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 identifieddonor 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:URLhttps://www.clinicaltrials.gov; Unique identifierNCT04117152.
Abstract
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.
Graphical Abstract
Graphical abstract
We report the case of a patient who had undergone injections of myoblasts in an infarct area 16 years before being referred for heart transplantation. The pathological examination of the explanted ...heart found persisting myotubes embedded in fibrosis. This finding supports the ability of myoblasts to survive in harsh environments, which can make them appealing candidates for transplantation in diseases requiring supply of new myogenic cells. Stem Cells Translational Medicine 2018;7:705–708
Persistence in the post‐myocardial infarction scar of skeletal muscle stem cells injected 16 years earlier.
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.
The frequency, characteristics and outcomes of primary prevention implantable cardioverter defibrillator (ICD) recipients who eventually undergo heart transplantation (HT) during follow-up have not ...been well described.
In a cohort of patients with heart failure implanted with an ICD for primary prevention of sudden cardiac death, to identify those at high risk of subsequent HT and evaluate ICD usefulness.
Between 2002 and 2012, 5539 patients received a primary prevention ICD across 12 centers, and were enrolled in the DAI-PP programme, including 5427 with full HT information available.
During a median follow-up of 1024 days (interquartile range 484–1702 days), 176 (3.2%) patients underwent HT. Median duration between ICD implantation and HT was 484 days (IQR 169–1117 days). Among those aged≤65 years (theoretical age limit for HT registration in France), the overall incidence per 1000 person-years was 18.03 (95% confidence interval CI: 15.32–20.74). Left ventricular ejection fraction<25% (hazard ratio HR: 3.43, 95% CI: 2.34–5.04; P<0.0001), younger age (HR: 0.95, 95% CI: 0.93–0.96; P<0.0001), New York Heart Association (NYHA) class III–IV (HR: 2.67, 95% CI: 1.79–4.00; P<0.0001) and no cardiac resynchronization therapy (HR: 2.09, 95% CI: 1.39–3.14; P=0.0004) were independently associated with HT. Patients with these three characteristics (excluding age) had a 1-year HT rate of 15.2%. Incidence of appropriate ICD therapies was 92.7 per 1000 person-years for patients who underwent HT versus 76.1 for those who did not (P=0.64).
The overall incidence of HT in this primary prevention population was relatively high, especially among young patients with a very low ejection fraction, an advanced NYHA class and were unsuitable for cardiac resynchronization therapy (up to 15% annually). Patients awaiting HT experienced a significant rate of appropriate ICD therapies, reinforcing the importance of specific cardiac rhythm management in these patients.
L’incidence, les caractéristiques et le devenir des patients implantés de défibrillateurs en prévention primaire qui bénéficieront au cours du suivi d’une transplantation cardiaque n’ont pas été précisément caractérisées jusqu’ici.
Dans une population de patients avec fraction d’éjection ventriculaire gauche inférieure à 35 % et implantés d’un DAI en prévention primaire, identifier les patients à haut risque de transplantation cardiaque et évaluer l’intérêt du DAI chez ces patients.
Entre 2002 et 2012, 5539 patients ont reçu un défibrillateur en prévention primaire au sein de 12 centres et ont été inclus dans le registre DAI-PP. Le statut vis-à-vis de la transplantation cardiaque était pleinement renseigné pour 5427 d’entre eux.
Au cours d’un suivi médian de 1024jours (écart interquartile EI 484–1702jours), 176 (3,2 %) patients furent transplantés cardiaques. Le délai médian entre l’implantation du défibrillateur et la transplantation était de 484jours (EI 169–1117jours). Parmi les patients de moins de 65 ans (âge limite théorique pour être inscrit sur une liste de greffe en France), l’incidence de transplantation était de 18,03 (IC95 % : 15,32–20,74) pour 1000 patients-années. Les facteurs associés à la transplantation de manière indépendante étaient un âge jeune (HR : 0,95, IC95 % : 0,93–0,96 ; p<0,0001), une fraction d’éjection ventriculaire<25 % (HR : 3,43, IC95 % : 2,34–5,04 ; p<0,0001), une classe NYHA III ou IV (HR : 2,67, IC95 % : 1,79–4,00 ; p<0,0001) et l’absence de thérapie de resynchronisation (HR : 2,09, IC95 % : 1,39–3,14 ; p=0,0004). Parmi les patients qui réunissaient ces trois derniers critères, l’incidence de transplantation cardiaque à un an était de 15,2 %. L’incidence de thérapies appropriées délivrées par le défibrillateur était de 92,7 pour 1000 patients-année pour les patients transplantés vs 76,1 pour les patients non transplantés (p=0,64).
L’incidence de transplantation cardiaque chez les patients implantés d’un défibrillateur en prévention primaire est relativement élevée, particulièrement chez les patients jeunes, avec une fraction d’éjection<25 %, une classe NYHA élevées et sans thérapie associée de resynchronisation (jusqu’à 15 % par an). Les patients en attente de transplantation présentaient des taux significatifs de thérapies appropriées délivrées par les défibrillateurs, ce qui souligne l’importance d’une prise en charge rythmologique spécifique chez ces patients.
BACKGROUND:Antibody-mediated rejection (AMR) contributes to heart allograft loss. However, an important knowledge gap remains in terms of the pathophysiology of AMR and how detection of immune ...activity, injury degree, and stage could be improved by intragraft gene expression profiling.
METHODS:We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006–January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR. We characterized all patients using histopathology (ISHLT International Society for Heart and Lung Transplantation 2013 grades), immunostaining, and circulating anti-HLA donor-specific antibodies at the time of biopsy, together with systematic gene expression assessments of the allograft tissue, using microarrays. Effector cells were evaluated with in vitro human cell cultures. We studied a validation cohort of 98 heart recipients transplanted in Edmonton, AB, Canada, including 27 cases of AMR and 71 controls.
RESULTS:A total of 240 heart transplant endomyocardial biopsies were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculatory inflammation by monocytes/macrophages and natural killer (NK) cells. We also observed selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and interferon-γ–inducible genes. The AMR-selective gene sets accurately discriminated patients with AMR from those without and included NK transcripts (area under the curve=0.87), endothelial activation transcripts (area under the curve=0.80), macrophage transcripts (area under the curve=0.86), and interferon-γ transcripts (area under the curve=0.84; P<0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pathological AMR (pAMR) International Society for Heart and Lung Transplantation grade (P<0.001) and association with donor-specific antibody levels. The unsupervised principal components analysis demonstrated a high proportion of molecularly inactive pAMR1(I+), and there was significant molecular overlap between pAMR1(H) and full-blown pAMR2/3 cases. Endothelial activation transcripts, interferon-γ, and NK transcripts showed association with chronic allograft vasculopathy. The molecular architecture and selective AMR transcripts, together with gene set discrimination capacity for AMR identified in the discovery set, were reproduced in the validation cohort.
CONCLUSIONS:Tissue-based measurements of specific pathogenesis-based transcripts reflecting NK burden, endothelial activation, macrophage burden, and interferon-γ effects accurately classify AMR and correlate with degree of injury and disease activity. This study illustrates the clinical potential of a tissue-based analysis of gene transcripts to refine diagnosis of heart transplant rejection.
Abstract Background The benefits of available automatic external defibrillators (AEDs) for out-of-hospital cardiac arrests (OHCAs) are well known, but strategies for their deployment outdoors remain ...somewhat arbitrary. Our study sought to assess different strategies for AED deployment. Methods All OHCAs in Paris between 2000 and 2010 were prospectively recorded and geocoded. A guidelines-based strategy of placing an AED in locations where more than one OHCA had occurred within the past five years was compared to two novel strategies: a grid-based strategy with a regular distance between AEDs and a landmark-based strategy. The expected number of AEDs necessary and their median (IQR) distance to the nearest OHCA were assessed for each strategy. Results Of 4,176 OHCAs, 1,372 (33%) occurred in public settings. The first strategy would result in the placement of 170 AEDs, with a distance to OHCA of 416 (180-614) meters and a continuous increase in the number of AEDS. In the second strategy, the number of AEDs and their distance to the closest OHCA would change with the grid size, with a number of AEDs between 200 and 400 seeming optimal. In the third strategy, median distances between OHCAs and AEDs would be 324 meters if placed at post offices (n = 195), 239 at subway stations (n = 302), 137 at bike-sharing stations (n = 957), and 142 at pharmacies (n = 1466). Conclusion This study presents an original evidence-based approach to strategies of AED deployment to optimize their number and location. This rational approach can estimate the optimal number of AEDs for any city.
Atrioventricular regurgitation is frequent in the setting of heart failure. It is due to atrial and ventricular remodelling, as well as rhythmic disturbances and loss of synchrony. Once ...atrioventricular regurgitation develops, it can aggravate the underlying heart failure, and further participate and aggravate its own severity. Its presence is therefore concomitantly a surrogate of advance disease and a predictor of mortality. Heart failure management, including medical therapy, cardiac resynchronization therapy, and restoration of sinus rhythm, are the initial steps to reduce atrioventricular regurgitation. In the current review, we analyse the current data assessing the epidemiology, pathophysiology, and impact of non-valvular intervention on atrioventricular regurgitation including medical treatment, cardiac resynchronization and atrial fibrillation ablation.
Since the earliest cases of coronavirus disease 2019 (COVID-19) infection were reported, our care delivery systems have been reorganized and challenged in unprecedent ways, specifically the ...cardiovascular community. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. Left Ventricular Assist Device (LVAD) therapy is currently a viable option for patients with end-stage heart failure as a bridge to heart transplantation or destination therapy. Here, we present a therapeutic strategy for the management of acute HF with Intermacs profiles from 1 to 4, with or without Covid-19 infection, exemplified by serie of patients presenting with severe HF and successfully treated by LVAD therapy during the spread of the Covid-19 pandemic and the French national lockdown. This experience has shown that we still have the capacity to provide the right therapy for the right disease to the right patient. LVAD implantation seems to be the treatment of choice for advanced HF due to the lack of healthy donor hearts for cardiac transplantation. Covid or non-Covid context, we have to take care of our patients with end-stage HF the best we can.
Abstract We aimed to assess if the outcome of primary prevention implantable cardioverter defibrillators (ICDs) without cardiac resynchronization therapy (CRT) is dependent on New York Heart ...Association (NYHA) class. Among the participants of Défibrillateur Automatique Implantable-Prévention Primaire (DAI-PP;NCT01992458) multicenter cohort study, 155 patients in NYHA class I, 504 in NYHA class II and 188 in NYHA class III had a QRS width <120ms and were implanted with an ICD without CRT, and thus were eligible for the purpose of this analysis. Total and specific mortalities, and the incidence of appropriate therapies were assessed for every NYHA. During 2,606 patient-years (3.1±2.1 years), 104 (12.3%) individuals died and 188 (22.2%) experienced appropriate therapies. After adjustment, overall mortality increased with NYHA class (adjusted HR=1.63, 95%CI 1.11-2.41, P=0.014), driven by an increase in cardiovascular death. Conversely, incidence of appropriate ICD intervention was comparable among the 3 NYHA groups (NYHA class I 7.43, NYHA class II 7.91 and NYHA class III 12.10 per 100 patient-years; HR=1.19, 95%CI 0.89-1.59, P=0.231). Incidence of ICD-unresponsive sudden death was very low and also comparable (NYHA class I 0.22, NYHA class II 0.36, and NYHA class III 0.83 per 100 patient-years; (HR=6.34, 95%CI 0.32-124.49, P=0.224). No significant differences were observed in the other specific modes of death. In conclusion, even though patients in NYHA class III have higher overall mortality, they experience a comparable incidence of appropriate ICD therapies. The low incidence of ICD-unresponsive sudden death in all assessed NYHA classes also supports the efficacy of ICDs, irrespective of NYHA class.
PDF
