Heart Transplant Survival Research Articles

Increasing Pretransplant Panel Reactive Antibodies Worsens Survival in A Contemporary Heart Transplantation Cohort

Background Allosensitization as measured by presence of panel reactive antibodies (PRA) negatively impacts survival in adult heart transplant (HT) recipients. Questions remain whether these trends remain in more contemporary cohorts. We examined the interaction between long-term survival and pre-transplant PRA level in HT recipients from 2000-2018. Methods We identified adult HT recipients between 2000 and 2018 who had a pretransplant PRA in the Scientific Registry of Transplant Recipients. Study cohort was divided into groups with PRA levels; group with 0%, 1-10%, 11-24% and ≥25% PRA levels. We compared 3- and 5-year survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk adjusted influence of PRA category and PRA as a continuous value on survival. Results We included 24,655 HT recipients. PRA was 0% in 17,391 (70.5%) recipients, 1-10% in 3,331 (13.5%) recipients, 11-24% in 1,330 (5.4%) recipients, and ≥25% in 2,603 (10.6%) recipients. Patients with a PRA ≥25% were younger, had fewer comorbidities, and were more likely to be on ECMO or LVAD prior to HT. Unadjusted 3- and 5-year estimated survival was lower with increasing PRA category (Figure). After risk-adjustment, 5-year survival was higher for the 0% cohort compared to the 1-10% (HR 1.10, 95% CI 1.02-1.18), 11-24% (HR 1.20, 95%CI 1.08-1.34), and ≥25% (HR 1.16, 95% CI 1.07-1.26). When analyzed continuously, increasing PRA was associated with a lower survival (HR 1.003, 95% CI 1.002-1.005). Sensitivity analysis of those transplanted from 2013-2018 showed similar results. Conclusions In this contemporary cohort of HT recipients, increasing pretransplant PRA was associated with lower survival. Given the appreciable portion of HT recipients with elevated PRA, improvements in recipient selection and HT management may help improve outcomes.

Heart Transplantation Survival Outcomes of HIV Positive and Negative Recipients

In the era of antiretroviral therapy, HIV-positive patients have reduced mortality from HIV infection and increased morbidity from end-stage heart failure. The number of HIV-positive heart transplantation recipients remains scant. Long-term survival has not been rigorously studied. We compared survival outcomes of heart transplantation in HIV-positive recipients with those of HIV-negative recipients. Clinical data from all adult heart transplantations were extracted from the United Network for Organ Sharing dataset. The impact of recipient HIV status was analyzed with Cox proportional hazards modeling, 1:3 propensity score matching, and Kaplan-Meier survival analysis. Seventy-five HIV-positive recipients and 29,848 HIV-negative recipients were identified. Race distributions differed between the recipient groups, with black patients comprising a larger proportion of the HIV-positive recipient group (46.7% vs 20.9%, P < .001). The mean year of transplant was significantly later in the HIV-positive recipient group. The rate of acute rejection in the HIV-positive group was higher than in the HIV-negative group (38.7% vs 17.7%, P < .001), as was rate of antirejection treatment administration such as intravenous immunoglobulin or plasmapheresis (26.7% vs 10.4%, P < .001). There was no difference in 30-day, 1-year, and 5-year survival of HIV-positive recipients vs HIV-negative recipients. Recipient HIV infection was not a significant covariate in predicting survival in a Cox proportional hazards model. Short-term and moderate-term survival after heart transplantation is similar for HIV-positive recipients and HIV-negative recipients, although data are very limited. This finding suggests that HIV-positive recipients should not be excluded from transplant candidacy solely based on HIV serostatus.

EXTERNAL VALIDATION OF CURRENT INTERNATIONAL SHORT- AND LONG-TERM PROGNOSTIC MODELS FOR SURVIVAL IN HEART TRANSPLANT RECIPIENTS USING MARGINAL DONOR HEARTS AT SINGLE JAPANESE CENTER

Introduction: Current prognostic models to predict survival in heart transplant (HTx) recipients, which are ‘Index for Mortality Prediction After Cardiac Transplantation (IMPACT) model’ using the recipient-factor and ‘International Heart Transplantation Survival Algorithm (IHTSA) model’ using both recipient- and donor-factors, have been verified the good adaptation on the global registry data in HTx recipients. In Japan, extremely serious donor shortages will necessitate a long waiting period, and using more marginal donor hearts. But several donor risk factors for HTx were not included enough in these prognostic models. It is unclear whether these prognostic models can be adapted with HTx using more marginal donor hearts. This study aimed to validate the usefulness of IMPACT and IHTSA models for the prediction of long-term mortality in recipients transplanted marginal hearts. Materials and Methods: Consecutive 126 adult HTx recipients who underwent HTx between May 1999 and February 2020 were included in this study. The risk score based on IMPACT model was calculated for each recipient. And we entered the clinical data of each recipient and donor into the web-based calculator of the IHTSA model and calculated predicted 5-year mortality rate based on the IHTSA model. The discrimination for survival in our subjects was evaluated using Harrell’s concordance index (C-index). Survival analysis was conducted to evaluate the actual mortality rate in our subjects. Results and Discussion: Over median follow-up of 4.9 years [interquartile range (IQR); 2.6-9.0 years] after HTx, 8 recipients (6.3%) died during follow-up. The IMPACT score was median of 6.0 (IQR; 3.0-8.0), and the estimated 5-year mortality rate based on IHTSA model was median of 0.25 (IQR; 0.21-0.29). The predicted versus actual 5-year survival rates were 73.7% versus 95.8%. The discrimination (C-index) for survival using IMPACT score and 5-year mortality rate based on the IHTSA model were 0.689 and 0.720, respectively. Conclusion: This study validated a usefulness of two current prognostic models, IMPACT and IHTSA, for survival in HTx recipients using marginal donor hearts. Our results suggest that these models might be useful even in HTx recipients using highly marginal donor hearts. Further validation is needed to adapt an appropriate prognostic model in such clinical situation as serious donor shortages.

A two-stage machine learning framework to predict heart transplantation survival probabilities over time with a monotonic probability constraint

The overarching goal of this paper is to develop a modeling framework that can be used to obtain personalized, data-driven and monotonically constrained probability curves. This research is motivated by the important problem of improving the predictions for organ transplantation outcomes, which can inform updates made to organ allocation protocols, post-transplantation care pathways, and clinical resource utilization. In pursuit of our overarching goal and motivating problem, we propose a novel two-stage machine learning-based framework for obtaining monotonic probabilities over time. The first stage uses the standard approach of using independent machine learning models to predict transplantation outcomes for each time-period of interest. In the second stage, we calibrate the survival probabilities over time using isotonic regression. To show the utility of our framework, we applied it on a national registry of U.S. heart transplants from 1987 to 2016. The first stage produces an area under the receiver operating curve (AUC) between 0.60 and 0.71 for years 1–10. While the 1-year prediction AUC result is comparable to the reported results in the literature, our 10-year AUC of 0.70 is higher than the current state-of-the-art results. More importantly, we show that the application of isotonic regression to calibrate the survival probabilities for each patient over the 10-year period guarantees monotonicity, while capitalizing on the data-driven and individualized nature of machine learning models. To promote future research, our code and analysis are publicly available on GitHub. Furthermore, we created a web app titled “H-TOP: Heart Transplantation Outcome Predictor” to encourage practical applications.

Heart Transplantation: An In-Depth Survival Analysis

ObjectivesThis study aims to understand the complex factors affecting heart transplant survival and to determine the importance of possible sex-specific risk factors. BackgroundHeart transplant allocation is primarily focused on preventing waitlist mortality. To prevent organ wastage, future allocation must balance risk of waitlist mortality with post-transplantation mortality. However, more information regarding risk factors after heart transplantation is needed. MethodsWe included all adults (30,606) in the Scientific Registry of Transplant Recipients database who underwent isolated heart transplantation from January 1, 2004, to July 1, 2018. Mortality (8,278 deaths) was verified with the complete Social Security Death Index with a median follow-up of 3.9 years. Temporal decomposition was used to identify phases of survival and phase-specific risk factors. The random survival forests method was used to determine importance of mortality risk factors and their interactions. ResultsWe identified 3 phases of mortality risk: early post-transplantation, constant, and late. Sex was not a significant risk factor. There were several interactions predicting early mortality such as pretransplantation mechanical ventilation with presence of end-organ function (bilirubin, renal function) and interactions predicting later mortality such as diabetes and older age (donor and recipient). More complex interactions predicting early-, mid-, and late-mortality existed and were identified with machine learning (i.e., elevated bilirubin, mechanical ventilation, and dialysis). ConclusionsPost–heart transplant mortality risk is complex and dynamic, changing with time and events. Sex is not an important mortality risk factor. To prevent organ wastage, end-organ dysfunction should be resolved before transplantation as much as possible.

Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients (IronIC) - A Randomized, Double Blind, Controlled Trial

Heart transplant recipients have reduced exercise capacity despite preserved graft function. Numerous mechanisms may contribute to this impaired exercise tolerance, one of which may be iron deficiency (ID). Among our heart transplant survivors, 48 % have ID. The IronIC trial (NCT03662789) was designed to test the hypothesis that intravenous (i.v.) iron therapy will improve exercise capacity assessed by peak oxygen consumption. 102 stable, cardiac transplant recipients with ID, defined as serum ferritin <100 µg/l, or ferritin between 100 and 300 µg/l in combination with transferrin saturation <20 %, have been randomized in a 1:1 manner to treatment with intravenous iron isomaltoside, 20 mg/kg, or NaCl. Care was taken to blind patients and personnel to the color of the infusate. All participants provided written, informed consent. Exclusion criteria included hemoglobin <100 g/l, red blood cell disorders, end-stage kidney failure, intolerance to iron isomaltoside, and ongoing infections or rejections. Prior to the intervention, all patients underwent a treadmill test to measure peak oxygen consumption. Muscle strength by a hand grip test, cognitive function, and self-reported quality of life were also measured. All tests are repeated at follow-up 6 months after intervention. The trial is powered to detect a 1.5 ml/kg/min between-group difference in the change in peak oxygen consumption. Last patient is scheduled for follow-up February 2020. The primary objective is to assess baseline-adjusted peak oxygen consumption, six months after one single dose of iron isomaltoside. Secondary objectives are to assess the impact of treatment on iron stores, muscle strength, cognitive function, quality of life, safety and tolerability. This study will give insight to whether heart transplant recipients with ID can benefit from intravenous iron supplement. Results will be ready for presentation at the 2020 ISHLT conference.

Impact of Mechanical Circulatory Support and Heart Transplantation on Survival of the Population of Transplant Eligible Advanced Heart Failure Patients - A Computer Simulation Study

Long term survival after heart transplantation is better than after implantation of VAD, however, the reported survival curves do not represent the whole population of transplant eligible patients, where some die while waiting for the transplantation and do not include the time on the waiting list. The aim of the present study was to use computer simulation model to assess the impact of left ventricular assist device implantation, heart transplantation and combination of both on the overall survival of a group of transplant eligible patients. A computer model was made in Mathematica v12.0 (Wolfram Research, Champaign, IL, USA) to simulate overall survival of a group of virtual patients eligible for heart transplantation in different scenarios, by using Seattle heart failure model score to define baseline survival and published survival curves after heart transplantation, ventricular assist device implantation and time to transplantation to generate individual survival times for each virtual patient. Computer generated data were compared with survival of the transplant eligible patients treated at the University Medical Center Ljubljana, Slovenia. Kaplan-Meier survival curves are presented for baseline, combined waiting list and heart transplantation, waiting list, combined waiting list and high-risk ventricular assist device implantation and combined ventricular assist device implantation and heart transplantation survival. The model has shown that overall group survival after heart transplantation only is much worse than published post-transplant survival due to waiting list mortality. Waiting list mortality is lower than true baseline mortality due to informative censoring. Ventricular assist device implantation is beneficial in higher risk patients but can do more harm in lower risk patients. The combined use of ventricular assist device implantation and heart transplantation has the greatest impact on survival, by decreasing early mortality with ventricular assist device and increasing the long-term survival with transplantation.

Carfilzomib for Heart Transplant Desensitization

Allosensitization in heart transplant (HT) candidates is associated with longer transplant wait times and post-transplant complications. We summarize our experience with desensitization using carfilzomib (CFZ), an irreversible proteasome inhibitor that causes plasma cell apoptosis. One cycle of desensitization consisted of plasmapheresis and CFZ 20mg/m2 on days 1, 2, 8, 9, 15, and 16 with intravenous immune globulin 2g/kg after CFZ on day 16. Patients underwent repeat cycles as indicated. We summarize treatment impact by depicting calculated PRA (cPRA) for neat combined Class I and II IgG and C1q pre- and post-treatment using a cutoff for cPRA entry of ≥ 4000 and 500 MFI, respectively. We fit a linear mixed model to evaluate treatment effect. From June 2013 to October 2019, 9 patients underwent 20 cycles of CFZ with 6 requiring multiple cycles. Each cycle of CFZ resulted in an average cPRA decrease of 33% (95% CI: 16-50) for combined IgG and 36% (95% CI: 17-55) for C1q. An example is shown in Figure 1. From treatment start to finish, mean cPRA fell from 76% to 35% (p=0.005) for combined IgG and 56% to 4% (p=0.017) for C1q (Table 1). Six of 9 patients have been transplanted with 5 of the transplanted hearts crossing historical antibodies. HT survival at 1 year was 100%. Patient 6 has not been transplanted due to obesity. Patients 3 and 4 only received 4 doses of CFZ due to acute kidney injury, which resolved. Neutropenia, thrombocytopenia, neuropathy, and hepatotoxicity did not occur. CFZ, as part of a desensitization regimen, appears to be safe and effective in sensitized patients awaiting HT. The number of cycles may depend on the HLA antibody titer prior to treatment.

Impact of Center Heart Transplant Volume on One-Year Survival or Retransplantation: A 2006 to 2016 UNOS Based Analysis

Previous studies have demonstrated a correlation between increasing center volume and improved post heart transplant (HTx) survival. We performed a contemporary analysis to evaluate this relationship. The UNOS database was analyzed to include adult (≥18 years) HTx recipients from years 2006 to 2016. Each center had to perform >65 transplants to be included. Centers were categorized based on annual transplant volume: 6-15, 16-25, 26- 39 and ≥40. Primary endpoint was one-year mortality or retransplantation. Survival analysis was performed using Kaplan-Meier method. Adjusted analysis were performed using Cox-regression modeling. Among 17,853 HTx recipients, distribution of patients was 32.1%, 30.8%, 14.5% and 22.6% in the order of increasing center Htx volume, respectively. Median recipient age was 56 years (IQR 47-63) and 75.5% were male. Primary endpoint of one-year mortality or retransplantation was similar across the centers irrespective of transplant volume (6-15/yr: 10.4%, 16-25/yr: 9.5%, 26-39/yr: 11.1%, ≥40/yr: 9.7%; χ2 p=0.10 and Log-rank p=0.11) as noted in figure 1. When adjusted for recipient and donor risk factors, the Cox-regression analysis showed that centers with ≥40 Htx/yr had a lower rate of one-year mortality/retransplantation (HR 0.86; 95% CI 0.75-0.98; p=0.029) compared to patients at centers with volume 6-15/yr. The two remaining categories 16-25/yr (HR 0.94; p=0.31) and 26-39/yr (HR 1.06; p=0.43) showed no difference in primary endpoint when compared to the lowest volume category (6-15 /yr). There was no difference in baseline rate of mortality or retransplantation at 1-year among Htx centers irrespective of volume. Among all categories, only centers with ≥40 Htx/yr had an improved risk adjusted primary endpoint compared to the centers with lowest volume. The correlation between increasing center volume and improved survival appears to have weakened in this updated analysis among US transplant centers.

Pre-Formed Donor-Specific Antibodies Impact Long Term Survival of Heart Transplants

We previously reported that heart transplant (HTx) recipients with pre-formed, anti-HLA antibodies at low titer had one-year survival that was comparable to patients without any anti-HLA antibodies. As a result, we defined unacceptable HLA antigens by MFI>1000 in serum at 1:16 dilution. The current study evaluates how pre-formed, low-titer, donor-specific antibodies (DSA) and positive crossmatch affect long term survival of HTx recipients. Total 495 adult recipients transplanted at our center between Jan. 2007 and Dec. 2016 were studied. Prior to HTx, recipients had HLA antibody screening (FlowPRA) and specificity testing (LABScreen). Unacceptable HLA antigens were defined by MFI>1000 in serum at 1:16 dilution. Acceptable donors were selected by virtual crossmatch using the criteria above, and flow cytometry crossmatch (FCXM) was performed peri- or post-HTx. Recipients transplanted across low titer DSA, positive in undiluted serum but negative at 1:16 dilution, received peri-operative plasmapheresis. We used log-rank testing to evaluate survival in the following groups compared to their controls: (1) presence of any pre-formed HLA antibodies; (2) presence of pre-formed DSA; and (3) positive FCXM. Of 495 HTx recipients, 179 (36%) had pre-existing HLA antibodies, and their overall survival was not different from patients without HLA antibodies (p=0.883). However, median survival time was reduced in patients with pre-formed DSA (n=62), compared to DSA-negative recipients (n=117): 9.1 years (95% CI 3.52 to 14.65) vs. 10.9 years (95% CI 6.13 to 15.70); p=0.02. The survival rates for 1-, 3-, 5-year of DSA-negative recipients were 91.5%, 85.4% and 79.5%, and the DSA-positive recipients were 83.9%, 66.1% and 61.7%, respectively. Total 62 recipients had pre-HTx DSA. Among them, 26 had a positive FCXM (46%). The survival rates of FCXM-positive cases were lower than FCXM-negative cases (n=36) at 1, 3, and 5 years: 80.8%, 57.9%, 52.1% vs. 86.1%, 71.4%, 67.6%. Our findings suggest that pre-formed DSA, even at low titer, negatively impacted HTx survival. Cases with positive FXCM had the worst outcomes. Avoiding all pre-formed DSA may improve survival for HTx patients, but may increase waitlist mortality. To improve the HTx survival, close post-transplant monitoring and proactive immunological management may be required when pre-formed DSA are present.

Tolerance Induction in Neonatal Mice: Exhaustion of CD8 T Cells in Allogeneic Bone Marrow Tolerizing Inoculum Fails to Induce GVHD and Leads to Prolonged Donor Heart Graft Survival

Adult allogeneic (allo) spleen cells (SC) induce lethal aGVHD in newborn mice whereas bone marrow cells (BMC) induce non-robust transplant tolerance. To understand these differences we examined CD8 T cells from both inocula before and after injection into neonatal mice, analyzing their molecular phenotypes and trafficking/fates. Neonatal C3H (H-2k) mice were injected iv with either total adult B6 (H-2b) GFP+ SC or BMC, or purified CD8 T cells. Cell trafficking and fates were monitored by whole body/organ imaging. GVHD was defined by reduced growth/viability and tolerance by donor-type heart transplant survival. Cell phenotypes were examined by flow cytometry. Neonates injected with allo-SC developed lethal aGVHD whereas those injected with allo-BMC acquired a non-robust heart transplant tolerance. Both allo-SC and -BMC trafficked to secondary lymphoid organs, proliferated and then spread throughout the body by day 6, suggesting systemic inflammation. CD8 T cells purified from both inocula also proliferated and spread throughout the mice, indicating direct activation. Despite similar proliferation/ trafficking, purified SC CD8 T cells induced lethal aGVHD in 100% mice (n=4/4) whereas the same number of purified BMC CD8 T cells did so infrequently (n=1/4). To understand these differences flow cytometry was performed on SC and BMC CD8 T cells before and after injection (isolated from liver on day 6). CD8 T cells from BMC inocula expressed high levels of CD28, KLRG1, CTLA-4, PD-1 and CD44 unlike those from SC, indicating SC CD8 T cells to be naïve and BMC CD8 T cells to have a memory-like phenotype. At 6 days post-injection, CD8 T cells from both SC and BMC showed higher CTLA-4 and PD-1 expression than pre-injection, implying dampening of their immune responses. KLRG1 expression in BMC CD8 T cells was lower on day 6 than in the starting inoculum, which together with higher CTLA-4 and PD-1 expression suggests they were undergoing exhaustion. At day10, injected BMC CD8 T cells were observed in liver interacting with host CD8 T cells and undergoing fragmentation. In tolerizing inocula, BMC CD8 T cells start to undergo exhaustion and are attacked by the neonatal host immune system, mitigating the risk of lethal aGVHD and ultimately prolonging donor-type heart graft survival.

Waitlist Outcomes in Patients with Blood Group O during Continuous Flow Left Ventricular Assist Device Support

Continuous flow left ventricular assist device (CF LVAD) supported patients with blood group O may wait longer for heart transplantation (HT), but it remains uncertain if during this waiting period such patients have greater morbidity and mortality from major adverse events (AEs). We conducted a UNOS database analysis of all patients that were waitlisted for HT after CF LVAD implantation from January 2006 to March 2019. Major demographics, waitlist times, waitlist mortality and occurrence of major AEs were retrieved. Patients were categorized as blood group O and non-blood group O. Post-transplant survival was also retrieved. Waitlist and post HT survival were assessed by Kaplan Meier analysis and Cox proportional hazard ratios were calculated. AEs during device support were compared by logistic regression. Overall, 8,578 patients with CF LVADs were placed on the UNOS waitlist during the study period. As expected, Blood group O (n=4,115) had longer waitlist times (412 days, IQR: 102-576; non-O 250 days, IQR 39-323 days, p<0.0001) than non-blood group O (n=4,461) patients. There were no significant differences between groups in age and gender. Blood group O had a higher likelihood of driveline infections (OR: 1.40, 95% CI 1.19-1.64, p<0.001) and life-threatening ventricular arrhythmias (OR: 2.22, 95% CI 1.44-3.42, <p=0.001, figure1A). Interestingly, waitlist mortality was similar in both groups (HR: 1.01, 95% CI 0.84-1.21, p=0.95, figure1B), as well as post HT survival (HR 0.96, 95% CI 0.85-1.09, p=0.58, figure1C). Despite more major AEs during CF LVAD support, patients with blood group O experience similar wait list and post HT survival.

Outcomes of HIV-Positive Patients Post Cardiac Transplantation

Contrary to prior practice, human immunodeficiency virus (HIV) positive status is no longer a contraindication to heart transplantation (HT) in many centers due to demonstrated satisfactory outcomes post-HT. However, knowledge about the long-term outcomes post-HT of this cohort is limited. We characterized the long-term post-HT outcomes of HIV+ patients compared to HIV- patients. A total of 59,796 HT patients were analyzed from the UNOS registry from 1987 to 2019, of which 76 were HIV+. Characteristics of HT patients with and without HIV infection were compared using standard statistical methods. Multivariate Cox proportional hazard regression analysis was performed for survival analysis. The mean age and gender between the HIV+ and HIV- HT recipients were comparable. HIV+ patients were less likely to have undergone prior cardiac surgery (65.8% vs 79.1%, p=0.004). In terms of transplant-related factors, HIV+ HT recipients had a trend towards receiving older donors (p=0.06) but had similar ischemic times. At the time of HT, HIV+ patients more frequently required intra-aortic balloon pump (IABP) (11.8% vs 5.5%, p=0.016) and ventricular assist device (VAD) support (47.4% vs 26.7%, p<0.001). The use of extracorporeal membrane oxygenation (ECMO) and mechanical ventilation were similar between both groups. Median wait time to HT did not differ between the two groups and there was no difference in the post-transplant survival between the HIV+ and HIV- HT recipients (p=0.31). Post HT survival of HIV+ recipients was similar to HIV- recipients despite greater acuity as demonstrated by the increased use of IABP and VADs. Therefore, HT is a feasible and safe option for carefully selected HIV+ recipients. Further study is warranted to understand long-term implications.

Impact of mechanical circulatory support on survival in pediatric heart transplantation.

Evidence on the impact of MCS on pediatric heart transplant survival is still scarce related to congenital heart disease patients including univentricular physiology as well as the risk factors for complications. We performed a retrospective review of all urgent pediatric (aged ≤16years) HT from 2004 to 2014 in the Spanish Pediatric Heart Transplant Registry Group. Patients were stratified into two groups: urgent 0 (MCS at HT) and urgent 1 (non-MCS at HT). The primary outcome measure was post-transplant survival; secondary outcome measures were complications and absence of infections and rejection during the first post-transplant year. One hundred twenty-one pediatric patients underwent urgent HT, 58 (47.9%) urgent 0 and 63 (52%) urgent 1. There were 30 (24.8%) deaths: 12 in the urgent 0 group and 18 in the urgent 1 group, P=n.s. Regarding the type of MCS, patients on ECMO had the highest rate of complications (80%) and mortality (40%). Patients in the urgent 1 group showed a higher risk of hospital re-admission for infection during the first year after transplantation (OR 2.31 [1.1-4.82]), P=.025. We did not identify a risk factor for mortality. MCS does not impact negatively on survival after HT. However, there is a significant increase in 30-day and 1-year mortality and complications in ECMO patients compared with VAD patients. Infants, congenital heart disease, and PediMACS were not found to be risk factors for mortality.

Differential gene expression in non-adherent heart transplant survivors: Implications for regulatory T-cell expression.

Survival despite prolonged non-adherence with immunosuppression is rare but has been reported in kidney, lung, and liver transplantation. Its occurrence in heart transplantation is quite rare. Our study was prompted by an index patient who survived despite prolonged medication non-adherence. Prospective consent and blood collection were conducted for seven additional patients who presented in a similar fashion. The blood of patients who were diagnosed with rejection, stable early post-transplant, and stable more than 5years post-transplant were all compared with a custom gene array focusing on T-regulatory cell processes. The two genes that were differentially expressed in every comparison were TGF beta and RNASEN with very low expression in the rejector group. The prolonged non-adherent group had the maximum expression for TGF beta but average RNASEN expression as compared to the low expression for rejectors and high for post-5years patients. The patients presented survived for varying lengths of time without immunosuppression. The gene array analysis showed intriguing differences between these rare patients and important patient cohorts. Further efforts should be directed to finding and studying more patients who survive despite lack of prescribed immunosuppression. The mechanisms underlying this phenomenon may inform future advances in transplant immunosuppression.

Conditional Survival in Heart Transplantation: An Organ Procurement and Transplantation Network Database Analysis

Survival after heart transplantation is typically reported only in terms of overall survival. Conditional survival may provide prognostic information for patients after surviving a given period. This study sought to provide an analysis of conditional survival in heart transplantation. Data from 29,000 patients who underwent heart transplantation between 2002 and 2016 were analyzed from the Organ Procurement and Transplantation Network database, and 5-year conditional survival rates were calculated according to age, sex, race, renal function, and hepatic function at transplantation. As time from transplantation increased from 0 to 5 years, the 5-year observed conditional survival changed from 74% to 82% for ages younger than 40 years, 79% to 82% for ages 40 to 49, 79% to 78% for ages 50 to 60, and 75% to 70% for ages older than 60 at transplantation. Conditional survival peaked at 1 and 2 years after transplantation for most subgroups. In recipients younger than 40 years, men had slightly higher conditional survival than women (absolute difference, 3%-4%). In recipients older than 60 years, women had slightly higher conditional survival (absolute difference, 1%-4%). Black recipients had lower survival than white and Hispanic recipients for nearly all time points. Recipients younger than 40 years with the worst renal (65% to 88%) and hepatic function (66% to 83%) at transplantation experienced the largest increase in conditional survival. The conditional survival of patients who undergo heart transplantation changes substantially over time. The largest increases in conditional survival are in young patients with impaired renal and hepatic function. Conditional survival can provide more accurate prognostic information for heart recipients who survive a given period after transplantation.

Impact of Preoperative Pulmonary Hypertension on Survival in Patients Undergoing Elective Heart Transplant

BackgroundPulmonary arterial hypertension (PAH) represents a marker of bad prognosis in left heart disease. Nonetheless, the effect on survival after heart transplant remains controversial. The objective was to study the impact of preoperative PAH on survival in patients undergoing elective heart transplant. MethodsA retrospective study of 173 transplant recipients was conducted at a single hospital from January 2009 to December 2018. Congenital etiology and emergent heart transplant were exclusion criteria as well as those patients without enough data in the hemodynamic study. Two groups were considered: A (without PAH) and B (with HTP). PAH was classified as mild (mean pulmonary arterial pressure [mPAP] 25-34 mm Hg, pulmonary vascular resistance [PVR] 2.5-3.4 Wood units and/or transpulmonary gradient [TPG] 13-16 mm Hg), moderate (mPAP 35-44 mm Hg, PVR 3.5-4.9 Wood units and/or TPG 17-19 mm Hg), and severe (mPAP > 44 mm Hg, PVR > 4.9 Wood units and/or TPG > 19 mm Hg). ResultsA total of 102 patients were enrolled; 71.6% were male and average age was 52.3 (SD, 10.02) years. The main etiology was ischemic cardiomyopathy; 13.7% underwent previous heart operations. A total of 61 patients (59.8%) had PAH prior to heart transplant: 25 mild, 34 moderate, and 2 severe. Mean overall survival after transplant was 79.9 (SD, 5.68) months, without differences between the 2 groups (P = .82). One-month survival was 89% (the main cause of mortality was primary graft dysfunction), and 1-year survival was 78%. Four patients required mechanical circulatory support during early post-transplant period. ConclusionsPreoperative PAH does not have a significant impact on survival in elective heart transplant.

T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation

The mammalian target of rapamycin (mTOR) inhibitors are valuable immunosuppressants in clinical transplantation; however, the mTOR regulation of allogeneic T-cell responses is not fully understood yet. Therefore, the objective of this study is to investigate the effects of T-cell-specific mTOR deletion on the allogeneic T-cell responses and heart transplant survival. BALB/c heart allografts, with or without BALB/c skin sensitization, were transplanted in the wild-type C57BL/6, Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-Cre mice. Graft survival and histology, as well as T-cell frequencies and phenotypes, were evaluated after transplantation. In the absence of donor skin sensitization, long-term heart allograft survival was achieved in the Mtorfl/flCd4-Cre recipients, which was associated with significantly decreased frequencies of CD62L-CD44+ effector T cells and BCL-6+CXCR5+ T follicular helper (Tfh) cells in the periphery. Long-term heart allograft survival was also achieved in the donor skin-sensitized Mtorfl/flStat3fl/flCd4-Cre mice, whereas the heart allograft survival was prolonged in the donor skin-sensitized Mtorfl/flCd4-Cre and Stat3fl/flCd4-Cre mice. mTOR is required for Tfh cell response in murine heart transplantation. T-cell-specific deletion of both mTOR and Stat3 abrogates the memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying the T cell immunity to transplanted organs.

Heart Transplantation in Children with Mitochondrial Disease

To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease. Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease. A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P=.009), require a longer duration of mechanical ventilation after heart transplantation (3days vs 1day; P<.001), and have a longer intensive care unit stay after heart transplantation (10 vs 6days; P=.007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P=.14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14days vs 8days; P=.03). Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease shouldnot be an absolute contraindication to heart transplantation in the appropriate clinical setting.

Marginal Improvement in Survival Post-Heart Transplantation in Patients With Prior Left Ventricular Assist Device: A Temporal Analysis of United Network of Organ Sharing Registry

An increasing number of patients undergoing heart transplantation are being bridged with left ventricular assist devices (LVADs). Bridge-to-transplantation (BTT) LVAD has improved wait list survival remarkably. Historically, post-heart transplantation survival in BTT-LVAD patients, however, has remained inferior to that of primary heart transplantation. The authors hypothesized that in the modern era, the difference between post-heart transplantation survival in BTT-LVAD versus primary heart transplantation should be reduced. The objective of the present study was to determine whether there has been a change in survival after heart transplantation in patients with prior LVAD. The present study's cohort was compared with a historical cohort using the United Network of Organ Sharing (UNOS) database from 1995 to 2004.5 DESIGN: Retrospective observational analysis of data from the United Network of Organ Sharing database. Registry-based, observational, retrospective. Patients undergoing adult orthotopic heart transplantation, excluding redo transplantation and multiorgan transplantations. None. From the UNOS database, 22,065 patients who underwent heart transplantation between January 1, 2006, and December 31, 2016, were analyzed. Of these, 7,008 (31.76%) patients had prior LVAD (BTT-LVAD). Data analysis was performed with R software (Version 3.5.1) for Kaplan-Meier survival analysis and Cox proportional hazard ratio (HR) modeling to identify variables influencing survival. For patients with prior LVAD, the overall HR was 1.15 (95% confidence interval [CI] 1.07-1.24) for survival. An HR of 3.22 (95% CI 2.23-4.68) for death in patients who received extracorporeal membrane oxygenation post-transplantation and an HR of 0.72 (95% CI 0.58-0.90) for survival in patients whose procedures were performed in high-volume centers performing more than 35 transplantations per year were identified. Reduced survival in patients who received an LVAD before heart transplantation persists. However, there may have been a slight improvement in the HR for survival in the study cohort in the recent decade compared with the historical cohort from previous decades. It is intriguing that despite the paramount advances in both technology and clinical practice of LVAD, relatively minor survival benefit, if any, has occurred in post-heart transplantation for patients bridged with prior LVAD.