Journal of Heart and Lung Transplantation最新文献

Background: Extending survival after heart transplant (HT) is of paramount importance for childhood recipients of HT. Acute rejection is a significant event, and biopsy remains the most specific means for distinguishing between cellular (ACR) and antibody-mediated rejection (AMR).

Methods: All children in the Pediatric Heart Transplant Society Registry who underwent HT between January 2015 and June 2022 and had ≥1 rejection episode were included. Survival was compared between AMR and ACR-only. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) were assessed. Risk factors for graft loss after AMR were identified using Cox proportional hazard modeling.

Results: Among 906 children with rejection, 697 (77%) with complete biopsy information were included. AMR was present on biopsy in 261 (37%) patients; ACR-only was present in 436 (63%). Time to rejection was earlier for AMR, median time from HT to rejection 0.11 versus 0.29 years, p = 0.0006. Survival after AMR in the 1st year was lower than survival after ACR-only. Predictors of graft loss after AMR were younger age at HT, congenital heart disease, and rejection with hemodynamic compromise. There was no difference in time to CAV, infection, or malignancy after rejection between groups.

Conclusions: The largest analysis of pediatric HT rejection with biopsy data to identify AMR underscores the continued importance of AMR on survival. AMR is associated with higher graft loss versus ACR when occurring in the first-year post-HT. Predictors of graft loss after AMR identify patients who may benefit from increased surveillance or augmented maintenance immunosuppression.

Background: There is limited evidence to support treatment recommendations in patients with pulmonary arterial hypertension (PAH) and comorbidities. To investigate the impact of riociguat treatment in this patient population, we analyzed pooled data from randomized controlled trials of riociguat.

Methods: This post hoc analysis included data from the PATENT-1, PATENT-2, PATENT PLUS, and REPLACE studies. Safety, efficacy (6-minute walk distance [6MWD], World Health Organization functional class [WHO-FC], and N-terminal probrain natriuretic peptide [NT-proBNP]), and COMPERA 2.0 risk status were assessed in patients with 0, 1 to 2, or 3 to 4 cardiometabolic comorbidities (obesity, systemic hypertension, diabetes mellitus, coronary artery disease) in the main phase of the studies. Safety was also assessed in the long-term extensions.

Results: The analysis included 686 patients (riociguat, n = 440; placebo, n = 132; phosphodiesterase type 5 inhibitors [PDE5i], n = 114), of whom 55%, 39%, and 6% had 0, 1 to 2, and 3 to 4 comorbidities, respectively. In the main phase, rates and severity of adverse events (AEs) were similar in riociguat-treated patients across comorbidity subgroups. After 2 years, discontinuations of riociguat due to AEs were also similar across subgroups. Compared with placebo and PDE5i, riociguat improved 6MWD and NT-proBNP across comorbidity groups and improved WHO-FC and COMPERA 2.0 risk status in patients with 0 or 1 to 2 comorbidities.

Conclusions: Riociguat had an acceptable safety profile in PAH patients with cardiometabolic comorbidities. Efficacy and risk assessment results suggest that riociguat can be beneficial for patients with PAH, irrespective of the presence of comorbidities.

Background: Mortality risk assessment informs clinical management of pulmonary arterial hypertension (PAH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 is a simplified risk calculator discriminating 1-year mortality risk.

Methods: This post-hoc analysis of the phase 3 GRIPHON study assessed changes in REVEAL Lite 2 risk score with selexipag versus placebo and whether changes were prognostic or predictive of time to first morbidity/mortality (M/M) event.

Results: REVEAL Lite 2 risk category discriminated M/M risk (landmark concordance indices: 0.68-0.76, selexipag; 0.65-0.70, placebo). Across baseline risk categories, hazard ratios supported a lower risk of M/M events with selexipag versus placebo: low, 0.573 (95% confidence interval [CI] 0.361-0.908; p = 0.0178); intermediate, 0.423 (95% CI 0.274-0.655; p = 0.0001); and high, 0.711 (9% CI 0.520-0.972; p = 0.0326). Odds ratios for risk improvement were 2.0 (95% CI 1.50-2.65), 1.8 (95% CI 1.38-2.43), and 2.0 (95% CI 1.43-2.72) for selexipag versus placebo at 16, 26, and 52 weeks, respectively (all p < 0.001). REVEAL Lite 2 risk improvement at week 16 explained 19.1% of the treatment effect in all patients and 47.0% in patients with REVEAL Lite 2 baseline risk score of ≥7.

Conclusions: REVEAL Lite 2 can monitor PAH M/M risk and facilitate treatment optimization. Baseline REVEAL Lite 2 risk score was prognostic of M/M risk in patients with PAH and mediates treatment effect up to 47% for those at higher risk. Lower M/M risk with selexipag versus placebo occurred irrespective of baseline risk category (ClinicalTrials.gov identifier: NCT01106014).

For patients with end-stage heart disease and borderline hemodynamics, high human leukocyte antigen allosensitization presents a barrier to heart transplantation in a timely manner. Conventional desensitization protocols are inadequate in this context due to time constraints and for the most highly reactive immunologically. We previously reported performing heart after liver transplant with domino liver transplant on a single patient without liver disease. We describe this patient's course to date as well as 4 subsequent patients listed for this novel therapy. This experience demonstrates that the liver effectively confers immunoprotection to the heart for patients with high-titer, preformed antibodies. This strategy may provide some measure of equity for demographic groups previously disadvantaged for heart transplantation due to allosensitization.

Background: Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes.

Methods: In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 10⁶ cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD).

Results: Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO₂/FiO₂ ratios and reduced incidence of PGD.

Conclusions: Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes.

Mechanical circulatory support devices have profoundly transformed the management of severe cardiothoracic disorders. While heart transplantation is the gold standard therapy for end-stage heart disease, long-term mechanical support devices are a viable alternative for those ineligible and/or those awaiting organ availability. Major technological advancements were made over first 5 decades of development, resulting in improved durability and survival with reduced adverse events. However, gains have tapered recently for various complications (e.g., internal bleeding, multisystem organ failure), which collectively represent a significant proportion of disability and/or mortality. Further, in light of mature ventricular assist devices failing during clinical trials or even after clinical approval (class I withdrawals), it is timely to consider: Are our preclinical assessment protocols vital in the design and development of mechanical circulatory support devices, providing a realistic and reliable profile of future clinical performance? This commentary explores this question and analyses development pathways through the lens of the various disciplines involved in the preclinical assessment of mechanical circulatory support technologies: Limitations in approaches to benchtop blood testing, computational design and simulation, and animal testing are discussed as likely contributors to some of the common hemocompatibility-related adverse events (HRAEs). While it is acknowledged that some shortcomings are pragmatic in nature, possible solutions are presented that will only be realized through truly transdisciplinary and open approaches that challenge the current nature of medical device development. We suggest that these can and must be overcome to diminish HRAEs and will potentially demarcate the fourth generation of cardiac assist devices.