The Impact of Midodrine on Guideline-Directed Medical Therapy in Patients Admitted With Systolic Heart Failure.

ABSTRACT: Midodrine is occasionally used off-label to treat hypotension associated with advanced heart failure (HF); however, its association with changes in prescription of guideline-directed medical therapy (GDMT) is unknown. We sought to evaluate the effect of midodrine on the GDMT prescription pattern and clinical outcomes of patients with decompensated systolic HF. We retrospectively identified 114 patients admitted to our hospital in 2020 with decompensated systolic HF who were prescribed midodrine on discharge and compared them with 358 patients with decompensated systolic HF who were not prescribed midodrine. At 6 months, the midodrine group had more initiation or up-titration of beta blockers, renin-angiotensin-aldosterone system inhibitors, and sodium-glucose cotransporter-2 inhibitors compared with the nonmidodrine group. Survival at 6 months was similar between the 2 groups, but the midodrine group had more frequent rehospitalization for HF. Our findings suggest that midodrine is associated with improved GDMT in patients with decompensated HF but may be associated with worse prognosis.

Intraprocedural delayed reassessment of paravalvular regurgitation in TAVR significantly reduces the use of postdilatation.

OBJECTIVES: We sought to investigate the effect of a 15-min delayed intraprocedural reassessment of paravalvular aortic regurgitation (PVR) after an immediate evaluation of posttranscatheter aortic valve replacement (TAVR) on the regurgitation grading and usage of postdilatation. BACKGROUND: PVR after TAVR is associated with poor prognosis, but postdilatation may increase the risk of other complications. METHODS: In a prospective cohort of consecutive patients treated with balloon-expandable valve ES-3 ultra, the degree of PVR was assessed immediately and 15 min after that first evaluation (excluded severe cases), with the indication of postdilatation based on the delayed assessment. As a control group, the previous consecutive series of patients also treated with the same model of valve prosthesis was used. RESULTS: A total of 180 patients were included in the prospective study cohort and 152 in the retrospective control group. In the study group, the immediate PVR assessment showed none-trace 27.5%, mild 52%, moderate 19%, and severe 1.5%, and the delayed re-evaluation graded PVR as none-trace 83%, mild 15.6%, and moderate 1.2% (p < 0.001 as compared to immediate). In the control group, the immediate PVR assessment showed none-trace 33.5%, mild 52%, moderate 13%, and severe 1.5%. The rate of postdilatation was 2.8% in the study group versus 10.5% in the control group (p = 0.006). At discharge, no differences were observed between groups in PVR echocardiographic grading. CONCLUSIONS: A post-TAVR delayed intraprocedural reassessment of the PVR shows a clearly lower degree of regurgitation as compared to immediate evaluation, which significantly decreased the indication of postdilatation.

Amphilimus- vs. zotarolimus-eluting stents in patients with diabetes mellitus and coronary artery disease: the SUGAR trial.

AIM: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes. METHODS AND RESULTS: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups. CONCLUSION: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT03321032.

Increased IGFBP2 Levels by Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism in a TAA-Injured Rat Model via AMPK Signaling Pathway.

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 106) 8 weeks after the experiment started. The expression of the IGFBP2 gene and glucose metabolism factors (e.g., AMPK, GLUT4) was significantly increased in the PD-MSC group compared to the nontransplantation (NTx) group (* p < 0.05). The levels of follicular development markers and the sex hormones AMH, FSH, and E2 were also higher than those in the TAA group. Using ex vivo cocultivation, the mRNA and protein expression of IGFBP2, AMPK, and GLUT4 were significantly increased in the cocultivation with the PD-MSCs group and the recombinant protein-treated group (* p < 0.05). These findings suggest that the increased IGFBP2 levels by PD-MSCs play an important role in glucose metabolism and ovarian function through the IGFBP2-AMPK signaling pathway.

Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function?

Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 105) and high (5 × 105) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p < 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p < 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems.

Estimation of Axle Torque for an Agricultural Tractor Using an Artificial Neural Network.

The objective of this study was to develop a model to estimate the axle torque (AT) of a tractor using an artificial neural network (ANN) based on a relatively low-cost sensor. ANN has proven to be useful in the case of nonlinear analysis, and it can be applied to consider nonlinear variables such as soil characteristics, unlike studies that only consider tractor major parameters, thus model performance and its implementation can be extended to a wider range. In this study, ANN-based models were compared with multiple linear regression (MLR)-based models for performance verification. The main input data were tractor engine parameters, major tractor parameters, and soil physical properties. Data of soil physical properties (i.e., soil moisture content and cone index) and major tractor parameters (i.e., engine torque, engine speed, specific fuel consumption, travel speed, tillage depth, and slip ratio) were collected during a tractor field experiment in four Korean paddy fields. The collected soil physical properties and major tractor parameter data were used to estimate the AT of the tractor by the MLR- and ANN-based models: 250 data points were used for developing and training the model were used, the 50 remaining data points were used to test the model estimation. The AT estimated with the developed MLR- and ANN-based models showed agreement with actual measured AT, with the R2 value ranging from 0.825 to 0.851 and from 0.857 to 0.904, respectively. These results suggest that the developed models are reliable in estimating tractor AT, while the ANN-based model showed better performance than the MLR-based model. This study can provide useful results as a simple method using ANNs based on relatively inexpensive sensors that can replace the existing complex tractor AT measurement method is emphasized.

Weakly Supervised Crop Area Segmentation for an Autonomous Combine Harvester.

Machine vision with deep learning is a promising type of automatic visual perception for detecting and segmenting an object effectively; however, the scarcity of labelled datasets in agricultural fields prevents the application of deep learning to agriculture. For this reason, this study proposes weakly supervised crop area segmentation (WSCAS) to identify the uncut crop area efficiently for path guidance. Weakly supervised learning has advantage for training models because it entails less laborious annotation. The proposed method trains the classification model using area-specific images so that the target area can be segmented from the input image based on implicitly learned localization. This way makes the model implementation easy even with a small data scale. The performance of the proposed method was evaluated using recorded video frames that were then compared with previous deep-learning-based segmentation methods. The results showed that the proposed method can be conducted with the lowest inference time and that the crop area can be localized with an intersection over union of approximately 0.94. Additionally, the uncut crop edge could be detected for practical use based on the segmentation results with post-image processing such as with a Canny edge detector and Hough transformation. The proposed method showed the significant ability of using automatic perception in agricultural navigation to infer the crop area with real-time level speed and have localization comparable to existing semantic segmentation methods. It is expected that our method will be used as essential tool for the automatic path guidance system of a combine harvester.

Electrocardiographic Changes Associated With Ibrutinib Exposure.

Although ibrutinib-associated atrial and ventricular arrhythmias have been well described, there is little information about ibrutinib's effects on other electrocardiographic parameters, particularly the QT interval. Using our database of 137 patients treated with ibrutinib, we retrospectively identified 21 patients in whom an electrocardiogram (ECG) was obtained both prior to and after ibrutinib exposure. All traditional ECG parameters as well as QT dispersion were manually measured by an electrophysiologist. Compared to baseline ECGs, post ibrutinib ECGs demonstrated QT interval shortening from 386 ms to 356 ms (P = .007), corrected QT interval shortening using Bazett's formula from 446 ms to 437 ms (P = .04), and corrected QT interval shortening using Fridericia's formula from 425 ms to 407 ms (P = .003). QT dispersion also increased post ibrutinib exposure compared to baseline (39.8 ms vs 57.3 ms, P = .002). There was no significant change in other ECG parameters. In conclusion, both the absolute and corrected QT intervals significantly shortened after ibrutinib exposure, while there was a significant increase in QT dispersion. These findings may point to a common underlying electrophysiologic mechanism of ibrutinib-associated arrhythmias.

Predicting severe clinical events by learning about life-saving actions and outcomes using distant supervision.

Medical error is a leading cause of patient death in the United States. Among the different types of medical errors, harm to patients caused by doctors missing early signs of deterioration is especially challenging to address due to the heterogeneity of patients' physiological patterns. In this study, we implemented risk prediction models using the gradient boosted tree method to derive risk estimates for acute onset diseases in the near future. The prediction model uses physiological variables as input signals and the time of the administration of outcome-related interventions and discharge diagnoses as labels. We examine four categories of acute onset illness: acute heart failure (AHF), acute lung injury (ALI), acute kidney injury (AKI), and acute liver failure (ALF). To develop and test the model, we consider data from two sources: 23,578 admissions to the Intensive Care Unit (ICU) from the MIMIC-3 dataset (Beth-Israel Hospital) and 16,612 ICU admissions on hospitals affiliated with our institution (University of Washington Medical Center and Harborview Medical Center, the UW-CDR dataset). We systematically identify outcome-related interventions for each acute organ failure, then use them, along with discharge diagnoses, to label proxy events to train gradient boosted trees. The trained models achieve the highest F1 score with a value of 0.6018 when predicting the need for life-saving interventions for ALI within the next 24 h in the MIMIC-3 dataset while showing a median F1 score of 0.3850 from all acute organ failures in both datasets. The approach also achieves the highest F1 score of 0.6301 when classifying a patient's ALI status at the time of discharge from the MIMIC-3 dataset, with a median F1 score of 0.4307 in both datasets. This study shows the potential for using the time of outcome-related intervention administrations and discharge diagnoses as labels to train supervised machine learning models that predict the risk of acute onset illnesses.

Cardiovascular Toxicities of Bruton's Tyrosine Kinase Inhibitors.

OPINION STATEMENT: There has been a significant shift in the management of B cell malignancies over the past decade. Initial strategies involving the use of systemic chemotherapies have been gradually replaced by more targeted therapies to improve survival and overall tolerability. Bruton's tyrosine kinase inhibitors are breakthrough drugs that have been approved to treat many B cell malignancies. Despite their demonstrated benefits, unintended events still occur including various cardiotoxicities. In this review, we discuss the rationale behind developing these agents, their common cardiovascular toxicities, and associated management challenges.

Case of pembrolizumab-induced myocarditis presenting as torsades de pointes with safe re-challenge.

INTRODUCTION: Pembrolizumab is an immune checkpoint inhibitor targeting the programmed death receptor with clinical effect on multiple malignancies including sarcoma. Associated cardio-toxicities include myocarditis, cardiomyopathy, heart failure, and arrhythmias. Although in most cases of immune checkpoint inhibitor cardiotoxicity the offending agent is discontinued, we report a case of successful and safe re-challenge with a checkpoint inhibitor in a patient with mild myocarditis. CASE REPORT: We describe a 37-year-old female with alveolar soft part sarcoma, metastatic to the lungs on cycle 13 of pembrolizumab who presented with dyspnea, cough, and vague chest discomfort. Telemetry showed bigeminal bradycardia that transitioned to self-terminating torsades de pointes. Cardiac MRI showed subtle patchy T2 signal increase within the left ventricular septum without late gadolinium uptake, suggesting mild focal myocarditis.Management and outcome: The patient was started on a steroid taper without additional arrhythmias. We have re-challenged the patient who safely tolerated re-challenge with pembrolizumab despite an episode of torsades de pointes and documented myocarditis. She continues to receive pembrolizumab at seven months after the initial event without further cardiovascular events. DISCUSSION: To the best of our knowledge, this is the first reported case of successful re-challenge of pembrolizumab after an episode of myocarditis. In patients with mild myocarditis and no evidence of left ventricular dysfunction, re-challenge may be a viable option. However, close monitoring for the development of heart failure, cardiomyopathy, or serious arrhythmias is necessary to ensure patient safety.

Estimation of carcass weight of Hanwoo (Korean native cattle) as a function of body measurements using statistical models and a neural network.

OBJECTIVE: The objective of this study was to develop a model for estimating the carcass weight of Hanwoo cattle as a function of body measurements using three different modeling approaches: i) multiple regression analysis, ii) partial least square regression analysis, and iii) a neural network. METHODS: Data from a total of 134 Hanwoo cattle were obtained from the National Institute of Animal Science in South Korea. Among the 372 variables in the raw data, 20 variables related to carcass weight and body measurements were extracted to use in multiple regression, partial least square regression, and an artificial neural network to estimate the cold carcass weight of Hanwoo cattle by any of seven body measurements significantly related to carcass weight or by all 19 body measurement variables. For developing and training the model, 100 data points were used, whereas the 34 remaining data points were used to test the model estimation. RESULTS: The R2 values from testing the developed models by multiple regression, partial least square regression, and an artificial neural network with seven significant variables were 0.91, 0.91, and 0.92, respectively, whereas all the methods exhibited similar R2 values of approximately 0.93 with all 19 body measurement variables. In addition, relative errors were within 4%, suggesting that the developed model was reliable in estimating Hanwoo cattle carcass weight. The neural network exhibited the highest accuracy. CONCLUSION: The developed model was applicable for estimating Hanwoo cattle carcass weight using body measurements. Because the procedure and required variables could differ according to the type of model, it was necessary to select the best model suitable for the system with which to calculate the model.

Appropriateness of task of public health doctors in South Korea.

INTRODUCTION: Public health doctors (PHDs) in South Korea serve the medically underserved region of South Korea as part of national service duty, but their number has declined in recent years (due to changes in the medical education system). Therefore, there is an increasing need to deploy PHDs efficiently. Consisting of 2138 medical doctors of different specialties, they serve as both primary care physicians and public health experts. METHODS: The purpose of this study was to investigate the appropriateness of tasks of PHDs in South Korea. RESULTS: Of the 2138 PHDs invited, 1015 participated in the survey. Most PHDs performed primary care and vaccination duties (96.8% and 85.8%). PHDs evaluated the appropriateness of tasks and number of PHDs as above the midpoint of a five-point Likert scale (3.5±1.1 and 3.4±1.1). The majority of offices were located within 5 km of private clinics and hospitals (72.7% and 45.2%). CONCLUSIONS: PHDs on remote islands highly value the validity and deployment needs of PHDs, while PHDs in close proximity to private clinics or hospitals give a low score. This suggests that there is a need to more efficiently deploy PHDs depending on local characteristics and the presence or absence of nearby private medical clinics and hospitals.

Procedural resources utilization and clinical outcomes with bioresorbable everolimus-eluting scaffolds and Pt-Cr everolimus-eluting stent with resorbable abluminal polymer in clinical practice. A randomized trial.

OBJECTIVES: We sought to compare the procedural implications of using bioresorbable everolimus-eluting scaffolds (BVS) and Pt-Cr everolimus-eluting stent with abluminal bioabsorbable polymer (Synergy). BACKGROUND: There are important differences in the respective platforms, which could impact on procedural performance, complications and outcomes. METHODS: A prospective, randomized single center study including consecutive patients in stable clinical condition and with lesions amenable to be treated with BVS according to predefined criteria. Patients were randomized to either treatment with BVS or Synergy. All procedural data were collected and 12 months clinical follow up conducted. Primary objectives were fluoroscopy time, median dose-area product, contras agent volumen, and peri-procedural troponin release. RESULTS: A total of 200 patients were included, 100 in BVS group and 100 in Synergy group. No significant differences were observed in baseline clinical and angiographic characteristics. Predilatation (97.6 vs. 25.4%; P < 0.001), postdilatation (64.8 vs. 38.4%: P < 0.01), and use of 2 wires (20.8 vs. 10%; P = 0.02) were more frequent with BVS. The BVS group showed a significant increase in fluoroscopy time (18%), dose-area product (20%), and contrast volume (10%). Post-procedural increase of creatinine was similar and amount of TnI release was significantly higher with BVS but incidence of peri-procedural infarction was comparable. Clinical outcomes at 12 months were similar with definite thrombosis being 1% with BVS and 0% with Synergy. CONCLUSIONS: The use of BVS in comparison with the Synergy stent in a similar lesional setting is associated with a higher use of resources in the procedure, more radiation, and higher TnI release. © 2016 Wiley Periodicals, Inc.

Early healing assessment with optical coherence tomography of everolimus-eluting stents with bioabsorbable polymer (synergy™) at 3 and 6 months after implantation.

OBJECTIVES: In this study we sought to evaluate coverage and apposition of Synergy™ stent at 3 and 6 months after implantation. BACKGROUND: The Pt-Cr everolimus-eluting stent with abluminal bioabsorbable polymer (Synergy™) is a new generation drug-eluting stent with features potentially favoring an early healing process which could make safe a shorter period of dual antiplatelet-therapy treatment. METHODS: Prospective, two-centers study enrolling patients with similar lesions treated with Synergy™ stents undergoing examination with OCT at 3 and 6 months in the respective centers. Blinded analysis was done at a core lab. Co-primary endpoints were proportion of struts with coverage and with apposition at 3 and 6 months. RESULTS: Finally, 22 patients (30 stents) in the 3 months group and 20 patients (30 stents) in the 6 months group were included. There were no significant differences between groups regarding clinical, angiographic measurements, and procedural data. The rate of strut coverage was 94.5% at 3 months and 96.6% at 6 months (P < 0.001), the rates of apposition were 93.8% and 96.2%, respectively, (P < 0.001), the proportion of uncovered but apposed struts was 2.5% and 1.9% (P = 0.03) and the proportion of uncovered and malapposed struts was 3% and 1.8%, respectively (P < 0.001). The maximal area of malapposition related with uncovered struts was 0.43 ± 0.4 mm(2) at 3 months and 0.14 ± 0.2 mm(2) at 6 months (P = 0.001). CONCLUSIONS: The everolimus-eluting stent with absorbable polymer, Synergy™, is associated to a high degree of intimal coverage and apposition at 3 months after implantation with additional increase at 6 months. © 2015 Wiley Periodicals, Inc.

A microscopic view on the renal endothelial glycocalyx.

Endothelial cells perform key homeostatic functions such as regulating blood flow, permeability, and aiding immune surveillance for pathogens. While endothelial activation serves normal physiological adaptation, maladaptation of these endothelial functions has been identified as an important effector mechanism in the progression of renal disease as well as the associated development of cardiovascular disease. The primary interface between blood and the endothelium is the glycocalyx. This carbohydrate-rich gel-like structure with its associated proteins mediates most of the regulatory functions of the endothelium. Because the endothelial glycocalyx is a highly dynamic and fragile structure ex vivo, and traditional tissue processing for staining and perfusion-fixation usually results in a partial or complete loss of the glycocalyx, studying its dimensions and function has proven to be challenging. In this review, we will outline the core functions of the glycocalyx and focus on different techniques to study structure-function relationships in kidney and vasculature.

Enhanced phase II detoxification contributes to beneficial effects of dietary restriction as revealed by multi-platform metabolomics studies.

Dietary restriction (DR) has many beneficial effects, but the detailed metabolic mechanism remains largely unresolved. As diet is essentially related to metabolism, we investigated the metabolite profiles of urines from control and DR animals using NMR and LC/MS metabolomic approaches. Multivariate analysis presented distinctive metabolic profiles and marker signals from glucuronide and glycine conjugation pathways in the DR group. Broad profiling of the urine phase II metabolites with neutral loss scanning showed that levels of glucuronide and glycine conjugation metabolites were generally higher in the DR group. The up-regulation of phase II detoxification in the DR group was confirmed by mRNA and protein expression levels of uridinediphospho-glucuronosyltransferase and glycine-N-acyltransferase in actual liver tissues. Histopathology and serum biochemistry showed that DR was correlated with the beneficial effects of low levels of serum alanine transaminase and glycogen granules in liver. In addition, the Nuclear factor (erythroid-derived 2)-like 2 signaling pathway was shown to be up-regulated, providing a mechanistic clue regarding the enhanced phase II detoxification in liver tissue. Taken together, our metabolomic and biochemical studies provide a possible metabolic perspective for understanding the complex mechanism underlying the beneficial effects of DR.

Relationship between blood and tissue-based rejection-related transcripts in heart transplantation.

BACKGROUND: The purpose of the study is to investigate the relationship between blood and tissue-derived rejection-related transcripts from blood gene expression profiling (GEP) and molecular microscope in the setting of allograft rejection in heart transplant. METHODS: All heart transplant patients from August 2021 to May 2022 with both circulating blood GEP (AlloMap) and endomyocardial biopsy with molecular microscope diagnostic system (MMDx) within 4 weeks were included (N = 173 samples). We obtained individual blood GEP-based messenger RNA transcript expression levels of the 11 target genes from CareDx. Student's t-test was performed to compare blood GEP transcript expression levels between no rejection and rejection as assessed by MMDx. A Scatter plot with Spearman correlation analysis was performed to compare the relationship between transcript expression levels from AlloMap and MMDx, with and without allograft rejection. RESULTS: There were 52 samples (30.1%) with antibody-mediated rejection (ABMR) and 15 samples (8.7%) with T-cell-mediated rejection (TCMR), as assessed by MMDx. Expression of one of the blood ITGA4 (Integrin alpha 4) expression level was elevated in ABMR, compared to no ABMR (4,607.5 vs 4,217.5; p = 0.019). Most tissue rejection-associated transcript expression levels were elevated in ABMR, and tissue ROBO4 expression correlated with the blood ITGA4 expression with moderate or greater effect size in all samples (Spearman's R = 0.31; p < 0.001). There was also a positive correlation between blood ITGA4 and tissue ROBO4 expression in samples without ABMR (Spearman's R = 0.33; p < 0.001), but no correlation between blood ITGA4 and tissue ROBO4 expression in samples with ABMR (Spearman's R = 0.009; p = 0.513). CONCLUSIONS: Circulating blood ITGA4 expression is elevated in antibody-mediated rejection (AMR) and correlates with myocardial expression of ROBO4. The knowledge of individual transcript expression levels in blood and in tissue may provide insights into various disease processes in heart transplant patients. Taken together, the results of our study reveal an overlap between 2 objective post-heart transplant rejection surveillance methods, identify potential novel markers for ABMR, and reveal the need for a deeper understanding of molecular mechanisms underlying allograft rejection.

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

BACKGROUND: Endomyocardial 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. METHODS: This is a retrospective observational study of 156 EMB evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood before EMB (up to 9 days). Diagnostic agreement between traditional histopathology, MMDx, and dd-cfDNA (threshold of 0.20%) was compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated. RESULTS: MMDx characterized allograft tissue as no rejection (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 were 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 nonrejection and rejection as assessed by MMDx. CONCLUSIONS: Collectively, 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, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to acute cellular rejection.