Journal of Heart and Lung Transplantation最新文献

Background: Donation after circulatory death (DCD) and ex-vivo lung perfusion (EVLP) have been adopted to expand the donor pool in lung transplantation, but outcomes data have been conflicting. This study explores outcomes of DCD and EVLP lung transplantation in the modern era.

Methods: The United Network for Organ Sharing database was queried for adult lung transplants from January 1, 2015 to March 1, 2023. Loss to follow-up, multiorgan, and prior lung transplants were excluded. DCD versus donation after brain death (DBD) lung transplants were compared with subgroup analysis +/- EVLP. Outcomes were survival and postoperative complications.

Results: The study included 1,103 DCD (221 with EVLP and 882 without) and 17,973 DBD lung transplants (524 with EVLP and 17,449 without). Median follow-up was 3 years. DCD donors were less likely to be CDC high risk (19.3% vs 24.1%, p < 0.001), have purulence on bronchoscopy (13.3% vs 18.3%, p < 0.001), or infiltrates on chest X-ray (66.7% vs 67.8%, p = 0.013). EVLP was more likely to be used for DCD transplants (20.0% vs 2.9%, p < 0.001). After transplant, DCD recipients were more likely to be reintubated (24.3% vs 18.5%, p < 0.001) and require ECMO within 72 hours (14.9% vs 7.8%, p < 0.001), and DCD donation was an independent risk factor for these complications on multivariable logistic regression. Overall survival did not differ significantly between DCD and DBD transplants on adjusted survival analysis in the early or modern era (p = 0.774 and p = 0.468, respectively). On subgroup analysis, the DCD+EVLP cohort had significantly worse survival in the modern era, which remained significant after adjusting for donor and recipient factors (p = 0.005). EVLP was an independent risk factor for graft failure in the DCD cohort (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.00-1.77, p = 0.047) but did not significantly affect DBD graft survival (p = 0.870). Risk factors for graft failure and mortality in the DCD+EVLP cohort included pulmonary hypertension (HR 77.5, 95% CI 6.15-979, p < 0.001), transfusion before transplant (HR 2.60, 95% CI 1.07-6.31, p = 0.035), elevated creatinine (HR 2.82, 95% CI 1.34-5.90, p = 0.006), and higher allocation score (HR 1.02, 95% CI 1.00-1.04, p = 0.017) CONCLUSIONS: Study findings suggest increased risks of mortality and perioperative complications following transplantation with DCD lungs that have undergone EVLP. DCD lung transplantation without EVLP confers equivalent survival but with some increase in perioperative complications. Further investigation and careful recipient selection are warranted to optimize the use of these extended criteria donors in the modern era.

Background: Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD.

Methods: Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1^-/-) mice.

Results: NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1^-/- donors significantly improved pulmonary graft function compared to wild-type donors. Histological analysis showed decreased microvascular endothelial cell death, neutrophil infiltration, and albumin leakage. Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1^-/- donors, correlating with diminished pulmonary edema. However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1^-/- recipient.

Conclusions: Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

Despite increasing therapeutic options and evolving treatment strategies, including targeting 3 therapeutic pathways, in the management of pulmonary arterial hypertension (PAH), morbidity and mortality have remained unacceptably high. Sotatercept is a first-in-class, novel activin signaling inhibitor approved for treating PAH based on evolving efficacy and safety evidence. This state-of-the-art review summarizes the current understanding of the mechanism of action, the impact on outcomes that improve how patients feel, function, and survive, and the safety and adverse event profile to inform readers of this breakthrough novel therapy.

Background: Microvascular dysfunction after heart transplantation leads to restrictive cardiac allograft physiology (RCP), which is classified as severe coronary allograft vasculopathy (CAV); however, the prognosis of RCP remains unclear. Therefore, in this study, we aimed to elucidate the prognosis of RCP in comparison with that of severe angiographic CAV.

Methods: We assessed 116 patients with severe CAV who underwent heart transplantation between 2004 and 2023. RCP was defined as symptomatic heart failure with restrictive hemodynamic values (mean right atrial pressure >12 mm Hg, pulmonary capillary wedge pressure >25 mm Hg, and cardiac index <2.0 liter/min/m²). The primary outcome was death or retransplantation.

Results: Of the 116 patients with severe CAV, 42 had RCP (RCP-CAV group) and 74 had severe angiographic CAV without RCP (Angio-CAV group). A significantly shorter time from heart transplantation to diagnosis and lower subsequent percutaneous catheter intervention after diagnosis were seen in the RCP-CAV group than in the Angio-CAV group (both p < 0.001). Freedom from death or retransplantation at 5 years was significantly worse in the RCP-CAV group compared to the Angio-CAV group (18.4% vs 35.4%, p = 0.001). In the Cox proportional hazard model, RCP was independently associated with an increased risk of death or retransplantation (hazard ratio 2.08, 95% confidence intervals 1.26-3.44, p = 0.004).

Conclusions: The prognosis of patients with RCP was significantly worse than that of patients with severe angiographic CAV. The early detection of microvascular dysfunction and retransplantation listing may improve the prognosis of patients with RCP.

Hypothermic oxygenated perfusion (HOPE) is an emerging technique for donor heart preservation that is currently being studied in multiple clinical trials with promising results. When compared to HOPE for other organs, cardiac protocols involve red blood cell (RBC) supplementation, despite absence of comparative evidence for its benefits. In this perspective paper, we discuss the pros and cons of the addition of RBCs during cardiac HOPE. Although the current clinical results with RBC supplementation during HOPE seem promising, potential downsides of RBC supplementation cannot be ruled out. The impact of supplemented RBCs during cardiac HOPE requires further investigation to improve HOPE protocols, to optimize heart preservation using this promising technology.

Background: Recent clinical series on donation after uncontrolled cardiovascular death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3 hours postmortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model.

Methods: After uDCD induction, donor pigs were allocated to one of the following groups: control-static lung inflation only (SLI); TC - SLI + continuous intrapleural topical cooling (TC); or TC+Sevo - SLI + TC + sevoflurane. Lungs were retrieved 6 hours postasystole and evaluated via ex vivo lung perfusion (EVLP) for 6 hours. A left single lung transplant was performed using lungs from the best performing group, followed by 4 hours of graft evaluation.

Results: Animals that received TC achieved intrathoracic temperature <15°C within 1 hour after chest filling of coolant. Only lungs from donors that received TC and TC+Sevo completed the planned postpreservation 6 hours EVLP assessment. Despite similar early performance of the 2 groups on EVLP, the TC+Sevo group was superior-associated with overall lower airway pressures, higher pulmonary compliances, less edema development, and less inflammation. Transplantation was performed using lungs from the TC+Sevo group, and excellent graft function was observed postreperfusion.

Conclusions: Preservation of uDCD lungs with a combination of static lung inflation, TC and sevoflurane treatment maintains good pulmonary function up to 6 hours postmortem with excellent early post lung transplant function. These interventions may significantly expand the clinical utilization of uDCD donor lungs.

Long-term survival after lung transplantation remains limited by chronic lung allograft dysfunction (CLAD), with 2 main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). We aimed to assess CLAD lung allografts using imaging mass cytometry (IMC), a high dimensional tissue imaging system allowing a multiparametric in situ exploration at a single cell level. Four BOS, 4 RAS, and 4 control lung samples were stained with 35 heavy metal-tagged antibodies selected to assess structural and immune proteins of interest. We identified 50 immune and non-immune cell clusters. CLAD lungs had significantly reduced club cells. A Ki67-high basal cell population was mostly present in RAS and in proximity to memory T cells. Memory CD8⁺ T cells were more frequent in CLAD lungs, regulatory T cells more prominent in RAS. IMC is a powerful technology for detailed cellular analysis within intact organ structures that may shed further light on CLAD mechanisms.