The value of extracorporeal photopheresis as an immunosuppression-modifying approach in solid organ transplantation: a potential solution to an unmet medical need.

Allograft rejection is a critical issue following solid organ transplantation (SOT). Immunosuppressive therapies are crucial in reducing risk of rejection yet are accompanied by several significant side effects, including infection, malignancy, cardiovascular diseases, and nephrotoxicity. There is a current unmet medical need with a lack of effective minimization strategies for these side effects. Extracorporeal photopheresis (ECP) has shown potential as an immunosuppression (IS)-modifying technique in several SOT types, with improvements seen in acute and recurrent rejection, allograft survival, and associated side effects, and could fulfil this unmet need. Through a review of the available literature detailing key areas in which ECP may benefit patients, this review highlights the IS-modifying potential of ECP in the four most common SOT procedures (heart, lung, kidney, and liver transplantation) and highlights existing gaps in data. Current evidence supports the use of ECP for IS modification following SOT, however there is a need for further high-quality research, in particular randomized control trials, in this area.

Early Outcomes in Patients With LVAD Undergoing Heart Transplant via Use of the SherpaPak Cardiac Transport System.

BACKGROUND: Heart transplant (HT) in recipients with left ventricular assist devices (LVADs) is associated with poor early post-HT outcomes, including primary graft dysfunction (PGD). As complicated heart explants in recipients with LVADs may produce longer ischemic times, innovations in donor heart preservation may yield improved post-HT outcomes. The SherpaPak Cardiac Transport System is an organ preservation technology that maintains donor heart temperatures between 4 °C and 8 °C, which may minimize ischemic and cold-induced graft injuries. This analysis sought to identify whether the use of SherpaPak versus traditional cold storage was associated with differential outcomes among patients with durable LVAD undergoing HT. METHODS: Global Utilization and Registry Database for Improved Heart Preservation-Heart (NCT04141605) is a multicenter registry assessing post-HT outcomes comparing 2 methods of donor heart preservation: SherpaPak versus traditional cold storage. A retrospective review of all patients with durable LVAD who underwent HT was performed. Outcomes assessed included rates of PGD, post-HT mechanical circulatory support use, and 30-day and 1-year survival. RESULTS: SherpaPak (n=149) and traditional cold storage (n=178) patients had similar baseline characteristics. SherpaPak use was associated with reduced PGD (adjusted odds ratio, 0.56 [95% CI, 0.32-0.99]; P=0.045) and severe PGD (adjusted odds ratio, 0.31 [95% CI, 0.13-0.75]; P=0.009), despite an increased total ischemic time in the SherpaPak group. Propensity matched analysis also noted a trend toward reduced intensive care unit (SherpaPak 7.5±6.4 days versus traditional cold storage 11.3±18.8 days; P=0.09) and hospital (SherpaPak 20.5±11.9 days versus traditional cold storage 28.7±37.0 days; P=0.06) lengths of stay. The 30-day and 1-year survival was similar between groups. CONCLUSIONS: SherpaPak use was associated with improved early post-HT outcomes among patients with LVAD undergoing HT. This innovation in preservation technology may be an option for HT candidates at increased risk for PGD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04141605.

Impact of controlled hypothermic preservation on outcomes following heart transplantation.

BACKGROUND: Severe primary graft dysfunction (PGD) is a major cause of early mortality after heart transplant, but the impact of donor organ preservation conditions on severity of PGD and survival has not been well characterized. METHODS: Data from US adult heart-transplant recipients in the Global Utilization and Registry Database for Improved Heart Preservation-Heart Registry (NCT04141605) were analyzed to quantify PGD severity, mortality, and associated risk factors. The independent contributions of organ preservation method (traditional ice storage vs controlled hypothermic preservation) and ischemic time were analyzed using propensity matching and logistic regression. RESULTS: Among 1,061 US adult heart transplants performed between October 2015 and December 2022, controlled hypothermic preservation was associated with a significant reduction in the incidence of severe PGD compared to ice (6.6% [37/559] vs 10.4% [47/452], p = 0.039). Following propensity matching, severe PGD was reduced by 50% (6.0% [17/281] vs 12.1% [34/281], respectively; p = 0.018). The Kaplan-Meier terminal probability of 1-year mortality was 4.2% for recipients without PGD, 7.2% for mild or moderate PGD, and 32.1%, for severe PGD (p < 0.001). The probability of severe PGD increased for both cohorts with longer ischemic time, but donor hearts stored on ice were more likely to develop severe PGD at all ischemic times compared to controlled hypothermic preservation. CONCLUSIONS: Severe PGD is the deadliest complication of heart transplantation and is associated with a 7.8-fold increase in probability of 1-year mortality. Controlled hypothermic preservation significantly attenuates the risk of severe PGD and is a simple yet highly effective tool for mitigating post-transplant morbidity.

Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Outcomes in Heart Transplant Recipients by Bridge to Transplant Strategy When Using the SherpaPak Cardiac Transport System.

The last several years have seen a rise in use of mechanical circulatory support (MCS) to bridge heart transplant recipients. A controlled hypothermic organ preservation system, the SherpaPak Cardiac Transport System (SCTS), was introduced in 2018 and has grown in utilization with reports of improved posttransplant outcomes. The Global Utilization And Registry Database for Improved heArt preservatioN (GUARDIAN)-Heart registry is an international, multicenter registry assessing outcomes after transplant using the SCTS. This analysis examines outcomes in recipients bridged with various MCS devices in the GUARDIAN-Heart Registry. A total of 422 recipients with donor hearts transported using SCTS were included and identified. Durable ventricular assist devices (VADs) were used exclusively in 179 recipients, temporary VADs or intra-aortic balloon pump (IABP) in 197, and extracorporeal membrane oxygenation (ECMO) in 14 recipients. Average ischemic times were over 3.5 hours in all cohorts. Severe primary graft dysfunction (PGD) posttransplant increased across groups (4.5% VAD, 5.1% temporary support, 21.4% ECMO), whereas intensive care unit (ICU) length of stay (18.2 days) and total hospital stay (39.4 days) was longer in the ECMO cohort than the VAD and IABP groups. A comparison of outcomes of MCS bridging in SCTS versus traditional ice revealed significantly lower rates of both moderate/severe right ventricular (RV) dysfunction and severe PGD in the SCTS cohort; however, upon propensity matching only the reductions in moderate/severe RV dysfunction were statistically significant. Use of SCTS in transplant recipients with various bridging strategies results in excellent outcomes.

Decoding cardiac reinnervation from cardiac autonomic markers: A mathematical model approach.

BACKGROUND: Although cardiac autonomic markers (CAMs) are commonly used to assess cardiac reinnervation in heart-transplant patients, their relationship to the degree of sympathetic and vagal cardiac reinnervation is not well understood yet. To study this relationship, we applied a mathematical model of the cardiovascular system and its autonomic control. METHODS: By simulating varying levels of sympathetic and vagal efferent sinoatrial reinnervation, we analyzed the induced changes in CAMs including resting heart rate (HR), bradycardic and tachycardic HR response to Valsalva maneuver, root mean square of successive differences between normal heartbeats (RMSSD), low-frequency (LF), high-frequency (HF), and total spectral power (TSP). RESULTS: For assessment of vagal cardiac reinnervation levels >20%, resting HR (ρ = 0.99, p < 0.05), RMSSD (ρ = 0.97, p < 0.05), and TSP (ρ = 0.96, p < 0.05) may be equally suitable as HF-power (ρ = 0.97, p < 0.05). To assess sympathetic reinnervation, LF/HF ratio (ρ = 0.87, p < 0.05) and tachycardic response to Valsalva maneuver (ρ = 0.9, p < 0.05) may be more suitable than LF-power (ρ = 0.77, p < 0.05). CONCLUSIONS: Our model reports mechanistic relationships between CAMs and levels of efferent autonomic sinoatrial reinnervation. The results indicate differences in the suitability of these markers to assess vagal and sympathetic reinnervation. Although our analysis is purely conceptual, the developed model can help to gain important insights into the genesis of CAMs and their relationship to efferent sinoatrial reinnervation and, thus, provide indications for clinical study evaluation.

Recipient Outcomes With Extended Criteria Donors Using Advanced Heart Preservation: An Analysis of the GUARDIAN-Heart Registry.

BACKGROUND: The prevalence of end-stage heart failure and patients who could benefit from heart transplantation requires an expansion of the donor pool, relying on the transplant community to continually re-evaluate and expand the use of extended criteria donor organs. Introduction of new technologies such as the Paragonix SherpaPak Cardiac Transport System aids in this shift. We seek to analyze the impact of the SherpaPak system on recipient outcomes who receive extended criteria organs in the GUARDIAN-Heart Registry. METHODS: Between October 2015 and December 2022, 1,113 adults from 15 US centers receiving donor hearts utilizing either SherpaPak (n = 560) or conventional ice storage (ice, n = 453) were analyzed from the GUARDIAN-Heart Registry using summary statistics. A previously published set of criteria was used to identify extended criteria donors, which included 193 SherpaPak and 137 ice. RESULTS: There were a few baseline differences among recipients in the 2 cohorts; most notably, IMPACT scores, distance traveled, and total ischemic time were significantly greater in SherpaPak, and significantly more donor hearts in the SherpaPak cohort had >4 hours total ischemia time. Posttransplant mechanical circulatory support utilization (SherpaPak 22.3% vs ice 35.0%, p = 0.012) and new extracorporeal membrane oxygenation/ventricular assist device (SherpaPak 7.8% vs ice 15.3%, p = 0.033) was significantly reduced, and the rate of severe primary graft dysfunction (SherpaPak 6.2% vs ice 13.9%, p = 0.022) was significantly reduced by over 50% in hearts preserved using SherpaPak. One-year survival between cohorts was similar (SherpaPak 92.9% vs ice 89.6%, p = 0.27). CONCLUSIONS: This subgroup analysis demonstrates that SherpaPak can be safely used to utilize extended criteria donors with low severe PGD rates.

Molecular states associated with dysfunction and graft loss in heart transplants.

BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.

Identifying High-Risk Patients for Severe Pulmonary Complications after Cardiosurgical Procedures as a Target Group for Further Assessment of Lung-Protective Strategies.

OBJECTIVES: It remains unclear whether intraoperative lung-protective strategies can reduce the rate of respiratory complications after cardiac surgery, partly because low-risk patients have been studied in the past. The authors established a screening model to easily identify a high-risk group for severe pulmonary complications (ie, pneumonia or acute respiratory distress syndrome) that may be the ideal target population for the assessment of the potential benefits of such measures. DESIGN: Retrospective observational trial. SETTING: Departments of cardiac surgery and cardiac anesthesia of a university hospital. PARTICIPANTS: Consecutive patients undergoing cardiac surgery on cardiopulmonary bypass and subsequent treatment at a dedicated cardiosurgical intensive care unit between January 2019 and March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 2,572 patients undergoing surgery, 84 (3.3%) developed pneumonia/acute respiratory distress syndrome that significantly affected the outcome (ie, longer ventilatory support [66% vs 11%], higher reintubation rate [39% vs 3%]), prolonged length of intensive care unit [33 ± 36 vs 4 ± 10 days] and hospital stay [10 ± 15 vs 6 ± 7 days], and higher in-hospital [43% vs 9%] as well as 30-day [7% vs 3%] mortality). The screening model for severe pulmonary complications included left ventricular ejection fraction <52%, EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) >5.9, cardiopulmonary bypass time >123 minutes, left ventricular assist device or aortic repair surgery, and bronchodilatory therapy. A cutoff for the predicted risk of 2.5% showed optimal sensitivity and specificity, with an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: The authors suggest that future research on intraoperative lung-protective measures focuses on this high-risk population, primarily aiming to mitigate severe forms of postoperative pulmonary dysfunction associated with poor outcomes and increased resource consumption.

Disparities in donor heart acceptance between the USA and Europe: clinical implications.

BACKGROUND AND AIMS: Given limited evidence and lack of consensus on donor acceptance for heart transplant (HT), selection practices vary widely across HT centres in the USA. Similar variation likely exists on a broader scale-across countries and HT systems-but remains largely unexplored. This study characterized differences in heart donor populations and selection practices between the USA and Eurotransplant-a consortium of eight European countries-and their implications for system-wide outcomes. METHODS: Characteristics of adult reported heart donors and their utilization (the percentage of reported donors accepted for HT) were compared between Eurotransplant (n = 8714) and the USA (n = 60 882) from 2010 to 2020. Predictors of donor acceptance were identified using multivariable logistic regression. Additional analyses estimated the impact of achieving Eurotransplant-level utilization in the USA amongst donors of matched quality, using probability of acceptance as a marker of quality. RESULTS: Eurotransplant reported donors were older with more cardiovascular risk factors but with higher utilization than in the USA (70% vs. 44%). Donor age, smoking history, and diabetes mellitus predicted non-acceptance in the USA and, by a lesser magnitude, in Eurotransplant; donor obesity and hypertension predicted non-acceptance in the USA only. Achieving Eurotransplant-level utilization amongst the top 30%-50% of donors (by quality) would produce an additional 506-930 US HTs annually. CONCLUSIONS: Eurotransplant countries exhibit more liberal donor heart acceptance practices than the USA. Adopting similar acceptance practices could help alleviate the scarcity of donor hearts and reduce waitlist morbidity in the USA.

A Paradigm Shift in Heart Preservation: Improved Post-transplant Outcomes in Recipients of Donor Hearts Preserved With the SherpaPak System.

Traditional ice storage has been the historic standard for preserving donor's hearts. However, this approach provides variability in cooling, increasing risks of freezing injury. To date, no preservation technology has been reported to improve survival after transplantation. The Paragonix SherpaPak Cardiac Transport System (SCTS) is a controlled hypothermic technology clinically used since 2018. Real-world evidence on clinical benefits of SCTS compared to conventional ice cold storage (ICS) was evaluated. Between October 2015 and January 2022, 569 US adults receiving donor hearts preserved and transported either in SCTS (n = 255) or ICS (n = 314) were analyzed from the Global Utilization And Registry Database for Improved heArt preservatioN (GUARDIAN-Heart) registry. Propensity matching and a subgroup analysis of >240 minutes ischemic time were performed to evaluate comparative outcomes. Overall, the SCTS cohort had significantly lower rates of severe primary graft dysfunction (PGD) ( p = 0.03). When propensity matched, SCTS had improving 1-year survival ( p = 0.10), significantly lower rates of severe PGD ( p = 0.011), and lower overall post-transplant MCS utilization ( p = 0.098). For patients with ischemic times >4 hours, the SCTS cohort had reduced post-transplant MCS utilization ( p = 0.01), reduced incidence of severe PGD ( p = 0.005), and improved 30-day survival ( p = 0.02). A multivariate analysis of independent risk factors revealed that compared to SCTS, use of ice results in a 3.4-fold greater chance of severe PGD ( p = 0.014). Utilization of SCTS is associated with a trend toward increased post-transplant survival and significantly lower severe PGD and MCS utilization. These findings fundamentally challenge the decades-long status quo of transporting donor hearts using ice.

Prospective assessment of pre-existing and de novo anti-HLA IgE in kidney, liver, lung and heart transplantation.

Introduction: Antibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and de novo anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients. Methods: We prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an in vitro mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients. Results: Pre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed de novo anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no de novo IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils in vitro, demonstrating functionality of anti-HLA IgE. Discussion: These data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation.

Clinical course of congestive hepatopathy pre/post heart transplantation.

BACKGROUND AND AIMS: Heart failure (HF) might lead to increased hepatic venous pressure, thereby impairing hepatic blood outflow and subsequently inducing congestive hepatopathy. We aimed to evaluate prevalence of congestive hepatopathy in patients undergoing heart transplantation (HTX) as well as their post-transplant course. METHODS: Patients undergoing HTX from 2015-2020 at the Vienna General Hospital were included (n = 205). Congestive hepatopathy was defined by hepatic congestion on abdominal imaging and hepatic injury. Laboratory parameters, ascites severity, and clinical events were assessed and post-HTX outcomes evaluated. RESULTS: At listing, 104 (54%) patients showed hepatic congestion, 97 (47%) hepatic injury, and 50 (26%) had ascites. Congestive hepatopathy was diagnosed in 60 (29%) patients, who showed more often ascites, lower serum sodium and cholinesterase activity, and higher hepatic injury markers. Mean albumin-bilirubin (ALBI)-score as well as (modified)-model for end-stage liver disease (MELD)-scores were higher in patients with congestive hepatopathy. Median levels of laboratory parameters/scores normalised after HTX, and ascites resolved in most patients with congestive hepatopathy (n = 48/56, 86%). The post-HTX (median follow-up 55.1 months) survival was 87% and liver-related events were rare (3%). Severe ascites, low cholinesterase, and MELD/MELD-XI were associated with ascites persistence/death 1­year after HTX. Age, male sex, and severe ascites were the only independent predictors of post-HTX mortality. Both ALBI and MELD-scores were robust indicators of post-HTX survival when measured 4 weeks after HTX (ALBI log-rank test p < 0.001; MELD log-rank test p = 0.012). CONCLUSION: Congestive hepatopathy and ascites were mostly reversible after HTX. Liver-related scores and ascites improve prognostication in patients after HTX.

Transcatheter tricuspid valve edge-to-edge repair after a heart transplant: a single-centre experience with a novel therapy†.

OBJECTIVES: Tricuspid regurgitation (TR) in patients who had heart transplants is associated with poor outcome. The increased risk for surgical and postoperative complications might be reduced in these vulnerable patients by transcatheter therapies. METHODS: All patients with a prior heart transplant (HTX) undergoing transcatheter edge-to-edge repair in the tricuspid position (T-TEER) were prospectively enrolled in an institutional registry. RESULTS: Seven patients who had heart transplants (5/7 female) at a mean age of 53 [48; 64] and median TRI-SCORE of 14 [7; 22] underwent T-TEER to treat symptomatic TR ≥ IV in an elective (n = 6) and urgent (n = 1) setting, respectively. The median time from HTX to T-TEER was 13 years. A total of 2 (n = 4) and 3 (n = 3) clips were implanted with a technical success in 6/7 (one single- device detachment). TR reduction was effective and durable within a median echocardiographic follow-up time of 10 months (TR baseline vs last follow-up: P = 0.03). Further, significant right ventricular remodelling (right ventricular end-diastolic diameter: 50 mm-36 mm, P = 0.02), decrease in the inferior vena cava diameter (24 mm-18 mm, P = 0.04) and in the gamma-glutamyl-transferase (255 U/l-159 U/l, P = 0.04) was found. Four of 7 patients were free of cardiovascular death (n = 1, 267 days after T-TEER), cardiac redo surgery (n = 1) and heart failure hospitalization (n = 2) and had no further clinical signs of right heart failure. CONCLUSIONS: T-TEER after HTX is feasible and effective regarding TR reduction in a short-term follow-up. The initial results may pave the way for a novel approach in TR management in patients having HTX.

European multicenter study on the real-world use and clinical impact of extracorporeal photopheresis after heart transplantation.

BACKGROUND: Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. METHODS: Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. RESULTS: Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. CONCLUSIONS: This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors.

Evaluation of perivascular fat attenuation with coronary CT angiography in cardiac transplantation patients: an imaging biomarker candidate for prediction of cardiac mortality and re-transplantation.

OBJECTIVES: In cardiac transplant recipients, non-invasive allograft surveillance for identifying patients at risk for graft failure remains challenging. The fat attenuation index (FAI) of the perivascular adipose tissue in coronary computed tomography angiography (CCTA) predicts outcomes in coronary artery disease in non-transplanted hearts; however, it has not been evaluated in cardiac transplant patients. METHODS: We followed 39 cardiac transplant patients with two or more CCTAs obtained between 2010 and 2021. We performed FAI measurements around the proximal 4 cm segments of the left anterior descending (LAD), right coronary artery (RCA), and left circumflex artery (LCx) using a previously validated methodology. The FAI was analyzed at a threshold of - 30 to - 190 Hounsfield units. RESULTS: FAI measurements were completed in 113 CCTAs, obtained on two same-vendor CT models. Within each CCTA, the FAI values between coronary vessels were strongly correlated (RCA and LAD R = 0.67 (p < 0.0001), RCA and LCx R = 0.58 (p < 0.0001), LAD and LCx R = 0.67 (p < 0.0001)). The FAIs of each coronary vessel between the patient's first and last CCTA completed at 120 kV were also correlated (RCA R = 0.73 (p < 0.0001), LAD R = 0.81 (p < 0.0001), LCx R = 0.55 (p = 0.0069). Finally, a high mean FAI value of all three coronary vessels at baseline (mean ≥ - 71 HU) was predictive of cardiac mortality or re-transplantation, however, not predictive of all cause-mortality. CONCLUSION: High baseline FAI values may identify a higher-risk cardiac transplant population; thus, FAI may support the implementation of CCTA in post-transplant surveillance. KEY POINT: • Perivascular fat attenuation measured with coronary CT is feasible in cardiac transplant patients and may predict cardiac mortality or need for re-transplantation.

Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation-A Case Control Study.

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.

Absolute Lymphocyte Count as a Marker for Cytomegalovirus Infection After Heart Transplantation.

BACKGROUND: Previous studies indicate an association between reduced absolute lymphocyte count (ALC) and cytomegalovirus (CMV) infection after solid organ transplantation and have therefore highlighted the potential of ALC as a simple tool to predict CMV infection in transplant patients. This study aimed to examine the utility of ALC as a valuable marker for CMV infection in heart transplant patients. METHODS: Clinical information and ALC data of all adult patients who received orthotopic heart transplantation at the Medical University of Vienna between January 2004 and May 2019 were collected. We performed a multivariable Cox regression model that incorporates repeated measurements of ALC as a time-varying continuous factor in 2 ways, first as continuous logarithmic factor considering a 50% decrease of ALC levels and second as binary factor using a threshold of 610 cells/µL. RESULTS: One hundred fifty-eight (39%) patients developed CMV infection over the course of 2 y. Patients with lymphopenia were shown to be at higher risk of developing CMV infection both in the continuous approach (HR [per 50% reduction] 1.29; confidence interval [CI], 1.09-1.53; P = 0.003) and the binary approach with a cutoff of 610 cells/µL (HR 1.74; CI, 1.20-2.51; P = 0.003). CONCLUSIONS: This study demonstrated a strong association between reduced ALC and the development of CMV infection after heart transplantation. ALC value monitoring could provide an additional tool to assess individualized CMV risk after solid organ transplantation.

Donor heart selection: Evidence-based guidelines for providers.

The proposed donor heart selection guidelines provide evidence-based and expert-consensus recommendations for the selection of donor hearts following brain death. These recommendations were compiled by an international panel of experts based on an extensive literature review.