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Background: The application of posttransplant predictive models is limited by their poor statistical performance. Neglecting the dynamic evolution of demographics and medical practice over time may be a key issue., Objectives: Our objective was to develop and validate era-specific predictive models to assess whether these models could improve risk stratification compared to non-era-specific models., Methods: We analyzed the United Network for Organ Sharing (UNOS) database including first noncombined heart transplantations (2001-2018, divided into four transplant eras: 2001-2005, 2006-2010, 2011-2015, 2016-2018). The endpoint was death or retransplantation during the 1st-year posttransplant. We analyzed the dynamic evolution of major predictive variables over time and developed era-specific models using logistic regression. We then performed a multiparametric evaluation of the statistical performance of era-specific models and compared them to non-era-specific models in 1000 bootstrap samples (derivation set, 2/3; test set, 1/3)., Results: A total of 34 738 patients were included, 3670 patients (10.5%) met the composite endpoint. We found a significant impact of transplant era on baseline characteristics of donors and recipients, medical practice, and posttransplant predictive models, including significant interaction between transplant year and major predictive variables (total serum bilirubin, recipient age, recipient diabetes, previous cardiac surgery). Although the discrimination of all models remained low, era-specific models significantly outperformed the statistical performance of non-era-specific models in most samples, particularly concerning discrimination and calibration., Conclusions: Era-specific models achieved better statistical performance than non-era-specific models. A regular update of predictive models may be considered if they were to be applied for clinical decision-making and allograft allocation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m 2 ( P < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m 2 , P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg -1 ( P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index. NEW & NOTEWORTHY This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.

Objectives: This study aimed to identify perioperative risk factors of acute kidney injury after heart transplantation and to evaluate 1-year clinical outcomes., Design: A retrospective single-center cohort study., Setting: At a university hospital., Participants: All patients who underwent heart transplantation from January 2015 to December 2020., Interventions: None., Measurements and Main Results: The authors recorded acute kidney injury after heart transplantation. One-year mortality and renal function also were recorded. Risk factors of acute kidney injury were evaluated using a multivariate logistic regression model. Long-term survival was compared between patients developing acute kidney injury and those who did not, using a log-rank test. Among 209 patients included in this study, 134 patients (64% [95% CI (58; 71)]) developed posttransplantation acute kidney injury. Factors independently associated with acute kidney injury were high body mass index (odds ratio [OR]: 1.18 [1.02-1.38] per kg/m 2 ; p = 0.030), prolonged duration of cold ischemic period (OR: 1.11 [1.01-1.24] per 10 minutes; p = 0.039), and high dose of intraoperative dobutamine support (OR: 1.24 [1.06-1.46] per µg/kg/min; p = 0.008). At 1 year, patients who developed postoperative acute kidney injury had higher mortality rates (20% v 8%, p = 0.015). Among 172 survivors at 1 year, 82 survivors (48%) had worsened their renal function compared with preheart transplantation., Conclusions: This study highlighted the high incidence of acute kidney injury after heart transplantation and its impact on patient outcomes. Risk factors such as body mass index, prolonged cold ischemic period duration, and level of inotropic support with dobutamine were identified, providing insights for preventive strategies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to • Determine current knowledge gaps in heart transplant pathology • Identify limitations of current pathology classification systems • Discuss next steps in addressing gaps and refining classification system., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed., Methods: In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models., Results: Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups ( P =0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19-1.38]; P =0.18; RCM, 1.04 [95% CI, 0.42-2.58]; P =0.94; congenital heart disease, 1.82 [95% CI, 0.78-4.26]; P =0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92-1.51]; P =0.19; RCM: HR, 1.19 [95% CI, 0.90-1.58]; P =0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53-1.09]; P =0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06-4.24]; P =0.03)., Conclusions: Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme., Competing Interests: Disclosures None.

While studies have shown an association between microRNAs and cardiac rejection, the clinical relevance of a preidentified miRNA signature as a noninvasive biomarker has never been assessed in prospective multicentric unselected cohorts. To address this unmet need, we designed a prospective study (NCT02672683) including recipients from 11 centers between August 2016 to March 2018. The objective was to validate the association between 3 previously identified circulating microRNA (10a, 92a, 155) and the histopathological diagnosis of rejection. Both relative and absolute (sensitivity analysis) quantifications of microRNAs were performed. Overall, 461 patients were included (831 biopsies, 79 rejections). A per-protocol interim analysis (258 biopsies, 49 rejections) did not find any association between microRNA and rejection (microRNA 10a: odds ratio (OR) = 1.05, 95% confidence intervals (CI) = 0.87-1.27, p = 0.61; 92a: OR = 0.98, 95%CI = 0.87-1.10, p = 0.68; 155: OR = 0.91, 95%CI = 0.76-1.10, p = 0.33). These results were confirmed in the sensitivity analysis. The analysis of the remaining sera was stopped for futility. This study shows no clinical utility of circulating microRNAs 10a, 92a, and 155 monitoring in heart allograft recipients., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Allosensitization represents a major barrier to heart transplantation. We previously reported favorable 1-year outcomes of complement inhibition at transplant in highly sensitized recipients. We now report a longer follow-up. In this single-arm trial (NCT02013037), 20 patients with panel reactive antibodies ≥70% and preformed donor-specific antibodies received eculizumab during the first 2 months post-transplant. The primary end-point was antibody-mediated rejection ≥ pAMR2 and/or left ventricular dysfunction. The median follow-up was 4.8 years. Beyond the first year post-transplant, there were no episodes of pAMR2 or greater and no Left Ventricular (LV) dysfunction. There were 3 deaths, 1 episode of pAMR1, and 1 patient with minimal de novo cardiac allograft vasculopathy. Compared to a matched control group, we observed a nonstatistically significant benefit of eculizumab with a lower incidence of the primary end-point or death (primary end-point: hazard ratio = 0.50, 95% confidence interval = 0.15-1.67, and p = 0.26; mortality: hazard ratio = 0.51, 95% confidence interval = 0.13-2.07, and p = 0.35). Our results support the utility of complement inhibition for high-immunological-risk recipients. CLINICAL TRIAL REGISTRATION: ClinincalTrials.gov, NCT02013037. https://clinicaltrials.gov/ct2/show/NCT02013037?term=eculizumab&cond=heart+transplantation&draw=2&rank=1., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT)., Methods and Results: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05)., Conclusions: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The molecular refinement of the diagnosis of heart allograft rejection based on whole-transcriptome analyses faces several hurdles that greatly limit its widespread clinical application. The targeted Banff Human Organ Transplant gene panel (B-HOT, including 770 genes of interest) has been developed to facilitate reproducible and cost-effective gene expression analysis of solid organ allografts. We aimed to determine in silico the ability of this targeted panel to capture the antibody-mediated rejection (AMR) molecular profile using whole-transcriptome data from 137 heart allograft biopsies (71 biopsies reflecting the entire landscape of histologic AMR, 66 non-AMR control biopsies including cellular rejection and non-rejection cases). Differential gene expression, pathway and network analyses demonstrated that the B-HOT panel captured biologically and clinically relevant genes (IFNG-inducible, NK-cells, injury, monocytes-macrophage, B-cell-related genes), pathways (interleukin and interferon signaling, neutrophil degranulation, immunoregulatory interactions, endothelial activation) and networks reflecting the pathophysiological mechanisms underlying the AMR process previously identified in whole-transcriptome analysis. Our findings support the potential clinical use of the B-HOT-gene panel as a reliable proxy to whole-transcriptome analysis for the gene expression profiling of cardiac allograft rejection., Competing Interests: MM is the chairman of the Board of Trustees of the Banff Foundation for Allograft Pathology and receives consultancy honoraria from CSL Behring and Novartis as a central review pathologist for clinical trials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giarraputo, Coutance, Aubert, Fedrigo, Mezine, Zielinski, Mengel, Bruneval, Duong van Huyen, Angelini and Loupy.)

Competing Interests: The authors declare no funding or conflict of interest.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versu s 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tamzali, Pourcher, Azoyan, Ouali, Barrou, Conti, Coutance, Gay, Tourret and Boutolleau.)

Aims: The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population., Methods and Results: Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years [95% confidence interval (CI), 9.7-15.9] in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53-0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048)., Conclusion: HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

SARS-CoV-2 Omicron variant was first detected in France mid-November 2021 in wastewater treatment plants while cases started to increase at the beginning of December. The maximum incidence occurred in mid-January 2022. The Omicron wave spread rapidly throughout France in general population with lower case-fatality rate compared with previous waves. Little is known about infection with Omicron variant in heart transplant (HT) recipients. In this study, we examined incidence and mortality rate of COVID-19 in the general population and among 1,263 HT recipients during the period from June, 2021 to February, 2022, described characteristics of HT recipients infected with SARS-CoV-2 during Omicron (December 1st, 2021-February 7, 2022) and Delta (June 1st- November 30, 2021) periods, and compared hospital course of HT recipients with Omicron and Delta variant infection. Our findings contrast with the reported lower severity for Omicron variant infection compared with Delta variant infection in immunocompetent individuals., Competing Interests: Disclosure statement The authors have no disclosure regarding the present study., (Copyright © 2023 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the association between vasoactive-inotropic score (VIS), calculated in the 24 h after heart transplantation, and post-transplant mortality and morbidity., Methods: This was an observational single-centre retrospective study. Patients admitted to surgical intensive care unit after transplantation, between January 2015 and December 2018, were reviewed consecutively. VISmax was calculated as dopamine+ dobutamine+ 100 × epinephrine + 100 × norepinephrine + 50 × levosimendan + 10 × milrinone (all in µg/kg/min) + 10 000 × vasopressin (units/kg/min), using the maximum dosing rates of vasoactive and inotropic medications in the 24 h after intensive care unit admission. The primary outcome was mortality at 1 year post-transplant. The secondary outcomes included length of stay, duration of mechanical ventilation and inotropic support and the occurrence of septic shock, ventilator-associated pneumonia, bloodstream infection or renal replacement therapy., Results: A total of 151 patients underwent heart transplantation and admitted to intensive care unit. The median VISmax was 39.2 (interquartile range = 19.4-83.0). VISmax was independently associated with 1-year post-transplant mortality, as well as recipient age [hazard ratio (HR) = 1.004, P-value = 0.013], recipient gender (female to male: hazard ratio = 2.23, P-value = 0.047) and combined transplantation (hazard ratio = 2.85, P-value = 0.048). There was a significant association between VISmax and duration of mechanical ventilation (P-value < 0.001), length of stay (P-value = 0.002), duration of infused inotropes (P-value < 0.001), occurrence of bloodstream infections, septic shocks, ventilation-acquired pneumonia and renal replacement therapy., Conclusions: VISmax calculated during the first 24 h after postoperative intensive care unit admission in transplanted patients is independently associated with 1-year mortality. In addition, length of stay, duration of mechanical ventilation and infused inotropes increased with increasing VISmax., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: In 2018, a cardiac allocation scheme based on an individual score considering the risk of death both on the waitlist and after heart transplantation was implemented in France., Aims: To analyse the practical application of the pre- and post-transplant risk score in a French high-volume heart transplantation centre., Methods: All consecutive adult patients listed for a first non-combined heart transplantation between 02 January 2018 and 30 June 2022 at our centre were included. Baseline characteristics of candidates and recipients were retrieved from the national CRISTAL registry. Both scores were calculated at listing and at transplant., Results: Overall, 364 patients were included. During follow-up, 257 patients (70.6%) were transplanted, and 57 (15.6%) died or were removed from the waitlist. Post-transplant 3-month survival was 84.8%. Total bilirubin and natriuretic peptides had the most important weight in the pretransplant risk score. This score had a major impact on waitlist outcomes: quartile 1 was characterized by low access to heart transplantation (58.2%) and risk of death on the waitlist (9.9%) compared with quartile 4 (heart transplantation rate 74.1%, mortality on the waiting list>20%). According to the post-transplant risk score, a minimal number of candidates were considered ineligible for heart transplantation (<1%), but 12.4% were contraindicated to at least one donor category. The number of contraindicated donor categories had a significant impact on waitlist outcomes. Although adequately calibrated, the post-transplant score had a limited discrimination (area under the curve 0.65, 95% confidence interval 0.59-0.71)., Conclusion: Our results highlight the major impact of pre- and post-transplantation risk scores on waitlist outcomes following the allocation scheme update., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: In 2018, a new cardiac allograft allocation scheme, based on an individual scoring system, considering the risk of death both on the waiting list and after heart transplantation, was implemented in France., Aim: To assess the impact of this new scheme on the profile of transplantation candidates and recipients., Methods: In this single-centre retrospective study, we included consecutive patients listed and/or transplanted between 01 January 2012 and 30 September 2021 at La Pitié-Salpêtrière Hospital. Baseline characteristics of patients were retrieved from the national CRISTAL registry and were compared according to the type of allocation scheme (before or after 2018)., Results: A total of 1098 newly listed transplantation candidates and 855 transplant recipients were included. One-year mortality rates after listing and after transplantation were 12.4% and 20%, respectively. At listing, the proportion of candidates on inotropes significantly declined following the scheme update (26.3 versus 20.9%; P=0.038), reflecting a change in medical practice. At transplantation, recipients had worse kidney function (estimated glomerular filtration rate<60mL/min/1.73 m 2 : old scheme, 29.7%; new scheme, 46.4%; P<0.001) and were more likely to be on extracorporeal membrane oxygenation support (33.5% versus 28.1%; P=0.080) under the new scheme, reflecting the prioritization of more severe patients. Outcomes after transplantation were not significantly influenced by the allocation system., Conclusions: The implementation of the 2018 French allocation scheme had a limited impact on the profile of transplantation candidates, but selected more severe patients for transplantation without significant impact on outcomes after transplantation., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Few data exist on the characteristics and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy and advanced heart failure who undergo heart transplantation., Aim: To explore the pretransplant course and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy after heart transplantation., Methods: This observational retrospective monocentric study included all consecutive patients with arrhythmogenic right ventricular cardiomyopathy who underwent heart transplantation during a 13-year period (2006-2019) at Pitié-Salpêtrière University Hospital (Paris)., Results: A total of 23 patients with arrhythmogenic right ventricular cardiomyopathy underwent heart transplantation between 2006 and 2019. The median time from diagnosis to heart transplantation was 9 years, and the median age at transplantation was 50 years. At diagnosis, half of the patients had left ventricular dysfunction, 59% had extensive T-wave inversion and 43% had a history of sustained ventricular tachycardia. Only five patients were involved in intensive sport activity. Indications for heart transplantation were end-stage biventricular dysfunction in 13 patients, end-stage right ventricular heart failure in seven and electrical storm in three. Only three patients had pulmonary hypertension, and half of the patients had atrial arrhythmias. The survival rate 1 year after heart transplantation was 74% (95% confidence interval 53-88%). Eight patients experienced primary graft dysfunction needing extracorporeal membrane oxygenation., Conclusions: Patients with arrhythmogenic right ventricular cardiomyopathy who eventually needed heart transplantation mostly exhibited extended disease with biventricular dysfunction at diagnosis. Intensive sport activity did not seem to be a major determinant. Advanced heart failure usually occurred late in the course of the disease. Primary graft dysfunction after heart transplantation was frequent, and should be anticipated. Additional data are needed to identify the optimal timing for heart transplantation and predictors of end-stage heart failure in patients with arrhythmogenic right ventricular cardiomyopathy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Aims: The value of Forrester's perfusion/congestion profiles assessed by invasive catheter evaluation in non-inotrope advanced heart failure patients listed for heart transplant (HT) is unclear. We aimed to assess the value of haemodynamic evaluation according to Forrester's profiles to predict events on the HT waitlist., Methods and Results: All non-inotrope patients (n = 837, 79% ambulatory at listing) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 with right heart catheterization (RHC) were included. The primary outcome was a combined criteria of waitlist death, delisting for aggravation, urgent HT or left ventricular assist device implantation. Secondary outcome was waitlist death. The 'warm-dry', 'cold-dry', 'warm-wet', and 'cold-wet' profiles represented 27%, 18%, 27%, and 28% of patients, respectively. At 12 months, the respective rates of primary outcome were 15%, 17%, 25%, and 29% (P = 0.008). Taking the 'warm-dry' category as reference, a significant increase in the risk of primary outcome was observed only in the 'wet' categories, irrespectively of 'warm/cold' status: hazard ratios, 1.50; 1.06-2.13; P = 0.024 in 'warm-wet' and 1.77; 1. 25-2.49; P = 0.001 in 'cold-wet'., Conclusions: Haemodynamic assessment of advanced HF patients using perfusion/congestion profiles predicts the risk of the combine endpoint of waitlist death, delisting for aggravation, urgent heart transplantation, or left ventricular assist device implantation. 'Wet' patients had the worst prognosis, independently of perfusion status, thus placing special emphasis on the cardinal prominence of persistent congestion in advanced HF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In heart transplantation, antibody-mediated rejection (AMR) is a major contributor to patient morbidity and mortality. Multiple routine endomyocardial biopsies (EMB) remain the gold standard to detect AMR, but this invasive procedure suffers from many limitations. We aimed to develop and validate an AMR risk model to improve individual risk stratification of AMR., Methods: Heart recipients from 2 referral transplant centers, Cedars-Sinai (US) and Pitié-Salpêtrière (France), were included from 2012 to 2019. Database included detailed clinical, immunologic, imaging, and histological parameters. The US cohort was randomly distributed in a derivation (2/3) and in a test set (1/3). The primary end point was biopsy-proven AMR. A mixed effect logistic regression model with a random intercept was applied to identify variables independently associated with AMR. Simulation analyzes were performed., Results: The US and French cohorts comprised a total of 1341 patients, representing 12 864 EMB. Overall, 490 AMR episodes were diagnosed (3.8% of EMB). Among the 26 potential determinants of AMR, 5 variables showed independent association: time post-transplant ( P <0.001), pretransplant sensitizing event ( P =0.001), circulating donor-specific anti-human leukocyte antigen antibody ( P =0.001), graft dysfunction ( P =0.004), and prior history of definite AMR ( P <0.001). In the US test set, the calibration and the discrimination of the model were accurate (area under the curve, 0.79 [95% CI, 0.78-0.81]). Those results were confirmed in the external validation cohort (area under the curve, 0.78 [95% CI, 0.77-0.79]) and reinforced by various sensitivity analyses. The model also showed good performance to predict overall cause of rejection. Simulation models revealed that the AMR risk model could safely reduce the number of EMB., Conclusions: Our results support the use of the AMR risk model as a clinical decision tool to minimize the number of routine EMB after heart transplantation.

Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, suffers from many limitations including the low prevalence of rejection, sample bias, high inter-observer variability, and international working formulations based on arbitrary cut-offs that simplify the landscape of rejection. The development of innovative diagnostic and prognostic strategies-integrating conventional histology, molecular profiling of allograft biopsy, and the discovery of new tissue or circulating biomarkers-is one of the major challenges of translational medicine in solid organ transplantation, and particularly in heart transplantation. Major advances in the field of biomarkers of rejection have paved the way for a paradigm shift in the monitoring and diagnosis of cardiac allograft rejection. We review the recent developments in the field, including non-invasive biomarkers to minimize the number of protocol endomyocardial biopsies and tissue biomarkers as companion tools of pathology to refine the diagnosis of cardiac rejection. Finally, we discuss the potential role of these biomarkers to provide an integrated bio-histomolecular diagnosis of cardiac allograft rejection.

Background: The pathology-based diagnosis of cardiac antibody-mediated rejection (AMR) relies on the 2013 International Society for Heart and Lung Transplantation Working Formulation, in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMBs)., Methods: We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale in which MVI scores of 0, 1, 2, and 3 represented 0%, 1%-10%, 11%-50%, and >50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by microarrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pathologic AMR [pAMR]), anti-HLA donor-specific antibodies, and graft dysfunction., Results: Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%), and 44 (15.1%) EMB were given MVI scores of 0, 1, 2, and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogeneous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independent of the C4d or CD68 status (P < 0.001). Both the frequency and mean fluorescence intensity of donor-specific antibodies gradually increased with the MVI score (P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 (P < 0.001)., Conclusions: The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To evaluate the association between donors' and recipients' serum levels of soluble ST2 (sST2) and recipients' outcome after heart transplantation (HT)., Methods: Blood samples were collected in 50 heart donors before organ procurement and in 50 recipients before HT (D0), a week after HT (D7) and at every first year's endomyocardial biopsy (EMB); sST2 levels were evaluated by ELISA., Results: Donors who sustained a cardiac arrest, had significantly higher sST2 levels. Recipients on national high emergency waiting list had significantly higher preoperative sST2 levels compared to recipients who did not. Recipients with postoperative sepsis or continuous renal replacement therapy had significantly higher sST2 levels at D7. Recipients who needed a postoperative ECMO for allograft dysfunction had significantly higher sST2 levels in their corresponding donors. Recipients who died during the hospitalization after the transplantation had significantly higher sST2 levels at D7 compared to recipients who did not. No difference was observed in sST2 levels in recipients who had mild allograft rejection and recipient who did not., Conclusions: Higher sST2 levels in donors are associated to allograft dysfunction requiring ECMO in recipients; higher postoperative sST2 levels in recipients are associated with in-hospital mortality., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The clinical use of post-transplant risk scores is limited by their poor statistical performance. We hypothesized that developing specific prognostic models for each type of circulatory support at transplant may improve risk stratification., Methods: We analyzed the UNOS database including contemporary, first, non-combined heart transplantations (2013-2018). The endpoint was death or retransplantation during the first year post-transplant. Three different circulatory support statuses at transplant were considered: no support, durable mechanical support and temporary support (inotropes, temporary mechanical support). We generated 1,000 bootstrap samples that we randomly split into derivation and test sets. In each sample, we derived an overall model and 3 specific models (1 for each type of circulatory support) using Cox regressions, and compared, in the test set, their statistical performance for each type of circulatory support., Results: A total of 13,729 patients were included; 1,220 patients (8.9%) met the composite endpoint. Circulatory support status at transplant was associated with important differences in baseline characteristics and distinct prognosis (p = 0.01), interacted significantly with important predictive variables included in the overall model, and had a major impact on post-transplant predictive models (type of variables included and their corresponding hazard ratios). However, specific models suffered from poor discriminative performance and significantly improved risk stratification (discrimination, reclassification indices, calibration) compared to overall models in a very limited proportion of bootstrap samples (<15%). These results were consistent across several sensitivity analyzes., Conclusion: Circulatory support status at transplant reflected different disease states that influenced predictive models. However, developing specific models for each circulatory support status did not significantly improve risk stratification., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail., Methods: In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value., Results: We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival ( P =0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status ( P =0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype., Conclusions: Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed., (Copyright © 2021 by the American Society of Nephrology.)

Background: Cytomegalovirus (CMV) infection remains a common complication after heart transplantation (HTx). The association between CMV infection and allograft rejection is debated in the era of efficient prophylactic antiviral therapies., Methods: This single-center cohort study utilized a highly phenotyped database of HTx recipients (2012-2016). The primary endpoint was the analysis of the association between CMV infection (CMV load ≥ 500 IU/mL whole blood) and the risk of allograft rejection (cellular rejection ≥ 1R1B, antibody-mediated rejection ≥ pAMR1). Secondary endpoints included the analysis of a higher CMV load threshold (≥10 000 IU/mL) and different risk periods after PCR positivity. A mixed-effect logistic regression model with a random intercept was applied. Results were adjusted for important risk factors of rejection., Results: Overall, 384 patients were included and 6388 CMV loads and 3,494 endomyocardial biopsies were analyzed. CMV infections ≥ 500 IU/mL were diagnosed on 1223 (19.2%) blood samples from 284 (72.1%) patients and allograft rejections on 246 biopsies (7%) from 149 patients (38.8%). We did not find any association between CMV infection ≥ 500 IU/mL and rejection (univariable: OR 0.94, 95% CI [0.61, 1.45], P = .78, multivariable: OR 0.86, 95% CI [0.55, 1.33], P = .85). These results were consistent when analyzing a higher CMV load threshold and different periods of risk, reinforced by internal validation procedures and a posteriori calculation of the power (primary endpoint: power = 0.82, 95% CI [0.79-0.84]) and reproducible across different clinical scenarios., Conclusions: CMV infection was not associated with an increased risk of rejection in a contemporary cohort of HTx recipients., (© 2021 Wiley Periodicals LLC.)

Background: Sensitized patients, i.e. recipients with preformed donor-specific HLA antibodies (pfDSA), are at high-risk of developing antibody-mediated rejections (AMR) and dying after heart transplantation (HTx). Perioperative desensitization procedures are associated with better outcomes but can cause sensitization, which may influence their efficacy., Methods: In sensitized patients (pfDSA>1000 mean immunofluorescence (MFI) units), we assessed the effect of perioperative desensitization by comparing treated patients to a historical control cohort. Multivariable survival analyses were performed on the time to main outcome, a composite of death and biopsy-proven AMR with 5-year follow-up., Results: The study included 68 patients: 31 control and 37 treated patients. There was no difference in preoperative variables between the two groups, including cumulative pfDSA [4026 (1788;8725) vs 4560 (3162;13392) MFI units, p =0.28]. The cause of sensitization was pregnancy in 24/68, 35.3%, transfusion in 61/68, 89.7%, and previous HTx in 4/68, 5.9% patients. Multivariable analysis yielded significant protective association between desensitization and events (adjusted (adj.) hazard ratio (HR)=0.44 (95% confidence interval (95CI)=0.25-0.79), p =0.006) and deleterious association between cumulative pfDSA and events [per 1000-MFI increase, adj.HR=1.028 (1.002-1.053), p=0.031]. There was a sex-difference in the efficacy of desensitization: in men (n=35), the benefit was significant [unadj.HR=0.33 (95CI=0.14-0.78); p=0.01], but not in women (n=33) [unadj.HR=0.52 (0.23-1.17), p=0.11]. In terms of the number of patients treated, in men, 2.1 of patients that were treated prevented 1 event, while in women, 3.1 required treatment to prevent 1 event., Conclusion: Perioperative desensitization was associated with fewer AMR and deaths after HTx, and efficacy was more pronounced in men than women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nguyen, Salem, Bories, Coutance, Amour, Bougle, Suberbielle, Kheav, Carmagnat, Rouvier, Kirsch, Varnous, Leprince and Saheb.)

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Pathology is still the gold standard for the diagnosis of rejection in heart transplantation. During the last decade, molecular pathology has emerged as a powerful tool for the understanding of the processes implicated in allograft rejection. Transcriptomic analysis of the allograft may also help the pathologist for diagnosis and accurate classification of rejection. This review will describe the recent advances and perspectives of molecular pathology in the field of heart transplantation., (Copyright © 2020. Published by Elsevier Masson SAS.)

Accurate risk stratification of early heart transplant failure is required to avoid futile transplants and rationalize donor selection. We aimed to evaluate the statistical performance of existing risk scores on a contemporary cohort of heart transplant recipients. After an exhaustive search, we identified 16 relevant risk scores. From the UNOS database, we selected all first noncombined adult heart transplants performed between 2014 and 2017 for validation. The primary endpoint was death or retransplant during the first year posttransplant. For all scores, we analyzed their association with outcomes, sensitivity, specificity, likelihood ratios, and discrimination (concordance index and overlap of individual scores). The cohort included 9396 patients. All scores were significantly associated with the primary outcome (P < .001 for all scores). Their likelihood ratios, both negative and positive, were poor. The discriminative performance of all scores was limited, with concordance index ranging from 0.544 to 0.646 (median 0.594) and an important overlap of individual scores between patients with or without the primary endpoint. Subgroup analyses revealed important variation in discrimination according to donor age, recipient age, and the type of assist device used at transplant. Our findings raise concerns about the use of currently available scores in the clinical field., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Competing Interests: Disclosure: The authors have no conflicts of interest to report.

Background: To evaluate the early and late outcome of heart transplantation (HT) using marginal (MDs) and optimal donors (ODs)., Methods: Clinical records of recipients transplanted between July 2004 and December 2014 were retrospectively reviewed. MDs were defined as follows: age >55 years, high-dose inotropic support, left ventricular ejection fraction <45%, left ventricular hypertrophy, donor to recipient predicted heart mass ratio <0.86, ischemic time >4 hours., Results: A total of 412 (55%) recipients received an organ from a MD; recipients who received an organ from an OD had less primary graft dysfunction (PGD) (25% vs 38%; P < .001), less acute renal failure (23% vs 34%; P < .001), and higher survival rates (90.2% vs 81.8% at 30 days, 79.5% vs 71.1% at 1 year, 51.8% vs 45.4% at 12 years; P = .01) than recipients who received an organ from a MD. There was no statistically significant difference in 30-day conditional survival between the two groups (survival rates 57.4% vs 55.5% at 12 years; P = .43). PGD, perioperative hemodialysis, and sepsis were independent risk factors of mortality at multivariate analysis., Conclusions: Utilization of MDs for HT is associated with a higher incidence of PGD and acute renal failure, and a reduction of 30-day survival., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3 months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n = 128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P = .007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P = .002). These results were confirmed in the overall cohort (n = 213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development., Methods: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality., Results: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age ( P <0.001), donor male sex ( P <0.001), donor tobacco consumption ( P =0.001), recipient dyslipidemia ( P =0.009), class II anti-human leukocyte antigen donor-specific antibodies ( P =0.004), and acute cellular rejection ≥2R ( P =0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality ( P <0.001)., Conclusions: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.

Objectives: Heart transplantation in patients supported by venoarterial extracorporeal membrane oxygenation has been associated with poor prognosis. A specific protocol for extracorporeal membrane oxygenation management encompassing patient selection, implantation strategy, and preoperative and perioperative treatment is applied at our institution. Our aim was to compare posttransplant outcomes of patients supported or not by extracorporeal membrane oxygenation at the time of heart transplantation., Design: A large observational single-center retrospective study was conducted. The primary endpoint was overall survival after heart transplantation. Secondary endpoints included death-censored rejection-free survival and the frequency of extracorporeal membrane oxygenation-related complications., Setting: One heart transplantation and extracorporeal membrane oxygenation high-volume center., Patients: All consecutive patients over 18 years old with a first noncombined heart transplantation performed between 2012 and 2016 were included., Interventions: None (retrospective observational study)., Measurements and Main Results: Among the 415 transplanted patients, 118 (28.4%) were on extracorporeal membrane oxygenation at the time of transplantation (peripheral, 94%; intrathoracic, 6%). Median time on extracorporeal membrane oxygenation before heart transplantation was 9 days (interquartile range, 5-15 d) and median follow-up post heart transplantation was 20.7 months. Posttransplant survival did not differ significantly between the two groups (1-yr survival = 85.5% and 80.7% in extracorporeal membrane oxygenation vs nonextracorporeal membrane oxygenation patients; hazard ratio, 0.69; 95% CI, 0.43-1.11; p = 0.12, respectively). Donor age, body mass index, creatinine clearance, and ischemic time were independently associated with overall mortality, but not extracorporeal membrane oxygenation at the time of heart transplantation. Rejection-free survival also did not significantly differ between groups (hazard ratio, 0.85; 95% CI, 0.60-1.23; p = 0.39). Local wound infection was the most frequent complication after extracorporeal membrane oxygenation (37% of patients)., Conclusions: With the implementation of a specific protocol, patients bridged to heart transplantation on extracorporeal membrane oxygenation had similar survival compared with those not supported by extracorporeal membrane oxygenation.

Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation., Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed., Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB., Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection., (Copyright © 2019. Published by Elsevier Inc.)

Background: Pneumonia is a frequent complication in patients undergoing heart transplantation (HTx) that increases morbidity and mortality in this population. Nevertheless, the risk factors for postoperative pneumonia (POP) are still unknown. The aim of this study was to investigate the predictive risk factors for POP in HTx recipients., Methods: In this retrospective study, all patients undergoing HTx between January 2014 and December 2015 were included. All cases of POP occurring until hospital discharge were investigated. The study aimed to determine risk factors using univariate and multivariate Cox regression models. Data are expressed in Odds Ratio [95% CI]. P < 0.05 was necessary to reject the null hypothesis., Results: A total of 175 patients were included without any patients being lost to follow-up, and 89 instances of POP were diagnosed in 59 (34%) patients. Enterobacteriaceae and Pseudomonas aeruginosa were the most common pathogens. In the multivariate analysis, the risk factors were preoperative mechanical ventilation (OR 1.42 [1.12-1.80], P < 0.01) and perioperative blood transfusion (OR 1.42 [95% CI: 1.20-1.70], P < 0.01). POP significantly impacted mortality at 30 days (OR: 4 [1.3-12.4], P = 0.01) and 1 year (OR: 6.8 [2.5-8.4], P < 0.01) and was associated with a longer duration of mechanical ventilation, time to weaning from venoarterial extracorporeal membrane oxygenation and stay in an intensive care unit. Plasma exchanges and intravenous administration of immunoglobulins did not increase the risk of POP., Conclusion: After HTx, preoperative mechanical ventilation and blood transfusion were risk factors for POP and were associated with increased mortality. Enterobacteriaceae and Pseudomonas aeruginosa are the most common pathogens of POP.

Background: Management of the increasing number of sensitized heart transplant candidates has become a recurrent issue. Rather than using pretransplant desensitization therapies, we used a posttransplant prophylactic strategy. Our aim was to describe outcomes in transplant recipients with preformed donor-specific anti-HLA antibodies (pfDSA) managed with this strategy., Methods: A posttransplant protocol was applied to patients transplanted with pfDSA, consisting of perioperative management of DSA (polyvalent immunoglobulins +/- perioperative plasmapheresis sessions, according to DSA level, as well as induction therapy) and systematic treatment of subsequent antibody-mediated rejection (AMR), even when subclinical. We performed a retrospective analysis of this prospective protocol. The study included all consecutive first recipients of a noncombined heart transplant performed between 2009 and 2015 at our center. The primary endpoint was all-cause mortality. Secondary endpoints included primary graft dysfunction, early posttransplant bleeding, rejection, and cardiac allograft vasculopathy-free survival., Results: A total of 523 patients were studied, including 88 (17%) and 194 (37%) transplanted with DSA mean fluorescence intensity (MFI) of 500 to 1000 and greater than 1000, respectively. The median follow-up period was 4.06 years. Survival was not significantly different between groups. Rejection-free survival was worse in patients with pfDSA MFI >1000, evidenced by a fourfold increase in the risk of antibody-mediated rejection. The incidence of primary graft dysfunction and cardiac allograft vasculopathy-free survival did not significantly differ between groups. Perioperative plasmapheresis increased the risk for transfusion of packed red blood cells., Conclusions: This exclusively posttransplant prophylactic strategy achieved favorable outcomes in heart transplant recipients with pfDSA.

Gender-difference regarding antibody-mediated rejection (AMR) after heart transplantation has been described. However, no study accounted for the presence of preformed donor-specific antibodies (pfDSA), a known risk factor of AMR, more common among women than men. In a single-institution 6-year cohort (2010-2015), time to AMR was assessed, comparing men with women by survival analysis with a 1-year death-censored follow-up. All AMRs were biopsy proven. Confounding variables that were accounted for included mean intensity fluorescence (MFI) of pfDSA, recipient age, HLA-, size- and sex-mismatch. 463 patients were included. Overall incidence of AMR was 10.3% at 1 year. After adjusting for confounding variables, independent risk factors of AMR were female recipient gender (adjusted hazard-ratio [adj. HR] = 1.78 [1.06-2.99]), P = .03) and the presence of pfDSA (adj. HR = 3.20 [1.80-5.70], P < .001). This association remained significant when considering pfDSA by their MFI; female recipient gender had an adj. HR = 2.2 (P = .026) and MFI of pfDSA (per 1 MFI-increase) adj. HR = 1.0002 (P < .0001). In this cohort, women were at higher risk of AMR than men and this risk increase was additive to that of pfDSA. These findings may suggest a gender-related difference in the severity of pfDSA., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Several risk scores exist to help identify best candidate recipients for heart transplantation (HTx). This study describes the performance of five heart failure risk scores and two post-HTx mortality risk scores in a French single-centre cohort. All patients listed for HTx through a 4-year period were included. Waiting-list risk scores [Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC), Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) and Get With The Guidelines-Heart Failure (GWTG-HF)] and post-HTx scores Index for Mortality Prediction After Cardiac Transplantation (IMPACT and CARRS) were computed. Main outcomes were 1-year mortality on waiting list and after HTx. Performance was assessed using receiver operator characteristic (ROC), calibration and goodness-of-fit analyses. The cohort included 414 patients. Waiting-list mortality was 14.0%, and post-HTx mortality was 16.3% at 1-year follow-up. Heart failure risk scores had adequate discrimination regarding waiting-list mortality (ROC AUC for HFSS = 0.68, SHFM = 0.74, OPTIMIZE-HF = 0.72, MAGGIC = 0.70 and GWTG = 0.77; all P-values <0.05). On the contrary, post-HTx risk scores did not discriminate post-HTx mortality (AUC for IMPACT = 0.58, and CARRS = 0.48, both P-values >0.50). Subgroup analysis on patients undergoing HTx after ventricular assistance device (VAD) implantation (i.e. bridge-to-transplantation) (n = 36) showed an IMPACT AUC = 0.72 (P < 0.001). In this single-centre cohort, existing heart failure risk scores were adequate to predict waiting-list mortality. Post-HTx mortality risk scores were not, except in the VAD subgroup., (© 2018 Steunstichting ESOT.)

Background: Data are scarce on the prognosis of heart allograft antibody-mediated rejection (AMR) with cardiogenic shock (CS)., Methods: We performed a retrospective, single center, observational study. We included patients with biopsy-proven AMR and CS. We aimed to analyze the characteristics, treatment, and prognosis of patients treated for CS due to AMR. Patients alive after AMR were followed to analyze recurrences of AMR, graft function, and cardiac allograft vasculopathy (CAV)., Results: Seventeen patients met the inclusion criteria. Patients were mostly males (70%). Median age at diagnosis was 56 years, and median time between heart transplantation and AMR was 21 months. AMR was mostly due to high-level de novo class II DSA. Only 2 patients had past history of biopsy-proven AMR. Despite aggressive immunosuppressive therapies, in-hospital and 1-year mortality were as high as 76% and 82%, respectively. Four patients were discharged from hospital. Two of them were diagnosed with recurrent subclinical AMR: one died suddenly and the other presented rapidly progressive CAV., Conclusion: CS due to AMR occurred mostly in patients without history of AMR who developed de novo class II DSA. Despite aggressive conventional immunosuppressive therapies, prognosis after CS due to AMR was poor., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transdiaphragmatic peritoneopericardial hernia is a rare complication after peritoneopericardial window formation, coronary artery bypass grafting using the gastroepiploic artery, or subxiphoid epicardial pacemaker insertion. We describe two different clinical presentations of transdiaphragmatic peritoneopericardial hernia in patients who had undergone recent heart transplantation. One was an exceptional case of cardiac tamponade caused by small bowel strangulation through a diaphragmatic defect.