Faculty Bibliography

BACKGROUND:Porcine genome editing has revolutionized xenotransplantation, recently enabling the first pig-to-human heart xenotransplants. However, the xeno-immune response in heart xenografts remains largely unexplored. This study aimed to precisely characterize the xeno-immune response and injury in two heart xenografts, transplanted from 10-gene-edited pigs into brain-dead human recipients. METHODS:We analyzed xenograft biopsies at 66-hour post-reperfusion using a multimodal phenotyping approach combining: morphological evaluation, immunophenotyping, ultrastructural assessment, automated quantification of multiplex immunofluorescence staining and gene expression profiling. Xenografts before implantation and wild-type pig hearts with and without ischemia reperfusion injury and brain death were used as controls. RESULTS:Both xenografts showed evidence of endothelial activation and mild microvascular inflammation without capillary C4d deposition. Immune infiltrates were mainly composed of CD15+ and CD68+ innate immune cells. Ultrastructural assessment showed endothelial swelling with occasional intravascular leucocytes. Deep-learning based automated multiplex immunofluorescence analysis confirmed that microvascular inflammation was primarily associated with CD15+ and CD68+ innate immune cells. Both xenografts showed increased expression of genes and pathways associated with monocyte/macrophage activation, neutrophil activation, interferon-gamma response, natural killer cell burden, endothelial activation, apoptosis and injury repair. This phenotype was absent in all control pig hearts, independently from ischemia reperfusion injury and brain death. CONCLUSIONS:Multimodal phenotyping of pig-to-human heart xenografts revealed early signs of xeno-immune response, characterized by mild innate microvascular inflammation, endothelial activation, and molecular signature characteristic of antibody-mediated rejection. Developing such precision diagnostic system could improve graft monitoring in future clinical settings.

BACKGROUND:Despite the goal of the 2018 revision to the heart allocation policy to reduce reliance on exception requests through improved granularity in status criteria, there has been a dramatic rise in exception requests. OBJECTIVES/OBJECTIVE:This study evaluated trends in exception use over the first 6 years of the updated policy, assessing associated clinical factors, temporal changes, and impact on waitlist outcomes. METHODS:This retrospective transplant registry analysis included all adult isolated heart transplant candidates from October 18, 2018, to September 30, 2024. Candidates were stratified by exception use, listing era, and region. Exception use was compared using Wilcoxon rank-sum and chi-squared tests, with multilevel logistic regression assessing independent associations. Trends over time and across UNOS (United Network for Organ Sharing) regions were evaluated, and a competing risks framework examined time to transplant and waitlist mortality. RESULTS:Among 26,330 candidates, 38.6% used exception requests, with a statistically significant increase over time, particularly in higher priority statuses. Exception use was more common among Black, non-Hispanic candidates, and candidates with blood type O, and less likely for patients with blood type A (P < 0.001). Additionally, pretransplant isolated durable left ventricular assist devices were less common in candidates who requested exceptions (19.0% vs 31.6%; P < 0.001). Overall, 39.9% of exception candidates were listed at status 1 or 2 compared to 29% of nonexception candidates, and 69.2% of exception candidates were removed from the waitlist at status 1 or 2 compared with 37% of nonexception candidates. CONCLUSIONS:The rising use of exceptions underscores ongoing limitations in allocation criteria, and disparities suggesting inequities in access to higher listing status. Policy refinements are needed to ensure a balance between medical urgency and equitable allocation.

BACKGROUND:The diagnosis of cardiac sarcoidosis (CS) is often challenging, particularly in atypical cases. CASE SUMMARY/METHODS:This case involves a previously healthy 33-year-old woman who was found to have a biatrial mass and evidence of a diffuse inflammatory or neoplastic process on multimodality imaging. Percutaneous biopsy of the cardiac mass was performed, and histopathologic examination revealed granulomas consistent with CS. DISCUSSION/CONCLUSIONS:This case adds to the growing number of reports of CS manifesting as an intracardiac mass. TAKE-HOME MESSAGES/CONCLUSIONS:The clinical presentation of CS is highly variable, and it may rarely manifest as an intracardiac mass. The diagnosis of cardiac sarcoidosis is often challenging, particularly in patients with atypical presentations. Indeterminate cardiac masses often require direct tissue sampling because the changes in treatment and prognosis are substantial.

CLINICAL CONDITION/UNASSIGNED:The authors present the case of a young man who presented with cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation and microaxial flow pump complicated by acute spinal cord infarction (SCI) leading to bilateral lower extremity paraplegia. KEY QUESTIONS/UNASSIGNED:The key questions included the following: 1) What is the incidence and pathophysiology for SCI with mechanical circulatory support (MCS)?; 2) Which configurations of MCS carry a greater risk of SCI? How do we approach MCS escalation, recognizing that with each device we carry additive risk of complications?; 3) What data guide anticoagulation strategies for MCS?; and 4) What strategies can we implement to support patients who have suffered SCI from MCS? OUTCOME/RESULTS:Our patient was transitioned to a right ventricular assist device with Impella 5.5 as a bridge to therapy, and underwent cardiac transplantation 4 weeks after presentation with ongoing inpatient rehabilitation. TAKE-HOME MESSAGES/CONCLUSIONS:Contemporary MCS carries a small but significant risk of SCI which is often irreversible. More data are required to guide anticoagulation strategies for MCS and mitigate risk.

BACKGROUND:In the 2018 Organ Procurement and Transplantation Network donor heart allocation system, patients listed for re-transplantation due to cardiac allograft vasculopathy (CAV) are assigned to Status 4 unless hemodynamic criteria are met. We aim to examine waitlist outcomes of CAV patients among adult heart transplant candidates. METHODS:We examined waitlist mortality stratified by CAV and waitlist status among adult heart transplant candidates using Scientific Registry of Transplant Recipients data from 10/1/2018-11/1/2023. We analyzed waitlist mortality using Kaplan-Meier curves and doubly-robust Cox regressions adjusted for age, gender, sex, race, and dialysis. We compared CAV to non-CAV patients by initial waitlist status, first status of interest, and time-dependent status. RESULTS:Of 21,586 listed patients, 368 were listed for CAV. CAV patients were most often listed at Status 4 with lower proportions at Status 3/2/1 compared with non-CAV patients. Status 4 and Status 3 CAV candidates demonstrated higher than expected waitlist mortality compared to non-CAV counterparts (Status 4: HR 0.51, 95% CI 0.31-0.84; p < 0.01; Status 3: HR 0.61, 95% CI 0.23-1.64; p = 0.33) with similar mortality to non-CAV patients in Status 3 and 2, respectively (Status 4: HR 0.80, 95% CI 0.48-1.35; p = 0.4; Status 3: HR 1.07, 95% CI 0.40-2.86; p = 0.89). When stratifying by status tier, CAV waitlist patients ever listed at Status 4 and 3 had a higher probability of death compared to their non-CAV counterparts (Status 4: HR 1.99, 95% CI 1.20-3.31, p < 0.01; Status 3: HR 3.06, 95% CI 1.06-8.87, p = 0.04). CONCLUSIONS:After 2018, CAV patients had a higher risk of waitlist mortality at Status 4 and 3 compared to non-CAV patients. These results suggest that CAV patients are underprioritized in the current allocation system.

BACKGROUND/UNASSIGNED:Donation after circulatory death (DCD) with cardiopulmonary bypass for thoracoabdominal normothermic regional perfusion (TA-NRP) has led to increased use of donor hearts. Rejection rates and long-term survival outcomes are not known. METHODS/UNASSIGNED:A single-center retrospective cohort review of patients who underwent DCD heart transplantation from January 2020 to December 2023 was performed. Donor and recipient characteristics, operative characteristics, and posttransplantation outcomes were analyzed. Subgroup analysis comparing co-localized vs distant donors and recipients was performed. The primary end point was 1-year survival. Secondary end points included incidences of primary graft dysfunction (PGD), cardiac allograft vasculopathy (CAV), rejection rate, and overall mortality. Our TA-NRP protocol has remained the same, consisting of sternotomy, ligation of aortic arch vessels, establishment of cardiopulmonary bypass, reintubation, resuscitation of the heart, and cold static storage during transport. RESULTS/UNASSIGNED:< .005) ischemia times, without any other differences. CONCLUSIONS/UNASSIGNED:Outcomes after DCD heart transplantation using TA-NRP remain encouraging with acceptable rates of rejection, PGD, CAV, and survival at 1 year.

Radial artery occlusion (RAO), a complication of transradial access, has an incidence of 4.0% to 9.1% in patients with advanced chronic kidney disease (CKD) and may preclude its use creation of arteriovenous fistula. Distal transradial access (dTRA) has lower rates of RAO compared with TRA, but prior studies excluded patients with advanced CKD. This was a single center study of patients with advanced CKD who underwent coronary procedures with dTRA from January 1, 2019 to May 12, 2022 who were retrospectively evaluated for radial artery patency in follow-up with reverse Barbeau testing or repeat access of the artery. Of 71 patients, 66% were on hemodialysis and the remainder had CKD 3 to 5. Access was ultrasound-guided, and all received adequate spasmolytic therapy and patent hemostasis. Proximal radial arteries were patent in 100% of the patients at follow-up. Our data suggest that dTRA is safe for patients with advanced CKD and preserves radial artery patency.

BACKGROUND/UNASSIGNED:Pyridostigmine bromide is a short-acting carbamate acetylcholinesterase inhibitor that has been shown to acutely augment parasympathetic signaling in cardiovascular disease populations. OBJECTIVE/UNASSIGNED:This study was undertaken to characterize pharmacodynamics, safety, and tolerability of pyridostigmine during repeated dosing in patients with heart failure. METHODS/UNASSIGNED:A prospective ascending-dose, forced titration, double-blind Phase II randomized clinical trial was conducted to compare the effects of pyridostigmine bromide (15, 30, and 60 mg TID over 8 weeks) versus matching placebo on red blood cell (RBC) acetylcholinesterase activity, cholinergic side effects, and physiologic measures of parasympathetic heart rate modulation and sympathovagal balance in ambulatory patients with chronic systolic heart failure. RESULTS/UNASSIGNED:< 0.001 vs placebo). Physiologic measures of parasympathetic heart rate modulation and sympathovagal balance did not differ between treatment groups. In the pyridostigmine bromide group, RBC acetylcholinesterase activity was not significantly associated with postexercise parasympathetic heart modulation. CONCLUSIONS/UNASSIGNED:Pyridostigmine bromide administered over 8 weeks was associated with a significant reduction of RBC acetylcholinesterase activity and relatively mild symptoms of cholinergic excess, but changes in parasympathetic signaling in the sinoatrial node previously reported after acute administration were not observed. Further investigations are needed to delineate pharmacodynamic and pathobiological factors contributing to these findings. ClinicalTrials.gov identifier: NCT01415921.

BACKGROUND:Because of advances in medical treatment of heart failure, patients are living longer than in previous eras and may approach the need for advanced therapies, including heart transplantation, at older ages. This study assesses practices surrounding heart transplant in older adults (> 70 years) and examines short- and medium-term outcomes. METHODS AND RESULTS/RESULTS:This study is a retrospective analysis using the United Network for Organ Sharing (UNOS) database from 2010 to 2021. The absolute number of older adults being transplanted is increasing. Older adults were more likely to have had a prior malignancy or ischemic cardiomyopathy and less likely to be on extra-corporeal membrane oxygenation or have a high UNOS status prior to transplant. Mortality at 1-year was higher for older adults (27.8% vs. 23.4%), but at 5 years there was no significant difference (22.3% vs. 19.4%.). Older adults were more likely to die of malignancy or infection. Adults under 70 were more likely to die of cardiovascular causes or graft failure. There was less rejection in older adults. Mortality has not changed for older adults transplanted before versus after the 2018 UNOS allocation change. CONCLUSIONS:Carefully selected older adults may be considered for heart transplantation, given similar intermediate-term mortality.