Nuclear Osteopontin Is a Marker of Advanced Heart Failure and Cardiac Allograft Vasculopathy: Evidence From Transplant and Retransplant Hearts.
Ontology highlight
ABSTRACT: Background
Heart transplant is the gold standard therapy for patients with advanced heart failure. Over 5,500 heart transplants are performed every year worldwide. Cardiac allograft vasculopathy (CAV) is a common complication post-heart transplant which reduces survival and often necessitates heart retransplantation. Post-transplant follow-up requires serial coronary angiography and endomyocardial biopsy (EMB) for CAV and allograft rejection screening, respectively; both of which are invasive procedures. This study aims to determine whether osteopontin (OPN) protein, a fibrosis marker often present in chronic heart disease, represents a novel biomarker for CAV.Methods
Expression of OPN was analyzed in cardiac tissue obtained from patients undergoing heart retransplantation using immunofluorescence imaging (n = 20). Tissues from native explanted hearts and three serial follow-up EMB samples of transplanted hearts were also analyzed in five of these patients.Results
Fifteen out of 20 patients undergoing retransplantation had CAV. 13/15 patients with CAV expressed nuclear OPN. 5/5 patients with multiple tissue samples expressed nuclear OPN in both 1 st and 2 nd explanted hearts, while 0/5 expressed nuclear OPN in any of the follow-up EMBs. 4/5 of these patients had an initial diagnosis of dilated cardiomyopathy (DCM).Conclusion
Nuclear localization of OPN in cardiomyocytes of patients with CAV was evident at the time of cardiac retransplant as well as in patients with DCM at the time of the 1 st transplant. The results implicate nuclear OPN as a novel biomarker for severe CAV and DCM.
SUBMITTER: Irion CI
PROVIDER: S-EPMC7438570 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ImportanceExpansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015.ObjectiveTo develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant.Design, setting, and participantsThis multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017.Main outcomes and measuresEarly allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant.ResultsAt day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk.Conclusions and relevanceThis study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers.
| S-EPMC7593884 | biostudies-literature
Project description:We evaluated whether combined heart and liver transplant (H+LTx) can protect the heart graft from the development of cardiac allograft vasculopathy using coronary three-dimensional (3D) volumetric intravascular ultrasound (IVUS).From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 H+LTx recipients in whom two coronary 3D IVUS studies were performed 1 year apart. Baseline 3D IVUS was performed at 0.22 (0.17-1.16) years after transplantation, with follow-up 3D IVUS exams performed after baseline exam (0.96 [0.83-1.08]).Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+LTx group (0.3±1.1 vs. 1.5±2.9 mm/mm; P=0.08 and 0.01±0.03 vs. 0.1±0.1; P=0.004, respectively). Rejection burden was much lower in the H+LTx patients. Outcome analysis in 66 consecutive patients (56 HTx and 10 H+LTx) was performed irrespective of performance of second coronary IVUS. H+LTx was associated with reduced rate of cardiac events (P=0.04), which remained significant when adjusted for the difference in the primary etiology for heart disease (P=0.05).Our preliminary serial 3D coronary IVUS data show that H+LTx attenuates cardiac allograft vasculopathy by decreasing the rate of plaque volume and plaque index progression and improves coronary-related outcomes. Because of the small numbers and the differences in etiology of heart disease, our data should be interpreted cautiously, and larger clinical trials would be required to recommend H+LTx for improved coronary remodeling.
| S-EPMC3733541 | biostudies-literature
Project description:Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available.Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues.We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2.The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.
| S-EPMC4333500 | biostudies-other
Project description:Heart retransplant (HRT) recipients represent a growing number of transplant patients. The impact of concurrent kidney transplants (KTs) in this population has not been well studied. We tested the hypothesis that recipients of HRT with concurrent KT (HRT-KT) would have worse survival than recipients of HRT alone.A retrospective analysis of the United Network of Organ Sharing database was performed for all patients undergoing HRT from 1987 to 2011. There were 1660 HRT patients, of which 116 (7%) received concurrent KT. Those who received HRT-KT had older age, longer wait-list time, worse kidney function, and more known diabetes. Survival among recipients of HRT-KT was significantly better than that of recipients of HRT alone (P=0.005). A subgroup of 323 HRT patients with severe kidney dysfunction (estimated glomerular filtration rate <30 mL/min per 1.73 m(2) or on dialysis) was studied in more detail, and 76 (24%) received concurrent KT. Those on dialysis at the time of HRT had better survival with versus without concurrent KT (P<0.0001). On multivariable analysis, concurrent KT was independently associated with better outcomes for all patients with HRT and for the subgroup of patients with severe kidney dysfunction.Recipients of HRT-KT have better survival than recipients of HRT alone. Further research is needed to determine which HRT patients may benefit the most from concurrent KT.
| S-EPMC4845285 | biostudies-other
Project description:BackgroundSuccessful pancreas transplantation requires surgical expertise and multidisciplinary medical management. The impact of transplant center volume on pancreas allograft survival remains unclear.MethodsWe examined Organ Procurement and Transplantation Network data on 11 568 simultaneous pancreas-kidney (SPK) and 4308 solitary pancreas (pancreas transplant alone and pancreas after kidney) transplants between 2000 and 2013.ResultsAverage annual transplant center volume was categorized by tertiles into low, medium, and high volume, respectively, as follows: 1 to 6 (n = 3861), 7 to 13 (n = 3891), and 14 to 34 (n = 3888) for SPK, and 1 to 3 (n = 1417), 4 to 10 (n = 1518), and 11 to 33 (n = 1377) for solitary pancreas transplants. Favorable donor characteristics were seen in low-volume centers. For SPK transplantation, low (adjusted hazard ration [aHR], 1.55, 95% confidence interval [CI], 1.34-1.8) and medium (aHR, 1.24; 95% CI, 1.07-1.44) center volumes were associated with a higher risk of early pancreas graft failure at 3 months. The increased risk associated with low center volume extended to 1, 5, and 10 years. For solitary pancreas transplants, low, but not medium, center volume was associated with a higher risk of early pancreas graft failure at 3 months (aHR, 1.56; 95% CI, 1.232-1.976), and this risk persisted over 10 years. Patients transplanted at high-volume centers had better pancreas survival rates across all categories of the Pancreas Donor Risk Index.ConclusionOn average, low center volume were associated with higher risk for pancreas failure. Future studies should seek to identify care processes that support optimal outcomes after pancreas transplantation irrespective of center volume.
| S-EPMC6319571 | biostudies-literature
Project description:BACKGROUND:Cardiac allograft vasculopathy (CAV), the major cause of late allograft loss after cardiac transplantation, results from donor-directed cellular and humoral alloimmune responses. Graft vascular endothelial cells (EC) are primary targets of these destructive responses, suggesting that factors associated with endothelial injury and repair could serve as biomarkers of CAV. METHODS:Using a protein profiler array platform, we measured the levels of 55 angiogenesis-related proteins in sera from 33 adult heart transplant recipients, including 17 with angiographically documented CAV and 16 age- and gender-matched controls without CAV. All patients were >2 years after heart transplant. RESULTS:The study population was 75% male with a mean age of 62 ± 11 years. On average, patients were 12 ± 5 years after heart transplantation. We found that vascular endothelial growth factor (VEGF)-C, VEGF-A, angiopoietin-2, artemin, urokinase-type plasminogen activator and vasohibin were strongly associated with established CAV (all p < 0.01). Multivariable modeling identified VEGF-C, VEGF-A and platelet factor-4 (PF-4) as significant independent biomarkers of CAV. Furthermore, receiver-operating characteristic curve analysis demonstrated that the combination of all 3 molecules provided outstanding performance for the diagnosis of CAV (area under the curve [AUC] = 0.98; p < 0.001). CONCLUSIONS:Serum levels of VEGF-C, VEGF-A and PF-4 demonstrate strong associations with established CAV and, together with related angiogenesis factors, may serve as a reliable, non-invasive diagnostic test for CAV in cardiac transplant recipients.
| S-EPMC3597743 | biostudies-literature
Project description:BACKGROUND:Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS:We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. RESULTS:Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (? = -0.59, p = 0.02, R2 = 0.35). CONCLUSION:Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.
| S-EPMC5107129 | biostudies-literature
Project description:Cardiac allograft vasculopathy (CAV) accounts for about 30% of all heart-transplant (HTx) patient deaths. For patients at high risk for CAV complications after HTx, therapy must be initiated early to be effective. Therefore, new phenotyping approaches are needed to identify such HTx patients at the earliest possible time. Coronary optical coherence tomography (OCT) images were acquired from 50 HTx patients 1 and 12 months after HTx. Quantitative analysis of coronary wall morphology used LOGISMOS segmentation strategy to simultaneously identify three wall-layer surfaces for the entire pullback length in 3D: luminal, outer intimal, and outer medial surfaces. To quantify changes of coronary wall morphology between 1 and 12 months after HTx, the two pullbacks were mutually co-registered. Validation of layer thickness measurements showed high accuracy of performed layer analyses with layer thickness measures correlating well with manually-defined independent standard (Rautomated2 = 0.93, y=1.0x-6.2?m), average intimal+medial thickness errors were 4.98?±?31.24 µm, comparable with inter-observer variability. Quantitative indices of coronary wall morphology 1 month and 12 months after HTx showed significant local as well as regional changes associated with CAV progression. Some of the newly available fully-3D baseline indices (intimal layer brightness, medial layer brightness, medial thickness, and intimal+medial thickness) were associated with CAV-related progression of intimal thickness showing promise of identifying patients subjected to rapid intimal thickening at 12 months after HTx from OCT-image data obtained just 1 month after HTx. Our approach allows quantification of location-specific alterations of coronary wall morphology over time and is sensitive even to very small changes of wall layer thicknesses that occur in patients following heart transplant.
| S-EPMC6237624 | biostudies-literature
Project description:Endothelium-enriched microRNAs (miRs) are involved in the development of cardiac allograft vasculopathy (CAV). Recently, serum-derived miR-126-3p and -5p, known endothelial microRNAs with a crucial function in angiogenesis and re-endothelialization, provided additional predictive power for cardiac allograft vasculopathy in addition to clinical predictors. However, their myocardial expression in and relationship with CAV are still unknown. Our study aim was to investigate the expression of endomyocardial microRNA-126-3p and microRNA-126-5p levels in heart transplant recipients and their relationship with allograft vasculopathy.MethodsWe studied 39 heart transplant recipients, 21 with proven allograft vasculopathy (CAV+) and 18 without allograft vasculopathy (CAV-) with serial coronary angiograms. Additionally, 8 patients with end-stage native coronary artery disease (CAD) were added to the study to investigate disease specificity of the microRNA signature. The mRNA levels of miR-126-3p and miR-126-5p were determined by qRT-PCR in the right ventricular endomyocardial biopsies obtained at baseline and during routine follow-up.ResultsMiR-126-3p levels were significantly lower in the CAV+ group compared to the CAV- group at follow-up, while miR-126-5p levels were unaltered. This was in stark contrast to native CAD patients in whom miR-126-3p and -5p levels were significantly higher. qPCR levels of miR-126 targets are differentially regulated in CAV versus ischemic cardiomyopathy and are influenced by the administration of immunosuppressive agents in endothelial cells.ConclusionsOur data provide evidence for a distinct microRNA signature in heart transplantation patients with allograft vasculopathy. In contrast to CAD patients, lower miR-126-3p levels coincide with the development of cardiac allograft vasculopathy. Further studies in a larger patient population are warranted to determine if the serial measurement of myocardial microRNA-126 products could help in risk assessment and early detection of CAV.
| S-EPMC7213604 | biostudies-literature
Project description:Long-term survival of cardiac transplant recipients remains a significant hurdle largely due to cardiac allograft vasculopathy (CAV) as an expression of chronic rejection (CR). Currently, coronary angiography and intravascular ultrasound, invasive and expensive modalities, are considered the standard for diagnosis of CAV. In the current study, we combined assessment of blood mRNA and proteins to identify potential biomarkers for diagnosis of CAV. Whole blood Affymetrix microarrays and plasma iTRAQ-MALDI-TOF/TOF proteomic analyses were carried out on 25 cardiac transplant patient samples. CAV diagnosis was made based on blinded quantitative analysis of angiograms, intravascular ultrasound images and clinical chart review. The genomics and proteomics data were assessed by moderated t-tests and discriminant analysis. Two panels of 10 differentially expressed genes (FDR<5%), and 10 proteins with differential relative levels (p-values<0.025) between CAV and non-CAV samples were independently identified. Classification of new test samples revealed that the 10 genes together can discriminate between CAV and non-CAV samples with 83% sensitivity and specificity. Classification of the same samples using the 10 PGC’s dropped the sensitivity to 67%. A combinatorial panel derived from the genomic and proteomic panels provided improvement in performance, at 100% sensitivity and 83% specificity. Leave-one-out cross validation showed similar results. Genomic, proteomic and combinatorial blood-based biomarkers are promising as potential minimally-invasive, sensitive and specific modalities for the diagnosis of CAV. Classifier panels generated from current work are being evaluated in a prospective, multi-site observational trial.
2020-09-01 | GSE18656 | GEO