PCSK9 inhibitors safely and effectively lower LDL after heart transplantation: a systematic review and meta-analysis.

Coronary allograft vasculopathy (CAV) continues to afflict a high number of heart transplant (HT) recipients, and elevated LDL is a key risk factor. Many patients cannot tolerate statin medications after HT; however, data for alternative agents remains scarce. To address this key evidence gap, we evaluated the safety and efficacy of the PCSK9i after HT through systematic review and meta-analysis. We searched Medline, Cochrane Central, and Scopus from the earliest date through July 15th, 2021. Citations were included if they were a report of PCSK9i use in adults after HT and reported an outcome of interest. Outcomes included change in LDL cholesterol from baseline, incidence of adverse events, and evidence of CAV. Changes from baseline and outcome incidences were pooled using contemporary random-effects model methodologies. A total of six studies including 97 patients were included. Over a mean follow-up of 13 months (range 3-21), PCSK9i use lowered LDL by 82.61 mg/dL (95% CI - 119.15 to - 46.07; I2 = 82%) from baseline. Serious adverse drug reactions were rarely reported, and none was attributable to the PCSK9i therapy. Four studies reported stable calcineurin inhibitor levels during PCSK9i initiation. One study reported outcomes in 33 patients with serial coronary angiography and intravascular ultrasound, and PCSK9i were associated with stable coronary plaque thickness and lumen area. One study reported on immunologic safety, showing no DSA development within 1 month of therapy. Preliminary data suggest that long-term PCSK9i therapy is safe, significantly lowers LDL, and may attenuate CAV after HT. Additional study on larger cohorts is warranted to confirm these findings.

Early post-transplant leukopenia in heart transplant recipients and its impact on outcomes.

BACKGROUND: Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. METHODS: Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 103 /µL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. RESULTS: Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1 × 103 /µL vs. 6.9 × 103 /µL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. CONCLUSIONS: Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.

Letermovir for cytomegalovirus prophylaxis in high-risk heart transplant recipients.

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

Chronic intermittent intravenous immunoglobulin in heart transplant recipients with elevated donor-specific antibody levels.

Donor-specific antibodies (DSA) are associated with antibody-mediated rejection (AMR) and poor patient survival. In heart transplant, the efficacy of intermittent intravenous immunoglobulin (IVIg) in reducing de novo DSA levels and treating AMR has not been characterized. We retrospectively studied a cohort of 19 patients receiving intermittent IVIg for elevated DSA and examined changes in DSA levels and graft function. Intermittent IVIg infusions were generally safe and well tolerated. Overall, 23 of 62 total DSA (37%) were undetectable after treatment, 21 DSA (34%) had MFI decrease by more than 25%, and 18 (29%) had MFI decrease by less than 25% or increase. The average change in MFI was -51% ± 71% (P < .001). Despite reductions in DSA, among the six patients (32%) with biopsy-confirmed AMR, left ventricular ejection fraction (LVEF) decreased in five (83%) and cardiac index (CI) decreased in three (50%). Conversely, LVEF increased in 91% and CI increased in 70% of biopsy-negative patients. All six AMR patients were readmitted during treatment, four for confirmed or suspected rejection. IVIg infusions may stabilize the allograft in patients with elevated DSA and negative biopsies, but once AMR has developed does not appear to improve allograft function despite decreasing DSA levels.

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor ß chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFß) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.

How can we better inform our patients about post-heart transplantation survival? A conditional survival analysis.

BACKGROUND: Conditional survival (CS) is a dynamic method of survival analysis that provides an estimate of how an individual's future survival probability changes based on time post-transplant, individual characteristics, and post-transplant events. This study sought to provide post-transplant CS probabilities for heart transplant recipients based on different prognostic variables and provide a discussion tool for the providers and the patients. METHODS: Adult heart transplant recipients from January 1, 2004, through October 18, 2018, were identified in the UNOS registry. CS probabilities were calculated using data from Kaplan-Meier survival estimates. RESULTS: CS probability exceeded actuarial survival probability at all times post-transplant. Women had similar short-term, but greater long-term CS than men at all times post-transplant (10-year CS 1.8-11.5% greater [95% CI 1.2-12.9]). Patients with ECMO or a surgical BiVAD had decreased survival at the time of transplant, but their CS was indistinguishable from all others by 1-year post-transplant. Rejection and infection requiring hospitalization during the first year were associated with a persistently decreased CS probability. CONCLUSIONS: In this study, we report differential conditional survival outcomes based on time, patient characteristics, and clinical events post-transplant, providing a dynamic assessment of survival. The survival probabilities will better inform patients and clinicians of future outcomes.

Impact of Bridge to Transplantation With Continuous-Flow Left Ventricular Assist Devices on Posttransplantation Mortality.

BACKGROUND: Bridge to transplantation (BTT) with left ventricular assist devices (LVADs) is a mainstay of therapy for heart failure in patients awaiting heart transplantation (HT). Criteria for HT listing do not differ between patients medically managed and those mechanically bridged to HT. The objectives of the present study were to evaluate the impact of BTT with LVAD on posttransplantation survival, to describe differences in causes of 1-year mortality in medically and mechanically bridged patients, and to evaluate differences in risk factors for 1-year mortality between those with and those without LVAD at the time of HT. METHODS: Using the United Network of Organ Sharing database, we identified 5486 adult, single-organ HT recipients transplanted between 2008 and 2015. Patients were propensity matched for likelihood of LVAD at the time of HT. Kaplan-Meier survival estimates were used to assess the impact of BTT on 1- and 5-year mortality. Logistic regression analysis was used to evaluate the odds ratio of 1-year mortality for patients BTT with LVAD compared with those with medical management across clinically significant variables at various thresholds. RESULTS: Early mortality was higher in mechanically bridged patients: 9.5% versus 7.2% mortality at 1 year (P<0.001). BTT patients incurred an increased risk of 1-year mortality with an estimated glomerular filtration rate of 40 to 60 mL·min-1·1.73 m-2 (odds ratio, 1.69; P=0.003) and <40 mL·min-1·1.73 m-2 (odds ratio, 2.16; P=0.005). A similar trend was seen in patients with a body mass index of 25 to 30 kg/m2 (odds ratio, 1.88; P=0.024) and >30 kg/m2 (odds ratio, 2.11; P<0.001). When patients were stratified by BTT status and the presence of risk factors, including age >60 years, estimated glomerular filtration rate <40 mL·min-1·1.73 m-2, and body mass index >30 kg/m2, there were significant differences in 1-year mortality between medium- and high-risk medically and mechanically bridged patients, with 1-year mortality in high-risk BTT patients at 17.6% compared with 10.4% in high-risk medically managed patients. CONCLUSIONS: Bridge to HT with LVAD, although necessary because of organ scarcity and capable of improving wait list survival, confers a significantly higher risk of early posttransplantation mortality. Patients bridged with mechanical support may require more careful consideration for transplant eligibility after LVAD placement.

Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition.

HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement-dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor-specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1-3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies.

Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation.

Antibody-mediated rejection (AMR) driven by the development of donor-specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non-HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single-center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non-AMR (n = 21) were tested for reactivity against a panel of 44 non-HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non-AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA-positive AMR patients exhibited greater reactivity to autoantigens compared to DSA-negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta-tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non-AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non-HLA are associated with DSA-positive AMR although their specific role in mediating allograft injury is not yet understood.

Discontinuing amiodarone treatment prior to heart transplantation lowers incidence of severe primary graft dysfunction.

BACKGROUND: Recent studies have shown an increased incidence of primary graft dysfunction (PGD) in patients treated with amiodarone prior to orthotopic heart transplant (OHT). We hypothesized that discontinuation of amiodarone before OHT may lower the incidence of severe PGD. METHODS: This was a single-center retrospective study of 381 adult OHT recipients between January 2010 and June 2017. Within 6 months prior to OHT, 197 did not receive amiodarone (Group 1), 142 continued amiodarone to OHT (Group 2), and 42 had amiodarone treatment discontinued before OHT (Group 3). RESULTS: 53 (13.9%) participants developed severe PGD, 13 (6.6%) of which were in Group 1, 36 (25.4%) were in Group 2, and 4 (9.5%) were in Group 3 (P < .001). Multivariable analysis revealed continued amiodarone treatment to OHT (Group 2; OR, 3.70; 95% CI, 1.26-10.88; P = .018) to be an independent risk factor for the development of severe PGD when Group 1 served as the reference group. Moreover, patients in Group 3 had no difference in the risk of severe PGD (OR = 0.416, 95% CI = 0.08-2.15; P = .296). CONCLUSION: We found that discontinuing amiodarone treatment prior to OHT resulted a lower incidence of severe PGD.

United network for organ sharing outcomes after heart transplantation for al compared to ATTR cardiac amyloidosis.

Light-chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single-center study, we compared post-heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post-OHT. Thirty-nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non-amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post-OHT. Survival for non-amyloid patients was greater than ATTR (P = .034) and AL (P < .001) patients in the early era. One, 3-, and 5-year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non-amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post-OHT. In the late era, AL and ATTR patients had unadjusted 1-year, 3-year, and 5-year survival rates of 100%, which was comparable to non-amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post-OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non-amyloidosis patients.

Management of primary graft failure after heart transplantation: Preoperative risks, perioperative events, and postoperative decisions.

Primary graft failure (PGF) after heart transplantation (HT) is a devastating and unexpected event characterized by failure of the graft to adequately support recipient circulation necessitating high doses of vasopressors and inotropes and/or temporary mechanical circulatory support. Although it represents an increasingly common event in the current era, there remains a high degree of variability in prevalence, reported risk factors, and approach to this clinical entity. The purpose of the current review is to highlight preoperative considerations including known incidence and risk factors, perioperative issues involving the identification and management of PGF, and postoperative decisions related to weaning of mechanical circulatory support and titration of immunosuppressive therapy. Lastly, we highlight future directions in PGF research, involving basic and translational research, that have the potential to uncover novel strategies of risk stratification and treatment. CASE: Our patient is a 53-year-old man with end-stage non-ischemic dilated cardiomyopathy complicated by ventricular tachycardia (VT), post-capillary pulmonary hypertension, and renal insufficiency. After progressing to NYHA Class IV symptoms, he underwent implantation of a durable left ventricular assist device (LVAD) as bridge to transplant (BTT). On device support, he developed recurrent VT resulting in multiple defibrillator discharges and hospital admission for intravenous anti-arrhythmic therapy. He is subsequently upgraded to a higher status on the waiting list. A suitable donor is identified, with an appropriate predicted heart mass and an anticipated ischemic time of <4 hours. He is taken to the operating room, where at the time of anesthesia induction he develops vasodilatory shock, requiring high-dose vasopressors, and cardiopulmonary bypass (CPB) support for dissection. After surgical anastomosis, cross clamp removal and reperfusion, graft function is extremely poor, there is significant bradycardia requiring pacing, and the patient is unable to be weaned successfully from CPB. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is initiated, and the patient is transferred to the intensive care unit. Retrospective flow crossmatch is negative. This patient is suffering from severe primary graft failure.

Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab.

BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 ± 14.7 years) were younger than those receiving basiliximab (55.8 ± 11.2 years) or no induction therapy (54.9 ± 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support.

Impact of preheart transplant spirometry and DCLO measurement on post-transplant pulmonary outcomes.

BACKGROUND: Pulmonary function tests (PFT) are a frequent component of heart transplant evaluation. In cardiac surgery abnormal PFTs, especially reduced DLCO, have been associated with poor outcomes. We sought to evaluate the impact of pretransplant PFTs on post-transplant pulmonary outcomes and patient survival. METHODS: Among the 652 adult heart transplant recipients between January 1, 2010 and July 31, 2021, 462 had PFTs and constituted the patient cohort. Obstructive ventilatory defects (OVD), restrictive ventilatory defects (RVD), and reduced DLCO were defined according to established criteria. The primary outcome was the combined endpoint of a post-transplant pulmonary complication defined as reintubation, postoperative pneumonia, prolonged intubation, or tracheostomy. Secondary outcomes included 90-day all-cause mortality, length of stay, and the odds of individual pulmonary complications. Kaplan-Meier survival analysis, multivariable Cox proportional-hazards regression, and multivariable logistic regression were performed to compare outcomes between the groups. RESULTS: Patients with severe OVD (OR 1.48, 95% CI 1.18-5.23, p = 0.02) or severely reduced DLCO (OR 1.95, 95% CI 1.19-3.20, p = 0.008) had increased odds of post-transplant pulmonary complications. Following multivariable adjustment, severe OVD (aOR 2.67, 95% CI 1.15-6.19, p = 0.02) and severely reduced DLCO (aOR 1.79, 95% CI 1.05-3.04) remained strongly associated with post-transplant pulmonary complications. Patients with any degree of extrinsic RVD, moderate or less OVD, or moderately reduced DLCO or less did not have increased odds of post-transplant pulmonary complications. Ninety-day post-transplant survival was significantly reduced for both severe OVD (97.2% vs 86.5%, p = 0.04) and severely reduced DLCO (97.3% vs 90.4%, p = 0.004). Post-transplant ICU and hospital length of stay were nominally longer for both groups as well. CONCLUSIONS: Severe OVD or severely reduced DLCO on preheart transplant PFTs were associated with increased odds of post-transplant pulmonary complications and early mortality.

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.

Impact of Temporary Percutaneous Mechanical Circulatory Support Before Transplantation in the 2018 Heart Allocation System.

OBJECTIVES: This analysis sought to investigate the waitlist and post-transplant outcomes of individuals bridged to transplantation by using temporary percutaneous endovascular mechanical circulatory support (tMCS) through a status 2 designation (cardiogenic shock and exception). BACKGROUND: The 2018 donor heart allocation policy change granted a status 2 designation to patients supported with tMCS. METHODS: Adult patients in the United Network for Organ Sharing registry after October 18, 2018 who received a status 2 designation for tMCS were included and grouped by their status 2 criteria: cardiogenic shock with hemodynamic criteria (CS-HD), cardiogenic shock without hemodynamic criteria before tMCS (CS-woHD), and exception. Baseline characteristics, waitlist events (death and delisting), and post-transplant outcomes were compared. RESULTS: A total of 2,279 patients met inclusion criteria: 68.6% (n = 1,564) with CS-HD, 3.2% (n = 73) with CS-woHD, and 28.2% (n = 642) with exceptions. A total of 64.2% of patients underwent heart transplantation within 14 days of status 2 listing or upgrade, and 1.9% died or were delisted for worsening clinical condition. Among the 35.8% who did not undergo transplantation following 14 days, only 2.8% went on to receive a left ventricular assist device (LVAD). The 30-day transplantation likelihood was similar among groups: 80.1% for the CS-HD group vs 79.7% for the exception group vs 73.3% for the CS-woHD group; P = 0.31. However, patients who met criteria for CS-woHD had 2.3-fold greater risk of death or delisting (95% CI: 1.10-4.75; P = 0.03) compared with CS-HD patients after multivariable adjustment. Pre-tMCS hemodynamics were not associated with adverse waitlist events. CONCLUSIONS: The use of tMCS is an efficient, safe, and effective strategy as a bridge to transplantation; however, patients with CS-woHD may represent a high-risk cohort. Transition to a durable LVAD was a rare event in this group.

Alterations in the kallikrein-kinin system predict death after heart transplant.

Heart transplantation remains the definitive treatment for end stage heart failure. Because availability is limited, risk stratification of candidates is crucial for optimizing both organ allocations and transplant outcomes. Here we utilize proteomics prior to transplant to identify new biomarkers that predict post-transplant survival in a multi-institutional cohort. Microvesicles were isolated from serum samples and underwent proteomic analysis using mass spectrometry. Monte Carlo cross-validation (MCCV) was used to predict survival after transplant incorporating select recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. We identified six protein markers with prediction performance above AUROC of 0.6, including Prothrombin (F2), anti-plasmin (SERPINF2), Factor IX, carboxypeptidase 2 (CPB2), HGF activator (HGFAC) and low molecular weight kininogen (LK). No clinical characteristics demonstrated an AUROC > 0.6. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA). Differential expression analysis identified enriched pathways prior to transplant that were associated with post-transplant survival including activation of platelets and the coagulation pathway prior to transplant. Specifically, upregulation of coagulation cascade components of the kallikrein-kinin system (KKS) and downregulation of kininogen prior to transplant were associated with survival after transplant. Further prospective studies are warranted to determine if alterations in the KKS contributes to overall post-transplant survival.

Impact of Pretransplant Malignancy on Heart Transplantation Outcomes: Contemporary United Network for Organ Sharing Analysis Amidst Evolving Cancer Therapies.

BACKGROUND: An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression. METHODS: Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated. RESULTS: From 2000 to 2020, the proportion of HT recipients with PTM increased from 3.2% to 8.2%. From 2010 to 2020, 2113 (7.7%) of 27 344 HT recipients had PTM. PTM was associated with higher rates of 1-year mortality after HT (11.9% versus 9.2%; adjusted hazard ratio, 1.25 [95% CI, 1.09-1.44], P=0.001), driven by increased mortality in patients with hematologic PTM (adjusted hazard ratio, 2.00 [95% CI, 1.61-2.48]; P<0.001). For recipients who survived the first year, 5-year survival was similar between patients with and without PTM. Rates of malignancy at 5-years posttransplant were higher in the PTM group (20.4% versus 13.1%; adjusted hazard ratio, 1.57 [95% CI, 1.38-1.79], P<0.001). CONCLUSIONS: Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.

De Novo Human Leukocyte Antigen Allosensitization in Heartmate 3 Versus Heartmate II Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVADs) are associated with the development of antihuman leukocyte antigen (HLA) antibodies, which can create a challenge for future transplantation in these patients. The differential effects of Heartmate 3 (HM3) versus Heartmate II (HMII) on de novo HLA allosensitization remain unknown. Patients who underwent HMII or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing were included in this study. Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels and Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Electronic medical records were reviewed to examine posttransplant outcomes. Thirty-eight HM3 and 34 HMII patients with complete data were followed for 1.5 ± 1.1 years on device support. HM3 and HMII groups had similar age at implant, female gender, ischemic heart failure etiology, bridge strategy at implant, as well as intraoperative and postoperative transfusion requirements. 39.5% of HM3 and 47.1% of HMII patients developed detectable HLA antibodies by Luminex testing (p = 0.516). Development of high-level (mean fluorescence intensity >10,000) antibodies was significantly lower in HM3 than HMII patients (5.3 vs. 20.6%, p = 0.049). CDC PRA testing showed fewer HM3 patients with a positive result (PRA > 0%) than HMII patients (39.4 vs. 70.0%, p = 0.015). Among transplanted patients, those who had developed de novo sensitization on LVAD support showed a trend toward incidence of moderate to severe grade rejection compared with unsensitized patients (23.8 vs. 4.8%, p = 0.078). HM3 is associated with lower risk of de novo HLA sensitization compared with HMII.

Temporal shifts in safety and efficacy profile of mycophenolate mofetil 2 g versus 3 g daily early after heart transplantation.

STUDY OBJECTIVE: Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria ß-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS. MEASUREMENTS: We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing. MAIN RESULTS: A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p = 0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p = 0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p = 0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients. CONCLUSIONS: MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.