Publications by authors named "Mario Deng"

157 Publications

NK and CD8 T cell phenotypes predict onset and control of CMV viremia post-kidney transplant.

JCI Insight 2021 Oct 5. Epub 2021 Oct 5.

Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, United States of America.

Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV's impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three- and twelve-months post-transplant, with additional samples one-week and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. Post-viremia, mature CD56dim NK cells and CD28- CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Phenotype of NK cells and CD28- CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation post-transplant, while CD8 T cell functionality is critical for effective control of CMV.
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http://dx.doi.org/10.1172/jci.insight.153175DOI Listing
October 2021

Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes.

J Heart Lung Transplant 2021 Aug 26. Epub 2021 Aug 26.

Medical University of Vienna, Vienna, Austria.

Background: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.

Methods: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).

Results: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.

Conclusions: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).
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http://dx.doi.org/10.1016/j.healun.2021.08.004DOI Listing
August 2021

Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery.

ESC Heart Fail 2021 Oct 13;8(5):4301-4306. Epub 2021 Aug 13.

Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare, potentially life-threatening complication of immunotherapy. We report a case of a 60-year-old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI-associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.
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http://dx.doi.org/10.1002/ehf2.13545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497199PMC
October 2021

Identification of molecular signatures associated with early relapse after complete resection of lung adenocarcinomas.

Sci Rep 2021 05 5;11(1):9532. Epub 2021 May 5.

LungenClinic Grosshansdorf, 22927, Grosshansdorf, Germany.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA-IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-021-89030-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099905PMC
May 2021

The evolution of patient-specific precision biomarkers to guide personalized heart-transplant care.

Authors:
Mario C Deng

Expert Rev Precis Med Drug Dev 2021 28;6(1):51-63. Epub 2020 Oct 28.

Advanced Heart Failure/Mechanical Support/Heart Transplant, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, 100 Medical Plaza Drive, Suite 630, Los Angeles, CA 90095.

Introduction: In parallel to the clinical maturation of heart transplantation over the last 50 years, rejection testing has been revolutionized within the systems biology paradigm triggered by the Human Genome Project.

Areas Covered: We have co-developed the first FDA-cleared diagnostic and prognostic leukocyte gene expression profiling biomarker test in transplantation medicine that gained international evidence-based medicine guideline acceptance to rule out moderate/severe acute cellular cardiac allograft rejection without invasive endomyocardial biopsies. This work prompted molecular re-classification of intragraft biology, culminating in the identification of a pattern of intragraft myocyte injury, in addition to acute cellular rejection and antibody-mediated rejection. This insight stimulated research into non-invasive detection of myocardial allograft injury. The addition of a donor-organ specific myocardial injury marker based on donor-derived cell-free DNA further strengthens the non-invasive monitoring concept, combining the clinical use of two complementary non-invasive blood-based measures, host immune activity-related risk of acute rejection as well as cardiac allograft injury.

Expert Opinion: This novel complementary non-invasive heart transplant monitoring strategy based on leukocyte gene expression profiling and donor-derived cell-free DNA that incorporates longitudinal variability measures provides an exciting novel algorithm of heart transplant allograft monitoring. This algorithm's clinical utility will need to be tested in an appropriately designed randomized clinical trial which is in preparation.
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http://dx.doi.org/10.1080/23808993.2021.1840273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986584PMC
October 2020

Orthotopic Heart and Combined Heart Liver Transplantation: the Ultimate Treatment Option for Failing Fontan Physiology.

Curr Transplant Rep 2021 Feb 4:1-12. Epub 2021 Feb 4.

Ahmanson/UCLA Adult Congenital Heart Disease Center, Division of Adult Cardiology, 100 UCLA Medical Plaza Suite 630E, Los Angeles, CA 90095 USA.

Purpose Of The Review: This is a comprehensive update on failing Fontan physiology and the role of heart and combined heart and liver transplantation in the current era.

Recent Findings: Single ventricle physiology encompasses a series of rare congenital cardiac abnormalities that are characterized by absence of or hypoplasia of one ventricle. This effectively results in a single ventricular pumping chamber. These abnormalities are rarely compatible with long-term survival if left without surgical palliation in the first few years of life. Surgical treatment of single ventricle physiology has evolved over the past 60 years and is characterized by numerous creative innovations. These include the development of arteriopulmonary shunts, the evolution of partial cavopulmonary connections, and the eventual development of the "Fontan" operation. Regardless of the type of Fontan modification, the long-term consequences of the Fontan operation are predominantly related to chronic central venous hypertension and the multi-organ consequences thereof. Atrial arrhythmias can further compromise this circulation.Patients with single ventricle physiology represent a special sub-segment of congenital cardiac transplants and are arguably the most challenging patients considered for transplantation.

Summary: This review describes in detail the challenges and opportunities of heart and liver transplantation in Fontan patients, as viewed and managed by the experienced team at the Ahmanson/UCLA Adult Congenital Heart Center.
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http://dx.doi.org/10.1007/s40472-021-00315-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861581PMC
February 2021

Noninvasive biomarkers for prediction and diagnosis of heart transplantation rejection.

Transplant Rev (Orlando) 2021 01 21;35(1):100590. Epub 2020 Nov 21.

Division of Cardiovascular Medicine, University of California Davis, Davis, CA, United States of America.

For most patients with end-stage heart failure, heart transplantation is the treatment of choice. Allograft rejection is one of the major post-transplantation complications affecting graft outcome and survival. Recent advancements in science and technology offer an opportunity to integrate genomic and other omics-based biomarkers into clinical practice, facilitating noninvasive evaluation of allograft for diagnostic and prognostic purposes. Omics, including gene expression profiling (GEP) of blood immune cell components and donor-derived cell-free DNA (dd-cfDNA) are of special interest to researchers. Several studies have investigated levels of dd-cfDNA and miroRNAs in blood as potential markers for early detection of allograft rejection. One of the achievements in the field of transcriptomics is AlloMap, GEP of peripheral blood mononuclear cells (PBMC), which can identify 11 differentially expressed genes and help with detection of moderate and severe acute cellular rejection in stable heart transplant recipients. In recent years, the utilization of GEP of PBMC for identifying differentially expressed genes to diagnose acute antibody-mediated rejection and cardiac allograft vasculopathy has yielded promising results. Advancements in the field of metabolomics and proteomics as well as their potential implications have been further discussed in this paper.
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http://dx.doi.org/10.1016/j.trre.2020.100590DOI Listing
January 2021

Multi-dimensional COVID-19 short- and long-term outcome prediction algorithm.

Authors:
Mario C Deng

Expert Rev Precis Med Drug Dev 2020 24;5(4):239-242. Epub 2020 Jun 24.

Advanced Heart Failure/Mechanical Support/Heart Transplant, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, 100 Medical Plaza Drive, Suite 630, Los Angeles, CA 90095.

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http://dx.doi.org/10.1080/23808993.2020.1785286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709963PMC
June 2020

Rejection-associated Mitochondrial Impairment After Heart Transplantation.

Transplant Direct 2020 Nov 19;6(11):e616. Epub 2020 Oct 19.

Division of Cardiovascular Medicine, UC Davis Medical Center, Sacramento, CA.

Background: Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs.

Methods: We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters.

Results: The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis-derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules.

Conclusions: During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.
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http://dx.doi.org/10.1097/TXD.0000000000001065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575170PMC
November 2020

Heart transplantation in the early phase of the COVID-19 pandemic: A single-center case series.

Clin Transplant 2020 09 6;34(9):e14042. Epub 2020 Aug 6.

Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

The infectious disease coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID-19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re-evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID-19 screening scrutiny and recipient waiting list management in anticipation of COVID-19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end-stage cardiomyopathies is challenging. Here, we describe our center's experience with orthotopic heart transplantation (OHT) in one of the country's pandemic epicenters, where we performed eight OHTs in the first 2 months after community spread began in late February 2020.
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http://dx.doi.org/10.1111/ctr.14042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404366PMC
September 2020

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

Am J Transplant 2020 10 26;20(10):2768-2780. Epub 2020 Apr 26.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.
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http://dx.doi.org/10.1111/ajt.15863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494540PMC
October 2020

Comparing NGS and NanoString platforms in peripheral blood mononuclear cell transcriptome profiling for advanced heart failure biomarker development.

J Biol Methods 2020 3;7(1):e123. Epub 2020 Jan 3.

David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, CA 90095, USA.

In preparation to create a clinical assay that predicts 1-year survival status of advanced heart failure (AdHF) patients before surgical/interventional therapies and to select the appropriate clinical assay platform for the future assay, we compared the properties of next generation sequencing (NGS) used in the gene discovery phase to the NanoString platform used in the clinical assay development phase. In 25 AdHF patients in a tertiary academic medical center from 2015 to 2016, PBMC samples were collected and aliquoted for NGS RNA whole transcriptome sequencing and compared to 770 genes represented on NanoString's PanCancer IO 360 Gene Expression research panel. Prior to statistical analysis, NanoString and NGS expression values were log transformed. We computed Pearson correlation coefficients for each sample, comparing gene expression values between NanoString and NGS across the set of matched genes and for each of the matched genes across the set of samples. Genes were grouped by average NGS expression, and the NanoString-NGS correlation for each group was computed. Out of 770 genes from the NanoString panel, 734 overlapped between both platforms and showed high intrasample correlation. Within an individual sample, there was an expression-level dependent correlation between both platforms. The low- . intermediate/high-expression groups showed NGS average correlation 0.21 . 0.58-0.68, respectively, and NanoString average correlation 0.07-0.34 . 0.59-0.70, respectively. NanoString demonstrated high reproducibility ( > 0.99 for 100 ng input), sensitivity (probe counts between 100 and 500 detected and quantified), and robustness (similar gene signature scores across different RNA input concentrations, cartridges, and outcomes). Data from NGS and NanoString were highly correlated. These platforms play a meaningful, complementary role in the biomarker development process.
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http://dx.doi.org/10.14440/jbm.2020.300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974694PMC
January 2020

Temporal expression of cytokines and B-cell phenotypes during mechanical circulatory support.

J Thorac Cardiovasc Surg 2019 Apr 4. Epub 2019 Apr 4.

Division of Cardiac Surgery, UCLA Medical Center, Los Angeles, Calif. Electronic address:

Background: Allosensitization during mechanical circulatory support (MCS) is a well-described phenomenon, although its mechanism remains unknown. Although immune-mediated interactions from devices or blood transfusions have been proposed, the role of inflammation in this development is less clear. This study was undertaken to further investigate the temporal association of cytokines and B-cell phenotypes in the MCS population.

Methods: Adult patients who received the Heartmate II (Thoratec, Pleasanton, Calif) at our center between September 2012 and March 2015 were prospectively followed after device implantation. Blood draws for anti-human leukocyte antigen (HLA) antibody, cytokine expression, and B-cell immunophenotyping were performed before implantation and for 3 weeks postoperatively. Time courses for cytokines and B-cell subsets were expressed using visual representations of median levels as heat maps, and mixed modeling analysis was used to model changes with time and patient factors.

Results: Twenty patients who received the Heartmate II (Thoratec) were analyzed during the study period. Four patients showed measureable levels of anti-HLA antibody during the follow-up period, although 3 of these had evidence of antibodies preoperatively. Analysis of cytokine trends revealed early (interleukin [IL]-6, IL-8, and IL-10) and late peaking (IL-3, IL-4, fibroblast growth factor 2, and CD40L) patterns. Upregulation of switched memory, transitional, and plasma blast B cells occurred over time. Right ventricular assist device use and low Interagency Registry for Mechanically Assisted Circulatory Support score were associated with decreased mature naive and increased antibody-secreting cells.

Conclusions: MCS device implantation was associated with increased inflammatory cytokines and maturation of B-cell phenotypes. No patients developed de novo HLA antibodies, whereas several showed increases in anti-HLA antibody levels detected before implantation. This suggests that inflammation and maturation of existing sensitized B cells might play an important role in the pathogenesis of allosensitization in MCS.
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http://dx.doi.org/10.1016/j.jtcvs.2019.03.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220810PMC
April 2019

An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms.

J Heart Lung Transplant 2019 06 6;38(6):636-646. Epub 2019 Feb 6.

Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA) or 4-archetype (4AA) unsupervised algorithms to estimate rejection. In the present study we examined the stability of machine-learning algorithms in new biopsies, compared 3AA vs 4AA algorithms, assessed supervised binary classifiers trained on histologic or molecular diagnoses, created a report combining many scores into an ensemble of estimates, and examined possible automated sign-outs.

Methods: We studied 889 EMBs from 454 transplant recipients at 8 centers: the initial cohort (N = 331) and a new cohort (N = 558). Published 3AA algorithms derived in Cohort 331 were tested in Cohort 558, the 3AA and 4AA models were compared, and supervised binary classifiers were created.

Results: A`lgorithms derived in Cohort 331 performed similarly in new biopsies despite differences in case mix. In the combined cohort, the 4AA model, including a parenchymal injury score, retained correlations with histologic rejection and DSA similar to the 3AA model. Supervised molecular classifiers predicted molecular rejection (areas under the curve [AUCs] >0.87) better than histologic rejection (AUCs <0.78), even when trained on histology diagnoses. A report incorporating many AA and binary classifier scores interpreted by 1 expert showed highly significant agreement with histology (p < 0.001), but with many discrepancies, as expected from the known noise in histology. An automated random forest score closely predicted expert diagnoses, confirming potential for automated signouts.

Conclusions: Molecular algorithms are stable in new populations and can be assembled into an ensemble that combines many supervised and unsupervised estimates of the molecular disease states.
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http://dx.doi.org/10.1016/j.healun.2019.01.1318DOI Listing
June 2019

Association of pro-inflammatory cytokines and monocyte subtypes in older and younger patients on clinical outcomes after mechanical circulatory support device implantation.

Hum Immunol 2019 Feb 14;80(2):126-134. Epub 2018 Nov 14.

Division of Cardiology, Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095, United States.

Noninvasive immunologic analysis of peripheral blood holds promise for explaining the mechanism of development of adverse clinical outcomes, and may also become a method for patient risk stratification before or after mechanical circulatory support device (MCSD) implantation. Dysregulation of the innate immune system is associated with increased patient age but has yet to be evaluated in the older patient with advanced heart failure undergoing MCSD surgery. Patients pre- and post-MCSD implantation had peripheral blood mononuclear cells (PBMC) and serum isolated. Multiparameter flow cytometry was used to analyze markers of innate cell function, including monocyte subtypes. Multiplex cytokine analysis was performed. MELD-XI and SOFA scores were utilized as surrogate markers of outcomes. Increased levels of pro-inflammatory cytokines including IL-15, TNF-α, and IL-10 were associated with increased MELD-XI and SOFA scores. IL-8, TNF- α, and IL-10 were associated with risk of death after MCSD implantation, even with correction for patient age. Increased frequency of 'classical' monocytes (CD14 + CD16-) were associated with increased MELD-XI and SOFA scores. This suggests that inflammation and innate immune system activation contribute to progression to multiorgan system failure and death after MCSD surgery. Development of noninvasive monitoring of peripheral blood holds promise for biomarker development for candidate selection and patient risk stratification.
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http://dx.doi.org/10.1016/j.humimm.2018.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115755PMC
February 2019

Exploring the cardiac response to injury in heart transplant biopsies.

JCI Insight 2018 10 18;3(20). Epub 2018 Oct 18.

Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada.

Background: Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury.

Methods: Microarray data from 889 prospectively collected endomyocardial biopsies from 454 transplant recipients at 14 centers were subjected to unsupervised principal component analysis and archetypal analysis to detect variation not explained by rejection. The resulting principal component and archetype scores were then examined for their transcript, transcript set, and pathway associations and compared to the histology diagnoses and left ventricular function.

Results: Rejection was reflected by principal components PC1 and PC2, and by archetype scores S2TCMR, and S3ABMR, with S1normal indicating normalness. PC3 and a new archetype score, S4injury, identified unexplained variation correlating with expression of transcripts inducible in injury models, many expressed in macrophages and associated with inflammation in pathway analysis. S4injury scores were high in recent transplants, reflecting donation-implantation injury, and both S4injury and S2TCMR were associated with reduced left ventricular ejection fraction.

Conclusion: Assessment of injury is necessary for accurate estimates of rejection and for understanding heart transplant phenotypes. Biopsies with molecular injury but no molecular rejection were often misdiagnosed rejection by histology.TRAIL REGISTRATION. ClinicalTrials.gov NCT02670408FUNDING. Roche Organ Transplant Research Foundation, the University of Alberta Hospital Foundation, and Alberta Health Services.
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http://dx.doi.org/10.1172/jci.insight.123674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237487PMC
October 2018

Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans.

G3 (Bethesda) 2018 11 6;8(11):3499-3506. Epub 2018 Nov 6.

Department of Medicine, Division of Cardiology

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic β-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.
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http://dx.doi.org/10.1534/g3.118.200655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222577PMC
November 2018

Heart and heart-liver transplantation in adults with failing Fontan physiology.

Clin Transplant 2018 08 18;32(8):e13329. Epub 2018 Jul 18.

Ahmanson/UCLA Adult Congenital Heart Disease Center, Los Angeles, California.

Background: As the population of patients with a Fontan palliation grows so does, the number of patients with cardiac failure necessitating orthotopic heart transplant (OHT) and combined heart-liver transplant (CHLT). There is recent evidence that current era cardiac transplant in Fontan patients has improved outcomes, but most studies have a preponderance of pediatrics patients in their cohorts. We examine our institutional experience with adult OHT and CHLT transplantation for failed Fontan physiology.

Methods And Results: Retrospective analysis of patients at the Ahmanson/UCLA Adult Congenital Heart Disease Center who underwent OHT or CHLT for failing Fontan physiology from January 1, 2002 to May 31, 2017. We identified 20 patients with single-ventricle physiology and Fontan palliation who underwent OHT or CHLT. The median age was 29.5 years (range 19-44). Five patients underwent CHLT because of biopsy proven hepatic cirrhosis. The median length of hospital stay was 23 days (range 8-76) post-OHT and 51 days (range 26-77) post-CHLT. During a median follow-up of 56 months (range 2-178), there was one mortality occurring at 34 months post-OHT due to coronary vasculopathy. Most frequent early postoperative complications included bleeding and infection (55% and 20%, respectively) and surgical reintervention for bleeding complications (n = 8, 40%). One CHLT patient experienced clinically significant hepatic rejection requiring admission and steroid treatment.

Conclusions: Despite inherent risks and complexities of OHT or CHLT in patients with a failed Fontan, transplant is a reasonable therapy. Peri- and postoperative complications are common and may require surgical reintervention. Continued observation of practices and unifying themes may help improve patient selection, pre- and postoperative treatment and ultimately outcomes.
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http://dx.doi.org/10.1111/ctr.13329DOI Listing
August 2018

Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients.

Transplantation 2018 10;102(10):e431-e438

UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.

Background: Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients.

Methods: The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria.

Results: In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01).

Conclusions: Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.
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http://dx.doi.org/10.1097/TP.0000000000002333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153056PMC
October 2018

Clinical phenomapping and outcomes after heart transplantation.

J Heart Lung Transplant 2018 08 22;37(8):956-966. Epub 2018 Mar 22.

Division of Cardiology, Department of Medicine, David Geffen School of Medicine. Electronic address:

Background: Survival after heart transplantation (HTx) is limited by complications related to alloreactivity, immune suppression, and adverse effects of pharmacologic therapies. We hypothesize that time-dependent phenomapping of clinical and molecular data sets is a valuable approach to clinical assessments and guiding medical management to improve outcomes.

Methods: We analyzed clinical, therapeutic, biomarker, and outcome data from 94 adult HTx patients and 1,557 clinical encounters performed between January 2010 and April 2013. Multivariate analyses were used to evaluate the association between immunosuppression therapy, biomarkers, and the combined clinical end point of death, allograft loss, retransplantation, and rejection. Data were analyzed by K-means clustering (K = 2) to identify patterns of similar combined immunosuppression management, and percentile slopes were computed to examine the changes in dosages over time. Findings were correlated with clinical parameters, human leucocyte antigen antibody titers, and peripheral blood mononuclear cell gene expression of the AlloMap (CareDx, Inc., Brisbane, CA) test genes. An intragraft, heart tissue gene coexpression network analysis was performed.

Results: Unsupervised cluster analysis of immunosuppressive therapies identified 2 groups, 1 characterized by a steeper immunosuppression minimization, associated with a higher likelihood for the combined end point, and the other by a less pronounced change. A time-dependent phenomap suggested that patients in the group with higher event rates had increased human leukocyte antigen class I and II antibody titers, higher expression of the FLT3 AlloMap gene, and lower expression of the MARCH8 and WDR40A AlloMap genes. Intramyocardial biomarker-related coexpression network analysis of the FLT3 gene showed an immune system-related network underlying this biomarker.

Conclusions: Time-dependent precision phenotyping is a mechanistically insightful, data-driven approach to characterize patterns of clinical care and identify ways to improve clinical management and outcomes.
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http://dx.doi.org/10.1016/j.healun.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064662PMC
August 2018

A peripheral blood transcriptome biomarker test to diagnose functional recovery potential in advanced heart failure.

Authors:
Mario C Deng

Biomark Med 2018 06 8;12(6):619-635. Epub 2018 May 8.

Professor of Medicine Advanced Heart Failure/Mechanical Support/Heart Transplant, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, 100 Medical Plaza Drive, Suite 630, Los Angeles, CA 90095, USA.

Heart failure (HF) is a complex clinical syndrome that causes systemic hypoperfusion and failure to meet the body's metabolic demands. In an attempt to compensate, chronic upregulation of the sympathetic nervous system and renin-angiotensin-aldosterone leads to further myocardial injury, HF progression and reduced O delivery. This triggers progressive organ dysfunction, immune system activation and profound metabolic derangements, creating a milieu similar to other chronic systemic diseases and presenting as advanced HF with severely limited prognosis. We hypothesize that 1-year survival in advanced HF is linked to functional recovery potential (FRP), a novel clinical composite parameter that includes HF severity, secondary organ dysfunction, co-morbidities, frailty, disabilities as well as chronological age and that can be diagnosed by a molecular biomarker.
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http://dx.doi.org/10.2217/bmm-2018-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479277PMC
June 2018

Current indications for transplantation: stratification of severe heart failure and shared decision-making.

Ann Cardiothorac Surg 2018 Jan;7(1):56-66

David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.

Heart failure (HF) is a complex clinical syndrome that results from structural or functional cardiovascular disorders causing a mismatch between demand and supply of oxygenated blood and consecutive failure of the body's organs. For those patients with stage D HF, advanced therapies, such as mechanical circulatory support (MCS) or heart transplantation (HTx), are potentially life-saving options. The role of risk stratification of patients with stage D HF in a value-based healthcare framework is to predict which subset might benefit from advanced HF (AdHF) therapies, to improve outcomes related to the individual patient including mortality, morbidity and patient experience as well as to optimize health care delivery system outcomes such as cost-effectiveness. Risk stratification and subsequent outcome prediction as well as therapeutic recommendation-making need to be based on the comparative survival benefit rationale. A robust model needs to (I) have the power to discriminate (i.e., to correctly risk stratify patients); (II) calibrate (i.e., to show agreement between the predicted and observed risk); (III) to be applicable to the general population; and (IV) provide good external validation. The Seattle Heart Failure Model (SHFM) and the Heart Failure Survival Score (HFSS) are two of the most widely utilized scores. However, outcomes for patients with HF are highly variable which make clinical predictions challenging. Despite our clinical expertise and current prediction tools, the best short- and long-term survival for the individual patient, particularly the sickest patient, is not easy to identify because among the most severely ill, elderly and frail patients, most preoperative prediction tools have the tendency to be imprecise in estimating risk. They should be used as a guide in a clinical encounter grounded in a culture of shared decision-making, with the expert healthcare professional team as consultants and the patient as an empowered decision-maker in a trustful safe therapeutic relationship.
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http://dx.doi.org/10.21037/acs.2017.12.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827132PMC
January 2018

Serum miR-122-5p and miR-206 expression: non-invasive prognostic biomarkers for renal cell carcinoma.

Clin Epigenetics 2018 23;10:11. Epub 2018 Jan 23.

1Department of Urology, University Hospital Bonn, Bonn, Germany.

Background: MicroRNAs (miRNA) play a relevant role in carcinogenesis, cancer progression, invasion, and metastasis. Thus, they can serve as diagnostic/prognostic biomarkers. The knowledge on circulating miRNAs for clear cell renal cell carcinomas (ccRCC) is limited. Our study was designed to identify novel biomarkers for ccRCC patients.

Results: The serum small RNA expression profile was determined in 18 ccRCC and 8 patients with benign renal tumors (BRT) using small RNA sequencing. We detected 29 differentially expressed miRNAs (17 upregulated and 12 downregulated in ccRCC) in the expression profiling cohort. Based on the expression levels, we next validated serum miR-122-5p, miR-193a-5p, and miR-206 levels in an independent cohort (68 ccRCC, 47 BRT, and 28 healthy individuals) using quantitative real-time PCR. Serum expression levels of miR-122-5p and miR-206 were significantly decreased in ccRCC compared to healthy individuals. Both miRNAs were circulating at similar levels in ccRCC and BRT patients. miR-193a-5p expression levels were not different within the study cohort. High serum miR-122-5p and miR-206 levels were associated with adverse clinicopathological parameters: miR-122-5p levels were correlated with metastatic RCC and grade, and miR-206 with pT-stage and metastasis. Furthermore, high miR-122-5p and miR-206 serum levels were associated with a shorter period of progression-free, cancer-specific, and overall survival in patients with ccRCC.

Conclusion: We identified serum miR-122-5p and miR-206 as novel non-invasive prognostic biomarkers for patients with ccRCC.
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http://dx.doi.org/10.1186/s13148-018-0444-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5781339PMC
February 2019

T cell dysfunction and patient age are associated with poor outcomes after mechanical circulatory support device implantation.

Hum Immunol 2018 Apr 1;79(4):203-212. Epub 2018 Feb 1.

Division of Cardiology, Department of Medicine, David Geffen School of Medicine, Los Angeles, CA 90095, United States.

Immunologic impairment may contribute to poor outcomes after implantation of mechanical circulatory support device (MCSD), with infection often as a terminal event. The study of immune dysfunction is of special relevance given the growing numbers of older patients with heart disease. The aim of the study was to define which immunologic characteristics are associated with development of adverse clinical outcomes after MCSD implantation. We isolated peripheral blood mononuclear cells (PBMC) from patients pre- and up to 20 days post-MCSD implantation and analyzed them by multiparameter flow cytometry for T cell dysfunction, including terminal differentiation, exhaustion, and senescence. We used MELD-XI and SOFA scores measured at each time point as surrogate markers of clinical outcome. Older patients demonstrated increased frequencies of terminally differentiated T cells as well as NKT cells. Increased frequency of terminally differentiated and immune senescent T cells were associated with worse clinical outcome as measured by MELD-XI and SOFA scores, and with progression to infection and death. In conclusion, our data suggest that T cell dysfunction, independently from age, is associated with poor outcomes after MCSD implantation, providing a potential immunologic mechanism behind patient vulnerability to multiorgan dysfunction and death. This noninvasive approach to PBMC evaluation holds promise for candidate evaluation and patient monitoring.
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http://dx.doi.org/10.1016/j.humimm.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476571PMC
April 2018

Perceived control and health-related quality of life in heart transplant recipients.

Eur J Cardiovasc Nurs 2018 08 20;17(6):513-520. Epub 2017 Dec 20.

5 Columbia University School of Nursing, New York, USA.

Background: Perceived control has been associated with improved mental health and health-related quality of life (HRQOL) in cardiac populations. However, this concept has not been well-studied in heart transplant groups.

Aims: We examine the relationship of perceived control to symptoms of anxiety and depression and HRQOL after transplant. We also examine the extent to which anxiety and depressive symptoms mediate the relationship between perceived control and HRQOL.

Methods: Our cross-sectional analysis included 113 adult heart transplant patients from the NEW HEART study. High versus low perceived control groups were determined by median split for chi-square and t-test analyses. Hierarchical multiple linear regression models were used to examine the influence of perceived control on symptoms of depression and anxiety and HRQOL. Mediation analyses included Baron and Kenny's four-step regression approach and Preacher and Hayes' bootstrapping technique to test the indirect effect of perceived control on HRQOL.

Results: Heart transplant patients who reported lower perceived control were more likely to be female ( p=0.003), and had significantly more depressive symptoms ( p<0.001) and anxiety ( p<0.001), and lower HRQOL ( p<0.001) than those with higher perceived control. Perceived control was a significant predictor in regression models of depressive and anxiety symptoms and HRQOL. In mediation analyses, depressive and anxiety symptoms mediated the effect of perceived control on HRQOL.

Conclusion: Perceived control is associated with improved depressive and anxiety symptoms and HRQOL after transplant. The relationship between perceived control and HRQOL is mediated by depressive and anxiety symptoms. Future interventions should target perceived control to improve overall HRQOL.
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http://dx.doi.org/10.1177/1474515117749225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984108PMC
August 2018

Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support.

PLoS One 2017 13;12(12):e0189420. Epub 2017 Dec 13.

David Geffen School of Medicine, University of California Los Angeles Medical Center, Los Angeles, California, United States of America.

Background: Multiorgan dysfunction syndrome contributes to adverse outcomes in advanced heart failure (AdHF) patients after mechanical circulatory support (MCS) implantation and is associated with aberrant leukocyte activity. We tested the hypothesis that preoperative peripheral blood mononuclear cell (PBMC) gene expression profiles (GEP) can predict early postoperative improvement or non-improvement in patients undergoing MCS implantation. We believe this information may be useful in developing prognostic biomarkers.

Methods & Design: We conducted a study with 29 patients undergoing MCS-surgery in a tertiary academic medical center from 2012 to 2014. PBMC samples were collected one day before surgery (day -1). Clinical data was collected on day -1 and day 8 postoperatively. Patients were classified by Sequential Organ Failure Assessment score and Model of End-stage Liver Disease Except INR score (measured eight days after surgery): Group I = improving (both scores improved from day -1 to day 8, n = 17) and Group II = not improving (either one or both scores did not improve from day -1 to day 8, n = 12). RNA-sequencing was performed on purified mRNA and analyzed using Next Generation Sequencing Strand. Differentially expressed genes (DEGs) were identified by Mann-Whitney test with Benjamini-Hochberg correction. Preoperative DEGs were used to construct a support vector machine algorithm to predict Group I vs. Group II membership.

Results: Out of 28 MCS-surgery patients alive 8 days postoperatively, one-year survival was 88% in Group I and 27% in Group II. We identified 28 preoperative DEGs between Group I and II, with an average 93% prediction accuracy. Out of 105 DEGs identified preoperatively between year 1 survivors and non-survivors, 12 genes overlapped with the 28 predictive genes.

Conclusions: In AdHF patients following MCS implantation, preoperative PBMC-GEP predicts early changes in organ function scores and correlates with long-term outcomes. Therefore, gene expression lends itself to outcome prediction and warrants further studies in larger longitudinal cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728510PMC
January 2018

Integrative model of leukocyte genomics and organ dysfunction in heart failure patients requiring mechanical circulatory support: a prospective observational study.

BMC Med Genomics 2017 08 29;10(1):52. Epub 2017 Aug 29.

Department of Medicine, Division of Cardiology, University of California Los Angeles, 100 UCLA Medical Plaza, Suite 630, Los Angeles, California, 90095, USA.

Background: The implantation of mechanical circulatory support devices in heart failure patients is associated with a systemic inflammatory response, potentially leading to death from multiple organ dysfunction syndrome. Previous studies point to the involvement of many mechanisms, but an integrative hypothesis does not yet exist. Using time-dependent whole-genome mRNA expression in circulating leukocytes, we constructed a systems-model to improve mechanistic understanding and prediction of adverse outcomes.

Methods: We sampled peripheral blood mononuclear cells from 22 consecutive patients undergoing mechanical circulatory support device (MCS) surgery, at 5 timepoints: day -1 preoperative, and postoperative days 1, 3, 5, and 8. Clinical phenotyping was performed using 12 clinical parameters, 2 organ dysfunction scoring systems, and survival outcomes. We constructed a strictly phenotype-driven time-dependent non-supervised systems-representation using weighted gene co-expression network analysis, and annotated eigengenes using gene ontology, pathway, and transcription factor binding site enrichment analyses. Genes and eigengenes were mapped to the clinical phenotype using a linear mixed-effect model, with Cox models also fit at each timepoint to survival outcomes.

Results: We inferred a 19-module network, in which most module eigengenes correlated with at least one aspect of the clinical phenotype. We observed a response of advanced heart failure patients to surgery orchestrated into stages: first, activation of the innate immune response, followed by anti-inflammation, and finally reparative processes such as mitosis, coagulation, and apoptosis. Eigengenes related to red blood cell production and extracellular matrix degradation became predictors of survival late in the timecourse corresponding to multiorgan dysfunction and disseminated intravascular coagulation.

Conclusions: Our model provides an integrative representation of leukocyte biology during the systemic inflammatory response following MCS device implantation. It demonstrates consistency with previous hypotheses, identifying a number of known mechanisms. At the same time, it suggests novel hypotheses about time-specific targets.
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http://dx.doi.org/10.1186/s12920-017-0288-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576384PMC
August 2017

Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

Curr Oncol Rep 2017 Jul;19(7):46

Division of Cardiology, Department of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.
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http://dx.doi.org/10.1007/s11912-017-0607-4DOI Listing
July 2017

Evaluation of the SIPAT instrument to assess psychosocial risk in heart transplant candidates: A retrospective single center study.

Heart Lung 2017 Jul - Aug;46(4):273-279. Epub 2017 May 17.

Department of Medicine, Division of Cardiology, University of California Los Angeles, 100 Medical Plaza, Suite 630E, Los Angeles, CA, 90095, USA.

Objectives: We evaluated the reliability of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in heart transplant (HT) recipients and explored its usefulness in predicting post-transplant outcomes.

Background: Pre-transplant psychosocial and behavioral risk is associated with post-transplant clinical outcomes. SIPAT is a risk assessment tool created for pre-transplant psychosocial evaluation.

Methods: Via retrospective chart review, three examiners applied the SIPAT to 51 adult HT recipients. Examiners blinded to SIPAT scores extracted data and interviewed clinicians for one-year post-transplant outcomes. Analysis included Intra-class correlation coefficient (ICC), Pearson's correlation coefficient and Chi-square.

Results: SIPAT demonstrated strong inter-rater reliability (ICC = 0.89, 95% CI = 0.76-0.96). Compared to those with SIPAT ratings of "Excellent/Good", the "Minimally Acceptable Candidate/High Risk" group was more likely to miss clinic visits (p = 0.004).

Conclusions: The SIPAT tool had strong IRR. Less favorable SIPAT ratings were associated with nonadherence to clinic visits. Further study is warranted to determine association of SIPAT ratings to clinical outcomes.
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http://dx.doi.org/10.1016/j.hrtlng.2017.04.005DOI Listing
August 2017

Anthracycline induced cardiotoxicity: biomarkers and "Omics" technology in the era of patient specific care.

Clin Transl Med 2017 Dec 10;6(1):17. Epub 2017 May 10.

Division of Cardiology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.

Anthracyclines are highly effective against a variety of malignancies. However, their dose-dependent cardiotoxic effects can potentially limit their use. In the past decade, serum biomarkers have been used to diagnose, monitor, predict, and prognosticate disease. Biomarkers such as cardiac troponin and natriuretic peptides have some predictive value, but still lack reliability in this patient population. Novel biomarkers such as galectin-3, soluble ST-2 proteins, myeloperoxidase, and fibrocytes are being explored as potential biomarkers to reliably predict the onset of cardiotoxicity. Leveraging multiomics technology to map highly sensitive biomarkers in an integrated approach through pattern deconvolution may better define those at highest risk of developing cardiotoxicity and further the goal of precision medicine. In this work, we aim to provide a brief overview of traditional serum biomarkers, summarize current investigations on novel circulating biomarkers, and discuss a systems-based approach to anthracycline-induced cardiotoxicity through "omics" technology.
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http://dx.doi.org/10.1186/s40169-017-0148-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425361PMC
December 2017
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