Impact of Extracorporeal Membrane Oxygenation Bridging Duration on Lung Transplant Outcomes.

BACKGROUND: We sought to characterize the association between venovenous extracorporeal membrane oxygenation (VV-ECMO) bridging duration and outcomes in patients listed for lung transplantation. METHODS: A retrospective observational study was conducted using the Organ Procurement and Transplantation Network (OPTN) database to identify adults (aged ≥18 years) who were listed for lung transplantation between 2016 and 2020 and were bridged with VV-ECMO. Patients were then stratified into groups, determined by risk inflection points, depending on the amount of time spent on pretransplant ECMO: group 1 (≤5 days), group 2 (6-10 days), group 3 (11-20 days), and group 4 (>20 days). Waiting list survival between groups was analyzed using Fine-Gray competing risk models. Posttransplant survival was compared using Cox regression. RESULTS: Of 566 eligible VV-ECMO bridge-to-lung-transplant patients (median age, 54 years, 49% men), 174 (31%), 124 (22%), 130 (23%), and 138 (24%) were categorized as groups 1, 2, 3, and 4, respectively. Overall, median duration of VV-ECMO was 10 days (interquartile range, 1-211 days), and 178 patients (31%) died on the waiting list. In the Fine-Gray model, compared with group 1, patients bridged with longer ECMO durations in group 2 (subdistribution hazard ratio [SHR], 2.95; 95% CI, 1.63-5.35), group 3 (SHR, 3.96; 95% CI, 2.36-6.63), and group 4 (SHR, 4.33; 95% CI, 2.59-7.22, all P < .001) were more likely to die on the waiting list. Of 388 patients receiving a transplant, pretransplant ECMO duration was not associated with 1-year survival in Cox regression. CONCLUSIONS: Prolonged duration of ECMO bridging was associated with worse waiting list mortality but did not impact survival after lung transplant. Prioritization of very early transplantation may improve waiting list outcomes in this population.

Heart Allocation Change and Multiple Temporary Circulatory Support as Bridge-to-Bridge.

INTRODUCTION: We investigated how the 2018 Organ Procurement and Transplantation Network heart allocation policy change was associated with changes in characteristics and outcomes of candidates receiving multiple temporary mechanical circulatory support (mtMCS) devices. MATERIALS AND METHODS: We included adult heart transplant candidates listed October 2014-January 2018 and October 2018-January 2022 in the United Network of Organ Sharing dataset. Prepolicy and postpolicy mtMCS recipients were compared at listing, transplant, 90-days, and 1-year post-transplant. Time between first and second devices and time between first device and transplant were modeled via multivariable linear regression. Transplantation likelihood was modeled using competing risks analysis. RESULTS: Postpolicy, a higher proportion of transplant candidates received mtMCS (4% versus 1%, P < 0.001), and received their second device an adjusted 49 d sooner versus prepolicy (P = 0.001). Time to transplant was also an adjusted 35 d shorter postpolicy, with an 80% increased transplantation likelihood versus prepolicy (95% confidence interval: 1.6-1.9, P < 0.001). Postpolicy patients experienced reduced waitlist mortality (8% versus 14%, P = 0.04) with marked improvements in 90-day (93% versus 85%, P < 0.001) and 1-year (88% versus 70%, P = 0.01) post-transplant survival. CONCLUSIONS: Postpolicy mtMCS recipients are more likely to progress to transplantation sooner on the waitlist and their shorter waitlist course together with earlier change to a secondary device was associated with improved post-transplant survival versus prepolicy.

Lung Transplantation in Patients With COVID-19-The Early National Experience.

Lung transplant (LT) has become a viable option for COVID-19 patients suffering from end-stage Acute Respiratory Distress Syndrome (ARDS). This analysis sought to describe the early national experience of COVID-19 patients who received LT and compare transplant characteristics and short-term outcomes of COVID-19 and non-COVID-19 ARDS LT recipients. We queried the Organ Procurement and Transplantation database for adults (≥18 years old) receiving LT from January 2009 to March 31, 2022 with diagnoses of COVID-19 or ARDS. We identified 353 COVID-19 and 64 non-COVID-19 ARDS LT recipients. COVID-19 recipients were older (median age: 51, interquartile range [40-57] years vs 41 [26-52]; P < 0.001), more predominantly male (78% (n = 274) vs 55% (n = 35), P < 0.001), and had higher body mass indices (median 27.2 interquartile range [24.5-30.9] vs 25.4 [22.1-28.6]; P < 0.01) than non-COVID-19 ARDS recipients. COVID-19 LT recipients were less frequently reliant on extra-corporeal membrane oxygenation at 72 hours after transplant (26% (n = 80) vs 31% (n = 15), P < 0.001), and were less frequently dependent on dialysis post-transplant than non-COVID-19 ARDS LT recipients (14% (n = 43) vs 23% (n = 14); P = 0.01). Survival at 90 days post-transplant was comparable for the non-COVID ARDS (90%, n = 54) and COVID-19 (94%, n = 202) LT recipients with available follow-up (P = 0.17). LT appears to be a viable therapy for COVID-19 patients with end-stage lung disease. COVID-19 LT and non-COVID-19 ARDS LT recipients have comparable 90 days post-transplant survival.

Costs and Readmissions Associated with Type A Aortic Dissections at High- and Low-Volume Centers.

BACKGROUND: Costs and readmissions associated with type A aortic dissection repairs are not well understood. We investigated statewide readmissions, costs, and outcomes associated with the surgical management of type A aortic dissection repairs at low- and high-volume centers. METHODS: We identified all adult type A aortic dissection patients who underwent operative repair in the Maryland Health Services Cost Review Commission's database (2012-2020). Hospitals were stratified into high- (top quartile of total repairs) or low-volume centers. RESULTS: Of the 249 patients included, 193 (77.5%) were treated at a high-volume center. Patients treated at high- and low-volume centers had no differences in age, sex, race, primary payer, or severity (all p > 0.5). High- compared to low-volume centers had a greater proportion of patients transferred in (71.5% vs. 17.9%, p < 0.001). High-volume centers also had longer lengths of stay (12 vs. 8 days, p < 0.001), similar inpatient mortality (13.0% vs. 16.1%, p = 0.6), and similar proportion of patients readmitted (54.9% vs. 51.8%, p = 0.7). High-volume centers had greater index admission costs ($114,859 vs. $72,090, p < 0.001) and similar readmission costs ($48,367 vs. $42,204, p = 0.5). At high-volume centers, transferred patients compared to direct admissions had greater severity of illness (p = 0.05), similar mortality (p = 0.53), and greater lengths of stay (p = 0.05). CONCLUSIONS: High-volume centers had a greater number of patients transferred from other institutions compared to low-volume centers. High-volume centers were associated with increased index admission resource utilization, with transfer patients having higher illness severity and greater resource utilization, yet similar mortality, compared to direct admission patients.

Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination.

OBJECTIVE: To evaluate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMDs) following 2-dose SARS-CoV-2 messenger RNA (mRNA) vaccination. METHODS: RMD patients (n = 1,377) who received 2-dose SARS-CoV-2 mRNA vaccination between December 16, 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (dose 1 and dose 2), and 1 month after dose 2, detailing any flares of RMD. Associations between demographic/clinical characteristics and flares requiring treatment were evaluated using modified Poisson regression. RESULTS: Among the patients, 11% reported flares requiring treatment; there were no reports of severe flares. Flares were associated with prior SARS-CoV-2 infection (incidence rate ratio [IRR] 2.09, P = 0.02), flares in the 6 months preceding vaccination (IRR 2.36, P < 0.001), and the use of combination immunomodulatory therapy (IRR 1.95, P < 0.001). The most frequently reported local and systemic reactions included injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2). Reactogenicity increased after dose 2, particularly for systemic reactions. No allergic reactions or SARS-CoV-2 diagnoses were reported. CONCLUSION: Flares of underlying RMD following SARS-CoV-2 vaccination were uncommon. There were no reports of severe flares. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in RMD patients.

Outcomes after heart transplantation in patients who have undergone a bridge-to-bridge strategy.

Objectives: We compared posttransplant outcomes between patients bridged from temporary mechanical circulatory support to durable left ventricular assist device before transplant (bridge-to-bridge [BTB] strategy) and patients bridged from temporary mechanical circulatory support directly to transplant (bridge-to-transplant [BTT] strategy). Methods: We identified adult heart transplant recipients in the Organ Procurement and Transplantation Network database between 2005 and 2020 who were supported with extracorporeal membrane oxygenation, intra-aortic balloon pump, or temporary ventricular assist device as a BTB or BTT strategy. Kaplan-Meier survival analysis and Cox regressions were used to assess 1-year, 5-year, and 10-year survival. Posttransplant length of stay and complications were compared as secondary outcomes. Results: In total, 201 extracorporeal membrane oxygenation (61 BTB, 140 BTT), 1385 intra-aortic balloon pump (460 BTB, 925 BTT), and 234 temporary ventricular assist device (75 BTB, 159 BTT) patients were identified. For patients supported with extracorporeal membrane oxygenation, intra-aortic balloon pump, or temporary ventricular assist device, there were no differences in survival between BTB and BTT at 1 and 5 years posttransplant, as well as 10 years posttransplant even after adjusting for baseline characteristics. The extracorporeal membrane oxygenation BTB group had greater rates of acute rejection (32.8% vs 13.6%; P = .002) and lower rates of dialysis (1.6% vs 21.4%; P < .001). For intra-aortic balloon pump and temporary ventricular assist device patients, there were no differences in posttransplant length of stay, acute rejection, airway compromise, stroke, dialysis, or pacemaker insertion between BTB and BTT recipients. Conclusions: BTB patients have similar short- and midterm posttransplant survival as BTT patients. Future studies should continue to investigate the tradeoff between prolonged temporary mechanical circulatory support versus transitioning to durable mechanical circulatory support.

Improving contemporary outcomes following heart transplantation for cardiac amyloidosis.

BACKGROUND: The incidence of systemic amyloidosis is rising, and there is a concomitant rise in heart transplant for an indication of cardiac amyloidosis. METHODS: We utilized the Organ Procurement and Transplantation Network (OPTN) database to retrospectively assess survival and outcomes in adult patients undergoing heart transplant for cardiac amyloidosis from 1999 to 2019. We also compared survival among four distinct time periods: 1999-2001, 2002-2008, 2008-2015, 2016-2019. RESULTS: Of 41,103 patients, 425 (1.03%) were transplanted for an indication of restrictive cardiomyopathy due to cardiac amyloidosis (RCM-Amyloidosis). The percent of all transplants occurring for RCM-Amyloidosis increased from 0.25% in the 1999-2001 era to 1.74% in the 2015-2019 era (p < .001). Across eras, Kaplan-Meier survival functions were comparable between RCM-Amyloidosis and non-RCM patients at 1 year (88% vs. 89%, p = .56) and at 5 years (72% vs. 77%, p = .092), but worse for RCM-Amyloidosis patients at 10 years (44% vs. 59%, p = .002). With adjustment for other clinical variables in multivariable Cox regression model, RCM-Amyloidosis was not associated with increased risk of death at 1 year (hazard ratio [HR] = 1.11, p = .56) or at 5 years (HR = 1.20, p = .18), but it was associated with increased risk of death at 10 years (HR = 1.35, p = .01). Cardiac amyloidosis was not associated with any morbidity outcomes following transplant, including graft failure, acute rejection, or hospitalization for infection or rejection. CONCLUSIONS: Our data suggest a trend of improving survival among RCM-Amyloidosis patients compared with non-RCM patients across transplant eras, with current similarities in 1- and 5-year survival but a persistent, increased risk of mortality at 10 years.

Long-term survival after heart transplantation for cardiac sarcoidosis.

BACKGROUND: Cardiac sarcoidosis is an increasingly common indication for a heart transplant, but there is a paucity of knowledge with regard to long-term outcomes following transplant. METHODS: We utilized the Organ Procurement and Transplantation Network database to retrospectively analyze adult patients undergoing first-time, single-organ heart transplant between January 1999 and March 2020. RESULTS: Of the 41,447 patients that underwent heart transplant during the study period, 289 (0.7%) were transplanted for a primary diagnosis of restrictive cardiomyopathy due to cardiac sarcoidosis (RCM-Sarcoidosis). RCM-Sarcoidosis was associated with 33% reduced risk of mortality over 10 years compared to non-RCM indications in a multivariable Cox proportional hazards model (p = .03). Ten-year survival functions were improved among RCM-Sarcoidosis compared to this reference group (73.4% [64.2%-80.6%] vs. 59.5% [58.8%-60.1%], p = .002). Among patients transplanted after 1999 who had at least 10 years of follow-up (n = 19,489), median survival of RCM-Sarcoidosis patients was 11.9 [8.3-14.6] years while that of non-RCM patients was 9.9 [4.0-13.1] years. RCM-Sarcoidosis was not associated with an increased risk of secondary outcomes such as graft failure, rejection, or infection. The incidence of retransplant was comparable between RCM-Sarcoidosis and non-RCM patients (1.38% vs. 1.50%, p = .93). CONCLUSIONS: These data suggest that long-term outcomes following transplant for cardiac sarcoidosis are favorable compared to heart transplant for other indications.

Adipokine Resistin Levels at Time of Pediatric Crohn Disease Diagnosis Predict Escalation to Biologic Therapy.

BACKGROUND: Hypertrophy of visceral adipose tissue (VAT) is a hallmark of Crohn disease (CD). The VAT produces a wide range of adipokines, biologically active factors that contribute to metabolic disorders in addition to CD pathogenesis. The study aim was to concomitantly evaluate serum adipokine profiles and VAT volumes as predictors of disease outcomes and treatment course in newly diagnosed pediatric patients with CD. METHODS: Pediatric patients ages 6 to 20 years were enrolled, and their clinical data and anthropometric measurements were obtained. Adipokine levels were measured at 0, 6, and 12 months after CD diagnosis and baseline in control patients (CP). The VAT volumes were measured by magnetic resonance imaging or computed tomography imaging within 3 months of diagnosis. RESULTS: One hundred four patients undergoing colonoscopy were prospectively enrolled: 36 diagnosed with CD and 68 CP. The serum adipokine resistin and plasminogen activator inhibitor (PAI)-1 levels were significantly higher in patients with CD at diagnosis than in CP. The VAT volume was similar between CD and CP. Baseline resistin levels at the time of diagnosis in patients with CD who were escalated to biologics was significantly higher than in those not treated using biologic therapy by 12 months (29.8 ng/mL vs 13.8 ng/mL; P = 0.004). A resistin level of ≥29.8 ng/mL at the time of diagnosis predicted escalation to biologic therapy in the first year after diagnosis with a specificity of 95% (sensitivity = 53%; area under the curve = 0.82; P = 0.015 for model with log-scale). There was a significantly greater reduction in resistin (P = 0.002) and PAI-1 (P = 0.010) at the 12-month follow-up in patients on biologics compared with patients who were not treated using biologics. CONCLUSIONS: Serum resistin levels at diagnosis of pediatric CD predict the escalation to biologic therapy at 12 months, independent of VAT volumes. Resistin and PAI-1 levels significantly improved in patients with CD after treatment using biologics compared with those not on biologics. These results suggest the utility of resistin as a predictive biomarker in pediatric CD.

Notch signaling regulates arterial vasoreactivity through opposing functions of Jagged1 and Dll4 in the vessel wall.

Functional interactions between endothelial cells (ECs) and smooth muscle cells (SMCs) in the arterial wall are necessary for controlling vasoreactivity that underlies vascular resistance and tone. Key signaling pathways converge on the phosphorylation of myosin light chain (p-MLC), the molecular signature of force production in SMCs, through coordinating the relative activities of myosin light chain kinase (MLCK) and myosin phosphatase (MP). Notch signaling in the vessel wall serves critical roles in arterial formation and maturation and has been implicated in arterial vasoregulation. In this report, we hypothesized that Notch signaling through ligands Jagged1 (in SMCs) and delta-like protein-4 (Dll4; in ECs) regulates vasoreactivity via homotypic (SMC-SMC) and heterotypic (EC-SMC) cell interactions. Using ligand induction assays, we demonstrated that Jagged1 selectively induced smooth muscle MLCK gene expression and p-MLC content while inhibiting MP function (i.e., increased Ca2+ sensitization) in a Rho kinase II-dependent manner. Likewise, selective deficiency of smooth muscle Jagged1 in mice resulted in MLCK and p-MLC loss, reduced Ca2+ sensitization, and impaired arterial force generation measured by myography. In contrast, smooth muscle Notch signaling triggered by Dll4 increased expression of MP-targeting subunit 1 (MYPT1; the MP regulatory subunit), whereas arteries from endothelial Dll4-deficient mice featured reduced MYPT1 levels, enhanced force production, and impaired relaxation independent of endothelium-derived nitric oxide signaling. Taken together, this study identifies novel opposing vasoregulatory functions for ligand-specific Notch signaling in the vessel wall, underscoring instructional signaling between ECs and SMCs and suggesting that Notch signals might behave as a "rheostat" in arterial tone control. NEW & NOTEWORTHY The present study unveils novel roles for ligand-specific Notch signaling in arterial function. Smooth muscle Jagged1 and endothelial cell delta-like protein-4 ligands exhibit selective regulation of myosin light chain kinase and myosin phosphatase-targeting subunit 1/myosin phosphatase, respectively, providing a mechanistic link through which Notch signals modulate contractile activities in vascular smooth muscle. These findings may inform vascular derangements observed in human syndromes of Notch signaling deficiency while offering fundamental molecular insights into arterial physiological function.