities that can be detected by an increase in QTc dispersion15 and that QT dispersion might serve as a noninvasive marker of resolution of allograft dysfunction.16 Here we report the results of a study of the relationship between QT dispersion and AR status as determined by EMB.

Detection of acute cardiac rejection by analysis of heart rate variability in heterotopically transplanted rats

Background A less-invasive method for cardiac allograft surveillance than endocardial biopsy is needed. We analyzed heart rate variability of heterotopically transplanted rat hearts as a method of detecting rejection of rat cardiac allografts. Methods Two kinds of heterotopic transplants were performed: 1) Brown-Norway rats received Brown-Norway rat isografts, and 2) Lewis rats received Brown-Norway rat allografts. The electrocardiogram (ECG) of the grafts were serially recorded under non-anesthetized and non-restricted conditions using a telemetric ECG transmitter implanted in the recipient’s abdomen. Frequency domain analysis of the ECGs was performed using a fast Fourier algorithm. Results Total power of the heart rate variability in the isograft heart was reduced to 1.1%, compared to normal subjects without transplantation ( p < .001). In the allograft heart, it was also reduced to 1.0% on days 1.5 (rejection score 0 to 1), but gradually increased thereafter up to 185% on day 6 (rejection score 3.75 ± 0.50). The increase in spectral power was frequency-dependent (i.e., changes in the power in lower frequency range [LF, 0.04 to 0.67 Hz] were significantly higher than other ranges). This increase was reversible when immunosuppressive therapy was performed with the use of cyclosporine A. In the allograft group, peak-to-peak amplitudes of the QRS complex and heart rate were significantly decreased on day 5.5 or later, whereas the power of the LF was significantly increased by day 3.5 or later. Conclusions Our data suggest that heart rate variability analysis is a promising noninvasive marker for early detection of cardiac allograft rejection. This method may also provide a sensitive means of assessing the effects of immunosuppressive therapy.

Major histocompatibility complex class II antigen expression in rejecting cardiac allografts: detection using in vivo imaging with radiolabeled monoclonal antibody.

Increased expression of major histocompatibility complex class II (MHC-II) antigen occurs during cardiac allograft rejection. We tested the hypotheses that (1) radiolabeled antibody to MHC-II antigen allows detection of cardiac allograft rejection using nuclear imaging techniques and (2) uptake of radiolabeled antibody to MHC-II antigen correlates with severity of rejection. Thirteen beagles with cervical cardiac allografts were studied for 64+/-23 days by use of myocardial biopsy and in vivo imaging. Uptake of radiolabeled (131I [n=2], 123I [n=1], or 111In [n=10]) antibody to MHC-II increased over baseline in 7 animals that developed histological evidence of progressively worsening allograft rejection (group A), from 72.2+/-46.1 to 176.8+/-102.0 counts/pixel/mCi (P<.009). In 4 beagles without progressively worsening allograft rejection (group B), uptake was unchanged during follow-up (74.4+/-43.8 and 60.2+/-37.4 counts/pixel/mCi; P=NS). In animals studied with 111In-labeled antibody, uptake increased from 102.9+/-23.1 at baseline to 233.2+/-82.7 counts/pixel/mCi at follow-up in group A animals (P=.036), with no significant change in group B (91.1+/-34.9 and 75.9+/-24.9 counts/pixel/mCi; P=NS). Uptake of 111In-labeled antibody was 107.5+/-35.7, 135.9+/-70.8, and 307.8+/-90.1 counts/pixel/mCi in biopsy samples showing evidence of mild, moderate, and severe rejection, respectively (P=.001). Biopsy samples showing mild, moderate, and intense MHC-II expression antibody uptake had uptakes of 92.6+/-36.3, 158.5+/-54.7, and 307.8+/-90.1 counts/pixel/mCi, respectively (P=.00004). Radiolabeled monoclonal antibodies to MHC-II antigen can detect cardiac allograft rejection in this large mammal model of cardiac allograft transplantation, and this technique may have a potential role in the detection of rejection in patients after cardiac transplantation.