Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

Utility of preoperative troponin I to predict mortality in adult liver transplant recipients: Revisiting pretransplant cardiac risk in the current MELD-allocation era.

BACKGROUND: Preoperative risk assessment in liver transplant (LT) candidates, particularly related to cardiac risk, is an area of intense interest for transplant clinicians. Various cardiac testing methods are employed by transplant centers to characterize cardiac risk. Serum troponin is an established method for the detection of myocardial injury in a wide variety of clinical settings. Preoperative troponin screening has been reported to predict postoperative cardiac events and mortality in various surgical patient populations, however, the utility of preoperative troponin to predict posttransplant outcomes in current LT candidate populations requires further investigation. METHODS: We performed a prospective blinded study in a cohort of 275 consecutive LT recipients at a single transplant center to determine if preoperative serum troponin I (TnI) was predictive for postoperative 1-year mortality. RESULTS: Abnormal preoperative TnI levels (>.1 ng/mL) were found in 38 patients (14%). One-year mortality occurred in 19 patients (7%). There was no significant difference in mortality between patients with normal and abnormal troponin levels. Additionally, we found that there was no significant difference in early postoperative major adverse cardiac events between patient groups. CONCLUSIONS: Contrary to previous reports, elevated preoperative TnI was not significantly predictive of posttransplant mortality in LT recipients at our institution.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation.

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

International Liver Transplantation Society/Society for Advancement of Transplant Anesthesia Consensus Statement on Essential Attributes of a Liver Transplant Anesthesiologist.

BACKGROUND: We sought to establish consensus on the essential skills, knowledge, and attributes that a liver transplant (LT) anesthesiologist should possess in a bid to help guide the further training process. METHODS: Consensus was achieved via a modified Delphi methodology, surveying 15 identified international experts in the fields of LT anesthesia and critical care. RESULTS: Key competencies were identified in preoperative management and optimization of a potential LT recipient; intraoperative management, including hemodynamic monitoring; coagulation and potential crisis management; and postoperative intensive and enhanced recovery care. CONCLUSIONS: This article provides an essential guide to competency-based training of an LT anesthesiologist.

Applications and Outcomes of Extracorporeal Life Support Use in Adult Liver Transplantation: A Case Series and Review of Literature.

The use of extracorporeal life support (ECLS) is increasingly reported in adult liver transplantation (LT). However, neither the role of ECLS in the perioperative setting for LT nor its outcomes has been well defined. We performed a retrospective chart review of all adult LT patients at our institution who received ECLS from 2004 to 2021. We also conducted a comprehensive literature search for adult LT cases that involved perioperative ECLS for respiratory or cardiac failure. Over the study period, 11 LT patients required ECLS at our institution, two for respiratory and nine for cardiac failure. Both patients with respiratory failure received ECLS as a bridge to LT and survived to discharge. Nine patients required ECLS for acute cardiac failure either intraoperatively or postoperatively, and two survived to discharge. In the literature, we identified 35 cases of respiratory failure in LT patients requiring perioperative ECLS. Applications included preoperative bridge to LT (n = 6) and postoperative rescue (n = 29), for which overall survival was 44%. We identified 31 cases of cardiac failure in LT patients requiring either ECLS or cardiopulmonary bypass for cardiac support or rescue for intraoperative or postoperative cardiac failure (n = 30). There is evidence for consideration of ECLS as a bridge to LT in patients with potentially reversible respiratory failure or as rescue therapy for respiratory failure in posttransplant patients. ECLS has a prohibitively high risk of futility in pretransplant patients with cardiac failure but may have a role in LT patients with a functioning graft and potentially reversible cardiac failure.

Orthotopic Heart and Combined Heart Liver Transplantation: the Ultimate Treatment Option for Failing Fontan Physiology.

Purpose of the Review: This is a comprehensive update on failing Fontan physiology and the role of heart and combined heart and liver transplantation in the current era. Recent Findings: Single ventricle physiology encompasses a series of rare congenital cardiac abnormalities that are characterized by absence of or hypoplasia of one ventricle. This effectively results in a single ventricular pumping chamber. These abnormalities are rarely compatible with long-term survival if left without surgical palliation in the first few years of life. Surgical treatment of single ventricle physiology has evolved over the past 60 years and is characterized by numerous creative innovations. These include the development of arteriopulmonary shunts, the evolution of partial cavopulmonary connections, and the eventual development of the "Fontan" operation. Regardless of the type of Fontan modification, the long-term consequences of the Fontan operation are predominantly related to chronic central venous hypertension and the multi-organ consequences thereof. Atrial arrhythmias can further compromise this circulation.Patients with single ventricle physiology represent a special sub-segment of congenital cardiac transplants and are arguably the most challenging patients considered for transplantation. Summary: This review describes in detail the challenges and opportunities of heart and liver transplantation in Fontan patients, as viewed and managed by the experienced team at the Ahmanson/UCLA Adult Congenital Heart Center.

Training and Validation of Deep Neural Networks for the Prediction of 90-Day Post-Liver Transplant Mortality Using UNOS Registry Data.

Prediction models of post-liver transplant mortality are crucial so that donor organs are not allocated to recipients with unreasonably high probabilities of mortality. Machine learning algorithms, particularly deep neural networks (DNNs), can often achieve higher predictive performance than conventional models. In this study, we trained a DNN to predict 90-day post-transplant mortality using preoperative variables and compared the performance to that of the Survival Outcomes Following Liver Transplantation (SOFT) and Balance of Risk (BAR) scores, using United Network of Organ Sharing data on adult patients who received a deceased donor liver transplant between 2005 and 2015 (n = 57,544). The DNN was trained using 202 features, and the best DNN's architecture consisted of 5 hidden layers with 110 neurons each. The area under the receiver operating characteristics curve (AUC) of the best DNN model was 0.703 (95% CI: 0.682-0.726) as compared to 0.655 (95% CI: 0.633-0.678) and 0.688 (95% CI: 0.667-0.711) for the BAR score and SOFT score, respectively. In conclusion, despite the complexity of DNN, it did not achieve a significantly higher discriminative performance than the SOFT score. Future risk models will likely benefit from the inclusion of other data sources, including high-resolution clinical features for which DNNs are particularly apt to outperform conventional statistical methods.

Recommendations From the Society for the Advancement of Transplant Anesthesiology: Liver Transplant Anesthesiology Fellowship Core Competencies and Milestones.

Liver transplantation is a complex procedure performed on critically ill patients with multiple comorbidities, which requires the anesthesiologist to be facile with complex hemodynamics and physiology, vascular access procedures, and advanced monitoring. Over the past decade, there has been a continuing debate whether or not liver transplant anesthesia is a general or specialist practice. Yet, as significant data have come out in support of dedicated liver transplant anesthesia teams, there is not a guarantee of liver transplant exposure in domestic residencies. In addition, there are no standards for what competencies are required for an individual seeking fellowship training in liver transplant anesthesia. Using the Accreditation Council for Graduate Medical Education guidelines for residency training as a model, the Society for the Advancement of Transplant Anesthesia Fellowship Committee in conjunction with the Liver Transplant Anesthesia Fellowship Task Force has developed the first proposed standardized core competencies and milestones for fellowship training in liver transplant anesthesiology.

Liver Transplantation in Patients With Cardiac Disease.

Liver transplantation (LT) is a unique surgical procedure that has major hemodynamic and cardiovascular implications. Recently, there has been significant interest focused on cardiovascular issues that affect LT patients in all phases of the perioperative period. The preoperative cardiac evaluation is a major step in the selection of LT candidates. LT candidates are aging in concordance with the general population; cardiovascular disease and their risk factors are highly associated with older age. Underlying cardiovascular disease has the potential to affect outcomes in LT patients and has a major impact on candidate selection. The prolonged hemodynamic and metabolic instability during LT may contribute to adverse outcomes, especially in patients with underlying cardiovascular disease. Cardiovascular events are not unusual during LT; transplant anesthesiologists must be prepared for these events. Advanced cardiovascular monitoring techniques and treatment modalities are now routinely used during LT. Postoperative cardiovascular complications are common in both the early and late posttransplant periods. The impact of cardiac complications on posttransplant mortality is well recognized. Emerging knowledge regarding cardiovascular disease in LT patients and its impact on posttransplant outcomes will have an important role in guiding the future perioperative management of LT patients.

Society for the Advancement of Transplant Anesthesia: Liver Transplant Anesthesia Fellowship-White Paper Advocating Measurable Proficiency in Transplant Specialties Training.

The anesthesia community has openly debated if the care of transplant patients was generalist or specialist care ever since the publication of an opinion paper in 1999 recommended subspecialty training in the field of liver transplantation anesthesia. In the past decade, liver transplant anesthesia has become more complex with a sicker patient population and evolving evidence-based practices. Transplant training is currently not required for accreditation or certification in anesthesiology, and not all anesthesia residency programs are associated with transplant centers. Yet there is evidence that patient outcome is affected by the experience of the anesthesiologist with liver transplants as part of a multidisciplinary care team. Requests for a formal review of the inequities in training opportunities and requirements led the Society for the Advancement for Transplant Anesthesia (SATA) to begin the task of developing post-graduate fellowship training recommendations. In this article, members of the SATA Working Group on Transplant Anesthesia Education present their reasoning for specialized education and conclusions about which pathways can better prepare trainees to care for complex transplant patients.

Myocardial injury in patients with hemodynamic derangements during and/or after liver transplantation.

Myocardial injury, defined as an elevation of cardiac troponin (cTn) resulting from ischemia, is associated with substantial mortality in surgical patients, and its incidence, risk factors, and impact on patients undergoing liver transplantation (LT) are poorly understood. In this study, adult patients who experienced perioperative hemodynamic derangements and had cTn measurements within 30 days after LT between 2006 and 2013 were studied. Of 502 patients, 203 (40.4%) met the diagnostic criteria (cTn I ≥0.1 ng/mL) of myocardial injury. The majority of myocardial injury occurred within the first three postoperative days and presented without clinical signs or symptoms of myocardial infarction. Thirty-day mortality in patients with myocardial injury was 11.4%, significantly higher compared with that in patients without myocardial injury (3.4%, P<.01). Cox analysis indicated the peak cTn was significantly associated with 30-day mortality. Multivariable logistic analysis identified three independent risk factors: requirement of ventilation before transplant (odds ratios (OR) 1.6, P=.006), RBC≥15 units (OR 1.7, P=.006), and the presence of PRS (OR 2.0, P=.028). We concluded that post-LT myocardial injury in this high-risk population was common and associated with mortality. Our findings may be used in pretransplant stratification. Further studies to investigate this postoperative cardiac complication in all LT patients are warranted.