Hospital Readmissions in Patients Supported with Durable Centrifugal-Flow Left Ventricular Assist Devices.

Background: Centrifugal-flow left ventricular assist devices (CF-LVADs) have improved morbidity and mortality for their recipients. Hospital readmissions remain common, negatively impacting quality of life and survival. We sought to identify risk factors associated with hospital readmissions among patients with CF-LVADs. Methods: Consecutive patients receiving a CF-LVAD between February 2011 and March 2021 were retrospectively evaluated using prospectively maintained institutional databases. Hospital readmissions within three years post-LVAD implantation were dichotomized into heart failure (HF)/LVAD-related or non-HF/LVAD-related readmissions. Multivariable Cox regression models augmented using a machine learning algorithm, the least absolute shrinkage and selection operator (LASSO) method, for variable selection were used to estimate associations between HF/LVAD-related readmissions and pre-, intra- and post-operative clinical variables. Results: A total of 204 CF-LVAD recipients were included, of which 138 (67.7%) had at least one HF/LVAD-related readmission. HF/LVAD-related readmissions accounted for 74.4% (436/586) of total readmissions. The main reasons for HF/LVAD-related readmissions were major bleeding, major infection, HF exacerbation, and neurological dysfunction. Using pre-LVAD variables, HF/LVAD-related readmissions were associated with substance use, previous cardiac surgery, HF duration, pre-LVAD inotrope dependence, percutaneous LVAD/VA-ECMO support, LVAD type, and the left ventricular ejection fraction in multivariable analysis (Harrell's concordance c-statistic; 0.629). After adding intra- and post-operative variables in the multivariable model, LVAD implant hospitalization length of stay was an additional predictor of readmission. Conclusions: Using machine learning-based techniques, we generated models identifying pre-, intra-, and post-operative variables associated with a higher likelihood of rehospitalizations among patients on CF-LVAD support. These models could provide guidance in identifying patients with increased readmission risk for whom clinical strategies to mitigate this risk may further improve LVAD recipient outcomes.

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.

Temporal Trends, Risk Factors, and Clinical Outcomes of De Novo Lymphoproliferative Disorders After Heart Transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is an important cause of morbidity and mortality in heart transplant (HTx) recipients. However, previous studies of PTLD after HTx are limited to single-center analyses or extrapolated from all solid organ transplantations. OBJECTIVES: The authors analyzed the temporal trends, risk factors, and clinical outcome of de novo PTLD specifically after HTx. METHODS: Using multi-institutional, multinational data from the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry, the authors evaluated the real-world data of PTLD after HTx, transplanted between January 2000 and June 2015. Multivariable analysis was done to identify risk factors for PTLD development after HTx. RESULTS: Among 28,136 HTx recipients, 1,069 (3.8%) developed PTLD within 10 years of transplantation. PTLD showed a bimodal age pattern with peak incidence in patients of pediatric age and late adulthood at transplantation. The early transplant era (2000-2007 vs 2008-2015), male recipient, and EBV donor-positive-recipient-negative match were independent risk factors of PTLD development within 3 years of transplantation, whereas maintenance therapy with cyclosporine vs tacrolimus at initial discharge was associated with a lower incidence. PTLD development within 3 years of transplantation was significantly associated with mortality (HR: 2.42 [95% CI: 2.01-2.91]; P < 0.001). Survival after PTLD diagnosis was higher in the recent transplant era. CONCLUSIONS: PTLD is relatively rare, but potentially fatal, post-transplant malignancy. PTLD incidence and mortality after HTx have decreased in the recent era. Strategies to minimize the risk of PTLD, and ensure early diagnosis and effective treatment are likely to improve outcomes in HTx.

Cardiac Involvement in Neurosarcoidosis: A Single-Center Investigation

BACKGROUND AND OBJECTIVES: Sarcoidosis is a multisystem inflammatory granulomatous disease. Among systemic sarcoidosis manifestations, cardiac or nervous system involvement can result in significant morbidity and mortality. We describe the overlapping incidence of cardiac sarcoidosis (CS) within a neurosarcoidosis (NS) cohort and determine the frequency of other nonsarcoid cardiac diseases in these patients. METHODS: We performed a retrospective chart review of patients evaluated at the University of Utah from 2010 to 2022. Patients were included if they had (1) at least one instance of a diagnostic code for sarcoidosis in their medical record-International Classification of Diseases (ICD) 9 code 135 or ICD 10 code D86; (2) at least one outpatient visit in the Neurology Department within the University of Utah electronic health record with a diagnosis of definite, probable, or possible NS based on 2018 consensus criteria; (3) at least one outpatient visit in the Cardiology Department within the University of Utah electronic health record; and (4) ECG available in their medical record for review. Of 64 definite, probable, or possible patients with NS in the University of Utah cohort, 52 met our inclusion criteria and were included in this study. RESULTS: Of 52 patients with NS who met our inclusion criteria, 65.38% were female, with an average age of 60.9 years (range 38-84). More than half (58%) were obese (BMI ≥ 30). CS was diagnosed in 6 patients with NS (12%). Symptoms suggestive of possible cardiac dysfunction included lower extremity edema (50%), palpitations (46%), chest pain (44%), and shortness of breath (27%). ECG abnormalities included nonspecific T-wave change (40%) and right bundle branch block (17%). Three patients experienced ventricular tachycardia: sustained in one patient and nonsustained in 2 patients. Cardiac MRI was performed in 17 patients (32.7%) and in 3 patients (17.6%), which revealed diffuse myocardial enhancement suggesting CS. DISCUSSION: In this cohort, 12% of patients with NS also had confirmed CS. In addition, these patients had a high burden of cardiovascular disease not directly attributed to sarcoidosis. Our data suggest that patients with NS require comprehensive cardiac evaluation. Future studies are needed to clarify the extent of the direct contribution of granulomatous inflammation on the cardiovascular system from the indirect contribution of treatments such as glucocorticoids that lead to increased risk of cardiovascular disease in sarcoidosis.

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.

A Case Report of Triple Organ Transplantation From a Donor After Circulatory Death Using Thoraco-Abdominal Normothermic Regional Perfusion.

Organ transplantation with donation after circulatory death can potentially increase the donor pool. Here, we report the rare case of triple-organ (heart/liver/kidney) transplantation from a donor after circulatory death using thoraco-abdominal normothermic regional perfusion. The recipient was a 61-year-old man with end-stage heart failure, liver failure, and kidney failure secondary to arrhythmogenic right ventricular dysplasia. He received a heart/liver/kidney transplantation from a donor after circulatory death. The course was complicated with primary graft dysfunction of the heart that resolved on postoperative day 3. The patient was discharged on postoperative day 39. He has no evidence for rejection on heart biopsy, and all 3 organs exhibit stable function. The use of donation after cardiac death donors greatly increases the donor pool and should be considered for patients requiring multiorgan transplantation. The use of thoraco-abdominal normothermic reperfusion is not only a feasible method for multiorgan procurement but also provides enhanced protection for all transplanted organs.

Comparison of two donor-derived cell-free DNA tests and a blood gene-expression profile test in heart transplantation.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) testing is an emerging screening modality for noninvasive detection of acute rejection (AR). This study compared the testing accuracy for AR of two commercially available dd-cfDNA and gene-expression profiling (GEP) testing in heart transplant (HTx) recipients. METHODS: This is a retrospective, observational study of HTx only patients who underwent standard and expanded single nucleotide polymorphism (SNP) dd-cfDNA between October 2020 to January 2022. Comparison with GEP was also performed. Assays were compared for correlation, accurate classification, and prediction for AR. RESULTS: A total of 428 samples from 112 unique HTx patients were used for the study. A positive standard SNP correlated with the expanded SNP assay (p < .001). Both standard and expanded SNP tests showed low sensitivity (39%, p = 1.0) but high specificity (82% and 84%, p = 1.0) for AR. GEP did not improve sensitivity and showed worse specificity (p < .001) compared to standard dd-cfDNA. CONCLUSION: We found no significant difference between standard and expanded SNP assays in detecting AR. We show improved specificity without change in sensitivity using dd-cfDNA in place of GEP testing. Prospective controlled studies to address how to best implement dd-cfDNA testing into clinical practice are needed.

Influence of chronic kidney disease and other risk factors pre-heart transplantation on malignancy incidence post-heart transplantation.

Aims: Chronic kidney disease (CKD) pre-heart transplantation (HTx) has been proposed as a risk factor for malignancy risk post-HTx. Using multicenter registry data, our aim was to calculate the death-adjusted annual incidence of malignancies post-HTx, corroborate the association between CKD pre-HTx and malignancy risk post-HTx, and determine other risk factors for post-HTx malignancies. Methods and materials: We used data from patients transplanted in North American HTx centers between January 2000 and June 2017 and registered in the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. We excluded recipients with missing data on post-HTx malignancies, heterotopic heart transplant, retransplantation, multi-organ transplantation, and patients with a total artificial heart pre-HTx. Results: Overall, 34,873 patients were included to determine the annual incidence of malignancies, 33,345 patients were included in the risk analyses. The incidence of any malignancy, solid-organ malignancy, post-transplant lymphoproliferative disease (PTLD), and skin cancer adjusted for death 15 years post-HTx, was 26.6%, 10.9%, 3.6%, and 15.8% respectively. Besides widely acknowledged risk factors, CKD stage ≥4 pre-HTx was associated with the development of all malignancies post-HTx (HR 1.17 compared to CKD stage 1, p = 0.023), as well as solid-organ malignancies (HR 1.35, p = 0.01), but not for PTLD (HR 0.73, p = 0.057), and skin cancer (HR 1.06, p = 0.59). Conclusion: Risk of malignancy post-HTx remains high. CKD stages ≥4 pre-HTx was associated with an increased risk for any malignancy and solid-organ malignancy post-HTx. Strategies to mitigate the impact of pre-HTx patient factors on the risk of post-HTx malignancy are needed.

A multicenter evaluation of external outflow graft obstruction with a fully magnetically levitated left ventricular assist device.

BACKGROUND: The HeartMate 3 (HM 3; Abbott) left ventricular assist device (LVAD) has improved hemocompatibility-related adverse outcomes. In sporadic cases, external compression of the outflow graft causing obstruction (eOGO) can result from substance accumulation between the outflow graft and its bend relief. We sought to evaluate the prevalence, course, and clinical implications of eOGO in an international study. METHODS: A multicenter retrospective analysis of HM 3 LVADs implanted between November 2014 and April 2021 (n = 2108) was conducted across 17 cardiac centers in 8 countries. We defined eOGO as obstruction >25% in the cross-sectional area in imaging (percutaneous angiography, computed tomography, or intravascular ultrasound). The prevalence and annual incidence were calculated. Serious adverse events and outcomes (death, transplantation, or device exchange) were analyzed for eOGO cases. RESULTS: Of 2108 patients, 62 were diagnosed with eOGO at a median LVAD support duration of 953 (interquartile range, 600-1267) days. The prevalence of eOGO was 3.0% and the incidence at 1, 2, 3, 4, and 5 years of support was 0.6%, 2.8%, 4.0%, 5.2%, and 9.1%, respectively. Of 62 patients, 9 were observed, 27 underwent surgical revision, 15 underwent percutaneous stent implantation, 8 received a heart transplant, and 2 died before intervention. One patient underwent surgical revision and later stent implantation. The mortality with therapeutic intervention was 9/53 (17.0%). CONCLUSIONS: Although uncommon, HM 3 LVAD-supported patients might develop eOGO with an increasing incidence after 1 year of support. Although engineering efforts to reduce this complication are under way, clinicians must maintain a focus on early detection and remain vigilant.

Epidemiology, risk factors, and outcomes of lung retransplantation: An analysis of the International Society for Heart and Lung Transplantation Thoracic Transplant Registry.

BACKGROUND: Lung retransplantation is a complex surgical decision that represents the only potential treatment option for recipients suffering from lung allograft failure. We sought to describe the modern landscape of lung retransplantation and to compare the relative importance of selected clinical, donor, and recipient factors on mortality in the year following lung retransplantation. METHODS: We conducted a retrospective cohort study of first-time adult recipients of deceased donor lung retransplants reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry from May 2005 through June 2017. In addition to describing the characteristics of lung retransplant recipients, we examined 1 year survival overall, and by initial transplant-retransplant procedure type, recipient age, retransplant indication, and time-to-lung retransplantation (i.e., inter-transplant interval). We used the Somers' Dxy rank correlation statistic for censored data to assess the relative importance of several potential prognostic risk factors for mortality in the year following lung retransplantation. RESULTS: Our cohort included 1,597 lung retransplant recipients. 2005 was the first year with more than 100 retransplants, and since 2007, 138 to 188 retransplants (approximately 4%-6% of all transplants) were reported annually to the ISHLT Registry. The median inter-transplant interval was 3.4 years (interquartile range: 1.6-6.2 years). Forty-three percent of the cohort had an obliterative bronchiolitis retransplant indication, whereas 17% had primary graft failure. One-third (32%) were retransplanted within 2 years of their primary transplant, and 64% received a double lung transplant both times, whereas 36% received consecutive single lung transplants. Six-month and 1 year survival (82% and 76%) were higher for double-double lung retransplant recipients than for single-single recipients (76% and 69%). The 3 strongest prognostic factors for 1 year mortality were the inter-transplant interval (decreasing hazard with longer intervals), donor age (increasing hazard with older age), and need for mechanical ventilation preceding lung retransplantation. CONCLUSIONS: Retransplants comprise approximately 5% of annual lung transplants worldwide. The factor most strongly associated with 1 year mortality in this population was the duration of time since the primary lung transplant, with a persistent reduction in risk as more time elapses.

Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies.

BACKGROUND: The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury. METHODS: In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups. RESULTS: Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell-mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state. CONCLUSIONS: Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell-mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction.

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

BACKGROUND: Endomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients. METHODS: Plasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures. RESULTS: A total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, pc < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples. CONCLUSIONS: This novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

Fatal Allograft Rejection and Cardiac Allograft Vasculopathy After Treatment With Pembrolizumab for Metastatic Melanoma in a Heart Transplant Recipient: A Case Report.

Checkpoint inhibitors decrease the progression of many cancers. However, the experience in immunosuppressed patients is limited, with reports of possible serious adverse events. We present a heart transplant recipient treated with pembrolizumab for metastatic melanoma who developed fatal rejection. The patient was a 29 year-old man who underwent heart transplantation at the age of 10 years for congenital heart disease. Seventeen years after transplant, he was diagnosed with scalp melanoma pT3a, N2a, M0, Stage IIIA, positive for BRAF V600E mutation treated with excision, which metastasized to his lungs and brain a year later. Dabrafenib and trametinib were started with transient response. Additional options and their risks were discussed, and pembrolizumab was started 4 months later due to the incomplete response to previous therapy. Five days after initiation the patient presented with moderate cellular rejection and possible antibody mediated rejection (ISHLT Grade 2R, pAMR 1H). Pembrolizumab was discontinued, and he was treated with steroids. Seven months later he presented in cardiogenic shock and severe coronary allograft vasculopathy. Biopsy was negative for cellular rejection, but suspicious for antibody mediated rejection (ISHLT Grade 0R, pAMR 1H), and he had a new serum alloantibody. Despite steroids and plasmapheresis he remained in refractory cardiogenic shock and died of cardiac arrest.

HVAD to Heartmate 3 Device Exchange: A Society of Thoracic Surgeons Intermacs Analysis.

BACKGROUND: On June 3, 2021 Medtronic, Inc announced discontinuation of the HVAD left ventricular assist device. The purpose of this analysis was to provide summary data on surgical risks of HVAD to HeartMate 3 exchange and compare survival after HVAD to HeartMate 3 exchange to survival after primary HVAD implantation. METHODS: Three cohorts within The Society of Thoracic Surgeons Intermacs database were identified: primary HVAD implant cohort (January 2017 to March 2021, n = 3797), HVAD to HeartMate 3 exchange cohort (December 2017 to March 2021, n = 45), and HVAD to HVAD exchange cohort (January 2017 to March 2021, n = 234). Mortality after HVAD to HeartMate 3 exchange was modeled and compared with the constant hazard phase for risk of mortality while on continued HVAD support. As a secondary analysis outcomes and survival were compared between patients who underwent HVAD to HeartMate 3 and HVAD to HVAD exchange. RESULTS: HVAD to HeartMate 3 exchange was associated with significantly reduced survival compared with survival while remaining on HVAD support (6 months after exchange, 73.8% [70% confidence interval, 68.6-77.8] vs 79.0% [70% confidence interval, 78.3-79] for continued HVAD support). Compared with HVAD to HVAD exchange, survival was higher after replacement with HeartMate 3 (1 year: 85.9% [70% confidence interval, 79.5-90.5] vs 66.6% [70% confidence interval, 63.0-70.0], P = .009). CONCLUSIONS: Compared with continued support on HVAD, an exchange to HeartMate 3 was found to be associated with a significant increase in mortality. For patients who required pump exchange on HVAD support, exchange to HeartMate 3 demonstrated superior survival. Currently there is insufficient evidence to support elective exchange from an HVAD to HeartMate 3.

Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes.

BACKGROUND: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies. METHODS: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359). RESULTS: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss. CONCLUSIONS: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient characteristics.

For over 30 years, the International Society for Heart and Lung Transplantation (ISHLT) International Thoracic Organ Transplant (TTX) Registry has gathered data regarding transplant procedures, donor and recipient characteristics, and outcomes from a global community of transplant centers. Almost 70,000 adult lung transplant procedures have been reported to the Registry since its inception, each one providing an opportunity for a recipient with end-stage lung disease to regain quality of life and longevity. With each year's report, we provide more detailed analyses on a particular focus theme important to recipient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; multiorgan transplantation; and donor and recipient size matching.1-7 In response to a changing regulatory environment, the ISHLT TTX Registry is undergoing an update in data acquisition, and the patient cohort examined in this report is therefore derived from the same data source or datasets as that examined in the 2019 annual reports.2,8-10 We refer the reader to the 2019 and prior reports for a detailed description of the baseline characteristics of the cohort, and additional core analyses not directly related to the focus explored in this year's report. To complement the 2020 report which focussed on donor characteristics, the goal of this year's report was to focus entirely on changes in recipient factors over the past 3 decades and to identify important recipient characteristics and transplant processes that may influence post-transplant outcomes. Due to small numbers, heart-lung transplant recipient characteristics and transplant outcomes have not been included. This 38th annual adult lung transplant report is hence based on data submitted to the ISHLT TTX Registry on 67,493 adult recipients of deceased recipient transplants between January 1, 1992 and June 30, 2018.

Sacubitril-valsartan improves conduit vessel function and functional capacity and reduces inflammation in heart failure with reduced ejection fraction.

The Prospective comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan (trade name Entresto), but the physiological processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF (n = 11, 10 M/1 F, left ventricular ejection fraction = 27 ± 8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function [brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)], functional capacity [six-minute walk test (6MWT) distance], and the proinflammatory biomarkers tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and at 1, 2, and 3 mo of treatment. %FMD improved after 1 mo of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25 ± 1.75%; 1 mo: 5.23 ± 2.36%; 2 mo: 5.81 ± 1.79%; 3 mo: 6.35 ± 2.77%), whereas RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420 ± 92 m; 1 mo: 436 ± 98 m; 2 mo: 465 ± 115 m; 3 mo: 460 ± 110 m), and there was a sustained reduction in TNF-α (baseline: 2.38 ± 1.35 pg/mL; 1 mo: 2.06 ± 1.52 pg/mL; 2 mo: 1.95 ± 1.34 pg/mL; 3 mo: 1.92 ± 1.37 pg/mL) and a reduction in IL-18 at month 3 (baseline: 654 ± 150 pg/mL; 1 mo: 595 ± 140 pg/mL; 2 mo: 601 ± 176 pg/mL; 3 mo: 571 ± 127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF.NEW & NOTEWORTHY We observed an approximately twofold improvement in conduit vessel function (brachial artery FMD), increased functional capacity (6MWT distance), and a reduction in inflammation (TNF-α and IL-18) following 3 mo of sacubitril-valsartan therapy. These findings provide important new information concerning the physiological mechanisms by which this new drug class provokes favorable changes in HFrEF pathophysiology.