Publications by authors named "Abbas Ardehali"

105 Publications

Left main coronary artery compression in pulmonary hypertension.

Catheter Cardiovasc Interv 2020 Nov 25. Epub 2020 Nov 25.

Division of Cardiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) in the setting of pulmonary arterial hypertension (PAH) is an increasingly recognized disease entity. LMCA compression has been associated with angina, arrhythmia, heart failure, and sudden cardiac death in patients with PAH. Recent studies suggest that at least 6% of patients with PAH have significant LMCA compression. Screening for LMCA compression can be achieved with computed coronary tomography angiography, with a particular emphasis on assessment of PA size and any associated downward displacement and reduced takeoff angle of the LMCA. Indeed, evidence of a dilated PA (>40 mm), a reduced LMCA takeoff angle (<60°), and/or LMCA stenosis on CCTA imaging should prompt further diagnostic evaluation. Coronary angiography in conjunction with intravascular imaging has proven effective in diagnosing LMCA compression and guiding subsequent treatment. While optimal medical therapy and surgical correction remain in the clinician's arsenal, percutaneous coronary intervention has emerged as an effective treatment for LMCA compression. Given the prevalence of LMCA compression, its associated morbidity, and mortality, and the wide array of successful treatment strategies, maintaining a high degree of suspicion for this condition, and understanding the potential treatment strategies is critical.
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http://dx.doi.org/10.1002/ccd.29401DOI Listing
November 2020

Plasma Donor-derived Cell-free DNA Levels Are Increased During Acute Cellular Rejection After Lung Transplant: Pilot Data.

Transplant Direct 2020 Oct 24;6(10):e608. Epub 2020 Sep 24.

David Geffen-UCLA School of Medicine, CareDx, Inc., Los Angeles, CA.

Telehealth platforms with remote phlebotomy and biomarker implementation represent a novel paradigm for surveillance after lung transplantation (LT). In a pilot study, we investigated donor-derived cell-free DNA (dd-cfDNA) in plasma using a clinical-grade "next-generation sequencing" assay.

Methods: dd-cfDNA levels determined in biorepository venous plasma samples obtained during the lung allograft rejection gene expression observation study, implementing a clinical-grade next-generation sequencing assay. Sixty-nine unique LT patients encompassing 9 LT centers, with associated clinical-histopathologic diagnoses, were examined-allograft infection (n = 26), normal histopathology without infection (n = 30), and acute cellular rejection (ACR; n = 13).

Results: dd-cfDNA in ACR patients were significantly elevated (1.52%; interquartile range [IQR], 0.520-2.2550) compared with the normal stable patients (0.485%; IQR, 0.220-0.790) ( = 0.026). During allograft infection, dd-cfDNA values were not different (0.595; IQR, 0.270-1.170) from normal ( = 0.282) and ACR ( = 0.100). AUC-receiver operator characteristics curve analysis for allograft ACR was 0.717 (95% confidence interval, 0.547-0.887;  = 0.025). At a 0.87% threshold dd-cfDNA-sensitivity = 73.1%, specificity = 52.9%, positive predictive value = 34.1%, and negative predictive value = 85.5%.

Conclusions: dd-cfDNA assessment holds promise as a noninvasive biomarker of "allograft injury" with acute rejection following LT while prospective, multicenter studies should further refine utility across the spectrum of allograft rejection and infection.
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http://dx.doi.org/10.1097/TXD.0000000000001063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515612PMC
October 2020

Prognosis of heart transplant patients in Mashhad University of Medical Sciences.

Kardiochir Torakochirurgia Pol 2020 Mar 7;17(1):33-38. Epub 2020 Apr 7.

Thoracic Surgeon Ronald Reagan UCLA Medical Center, Santa Monica, USA.

Introduction: Heart transplant is the ultimate treatment for patients with end-stage heart failure.

Aim: To assess 50 heart transplant patients for underlying diseases, transplantation outcome and mortality rate during a 5-year follow-up program.

Material And Methods: Fifty heart transplant patients who underwent heart transplantation from 2012 to 2017 were assessed for underlying diseases, organ rejection, duration of hospitalization, extubation time, cardiac output and survival. Biopsy samples were obtained after surgery for evaluation of rejection.

Results: Dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) were the most common underlying diseases with prevalence of 56% and 12%, respectively. Significant improvement in ejection fraction was observed following heart transplant. Minimum and maximum extubation and hospitalization times were 3-408 hours and 1-51 days, respectively. Organ rejection evaluation 10 days after heart transplantation revealed that 50% of patients did not show any rejection while 10% had severe rejection. At 30 days post-operatively the number of patients with grade III rejection decreased to 2% while 56% of patients had no sign of rejection. The 5-year survival rate was 66% while infection and arrhythmia were the most common causes of death.

Conclusions: DCM and ICM are considered the most prevalent underlying diseases in heart transplant candidates. Ejection fraction reached normal ranges following transplant, which provides good quality of life. Low incidence of severe acute rejection demonstrates the effectiveness of our immunosuppressive therapy. In the cases of increased rejection, the patient's immunosuppressive regimen was re-assessed accordingly.
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http://dx.doi.org/10.5114/kitp.2020.94189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379209PMC
March 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

Current status of normothermic ex-vivo perfusion of cardiac allografts.

Curr Opin Organ Transplant 2020 06;25(3):237-240

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

Purpose Of Review: Ex-vivo perfusion has emerged in recent years as an alternative to cold static preservation of organs harvested for transplant. Normothermic ex-vivo perfusion, the subject of this review, maintains the donor heart in a near physiologic state, and allows the transplant team to monitor and control perfusion to the organ prior to implantation. A growing body of evidence has established the safety and viability of this technique, which may improve on current standards of donor management.

Recent Findings: Following initial single-arm studies over a decade ago, ex-vivo perfusion has been studied in a prospective, randomized fashion in standard donor hearts (PROCEED II trial). The short and intermediate-term results demonstrated similar outcomes compared with cold storage with significantly shorter cold ischemic time. Since then, ex-vivo perfusion has been studied in extended-criteria donor hearts, first in observational studies, and currently in randomized, prospective fashion in the recently completed EXPAND-Heart trial, which is anticipated to be reported in 2020.

Summary: Normothermic ex-vivo perfusion has an established literature base and holds promise for changing current practices of heart preservation. Results of forthcoming pivotal studies will help determine its role in more widespread clinical adoption.
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http://dx.doi.org/10.1097/MOT.0000000000000759DOI Listing
June 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

Involvement of Low-Density Lipoprotein Receptor in the Pathogenesis of Pulmonary Hypertension.

J Am Heart Assoc 2020 01 9;9(2):e012063. Epub 2020 Jan 9.

Department of Anesthesiology David Geffen School of Medicine at UCLA Los Angeles CA.

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the role of LDL-R in the development of PH and determined the efficacy of high-density lipoprotein mimetic peptide 4F in mitigating PH. Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL-R null (LDL-R knockout) mice (12-15 months old) were fed chow, Western diet (WD), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real-time quantitative reverse transcription-polymerase chain reaction, and histological analysis were performed. The effect of LDL-R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL-R and CD36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL, E06 immunoreactivity, and plasma oxidized LDL/LDL ratio. LDL-R knockout mice on WD developed PH, right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL-R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.
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http://dx.doi.org/10.1161/JAHA.119.012063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033825PMC
January 2020

Prospective, multicenter, randomized, controlled trial evaluating the performance of a novel combination powder vs hemostatic matrix in cardiothoracic operations.

J Card Surg 2020 Feb 25;35(2):313-319. Epub 2019 Nov 25.

Biom'up SA, Lyon, France.

Aim: This trial compared the hemostatic performance of a novel combination powder (CP) to a control hemostatic matrix (HM) in cardiothoracic operations.

Methods: Patients meeting eligibility criteria were enrolled after providing informed consent. Subjects were randomized intraoperatively to receive CP (HEMOBLAST Bellows; Biom'up, France) or HM (FLOSEAL Hemostatic Matrix; Baxter Healthcare Corporation, Hayward, CA). Bleeding was assessed using a clinically validated, quantitative bleeding severity scale. The primary endpoint was total time to hemostasis (TTTH), from the start of device preparation, as an indicator of when a surgeon asks for a surgical hemostat until hemostasis was achieved. TTTH at 3 minutes was utilized for the primary analysis, while TTTH at 5 minutes was considered as a secondary endpoint.

Results: A total of 105 subjects were enrolled across four institutions. The primary efficacy endpoint for the superiority of CP relative to HM for success at achieving hemostasis within 3 minutes was met, with 64.2% of the CP group achieving hemostasis compared with 9.6% of the HM group, a difference of 54.54% (37.4%-71.6%; P < .001 for superiority). The secondary efficacy endpoint was also met, with 92.5% of the CP group achieving hemostasis at 5 minutes versus 44.2% in the HM group, a difference of 48.2% (31.1%-65.4%; P < .001 for noninferiority). There were no device-related adverse events.

Conclusions: In this multicenter, randomized, controlled trial, comparison of CP to HM revealed CP superiority and noninferiority for TTTH at 3 and 5 minutes, respectively.
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http://dx.doi.org/10.1111/jocs.14376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003826PMC
February 2020

Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease.

EBioMedicine 2019 Dec 12;50:379-386. Epub 2019 Nov 12.

Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA. Electronic address:

Background: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology.

Methods: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex.

Findings: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93·0 pg/ml [±97·2] vs. 37·5 pg/ml [±35·4], p < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], p < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], p = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], p < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], p < 0·001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs.

Interpretation: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (∼45-50%).

Funding: Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).
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http://dx.doi.org/10.1016/j.ebiom.2019.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921223PMC
December 2019

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
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http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Ambulatory central veno-arterial extracorporeal membrane oxygenation in lung transplant candidates.

J Heart Lung Transplant 2019 12 11;38(12):1317-1319. Epub 2019 Sep 11.

Division of Cardiac Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2019.09.006DOI Listing
December 2019

Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis.

EMBO Mol Med 2019 09 29;11(9):e10061. Epub 2019 Aug 29.

Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, UCLA, Los Angeles, CA, USA.

Pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF-PH and underlying mechanism of why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non-fibrotic areas of PF-PH patient lungs compared to PF patients. The increased vascular wall thickness in PF-PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin-induced protein (PIP), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF-PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF-PH. We found Slug inhibition decreases PH severity in our animal model of PF-PH. Our study highlights the role of Slug/PIP axis in PF-PH.
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http://dx.doi.org/10.15252/emmm.201810061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728601PMC
September 2019

Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extended-criteria donors (EXPAND): a single-arm, pivotal trial.

Lancet Respir Med 2019 11 1;7(11):975-984. Epub 2019 Aug 1.

Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium.

Background: Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used.

Methods: In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO) to fractional concentration of oxygen inspired air (FiO) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO:FiO was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete.

Findings: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5).

Interpretation: Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research.

Funding: TransMedics Inc.
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http://dx.doi.org/10.1016/S2213-2600(19)30200-0DOI Listing
November 2019

A Febrile, Hypotensive Patient With Bilateral Lung Crackles.

JAMA 2019 Jun;321(24):2460-2461

Department of Cardiac Surgery, University of California, Los Angeles.

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http://dx.doi.org/10.1001/jama.2019.6546DOI Listing
June 2019

Evaluation of the safety and efficacy of a new hemostatic powder using a quantitative surface bleeding severity scale.

J Card Surg 2019 Jan 10;34(1):50-62. Epub 2019 Jan 10.

Advanced Powder Investigators Group (APIG).

Aims Of The Study: The safety and efficacy of a hemostatic powder (HP) versus a control agent, absorbable gelatin sponge and thrombin (G + T), were assessed, using a validated, quantitative bleeding severity scale.

Methods: Subjects were randomized to receive HP (256 subjects) or G + T (132 subjects) for treatment of minimal, mild, or moderate bleeding at 20 investigational sites. The primary efficacy endpoint was non-inferiority of HP relative to G + T for success at achieving hemostasis within 6 minutes. Secondary endpoints in rank order included: superiority of HP relative to G + T in mean preparation time; non-inferiority of HP relative to G + T for achieving hemostasis within 3 min; superiority of HP relative to G + T for achieving hemostasis within 6 min; and superiority of HP relative to G + T for success for achieving hemostasis within 3 min.

Results: A total of 388 subjects were included in the primary efficacy analysis. At 6 min, hemostasis was achieved in 93.0% (238/256) of the HP group compared to 77.3% (102/132) of the G + T group (non-inferiority P < 0.0001, superiority P < 0.0001). All secondary endpoints were met. Complications were comparable between treatment groups.

Conclusions: HP had superior rates of hemostasis, shorter preparation time, and a similar safety profile compared to G + T in this prospective, randomized trial using quantitative bleeding severity criteria.
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http://dx.doi.org/10.1111/jocs.13982DOI Listing
January 2019

Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis.

PLoS One 2018 20;13(11):e0206545. Epub 2018 Nov 20.

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Background: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial.

Methods: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed.

Results: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH.

Conclusion: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206545PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245508PMC
April 2019

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

Lung transplantation in the Lung Allocation Score era: Medium-term analysis from a single center.

Clin Transplant 2018 08 15;32(8):e13298. Epub 2018 Jun 15.

Division of Cardiac Surgery, UCLA Medical Center, Los Angeles, CA, USA.

In 2005, the Lung Allocation Score (LAS) was implemented as the allocation system for lungs in the US. We sought to compare 5-year lung transplant outcomes before and after the institution of the LAS. Between 2000 and 2011, 501 adult patients were identified, with 132 from January 2000 to April 2005 (Pre-LAS era) and 369 from May 2005 to December 2011 (Post-LAS era). Kruskal-Wallis or chi-squared test was used to determine significance between groups. Survival was censored at 5 years. Overall, the post-LAS era was associated with more restrictive lung disease, higher LAS scores, shorter wait-list times, more preoperative immunosuppression, and more single lung transplantation. In addition, post-LAS patients had higher O requirements with greater preoperative pulmonary impairment. Postoperatively, 30-day mortality improved in post-LAS era (1.6% vs 5.3%, P = .048). During the pre- and post-LAS eras, 5-year survival was 52.3% and 55.3%, respectively (P = .414). The adjusted risk of mortality was not different in the post-LAS era (P = .139). Freedom from chronic lung allograft dysfunction was significantly higher in the post-LAS era (P = .002). In this single-center report, implementation of the LAS score has led to allocation to sicker patients without decrement in short- or medium-term outcomes. Freedom from CLAD at 5 years is improving after LAS implementation.
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http://dx.doi.org/10.1111/ctr.13298DOI Listing
August 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

Evolving challenges in thoracic transplantation.

Authors:
Abbas Ardehali

Curr Opin Organ Transplant 2018 06;23(3):279-280

David Geffen school of Medicine at University of California, Los Angeles, California, USA.

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http://dx.doi.org/10.1097/MOT.0000000000000533DOI Listing
June 2018

Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study.

Lancet Respir Med 2018 05 9;6(5):357-367. Epub 2018 Apr 9.

Department of Surgery, Division of Cardiothoracic Surgery, Ronald Reagan University of California, Los Angeles Medical Center, Los Angeles, CA, USA.

Background: Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage.

Methods: In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434.

Findings: Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116 (70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141 patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0) in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients (83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients (81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%) of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015). The primary safety endpoint was met (0·23 lung graft-related serious adverse events in the OCS group compared with 0·28 events in the control group [point estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1).

Interpretation: The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation.

Funding: TransMedics Inc.
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http://dx.doi.org/10.1016/S2213-2600(18)30136-XDOI Listing
May 2018

Primary graft dysfunction in heart transplantation.

Curr Opin Organ Transplant 2018 06;23(3):286-294

Division of Cardiac Surgery, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Purpose Of Review: Primary graft dysfunction (PGD) is common early postheart transplantation; however, use of standardized definitions remains inconsistent. This review focuses on understanding the incidence, classification, risk factors, and management of PGD.

Recent Findings: The incidence and mortality of PGD in heart transplant varies considerably in the published literature ranging from 1.0% to 31% and 3% to 75%, respectively. There is also considerable variation in management strategies with current data favoring early intervention.

Summary: PGD in heart transplantation remains a challenging problem associated with significant mortality and morbidity. There is need for a consistent and accessible definition to better define associated risk factors and optimize management strategies.
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http://dx.doi.org/10.1097/MOT.0000000000000523DOI Listing
June 2018

The Impact of Allograft CXCL9 during Respiratory Infection on the Risk of Chronic Lung Allograft Dysfunction.

OBM Transplant 2018 30;2(4). Epub 2018 Nov 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA.

Background: The long term clinical significance of respiratory infections after lung transplantation remains uncertain.

Methods: In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between respiratory infection and chronic lung allograft dysfunction (CLAD). We furthermore hypothesized that bronchoalveolar lavage fluid (BALF) CXCL9 concentrations are augmented during respiratory infections, and that episodes of infection with elevated BALF CXCL9 are associated with greater CLAD risk.

Results: In univariable and multivariable models adjusted for other histopathologic injury patterns, respiratory infection, regardless of the causative organism, was a strong predictor of CLAD development (adjusted HR 1.8 95% CI 1.3-2.6). Elevated BALF CXCL9 concentrations during respiratory infections markedly increased CLAD risk in a dose-response manner. An episode of respiratory infection with CXCL9 concentrations greater than the 25, 50, and 75 percentile had adjusted HRs for CLAD of 1.8 (95% CI 1.1-2.8), 2.4 (95% CI 1.4-4.0) and 4.4 (95% CI 2.4-8.0), respectively.

Conclusions: Thus, we demonstrate that respiratory infections, regardless of the causative organism, are strong predictors of CLAD development. We furthermore demonstrate for the first time, the prognostic importance of BALF CXCL9 concentrations during respiratory infections on the risk of subsequent CLAD development.
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http://dx.doi.org/10.21926/obm.transplant.1804029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693350PMC
November 2018

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft.

Transplantation 2018 06;102(6):986-993

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.

Background: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.

Methods: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant.

Results: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD.

Conclusions: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.
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http://dx.doi.org/10.1097/TP.0000000000002058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962368PMC
June 2018

The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation.

PLoS One 2017 7;12(7):e0180281. Epub 2017 Jul 7.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.

Rationale: Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk.

Methods: All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and "healthy" biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates.

Results: There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as "healthy" biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with "healthy" biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0-2.3), 1.9 (95% CI 1.2-2.8) and 2.2 (95% CI 1.4-3.4), respectively.

Conclusions: This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180281PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501470PMC
September 2017

The In-Hospital Cost of Ventricular Assist Device Therapy: Implications for Patient Selection.

ASAIO J 2017 Nov/Dec;63(6):725-730

From the *David Geffen School of Medicine, UCLA Medical Center, Los Angeles, California; and †Division of Cardiac Surgery, UCLA Medical Center, Los Angeles, California.

Ventricular assist device (VAD) therapy is increasingly utilized to support patients in end-stage heart failure. However, VAD programs are resource intensive and demand active monitoring to ensure long-term sustainability. The purpose of this study was to analyze total cost trends of the VAD program at our academic medical center. Retrospective analysis of University of California - Los Angeles's VAD program between 2013 and 2014 was performed. Total in-hospital costs from the date of VAD surgery admission were queried and normalized to a z score. Multivariable linear regression analysis with step-wise elimination was used to model total costs. Overall, 42 patients received a VAD during the study period, with 19 (45%) receiving biventricular support. On univariate analysis, high body mass index, biventricular support, time between VAD implantation and discharge, and total length of hospital stay were correlated with higher costs (all p < 0.02). On multivariable analysis, time between VAD implantation and discharge and biventricular support remained significantly related to total costs (overall R = 0.831, p < 0.001). The time between VAD implantation and discharge and the use of biventricular support were the most predictive factors of total cost in our VAD population. Reducing hospital stay post-VAD implantation is important in minimizing the cost of VAD care.
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http://dx.doi.org/10.1097/MAT.0000000000000545DOI Listing
May 2018

Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction.

PLoS One 2017 19;12(1):e0169894. Epub 2017 Jan 19.

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

Background: Chronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.

Methods: In a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).

Results: The cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.

Conclusions: These findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169894PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245825PMC
August 2017

Voriconazole increases the risk for cutaneous squamous cell carcinoma after lung transplantation.

Transpl Int 2017 Jan 24;30(1):41-48. Epub 2016 Oct 24.

Department of Medicine, University of California, Los Angeles, CA, USA.

Lung transplant recipients (LTR) are at high risk of cutaneous squamous cell carcinoma (SCC). Voriconazole exposure after lung transplant has recently been reported as a risk factor for SCC. We sought to study the relationship between fungal prophylaxis with voriconazole and the risk of SCC in sequential cohorts from a single center. We evaluated 400 adult LTR at UCLA between 7/1/2005 and 12/22/2012. On 7/1/2009, our center instituted a protocol switch from targeted to universal antifungal prophylaxis for at least 6 months post-transplant. Using Cox proportional hazards models, time to SCC was compared between targeted (N = 199) and universal (N = 201) prophylaxis cohorts. Cox models were also used to assess SCC risk as a function of time-dependent cumulative exposure to voriconazole and other antifungal agents. The risk of SCC was greater in the universal prophylaxis cohort (HR 2.02, P < 0.01). Voriconazole exposure was greater in the universal prophylaxis cohort, and the cumulative exposure to voriconazole was associated with SCC (HR 1.75, P < 0.01), even after adjustment for other important SCC risk factors. Voriconazole did not increase the risk of advanced tumors. Exposure to other antifungal agents was not associated with SCC. Voriconazole should be used cautiously in this population.
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http://dx.doi.org/10.1111/tri.12865DOI Listing
January 2017