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Background:Right heart failure (RHF) is associated with worse clinical outcomes. In addition to hemodynamic perturbations, the syndrome of RHF involves liver congestion and dysfunction. The mechanisms that underlie heart-liver interactions are poorly understood and may involve secreted factors. As a first step to understand the cardiohepatic axis, we sought to elucidate the circulating inflammatory milieu in patients with RHF.Methods:Blood samples were collected from the IVC and hepatic veins during right heart catheterization from 3 groups of patients: 1) controls with normal cardiac function, 2) patients with heart failure (HF) who did not meet all criteria of RHF, and 3) patients who met prespecified criteria for RHF defined by hemodynamic and echocardiographic parameters. We performed multiplex protein assay to survey levels of several circulating markers and analyzed their association with mortality and need for left ventricular assist device or heart transplant. Finally, we leveraged publicly available single cell RNA sequencing (scRNAseq) data and performed tissue imaging to evaluate expression of these factors in the liver.Results:In this study of 43 patients, RHF was associated with elevated levels of a subset of cytokines/chemokines/growth factors compared to controls. In particular, soluble CD163 (sCD163) and CXCL12 were higher in RHF and predicted survival in an independent validation cohort. Furthermore, scRNAseq and immunohistochemistry of human liver biopsies suggest that these factors are expressed by Kupffer cells and may be liver derived.Conclusions:RHF is associated with a distinct circulating inflammatory profile. sCD163 and CXCL12 are novel biomarkers that can prognosticate patient outcomes. Future studies to define how these molecules influence HF phenotypes and disease progression may lead to new approaches to management of patients with RHF.

Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT.This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers.The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up.The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.

Zusammenfassung Hintergrund Eine repräsentative Beschreibung der aktuellen Arbeitsbedingungen, Änderungen und Perspektiven in nicht-universitären gastroenterologischen Kliniken/Abteilungen in Deutschland, insbesondere auch im zeitlichen Verlauf der Corona-Krise, ist bisher nicht vorhanden. Die Arbeitsgemeinschaft Leitender Gastroenterologischer Krankenhausärzte (ALGK) repräsentiert mehr als 70% der gastroenterologischen Chefärzte und spiegelt daher die Situation in der stationären Gastroenterologie repräsentativ wider. Methode Die ALGK führte in den Jahren 2020 während der ersten und 2021 während der zweiten Corona-Welle eine Umfrage ihrer Mitglieder über den Link https://www.surveymonkey.de/r/TFBFGMV durch. Hierbei wurden 369 Mitglieder mit gültiger E-Mail-Adresse angeschrieben. In der ersten Umfrage wurden 17 und in der zweiten Umfrage 21 Fragen gestellt. Ergebnisse 58 % der Antworten repräsentierten Grund- und Regelversorger, 36 % Schwerpunktversorger, 6 % Maximalversorger, 43 % kommunale Krankenhäuser, 38 % konfessionelle Träger und 18 % private Träger. 87 % der befragten Abteilungen/Kliniken gaben eine Absage der elektiven stationären Versorgung überwiegend und unverändert durch den Patienten (87 %/85 %) an. In der zweiten Umfrage waren die durch den Arzt abgesagten Untersuchungen (58 % vs. 84 %), die Angabe rückläufiger Notfälle (16 % vs. 29 %), die Verschiebung der elektiven Diagnostik bzw. Therapie (85 % vs. 99 %) und der Rückgang geplanter stationärer (65 vs. 91 %) bzw. ambulanter Behandlungen (15 % vs. 84 %) deutlich geringer als bei der ersten Umfrage. Im Mittel war in den Kliniken/Abteilungen ein Rückgang der diagnostischen Endoskopien von 337/Monat auf 151/Monat (55 %), der therapeutischen von 174/Monat auf 84/Monat (52 %) und der Vorsorgekoloskopien von 56/Monat auf 7/Monat (87,5 %) zu verzeichnen. Der Vergleich zwischen den Krankenhausträgern ergab eine häufigere Angabe von quarantänepflichtigen Mitarbeitern, von sehr starker bzw. starker psychischer Belastung, von Angst vor Corona-Infektionen und die Vermutung einer zunehmenden Ambulantisierung der Gastroenterologie bei privaten Trägern. Die Impfbereitschaft war trägerunabhängig bei den Ärzten/Endoskopiepersonal mit insgesamt 92 %/89 % sehr hoch. Ebenfalls trägerunabhängig befürchteten 38 % der Befragten, dass ihr Haus aufgrund der Corona-Krise existenzgefährdet sei. Schlussfolgerung Die beiden ALGK-Umfragen geben ein repräsentatives Bild über die Situation der nicht-universitären gastroenterologischen Kliniken/Abteilungen während der Corona-Krise und im Zeitverlauf in Deutschland.

Nucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.We observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1. Treatment of cultured primary murine HSC with recombinant mouse IL-18 accelerated their transdifferentiation into myofibroblasts. In vivo, IL-18 receptor-deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC-specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH-induced fibrosis by feeding a choline-deficient, L-amino acid-defined, high fat diet showed that genes related to IL-18 and its downstream signaling were significantly upregulated, and Il18Our study highlights the role of IL-18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL-18 as a target to treat liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is a multisystem disease that affects not only the liver but also heart, pancreas, and kidney. We currently lack a comprehensive understanding of mechanisms responsible for the development of NASH-associated cardiomyopathy or the influence of sex on pathophysiology. There is a critical need to address these gaps in knowledge in order to accelerate translation of knowledge into clinical practice.NASH and cardiovascular disease share common risk factors such as chronic inflammation, hyperlipidemia, and insulin resistance. Early cardiac dysfunction in NASH that is independent of obesity or other cardiometabolic risk factors suggests roles for liver-heart crosstalk in disease pathogenesis. Inflammation is a driving force in the pathogenesis of NASH, and it is likely that 'spill over' of NASH inflammation contributes to the development of cardiomyopathy. However, molecular and cellular mechanisms that mediate NASH-associated cardiomyopathy remain unclear because of inherent limitations of experimental models. Even so, recent studies implicate inflammatory, metabolic, and physiologic mechanisms that enhance our understanding of NASH-associated cardiomyopathy and the role of liver-heart crosstalk.An innovative, detailed, and mechanistic understanding of NASH-associated cardiomyopathy is relevant to public health and will be fundamental for the comprehensive care of these patients.

Introduction: Right heart failure (RHF) is associated with worse clinical outcomes in patients with heart failure (HF) and pulmonary hypertension. Previous studies have shown elevated circulating proinflammatory cytokines in patients with HF; however, no study has compared the inflammatory signature in patients with RHF to those with HF and preserved right ventricular (RV) function. Hypothesis: We predicted that patients with RHF would have a distinct inflammatory milieu compared to normal and HF patients. Methods: We recruited adult patients undergoing right heart catheterization (RHC) and excluded those with a history of transplant, autoimmune disease, malignancy, or infection. Patients underwent blood sampling during RHC and were classified into normal, HF, and RHF cohorts a priori . We then performed multiplex protein assay on serum targeting cytokines, chemokines, and growth factors. Results: A total of 43 patients were included. HF and RHF patients had similar demographics and cardiac indices, but the RHF cohort had elevated markers of congestion characterized by higher right atrial pressure and creatinine, and a trend towards higher bilirubin (Figure). Patients with RHF had elevated levels of select proinflammatory cytokines, chemokines, and growth factors. Of the factors measured, VEGF-A, soluble CD163, and CXCL12 were predictive of all-cause mortality and LVAD/transplant-free survival. Conclusion: Patients with RHF have a distinct proinflammatory signature compared to those with preserved RV function. VEGF-A, soluble CD163, and CXCL12 predicted clinical outcomes in an advanced HF population.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system. Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase

Chimeric antigen receptor T cells (CAR-T) are genetically modified T cells with a chimeric antigen receptor directed against a specific tumor-associated antigen like CD19 in lymphoma. CAR-T cells have shown encouraging activity against recurrent and refractory diffuse large B cell lymphomas (DLBCL). However concurrent use of immunosuppressive agents was prohibited in most CAR-T trials effectively excluding patients with prior solid organ transplantation (SOT) and posttransplant lymphoproliferative disorders (PTLD). We report the outcomes for three patients with PTLD refractory to immunochemotherapy 10-20 years after SOT who received CAR-T therapy between January 2018 and December 2019. One patient had an orthotopic heart transplant, the second had a deceased donor kidney transplant, and the third had a pancreas after kidney transplant (PAK). All patients developed complications of CAR-T therapy such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and acute kidney injury requiring renal replacement therapy in the two out of three patients. All patients expired after withdrawal of care due to lack of response to CAR-T therapy. In addition, the PAK patient developed acute pancreatitis after CAR-T therapy. This case series identifies the challenges of using CAR-T therapy to manage refractory PTLD in SOT recipients and its possible complications.

Single cell transcriptomics has emerged as a powerful lens through which to study the molecular diversity of complex tissues such as the liver, during health and disease, both in animal models and in humans. The earliest gene expression methods measured bulk tissue RNA, but the results were often confusing because they derived from the combined transcriptomes of many different cell types in unknown proportions. To better delineate cell-type-specific expression, investigators developed cell isolation, purification, and sorting protocols, yet still, the RNA derived from ensembles of cells obscured recognition of cellular heterogeneity. Profiling transcriptomes at the single-cell level has opened the door to analyses that were not possible in the past. In this review, we discuss the evolution of single cell transcriptomics and how it has been applied for the study of liver physiology and pathobiology to date.

Heavy metals (HMs) are known to modify bacterial communities both in the laboratory and in situ. As a consequence, soils in HM contaminated sites like the U.S. Environmental Protection Agency (EPA) Superfund sites are predicted to have altered ecosystem functioning, with potential ramifications for the health of organisms, including humans, that live nearby. Further, several studies have shown that metal tolerant bacteria are often also resistant to antimicrobial agents (AMR), and therefore HM contaminated soils could potentially act as reservoirs that could disseminate AMR genes into human-associated pathogenic bacteria. To explore this possibility soil samples were collected from six public locations in the zip code 35207 (the home of the North Birmingham 35th Avenue Superfund site) and in six public areas in a neighboring reference zip code (35214). Sequencing of the V4 region of the bacterial 16S rRNA gene revealed that elevated concentrations of HMs As, Mn, Pb, and Zn reduced microbial diversity and altered community structure within each zip code. While there was no difference between zip codes in the proportion of total culturable microbes that survived antimicrobial or metal exposure, bacterial isolates with HMR almost always also exhibited AMR. Metagenomes inferred using PICRUST2 also predicted significantly higher mean relative frequencies in 35207 for several AMR genes related to both specific and broad-spectrum AMR phenotypes. Together, these results support the hypothesis that chronic HM pollution alters soil bacterial community structure in ecologically meaningful ways and may also select for bacteria with increased potential to contribute to AMR in human bacterial disease.

Das Screening auf kolorektale Karzinome der Zukunft wird nichtinvasiv sein. Die Tests mussen eine hohe Spezifitat, aber auch eine ausreichende Sensitivitat aufweisen, um moglich keine falsch-negativen Befunde zu generieren. Bis dato erfullt kein Bluttest die Kriterien, die fur den „faecal immunochemical test“ (FIT) erreicht werden. Aktuell ist die Kombination aus familienanamnestischer Erhebung, der Erfassung von klinischen Risikofaktoren und der genomweiten Analyse von Risikofaktoren (GWA) die beste nichtinvasive Filtertechnologie. Next Generation Sequencing (NGS) und die Nutzung der kunstlichen Intelligenz wird das nichtinvasive Screening des kolorektalen Karzinoms, aber auch anderer Karzinome vorantreiben.

Introduction: Peripartum cardiomyopathy (PPCM) is a severe complication of pregnancy which is hallmarked by non-ischemic reduction in left ventricular ejection fraction (LVEF) to Methods: Thirty female patients 18-46 years of age underwent cardiac surgery for PPCM between 2012-2020. Primary heart transplant patients (n=2) were excluded. PPCM patients with a new MCS requirement (n=28) were classified by device type and escalations in device support. Results: Mean age was 29±7 years and 21 patients (75%) were African American. Median time from delivery to MCS requirement was 418 [91-1201] days. Nineteen (68%) patients required temporary MCS (tMCS): 12 (63%) on intraaortic balloon pump, 9 (47%) on veno-arterial extracorporeal membrane oxygenation, and 4 (21%) on Impella. Nine (32%) patients underwent left ventricular assist device (LVAD) implant after failure of medical therapy. LVEF and left ventricular end-diastolic diameter (LVEDD) at MCS insertion were 14±5mm and 68±11mm, respectively. LVEF progressed to 24%±16% post-insertion and 29%±17% one year (Figure 1). Of the 19 tMCS patients, 5 (26%) required escalations with additional modalities. Ten (53%) patients were bridged to durable LVAD. Complications included right ventricular failure (n=4), stroke (n=2), sepsis (n=1), dialysis (n=5), and cardiac arrest (n=3). Duration of support was 9±7 days for tMCS and 996±625 days for LVAD. Overall survival to discharge was 89% (n=25). Twelve patients underwent transplant (43%) and two (7%) recovered native heart function. Conclusions: Severe PPCM can be effectively managed with tMCS as a bridging strategy to either transplant or durable LVAD. Patients will often require multiple escalations in resource-intensive therapy, but outcomes are excellent with vigilant management.

BACKGROUND Previous studies in heart transplantation have shown an association between institutional case volume and outcomes. We aim to determine the case volume associated with optimal 1-year survival after transplantation. METHODS AND RESULTS The United Network for Organ Sharing (UNOS) national database was analyzed for adult patients who underwent orthotopic heart transplantation between January 2013 and December 2017. A total of 11,196 cases at 128 transplant centers were included. Risk-adjusted restricted cubic splines revealed a non-linear association between institutional case volume and 1-year post-transplant survival. In the risk-adjusted, random-effect Cox model with segmented linear splines, higher heart transplant volume up to 24 cases per year was associated with better 1-year survival (HR = .978 every additional case, 95% CI .963-.993), and optimal survival was maintained between 24 and 38 cases per year. However, further increase in volume above 38 transplants per year was associated with mildly decreased 1-year survival (HR = 1.007 every additional case, 95% CI 1.002-1.013). CONCLUSIONS The relationship between institutional case volume and heart transplant 1-year survival is non-linear, with optimal survival observed at institutional case volume of 24-38 cases per year.

Tissue-resident macrophages are increasingly recognized as important determinants of organ homeostasis, tissue repair, remodeling and regeneration. Although the ontogeny and function of tissue-resident macrophages has been identified as distinct from postnatal hematopoiesis, the inability to specify, in vitro, similar populations that recapitulate these developmental waves has limited our ability to study their function and potential for regenerative applications. We took advantage of the concept that tissue-resident macrophages and monocyte-derived macrophages originate from distinct extra-embryonic and definitive hematopoietic lineages to devise a system to generate pure cultures of macrophages that resemble tissue-resident or monocyte-derived subsets. We demonstrate that human pluripotent stem cell-derived extra-embryonic-like and intra-embryonic-like hematopoietic progenitors differentiate into morphologically, transcriptionally and functionally distinct macrophage populations. Single-cell RNA sequencing of developing and mature cultures uncovered distinct developmental trajectories and gene expression programs of macrophages derived from extra-embryonic-like and intra-embryonic-like hematopoietic progenitors. These findings establish a resource for the generation of human tissue resident-like macrophages to study their specification and function under defined conditions and to explore their potential use in tissue engineering and regenerative medicine applications.

Summary Recently, it has become evident that macrophage diversity increases in the liver during the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we provide a detailed protocol for the analysis of liver macrophage subsets in mice with non-alcoholic fatty liver disease (NAFLD) and early NASH using flow cytometry and immunofluorescence (IF). These methods can be used to assess the composition and localization of macrophage subsets during NASH. For complete details on the use and execution of this protocol, please refer to Daemen et al. (2021) .

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype–phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 −1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.

Acute kidney injury is a common complication following heart transplantation, and the factors contributing to acute kidney injury are not well understood. We conducted a retrospective cohort study evaluating patients who underwent heart transplantation between 2009 and 2016 at a single institution. The primary endpoint was incidence of acute kidney injury as defined by Kidney Disease Improving Global Outcomes criteria. Secondary endpoints included 30‐day hospital readmission, 30‐day mortality, and 1‐year mortality. A total of 228 heart transplant patients were included in the study for analysis. In total, 145 (64%) developed acute kidney injury, where 43 (30%) were classified as stage I, 28 (19%) as stage II, and 74 (51%) as stage III. Risk factors found to be associated with the presence of acute kidney injury included increased use of vasopressors and inotropes post‐transplant. Protective factors included cardiopulmonary bypass time

Muscle regeneration is sustained by infiltrating macrophages and consequent satellite cell (SC) activation1–4. Macrophages and SC communicate in different ways1–5 but their metabolic interplay was never investigated so far. Here, we found that muscle injuries and aging are characterized by intratissutal glutamine restriction. Low glutamine levels endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity at the expense of glutamate dehydrogenase-1 (GLUD1)-mediated glutamine oxidation. Glud1 knockout (KO) macrophages display constitutively high GS activity which prevents glutamine shortage. Import of macrophage-derived glutamine by SC through the glutamine-transporter SLC1A5 activates mTOR and promotes SC proliferation and differentiation. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischemia, or aging. Conversely, SLC1A5 blockade in SC or GS inactivation in macrophages negatively affects SC functions and muscle regeneration. These results highlight a metabolic cross-talk between SC and macrophages whereby macrophage-derived glutamine sustains SC functions. Thus, GLUD1 targeting offers new therapeutic opportunities for the regeneration of injured or aged muscles.

Continuous-flow left ventricular assist device (CF-LVAD) support is a mainstay in the hemodynamic management of patients with end-stage heart failure refractory to optimal medical therapy. In this report we evaluated waitlist complications and competing outcomes for CF-LVAD patients compared with primary transplant candidates listed for orthotopic heart transplantation at a single center.All patients listed for orthotopic heart transplantation between 2006 and 2020 at our institution were retrospectively reviewed (CF-LVAD, 300; primary transplant, 244). Kaplan-Meier methodology with log-rank testing was used to evaluate survival outcomes. Terminal outcomes of death, delisting, and transplant were assessed as competing risks and compared between groups using Gray's test. Multivariable Fine-Gray regression was used to identify predictors of transplantation.One-year rates of transplant, delisting, and death were 48%, 8%, and 2%, respectively, for CF-LVAD patients and 45%, 15%, and 9%, respectively, for primary transplant (all P.001). Waitlist mortality at 5 years was 4% among CF-LVAD patients and 13% for primary transplants. All-cause mortality after listing was lower for CF-LVAD patients (P = .017). There was no difference in posttransplant survival between groups (P = .250). On multivariable Fine-Gray regression stroke (P = .017), respiratory failure (P = .032), right ventricular failure (P = .019), and driveline infection (P = .050) were associated with decreased probability of transplantation. Posttransplant survival was not significantly worse for CF-LVAD patients who experienced device-related complications (P = .901).Although device-related complications were significantly associated with decreased rates of transplant, CF-LVAD patients had excellent waitlist outcomes overall. In light of the 2018 allocation score change the risk of complications should be taken into account when deciding whether to offer CF-LVAD as a bridge to transplant.

During the development of non-alcoholic steatohepatitis (NASH), liver resident Kupffer cells (KCs) are progressively lost and replaced by monocyte-derived macrophages (MdMs). The impact of KC loss on NASH pathology is not currently known. Given the important role of KCs in maintaining tissue homeostasis and clearing blood-borne antigens, we hypothesized that KC depletion contributes to NASH pathogenesis. Thus, we aimed to elucidate the mechanism(s) of KC loss and to devise a strategy to enhance KC survival during NASH. We had previously shown that lipids can cause lysosomal cell death in macrophages. Using a mouse model of NASH, we discovered that KCs also develop phagolysosomal pathology. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and lipid metabolism that has been shown to rescue lysosomal dysfunction in other metabolic diseases. To test whether TFEB activation could protect against KC death in NASH, we generated a mouse model in which a KC-specific Cre induces expression of a TFEB overexpression construct (KCTFEB). Despite having similar body and liver weight as WT mice fed a NASH-inducing diet, KCTFEB mice had a striking preservation of KC number. Moreover, KCTFEB mice had reduced recruitment of pro-inflammatory MdMs and this was associated with lower liver triglyceride and injury. RNA sequencing of KCs from transgenic and WT mice revealed that TFEB induced the expression of several lysosomal and lipid metabolic genes. Together these findings provide important proof-of-concept evidence that KC loss contributes to disease pathology in NASH and suggest that targeting macrophage lysosomal/lipid metabolic function could be a useful strategy to enhance resident macrophage survival. Supported by grants from ADA-118IBS280, DDRCC-P30DK052574, NIH T32-AI007163, and NSF GRFP-DGE-1745038

Objective: Intra-aortic balloon pump (IABP) support has been used as a bridge to transplant (BTT) therapy for acutely deteriorating patients awaiting orthotopic heart transplantation (OHT). Given recent changes to the heart allocation algorithm which have expanded IABP use for BTT, the evaluation of device strategy, complications, and near-term survival is warranted. Methods: Patients bridged with IABP who underwent OHT between October 2018 and January 2020 at our institution were retrospectively reviewed (n=21). Chart review was conducted to assess IABP insertion site, timing of support, device-related complications, removal strategy, and thirty-day post-transplant mortality. Results: Patients were bridged with femoral (n=6), axillary (n=9), or femoral with axillary conversion (n=6) approaches for IABP insertion. Common complications included pump malposition (n=5), hematuria (n=4), pump exchange (n=9), and insertion site bleeding (n=2). Median duration of IABP support was 12 [7, 18] days and median time to removal after OHT was 1 [1, 2] day. IABP removal occurred at the bedside with direct pressure application for all femoral pumps (n=6). Among axillary pumps (n=15), 11 were removed at the bedside with direct pressure, 3 were removed in the operating room, and 1 was removed in the catheterization lab with device closure. There was no thirty-day mortality following OHT. Conclusion: Following the changes to the heart allocation algorithm, IABP has become the most common method of temporary mechanical circulatory support for patients awaiting OHT at our center with excellent early survival and acceptable complication rates. In addition to allowing patients to ambulate while on IABP, we find that axillary insertion did not result in excess bleeding complications and that bedside removal with direct pressure was a safe method for postoperative decannulation.

Primary graft dysfunction (PGD) is a potentially devastating complication of heart transplantation. Understanding the risk factors for PGD in the modern era of heart transplantation is of vital importance. This study investigated the relationship between post-left ventricular assist device (LVAD) right heart failure (RHF) and transplant outcomes. Patients with durable, continuous-flow LVADs who were transplanted between 2010 and 2016 at Barnes-Jewish Hospital were included in the study. Data collection was performed through retrospective chart review. The primary outcome was the incidence of PGD stratified by pretransplant incidence of RHF while on LVAD support. Among the 141 patients included in the study, 41 developed RHF. In the RHF cohort, 18 patients developed PGD as compared to 14 patients in the group without RHF (44% vs. 14%; p < 0.001). Mortality was significantly higher in the RHF group at 30 days (20% vs. 1%; p < 0.001) and 1 year (22% vs. 6%; p = 0.013). In a multivariable logistic regression model adjusted for confounding variables, RHF was associated with a nearly fourfold increased risk of PGD (odds ratio, 3.91; p = 0.003). The results of this study show that patients supported with LVADs who develop early severe RHF or late RHF are at increased risk of PGD and death following cardiac transplantation.