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: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.

Colchicine has an expanding role in cardiovascular disease treatment. Colchicine overdose is a toxicologic emergency. Direct cellular toxicity interferes with myocardial contractility, leading to cardiovascular collapse. We present a case of a patient with a colchicine overdose supported with venoarterial extracorporeal membrane oxygenation, highlighting the challenges and limitations.

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

Background/UNASSIGNED:The hemodynamic effects of pre-transplant vaccination against COVID-19 among heart transplant candidates hospitalized for advanced heart failure remains unknown. Methods/UNASSIGNED:A retrospective chart review was conducted at a high-volume transplant center from January through December 2021. 22 COVID-19 vaccination events occurred among patients hospitalized for decompensated heart failure while awaiting transplantation. Primary outcomes included inotrope and vasopressor dosages. Secondary outcomes included vital signs, pulmonary artery catheter measurements, diuretic dosages, and renal function. Data were extracted 24 h before through 72 h after vaccination. Results/UNASSIGNED:One of 22 vaccination events was associated with hemodynamic changes requiring increased inotropic and vasopressor support post-vaccination. In all other cases, transient hemodynamic changes occurred without need for escalated therapy. Conclusions/UNASSIGNED:COVID-19 vaccination can be administered safely to most critically ill patients with advanced heart failure including those awaiting transplantation. All patients should be monitored closely as some may be susceptible to significant hemodynamic changes.

Purpose: The American Society of Transplantation and the International Society of Heart and Lung Transplantation recommend COVID-19 vaccination of transplant candidates to maximize immunity, as vaccination after initiation of immunosuppression may confer only partial immunity. However, there are concerns about the impact of vaccine-induced systemic inflammatory responses in critically ill patients with variable hemodynamic states. We aim to explore the safety of pre-transplant vaccination by examining the immediate impact of COVID-19 vaccination on the hemodynamics of hospitalized patients awaiting transplant.
Method(s): A retrospective chart review at a major transplant center was conducted among all heart transplant recipients from January 2021 through September 2021 who were hospitalized and listed or under consideration for listing for transplant at the time of COVID-19 vaccination. Primary outcomes included vital signs, hemodynamic parameters from pulmonary artery catheter-derived measurements, and changes in inotrope/vasopressor infusion rates. Data were extracted at fixed time points 24 hours before and up to 72 hours after vaccination. Given the small sample size and exploratory study nature, only univariate analysis was performed.
Result(s): Of the 50 patients who received heart transplants at our center from January 2021 through September 2021, 37 patients were vaccinated against COVID-19. 13 of those patients were vaccinated before transplant while hospitalized, and 10 of those 13 patients had a pulmonary artery catheter in place at the time of immunization. No significant changes in vital signs (blood pressure, heart rate), hemodynamics (cardiac index, pulmonary artery pressures, systemic vascular resistance), or vasopressor/inotrope infusion rates were observed after vaccination.
Conclusion(s): In this exploratory review of COVID-19 vaccination in heart transplant candidates, we did not detect any notable changes to hemodynamics in the first 72 hours after immunization. Although further investigative research is needed to assess COVID-19 vaccine safety comprehensively in patients with advanced heart failure, the absence of notable hemodynamic changes in this cohort of heart transplant candidates encourages the continued use of COVID-19 vaccination among hospitalized patients with advanced heart failure who are awaiting transplant.
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