Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. ...There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The COVID-19 pandemic has reduced access to endomyocardial biopsy (EMB) rejection surveillance in heart transplant (HT) recipients. This study is the first in Canada to assess the role for ...noninvasive rejection surveillance in personalizing titration of immunosuppression and patient satisfaction post-HT.
In this mixed-methods prospective cohort study, adult HT recipients more than 6 months from HT had their routine EMBs replaced by noninvasive rejection surveillance with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) testing. Demographics, outcomes of noninvasive surveillance score, hospital admissions, patient satisfaction, and health status on the medical outcomes study 12-item short-form health survey (SF-12) were collected and analyzed, using t tests and χ2 tests. Thematic qualitative analysis was performed for open-ended responses.
Among 90 patients, 31 (33%) were enrolled. A total of 36 combined GEP/dd-cfDNA tests were performed; 22 (61%) had negative results for both, 10 (27%) had positive GEP/negative dd-cfDNA results, 4 (11%) had negative GEP/positive dd-cfDNA results, and 0 were positive on both. All patients with a positive dd-cfDNA result (range: 0.19%-0.81%) underwent EMB with no significant cellular or antibody-mediated rejection. A total of 15 cases (42%) had immunosuppression reduction, and this increased to 55% in patients with negative concordant testing. Overall, patients’ reported satisfaction was 90%, and on thematic analysis they were more satisfied, with less anxiety, during the noninvasive testing experience.
Noninvasive rejection surveillance was associated with the ability to lower immunosuppression, increase satisfaction, and reduce anxiety in HT recipients, minimizing exposure for patients and providers during a global pandemic.
La pandémie de COVID-19 a réduit l’accès à la biopsie endomyocardique pour surveiller le risque de rejet après une greffe du cœur. Cette étude est la première à être menée au Canada pour évaluer le rôle de la surveillance non invasive du risque de rejet en personnalisant le titrage de l’immunosuppression et la satisfaction du patient après la greffe cardiaque.
Dans le cadre de cette étude de cohorte prospective à méthodes mixtes, des adultes ayant reçu une greffe cardiaque depuis plus de six mois ont vu leurs biopsies endomyocardiques régulières remplacées par une surveillance non invasive du risque de rejet qui consiste à établir le profil de l’expression génique et à analyser l’ADN acellulaire dérivé du donneur. Les données démographiques, les résultats du score de surveillance non invasive, les admissions à l’hôpital, la satisfaction des patients et l’état de santé tirés du questionnaire SF-12 (questionnaire abrégé sur la santé comprenant 12 items) de l’étude sur les issues médicales ont été colligés et analysés au moyen des tests T et des tests χ2. Les réponses ouvertes ont fait l’objet d’une analyse qualitative thématique.
Parmi 90 patients, 31 (33 %) ont été recrutés. Au total, 36 tests combinés de profilages de l’expression génique et d’ADN acellulaire dérivé du donneur ont été réalisés; les résultats ont été négatifs pour les deux tests dans 22 cas (61 %), positifs pour le profilage de l’expression génique et négatifs pour l’ADN acellulaire dans 10 cas (27 %), négatifs pour le profilage de l’expression génique et positifs pour l’ADN acellulaire dans quatre cas (11 %) et aucun cas n’a donné de résultats positifs pour les deux types de tests. Tous les patients qui ont donné des résultats positifs à l’analyse de l’ADN acellulaire dérivé du donneur (fourchette : 0,19 % à 0,81 %) ont subi une biopsie endomyocardique n’ayant révélé aucun rejet cellulaire ou à médiation par anticorps important. Au total, 15 cas (42 %) affichaient une immunosuppression réduite, proportion qui a grimpé à 55 % chez les patients dont les tests de concordance ont donné des résultats négatifs. Dans l’ensemble, le niveau de satisfaction rapporté par les patients était de 90 % et, à l’analyse thématique, ils étaient plus satisfaits et moins anxieux pendant les tests non invasifs.
La surveillance non invasive du risque de rejet a été associée à la capacité de diminuer l’immunosuppression, d’augmenter la satisfaction et de réduire l’anxiété chez les patients qui ont reçu une greffe cardiaque, en plus de réduire l’exposition des patients et du personnel médical dans le contexte d’une pandémie.
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Background
The number of solid organ transplants in Canada has increased 33% over the past decade. Hospital readmissions are common within the first year after transplant and are linked to increased ...morbidity and mortality. Nearly half of these admissions to the hospital appear to be preventable. Mobile health (mHealth) technologies hold promise to reduce admission to the hospital and improve patient outcomes, as they allow real-time monitoring and timely clinical intervention.
Objective
This study aims to determine whether an innovative mHealth intervention can reduce hospital readmission and unscheduled visits to the emergency department or transplant clinic. Our second objective is to assess the use of clinical and continuous ambulatory physiologic data to develop machine learning algorithms to predict the risk of infection, organ rejection, and early mortality in adult heart, kidney, and liver transplant recipients.
Methods
Remote Mobile Outpatient Monitoring in Transplant (Reboot) 2.0 is a two-phased single-center study to be conducted at the University Health Network in Toronto, Canada. Phase one will consist of a 1-year concealed randomized controlled trial of 400 adult heart, kidney, and liver transplant recipients. Participants will be randomized to receive either personalized communication using an mHealth app in addition to standard of care phone communication (intervention group) or standard of care communication only (control group). In phase two, the prior collected data set will be used to develop machine learning algorithms to identify early markers of rejection, infection, and graft dysfunction posttransplantation. The primary outcome will be a composite of any unscheduled hospital admission, visits to the emergency department or transplant clinic, following discharge from the index admission. Secondary outcomes will include patient-reported outcomes using validated self-administered questionnaires, 1-year graft survival rate, 1-year patient survival rate, and the number of standard of care phone voice messages.
Results
At the time of this paper’s completion, no results are available.
Conclusions
Building from previous work, this project will aim to leverage an innovative mHealth app to improve outcomes and reduce hospital readmission in adult solid organ transplant recipients. Additionally, the development of machine learning algorithms to better predict adverse health outcomes will allow for personalized medicine to tailor clinician-patient interactions and mitigate the health care burden of a growing patient population.
Trial Registration
ClinicalTrials.gov NCT04721288; https://www.clinicaltrials.gov/ct2/show/NCT04721288
International Registered Report Identifier (IRRID)
PRR1-10.2196/26816
For patients diagnosed with heart failure with reduced ejection fraction (HFrEF), current Guidelines recommend the use of a mineralocorticoid receptor antagonist (MRA) as a pillar of GDMT. Despite ...these recommendations, registry studies have shown that only 33.4% of patient with HFrEF are on adequate MRA therapy. Subtarget use of MRA is likely multifactorial, but one of the most important barriers is related to hyperkalemia. Through a nurse and dietitian led initiative, the aim was to improve MRA adherence to 90% by 6 months with the assistance of an interdisciplinary approach enabled with technology.
This is a prospective Quality Improvement Initiative with rapid cycle interventions to improve MRA adherence. Exclusion criteria included ejection fraction> 40%, eGFR < 25 ml/kg/min or dialysis requirement. Interventions were Dietitian counseling accompanied by a Food Application (Rx Food) which uses photo Artificial intelligence to estimate potassium intake. Additional interventions included onboarding patient on MedlyTM (a local remote heart failure monitoring platform) to monitor vitals, symptoms, blood work and facilitate potassium binder with MRA uptitration. Data was collected into a REDCap registry. The initiative was approved by the local QI board.
Overall 21 patients were enrolled over a 3 month period, 16 (76%) male with a predominant non-ischemic cardiomyopathy (53%). Over 70% were not on an optimal dose of an MRA at the outset of enrollment. The mean potassium at baseline was 5.0± 0.6mmol/L, post dietitian 4.7±0.3 mmol/L and post MRA 4.8± 0.6 mmol/L. 1 in 4 patients used the Food Rx app in addition to the dietitian counseling and reported very high satisfaction. In this cohort, 38% of patients required a potassium binder to further uptitrate MRA. 57% of patients have completed the program and achieved full dose guideline-directed MRA (Figure 1 - Dashboard).
There is a critical need for GDMT implementation and innovation. An interdisciplinary approach enhanced by technology has allowed us to successfully and safely uptitrate MRA therapy in HFrEF patients. Lessons learned can be adapted to other local contexts.
Gastrointestinal (GI) intolerance to mycophenolate mofetil (MMF) is a frequent problem. We conducted a retrospective analysis of all the heart transplant patients followed up at the Toronto General ...Hospital from the years 1999 to 2006 to determine the impact of dose reductions for GI intolerance on rejection rates.
The charts of all patients followed up in the heart transplant clinic at the Toronto General Hospital from the years 1999 to 2006 were reviewed. Sustained significant rejection was defined as an International Society of Heart and Lung Transplantation grade 2 or higher on 2 successive biopsies. The Student's t-test was used to compare rates of rejection between populations.
Mycophenolate mofetil was part of the anti-rejection regimen in 182 of 189 patients (98%), and the medication dose in 71% of these patients had to be reduced at some point because of intolerance or toxicity. The prevalence of sustained significant rejection was significantly higher in the group of patients with GI intolerance to MMF compared with patients maintained on target doses (66% vs 35%, p = 0.002) or patients with non-GI related toxicities necessitating dose reduction (67% vs 35%, p = 0.003).
Gastrointestinal intolerance is a common reason for MMF dose reduction in heart transplant patients and was associated with a significantly increased rate of sustained rejection, suggesting that these individuals need to have particularly close follow-up.
Cardiac allograft vasculopathy (CAV) is an important cause of mortality after pediatric heart transplantation (HT) but there is a paucity of data regarding its incidence and impact on survival in ...pediatric recipients transitioned to adult care.
We conducted a retrospective review of consecutive pediatric HT patients from 1989 to 2017 at the Hospital for Sick Children who transitioned to adult care at ≥18 years at Toronto General Hospital. We evaluated the incidence of International Society of Heart and Lung Transplantation CAV grade ≥1 using competing risk models. We assessed the association between all-cause mortality and CAV using Cox proportional hazards and used Kaplan Meier methods to evaluate all-cause mortality stratified by CAV and transplant era (1989-2001, 2002-2017).
Ninety-six patients were transitioned to adult care by January 2022, of which 53 underwent repeat coronary angiography as adults. CAV was newly diagnosed in 49% patients after transition to adult care. The overall incidence of CAV was 3.9 cases per 100 person-years. There was no difference in the adjusted incidence of CAV according to transplant era (subdistribution hazard ratios = 1.17, 95% confidence interval (CI) 0.54-2.66). CAV was associated with a higher risk of death in the early era (hazard ratio (HR) 10.29, 95% CI 2.16-49.96), but not in the recent era (HR 1.61, 95% 0.35-7.47).
There is a role for continued CAV surveillance after the transition to adult care. The implications of diagnosing CAV after the transition to adult care require further study, particularly because the risk of death in pediatric HT recipients diagnosed with CAV in the more recent era may be attenuated compared to the earlier HT era.
Background
The use of induction therapy (IT) agents in the early post‐heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, ...including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx).
Methods
We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient‐important outcomes, and another on patients’ values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post‐operative use of Thymoglobulin or Basiliximab.
Results
The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post‐operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab.
Conclusion
This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.
Introduction
Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical‐practice guidelines panel to evaluate the effectiveness and safety of IT in ...adult HT patients, we conducted this systematic review and network meta‐analysis (NMA).
Methods
We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient‐important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework.
Results
From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily‐used IT agents—basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30‐day (OR 1.13; 95% CI 1.06–1.20) and 1‐year (OR 1.11; 95% CI 1.02–1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5‐year cardiac allograft vasculopathy (OR .82; 95% CI .74–.90) compared to no IT, as well as 30‐day (OR .85; 95% CI .80–.92), 1‐year (OR .87; 95% CI .79–.96), and overall (HR .84; 95% CI .76–.93) mortality compared to basiliximab.
Conclusion
With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.
Dyslipidemia is common in patients undergoing heart transplantation and is associated with the progression of cardiac allograft vasculopathy. Two monoclonal antibodies directed against ...PCSK9i—evolocumab and alirocumab—are currently available. However, their use, safety and efficacy in the post-transplant setting have not been studied. We present our experience with 6 heart transplant recipients treated with a PCSK9i. A > 70% reduction in LDL-cholesterol was observed after evolocumab therapy. PCSK9 inhibitors are a potentially lipid-lowering therapeutic option for heart transplant patients with suboptimal LDL despite maximal tolerated statin doses.
La dyslipidémie, couramment observée chez les patients subissant une transplantation cardiaque, est associée à la progression de la vasculopathie du greffon cardiaque. Deux anticorps monoclonaux dirigés contre la protéine PCSK9 — l’évolocumab et l’alirocumab — sont actuellement offerts. Toutefois, leur utilisation, leur innocuité et leur efficacité lorsqu’ils sont administrés après une transplantation n’ont pas été étudiées. Nous présentons les observations tirées de notre expérience auprès de six patients traités par un inhibiteur de la PCSK9 après une transplantation cardiaque. Une réduction > 70 % du taux de cholestérol LDL a été observée après le traitement par l’évolocumab. Les inhibiteurs de la PCSK9 représentent une option thérapeutique hypolipidémiante envisageable chez les patients ayant subi une transplantation cardiaque qui affichent une concentration de cholestérol LDL sous-optimale malgré la prise de statines à la dose maximale tolérée.
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