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.

Heart transplantation in patients from socioeconomically distressed communities.

BACKGROUND: Studies examining heart transplantation disparities have focused on individual factors such as race or insurance status. We characterized the impact of a composite community socioeconomic disadvantage index on heart transplantation outcomes. METHODS: From the Scientific Registry of Transplant Recipients (SRTR), we identified 49,340 primary, isolated adult heart transplant candidates and 32,494 recipients (2005-2020). Zip code-level socioeconomic disadvantage was characterized using the Distressed Community Index (DCI: 0-most prosperous, 100-most distressed) based on education, poverty, unemployment, housing vacancies, median income, and business growth. Patients from distressed communities (DCI ≥ 80) were compared to all others. RESULTS: Patients from distressed communities were more often non-white, less educated, and had public insurance (all p < 0.01). Distressed patients were more likely to require ventricular assist devices at listing (29.4 vs 27.1%) and before transplant (44.8 vs 42.0%, both p < 0.001), and they underwent transplants at lower-volume centers (23 vs 26 cases/year, p < 0.01). Distressed patients had higher 1-year waitlist mortality or deterioration (12.3% [95% confidence interval (CI) 11.6-13.0] vs 10.9% [95% CI 10.5-11.3]) and inferior 5-year survival (75.3% [95% CI 74.0-76.5] vs 79.5% [95% CI 79.0-80.0]) (both p < 0.001). After adjustment, living in a distressed community was independently associated with an increased risk of waitlist mortality or deterioration hazard ratio (HR 1.10, 95% CI 1.02-1.18) and post-transplant mortality (HR 1.13, 95% CI 1.06-1.20). CONCLUSIONS: Patients from socioeconomically distressed communities have worse waitlist and post-transplant mortality. These findings should not be used to limit access to heart transplantation, but rather highlight the need for further studies to elucidate mechanisms underlying the impact of community-level socioeconomic disparity.

Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

IgM marks persistent IgG anti-human leukocyte antigen antibodies in highly sensitized heart transplant patients.

BACKGROUND: Sensitization to human leukocyte antigens (HLA) is a persistent problem in heart transplant (HT) candidates. We sought to characterize the anti-HLA antibody and circulating B cell repertoire in a cohort of highly sensitized HT candidates. METHODS: We assessed immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-HLA antibodies using Luminex single antigen bead assays in a cohort of 11 highly sensitized (HS; calculated panel reactive antibody ≥ 90%) and 3 mildly sensitized (MS) candidates. We also performed B cell receptor repertoire sequencing (BCRseq) in HS candidates and 33 non-candidate controls. HLA antibody strength was measured by mean fluorescence intensity (MFI). RESULTS: We found that IgM anti-HLA antibodies were present in all HS candidates, but with a lower breadth and strength as compared to IgG. When anti-HLA IgG specificities intersected with IgM, binding strength was higher. In contrast, there were IgM but no intersecting IgG specificities for the MS group. In four candidates in the HS group, IgG anti-HLA antibodies decreased in both breadth and strength after HT, but the decrease in strength was smaller if the IgG possessed a specificity that intersected with pre-transplant IgM. BCRseq revealed larger B cell clonotypes in HS candidates but similar diversity as compared to controls. CONCLUSIONS: IgM marks IgG anti-HLA antibodies with higher strength before HT and persistence after HT. The presence of IgM intersecting IgG for an anti-HLA specificity may be a useful approach to determine which donor HLA should be avoided for a sensitized candidate.

Wild-Type Transthyretin Cardiac Amyloidosis in a Transplanted Heart.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is more prevalent than appreciated in the elderly. We present the case of an 88-year-old woman who underwent heart transplantation for ischemic cardiomyopathy and then presented 21 years later with new onset atrial flutter, found on endomyocardial biopsy to have new ATTRwt-CM. (Level of Difficulty: Advanced.).

Successful Reuse of a Donor Heart.

At a time when transplantable organs are in a shortage, few cases have noted the reuse of donor hearts in a second recipient in an effort to expand the donor network. Here, we present a case in which an O Rh-positive donor heart was first transplanted into a B Rh-positive recipient and later successfully retransplanted into a second O Rh-positive recipient 10 days after the initial transplant at the same medical center. On postoperative day 1, the first recipient, a 21-year-old man with nonischemic cardiomyopathy, sustained a devastating cerebrovascular accident with progression to brain death. With preserved left ventricle and mildly depressed right ventricle function, the heart was allocated to the second recipient, a 63-year-old male patient with familial restrictive cardiomyopathy. The bicaval technique was used, and the total ischemic time was 100 minutes. His postoperative course was uncomplicated with no evidence of rejection on 3 endomyocardial biopsies. Follow-up transthoracic echocardiogram revealed a left ventricular ejection fraction of 60% to 70%. Seven months posttransplant, the second recipient was doing well with appropriate left and right ventricular function. With careful organ selection, short ischemic time, and proper postoperative care, retransplant of donor hearts may be an option for select patients in need of heart transplant.

Three year post heart transplant outcomes of desensitized durable mechanical circulatory support patients.

BACKGROUND: The risks and benefits of desensitization therapy (DST) in highly sensitized mechanical circulatory support (MCS) patients are not well known. We investigated 3 year post-transplant outcomes of desensitized durable MCS patients. METHODS: Among 689 consecutively enrolled heart transplantation recipients between 2010 and 2016, we categorized them into Group A (desensitized MCS patients, n = 21), Group B (desensitized non-MCS patients, n = 28) and Group C (all nondesensitized patients, n = 640). Post-transplant outcomes included the incidence of primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, antibody mediated rejection (AMR) and infectious complications. RESULTS: The types of DST in Groups A and B were similar and included combinations of rituximab/intravenous immunoglobulin and plasmapheresis/bortezomib. Group A, compared with Group B, showed significantly higher pre-DST panel reactive antibody (PRA) (92.2 ± 9.8 vs. 83.3 ± 15.6, P = 0.007) and higher PRA reduction after DST (-22.2 ± 26.9 vs. -6.3 ± 7.5, P = 0.015). Groups A and C showed comparable primary graft dysfunction, 3-year survival, freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any treated rejection, acute cellular rejection, and AMR. Although statistically not significant, Group A showed numerically higher 3-year freedom from AMR than Group B. Infectious complications were similar in both Groups A and B. CONCLUSIONS: DST for MCS patients showed significant PRA reduction, resulting in an expansion of the donor pool. The post-transplant outcome of desensitized MCS patients showed comparable clinical outcomes to non-desensitized control patients in the same study period, revealing the safety and efficacy of DST.

Intermediate-term outcomes of complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation. We previously reported favorable 1-year outcomes of complement inhibition at transplant in highly sensitized recipients. We now report a longer follow-up. In this single-arm trial (NCT02013037), 20 patients with panel reactive antibodies ≥70% and preformed donor-specific antibodies received eculizumab during the first 2 months post-transplant. The primary end-point was antibody-mediated rejection ≥ pAMR2 and/or left ventricular dysfunction. The median follow-up was 4.8 years. Beyond the first year post-transplant, there were no episodes of pAMR2 or greater and no Left Ventricular (LV) dysfunction. There were 3 deaths, 1 episode of pAMR1, and 1 patient with minimal de novo cardiac allograft vasculopathy. Compared to a matched control group, we observed a nonstatistically significant benefit of eculizumab with a lower incidence of the primary end-point or death (primary end-point: hazard ratio = 0.50, 95% confidence interval = 0.15-1.67, and p = 0.26; mortality: hazard ratio = 0.51, 95% confidence interval = 0.13-2.07, and p = 0.35). Our results support the utility of complement inhibition for high-immunological-risk recipients. CLINICAL TRIAL REGISTRATION: ClinincalTrials.gov, NCT02013037. https://clinicaltrials.gov/ct2/show/NCT02013037?term=eculizumab&cond=heart+transplantation&draw=2&rank=1.

Blood Type A1 Mismatch Does Not Affect Heart Transplant Outcomes at One Year.

There are subtypes within blood type A, termed non-A1, that have reduced expression of A antigen on cell surfaces. This can result in the development of anti-A1 antibodies. There is limited information regarding the impact of this in heart transplant (HTx) recipients. We conducted a single-center cohort study of 142 Type A HTx recipients in which we compared outcomes of a match group (an A1/O heart into an A1 recipient or a non-A1/O heart into a non-A1 recipient) with a mismatch group (an A1 heart into a non-A1 recipient or a non-A1 heart into an A1 recipient). At one year post-transplant, there were no differences between the groups in survival, freedom from non-fatal major adverse cardiovascular events, freedom from any treated rejection, or freedom from cardiac allograft vasculopathy. There was an increased hospital length of stay in the mismatch group (13.5 vs. 17.1 days, p = 0.04). Our study showed that A1 mismatch was not associated with worse outcomes at one year post-HTx.

Temporary Mechanical Circulatory Support in Patients with Cardiogenic Shock: Clinical Characteristics and Outcomes.

Patients with cardiogenic shock may require stabilization with temporary mechanical circulatory support (tMCS) to assess candidacy for definitive therapy, including heart transplantation (HTx) or durable MCS, and/or maintain stability while on the HTx waiting list. We describe the clinical characteristics and outcomes of patients with cardiogenic shock who underwent intra-aortic balloon pump (IABP) vs. Impella [Abiomed, Danvers, MA, USA] placement at a high-volume advanced heart failure center. We assessed patients ≥ 18 years who received IABP or Impella support for cardiogenic shock from 1 January 2020 to 31 December 2021. Ninety patients were included, 59 (65.6%) with IABP and 31 (34.4%) with Impella. Impella was used more frequently in less stable patients, as evidenced by higher inotrope scores, greater ventilator support, and worse renal function. While patients on Impella support had higher in-hospital mortality, despite the worse cardiogenic shock in patients for whom clinicians chose Impella support, over 75% were successfully stabilized to recovery or transplantation. Clinicians elect Impella support over IABP for less stable patients, though a high proportion are successfully stabilized. These findings demonstrate the heterogeneity of the cardiogenic shock patient population and may inform future trials to assess the role of different tMCS devices.

Donor hyperoxia is a novel risk factor for severe cardiac primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). Donor risk factors for the development of PGD are incompletely characterized. Donor management goals (DMG) are predefined critical care endpoints used to optimize donors. We evaluated the relationship between DMGs as well as non-DMG parameters, and the development of PGD after HT. METHODS: A cohort of HT recipients from 2 transplant centers between 1/1/12 and 12/31/19 was linked to their respective donors in the United Network for Organ Sharing (UNOS) DMG Registry (n = 1,079). PGD was defined according to modified ISHLT criteria. Variables were subject to univariate and multivariable multinomial modeling with development of mild/moderate or severe PGD as the outcome variable. A second multicenter cohort of 4,010 donors from the DMG Registry was used for validation. RESULTS: Mild/moderate and severe PGD occurred in 15% and 6% of the cohort. Multivariable modeling revealed 6 variables independently associated with mild/moderate and 6 associated with severe PGD, respectively. Recipient use of amiodarone plus beta-blocker, recipient mechanical circulatory support, donor age, donor fraction of inspired oxygen (FiO2), and donor creatinine increased risk whereas predicted heart mass ratio decreased risk of severe PGD. We found that donor age and FiO2 ≥ 40% were associated with an increased risk of death within 90 days post-transplant in a multicenter cohort. CONCLUSIONS: Donor hyperoxia at heart recovery is a novel risk factor for severe primary graft dysfunction and early recipient death. These results suggest that excessive oxygen supplementation should be minimized during donor management.

Detection and management of HLA sensitization in candidates for adult heart transplantation.

Heart transplantation (HT) remains the preferred therapy for patients with advanced heart failure. However, for sensitized HT candidates who have antibodies to human leukocyte antigens , finding a suitable donor can be challenging and can lead to adverse waitlist outcomes. In recent years, the number of sensitized patients awaiting HT has increased likely due to the use of durable and mechanical circulatory support as well as increasing number of candidates with underlying congenital heart disease. This State-of-the-Art review discusses the assessment of human leukocyte antigens antibodies, potential desensitization strategies including mechanisms of action and specific protocols, the approach to a potential donor including the use of complement-dependent cytotoxicity, flow cytometry, and virtual crossmatches, and peritransplant induction management.

Assessment and management of allosensitization following heart transplant in adults.

Immunological injury to the allograft, specifically by antibodies to de novo donor specific human leukocyte antigen (dnDSA) and antibody mediated injury and rejection are the major limitations to graft survival after heart transplantation (HT). As such, our approach to allosensitization remains limited by the inability of contemporaneous immunoassays to unravel pathogenic potential of dnDSA. Additionally, the role of dnDSA is continuously evaluated with emerging methods to detect rejection. Moreover, the timing and frequency of dnDSA monitoring for early detection and risk mitigation as well as management of dnDSA remain challenging. A strategic approach to dnDSA employs diagnostic assays to determine relevant antibodies in conjunction with clinical presentation and injury/rejection of allograft to tailor therapeutics. In this review, we aim to outline contemporary knowledge involving detection, monitoring and management of dnDSA after HT. Subsequently, we propose a diagnostic and therapeutic approach that may mitigate morbidity and mortality while balancing adverse reactions from pharmacotherapy.

The impact of the United Network of Organ Sharing allocation change on waitlist trajectories of inpatients listed with inotropic support: A single-center analysis.

BACKGROUND: In the United Network of Organ Sharing (UNOS) allocation scheme prior to October 18, 2018, heart transplant (HTx) candidates with extracorporeal membrane oxygenation (ECMO), temporary mechanical circulatory support (MCS), or pulmonary artery (PA) catheter inotropic support all received Status 1A priority. In revised scheme, patients with PA catheter and inotropic support are Status 3 after those on ECMO (Status 1) or temporary MCS (Status 2). We examined the impact of the allocation change on HTx candidates listed Status 1A versus Status 3 at a high-volume transplant center. METHODS: Between January 2017 and January 2021, 75 patients were listed with a PA catheter and inotropic support prior to the allocation change (Era 1) and 48 were listed after (Era 2). Clinical characteristics and outcomes were compared for these 123 patients. RESULTS: Heart transplant (HTx) candidates in Era 2 had higher median inotrope doses at listing. There was no significant difference in inpatient wait list days (12 vs. 20 days, P = .15), transition to temporary MCS (33.3% vs. 22.7%, P = .15), or wait list mortality (6.3% vs. 4.0%, P = .68). There was also no significant difference in survival to transplantation (91.7% vs. 94.7%, P = .71). There were no differences in post-transplant outcomes including 1-year survival (88.6% vs. 93.0%, P = .38). CONCLUSION: At a high-volume transplant center, the UNOS allocation change did not result in increased wait list time, use of temporary MCS, or mortality on the waitlist or post-transplant for candidates on inotropic support with continuous hemodynamic monitoring.

Coronary Vasospasm Causing Chest Pain in Early Postoperative Heart Transplantation.

Coronary vasospasm is a rare complication after heart transplant. Due to denervation of the donor heart, patients are typically asymptomatic but may present with cardiac arrhythmias or cardiac arrest. We present a patient with a recent heart transplant who experienced chest pain and was found to have coronary vasospasm.

Dapsone-Associated Anemia in Heart Transplant Recipients with Normal Glucose-6-Phosphate Dehydrogenase Activity.

Dapsone is considered an alternative for pneumocystis jirovecii pneumonia (PJP) prophylaxis in sulfa-allergic or -intolerant transplant patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Despite normal G6PD activity, anemia can still occur while on dapsone therapy. We retrospectively reviewed heart transplant patients transplanted at our center between January 2016 and June 2018 and identified those taking dapsone prophylaxis. There were 252 heart transplant recipients at our center between January 2016 and June 2018. 36 patients received dapsone prophylaxis. All had normal G6PD activity assessed prior to dapsone initiation. 8 (22%) patients developed significant anemia attributed to dapsone: 2 were hospitalized for anemia, 1 of whom required blood transfusion. These patients had a median reduction in hemoglobin of 2.1 g/dL from baseline prior to dapsone initiation. Overt evidence of hemolysis was present in six patients. Once dapsone was discontinued, Hgb increased by at least 2 g/dL in a median of 30 days. Anemia from dapsone may occur in a significant proportion of patients despite normal G6PD activity and resulting in significant morbidity. Careful monitoring of transplant recipients on dapsone prophylaxis is warranted, as well as consideration of alternative agents.