Characteristics and outcomes of heart transplant recipients with a pretransplant history of malignancy.

We aimed to investigate the characteristics and outcomes of HTx recipients with a history of pretransplant malignancy (PTM). Among 1062 HTx recipients between 1997 and 2013, 73 (7.1%) patients had PTMs (77 cancer cases). We analyzed post-HTx outcome, recurrence of PTM, and development of de novo malignancies. Post-HTx outcome included overall survival, 10-year survival, 10-year freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Four most common PTMs were lymphoproliferative disorders (18.2%), prostate cancers (18.2%), non-melanoma skin cancers (18.2%), and breast cancers (13.0%). Median time from PTM and HTx was 9.0 years. During a median follow-up of 8.6 years after HTx, patients with PTM, compared to those without, showed significantly higher incidence of posttransplant malignancies (43.8% vs. 20.8%, p < .001) including 9.6% (n = 7) of PTM recurrences. However, patients with PTM, compared to those without, showed comparable overall survival, 10-year survival, 10-year freedom from CAV, NF-MACE, ATR, ACR, and AMR. Therefore, a history of PTM should not disqualify patients from HTx listing, while further research is necessary for early detection of posttransplant malignancies in these patients.

Eculizumab for antibody-mediated rejection in heart transplantation: A case-control study.

Complement inhibition offers a novel treatment approach for antibody-mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010-2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non-significantly higher inotrope score (208.8 mcg/kg/min vs. 2.6 mcg/kg/min; P = .22), more extracorporeal membrane oxygenation (ECMO) (62.5% vs. 20%; P = .066), and worse 1-year survival (37.5% vs. 60%; P = .63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role.

Intermediate-term outcomes of heart transplantation for cardiac amyloidosis in the current era.

BACKGROUND: Cardiac amyloidosis (CA) has been historically noted with poor outcomes after heart transplant (HTx). However, strict patient selection, appropriate multi-organ transplant, and aggressive post-transplant therapy can result in favorable outcomes. We present the experience in the largest single-center cohort of CA patients post-HTx in the recent era. METHODS: Between January 2010 and December 2018, 51 CA patients underwent HTx-13 light-chain amyloidosis (AL) and 38 transthyretin amyloidosis (ATTR), 49 were included. Endpoints included 3-year survival, freedom from cardiac allograft vasculopathy (CAV), and freedom from non-fatal major adverse cardiac events (NF-MACE). RESULTS: Overall 3-year survival was 81.6% (69.2% for AL and 86% for ATTR) and was comparable to survival for patients transplanted for non-amyloid restrictive cardiomyopathy (RCM) in the same period (89%, p = .46). Three-year freedom from CAV (84% vs. 89%, p = .98), NF-MACE (82% vs. 83%, p = .96), and any-treated rejection (95% vs. 89%, p = .54) were also comparable in both groups. No recurrence in amyloid was noted in endomyocardial biopsies. Six patients (46%) with AL amyloidosis underwent autologous stem cell transplant 1-year post-HTx, and two patients (8%) with variant ATTR-CA underwent combined heart-liver transplant due to cardiac cirrhosis. CONCLUSION: In the current era, both AL and ATTR cardiac amyloidosis patients have acceptable outcomes after heart transplantation.

JC virus-associated nephropathy in a post-heart and -kidney transplantation patient.

JC virus-associated nephropathy is rare in kidney transplant recipients, and even rarer in recipients of other solid organ transplants. We present a case of JC virus-associated nephropathy in a heart-kidney transplant recipient, which to our knowledge is the first case reported in the literature. We discuss the findings on renal biopsy for JC virus nephropathy and our management approach to this rare complication.

Mechanical circulatory support for cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis, typically from abnormal deposition of AL or ATTR amyloid protein, can result in heart failure requiring transplantation (HTx). The role of mechanical circulatory support (MCS) is not well-established. The purpose of this study was to present our experience with MCS in patients with cardiac amyloidosis. METHODS: Consecutive patients with cardiac amyloidosis who received MCS at Cedars-Sinai Medical Center between 2010 and 2018 were reviewed. Clinical characteristics and outcomes were compared to a control group of MCS patients without amyloid matched 2:1 for age and INTERMACS Profile. RESULTS: 11 amyloid patients underwent durable MCS, two with paracorporeal biventricular assist devices and 9 with total artificial hearts. No patients received isolated left ventricular assist device support. By 1 year, 9 (82%) of patients in the MCS-Amyloid group had been transplanted and 2 (18%) had died. In the MCS-No Amyloid group, by 1 year, 8 (36%) of patients had been transplanted, 10 (46%) had died, and 4 (18%) were still living with MCS. CONCLUSIONS: Over a 9-year period, patients with amyloid cardiomyopathy who required MCS at our institution all received durable biventricular MCS. For carefully selected patients, this approach is feasible with acceptable outcomes as bridge to transplantation.

Desensitization strategies in the patient awaiting heart transplantation.

PURPOSE OF REVIEW: The aim of this review is to discuss the impact of antibody sensitization on heart transplant recipients. RECENT FINDINGS: We will discuss the current state of antibody identification, antibody strength and potential antibody pathogenicity. The prevalence of antibody sensitization has increased with increased utilization of mechanical circulatory support (MCS). Data on MCS-related antibody sensitization are reviewed. Important considerations to minimize the prozone effect in antibody testing will be discussed. We present an overview of strategies for desensitization in solid organ transplantation. Current protocols for desensitization therapies will be presented. Finally, future research avenues, including potential further refinement of the detection of human leukocyte antigen (HLA) epitopes to improve donor-recipient immunologic matching, future direction for prevention of donor-specific antibodies (DSAs), the potential role of non-HLA antibodies and further potential refinement of the immune system for management of sensitized patient will be proposed. SUMMARY: Antibody sensitization is a key immunologic issue prior to and after heart transplantation. Therapies aimed at immunomodulation, termed desensitization strategies, may improve immunologic matching at the time of heart transplantation.

Long-term clinical and angiographic outcomes of percutanenous coronary intervention with everolimus-eluting stents for the treatment of cardiac allograft vasculopathy.

BACKGROUND: Percutaneous coronary intervention (PCI) with bare-metal and first-generation drug-eluting stents (DES) for cardiac allograft vasculopathy (CAV) is associated with unexpectedly high restenosis rates and target lesion revascularization (TLR). Long-term outcomes of stenting for CAV using second-generation everolimus-eluting stents (EES) are not established. OBJECTIVE: To evaluate clinical and angiographic outcomes of CAV stenting with EES. METHODS: Patients who underwent PCI with EES for CAV were studied. Surveillance angiography was performed at 6-12 months post-PCI and as indicated. Patient survival, freedom from MACE, binary restenosis, TLR, target vessel revascularization (TVR), and non-TVR are reported. RESULTS: One-hundred and thirty two EES were placed in 113 discrete lesions in 48 patients. Pre-PCI stenosis was 82.1 ± 12.4%, and average stent length and diameter were 16.9 ± 5.7 and 3.0 ± 0.6 mm, respectively. Mean follow-up was 30.7 ± 18.8 months. Time from transplantation to PCI was 9.9 ± 5.1 years. Post-PCI survival at 1 (93.5 ± 3.6%), 2 (91.0 ± 4.3%), and 3 years (83.8 ± 6.3%), and freedom from MACE (87.2 ± 4.9%, 82.3 ± 5.7%, 75.8 ± 6.9%) were high. Binary restenosis at 1 (3.0 ± 1.7%), 2 (6.9 ± 3.2%), and 3 years (10.0 ± 4.3%) mirrored expected rates with EES use in native CAD. One-, two-, and three-year rates of TLR (5.1 ± 2.5%, 14.3 ± 4.6%, and 21.2 ± 6.3%), TVR (17.1 ± 4.5%, 39.0 ± 6.9%, and 46.2 ± 7.8%), and NTVR (26.3 ± 5.4%, 55.4 ± 7.0%, and 58.0 ± 7.0%) remain high. Diabetes was associated with an increased hazard ratio for binary restenosis 6.084 (95% CI 1.271-29.133, P = 0.024). CONCLUSIONS: PCI strategy using EES in the treatment of CAV was associated with a low binary restenosis rate, a high survival rate, and a high rate of freedom from MACE. However, at 3 years, TLR and TVR rates appeared similar to rates observed with first-generation DES. © 2016 Wiley Periodicals, Inc.

Prolonged corrected QT interval in the donor heart: Is there a risk?

BACKGROUND: Assessing the QT interval in donors is important to exclude long QT syndrome as the cause of death. A donor heart with a corrected QT (QTc ) >500 milliseconds is often concerning. We sought to evaluate first year outcomes for donors with a QTc interval >500 milliseconds. METHODS: Between 2010 and 2014, we assessed 257 donor hearts for QTc interval >500 milliseconds. Post-transplant outcomes included 1-year survival, 1-year freedom from any-treated rejection, 1-year freedom from cardiac allograft vasculopathy (CAV) defined as stenosis ≥30% by angiography, and 1-year freedom from nonfatal major adverse cardiac events. RESULTS: Patients with QTc interval >500 milliseconds had a significantly lower 1-year freedom from CAV development. There were no significant differences for other outcomes. A significantly higher percentage of donors with QTc >500 milliseconds had a stroke or subarachnoid hemorrhage. Multivariate analysis found that donor QTc >500 milliseconds was associated with a 6.7-fold increased risk of developing CAV (P=.029, 95% CI 1.21-36.6) after adjusting for other known risk factors. CONCLUSION: QTc >500 milliseconds in the donor heart appears to be an independent risk factor for the development of early CAV after heart transplantation possibly due to a higher immunological risk.

Elevated immune monitoring early after cardiac transplantation is associated with increased plaque progression by intravascular ultrasound.

BACKGROUND: Immune monitoring (IM) has not been shown to be associated with cardiac allograft vasculopathy (CAV). METHODS: Maximal intimal area, average percent stenosis, plaque volume, and maximal intimal thickness (MIT) were measured for matched baseline and one-yr IVUS segments in a blinded fashion. Patients were divided into quartiles by IM scores and outcomes compared. Optimal IM cutoff was determined. RESULTS: IM assays were measured at 63.7 ± 16.4 d after transplantation in fifty patients. Progression of maximal intimal area (p = 0.005), average percent stenosis (p < 0.001), plaque volume (p = 0.005), and MIT (p = 0.001) were increased across the quartiles. An optimal IM assay cutoff of 406.0 ng ATP/mL demonstrated a sensitivity of 66.7% and specificity of 94.3% for predicting rapid progression of MIT ≥ 0.5 mm. Mean IM scores for Group 1 vs. Group 2 were 176.4 ± 102.2 and 616.3 ± 239.5 ngATP/mL, respectively. Rapid progression of MIT ≥ 0.5 mm occurred in 5/38 patients (13.2%) in Group 1 vs. 10/12 patients (83.3%) in Group 2 (p < 0.001). The risk ratio for rapid progression with elevated IM was 11.7 (p < 0.001). CONCLUSION: Elevated early IM scores are associated with progression of CAV by IVUS. These findings suggest the potential of IM for tailoring of immunosuppressive regimens to minimize the progression of CAV in high-risk patients.

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.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

BACKGROUND: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF. METHODS: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity. RESULTS: The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L). CONCLUSIONS: The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

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.

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.

Characteristics, outcomes, and predictors of de novo malignancy after heart transplantation.

Background: Post-transplant malignancy (PTM) causes long-term morbidity and mortality in heart transplant (HTx) recipients. However, the detailed characteristics or predictors of PTM are not well-known. We evaluated the incidence, characteristics, long-term outcomes, and predictors of de novo PTM using a single center large-volume database. Methods: We retrospectively analyzed the types and characteristics of de novo PTM in 989 patients who underwent HTx. Univariate and multivariate logistic regression analyses were used for the PTM prediction model. Results: Two hundred and six patients (20.8%) had de novo PTMs (241 cancers) during a median follow-up of 11.5 years. PTM patients were older than non-PTM patients, received immunosuppressive therapy for a longer period, and were more likely to be male and white. Skin cancers were the most frequent types of malignancy (60.6%) followed by prostate (9.5%), lung (7.1%), and breast (4.1%) cancers. Although most cancers (88.8%) were surgically resected at initial presentation, about half (47.3%) recurred or progressed. Patients with skin cancer and non-skin cancer had significantly lower overall survival (P < 0.001) than patients without cancer. Older age (P < 0.001), white race (P = 0.001), and longer time receiving immunosuppressive therapy (P < 0.001) were independent predictors for PTM. Conclusion: Older age, white race, and longer administration of immunosuppressive therapies were independent risk factors for PTM, which was associated with increased mortality. Further research is necessary for the prevention and early detection of PTM in HTx recipients.

Post-transplantation outcomes of sensitized patients receiving durable mechanical circulatory support.

BACKGROUND: Sensitization, defined as the presence of circulating antibodies, presents challenges, particularly in patients undergoing heart transplantation (HTx) bridged with durable mechanical circulatory support (MCS). We aimed to investigate the post-transplantation outcomes of sensitized MCS patients. METHODS: Among 889 consecutively enrolled heart transplant (HTx) recipients between 2010 and 2018, 86 (9.7%) sensitized MCS patients (Group A) were compared with sensitized non-MCS patients (Group B, n = 189), non-sensitized MCS patients (Group C, n = 162), and non-sensitized non-MCS patients (Group D, n = 452) regarding post-HTx outcomes, including the incidence of primary graft dysfunction (PGD), 1-year survival, and 1-year freedom from antibody-mediated rejection (AMR). RESULTS: Sensitized MCS patients (Group A) showed comparable rates of PGD, 1-year survival, and 1-year freedom from AMR with Groups C and D. However, Group A showed significantly higher rates of 1-year freedom from AMR (95.3% vs 85.7%, p = 0.02) and an earlier decline in panel-reactive antibody (PRA) levels (p < 0.01) than sensitized non-MCS patients (Group B). Desensitization therapy effectively reduced the levels of PRA in both Groups A and B. When Group A was further divided according to the presence of preformed donor-specific antibodies (DSA), patients with preformed DSA showed significantly lower rates of 1-year freedom from AMR than those without (84.2% vs 98.5%, p = 0.01). CONCLUSIONS: Sensitized MCS patients showed significantly lower rates of AMR and an earlier decline in PRA levels following HTx than sensitized non-MCS patients. Removal of MCS at the time of transplantation might underlie these observations.

Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients.

Natural killer T (NKT) cells are distinct glycolipid reactive innate lymphocytes that are implicated in the resistance to pathogens and tumors. Earlier attempts to mobilize NKT cells, specifically, in vivo in humans met with limited success. Here, we evaluated intravenous injection of monocyte-derived mature DCs that were loaded with a synthetic NKT cell ligand, alpha-galactosyl-ceramide (alpha-GalCer; KRN-7000) in five patients who had advanced cancer. Injection of alpha-GalCer-pulsed, but not unpulsed, dendritic cells (DCs) led to >100-fold expansion of several subsets of NKT cells in all patients; these could be detected for up to 6 mo after vaccination. NKT activation was associated with an increase in serum levels of interleukin-12 p40 and IFN-gamma inducible protein-10. In addition, there was an increase in memory CD8+ T cells specific for cytomegalovirus in vivo in response to alpha-GalCer-loaded DCs, but not unpulsed DCs. These data demonstrate the feasibility of sustained expansion of NKT cells in vivo in humans, including patients who have advanced cancer, and suggest that NKT activation might help to boost adaptive T cell immunity in vivo.

Heart Transplant Immunosuppression Strategies at Cedars-Sinai Medical Center.

Heart transplant is the optimal treatment for selected patients with end-stage heart failure. Immunosuppression after heart transplantation has significantly reduced the incidence of rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes as well. The goal of induction therapy is to provide intense immunosuppression when the risk of allograft rejection is highest. Most maintenance immunosuppressive protocols employ a 3-drug regimen consisting of a calcineurin inhibitor, an antimetabolite agent and glucocorticoids. The management of rejection proceeds in a stepwise fashion based on the severity of rejection detected on biopsy and the patient's clinical presentation. This review will cover induction, maintenance, rejection therapy and some special considerations including sensitization, renal sparing protocol, and corticosteroid weaning. It will end in consideration of potential future directions in immunosuppressive strategies to promote patient and graft survival.

Total Artificial Heart as Bridge to Cardiac Retransplantation.

Mechanical circulatory support has been performed as a bridge to cardiac retransplantation in selected patients with graft failure. However, there is limited published experience on the use and potential benefit of the total artificial heart (TAH) as a bridge to cardiac retransplantation. We report on our institutional experience with 3 patients that received TAH as a bridge to retransplant, with 1 patient surviving post-retransplantation. This case series demonstrates the high-risk nature of this undertaking in cardiac retransplant candidates and highlights the issue of sensitization portending greater risk for poor outcomes after TAH as bridge to retransplantation.

Heart Transplantation for Giant Cell Myocarditis: A Case Series.

BACKGROUND: Giant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown. PURPOSE: To describe the post-transplant survival of patients with GCM at a large transplant center. METHODS: Seven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone. RESULTS: One patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant. CONCLUSIONS: Patients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.