Association of procurement technique with organ yield and cost following donation after circulatory death.

Donation after circulatory death (DCD) could account for the largest expansion of the donor allograft pool in the contemporary era. However, the organ yield and associated costs of normothermic regional perfusion (NRP) compared to super-rapid recovery (SRR) with ex-situ normothermic machine perfusion, remain unreported. The Organ Procurement and Transplantation Network (December 2019 to June 2023) was analyzed to determine the number of organs recovered per donor. A cost analysis was performed based on our institution's experience since 2022. Of 43 502 donors, 30 646 (70%) were donors after brain death (DBD), 12 536 (29%) DCD-SRR and 320 (0.7%) DCD-NRP. The mean number of organs recovered was 3.70 for DBD, 3.71 for DCD-NRP (P < .001), and 2.45 for DCD-SRR (P < .001). Following risk adjustment, DCD-NRP (adjusted odds ratio 1.34, confidence interval 1.04-1.75) and DCD-SRR (adjusted odds ratio 2.11, confidence interval 2.01-2.21; reference: DBD) remained associated with greater odds of allograft nonuse. Including incomplete and completed procurement runs, the total average cost of DCD-NRP was $9463.22 per donor. By conservative estimates, we found that approximately 31 donor allografts could be procured using DCD-NRP for the cost equivalent of 1 allograft procured via DCD-SRR with ex-situ normothermic machine perfusion. In conclusion, DCD-SRR procurements were associated with the lowest organ yield compared to other procurement methods. To facilitate broader adoption of DCD procurement, a comprehensive understanding of the trade-offs inherent in each technique is imperative.

Importance of social vulnerability on long-term outcomes after heart transplantation.

The relationship between social determinants of health and outcomes after heart transplantation has not been examined. The social vulnerability index (SVI) uses United States census data to determine the social vulnerability of every census tract based on 15 factors. This retrospective study seeks to examine the impact of SVI on outcomes after heart transplantation. Adult heart recipients who received a graft between 2012 and 2021 were stratified into SVI percentiles of <75% and SVI of ≥75%. The primary endpoint was survival. The median SVI was 48% (interquartile range: 30%-67%) among 23 700 recipients. One-year survival was similar between groups (91.4 vs 90.7%, log-rank P = .169); however, 5-year survival was lower among individuals living in vulnerable communities (74.8% vs 80.0%, P < .001). This finding persisted despite risk adjustment for other factors associated with mortality (survival time ratio 0.819, 95% confidence interval: 0.755-0.890, P < .001). The incidences of 5-year hospital readmission (81.4% vs 75.4%, P < .001) and graft rejection (40.3% vs 35.7%, P = .004) were higher among individuals living in vulnerable communities. Individuals living in vulnerable communities may be at increased risk of mortality after heart transplantation. These findings suggest there is an opportunity to focus on these recipients undergoing heart transplantation to improve survival.

Early United States experience with liver donation after circulatory determination of death using thoraco-abdominal normothermic regional perfusion: A multi-institutional observational study.

Mortality on the liver waitlist remains unacceptably high. Donation after circulatory determination of death (DCD) donors are considered marginal but are a potentially underutilized resource. Thoraco-abdominal normothermic perfusion (TA-NRP) in DCD donors might result in higher quality livers and offset waitlist mortality. We retrospectively reviewed outcomes of the first 13 livers transplanted from TA-NRP donors in the US. Nine centers transplanted livers from eight organ procurement organizations. Median donor age was 25 years; median agonal phase was 13 minutes. Median recipient age was 60 years; median lab MELD score was 21. Three patients (23%) met early allograft dysfunction (EAD) criteria. Three received simultaneous liver-kidney transplants; neither had EAD nor delayed renal allograft function. One recipient died 186 days post-transplant from sepsis but had normal presepsis liver function. One patient developed a biliary anastomotic stricture, managed endoscopically; no recipient developed clinical evidence of ischemic cholangiopathy (IC). Twelve of 13 (92%) patients are alive with good liver function at 439 days median follow-up; one patient has extrahepatic recurrent HCC. TA-NRP DCD livers in these recipients all functioned well, particularly with respect to IC, and provide a valuable option to decrease deaths on the waiting list.

DNMT3B shapes the mCA landscape and regulates mCG for promoter bivalency in human embryonic stem cells.

DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. Our analysis on ChIP-seq experiment in human embryonic stem cells (hESC) revealed that DNMT3B, mCA and H3K36me3 share the same genomic distribution profile. Deletion of DNMT3B or its histone-interacting domain (PWWP) demolished mCA in hESCs, suggesting that PWWP domain of DNMT3B directs the formation of mCA landscape. In contrast to the common presumption that PWWP guides DNMT3B-mediated mCG deposition, we found that deleting PWWP does not affect the mCG landscape. Nonetheless, DNMT3B knockout led to the formation of 2985 de novo hypomethylated regions at annotated promoter sites. Upon knockout, most of these promoters gain the bivalent marks, H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping the mCA landscape and for maintaining the fidelity of the bivalent promoters in hESCs.

Impact of increased donor distances following adult heart allocation system changes: A single center review of 1-year outcomes.

BACKGROUND: On October 18, 2018, several changes to the donor heart allocation system were enacted. We hypothesize that patients undergoing orthotopic heart transplantation (OHT) under the new allocation system will see an increase in ischemic times, rates of primary graft dysfunction, and 1-year mortality due to these changes. METHODS: In this single-center retrospective study, we reviewed the charts of all OHT patients from October 2017 through October 2019. Pre- and postallocation recipient demographics were compared. Survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 184 patients underwent OHT. Recipient demographics were similar between cohorts. The average distance from donor increased by more than 150 km (p = .006). Patients in the postallocation change cohort demonstrated a significant increase in the rate of severe left ventricle primary graft dysfunction from 5.4% to 18.7% (p = .005). There were no statistically significant differences in 30-day mortality or 1-year survival. Time on the waitlist was reduced from 203.8 to 103.7 days (p = .006). CONCLUSIONS: Changes in heart allocation resulted in shorter waitlist times at the expense of longer donor distances and ischemic times, with an associated negative impact on early post-transplantation outcomes. No significant differences in 30-day or 1-year mortality were observed.

Noteworthy in Cardiothoracic Surgery 2023.

Noteworthy in Cardiothoracic Surgery 2023 summarizes a few of the most high-impact trials and provocative trends in cardiothoracic surgery and transplantation this past year. Transplantation using organs procured from donation after circulatory death (DCD) continues to increase, and the American Society of Transplant Surgeons released recommendations on best practices in 2023. We review a summary of data on the impact of DCD on heart and lung transplantation. There has been increased interest in extracorporeal life support (ECLS), particularly after the COVID-19 pandemic, and we review the results of the highly discussed ECLS-SHOCK trial, which randomized patients in cardiogenic shock with planned revascularization to ECLS vs usual care. With improving survival outcomes in complex aortic surgery, there is a need for higher-quality evidence to guide which cooling and cerebral perfusion strategies may optimize cognitive outcomes in these patients. We review the short-term outcomes of the GOT ICE trial (Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest), a multicenter, randomized controlled trial of three different nadir temperatures, evaluating outcomes in cognition and associated changes in functional magnetic resonance imaging. Finally, both the Society of Thoracic Surgeons (STS) and the American College of Cardiology, American Heart Association, American College of Chest Physicians and Heart Rhythm Society (ACC/AHA/ACCP/HRS) updated atrial fibrillation guidelines in 2023, and we review surgically relevant updates to the guidelines and the evidence behind them.

Post-transplant survival after normothermic regional perfusion versus direct procurement and perfusion in donation after circulatory determination of death in heart transplantation.

BACKGROUND: Since 2019, the annual transplantation rate of hearts donated following circulatory death (DCD) has increased significantly in the United States. The 2 major heart procurement techniques following circulatory death are direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP). Post-transplant survival for heart recipients has not been compared between these 2 techniques. METHODS: This observational study uses data on adult heart transplants from donors after circulatory death from January 1, 2019 to December 31, 2021 in the Scientific Registry of Transplant Recipients. We identified comparable transplant cases across procurement types using propensity-score matching and measured the association between procurement technique and 1-year post-transplant survival using Kaplan-Meier and Cox proportional hazards model stratefied by matching pairs. RESULTS: Among 318 DCD heart transplants, 216 (68%) were procured via DPP, and 102 (32%) via NRP. Among 22 transplant centers that accepted circulatory-death donors, 3 used NRP exclusively, and 5 used both procurement techniques. After propensity-score matching on recipient and donor factors, there was no significant difference in 1-year post-transplant survival (93.1% for NRP vs 91.1% for DPP, p = 0.79) between procurement techniques. CONCLUSIONS: NRP and DPP procurements are associated with similar 1-year post-transplant survival. If NRP is ethically permissible and improves outcomes for abdominal organs, it should be the preferred procurement technique for DCD hearts.

Characterization of pulmonary arterial stiffness using cardiac MRI.

Pulmonary arterial stiffness (PAS) is a pathologic hallmark of all types of pulmonary hypertension (PH). Cardiac MRI (CMR), a gold-standard imaging modality for the evaluation of pulmonary flow, biventricular morphology and function has been historically reserved for the longitudinal clinical follow-up, PH phenotyping purposes, right ventricular evaluation, and research purposes. Over the last two decades, numerous indices combining invasive catheterization and non-invasive CMR have been utilized to phenotype the character and severity of PAS in different types of PH and to assess its clinically prognostic potential with encouraging results. Many recent studies have demonstrated a strong role of CMR derived PAS markers in predicting long-term clinical outcomes and improving currently gold standard risk assessment provided by the REVEAL calculator. With the utilization of a machine learning strategies, strong diagnostic and prognostic performance of CMR reported in multicenter studies, and ability to detect PH at early stages, the non-invasive assessment of PAS is on verge of routine clinical utilization. In this review, we focus on appraising important CMR studies interrogating PAS over the last 20 years, describing the benefits and limitations of different PAS indices, and their pathophysiologic relevance to pulmonary vascular remodeling. We also discuss the role of CMR and PAS in clinical surveillance and phenotyping of PH, and the long-term future goal to utilize PAS as a biomarker to aid with more targeted therapeutic management.

Association of cardiac preservation solution with short-term outcomes after heart transplantation.

AIMS: There is wide variability in the practice of cardiac preservation for heart transplantation. Prior reports suggest that the type of solution may be linked with a reduced incidence of posttransplantation complications. METHODS: Adult (≥18 years old) heart recipients who underwent transplantation between 2015 and 2021 in the United States were examined. Recipients were stratified by solution utilized for their grafts at the time of recovery: University of Wisconsin, histidine-tryptophan-ketoglutarate (HTK), or Celsior solution. The primary endpoint was a composite of 30-day mortality, primary graft dysfunction, or re-transplantation. Risk adjustment was performed for the recipient, donor, and procedural characteristics using regression modeling. RESULTS: Among 16 884 recipients, the group distribution was University of Wisconsin solution 53%, HTK 22%, Celsior solution 15%, and other 10%. The observed incidence of the composite endpoint (University of Wisconsin solution = 3.6%, HTK = 4.0%, Celsior solution = 3.7%, P = 0.301) and 1-year survival (University of Wisconsin solution = 91.7%, HTK = 91.3%, Celsior solution = 91.7%, log-rank P = 0.777) were similar between groups. After adjustment, HTK was associated with a higher risk of the composite endpoint [odds ratio (OR) 1.249, 95% confidence interval (CI) 1.019-1.525, P = 0.030] in reference to University of Wisconsin solution. This association was substantially increased among recipients with ischemic periods of greater than 4 h (OR 1.817, 95% CI 1.188-2.730, P = 0.005). The risks were similar between University of Wisconsin solution and Celsior solution (P = 0.454). CONCLUSION: The use of the histidine-tryptophan-ketoglutarate solution during cold static storage for cardiac preservation is associated with increased rates of early mortality or primary graft dysfunction. Clinician discretion should guide its use, especially when prolonged ischemic times (>4 h) are anticipated.

Mitochondrial genomes in the iconic reindeer lichens: Architecture, variation, and synteny across multiple evolutionary scales.

Variation in mitochondrial genome composition across intraspecific, interspecific, and higher taxonomic scales has been little studied in lichen obligate symbioses. Cladonia is one of the most diverse and ecologically important lichen genera, with over 500 species representing an array of unique morphologies and chemical profiles. Here, we assess mitochondrial genome diversity and variation in this flagship genus, with focused sampling of two clades of the "true" reindeer lichens, Cladonia subgenus Cladina, and additional genomes from nine outgroup taxa. We describe composition and architecture at the gene and the genome scale, examining patterns in organellar genome size in larger taxonomic groups in Ascomycota. Mitochondrial genomes of Cladonia, Pilophorus, and Stereocaulon were consistently larger than those of Lepraria and contained more introns, suggesting a selective pressure in asexual morphology in Lepraria driving it toward genomic simplification. Collectively, lichen mitochondrial genomes were larger than most other fungal life strategies, reaffirming the notion that coevolutionary streamlining does not correlate to genome size reductions. Genomes from Cladonia ravenelii and Stereocaulon pileatum exhibited ATP9 duplication, bearing paralogs that may still be functional. Homing endonuclease genes (HEGs), though scarce in Lepraria, were diverse and abundant in Cladonia, exhibiting variable evolutionary histories that were sometimes independent of the mitochondrial evolutionary history. Intraspecific HEG diversity was also high, with C. rangiferina especially bearing a range of HEGs with one unique to the species. This study reveals a rich history of events that have transformed mitochondrial genomes of Cladonia and related genera, allowing future study alongside a wealth of assembled genomes.

Variability in Heart Yield From Donation After Brain Death Between Organ Procurement Organizations: An Opportunity for Improvement.

Increasing the number of available hearts for transplantation is the best strategy to decrease waitlist mortality. This study examines organ procurement organizations (OPOs) and their role in the transplantation network to determine whether variability in performance exists across them. Adult deceased donors who met the criteria for brain death between 2010 and 2020 (inclusive) in the United States were examined. A regression model was fitted and internally validated using donor characteristics available at the time of organ recovery to predict the likelihood of heart transplantation. Subsequently, an expected heart yield was calculated for each donor using this model. Observed-to-expected (O/E) heart yield ratios for each OPO were calculated by dividing the number of hearts recovered for transplantation by the expected number of recoveries. There were 58 OPOs active during the study period, and on average, OPO activity grew over time. The mean O/E ratio among OPOs was 0.98 (standard deviation ± 0.18). Twenty-one OPOs consistently performed below the expected level (95% confidence intervals < 1.0) and generated a deficit of 1,088 expected transplantations during the study period. The proportion of hearts that were recovered for transplantation varied significantly by OPO categories: low tier 31.8%, mid tier 35.6%, and high tier 36.2% (p < 0.01), even as the expected yield was similar across tiers (p = 0.69). OPO performance accounts for 28% of the variability in successfully transplanting a heart after accounting for the role of referring hospitals, donor families, and transplantation centers. In conclusion, there is significant variability in volume and heart yield from brain-dead donors across OPOs.

4D-Flow MRI intracardiac flow analysis considering different subtypes of pulmonary hypertension.

Intracardiac flow hemodynamic patterns have been considered to be an early sign of diastolic dysfunction. In this study we investigated right ventricular (RV) diastolic dysfunction between patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension with chronic lung disease (PH-CLD) via 4D-Flow cardiac MRI (CMR). Patients underwent prospective, comprehensive CMR for function and size including 4D-Flow CMR protocol for intracardiac flow visualization and analysis. RV early filling phase and peak atrial phase vorticity (E-vorticity and A-vorticity) values were calculated in all patients. Patients further underwent comprehensive Doppler and tissue Doppler evaluation for the RV diastolic dysfunction. In total 13 patients with PAH, 15 patients with PH-CLD, and 10 control subjects underwent the 4D-Flow CMR and echocardiography evaluation for RV diastolic dysfunction. Reduced E-vorticity differentiated PAH and PH-CLD from healthy controls (both p < 0.01) despite the same Doppler E values. E-vorticity was further decreased in PAH patients when compared to PH-CLD group (p < 0.05) with similar Doppler and tissue Doppler markers of diastolic dysfunction. A-vorticity was decreased in both PAH and PH-CLD groups compared to controls but with no difference between the disease groups. E-vorticity correlated with ejection fraction (R = 0.60, p < 0.001), end-systolic volume (R = 0.50, p = 0.001), stroke volume (R = 0.42, p = 0.007), and cardiac output (R = 0.30, p = 0.027). Intracardiac flow analysis using 4D-Flow CMR derived vorticity is a sensitive method to differentiate diastolic dysfunction in patients with different PH etiology and similar Doppler echocardiography profile.

Lung recovery utilizing thoracoabdominal normothermic regional perfusion during donation after circulatory death: The Colorado experience.

Objective: Donation after circulatory death (DCD) procurement and transplantation after thoracoabdominal normothermic regional perfusion (TA-NRP) remains a novel technique to improve cardiac and hepatic allograft preservation but may be complicated by lung allograft pulmonary edema. We present a single-center series on early implementation of a lung-protective protocol with strategies to mitigate posttransplant pulmonary edema in DCD lung allografts after TA-NRP procurement. Methods: Data from all lung transplantations performed using a TA-NRP procurement strategy from October 2022 to April 2023 are presented. Donor management consisted of key factors to reduce lung allograft pulmonary edema: aggressive predonation and early posttransplant diuresis, complete venous drainage at TA-NRP initiation, and early pulmonary artery venting upon initiation of systemic perfusion. Donor and recipient characteristics, procurement characteristics such as TA-NRP intervals, and 30-day postoperative outcomes were assessed. Results: During the study period, 8 lung transplants were performed utilizing TA-NRP procurement from DCD donors. Donor ages ranged from 16 to 39 years and extubation time to declaration of death ranged from 10 to 90 minutes. Time from declaration to TA-NRP initiation was 7 to 17 minutes with TA-NRP perfusion times of 49 to 111 minutes. Median left and right allograft warm ischemia times were 55.5 minutes (interquartile range, 46.5-67.5 minutes) and 41.0 minutes (interquartile range, 39.0-53.0 minutes, respectively, with 2 recipients supported with cardiopulmonary bypass or venoarterial extracorporeal membrane oxygenation during implantation. No postoperative extracorporeal membrane oxygenation was required. There were no pulmonary-related deaths; however, 1 patient died from complications of severe necrotizing pancreatitis with a normal functioning allograft. All patients were extubated within 24 hours. Index intensive care unit length of stay ranged from 3 to 11 days with a hospital length of stay of 13 to 37 days. Conclusions: Despite concern regarding quality of DCD lung allografts recovered using the TA-NRP technique, we report initial success using this procurement method. Implementation of strategies to mitigate pulmonary edema can result in acceptable outcomes following lung transplantation. Demonstration of short- and long-term safety and efficacy of this technique will become increasingly important as the use of TA-NRP for thoracic and abdominal allografts in DCD donors expands.

Unraveling usnic acid: a comparison of biosynthetic gene clusters between two reindeer lichen (Cladonia rangiferina and C. uncialis).

Lichenized fungi are known for their production of a diversity of secondary metabolites, many of which have broad biological and pharmacological applications. By far the most well-studied of these metabolites is usnic acid. While this metabolite has been well-known and researched for decades, the gene cluster responsible for its production was only recently identified from the species Cladonia uncialis. Usnic acid production varies considerably in the genus Cladonia, even among closely related taxa, and many species, such as C. rangiferina, have been inferred to be incapable of producing the metabolite based on analysis by thin-layer chromatography (TLC). We sequenced and examined the usnic acid biosynthetic gene clusters, or lack thereof, from four closely related Cladonia species (C. oricola, C. rangiferina, C. stygia, and C. subtenuis), and compare them against those of C. uncialis. We complement this comparison with tiered chemical profile analyses to confirm the presence or absence of usnic acid in select samples, using both HPLC and LC-MS. Despite long-standing reporting that C. rangiferina lacks the ability to produce usnic acid, we observed functional gene clusters from the species and detected usnic acid when extracts were examined by LC-MS. By contrast, C. stygia and C. oricola, have been previously described as lacking the ability to produce usnic acid, lacked the gene cluster entirely, and no usnic acid could be detected in C. oricola extracts via HPLC or LC-MS. This work suggests that chemical profiles attained through inexpensive and low-sensitivity methods like TLC may fail to detect low abundance metabolites that can be taxonomically informative. This study also bolsters understanding of the usnic acid gene cluster in lichens, revealing differences among domains of the polyketide synthase which may explain observed differences in expression. These results reinforce the need for comprehensive characterization of lichen secondary metabolite profiles with sensitive LC-MS methods.

Noteworthy Cardiac Literature From 2021: Coronary Guideline Change Without New Data, Heart Transplant Donation After Cardiac Death, Covid Effects on Global Cardiac Surgery, and Attempt to Improve Dissection Remodeling.

Cardiac surgery continues to evolve. The last year has been notable for many reasons. The guidelines for coronary revascularization introduced significant discord. The pandemic continues to affect the care on a global scale. Advances in organ procurement and dissection care move forward with better understanding and better technology.

Early US experience with cardiac donation after circulatory death (DCD) using normothermic regional perfusion.

BACKGROUND: Given the shortage of suitable donor hearts for cardiac transplantation and the growing interest in donation after circulatory death (DCD), our institution recently began procuring cardiac allografts from DCD donors. METHODS: Between October 2020 and March 2021, 15 patients with heart failure underwent cardiac transplantation using DCD allografts. Allografts were procured using a modified extracorporeal membrane oxygenation circuit for thoracic normothermic regional perfusion (TA-NRP) and were subsequently transported using cold static storage. Data collection and analysis were performed with institutional review board approval. RESULTS: The mean age of the DCD donors was 23 ± 7 years and average time on TA-NRP was 56 ± 8 minutes. Total ischemic time was 183 ± 31 minutes and distance from transplant center was 373 ± 203 nautical miles. Recipient age was 55 ± 14 years, with 8 (55.3%) recipients on durable left ventricular assist device support. Post-transplant, 6 (40%) recipients experienced mild left ventricle primary graft dysfunction (PGD-LV), 3 (20%) recipients experienced moderate PGD-LV, and no recipients experienced severe PGD-LV. Postoperative transthoracic echocardiogram demonstrated left ventricular ejection fraction >55% in all recipients. One recipient (6.6%) developed International Society for Heart and Lung Transplantation 2R acute cellular rejection on first biopsy. At last follow-up, all 15 recipients were alive past 30-days. CONCLUSIONS: Cardiac DCD provides an opportunity to increase the availability of donor hearts for transplantation. Utilizing TA-NRP with cold static storage, we have extended the cold ischemic time of DCD allografts to almost 3 hours, allowing for inter-hospital organ transport.

Detection of barriers to dispersal is masked by long lifespans and large population sizes.

Population genetic analyses of species inhabiting fragmented landscapes are essential tools for conservation. Occasionally, analyses of fragmented populations find no evidence of isolation, even though a barrier to dispersal is apparent. In some cases, not enough time may have passed to observe divergence due to genetic drift, a problem particularly relevant for long-lived species with overlapping generations. Failing to consider this quality during population structure analyses could result in incorrect conclusions about the impact of fragmentation on the species. We designed a model to explore how lifespan and population size influence perceived population structure of isolated populations over time. This iterative model tracked how simulated populations of variable lifespan and population size were affected by drift alone, using a freshwater mussel, Quadrula quadrula (mapleleaf), as a model system. In addition to exhibiting dramatic lifespan variability among species, mussels are also highly imperiled and exhibit fragmentation by dams throughout the range of many species. Results indicated that, unless population size was small (<50 individuals) or lifespan short (<22 years), observing genetic divergence among populations was unlikely. Even if wild populations are isolated, observing population structure in long-lived mussels from modern damming practices is unlikely because it takes longer for population structure to develop in these species than most North American dams have existed. Larger population sizes and longer lifespans increase the time needed for significant divergence to occur. This study helps illuminate the factors that influence genetic responses by populations to isolation and provides a useful model for conservation-oriented research.