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Data from Cardiac Transplant Research Database (CTRD) were analyzed from 1999 to 2006 to examine the effects of different induction strategies at the time of cardiac transplantation. A total of 2090 primary heart transplants were categorized by induction with interleukin-2 receptor blocker (IL-2RB), antithymocyte globulin (ATG), or no induction (NI). Probabilities for rejection and infection were estimated with parametric time-related models. Using these models, hazard was calculated for two theoretical patient profiles, one at lower risk for rejection and higher risk of infection (Profile 1) and higher risk for rejection and lower risk of infection (Profile 2). Of the 2090 transplants, 49.8% (1095) did not receive induction, 27.3% (599) received IL-2RB, and 18.0% (396) received ATG. Profile 1 patients had lower hazard for rejection with IL-2RB compared to ATG and NI (p < 0.01), but at the cost of increased risk of infection (5.0 vs. 1.8 vs. 1.6, respectively, at four wk, p < 0.01). Profile 2 patients experienced a fivefold decreased hazard for rejection when treated with IL-2RB compared with ATG and NI (p < 0.01). In patients at high risk of infection, IL-2RB reduced risk of rejection but at the expense of increased hazard for infection., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Total lymphoid irradiation (TLI) has been used in transplantation for over 20 years and is currently used in a number of major heart transplant centers as a secondary therapy for recalcitrant recurrent rejection or rejection with hemodynamic compromise. The purpose of this study is to evaluate the long-term risks and efficacy of TLI in the treatment of rejection., Methods: Between 1990 and 1996, 73 adult patients (from 211 adult transplant recipients) received TLI for recurrent rejection (71%), rejection with hemodynamic compromise (25%), and rejection with vasculitis (4%). The treatment consisted of 80 cGy twice per week for 5 weeks. Fifty-five patients received at least 80% of the full dose (>640 cGy). Follow-up ended December 31, 2007, comprising a total 18 year experience., Results: Patients treated with TLI exhibited a short-term decrease in hazard for rejection in the first 12 months posttransplantation (relative risk, 0.36) but exhibited increased cumulative rejection over the long term. There were no differences in the rates of infection, allograft coronary disease, or malignancy, but seven patients developed myelodysplasia or acute myelogenous leukemia, four of those being the rare but uniformly fatal acute megakaryocytic leukemia type 7., Conclusions: Patients treated with TLI seemed to experience a reduction in the early hazard for rejection, but long-term outcomes indicate that such patients continued to accumulate more rejection and rejection-death events, likely because these patients were overall at much higher risk for rejection than the other patient groups. We observed minimal long-term complications, except for the unique occurrence of myelodysplasia and acute megakaryocytic leukemia type 7.

Background: The purpose of this study was to estimate the relationship of age, race and gender to rejection and infection across time with respect to age at time of transplant, year of transplantation and immunosuppressive era., Methods: The study group consisted of 10,131 patients from 29 institutions in the Cardiac Transplant Research Database (n = 7,368, from 1990 to 2008) and 32 institutions in the Pediatric Heart Transplant Study (n = 2,763, from 1993 to 2008). The probabilities of rejection death and infection death were estimated with a parametric time-related model and adjusted for gender, ethnicity, date of transplant and age., Results: Actuarial survival by age at transplant showed that, when compared with the majority of patients transplanted between the ages of 30 to 60 years, death due to rejection at 5 years was highest among those transplanted at 10 to 30 years of age (p < 0.0001) and lowest in those transplanted at >60 years of age. Death due to infection at 5 years was highest among patients >60 years of age. Risk factors for death from rejection included age (p < 0.0001), female gender (p = 0.0001), black race (p < 0.0001) and transplant date (p < 0.0001); for infection death, risk factors were age (p < 0.0001), date of transplant (p < 0.0001), age (p = 0.002) and black race (p = 0.01). Modeling with respect to age at time of transplant showed an inverse relationship between infection and rejection death. Among patients transplanted at >60 years of age, there was a steep increase in infection-related deaths and a decrease in rejection deaths. Risk for rejection was elevated among young adults 10 to 30 years of age at time of transplant, particularly for black females., Conclusion: Death from rejection affects adolescents and young adults preferentially, especially black recipients, whereas death from infection preferentially affects patients >60 years of age. Relative risk of infection vs rejection death with respect to recipient age should be considered in therapeutic plans for recurrent rejection, particularly in adolescents and the elderly., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Donor and recipient risk factors for rejection and infection have been well characterized. The contribution of demographic factors, especially age at the time of transplantation to morbidity and mortality due to rejection and infection, is much less well understood., Methods: Using parametric hazard analysis and multivariate risk-factor equations for infection and rejection events, we quantitatively determined the relationship of fundamental demographic variables (age, race and gender) to infection and rejection. These analyses were conducted with respect to date of transplant and age at the time of transplantation. The patient group consisted of all primary heart transplants performed at the University of Alabama at Birmingham during the years 1990 to 2007 (n = 526)., Results: Risk factors for rejection within 12 months post-transplantation were date of transplant (p < 0.0001) and age at the time of transplantation (young adults 10 to 30 years of age, p < 0.0001). Risk factors for infection were date of transplant (p < 0.0001) and age at the time of transplantation (young children and older adults, p < 0.0001). There were three immunosuppressive eras in 1990 to 2007. Notably, although the proportion of patients experiencing rejection and infection events decreased during each successive immunosuppressive era, the relative relationship of infection to rejection, as well as age at the time of transplantation, remained similar into the most recent era. The maximal frequency of rejection events and rejection death occurred among patients transplanted at ages 10 to 30 years. Conversely, the frequency of infection events was minimal within the same group. In the oldest and youngest patients receiving transplants, infection was the predominant cause of death and rates of rejection events decreased., Conclusions: These data show that evolving immunosuppressive strategies have successfully reduced rejection and infection frequencies, and those patients transplanted at 30 to 60 years of age have the lowest frequency of rejection/infection events. However, individuals transplanted at younger or older ages, especially non-white recipients in the 10- to 30-year age group, experience significantly more infection or rejection. Therefore, programs should increase the level of surveillance in these patients and consider modification of immunosuppressive regimens in order to lower the frequency of infection and rejection events., (Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Post-heart transplantation bradycardic syncope and arrest could be due to preferential rejection of the conduction system. We present six heart transplant patients with this presentation, two of whom died. The autopsy of one of those patients demonstrated severe rejection of the conduction system, with only mild rejection throughout the rest of the myocardium. We postulate that aggressive therapy for rejection and pacemaker placement may result in improved survival in heart transplant recipients with this clinical presentation.

Background: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation., Methods: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function., Results: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006)., Conclusions: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

Background: The clinical significance of HLA-directed antibodies newly detected after transplantation (HT) is controversial., Methods: Seventy-one HT recipients consented to enroll. Mean follow-up time was 28 months (range 6-48). Panel reactive antibody (PRA) analysis was performed on posttransplant sera (2 weeks, 1, 2, 3, 6, and 12 months and annually thereafter) using Flow-PRA. A mean of 6.9+/-1.2 serum samples per patient were obtained. Severity of cellular rejection was measured using the ISHLT grading system. Coronary angiography and intravascular ultrasound (IVUS) studies were performed annually to evaluate severity of allograft vasculopathy., Results: Twenty-five recipients had newly detected HLA-directed antibodies during the first year postHT. HLA class I antibodies were detected in 18 patients (25.4%), and class II in 11 patients (15.5%). The majority of donor recipient pairs were HLA mismatched (4.6+/-1.2 of the six major HLA antigens). Only mismatches at HLA-A locus had significant association with de novo posttransplant antibody formation. Length of ischemia time was correlated with early and sustained presence of de novo HLA-directed antibodies postheart transplant. Importantly, an association between de novo HLA-directed antibodies and cellular rejection was notes (P=0.0002). De novo HLA class II directed antibodies are also associated with IVUS documented vasculopathy (P<0.002). Finally, death due to allograft failure is associated with the presence of de novo formed HLA class II directed antibodies (P=0.008)., Conclusions: Identifying the formation of de novo HLA-directed antibodies following heart transplantation may predict allograft outcome. This, in turn, may serve as a tool for individualization of immunosuppression protocols in heart transplant recipients.

Background: Ventricular assist devices (VADs) are commonly used to bridge patients to heart transplantation. Recipients of VADs may develop anti-human histocompatibility leukocyte antigen antibodies, as reflected by elevated panel-reactive antibodies (PRA). The purpose of this study was to evaluate the relationship between bridging with VAD before heart transplantation and development of cellular rejection, humoral rejection, and allograft vasculopathy after transplantation., Methods: Data on all patients who underwent cardiac transplantation between July 1994 and February 2001 at Rush Presbyterian St Luke's Medical Center were retrospectively reviewed. Data collected included sex, age, etiology of cardiomyopathy, percentage panel reactive antibodies (by cytotoxic method), type and duration of mechanical circulatory support, transfusion history, rejection history (both cellular and humoral) after cardiac transplantation, and development of allograft vasculopathy. Cellular rejection was treated when International Society of Heart and Lung and Transplantation Grade 2 or greater in the first 12 months after transplant and Grade 3 or greater after 12 months and treated with intensification of immunosuppression. Humoral rejection was defined clinically as allograft dysfunction by echocardiography without evidence of cellular rejection on endomyocardial biopsy or allograft vasculopathy. Allograft vasculopathy was defined by presence of any degree of luminal narrowing or pruning of distal vessels by coronary arteriography. Statistical analyses were performed by chi-square test, Fisher's exact test, and Wilcoxon rank sum test, as appropriate., Results: Ninety-eight patients underwent cardiac transplantation during the study period (87 men, mean age 49 years, 46 ischemic etiology). Of these, 48 were bridged with HeartMate VAD (20 patients received vented electric device, 28 received pneumatic device). Nineteen percent of VAD patients had a peak pretransplant PRA > or =10% vs 2% of patients without VAD (p = 0.014). PRA > or =10%, use of VAD, or duration of VAD support did not predict development of humoral rejection. Use of VAD did not predict development of cellular rejection or allograft vasculopathy. VAD use was not associated with sudden death after heart transplantation. In the entire group of 98 patients, neither humoral nor cellular rejection predicted development of allograft vasculopathy. Longer ischemic time correlated with increased cellular rejection and humoral rejection after transplantation (p = 0.01)., Conclusions: Some patients bridged to cardiac transplantation with VADs have increased PRA before heart transplantation, but this does not appear to translate into increased risk of either humoral or cellular rejection after transplantation or development of allograft vasculopathy as detected by coronary angiography.