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BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

Purpose The INTERHEART study previously used microarray assessment of 889 heart transplant biopsies to develop the Molecular Microscope Diagnostic System (MMDx) based on expression of rejection-associated transcripts (RATs). The present study reclassified the rejection-related states in an expanded set of 1320 prospectively collected biopsies from 645 patients from 13 centers. Methods Biopsies were classified by ensembles of classifiers and analyzed for left ventricular ejection fraction (LVEF) and survival. Results New algorithms identified 853 No rejection (NR), 179 ABMR, 76 TCMR, 13 Mixed, 161 possible ABMR (pABMR), and 38 possible TCMR (pTCMR). No rejection was subclassified as NR-Normal 462, NR-Minor 359, and NR-Early-injury 32 (Figure 1A). Compared to NR-Normal, NR-Minor biopsies had mild elevation of many inflammation transcripts (e.g. IFNG-inducible genes) and to a lesser extent parenchymal injury transcripts. NR-minor biopsies were often designated as TCMR1R by histology. In all NR biopsies, NR-Minor scores and histologic TCMR1R increased through the first year, peaking about one year, suggesting that Minor inflammation is a late response to injury, unrelated to rejection. LVEF was similar in NR-Normal and NR-Minor but depressed in TCMR and Early injury. In a 3-year post-biopsy survival analysis, NR-Minor and NR-Normal had similar survival. TCMR and Early-injury were associated with increased graft loss, but many losses were not related to rejection. Surprisingly, 76 hearts with ABMR (149 biopsies) and follow-up data had only 3 losses within 3 years post-biopsy (Figure 1B). Conclusion Many biopsies with molecular no rejection develop minor increases in rejection-related transcripts in the first year, often called TCMR1R by histology, with no apparent effects on function or survival. An unexpected finding was that molecular ABMR was associated with very few graft losses over three years. (ClinicalTrials.gov #NCT02670408).

Purpose End-stage heart failure (HF) is often associated with malnutrition and sarcopenia, both of them are related to adverse HF outcomes. Skeletal muscle mass and attenuation are predictors of mortality after continuous flow left ventricular devices (LVAD) implantation. Our purpose was to assess the prognostic impact of skeletal muscle mass on patients undergoing heart transplantation (HT). Methods Retrospective study of a single-center HT population, between 2009 and 2019. Patients > 18 years-old with a computed chest scan in the previous 6 months before HT were included. Multiorgan transplants were excluded. Unilateral pectoralis muscle mass indexed (PMMi) to body surface area and attenuation (by mean Hounsfield units [PHUm]) were measured in each patient. HT patients were classifiedin tertiles according to PMMi and PHUm and characteristics of patients were compared by Chi-square, t-student and Kruskall-Wallis. Multivariate Cox regression analyses were performed to assess the impact of preoperative PMMi and PHUm on survival after HT. Results 132 patients were included, mean age 58.9, 16.7% female, median follow-up 3.67 years (interquartile range 1.7-5.9 years). 41.7% of patients underwent urgent HT (1.5% INTERMACS 1 situation, 15.2% INTERMACS 2 and 28% INTERMACS 3). Both PMMi and PHUm were lower in females and for lowest weight recipients. Urgent HT frequency was similar between tertiles of PMMi, but recipients in the higher tertile of PHUm were more frequently transplanted in an urgent status (38.2% vs 21.8% in the lowest tertile, p= 0.029). 26 patients (19.7%) died during follow-up, 12 (9.1% of total cohort) during HT admission. In the Cox regression analyses, neither PMMi (HR 1.034, 95% CI 0.891-1.2, p= 0.659) nor PHUm (HR 1.02, 95% CI 0.992-1.050, p=0.160) were associated with an increased mortality. Only the needed of mechanical circulatory support and hemofiltration after HT were associated with a higher risk of death. Conclusion Among this single-center HT recipients population, neither lower PMMi nor lower PHUm were associated with worse outcomes after HT.

Purpose Heart Transplant (HT) patients need complex drug treatment for life: many drugs and several daily doses (usually 5 times a day). This complexity may make it difficult to adhere to the treatment, which is key to therapeutic success. In order to facilitate medication preparation, a Weekly Multi-Dose Pillbox (WMDP-5), 5 doses/day, was designed in our HT program. The aim is to assess the improvement in adherence and satisfaction with the use of the WMDP-5 within a multifactorial intervention. Methods Prospective single-center study started in April 2019. All HT patients were invited to participate. The multilevel intervention included the provision of the WMDP-5 as well as a training session with a specific video and information leaflets. The study was approved by regional ethics committee. To evaluate adherence, the Spanish version of BAASIS (Basel Assessment of Adherence with Immunosuppressive Medication Scale) Patient Questionnaire Interview and the Simplified Medication Adherence Questionnaire (SMAQ) were used at delivery and at the follow-up visit. A Likert Scale (1-5) evaluate satisfaction at the follow-up visit (the next one to the center ≥ 1 months after using the WMDP). Patients with the follow-up visit until October 2019 were analyzed. Results A total of 214 HT patients (mean age 61,8±12,89 years, 79,4% males, with mean time after HT of 9,86±6,9 years) were included in the analysis. The highest level of education was primary school in 45,3%, 67,3% were married and 85% lived with someone. According to the SMAQ, there were 156/214 (72.89%) adherents at baseline and 193/214 (90,2%) at follow-up visit (p=0.006). Of 58 non-adherent patients at the baseline visit, 47 (81%) were adherent (improved) at the follow-up visit; while of 156 adherents at the basal visit, only 10 (6,4%) became non-adherents (worsened). The BAASIS questionnaire documented an overall improvement. Thus, the fist BAASIS question (if any pill was forgotten) at the baseline visit was 8%, while at the follow-up visit was 1,7%. Finally, according to the Likert Scale, 71,5% of the patients responded that the WMDP-5 helped them to take the treatment well. Conclusion The use of a WMDP-5 in the context of a multilevel intervention improves therapeutic adherence in HT patients. It should be noted that this improvement occurs in a cohort of HT patients with already high adherence.

Purpose In heart and kidney transplants, rejection is a major cause of graft loss. In kidneys, antibody-mediated rejection (ABMR) is more important than T cell-mediated rejection (TCMR), and molecules predict graft loss better than histology (JASN 26 (7):1711-1720, 2015). We examined the relative importance of ABMR vs TCMR in heart transplant endomyocardial biopsies (EMBs), and the molecules predicting graft survival. Methods The INTERHEART population includes 1219 transplant biopsies from 8 centers in Canada, USA, Australia and Europe. Gene expression was studied using microarrays, selecting the most recent biopsy per patient. Random forest classifiers were used to assess predictive accuracy and determine the importance of molecular predictors, including gene sets and scores from analyses in a reference set of 889 EMBs. Results We studied 3-year survival in 484 patients with follow-up times. Graft failure occurred in 60 patients. Median follow-up was 435 days; biopsies were mainly for indications. Surprisingly, TCMR was a greater short-term hazard than ABMR. The molecular archetype clusters for TCMR and injury (Fig. 1) had the highest risk of graft failure. Fig. 2 combines these clusters since they have similar characteristics. Conclusion Unlike kidneys, graft loss (particularly within one year) after EMB is highly associated with TCMR but not ABMR. TCMR may reflect failure of immunosuppression or non-adherence. This difference between the heart and renal transplant populations raises the possibility that TCMR is relatively more destructive, and ABMR less destructive, in heart than in kidney transplants. ClinicalTrials.gov # NCT02670408

We summarize the results of the most important research of the past decade on the post-transplant monitoring of heart transplant patients by gene expression profiling and the quantification of immunoactivity, donor-derived cell-free DNA and rejection-related microRNAs.

Purpose Gene expression profiling testing (GEP; AlloMap) and donor-derived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the performance of these two molecular diagnostic methods when used together. Methods A retrospective cohort of 26 heart transplant patients with endomyocardial biopsy-based diagnosis of grade 0 ACR were demographically matched to 27 patients with grade ≥ 2R ACR. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-39) results were correlated with the biopsy-based diagnosis of ACR. Results Patients with ACR had significantly higher dd-cfDNA (0.48 vs. 0.07; P 0.2% and GEP scores > 34, we calculated a 26% sensitivity and 92% specificity, and an NPV of 98% and a PPV of 6%. When GEP Conclusion In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels together with GEP scores may improve patient management decisions.

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

Chronic renal failure (CRF) due to calcineurin inhibitor (CNI) nephrotoxicity is a frequent complication among heart transplant (HT) recipients. Small studies have suggested that the introduction of mycophenolate mofetil (MMF) can help to reduce CNI doses thereby to maintaining or improving renal function. We conducted a 4-year, prospective, multicenter study in 89 maintenance HT recipients at 5.6 ± 2.7 years postgrafting who displayed CRF (serum creatinine1.4 mg/dL) and were undergoing treatment with cyclosporine and prednisone ± azathioprine. We introduced MMF and reduced cyclosporine to level below 100 ng/mL. Creatinine clearance (CrCl), acute rejection episodes, and survival were through retrospectively compared with a contemporary cohort of HT recipients who were not treated with MMF (control group; n = 38). After conversion to MMF, a rapid increase was observed in the CrCl, which was maintained over the follow-up: namely, CrCl at month 6 and at 4 years were 51.0 ± 15.6 and 54.1 ± 15.6 mL/min versus 41.9 ± 11.1 mL/min at baseline (P.0001). No renal function changes were observed among the control group. Acute rejection rates were 5.6% and 2.6% in the MMF versus control groups (P = NS) with 4-year survivals85%. In conclusion, the introduction of MMF allowed a safe reduction of cyclosporine and significantly improved renal function after 4 years.

Barge-Caballero, E., Segovia-Cubero, J., Gonzalez-Vilchez, F., Delgado-Jimenez, J., Perez-Villa, F., Almenar-Bonet, L., Arizon-Del Prado, J.L., Lage-Galle, E., De La Fuente-Galan, L., Manito-Lorite, N., Sanz-Julve, M., Villa-Arranz, A., Lambert Rodriguez, J.L., Brossa-Loidi, V., Pascual-Figal, D., Muniz-Garcia, J., Crespo-Leiro, M.

Background Renal dysfunction (RD) is a common complication after heart transplantation (HT), but predictors of post-HT RD have not been clearly identified. Methods We studied 262 HT patients (mean age 54 years, 221 men) with normal baseline renal function. Potential risk factors examined were age, sex, pre-HT ischemic cardiomyopathy, pre- and post-HT diabetes mellitus, pre- and post-HT arterial hypertension, initial immunosuppressive protocol (before 1998 [high cyclosporine, azathioprine, and prednisone] vs after 1998 [low cyclosporine, mycophenolate mofetil, and prednisone]), occurrence of rejection episodes ≥ISHLT Grade 3A, and creatinine level 1 month after HT. RD was considered mild if creatinine level was 1.5 to 2.5 mg/dl, moderate if creatinine level was >2.5 mg/dl, and severe if dialysis or kidney transplant was required. Results The cumulative incidence of RD (creatinine >1.5 mg/dl) was 35% at 12 months, 42% at 24 months, and 47% at 60 months (mean follow-up 59 ± 31 months). Only 1% of patients had severe RD 60 months after HT. Independent predictors of RD 24 months after HT were older age (odds ratio [OR] 1.1 [95% confidence interval (95% CI) 1.0–1.1]; p = 0.001), male sex (OR 3.3 [95% CI 1.3–8.1]; p = 0.008), pre-1998 immunosuppressive protocol (OR 2.8 [95% CI 1.4–5.4]; p = 0.003), and creatinine level 1 month after HT (OR 3.2 [95% CI 1.0–5.4]; p Conclusions The cumulative incidence of RD in HT patients treated with calcineurin inhibitors increased with time after HT. Age, male sex, an immunosuppressive protocol with relatively high cyclosporine levels and creatinine level 1 month after HT were independent predictors of the presence of RD 24 months after HT.

s S113 S. Rao , C. Hayward, P. MacDonald, A. Jabbour, E. Kotlyar, A. Keogh. Heart and Lung Transplantation Unit, St Vincent’s Hospital, Sydney, Australia. Purpose: Since the broadening of age eligibility criteria for orthotropic heart transplantation (OHT) in 2006, there has been an increase in the number of transplants being performed in recipients 60 years and older. Outcomes for older patients have not been reassessed since this guideline change has occurred. Methods: We retrospectively reviewed the UNOS dataset to identify first time OHT recipients from 2006 onwards (n= 18,130). All cause mortality was assessed and modelled using Kaplan-Meier method, and comparison was made between those aged more 60 years vs 18-59 years. Further analysis within the older age group was performed between the 60 to 64 years, 65 to 70 years and ≥ 70 years. Results: Of the 18,130 patients identified, 35% were aged 60 years or more (n= 6,454). Within the older group, 53% were aged 60-64 (n= 3,420), 39% were aged 65-69 (n= 2,505) and 8% were aged 70 or older (n= 529). Survival at 30 days, 1 year and 5 years was 96%, 90% and 79% for the younger group and 96%, 88% and 77% for the older group (p < 0.001). There was no significant difference in survival within the older group (see table, p = 0.18). Conclusion: Recipient age has minimal impact on 5-year survival after heart transplantation in the current era. Broadening the transplant eligibility criteria for OHT has led to an increase in the number of OHT performed in older recipients; however appropriate selection of older patients has led significant improvement in survival in this group such that it now is similar to outcomes for younger patients prior to 2006.

Background A number of changes in the management of heart transplantation (HT) patients have each tended to reduce the risk of post-HT hematologic cancer, but little information is available concerning the overall effect on incidence in the HT population. Methods Comparison of data from the Spanish Post-Heart-Transplantation Tumour Registry for the periods 1991–2000 and 2001–2010. Results The incidence among patients who underwent HT in the latter period was about half that observed in the former, with a particularly marked improvement in regard to incidence more than five yr post-HT. Conclusions Changes in HT patient management have jointly reduced the risk of hematologic cancer in the Spanish HT population. Long-term risk appears to have benefited more than short-term risk.

[Abstract] Objectives. We sought to investigate the potential impact of preoperative short-term mechanical circulatory support (MCS) with extracorporeal devices on postoperative outcomes after emergency heart transplantation (HT). Methods. We conducted an observational study of 669 patients who underwent emergency HT in 15 Spanish hospitals between 2000 and 2009. Postoperative outcomes of patients bridged to HT on short-term MCS (n = 101) were compared with those of the rest of the cohort (n = 568). Short-term MCS included veno-arterial extracorporeal membrane oxygenators (VA-ECMOs, n = 23), and both pulsatile-flow (n = 53) and continuous-flow (n = 25) extracorporeal ventricular assist devices (VADs). No patient underwent HT on intracorporeal VADs. Results. Preoperative short-term MCS was independently associated with increased in-hospital postoperative mortality (adjusted odds-ratio 1.75, 95% CI 1.05–2.91) and overall post-transplant mortality (adjusted hazard-ratio 1.60, 95% CI 1.15–2.23). Rates of major surgical bleeding, cardiac reoperation, postoperative infection and primary graft failure were also significantly higher among MCS patients. Causes of death and survival after hospital discharge were similar in MCS and non-MCS candidates. Increased risk of post-transplant mortality affected patients bridged on pulsatile-flow extracorporeal VADs (adjusted hazard-ratio 2.21, 95% CI 1.48–3.30) and continuous-flow extracorporeal VADs (adjusted hazard-ratio 2.24, 95% CI 1.20–4.19), but not those bridged on VA-ECMO (adjusted hazard-ratio 0.51, 95% CI 0.21–1.25). Conclusions. Patients bridged to emergency HT on short-term MCS are exposed to an increased risk of postoperative complications and mortality. In our series, preoperative bridging with VA-ECMO resulted in comparable post-transplant outcomes to those of patients transplanted on conventional support.

Introduction. Because of improved long-term survival of heart transplants (HT), patients often need noncardiac surgery (NCS). Immunosuppression may increase the infection rate. Inadequate management may increase the risk of dysfunction or acute rejection episodes (ARE). Long-term outcomes of NCS and optimal immunosuppressive management in the perioperative period are not well known. The objective of this study was to analyze the incidence, morbidity, and mortality of late NCS after HT. Methods. We retrospectively evaluated the incidence and type of late NCS as well as the risk factors for complications and the mortality among 207 HT patients. Immunosuppression and ARE rates were also analyzed. Results. One hundred and sixteen late NCS (84.5% elective) were performed in 72 HT patients (34.8%). Interventions were: 35 urologic (30.2%), 29 abdominal (25%), 14 vascular (12.1%), 13 ENT (11.2%), 11 skin and soft tissue (9.5%), and 7 orthopedic (6%). Malignancy was the main indication for NCS (33.6%). Only 4 patients (5.6%) died preoperatively. Mortality was higher among emergent vs elective procedures (16.6% vs 1%; P = .012) and among patients with preoperative high vs middle/low risk (26.6% vs 0%). Postsurgical infection was the most frequent complication (6.9%). However, there were no relevant complications in 82.8% of HT patients. Hospitalization time was

Background Steroid withdrawal (SW) after heart transplantation (HT) reduces steroid-associated side effects, although it can increase acute rejection episodes (ARE). Patient selection criteria for SW and the time elapsed after HT for this maneuver are controversial issues. The objective of this study was to assess the safety of late SW after HT with regard to the occurrence of ARE and to analyze risk factors resulting in a poor evolution. Methods We studied a cohort of 24 patients who underwent SW late after HT. All of them had gone at least 4 years without any ARE. Independent variables were time after HT, general recipient and donor data, risk factors for ARE, and immunosuppression. The dependent variables were occurrence of ARE (proven or not proven with endomyocardial biopsy) and time and severity of ARE. Results Among 24 HT patients including 96% men with an overall mean age of 57 years who underwent SW, the mean follow-up was 2.32 ± 0.86 years. Six patients (25%) displayed an ARE ≥2R according to the International Society for Heart and Lung Transplantation (ISHLT) at 5 ± 3 months after SW. There were no deaths. Time from the last rejection episode to SW was 6.6 ± 2 years. All ARE were treated with steroid boluses (mean total dose 1583 ± 1044 mg). Among the HT patients with ARE, 5 (85%) had never experienced ARE after HT. Upon long-term follow-up, there were 2 deaths: 1 sudden death at 30 months after SW and 1 due to allograft vasculopathy at 20 months post-SW. Currently 92% are New York Heart Association (NYHA) functional class I with a mean left ventricular ejection fraction of 67% ± 10%. Conclusions In our series of HT with late SW after HT (even among an HT population with a low risk of rejection), there was a 25% rate of ARE. This study did not allow us to identify risk factors for ARE after SW. We believe that based upon these observations SW should be implemented with caution.

s S31 received non-specific IVIG (Flebogamma 5%) in addition to conventional antimicrobial therapy. The the aim was contributing to control of infection. Monthly doses of 300-400 mg/kg were administered up to three months after infections were resolved (negative bacterial culture or CMV antigenemia). 126 heart recipients from the same center, who where not treated with IVIG, were analyzed as controls. Clinical data were prospectively collected during routine visits without loss of follow-up. Results: Both groups were comparable in terms of demographic and clinical variables (age, sex, pre-HT infections, diabetes, renal failure, CMV serological status; ischemia time and extracorporeal circulation time; type of induction and maintenance therapy; antimicrobial prophylaxis; prevalence of primary allograft failure. IVIG group tended to have a lower rate of neoplasia (4 vs 9%, p= 0.14). IVIG treated recipients disclosed a lower rate of death (8.5% vs 22.2%, p= 0.018). In multivariate regression analysis, IVIG use (RH 0.28, 95%CI 0.10-0.75, p= 0.011) and use of non-cytolitic induction (anti-25) vs cytolitic (ATG) (RH 0.22, 95%CI 0.09-0.50, p= 0.0003) remained in the final model as protective factors. Conclusion: Personalized immunemodulation of HGG in heart recipients with severe infections is associated with better outcome. The efficacy of this IVIG indication in solid organ transplantation warrants further evaluation in a multicenter randomized clinical trial.

Background— Postoperative outcomes of patients with advanced heart failure undergoing ventricular assist device implantation are strongly influenced by their preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles. We sought to investigate whether a similar association exists in patients undergoing emergency heart transplantation. Methods and Results— By means of the Spanish National Heart Transplant Registry database, we identified 704 adult patients treated with emergency heart transplantation in 15 Spanish centers between 2000 and 2009. Post-transplant outcomes were analyzed pertaining to patient preoperative INTERMACS profiles, which were retrospectively assigned by 2 blinded cardiologists. Before transplantation, INTERMACS profile 1 (critical cardiogenic shock) was present in 207 patients, INTERMACS profile 2 (progressive decline) in 291, INTERMACS profile 3 (inotropic dependence) in 176, and INTERMACS profile 4 (resting symptoms) was present in 30 patients. In-hospital postoperative mortality rates were, respectively, 43%, 26.8%, and 18% in patients with profiles 1, 2, and 3 to 4 ( P P =0.03) and postoperative need for dialysis (1: 33.2%, 2: 18.9%, 3–4: 21.5%; P Conclusions— Preoperative INTERMACS profiles determine outcomes after emergency heart transplantation. Results call for a change in policies related to the management of heart transplant candidates presenting with INTERMACS profiles 1 and 2.

Background: In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. Methods: In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR - 60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. Results: Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5 years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p = 0.07). Conclusion: In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Introduction Cardiac allograft vasculopathy (CAV) remains a major impediment to long-term survival after heart transplantation (HT). Limited data exist regarding the impact of coronary revascularization in these patients. Objective To evaluate the outcomes of revascularization procedures in patients with CAV compared with patients who did not undergo revascularization. Methods Retrospective analysis of 249 patients who underwent HT at our center between June 1998 and December 2009 and who were examined by coronary angiography after HT. We included patients with moderate or severe CAV according to the International Society for Heart and Lung Transplantation (ISHLT) nomenclature to evaluated outcomes after revascularization or diagnostic angiography. Major adverse cardiovascular events (MACE) comprised death, acute coronary syndrome, coronary revascularization, admission because of heart failure not due to an acute rejection episode, and cardiac retransplantation. Results Moderate or severe CAV was detected in 43 patients. Twelve (27.9%) underwent coronary revascularization: eight percutaneous interventions and four bypass surgeries. Indications for revascularization were symptomatic ischemia or noninvasive evidence of ischemia ( n = 6, 14.0%) or high-risk asymptomatic CAV ( n = 6; 14.0%), namely, lesions located in the left main or proximal anterior descending arteries or multivessel disease with left ventricular dysfunction. The remaining 31 (72.1%), who did not undergo revascularization showed an absence of ischemia during exercise echocardiography ( n = 11; 25.6%) or diffuse disease not amenable to revascularization ( n = 20; 46.5%). During a mean follow-up of 3.0 ± 2.4 years, MACE occurred in three revascularized patients (25.0%), in one with absence of stress-induced ischemia (9.1%) and in 13 with nonrevascularizable disease (65%; P = .012). Conclusions Revascularization procedures were effective in HT patients with evidence of ischemia or high-risk CAV. Patients with absence of stress-induced ischemia have a good prognosis without revascularization. On the other hand, diffuse nonrevascularizable CAV is associated with a poor prognosis.

Background Little information is available regarding the consequences of steroid withdrawal following heart transplantation (HT) in Spain. Methods We analyzed the records of 1068 patients (81.6% men) who underwent HT between 2000 and 2005 in 13 Spanish centers who were aged ≥ 18 years and who survived at least 1 year. Death rates and Kaplan-Meier survival curves for 1 to 5 years post-HT were compared among four groups: groups A and B, patients on steroids throughout the first 5 years post-HT at dosages of ≤5 mg/d between 1-year and 5-year follow-up (group A; n = 148), or >5 mg/d for some part of this period (group B; n = 578). Groups C and D were patients from whom steroids were at some point withdrawn including group D ( n = 73) with and group C ( n = 269) without subsequent reintroduction into the maintenance regimen. Results Steroids were withdrawn at 1.6 ± 0.9 years post-HT in group C, and 1.7 ± 1.2 years post-HT in group D. The death rate between 1- and 5-year follow-up (deaths per 1000 person-years) was 44.3% (95% confidence interval 26.2–62.5) in group A, 42.6% (33.7–51.4) in group B, 30.5% (19.6–41.4) in group C, and 47.8% (21.8–73.7) in group D. There was no significant difference among them or among Kaplan-Meier survival curves of the four groups ( P = .34 in both cases). Comparison of combined groups C + D with groups A + B showed no evidence of a greater mortality among combined groups C + D. Conclusions The late withdrawal of steroids following HT was not associated with increased mortality.

[Abstract] In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan–Meier 2−year survival to 70% versus 16% among inoperable patients.

Background The incidence of aspergillosis (ASP) after heart transplantation (HTx) is low ( 78%). Aim To determine the incidence of ASP in the first 3 months post-HTx according to the type of prophylaxis and assess the tolerance to these regimens. Methods This retrospective study of 571 adult HTx patients engrafted from 1991 to December 2009 included 83% males with an overall group age of 54.9 ± 11 years. Three types of prophylaxis were compared: group A was no prophylaxis (n = 99; 1991–1994); group B, itraconazole for 3 months (n = 352; 1995–November 2004); and group C, inhaled amphotericin for 3 months (n = 120; December 2004–2009). The dependent variables were the presence and severity or tracheobronchitis and invasive/disseminated disease as well as, prognosis of Aspergillus infection and tolerance to the regimen. Results The incidences of aspergillosis were 5% in group A (n = 5); 1.4% in group B (n = 5); and 0% in group C. Significant differences were observed between groups A versus B (P = .030) and between groups A versus C (P = .013), but there were no differences between groups B versus C. In terms of severity, there were no significant differences among the five cases of tracheobronchitis (20% group A/80% group B), five of invasive/disseminated disease (80% group A /20% group B). There were two deaths (20%) from invasive/disseminated ASP at 0.67 months after diagnosis. The mean time from HTx to ASP was 0.98 ± 0.40 months. There were no adverse effects associated with itraconazole, but they occurred in 3/120 patients (2.5%) treated with inhaled amphotericin, all of whom were on mechanical ventilation, developing respiratory failure requiring amphotericin withdrawal. Conclusions Prophylaxis with itraconazole or inhaled amphotericin was effective for the prevention and severity of pulmonary ASP in the first 3 months post-HTx. Although the incidence of early ASP was low in our series, the 20% mortality rate justified the use of preventive measures. Tolerance to both prophylactic treatments was good.

[Abstract] Introduction. Malignancy is a major complication in the management of solid organ transplant patients. Skin cancers show a better prognosis than other neoplasms, but not all others are equal: Ideally, patient management must take into account the natural history of each type of cancer in relation to the transplanted organs. We sought to determine the prognosis of various groups of noncutaneous nonlymphomatous (NCNL) cancers after heart transplantation (HT). Methods. We retrospectively analyzed the records of the Spanish Post-Heart-Transplant Tumour Registry, which collects data on posttransplant tumors in all patients who have undergone HT in Spain since 1984. Data were included in the study up to December 2008. We considered only the first NCNL post-HT tumors. Results. Of 4359 patients, 375 developed an NCNL cancer. The most frequent were cancers of the lung (n = 97; 25.9%); gastrointestinal tract (n = 52; 13.9%); prostate gland (n = 47; 12.5%; 14.0% of men), bladder (n = 32; 8.5%), liver (n = 14; 3.7%), and pharynx (n = 14; 3.7%), as well as Kaposi's sarcoma (n = 11; 2.9%). The corresponding Kaplan-Meier survival curves differed significantly (P < .0001; log-rank test), with respective survival rates of 47%, 72%, 91%, 73%, 36%, 64%, and 73% at 1 year versus 26%, 62%, 89%, 56%, 21%, 64%, and 73% at 2 years; and 15%, 51%, 77%, 42%, 21%, 64%, and 52% at 5 years post-diagnosis, respectively. Conclusion. Mortality among HT patients with post-HT NCNL solid organ cancers was highest for cancers of the liver or lung (79%–85% at 5 years), and lowest for prostate cancer (23%).

Objective. Steroid withdrawal (SW) from maintenance therapy in heart transplant patients is still a controversial subject. We designed a questionnaire to ascertain the attitudes and procedures of a number of Spanish heart transplant units (16) regarding the use/withdrawal of steroids as part of the immunosuppressive maintenance therapy. Materials and Methods. We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units. Results. In 21.5% of the centers SW was performed in all patients, while 78.5% of the centers only performed SW in selected patients. In 57% of units SW was performed at 12 months posttransplantation and between 6 and 12 months in the rest. Fewer than 20% of patients were steroid-free in 46% of units while in 23% of units this proportion was >50%. In 11 units, the minimum prednisone dose administered was

Introduction Statins, although the treatment of choice for dyslipidemia after heart transplantation (HT), are not always well tolerated or effective. In such cases, administration of ezetimibe may be useful. Aim The aim of this study was to assess the efficacy and safety of ezetimibe, with or without statins, after HT. Method Thirty-six HT patients, 97% of whom were males of overall mean age of 57 ± 13 years, were all unable to reach target lipid levels with statins alone and/or were intolerant of statins. They were prescribed ezetimibe, with or without a statin. Efficacy and safety were evaluated after 1, 3, 6, and 12 months. Results Thirty-four patients were evaluated at 1 month and 12 months. Ezetimibe was prescribed to 27 patients (75%) because of statin inefficacy, and to 9 patients (25%) because of statin intolerance, manifested by myalgia in 4 cases (11%), hepatotoxicity in 2 cases (6%), and rhabdomyolysis in 3 cases (8%). Lipid levels (mg/dL; baseline vs 1 year) were as follows: cholesterol, 235 ± 49 versus 167 ± 32 ( P = .013); LDL cholesterol, 137 ± 47 versus 89 ± 29 ( P = .001); HDL cholesterol, 54 ± 13 versus 51 ± 10 ( P = .235); and triglycerides, 243 ± 187 versus 143 ± 72 ( P = .022). There were no cases of liver toxicity, renal dysfunction, or significant alteration of immunosuppressive pharmacokinetics. Ezetimibe was withdrawn from 2 patients because of hand edema or asymptomatic recurrence of rhabdomyolysis first caused by statins. Conclusions With or without a statin, ezetimibe was generally well tolerated, reducing total cholesterol, LDL cholesterol, and triglyceride levels with no long-term alteration of HDL cholesterol levels. CPK surveillance is recommended because of a slight continued risk of adverse effects. Further studies should evaluate the benefit for survival.

[Abstract] The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984–2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

s S115 additional serial samples were obtained from each pt (82 samples total). 21 pts were treated for the rejection event, with 17 having consecutive samples available from both the treatment and post-treatment visits required to determine the change in dd-cfDNA following treatment for rejection. Results: For these 17 cases, dd-cfDNA increased more than 2-fold in 3 cases, decreased more than 2-fold in 6 cases, and changed modestly (less than a 2-fold increase or decrease) in 8 cases. In 5 cases where the post-treatment biopsy was graded 0R, suggesting the pt responded favorably to treatment, dd-cfDNA decreased by more than 1.8-fold in 3 cases. Of the 11 samples that did not decrease by at least 2-fold, 6 cases experienced a subsequent 1R or 2R grade rejection event within 30 days of the post-treatment visit, suggesting that the initial treatment may not have been sufficient. Two samples with relatively large (1.9and 3.6-fold) increases in dd-cfDNA following treatment did not show any clinical signs of rejection. Conclusion: Consistent with previously observed rapid-clearance of ddcfDNA from peripheral blood, dd-cfDNA is a quantitative indicator of allograft health. Preliminary data suggest that levels of dd-cfDNA immediately following treatment of a rejection event often decrease when the rejection resolves, but may stay elevated or increase if signs of rejection persist. ddcfDNA may be a useful, non-invasive biomarker to ascertain clinical response to rejection treatment. (Study sponsored by CareDx, Inc.)

Purpose To date, there are no specific scales to assess the cardiovascular risk (CVR) of heart transplant (HT) recipients. The Cardiac Transplantation & Cardiovascular risk factors (CTC) study is the first to assess the CVR of HT recipients, and the impact of the different cardiovascular risk factors (CVRF) on the morbidity and mortality of this population. Methods and Materials A 3-year, prospective, multicenter, epidemiological study of adult recipients of a first HT in Spain. Both general population- and HT-specific- CVRF were recorded at month 6 (baseline CVR), 12, 18, 24, 30 and 36 post-HT. The main endpoint was to assess the impact of CVRF on the incidence of chronic allograft vasculopathy (CAV), mortality and re-transplantation at 3 years. A HT-specific CVR scale will be developed based on the data analysis. In this preliminary report we present the epidemiological data at 18 months post-HT. Results 404 patients were included (males: 76.3%; mean age: 54.0±10.7 years). The most common reasons for HT were ischemic cardiopathy (41.2%) and dilated cardiomyopathy (39.9%). At 18 months post-HT the accumulated incidence of CAV, mortality and re-transplantation were 11%, 12,9% and 0%, respectively. The most common CVRF were hypertension (72.8%), hyperhomocysteinemia (63.6%) and left ventricular hypertrophy (48.5%). A significant increase in the body mass index (BMI) and in the systolic/diastolic blood pressure was observed between months 6 and 18 post-HT (from 25.6±4.0 kg/m² to 26.8±4.2 kg/m² [p Conclusions After HT a progressive increase in the BMI, blood pressure and estimated CVR are seen. The 3-year data from the CTC study may define the impact of the different CVRF on the outcomes of HT in Spain.

Purpose GEP (AlloMap) score instability has been shown to predict of events of graft dysfunction or death in an analysis of the IMAGE data set by Deng et al. Our goal is to test this hypothesis in the independent CARGO 2 patient data set. Methods and Materials In a case-cohort design, patients with >2 serial GEP tests were studied in multivariate Cox regression models to predict future clinical events. Intra-patient GEP score instability was defined as the standard deviation of an individual’s cumulative test scores. GEP score (range 0-39), GEP score ≥34, and GEP score stability were studied. Results GEP scores tend to rise and become more stable in the whole population during the first year post-transplantation than after 1 year. After 12 months, GEP score instability (p=0.001) and GEP ≥34 (p=0.06) predict future events. [ figure 1 ]

[Abstract] Background. HAV syndrome, the combination of hypotension, acidosis and vasodilation (HAV), is a serious postoperative complication after heart transplantation (HT). Its etiology and prognosis are poorly understood. Aim. To determine the incidence and prognosis of post-HT HAV syndrome and examine possible risk factors. Methods. Retrospective examination of the records of 85 consecutive patients who underwent HT between December 1999 and June 2002 sought the HAV criteria: systolic BP

[Abstract] Background. Renal dysfunction is a common complication after orthotopic heart transplantation (HT). The importance of factors other than exposure to immunosuppressive drugs is unclear. The purpose of this study was to determine the incidence and natural history of renal dysfunction following heart transplantation, and to evaluate a number of variables as risk factors for this condition. Methods. We examined the creatinine levels at 1, 6, 12, 24, and 60 months in 262 consecutive heart transplant patients who survived at least 1 year. The potential risk factors included pre- and posttransplantation diabetes mellitus, arterial hypertension, and drugs used to control arterial hypertension. Results. 17.2% of patients showed mild renal dysfunction (creatinine 1.5-2.5 mg/dL) and 1.9% moderate dysfunction (creatinine >2.5 mg/dL) at 1 month; 29.8% showed mild and 1.1% moderate dysfunction at 6 months; 33.2% showed mild and 1.9% moderate dysfunction at 1 year; 40% showed mild, 0.9% moderate and 0.4% severe dysfunction (requiring dialysis or renal transplantation) at 2 years; and 43.6% showed mild, 1.7% moderate and 0.9% severe dysfunction at 5 years. None of the conditions analyzed as possible risk factors showed a significant association with renal dysfunction except the use of diuretics. Conclusion. The incidence of renal dysfunction after orthotopic heart transplantation was 33.6% within the first year after transplant and 44% within the first five years, although more than 95% of cases were mild. The incidence increased with time after transplantation. Renal dysfunction seems likely to be multifactorial in origin, but no individual risk factors were identified.

1/2 }, are measures of the spatial irregularity of myocardial electrical conduction. Both have been identified as risk markers in relation to several cardiopathies, and increased QTc dispersion has been related to increased risk of life-threatening ventricular arrhythmias and sudden death.5 and 6 For example, there is growing evidence that QT dispersion and QTc dispersion are correlated with the risk of sudden death among patients with congestive heart failure,7 left ventricle (LV) hypertrophy due to hypertrophic cardiomyopathy,8 ischemic cardiopathy,9 or mitral valve prolapse.10 QT dispersion is also increased in patients with arrhythmogenic right ventricular dysplasia.11 It has been suggested that QT dispersion may be a useful marker or predictor of cardiovascular morbidity and mortality due to complex ventricular arrhythmias in patients with rheumatoid arthritis12 or Duchenne muscular dystrophy13 or of increased risk of cardiac complications in liver transplant candidates.14 The usefulness of QT dispersion analysis in heart transplant patients is still unknown, and few studies have been done in this area. It has been suggested that cardiac allograft vasculopathy results in ventricular repolarization abnormalities that can be detected by an increase in QTc dispersion15 and that QT dispersion might serve as a noninvasive marker of resolution of allograft dysfunction.16 Here we report the results of a study of the relationship between QT dispersion and AR status as determined by EMB.