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International audience; 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.

Heart transplantation (HTX) is a well-established treatment for suitable patients with end-stage heart failure, intended to prolong their survival and improve their health-related quality of life (HR-QoL). No international consensus exists, however, about the preferred patient-reported outcomes (PROs) and their measures (PROMs) for heart transplant recipients. The purpose of this study, the first step in a mixed-method investigation, was to review the PROMs developed and used in this population to identify the instruments for measuring HR-QoL and adherence to immunosuppressive medications most appropriate for heart transplant patients.This systematic search of the literature in the PubMed database focused on the assessment of PROMs for patients after HTX. We analyzed 66 studies with cross-sectional, 28 with longitudinal, and 2 with mixed-methods designs, as well as 6 literature reviews.These 102 articles used 115 different PROMs, which we categorized as generic HR-QoL instruments (n = 19), domain-specific instruments (n = 71), heart disease-specific instruments (n = 9), and heart transplant-specific instruments (n = 16). They cover different dimensions of HR-QoL and of immunosuppressive-drug experience, with diverse numbers of items, types of scales, and psychometric properties.Despite the abundance of instruments, PROMs for HTX can be improved to meet other patient expectations (i.e., by including important issues such as coping strategies, employment, social support, sexual relationships, spirituality, and beliefs), while paying attention to ease of use, reliability, validity, and the contribution of new technologies. A qualitative approach will complete our project of developing a patient-centered instrument for HTX patients.

Ex vivo lung perfusion (EVLP) is a valuable method for expanding the lung donor pool. Its indications currently differ across centers. This national retrospective cohort study aimed to describe the profile of donors with lungs transplanted after EVLP and determine the effectiveness of EVLP on lung utilization. We included brain-dead donors with at least one lung offered between 2012 and 2019 in France. Lungs transplanted without or after EVLP were compared with those that were rejected. Donor group phenotypes were determined with multiple correspondence analysis (MCA). The association between donor factors and lung transplantation was assessed with a multivariable multinomial logistic regression. MCA revealed that donors whose lungs were transplanted after EVLP had profiles similar to the donors whose lungs were declined and quite different from those of donors with lungs transplanted without EVLP. Donor predictors of graft nonuse included age ≥50 years, smoking history, PaO

A new lung allocation system was introduced in France in September 2020. It aimed to reduce geographic disparities in lung allocation while maintaining proximity. In the previous two-tiered priority-based system, grafts not allocated through national high-urgency status were offered to transplant centres according to geographic criteria. Between 2013 and 2018, significant geographic disparities in transplant allocation were observed across transplant centres with a mean number of grafts offered per candidate ranging from 1.4 to 5.2. The new system redistricted the local allocation units according to supply/demand ratio, removed regional sharing and increased national sharing. The supply/demand ratio was defined as the ratio of lungs recovered within the local allocation unit to transplants performed in the centre. A driving time between the procurement and transplant centres of less than 2 h was retained for proximity. Using a brute-force algorithm, we designed new local allocation units that gave a supply/demand ratio of 0.5 for all the transplant centres. Under the new system, standard-deviation of graft offers per candidate decreased from 0.9 to 0.5 (p = 0.08) whereas the mean distance from procurement to transplant centre did not change. These preliminary results show that a supply/demand ratio-based allocation system can achieve equity while maintaining proximity.

The new French heart allocation system is designed to minimize waitlist mortality and extend the donor pool without a detrimental effect on posttransplant survival. This study was designed to construct a 1-year posttransplant graft-loss risk score incorporating recipient and donor characteristics. The study included all adult first single-organ recipients transplanted between 2010 and 2014 (N = 1776). This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables with 1-year graft loss was determined with a mixed Cox model with center as random effect. The predictors were used to generate a transplant-risk score (TRS). Donor-recipient matching was assessed using 2 separate recipient- and donor-risk scores. Factors associated with 1-year graft loss were recipient age >50 years, valvular cardiomyopathy and congenital heart disease, previous cardiac surgery, diabetes, mechanical ventilation, glomerular filtration rate and bilirubin, donor age >55 years, and donor sex: female. The C-index of the final model was 0.70. Correlation between observed and predicted graft loss rate was excellent for the overall cohort (r = 0.90). Hearts from high-risk donors transplanted to low-risk recipients had similar survival as those from low-risk donors. The TRS provides an accurate prediction of 1-year graft-loss risk and allows optimal donor-recipient matching.

Cancer is a leading cause of morbidity and deaths in solid organ transplant recipients. In immunocompetent patients, cancer prognosis has been dramatically improved with the development of immune checkpoint inhibitors (ICI), as programmed cell death protein 1/programmed death-ligand 1 and cytotoxic T lymphocyte-associated antigen 4 inhibitors, that increase antitumor immune responses. ICI has been developed outside of the scope of transplantation because of the theoretical risk of graft rejection, which has later been confirmed by the publication of several cases and small series. The use of ICI became unavoidable for treating advanced cancers including in organ transplant patients, but their management in this setting remains highly challenging, as to date no strategy to adapt the immunosuppression and to prevent graft rejection has been defined. In this article, we report a monocentric series of 5 solid organ transplant recipients treated with ICI and provide a comprehensive review of current knowledge of ICI management in the setting of solid organ transplantation. Strategies warranted to increase knowledge through collecting more exhaustive data are also discussed.

Rationale: Previous studies have shown that a lung-protective strategy, which aims at minimizing ventilator-induced lung injury (with low Vt/high positive end-expiratory pressure as the main pillar...

SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors.

Purpose Data on outcomes in lung transplant recipients with SARS-CoV-2 infection remains limited. Given the potential higher COVID-19 severity in lung recipients, the Agence de la biomedecine has limited the transplant program to patients with high-urgency status during the first epidemic wave. The program has been fully restored where possible during the second epidemic wave. This study aimed to assess the impact of COVID-19 on lung recipient mortality in France. Methods All lung recipients with COVID-19 reported in the French national registry CRISTAL between February 1st and September 30th 2020 were included in the study. Patient characteristics were extracted from CRISTAL. Cumulative number of cases by month since February (Figure 1) and case fatality rate (CFR) were calculated. Mortality rates from February to September in the whole 2019 and 2020 recipient cohorts were compared. Survival curves were estimated using Kaplan-Meier method and compared using the log-rank test. Results Of the 46 patients (median age (IQR) 51 years (39-60), 54% female, median time from transplantation 3.5 years (0.8-7.1)) 88% required hospitalization including 21% in ICU. Eight patients died (CFR: 17.4%). No difference in 3-month survival was observed between 2020 and 2019 recipient cohorts (98.6% 95%CI [98.0%-99.0%] vs 98.4% [97.8%-98.8%], respectively) (Figure 2). Conclusion COVID-19 was associated with lower fatality rate in lung recipients than in other organ transplant recipients and did not result in an excess mortality. These findings suggest that continuing lung transplant activity during the COVID-19 pandemic was a reasonable option.

Background Dilated cardiomyopathy (DCM) is a major cause of systolic heart failure and therefore a major public health issue. Purpose Our objective was to better understand the genetic bases of dilated cardiomyopathy. Methods We conducted a 1000G based genome-wide association study for 9,152,885 SNPs on 2,719 sporadic DCM cases and 4,440 controls of European origin followed by a replication step. We then sought for the most likely culprit genes at the new replicated loci through a dedicated strategy including in silico data mining (including tissue specific gene expressions, expression and methylation quantitative trait loci) as well as functional 4C-sequencing analysis on iPSC-derived cardiomyocytes ( Fig. 1 ). Results We identified two new DCM loci, on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively) and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3, respectively), while confirming two previously identified ones, BAG3 and HSPB7. A Genetic Risk Score was built from the number of risk allele at these four loci and revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). At chr3p25, our selection strategy pinpointed SLC6A6 as the most likely culprit gene. SLC6A6 encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, the same strategy strongly suggested SMARCB1 as the best candidate gene. Conclusion This study provides new insights in the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective especially through taurine modulation.

Background The potential prognostic value of hypertension and proteinuria of anti- vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in metastatic renal cell carcinoma (mRCC). The objectives were to (i) assess the prevalence of proteinuria and hypertension at baseline; (ii) their incidence under anti-VEGF drug treatment; and (iii) evaluate a possible link with overall survival. Methods Patients from 8 centers were included between 2009 and 2011 with a follow-up of 1 year. They were naïve of any previous anti-VEGF drug treatment and planned to be started on one. The results of the group of patients with mRCC receiving sunitinib are presented. Results A total of 1,124 patients were included, among whom 137 had mRCC and 112 received sunitinib. At inclusion, hypertension prevalence was 44%, proteinuria 16%, hematuria 8%, mean modification of diet in renal disease (MDRD) formula 69 mL/min/1.73m2. The incidence of de novo proteinuria and hypertension during follow-up was 75% and 21%, respectively. Among patients with de novo proteinuria, 76% afterwards improved/normalized. Mean MDRD was 72 at the end of follow-up. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria or hypertension were not associated with OS in mRCC patients treated with sunitinib. Conclusions These results showed that (i) hypertension and proteinuria were frequent at baseline in mRCC patients; (ii) de novo hypertension and proteinuria frequently occur under sunitinib treatment; and (iii) neither hypertension nor proteinuria, either at baseline or de novo, were associated with overall survival in our cohort of “real-life” patients.

Graft allocation rules for heart transplantation are necessary because of the shortage of heart donors, resulting in high waitlist mortality. The Agence de la biomedecine is the agency in charge of the organ allocation system in France. Assessment of the 2004 urgency-based allocation system identified challenging limitations. A new system based on a score ranking all candidates was implemented in January 2018. In the revised system, medical urgency is defined according to candidate characteristics rather than the treatment modalities, and an interplay between urgency, donor-recipient matching, and geographic sharing was introduced. In this article, we describe in detail the new allocation system and compare these allocation rules to Eurotransplant and US allocation policies.

Background Osteoporosis is common among patients with end-stage heart disease. A rapid decrease of bone mineral density (BMD) is usually observed after heart transplantation. Bone loss is probably linked to glucocorticoids and calcineurin inhibitors use and vitamin D deficiency. Objectives The aim of this study was to evaluate the interest of a systematic screening of osteoporosis in heart transplant patients. Methods We performed a prospective monocentric study including patients, who had of heart transplantation in our hospital, from December 2016 to January 2019.The following parameters were systematically assesses: history of cardiac disease, immunosuppressive therapies, glucocorticoids, previous history of low trauma fracture, known risk factors of osteoporosis, treatment received for bone disease management (calcium, vitamin D and bisphosphonates). Blood tests with creatinine clearance, calcium and vitamin D levels, were assessed. Bone densitometry and spine radiographs (to search asymptomatic vertebral fractures) were assessed in all patients. Osteoporosis was defined respectively for patients ≥50 years and Results A total of 42 patients were included (76.7% male), mean age was 58.1±10.6 years, mean duration after transplantation was 2.6±3.1 years. Past or active smoking statues were observed in 26 patients (mean 23.9 pack-years). Calcium, vitamin D and bisphosphonates were administered in 13 (30.9%), 10 (23.8%) and one patients, respectively. All patients received prednisone (mean dose: 10.7±4.9 per day). Mean lumbar spine BMD was 1.03±0.25 g/cm2 and left femoral neck BMD 0.85±0.15g/cm2. Osteoporosis was observed in 18 (45%) patients. Only one hip fracture was known before heart transplantation. Incidental low trauma fractures after transplantation were diagnosed in 14 patients (33.3%): 11 patients with vertebral fractures (mean 2 vertebral fractures per patient) including 4 patients with asymptomatic vertebral fractures. Others low trauma fractures were hip fracture, proximal humerus and fibula for one patient each. Mean duration between transplantation and the first low trauma fracture was 7.5±3.7 months. Low level of calcemia was found in 20 patients (47.6%) and low level of vitamin D (≤30mg/l) in 32 patients (76.2%) associated with secondary hyperparathyroidism in 21 patients (51.2%), mean creatinine clearance was 51.7±19.9ml/min. After evaluation, specific treatment of osteoporosis was started for 33 patients (78.6%): zoledronic acid (n=20), denosumab (n=8), alendronate (n=4) and teriparatide (n=1). Conclusion Systematic screening of osteoporosis seems to be useful in heart transplant patients. Osteoporosis was observed in half of these patients with a high frequency of low trauma fracture after heart transplantation, particularly in the first year. Disclosure of Interests None declared

Background Etiological diagnosis is a key to therapeutic adaptation and improved prognosis, particularly for infections such as endocarditis. In blood culture–negative endocarditis (BCNE), 22% of cases remain undiagnosed despite an updated comprehensive syndromic approach. This prompted us to develop a new diagnostic approach. Methods Eleven valves from 10 BCNE patients were analyzed using a method that combines human RNA bait-depletion with phi29 DNA polymerase-based multiple displacement amplification and shotgun DNA sequencing. An additional case in which a microbe was serendipitously visualized by immunofluorescence was analyzed using the same method, but after laser capture microdissection. Results Background DNA prevented any diagnosis in cases analyzed without microdissection because the majority of sequences were contaminants. Moraxella sequences were dramatically enriched in the stained microdissected region of the additional case. A consensus genome sequence of 2.4 Mbp covering more than 94% of the Moraxella osloensis KSH reference genome was reconstructed with 234X average coverage. Several antibiotic-resistance genes were observed. Etiological diagnosis was confirmed using Western blot and specific polymerase chain reaction with sequencing on a different valve sample. Conclusions Microdissection could be a key to the metagenomic diagnosis of infectious diseases when a microbe is visualized but remains unidentified despite an updated optimal approach. Moraxella osloensis should be tested in blood culture–negative endocarditis.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI

Background Infectious complications are a major cause of morbidity and mortality after heart transplantation (HT). However, the epidemiology and outcomes of these infections in the recent population of adult heart transplant recipients have not been investigated. Methods We conducted a single-center retrospective study on infectious complications occurring within 180 days following HT on consecutive heart transplant recipients, from January 2011 to June 2015 at Bichat University Hospital in Paris, France. Risk factors for non-viral infections occurring within 8, 30 and 180 days after HT were investigated using competing risk analysis. Results Overall, 113 patients were included. Fifty-eight (51%) HTs were high-priority allocations. Twenty-eight (25%) patients had an extracorporeal membrane oxygenation (ECMO) support at the time of transplantation. Ninety-two (81%) patients developed at least one infection within 180 days after HT. Bacterial and fungal infections (n = 181 episodes) occurred in 80 (71%) patients. The most common bacterial and fungal infections were pneumonia (n = 95/181 episodes, 52%), followed by skin and soft tissue infections (n = 26/181, 14%). Multi-drug-resistant bacteria were responsible for infections in 21 (19%) patients. Viral infections were diagnosed in 44 (34%) patients, mostly Cytomegalovirus infection (n = 39, 34%). In multivariate subdistribution hazard model, prior cardiac surgery (subdistribution hazard ratio sHR = 2.7 [95% CI 1.5–4.6] p

Purpose The goal of the new French heart allocation system launched on January 2018 was to minimize death on the waiting list without detrimental effect on post-transplant outcome. The new system is based on the candidate risk score (CRS) considering donor-recipient matching and post-transplant risk of death as well as the distance between procurement and transplant centers. Exceptions to the score have been implemented for adults for whom the CRS does not accurately predict waitlist mortality. This study aimed to compare recipients’ profile and survival under the old and new allocation systems. Methods The study included all patients undergoing transplantation between January 2014 and June 2019 (n=2520) listed on the national registry CRISTAL. The main outcome was 6-month post-transplant mortality. Survival curves were estimated using the Kaplan-Meier method and compared between the old allocation system (2014-2017, N=1838) and the new system (2018-2019, N=682) using the log-rank test. To evaluate the independent effect of the period on post-transplant mortality, we used a multivariable Cox proportional hazard model adjusting on post-transplant mortality risk factors. Results Recipients from the new system (n=682) were more likely to be supported with VA-ECMO (29.6% vs 18.3%, p=0.01) and ventilator (10.6% VS 7.6%, p=0.02) and less likely to be on inotrope infusion (13.2% vs 26.2%, p Conclusion The new French heart allocation system has resulted in higher rate of recipients supported with VA-ECMO without change in 6-month post-transplant Survival.

Purpose The goal of the new French allocation system launched on January 2018 was to minimize death on the waiting list and offer the most equitable access to transplant without detrimental effect on post-transplant outcome. This national system is based on a candidate risk score. The aim of this study was to evaluate the effect of the new system on candidates profile and waitlist and post-transplant survival. Methods The study included all new candidates added to the French waiting list between January 2014 and September 2018. The profile and waitlist outcomes of the candidates registered before (2014-2017) and after (January-September 2018) the introduction of the new system were compared. The profile and post-transplant mortality of recipients were also compared according to the date of transplant. The main outcomes were 1-year waitlist and post-transplant survival. Survival curves were estimated using the Kaplan-Meier method. Results The characteristics of the patients changed after implementation of the new system with more patients on VA-ECMO at listing (22% vs 17%; p=0.01) and at transplant. In 2018, the number of new registrations and transplants increased by 14% and decreased by 4%, respectively. One-year waitlist (Figure 1) and post-transplant (Figure 2) survival did not change between the periods. A better donor-recipient age matching and a decrease in local allocation were observed. Conclusion Despite a-significant increase in the proportion of patients on VA-ECMO at listing and at transplant, 1-year waitlist and post-transplant survival did not change since the implementation of the new allocation system.

Purpose The new French allocation system grants priority to patients on long-term mechanical circulatory support (MCS) with device complications but does not prioritize stable long-term MCS candidates. Some experts expressed concerns regarding waiting time of long-term MCS candidates without complication. The aim of this study was to evaluate the access to transplantation of long-term MCS candidates. Methods The study included all candidates on long-term MCS without complication registered on the French heart transplant waiting list between January 2018 and March 2019 (group 1, n=65) and those ambulatory without circulatory support(group 2, n=220). The main outcomes were 6-month cumulative incidence (CI) of transplantation, and, of waitlist mortality or delisting for worsening medical condition. The CI were estimated using the competing risk analyses and compared using Gray's test. In addition, the restricted mean survival was used to estimate the difference in access to transplantation between the 2 groups. Results Among the 65 stable long-term MCS candidates, 37 were on support at listing and 28 were implanted while listed. The 6-month CI of transplantation was significantly lower in patients on long-term MCS than in ambulatory candidates (25% vs 49%; p Conclusion Access to transplantation was lower in stable long-term MCS patients than in ambulatory candidates. The increased waitlist mortality was only observed in candidates implanted while listed. The French allocation system is being revised with a new version granting a provision in stable long-term MCS candidates.

Purpose Donor-recipient age matching has been introduced into the new French allocation system launched on January 2018. The allocation score is currently weighted by the age difference between the donor and the candidate. The score decreases for candidates 15 to 40 years older than the donor from 100% to 0%. The aim of this study was to evaluate the effect of the new system on pediatric heart transplantation. Methods The study included all new pediatric candidates added to the French waiting list between January 2014 and March 2019 (n=179). The profile and waitlist outcomes of the candidates registered before (2014-2017, n=128) and after (January 2018- March 2019, n=51) the introduction of the new system were compared. The main outcomes were 3-month cumulative incidence (CI) of transplantation, and of waitlist mortality or delisting for worsening medical condition. The CI were estimated using the competing risk analyses and were compared using the Gray's test. Results The medical characteristics of the patients were similar between the 2 periods except for mechanical ventilation which tended to be more frequent in the first cohort (33% vs 18%, p=0.05). The number of new registrations per year increased by 28% in the second period. Donor heart donations decreased in 2018-2019 period but pediatric donor hearts were more often allocated to pediatric candidates (63% vs 48%). The 3-month CI of transplantation was similar between the 2 periods (53% vs 54%, p=0.41). The 3-month waitlist mortality or delisting for worsening medical condition tended to be lower in 2018-2019 (8% vs 17%, p=0.09). Conclusion While access to transplantation remains unchanged, a non-significant decrease in 3-month waitlist mortality has been observed since the implementation of the new system.

Purpose We derived and validated from the cohort of patients registered on the national registry CRISTAL, between January 2010 and December 2014, the Candidate Risk Score (CRS), predicting waitlist mortality. The CRS, converted into the Cardiac Risk Index (CRI), ranging from 0 to 40, includes 4 variables, venoarterial extracorporeal membrane oxygenator (VA-ECMO) use, plasma concentrations of natriuretic peptides (NP), glomerular filtration rate (GFR) and total serum bilirubin level. This study aimed to validate the CRI within the cohort of candidates listed on the CRISTAL registry between January 2018 and March 2019. Methods All patients, aged 16 years or older, registered on the national registry CRISTAL, for heart transplantation, between January 2018 and March 2019, without score exception, (N=617) were included. The main outcome was 3-month waitlist mortality or delisting for worsening medical condition. Survival curves were estimated using Kaplan Meier method. Three-month survival curves stratified by CRI category were compared with the log rank test. The CRI calibration was assessed by calculating the correlation between the observed and predicted 3-month mortality by CRI decile. The slope of the calibration straight line was calculated. Results The CRI showed a good discriminative capacity with 3-month survival ranging from 34.8% [17.7%-52.6%] and 63.4% [43.0%-78.2%] in the highest (35-40) and second highest (30-34) CRI categories to 97.7% [93.1%-99.3%] and 93.4% [84.7%-97.2%] in the lowest (0-14) and second lowest (15-20) CRI categories(Figure). The correlation between predicted and observed 3-month waitlist mortality was excellent (r=0.90) and the slope of the calibration straight line was 0.93. Conclusion This study validates the use of the CRI as a predictor of waitlist mortality in adult candidates. Currently the CRI is the cornerstone of the French heart allocation system.

Purpose The angiotensin receptor-neprilysin inhibitor, sacubitril-valsartan (SV), is indicated in patients with heart failure with reduced ejection fraction. The use of SV reduced the risk of death and of hospitalization for heart failure as compared to enalapril therapy in outpatients with NYHA class II-III symptoms. This study aimed to assess the outcomes of heart transplant candidates receiving SV at listing. Methods All candidates listed for transplantation between January 2018 and March 2019 on the French registry CRISTAL were included. Candidates on VA-ECMO, long-term MCS and inotropic support at listing were excluded. Patients receiving SV at listing (study group, n=151) were compared to patients not receiving SV (control group, n=249). The main outcome was 6-month waitlist mortality or delisting for worsening medical condition. The secondary outcomes were 6-month rates of hospitalization and need for circulatory support. Survival curves were estimated using the Kaplan-Meier method. Association of SV use with the main outcome was evaluated with multivariable Cox proportional hazards model. Results Patients from the study group were older and more likely to have dilated or ischemic cardiomyopathy. They had lower glomerular filtration rate, NT-proBNP concentration and serum bilirubin level. Their 1-year access to transplantation was significantly lower (56% vs 71%, p=0.003). The 6-month survival rate tended to be higher in the study group (95.2% vs 89.3%, p=0.11). In the multivariable Cox model, lack of SV use was non significantly associated with higher 6-month waitlist mortality (HR 1.9; p = 0.2). The 6-month rate of hospitalization and need for circulatory support did not differ between the groups. Conclusion Use of SV at listing is frequent in contemporary heart transplant candidates without circulatory support. Our findings suggest that SV use may be associated with reduced risk of waitlist mortality without effect on hospitalization rate.

Introduction Les insuffisants cardiaques en phase terminale peuvent beneficier de la pose d’un dispositif d’assistance circulatoire mecanique (DACM) en suppleance de leur cœur defaillant ou en attendant une greffe cardiaque. Les criteres de mise sous assistance versus transplantation en France ne sont pas etablis precisement. Cette etude vise a estimer la mortalite post-implantation, information inconnue mais importante dans le choix therapeutique. Methode Le nombre de poses de DACM realisees chez les adultes entre 2013 et 2018 a ete calcule grâce aux codes LPP et a la date de pose extraits du Systeme national des donnees de sante (SNDS) (extraction le 3 octobre 2019). Le taux d’incidence de deces post-implantation a ete estime grâce au chainage des informations avec la table referentiel des beneficiaires. Le delai de survie est calcule entre la date de pose et celle du deces ou de la date maximum de traitement de la prestation pour chaque pose. Resultat Entre 2013 et 2018, 1226 DACM ont ete posees, dont 1081 monoventriculaires gauche (88 %), 134 biventriculaires (11 %) et 10 EXCORs (1 %). Ces dispositifs qui concernaient 1182 malades, etaient majoritairement realises sur des hommes (85 %) âges de plus de 60 ans. Les adultes de moins de 46 ans representaient 15 % de la population. Le taux d’incidence cumulee de deces non ajuste etait de 28 % [25–30] a trois mois et de 38 % [35–40] a un an. La mediane de survenue d’un deces etait plus courte pour les EXCORs et les biventriculaires (mediane a 0,6 ; 4,8 mois respectivement versus 34,4 mois pour les monoventriculaires p Discussion/Conclusion L’utilisation des donnees medico-administratives permet d’estimer la mortalite post-implantation, information cruciale pour aider les cliniciens a choisir entre l’inscription sur liste ou la pose d’une assistance. Une analyse plus fine en tenant compte de la gravite des malades avec ajustement permettrait de mieux caracteriser les risques lies a la pose d’un DACM.

Background Previous experience in infants has shown that percutaneous insertion of a cannula into the left atrium incorporated into the extracorporeal membrane oxygenation (ECMO) circuit decreases left cardiac pressures and improves pulmonary edema (PE). However, data on adults is scarce. Purpose This study aimed to evaluate the feasibility and safety of percutaneous decompression of the left atrium (PDLA) in patients supported by ECMO with refractory PE. Methods A total of 23 consecutive patients were included between January 2015 and September 2018. A venous cannula incorporated to the ECMO circuit was inserted into the left atrium via transvenous transseptal catheterization. Data were retrospectively collected. Patients were classified as responders if the blood partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio increased at least by 20% or their respiratory failure improved to a less severe stage, or they were extubated during the first 48 hours. A successful procedure was defined as an adequate placement of the cannula in a patient who left the catheterization room alive. Results PDLA was successfully performed in all patients. One patient (4.3%) had a cardiac tamponade and one (4.3%) a hemothorax. No other procedural complications occurred. At day 2, PaO2/FiO2 ratio increased by 79 ± 143 (P = 0.161). Twelve patients (52.2%) were weaned from ECMO, 13 patients (56.5%) underwent heart transplantation and 10 patients (43.7%) were discharged alive from hospital. At a mean follow-up of 251 ± 288 days, 9 (39.1%) were alive. A total of 11 patients were classified as responders: they were more likely to be weaned from ECMO (54.5% vs. 44.4%, P = 0,391) and mechanical ventilatory support (54.5% vs. 22.2%, P = 0,142) and had a tendency to greater in-hospital survival (54.5% vs. 33.3%, P = 0,343). Conclusions PDLA was feasible, safe and allowed an improvement in oxygenation-status of patients with refractory PE during ECMO support.

Background Cardiac sarcoidosis (CS) is a challenging diagnosis. Patients may progress to end-stage congestive heart failure and require cardiac transplantation without ever having been diagnosed. Characteristics and outcomes of patients with granulomas in the explanted hearts are unknown. Methods All French heart transplantation centers were contacted to participate in the study. Each center searched through local databases for the cases of non-caseating granuloma in the explanted hearts between 2000 and 2017. Data before and after transplantation were recorded from medical charts. Survival of CS and all- cause heart transplantation patients were compared. Results Fifteen patients (10 men, 5 women) received a diagnosis of CS based on pathologic data of the explanted heart and were recruited for the study. All patients were diagnosed as non-ischemic dilated or hypertrophic cardiomyopathy and presented congestive heart failure. Eight patients (53%) had ventricular rhythm disturbances, and 3 (20%) a complete heart block. Ten out of 13 patients (77%) had extracardiac radiological signs compatible with sarcoidosis on chest computed tomography (CT) scans. One patient died 3 months after transplantation from infectious complications. The 14 remaining patients were still alive at the end of the study (median follow-up of 28.8 months). One patient had a second heart transplantation 5 years later because of chronic allograft vasculopathy. One patient presented a relapse of CS confirmed by myocardial biopsies 9 years after transplantation, requiring an escalation of immunosuppressive therapy. Conclusion CS may be undiagnosed before heart transplantation. In 77% of cases, sarcoidosis could have been detected before transplantation with non-invasive imaging techniques.

Resume Introduction Les valeurs pronostiques de l’hypertension et de la proteinurie des anti-VEGF (facteur de croissance endothelial vasculaire) n’ont pas encore ete evaluees dans la pratique clinique de routine dans le cancer du sein (CS). Les objectifs de l’etude MARS etaient d’apprecier la prevalence/incidence de la proteinurie et de l’hypertension a l’inclusion et durant le traitement par anti-VEGF, et de rechercher un lien potentiel avec la survie globale. Methodes Les patients naifs de tout anti-VEGF et debutant un traitement par anti-VEGF ont ete inclus dans 8 centres entre 2009 et 2011 avec une periode de suivi de 1 an. Les resultats du groupe de patientes atteintes de CS et traitees par bevacizumab sont presentes. Resultats Quatre cent deux patientes atteintes de CS et traitees par bevacizumab ont ete incluses. A l’inclusion, 12,4 % des patientes presentaient une hypertension, 23,9 % une proteinurie. Lors du suivi, l’incidence d’evenements de novo , proteinurie et hypertension, etait respectivement de 61,7 % et 16,8 %. Parmi les patientes avec une proteinurie de novo , 62,2 % l’ont amelioree ou normalisee par la suite. Aucune microangiopathie thrombotique n’a ete rapportee. A l’inclusion ou de novo , les analyses univariees/multivariees ont demontre que la proteinurie et l’hypertension n’etaient pas associees a la survie globale. Discussion Ces resultats montrent que la prevalence de l’hypertension et de la proteinurie a l’inclusion etait elevee et que les patientes traitees par bevacizumab developpaient frequemment une hypertension et/ou une proteinurie de novo . Enfin, ni l’hypertension ni la proteinurie, a l’inclusion ou de novo , n’etaient associees a la survie globale dans notre cohorte.

Transplantation represents the last option for patients with advanced heart failure. We assessed between-center disparities in access to heart transplantation in France 1 year after registration and evaluated the contribution of factors to these disparities. Adults (n = 2347) registered on the French national waiting list between January 1, 2010, and December 31, 2014, in the 23 transplant centers were included. Associations between candidate and transplant center characteristics and access to transplantation were assessed by proportional hazards frailty models. Candidate blood groups O and A, sensitization, and body mass index ≥30 kg/m2 were independently associated with lower access to transplantation, while female gender, severity of heart failure, and high serum bilirubin levels were independently associated with greater access to transplantation. Center factors significantly associated with access to transplantation were heart donation rate in the donation service area, proportion of high-urgency candidates among listed patients, and donor heart offer decline rate. Between-center variability in access to transplantation increased by 5% after adjustment for candidate factors and decreased by 57% after adjustment for center factors. After adjustment for candidate and center factors, five centers were still outside of normal variability. These findings will be taken into account in the future French heart allocation system.

From the ISHLT Transplant Registry, Dallas, Texas; University of Utah School of Medicine, Salt Lake City, Utah; Brigham and Women’s Hospital Heart and Vascular Center, Harvard University, Boston, Massachusetts; Hospital Universitario A Coruna, La Coruna, Spain; Hospital 12 de Octubre, Madrid, Spain; Agence de la biomedecine, Saint-Denis, France; Niguarda-Ca’ Granda Hospital, Milan, Italy; St. Vincent’s Hospital, Sydney, New South Wales, Australia; Freeman Hospital, Newcastle upon Tyne, United Kingdom; Centro Nazionale Trapianti, Roma, Italy; Duke University, Durham, North Carolina; The Johns Hopkins Hospital, Baltimore, Maryland; National Health Service Blood and Transplant, Bristol, United Kingdom; and the Wythenshawe Hospital, Manchester, United Kingdom.

Points essentiels Le nombre total de candidats pour un greffon est de 2,1 . En France, 48 % des candidats en attente sont greffes dans l’annee. En 2012, les 25 centres francais ont realise 397 greffes , soit 6,1 par million d’habitants. Actuellement, 48 % des greffes ont lieu dans le cadre d’une super-urgence (priorite nationale). La survie a un an apres greffe est de 76 % , la mortalite annuelle est ensuite de 2 a 3 %. Les principaux facteurs de risque de mortalite precoce sont les caracteristiques des donneurs, la duree d’ischemie et le retentissement sur les organes peripheriques de l’insuffisance cardiaque. Une attribution des greffons aux patients plutot qu’aux equipes passe par la prise en compte de l’urgence et du benefice individuel de la greffe.

IntroductionSince July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database.MethodsAll lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models.ResultsDuring the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22–1.64; pConclusionsThis exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.

Purpose The new French allocation system (NFAS) based on the candidate risk score has been launched on January 2, 2018. This study aimed to evaluate the effect of implementation of NFAS on newly registered candidates’ profile and their waitlist outcomes. Methods The study included all adults newly registered on the French waiting list for heart transplantation between January and July, 2014-2018 (n=1808). Characteristics and waitlist outcomes of candidates registered during the 7-month period in the 4 years before (n=1401) and the year after (n=407) introduction of NFAS were compared. The access to transplantation was calculated using competing risk estimation and waitlist survival was estimated using the Kaplan-Meier method. Inactive candidates were excluded from those analyses. Results After the new system implementation, new registrations increased by 27% and transplant activity decreased by 14% leading to a rise in organ shortage (candidate per graft ratio: 1.6 vs 1.3). Candidate demographics remained unchanged (75% male, 49±15 years, dilated cardiomyopathy 41%, coronary artery disease 35%). Compared to 2014-2017, the 2018 proportions of new candidates on VA-ECMO (20% vs 17%, p=0.4), long-term MCS (9% vs 8%), mechanical ventilation (13 % vs 11%, p=0.2), inotropic infusion (34% vs 38%, p=0.2) and dialysis (1.8% vs 2.8%, p=0.2) were not significantly different. The proportion of candidates always inactive during their waiting time increased (3% vs 1%, p=0.02). While the 3-month cumulative incidence of transplantation tended to decrease (48% vs 51%, p=0.15), the 3-month waitlist survival remained unchanged (88.5% vs 89.9% respectively in 2018 and 2014-17; p=0.6) (Figure 1). Conclusion The implementation of the new allocation system did not modify candidates’ profile although we observed a significantly higher proportion of candidates always inactive during their waiting time. Despite the increase of organ shortage, waitlist survival did not decrease.

Purpose Previous studies have shown that lung protective strategy in selected potential organ donors after brain death (DBD) increased lung eligibility and procurement. This prospective nationwide cohort study aimed to evaluate the impact of lung protective ventilation (PV) in nonselected DBD upon lung procurement and recipient survival. Methods All reported DBD aged 18-70 years without lung recovery contraindication and with at least one organ recovered between January 2016 and December 2017 were included. Donor characteristics and management were collected at several times until decision on lung offer to transplant teams (t2). PV was defined as tidal volume ≤8 ml/kg of predicted body weight and PEEP≥ 8 cm H2O. The association between PV and lung procurement was determined with multivariable logistic regression stratified by propensity score quintile to account for PV and non PV group differences in baseline characteristics. Survival rates were estimated using Kaplan-Meier method and compared using log-rank test. Results Of the 1,626 included lung donors, 1,109 (68%) had at least one lung offered among whom 678 (61%) had at least one lung recovered. Among donors with lung offered, factors associated with reduced lung procurement were female gender (OR:0.63; 95%CI: 0.43-0.92, p=0.02), age (OR:0.97; 95%CI: 0.96-0.98, p 3 days (OR:0.51 95%CI: 0.38-0.69, p Conclusion The use of lung protective ventilation in nonselected DBD increased probability of lung procurement by 43%. Intermediate analysis suggests that 1-year survival did not differ between recipients of lungs from donors with or without PV.

Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation (LTx). However, data concerning this approach remain limited.We retrospectively reviewed the medical records of all patients in France who received ECMO as a bridge to LTx from 2007 to 2011. Post-transplant survival and associated factors were assessed by the Kaplan-Meier method and the Cox model.Included were 36 patients from 11 centers. Indications for LTx were cystic fibrosis (CF) in 20 (56%), pulmonary fibrosis (PF) in 11 (30%), and other diagnoses in 5 (14%). ECMO was venovenous for 27 patients (75%) and venoarterial for 9 (25%). Mean follow-up was 17 months. Bridging to LTx was achieved in 30 patients (83%); however, only 27 patients (75%) survived the LTx procedure, and 20 (56%) were discharged from hospital. From ECMO initiation, 2-year survival rates were 50.4% overall, 71.0% for CF patients, 27.3% for PF patients, and 20.0% for other patients (p0.001). From LTx, 2-year survival rates were 60.5% overall, 71.0% for CF patients, 42.9% for PF patients, and 33.0% for other patients (p = 0.04).Our study confirms that the use of ECMO as a bridge to LTx in France could provide a medium-term survival benefit for LTx recipients with critical conditions. Survival differed by underlying respiratory disease. Larger studies are needed to further define the optimal use of ECMO.

The continuing significant number of patients who die while on a waiting list for lung transplantation (LTx) has led several countries to modify their lung allocation rules in recent years. France has implemented high-emergency allocation rules to allow patients at imminent risk of death to undergo priority transplantation within several days. The aim of this study was to report on the early (2-year) experience of high-emergency LTx (HELTx) in France.From July 1, 2007, to June 30, 2008, 186 patients underwent LTx in France in nine centers. Among them, 32 patients (17.2%) underwent HELTx (19 with cystic fibrosis, 7 pulmonary fibrosis, and 6 other diagnoses). The reasons for HELTx were risk of invasive mechanical ventilation (n=20), invasive mechanical ventilation (n=8), and extracorporeal membrane oxygenation (n=4).The median time between being placed on the HELTx waiting list and LTx was 3 days (interquartile range: 1-8 days). Survival rates in the HELTx group were 90.5%, 71%, 64.5%, 55%, and 51.5% at 1, 3, 6, 12, and 24 months, respectively, which were significantly lower than for 154 patients who underwent regular, nonurgent LTx during the study period (88.5%, 83%, 79%, 77%, and 71%, respectively).Our data demonstrate that the new LTx allocation rules implemented in France since 2007 allow for rapid organ procurement for patients at imminent high risk of death. HELTx is feasible but yields poorer survival than elective LTx. Further studies are needed to assess implications of this organ allocation policy on the long run.

International audience; Coronary angiography (CA) is the gold standard evaluation of coronary artery disease in potential multi-organ donors. This use of iodinated contrast media could lead to contrast-induced acute kidney injury and consequently to delayed graft function (DGF). All patients in France who received a kidney from a 45-70-year-old donor without medical contraindication for cardiac donation and with at least one cardiovascular risk factor were included. Recipients of preemptive kidney transplant or multi-organ transplant, or who died within the first 8 days post-transplantation were excluded. Data were obtained from CRISTAL database. From March 2012 to June 2014, 892 kidneys from 483 donors were transplanted. DGF was reported in 38.9% of the 375 kidney recipients grafted with a kidney from the 217 donors who had CA and in 45.5% of the 440 kidney recipients who received a kidney from the 257 donors without CA. Multivariate analysis showed that CA or repeated injection of iodinated contrast media did not influence the risk of DGF. CA did not increase the risk of primary non-function, the duration of DGF or post-transplantation hospital stay and did not affect the graft function at 1 year. Evaluation of potential multi-organ donors with CA does not affect kidney graft outcomes.

Introduction La greffe cardiaque reste le traitement ultime de l’insuffisance cardiaque terminale. Les registres nationaux permettent de decrire les caracteristiques cliniques des candidats et leur survie, mais pas leur consommation de soins, notamment hospitaliers. Methodes Les sejours pour greffe cardiaque entre 2010 et 2015 ont ete isoles a partir du PMSI et, pour chaque malade, chaines aux sejours d’au moins une nuitee en MCO et en SSR l’annee precedente. Les durees de sejour et delais, les diagnostics principaux (DP) et les actes (CCAM) ont ete analyses ainsi que le sejour en reanimation. Resultats Les 2379 greffes inclus etaient majoritairement des hommes (74 %) avec un âge moyen de 48 ans (SD 15). La duree mediane du sejour de greffe etait de 39 jours (Q1–Q3 : 26–62) et celle entre l’admission et la greffe de 5 jours (Q1–Q3 : 0–16). La mortalite hospitaliere etait de 18 %. L’annee precedente, 91 % des greffes avaient eu au moins un sejour en MCO (moyenne 4,3 SD 3,4) et 89 % avec un DP cardiovasculaire (4,6 jours, SD 3,4). Cela representait 9296 sejours avec une duree mediane de 4 jours par sejour. Un dispositif de ballon de contre-pulsion etait retrouve pour 5,3 % des malades, une assistance ventriculaire 7,6 %, une CEC 5,4 %, une assistance ventilatoire invasive 14,9 %. L’annee precedente, 61 % des futurs greffes avaient sejourne au moins une fois en reanimation. La proportion mensuelle de malades a domicile diminuait (45 % le 12e mois avant la greffe et 30 % le mois precedant la greffe) au profit de celle des malades sejournant a l’hopital (15 % versus 19 %) ou en USI (11 % versus 21 %). Celle de malades en SSR de 29 % etait stable. Des flux entre ces differents etats etaient constates. Discussion/Conclusion Les greffes cardiaques ont une consommation de soins hospitaliers importante, mais des parcours variables selon leur gravite, le moment de survenue de la defaillance cardiaque. L’appariement au SNDS devrait permettre de distinguer la prise en charge avant et apres l’inscription en attente.

The antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ) are used in long-term treatment of connective tissue diseases and dermatological disorders and are generally regarded as safe. We present one case of cardiotoxicity in a 59-year-old woman treated with antimalarials during 13 years for a discoid lupus erythematosus. She progressively developed conduction disturbances and congestive heart failure (CHF). When the diagnosis of antimalarials toxicity was suspected, CQ was withdrawn. However, heart transplantation had to be performed in the following 4 months for severe CHF. Indeed, rare but severe cardiotoxicity may develop following prolonged use of antimalarials with both conduction disturbances (45 patients) and CHF (25 patients). These cardiac toxic effects have been reported with CQ and less frequently with HCQ use alone. Diagnoses are often delayed since the toxicity of the drug might be misattributed to other factors in these patients. The endomyocardial biopsy, or in some cases the muscle biopsy, are essential to confirm the antimalarials toxicity. Antimalarials have been stopped in 12 cases of CHF, leading to improvement in 8 cases (within 3 months to 5 years) and to deaths or to heart transplantation in 4 cases (within 1 week to 3 months). In the latter cases, as in our patient, the lack of improvement may have been explained by the severity of the cardiomyopathy at diagnosis and the short delay since withdrawal. As a consequence, the potential for reversibility and the severity in undiagnosed cases of these toxic cardiomyopathies emphasize the importance of recognizing early signs of toxicity in order to withdraw antimalarials before the occurrence of life-threatening CHF.