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Open in new tab Download slide OBJECTIVES Malignancy is the leading cause of late mortality after orthotopic heart transplantation (OHT), and the burden of post-transplantation cancer is expected to rise in proportion to increased case volume following the 2018 heart allocation score change. In this report, we evaluated factors associated with de novo malignancy after OHT with a focus on skin and solid organ cancers. METHODS Patients who underwent OHT at our institution between 1999 and 2018 were retrospectively reviewed (n  = 488). Terminal outcomes of death and development of skin and/or solid organ malignancy were assessed as competing risks. Fine–Gray subdistribution hazards regression was used to evaluate the association between perioperative patient and donor characteristics and late-term malignancy outcomes. RESULTS By 1, 5 and 10 years, an estimated 2%, 17% and 27% of patients developed skin malignancy, while 1%, 5% and 12% of patients developed solid organ malignancy. On multivariable Fine–Gray regression, age [1.05 (1.03–1.08); P  <   0.001], government payer insurance [1.77 (1.20–2.59); P  =   0.006], family history of malignancy [1.66 (1.15–2.38); P  =   0.007] and metformin use [1.73 (1.15–2.59); P  =   0.008] were associated with increased risk of melanoma and basal or squamous cell carcinoma. Age [1.08 (1.04–1.12); P  <   0.001] and family history of malignancy [2.55 (1.43–4.56); P  =   0.002] were associated with an increased risk of solid organ cancer, most commonly prostate and lung cancer. CONCLUSIONS Vigilant cancer and immunosuppression surveillance is warranted in OHT recipients at late-term follow-up. The cumulative incidence of skin and solid organ malignancies increases temporally after transplantation, and key risk factors for the development of post-OHT malignancy warrant identification and routine monitoring. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

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 extraembryonic-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. [ABSTRACT FROM AUTHOR]

Survival after bridge to transplantation with mechanical circulatory support (MCS) has yielded varying outcomes on the basis of device type and baseline characteristics. Continuous-flow left ventricular assist devices (CF-LVADs) have significantly improved waitlist mortality, but recent changes to the transplantation listing criteria have dramatically altered the use of MCS for bridge to transplantation. Orthotopic heart transplantations from 1988 to 2019 at our institution (Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, MO) were retrospectively reviewed and stratified by pretransplantation MCS status into CF-LVAD (n = 224), pulsatile LVAD (n = 49), temporary MCS (n = 71), and primary transplantation (n = 463) groups. Patients who underwent heart transplantation after the approval of CF-LVAD for bridge to transplantation and before the 2018 allocation policy changes underwent subgroup analysis to evaluate predictors of survival and complications in a contemporary cohort. Rates of primary transplantation declined from 88% to 14% over the course of the study. No significant difference in survival was detected in the cohort stratified by MCS status (P =.18). In the modern era, survival of patients treated with CF-LVADs and temporary MCS was noninferior to that seen with primary transplantation (P =.22). Notable predictors of long-term mortality included lower body mass index, peripheral vascular disease, previous coronary artery bypass graft, ABO nonidentical transplant, and increased donor age (all P ≤.02). There were no differences in major postoperative complications. CF-LVAD has grown to account for the majority of transplantations at our center in the last decade, with no adverse effect on survival or postoperative complications. Temporary MCS increased after the 2018 listing criteria change, with acceptable early outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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 <170 min. Acute kidney injury was found to be associated with increased 30‐day and 1‐year mortality. [ABSTRACT FROM AUTHOR]